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Recent Articles in Proceedings of the National Academy of Sciences of the United States of America

Kim JN, Roth A, Breaker RR
Guanine riboswitch variants from Mesoplasma florum selectively recognize 2'-deoxyguanosine.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16092-7.
Several mRNA aptamers have been identified in Mesoplasma florum that have sequence and structural features resembling those of guanine and adenine riboswitches. Two features distinguish these RNAs from established purine-sensing riboswitches. All possess shortened hairpin-loop sequences expected to alter tertiary contacts known to be critical for aptamer folding. The RNAs also carry nucleotide changes in the core of each aptamer that otherwise is strictly conserved in guanine and adenine riboswitches. Some aptamers retain the ability to selectively bind guanine or adenine despite these mutations. However, one variant type exhibits selective and high-affinity binding of 2'-deoxyguanosine, which is consistent with its occurrence in the 5' untranslated region of an operon containing ribonucleotide reductase genes. The identification of riboswitch variants that bind nucleosides and reject nucleobases reveals that natural metabolite-sensing RNA motifs can accrue mutations that expand the diversity of ligand detection in bacteria. [Abstract/Link to Full Text]

Harari A, Cellerai C, Enders FB, K�stler J, Codarri L, Tapia G, Boyman O, Castro E, Gaudieri S, James I, John M, Wagner R, Mallal S, Pantaleo G
Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16233-8.
We studied CD8 T cell responses against HIV-1, cytomegalovirus, Epstein-Barr virus, and influenza in 128 subjects and demonstrate that polyfunctional CD8 T cell responses, also including IL-2 production and Ag-specific proliferation, are predominantly driven by virus epitopes restricted by HLA-B alleles. Interestingly, these protective CD8 T cells are equipped with low-avidity T cell receptors (TCRs) for the cognate virus epitope. Conversely, HLA-A-restricted epitopes are mostly associated with "only effector" IFN-gamma-secreting, with cytotoxicity, and with the lack of IL-2 production and Ag-specific proliferation. These CD8 T cells are equipped with high-avidity TCR and express higher levels of the T cell exhaustion marker PD-1. Thus, the functional profile of the CD8 T cell response is strongly influenced by the extent to which there is stimulation of polyfunctional (predominantly restricted by HLA-B) versus only effector (restricted by HLA-A) T cell responses. These results provide the rationale for the observed protective role of HLA-B in HIV-1-infection and new insights into the relationship between TCR avidity, PD-1 expression, and the functional profile of CD8 T cells. [Abstract/Link to Full Text]

Oberleithner H, Riethm�ller C, Schillers H, MacGregor GA, de Wardener HE, Hausberg M
Plasma sodium stiffens vascular endothelium and reduces nitric oxide release.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16281-6.
Dietary salt plays a major role in the regulation of blood pressure, and the mineralocorticoid hormone aldosterone controls salt homeostasis and extracellular volume. Recent observations suggest that a small increase in plasma sodium concentration may contribute to the pressor response of dietary salt. Because endothelial cells are (i) sensitive to aldosterone, (ii) in physical contact with plasma sodium, and (iii) crucial regulators of vascular tone, we tested whether acute changes in plasma sodium concentration, within the physiological range, can alter the physical properties of endothelial cells. The tip of an atomic force microscope was used as a nanosensor to measure stiffness of living endothelial cells incubated for 3 days in a culture medium containing aldosterone at a physiological concentration (0.45 nM). Endothelial cell stiffness was unaffected by acute changes in sodium concentration <135 mM but rose steeply between 135 and 145 mM. The increase in stiffness occurred within minutes. Lack of aldosterone in the culture medium or treatment with the epithelial sodium channel inhibitor amiloride prevented this response. Nitric oxide formation was found down-regulated in cells cultured in aldosterone-containing high sodium medium. The results suggest that changes in plasma sodium concentration per se may affect endothelial function and thus control vascular tone. [Abstract/Link to Full Text]

Est�banez-Perpi�� E, Arnold AA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJ
A surface on the androgen receptor that allosterically regulates coactivator binding.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16074-9.
Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target. [Abstract/Link to Full Text]

Wallace B, Cesarini D, Lichtenstein P, Johannesson M
Heritability of ultimatum game responder behavior.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15631-4.
Experimental evidence suggests that many people are willing to deviate from materially maximizing strategies to punish unfair behavior. Even though little is known about the origins of such fairness preferences, it has been suggested that they have deep evolutionary roots and that they are crucial for maintaining and understanding cooperation among non-kin. Here we report the results of an ultimatum game, played for real monetary stakes, using twins recruited from the population-based Swedish Twin Registry as our subject pool. Employing standard structural equation modeling techniques, we estimate that >40% of the variation in subjects' rejection behavior is explained by additive genetic effects. Our estimates also suggest a very modest role for common environment as a source of phenotypic variation. Based on these findings, we argue that any attempt to explain observed ultimatum bargaining game behavior that ignores this genetic influence is incomplete. [Abstract/Link to Full Text]

Lan K, Verma SC, Murakami M, Bajaj B, Kaul R, Robertson ES
Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16287-92.
Deregulation of the evolutionarily conserved Notch signaling is highly correlated with oncogenesis. Intracellular activated Notch (ICN) is a protooncogene linked to the transcription activation of a number of cellular genes involved in cell cycle regulation, differentiation, and proliferation. Stability of ICN is tightly regulated by the Sel10-mediated ubiquitin-proteasome pathway. Sel10 can function as a negative regulator of Notch and exhibits activities of a tumor-suppressor protein. This article shows that the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) directly interacts with Sel10 and forms a complex in KSHV-infected cells. This results in suppression of ICN ubiquitination and degradation. The carboxyl terminus of LANA interacts with the F-box and WD40 domains of Sel10 and competes with ICN for binding to Sel10. This elevated level of ICN is also critical for maintaining the enhanced proliferation of KSHV-infected tumor cells. These findings describe a mechanism by which the KSHV-encoded LANA protein regulates ubiquitination of ICN mediated by the F-box component of the E3 ligase Sel10, leading to proliferation of the virus-infected cells. [Abstract/Link to Full Text]

Bowles B, Crupi C, Mirsattari SM, Pigott SE, Parrent AG, Pruessner JC, Yonelinas AP, K�hler S
Impaired familiarity with preserved recollection after anterior temporal-lobe resection that spares the hippocampus.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16382-7.
It is well established that the medial-temporal lobe (MTL) is critical for recognition memory. The MTL is known to be composed of distinct structures that are organized in a hierarchical manner. At present, it remains controversial whether lower structures in this hierarchy, such as perirhinal cortex, support memory functions that are distinct from those of higher structures, in particular the hippocampus. Perirhinal cortex has been proposed to play a specific role in the assessment of familiarity during recognition, which can be distinguished from the selective contributions of the hippocampus to the recollection of episodic detail. Some researchers have argued, however, that the distinction between familiarity and recollection cannot capture functional specialization within the MTL and have proposed single-process accounts. Evidence supporting the dual-process view comes from demonstrations that selective hippocampal damage can produce isolated recollection impairments. It is unclear, however, whether temporal-lobe lesions that spare the hippocampus can produce selective familiarity impairments. Without this demonstration, single-process accounts cannot be ruled out. We examined recognition memory in NB, an individual who underwent surgical resection of left anterior temporal-lobe structures for treatment of intractable epilepsy. Her resection included a large portion of perirhinal cortex but spared the hippocampus. The results of four experiments based on three different experimental procedures (remember-know paradigm, receiver operating characteristics, and response-deadline procedure) indicate that NB exhibits impaired familiarity with preserved recollection. The present findings thus provide a crucial missing piece of support for functional specialization in the MTL. [Abstract/Link to Full Text]

Harris RC, Rudd JW, Amyot M, Babiarz CL, Beaty KG, Blanchfield PJ, Bodaly RA, Branfireun BA, Gilmour CC, Graydon JA, Heyes A, Hintelmann H, Hurley JP, Kelly CA, Krabbenhoft DP, Lindberg SE, Mason RP, Paterson MJ, Podemski CL, Robinson A, Sandilands KA, Southworth GR, St Louis VL, Tate MT
Whole-ecosystem study shows rapid fish-mercury response to changes in mercury deposition.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16586-91.
Methylmercury contamination of fisheries from centuries of industrial atmospheric emissions negatively impacts humans and wildlife worldwide. The response of fish methylmercury concentrations to changes in mercury deposition has been difficult to establish because sediments/soils contain large pools of historical contamination, and many factors in addition to deposition affect fish mercury. To test directly the response of fish contamination to changing mercury deposition, we conducted a whole-ecosystem experiment, increasing the mercury load to a lake and its watershed by the addition of enriched stable mercury isotopes. The isotopes allowed us to distinguish between experimentally applied mercury and mercury already present in the ecosystem and to examine bioaccumulation of mercury deposited to different parts of the watershed. Fish methylmercury concentrations responded rapidly to changes in mercury deposition over the first 3 years of study. Essentially all of the increase in fish methylmercury concentrations came from mercury deposited directly to the lake surface. In contrast, <1% of the mercury isotope deposited to the watershed was exported to the lake. Steady state was not reached within 3 years. Lake mercury isotope concentrations were still rising in lake biota, and watershed mercury isotope exports to the lake were increasing slowly. Therefore, we predict that mercury emissions reductions will yield rapid (years) reductions in fish methylmercury concentrations and will yield concomitant reductions in risk. However, a full response will be delayed by the gradual export of mercury stored in watersheds. The rate of response will vary among lakes depending on the relative surface areas of water and watershed. [Abstract/Link to Full Text]

Schuss Z, Singer A, Holcman D
The narrow escape problem for diffusion in cellular microdomains.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16098-103.
The study of the diffusive motion of ions or molecules in confined biological microdomains requires the derivation of the explicit dependence of quantities, such as the decay rate of the population or the forward chemical reaction rate constant on the geometry of the domain. Here, we obtain this explicit dependence for a model of a Brownian particle (ion, molecule, or protein) confined to a bounded domain (a compartment or a cell) by a reflecting boundary, except for a small window through which it can escape. We call the calculation of the mean escape time the narrow escape problem. This time diverges as the window shrinks, thus rendering the calculation a singular perturbation problem. Here, we present asymptotic formulas for the mean escape time in several cases, including regular domains in two and three dimensions and in some singular domains in two dimensions. The mean escape time comes up in many applications, because it represents the mean time it takes for a molecule to hit a target binding site. We present several applications in cellular biology: calcium decay in dendritic spines, a Markov model of multicomponent chemical reactions in microdomains, dynamics of receptor diffusion on the surface of neurons, and vesicle trafficking inside a cell. [Abstract/Link to Full Text]

Firestone RB, West A, Kennett JP, Becker L, Bunch TE, Revay ZS, Schultz PH, Belgya T, Kennett DJ, Erlandson JM, Dickenson OJ, Goodyear AC, Harris RS, Howard GA, Kloosterman JB, Lechler P, Mayewski PA, Montgomery J, Poreda R, Darrah T, Hee SS, Smith AR, Stich A, Topping W, Wittke JH, Wolbach WS
Evidence for an extraterrestrial impact 12,900 years ago that contributed to the megafaunal extinctions and the Younger Dryas cooling.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16016-21.
A carbon-rich black layer, dating to approximately 12.9 ka, has been previously identified at approximately 50 Clovis-age sites across North America and appears contemporaneous with the abrupt onset of Younger Dryas (YD) cooling. The in situ bones of extinct Pleistocene megafauna, along with Clovis tool assemblages, occur below this black layer but not within or above it. Causes for the extinctions, YD cooling, and termination of Clovis culture have long been controversial. In this paper, we provide evidence for an extraterrestrial (ET) impact event at approximately equal 12.9 ka, which we hypothesize caused abrupt environmental changes that contributed to YD cooling, major ecological reorganization, broad-scale extinctions, and rapid human behavioral shifts at the end of the Clovis Period. Clovis-age sites in North American are overlain by a thin, discrete layer with varying peak abundances of (i) magnetic grains with iridium, (ii) magnetic microspherules, (iii) charcoal, (iv) soot, (v) carbon spherules, (vi) glass-like carbon containing nanodiamonds, and (vii) fullerenes with ET helium, all of which are evidence for an ET impact and associated biomass burning at approximately 12.9 ka. This layer also extends throughout at least 15 Carolina Bays, which are unique, elliptical depressions, oriented to the northwest across the Atlantic Coastal Plain. We propose that one or more large, low-density ET objects exploded over northern North America, partially destabilizing the Laurentide Ice Sheet and triggering YD cooling. The shock wave, thermal pulse, and event-related environmental effects (e.g., extensive biomass burning and food limitations) contributed to end-Pleistocene megafaunal extinctions and adaptive shifts among PaleoAmericans in North America. [Abstract/Link to Full Text]

Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, Howard MC, Schall TJ
CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15735-40.
Chemokines and chemokine receptors have been posited to have important roles in several common malignancies, including breast and lung cancer. Here, we demonstrate that CXCR7 (RDC1, CCX-CKR2), recently deorphanized as a chemokine receptor that binds chemokines CXCL11 and CXCL12, can regulate these two common malignancies. Using a combination of overexpression and RNA interference, we establish that CXCR7 promotes growth of tumors formed from breast and lung cancer cells and enhances experimental lung metastases in immunodeficient as well as immunocompetent mouse models of cancer. These effects did not depend on expression of the related receptor CXCR4. Furthermore, immunohistochemistry of primary human tumor tissue demonstrates extensive CXCR7 expression in human breast and lung cancers, where it is highly expressed on a majority of tumor-associated blood vessels and malignant cells but not expressed on normal vasculature. In addition, a critical role for CXCR7 in vascular formation and angiogenesis during development is demonstrated by using morpholino-mediated knockdown of CXCR7 in zebrafish. Taken together, these data suggest that CXCR7 has key functions in promoting tumor development and progression. [Abstract/Link to Full Text]

Normark J, Nilsson D, Ribacke U, Winter G, Moll K, Wheelock CE, Bayarugaba J, Kironde F, Egwang TG, Chen Q, Andersson B, Wahlgren M
PfEMP1-DBL1alpha amino acid motifs in severe disease states of Plasmodium falciparum malaria.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15835-40.
An infection with Plasmodium falciparum may lead to severe malaria as a result of excessive binding of infected erythrocytes in the microvasculature. Vascular adhesion is mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP1), which is encoded for by highly polymorphic members of the var-gene family. Here, we profile var gene transcription in fresh P. falciparum trophozoites from Ugandan children with malaria through var-specific DBL1alpha-PCR amplification and sequencing. A method for subsectioning region alignments into homology areas (MOTIFF) was developed to examine collected sequences. Specific PfEMP1-DBL1alpha amino acid motifs correlated with rosetting and severe malaria, with motif location corresponding to distinct regions of receptor interaction. The method is potentially applicable to other families of variant proteins and may be useful in identifying sequence-phenotype relationships. The results suggest that certain PfEMP1 sequences are predisposed to inducing severe malaria. [Abstract/Link to Full Text]

Hu Z, Corwin JT
Inner ear hair cells produced in vitro by a mesenchymal-to-epithelial transition.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16675-80.
Sensory hair cell loss is a major contributor to disabling hearing and balance deficits that affect >250 million people worldwide. Sound exposures, infections, drug toxicity, genetic disorders, and aging all can cause hair cell loss and lead to permanent sensory deficits. Progress toward treatments for these deficits has been limited, in part because hair cells have only been obtainable via microdissection of the anatomically complex internal ear. Attempts to produce hair cells in vitro have resulted in reports of some success but have required transplantation into embryonic ears or coculturing with other tissues. Here, we show that avian inner ear cells can be cultured and passaged for months, frozen, and expanded to large numbers without other tissues. At any point from passage 6 up to at least passage 23, these cultures can be fully dissociated and then aggregated in suspension to induce a mesenchymal-to-epithelial transition that reliably yields new polarized sensory epithelia. Those epithelia develop numerous hair cells that are crowned by hair bundles, composed of a single kinocilium and an asymmetric array of stereocilia. These hair cells exhibit rapid permeance to FM1-43, a dye that passes through open mechanotransducing channels. Because a vial of frozen cells can now provide the capacity to produce bona fide hair cells completely in vitro, these discoveries should open new avenues of research that may ultimately contribute to better treatments for hearing loss and other inner ear disorders. [Abstract/Link to Full Text]

Purvis AR, Gross J, Dang LT, Huang RH, Kapadia M, Townsend RR, Sadler JE
Two Cys residues essential for von Willebrand factor multimer assembly in the Golgi.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15647-52.
Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. This unusual oxidoreductase reaction requires the VWF propeptide (domains D1D2), which acts as an endogenous pH-dependent chaperone. The cysteines involved in multimer assembly were characterized by using a VWF construct that encodes the N-terminal D1D2D'D3 domains. Modification with thiol-specific reagents demonstrated that secreted D'D3 monomer contained reduced Cys, whereas D'D3 dimer and propeptide did not. Reduced Cys in the D'D3 monomer were alkylated with N-ethylmaleimide and analyzed by mass spectrometry. All 52 Cys within the D'D3 region were observed, and only Cys(1099) and Cys(1142) were modified by N-ethylmaleimide. When introduced into the D1D2D'D3 construct, the mutation C1099A or C1142A markedly impaired the formation of D'D3 dimers, and the double mutation prevented dimerization. In full-length VWF, the mutations C1099A and C1099A/C1142A prevented multimer assembly; the mutation C1142A allowed the formation of almost exclusively dimers, with few tetramers and no multimers larger than hexamers. Therefore, Cys(1099) and Cys(1142) are essential for the oxidoreductase mechanism of VWF multimerization. Cys(1142) is reported to form a Cys(1142)-Cys(1142) intersubunit bond, suggesting that Cys(1099) also participates in a Cys(1099)-Cys(1099) disulfide bond between D3 domains. This arrangement of intersubunit disulfide bonds implies that the dimeric N-terminal D'D3 domains of VWF subunits align in a parallel orientation within VWF multimers. [Abstract/Link to Full Text]

Otto JC, Kelly P, Chiou ST, York JD
Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15653-8.
In mammals, many cellular stimuli evoke a response through G protein activation of phospholipase C, which results in the lipid-derived production of inositol 1,4,5-trisphosphate (IP(3)). Although it is well established that IP(3) is converted to numerous inositol phosphates (IPs) and pyrophosphates (PP-IPs) through the action of up to six classes of inositol phosphate kinases (IPKs), it is not clear that these metabolites are influenced by G protein signaling. Here we report that activation of Galpha(q) leads to robust stimulation of IP(3) to IP(8) metabolism. To expose flux through these pathways, genetic perturbation was used to alter IP homeostasis. Coupled expression of a constitutively active Galpha(q)QL and one or more IPK gene products synergistically generated dramatic changes in the patterns of intracellular IP messengers. Many distinct IP profiles were observed through the expression of different combinations of IPKs, including changes in previously unappreciated pools of IP(5) and IP(6), two molecules widely viewed as stable metabolites. Our data link the activation of a trimeric G protein to a plethora of metabolites downstream of IP(3) and provide a framework for suggesting that cells possess the machinery to produce an IPK-dependent IP code. We imply, but do not prove, that agonist-induced alterations in such a code would theoretically be capable of enhancing signaling complexity and specificity. The essential roles for IPKs in organism development and cellular adaptation are consistent with our hypothesis that such an IP code may be relevant to signaling pathways. [Abstract/Link to Full Text]

Gardberg AS, Dice LT, Ou S, Rich RL, Helmbrecht E, Ko J, Wetzel R, Myszka DG, Patterson PH, Dealwis C
Molecular basis for passive immunotherapy of Alzheimer's disease.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64.
Amyloid aggregates of the amyloid-beta (Abeta) peptide are implicated in the pathology of Alzheimer's disease. Anti-Abeta monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-Abeta mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize Abeta monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the Abeta(1-8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIP1 is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to Abeta(1-8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target Abeta with improved specificity and higher affinity. [Abstract/Link to Full Text]

Novak BJ, Blake DR, Meinardi S, Rowland FS, Pontello A, Cooper DM, Galassetti PR
Exhaled methyl nitrate as a noninvasive marker of hyperglycemia in type 1 diabetes.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15613-8.
Recent technical advances allow detection of several hundred volatile organic compounds (VOCs) in human exhaled air, many of which reflect unidentified endogenous pathways. Our group has previously estimated plasma glucose levels in healthy adults during a standard oral glucose tolerance test via exhaled VOC analysis. As a result of the metabolic characteristics of hyperglycemia in the diabetic (low insulin and increased free fatty acids and ketones), we hypothesized that different exhaled VOC profiles may be present in children with type 1 diabetes mellitus (T1DM) during spontaneous hyperglycemia. Exhaled methyl nitrate strongly correlated specifically with the acute, spontaneous hyperglycemia of T1DM children. Eighteen experiments were conducted among 10 T1DM children. Plasma glucose and exhaled gases were monitored during either constant euglycemia (n = 5) or initial hyperglycemia with gradual correction (n = 13); all subjects received i.v. insulin and glucose as needed. Gas analysis was performed on 1.9-liter breath samples via gas chromatography using electron capture, flame ionization, and mass selective detection. Among the approximately 100 measured exhaled gases, the kinetic profile of exhaled methyl nitrate, commonly present in room air in the range of 5-10 parts per trillion, was most strongly statistically correlated with that of plasma glucose (P = 0.003-0.001). Indeed, the kinetic profiles of the two variables paralleled each other in 16 of 18 experiments, including repeat subjects who at different times displayed either euglycemia or hyperglycemia. [Abstract/Link to Full Text]

Gledhill JR, Montgomery MG, Leslie AG, Walker JE
How the regulatory protein, IF(1), inhibits F(1)-ATPase from bovine mitochondria.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15671-6.
The structure of bovine F(1)-ATPase inhibited by a monomeric form of the inhibitor protein, IF(1), known as I1-60His, lacking most of the dimerization region, has been determined at 2.1-A resolution. The resolved region of the inhibitor from residues 8-50 consists of an extended structure from residues 8-13, followed by two alpha-helices from residues 14-18 and residues 21-50 linked by a turn. The binding site in the beta(DP)-alpha(DP) catalytic interface is complex with contributions from five different subunits of F(1)-ATPase. The longer helix extends from the external surface of F(1) via a deep groove made from helices and loops in the C-terminal domains of subunits beta(DP), alpha(DP), beta(TP), and alpha(TP) to the internal cavity surrounding the central stalk. The linker and shorter helix interact with the gamma-subunit in the central stalk, and the N-terminal region extends across the central cavity to interact with the nucleotide binding domain of the alpha(E) subunit. To form these complex interactions and penetrate into the core of the enzyme, it is likely that the initial interaction of the inhibitor with F(1) forms via the open conformation of the beta(E) subunit. Then, as two ATP molecules are hydrolyzed, the beta(E)-alpha(E) interface converts to the beta(DP)-alpha(DP) interface via the beta(TP)-alpha(TP) interface, trapping the inhibitor progressively in its binding site and a nucleotide in the catalytic site of subunit beta(DP). The inhibition probably arises by IF(1) imposing the structure and properties of the beta(TP)-alpha(TP) interface on the beta(DP)-alpha(DP) interface, thereby preventing it from hydrolyzing the bound ATP. [Abstract/Link to Full Text]

Zhou X, Merzenich MM
Intensive training in adults refines A1 representations degraded in an early postnatal critical period.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15935-40.
The spectral, temporal, and intensive selectivity of neurons in the adult primary auditory cortex (A1) is easily degraded in early postnatal life by raising rat pups in the presence of pulsed noise. The nonselective frequency tuning recorded in these rats substantially endures into adulthood. Here we demonstrate that perceptual training applied in these developmentally degraded postcritical-period rats results in the recovery of normal representational fidelity. By using a modified go/no-go training strategy, structured noise-reared rats were trained to identify target auditory stimuli of specific frequency from a set of distractors varying in frequency. Target stimuli changed daily on a random schedule. Consistent with earlier findings, structured noise exposure within the critical period resulted in disrupted tonotopicity within A1 and in degraded frequency-response selectivity for A1 neurons. Tonotopicity and frequency-response selectivity were normalized by perceptual training. Changes induced by training endured without loss for at least 2 months after training cessation. The results further demonstrate the potential utility of perceptual learning as a strategy for normalizing deteriorated auditory representations in older (postcritical-period) children and adults. [Abstract/Link to Full Text]

Lacy-Hulbert A, Smith AM, Tissire H, Barry M, Crowley D, Bronson RT, Roes JT, Savill JS, Hynes RO
Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15823-8.
The gastrointestinal tract is constantly challenged by foreign antigens and commensal bacteria but nonetheless is able to maintain a state of immunological quiescence. Recent advances have highlighted the importance of active suppression by regulatory lymphocytes and immunosuppressive cytokines in controlling mucosal immunity. Failures of these mechanisms contribute to the development of inflammatory bowel disease, but how these regulatory networks are established remains unclear. Here, we demonstrate key roles for alphav integrins in regulation of mucosal immunity. We report that deletion of alphav in the immune system causes severe colitis, autoimmunity, and cancer. Mice lacking immune cell alphav have fewer regulatory T (Treg) cells in the colon and corresponding increases in activated T cells and T cell cytokine production, leading to colitis. Using conditional gene targeting, we demonstrate that this is specifically attributable to loss of alphav from myeloid cells. Furthermore, we show that gut-associated macrophages and dendritic cells fail both to remove apoptotic cells efficiently and to induce Treg cells. Our results identify a vital role for myeloid alphav integrins in generating mucosal Treg cells and emphasize the importance of antigen-presenting cells in establishing immune tolerance. [Abstract/Link to Full Text]

Schrader TE, Schreier WJ, Cordes T, Koller FO, Babitzki G, Denschlag R, Renner C, L�weneck M, Dong SL, Moroder L, Tavan P, Zinth W
Light-triggered beta-hairpin folding and unfolding.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15729-34.
A light-switchable peptide is transformed with ultrashort pulses from a beta-hairpin to an unfolded hydrophobic cluster and vice versa. The structural changes are monitored by mid-IR probing. Instantaneous normal mode analysis with a Hamiltonian combining density functional theory with molecular mechanics is used to interpret the absorption transients. Illumination of the beta-hairpin state triggers an unfolding reaction that visits several intermediates and reaches the unfolded state within a few nanoseconds. In this unfolding reaction to the equilibrium hydrophobic cluster conformation, the system does not meet significant barriers on the free-energy surface. The reverse folding process takes much longer because it occurs on the time scale of 30 micros. The folded state has a defined structure, and its formation requires an extended search for the correct hydrogen-bond pattern of the beta-strand. [Abstract/Link to Full Text]

Dalal Y, Furuyama T, Vermaak D, Henikoff S
Structure, dynamics, and evolution of centromeric nucleosomes.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):15974-81.
Centromeres are defining features of eukaryotic chromosomes, providing sites of attachment for segregation during mitosis and meiosis. The fundamental unit of centromere structure is the centromeric nucleosome, which differs from the conventional nucleosome by the presence of a centromere-specific histone variant (CenH3) in place of canonical H3. We have shown that the CenH3 nucleosome core found in interphase Drosophila cells is a heterotypic tetramer, a "hemisome" consisting of one molecule each of CenH3, H4, H2A, and H2B, rather than the octamer of canonical histones that is found in bulk nucleosomes. The surprising discovery of hemisomes at centromeres calls for a reevaluation of evidence that has long been interpreted in terms of a more conventional nucleosome. We describe how the hemisome structure of centromeric nucleosomes can account for enigmatic properties of centromeres, including kinetochore accessibility, epigenetic inheritance, rapid turnover of misincorporated CenH3, and transcriptional quiescence of pericentric heterochromatin. Structural differences mediated by loop 1 are proposed to account for the formation of stable tetramers containing CenH3 rather than stable octamers containing H3. Asymmetric CenH3 hemisomes might interrupt the global condensation of octameric H3 arrays and present an asymmetric surface for kinetochore formation. We suggest that this simple mechanism for differentiation between centromeric and packaging nucleosomes evolved from an archaea-like ancestor at the dawn of eukaryotic evolution. [Abstract/Link to Full Text]

Tu D, Li W, Ye Y, Brunger AT
Inaugural Article: Structure and function of the yeast U-box-containing ubiquitin ligase Ufd2p.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15599-606.
Proteins conjugated by Lys-48-linked polyubiquitin chains are preferred substrates of the eukaryotic proteasome. Polyubiquitination requires an activating enzyme (E1), a conjugating enzyme (E2), and a ligase (E3). Occasionally, these enzymes only assemble short ubiquitin oligomers, and their extension to full length involves a ubiquitin elongating factor termed E4. Ufd2p, as the first E4 identified to date, is involved in the degradation of misfolded proteins of the endoplasmic reticulum and of a ubiquitin-beta-GAL fusion substrate in Saccharomyces cerevisiae. The mechanism of action of Ufd2p is unknown. Here we describe the crystal structure of the full-length yeast Ufd2p protein. Ufd2p has an elongated shape consisting of several irregular Armadillo-like repeats with two helical hairpins protruding from it and a U-box domain flexibly attached to its C terminus. The U-box of Ufd2p has a fold similar to that of the RING (Really Interesting New Gene) domain that is present in certain ubiquitin ligases. Accordingly, Ufd2p has all of the hallmarks of a RING finger-containing ubiquitin ligase: it associates with its cognate E2 Ubc4p via its U-box domain and catalyzes the transfer of ubiquitin from the E2 active site to Ufd2p itself or to an acceptor ubiquitin molecule to form unanchored diubiquitin oligomers. Thus, Ufd2p can function as a bona fide E3 ubiquitin ligase to promote ubiquitin chain elongation on a substrate. [Abstract/Link to Full Text]

Marb� N, Duarte CM, Agust� S
Allometric scaling of plant life history.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15777-80.
Plant mortality and birth rates are critical components of plant life history affecting the stability of plant populations and the ecosystems they form. Although allometric theory predicts that both plant birth and mortality rates should be size-dependent, this prediction has not yet been tested across plants ranging the full size spectrum. Here we show that both population mortality and population birth rates scale as the -(1/4) power and plant lifespan as the (1/4) power of plant mass across plant species spanning from the tiniest phototrophs to the largest trees. Whereas the controls on plant lifespans are as yet poorly understood, our findings suggest that plant mortality rates have evolved to match population birth rates, thereby helping to maintain plant communities in equilibrium and optimizing plant life histories. [Abstract/Link to Full Text]

Niklas KJ
Sizing up life and death.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15589-90. [Abstract/Link to Full Text]

Samuel D, Cheng H, Riley PW, Canutescu AA, Nagaswami C, Weisel JW, Bu Z, Walsh PN, Roder H
Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15693-8.
Factor XI (FXI) is a homodimeric blood coagulation protein. Each monomer comprises four tandem apple-domain repeats (A1-A4) and a serine protease domain. We report here the NMR solution structure of the A4 domain (residues 272-361), which mediates formation of the disulfide-linked FXI dimer. A4 exhibits characteristic features of the plasminogen apple nematode domain family, including a five-stranded beta-sheet flanked by an alpha-helix on one side and a two-stranded beta-sheet on the other. In addition, the solution structure reveals a second alpha-helix at the C terminus. Comparison with a recent crystal structure of full-length FXI, combined with molecular modeling, suggests that the C-terminal helix is formed only upon proteolytic activation. The newly formed helix disrupts interdomain contacts and reorients the catalytic domains, bringing the active sites into close proximity. This hypothesis is supported by small-angle x-ray scattering and electron microscopy data, which indicate that FXI activation is accompanied by a major change in shape. The results are consistent with biochemical evidence that activated FXI cleaves its substrate at two positions without release of an intermediate. [Abstract/Link to Full Text]

Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A
A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16227-32.
Genetic variants at chromosomes 1q31-32 and 10q26 are strongly associated with susceptibility to age-related macular degeneration (AMD), a common blinding disease of the elderly. We demonstrate, by evaluating 45 tag SNPs spanning HTRA1, PLEKHA1, and predicted gene LOC387715/ARMS2, that rs10490924 SNP alone, or a variant in strong linkage disequilibrium, can explain the bulk of association between the 10q26 chromosomal region and AMD. A previously suggested causal SNP, rs11200638, and other examined SNPs in the region are only indirectly associated with the disease. Contrary to previous reports, we show that rs11200638 SNP has no significant impact on HTRA1 promoter activity in three different cell lines, and HTRA1 mRNA expression exhibits no significant change between control and AMD retinas. However, SNP rs10490924 shows the strongest association with AMD (P = 5.3 x 10(-30)), revealing an estimated relative risk of 2.66 for GT heterozygotes and 7.05 for TT homozygotes. The rs10490924 SNP results in nonsynonymous A69S alteration in the predicted protein LOC387715/ARMS2, which has a highly conserved ortholog in chimpanzee, but not in other vertebrate sequences. We demonstrate that LOC387715/ARMS2 mRNA is detected in the human retina and various cell lines and encodes a 12-kDa protein, which localizes to the mitochondrial outer membrane when expressed in mammalian cells. We propose that rs10490924 represents a major susceptibility variant for AMD at 10q26. A likely biological mechanism is that the A69S change in the LOC387715/ARMS2 protein affects its presumptive function in mitochondria. [Abstract/Link to Full Text]

Haines JL, Spencer KM, Pericak-Vance MA
Bringing the genetics of macular degeneration into focus.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16725-6. [Abstract/Link to Full Text]

Freimer NB, Service SK, Ophoff RA, Jasinska AJ, McKee K, Villeneuve A, Belisle A, Bailey JN, Breidenthal SE, Jorgensen MJ, Mann JJ, Cantor RM, Dewar K, Fairbanks LA
A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15811-6.
Non-human primates (NHP) provide crucial research models. Their strong similarities to humans make them particularly valuable for understanding complex behavioral traits and brain structure and function. We report here the genetic mapping of an NHP nervous system biologic trait, the cerebrospinal fluid (CSF) concentration of the dopamine metabolite homovanillic acid (HVA), in an extended inbred vervet monkey (Chlorocebus aethiops sabaeus) pedigree. CSF HVA is an index of CNS dopamine activity, which is hypothesized to contribute substantially to behavioral variations in NHP and humans. For quantitative trait locus (QTL) mapping, we carried out a two-stage procedure. We first scanned the genome using a first-generation genetic map of short tandem repeat markers. Subsequently, using >100 SNPs within the most promising region identified by the genome scan, we mapped a QTL for CSF HVA at a genome-wide level of significance (peak logarithm of odds score >4) to a narrow well delineated interval (<10 Mb). The SNP discovery exploited conserved segments between human and rhesus macaque reference genome sequences. Our findings demonstrate the potential of using existing primate reference genome sequences for designing high-resolution genetic analyses applicable across a wide range of NHP species, including the many for which full genome sequences are not yet available. Leveraging genomic information from sequenced to nonsequenced species should enable the utilization of the full range of NHP diversity in behavior and disease susceptibility to determine the genetic basis of specific biological and behavioral traits. [Abstract/Link to Full Text]

Schulman R, Winfree E
Synthesis of crystals with a programmable kinetic barrier to nucleation.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15236-41.
A central goal of chemistry is to fabricate supramolecular structures of defined function and composition. In biology, control of supramolecular synthesis is often achieved through precise control over nucleation and growth processes: A seed molecule initiates growth of a structure, but this growth is kinetically inhibited in the seed's absence. Here we show how such control can be systematically designed into self-assembling structures made of DNA tiles. These structures, "zig-zag ribbons," are designed to have a fixed width but can grow arbitrarily long. Under slightly supersaturated conditions, theory predicts that elongation is always favorable but that nucleation rates decrease exponentially with increasing width. We confirm experimentally that although ribbons of different widths have similar thermodynamics, nucleation rates decrease for wider ribbons. It is therefore possible to program the nucleation rate by choosing a ribbon width. The presence of a seed molecule, a stabilized version of the presumed critical nucleus, removes the kinetic barrier to nucleation of a ribbon. Thus, we demonstrate the ability to grow supramolecular structures from rationally designed seeds, while suppressing spurious nucleation. Control over DNA tile nucleation allows for proper initiation of algorithmic crystal growth, which could lead to the high-yield synthesis of micrometer-scale structures with complex programmed features. More generally, this work shows how a self-assembly subroutine can be initiated. [Abstract/Link to Full Text]

Santer BD, Mears C, Wentz FJ, Taylor KE, Gleckler PJ, Wigley TM, Barnett TP, Boyle JS, Br�ggemann W, Gillett NP, Klein SA, Meehl GA, Nozawa T, Pierce DW, Stott PA, Washington WM, Wehner MF
Identification of human-induced changes in atmospheric moisture content.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15248-53.
Data from the satellite-based Special Sensor Microwave Imager (SSM/I) show that the total atmospheric moisture content over oceans has increased by 0.41 kg/m(2) per decade since 1988. Results from current climate models indicate that water vapor increases of this magnitude cannot be explained by climate noise alone. In a formal detection and attribution analysis using the pooled results from 22 different climate models, the simulated "fingerprint" pattern of anthropogenically caused changes in water vapor is identifiable with high statistical confidence in the SSM/I data. Experiments in which forcing factors are varied individually suggest that this fingerprint "match" is primarily due to human-caused increases in greenhouse gases and not to solar forcing or recovery from the eruption of Mount Pinatubo. Our findings provide preliminary evidence of an emerging anthropogenic signal in the moisture content of earth's atmosphere. [Abstract/Link to Full Text]

Nemeth MJ, Topol L, Anderson SM, Yang Y, Bodine DM
Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15436-41.
The mechanisms that regulate hematopoietic stem cell (HSC) fate decisions between proliferation and multilineage differentiation are unclear. Members of the Wnt family of ligands that activate the canonical Wnt signaling pathway, which utilizes beta-catenin to relay the signal, have been demonstrated to regulate HSC function. In this study, we examined the role of noncanonical Wnt signaling in regulating HSC fate. We observed that noncanonical Wnt5a inhibited Wnt3a-mediated canonical Wnt signaling in HSCs and suppressed Wnt3a-mediated alterations in gene expression associated with HSC differentiation, such as increased expression of myc. Wnt5a increased short- and long-term HSC repopulation by maintaining HSCs in a quiescent G(0) state. From these data, we propose that Wnt5a regulates hematopoiesis by the antagonism of the canonical Wnt pathway, resulting in a pool of quiescent HSCs. [Abstract/Link to Full Text]

Recent Articles in BMJ: British Medical Journal

Vasenwala M
Joy of rapid responses. Readers read articles more closely when they can respond.
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Colquitt PJ
Joy of rapid responses. Rapid responses are useful...
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Wharfield L
Joy of rapid responses. Rapid responses are useful...but perhaps not entirely effective.
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Twisselmann B
Joy of rapid responses. Summary of responses.
BMJ. 2004 Mar 13;328(7440):645. [Abstract/Link to Full Text]

Pewsner D, J�ni P, Egger M, Battaglia M, Sundstr�m J, Bachmann LM
Accuracy of electrocardiography in diagnosis of left ventricular hypertrophy in arterial hypertension: systematic review.
BMJ. 2007 Oct 6;335(7622):711.
OBJECTIVE: To review the accuracy of electrocardiography in screening for left ventricular hypertrophy in patients with hypertension. DESIGN: Systematic review of studies of test accuracy of six electrocardiographic indexes: the Sokolow-Lyon index, Cornell voltage index, Cornell product index, Gubner index, and Romhilt-Estes scores with thresholds for a positive test of > or =4 points or > or =5 points. DATA SOURCES: Electronic databases ((Pre-)Medline, Embase), reference lists of relevant studies and previous reviews, and experts. STUDY SELECTION: Two reviewers scrutinised abstracts and examined potentially eligible studies. Studies comparing the electrocardiographic index with echocardiography in hypertensive patients and reporting sufficient data were included. DATA EXTRACTION: Data on study populations, echocardiographic criteria, and methodological quality of studies were extracted. DATA SYNTHESIS: Negative likelihood ratios, which indicate to what extent the posterior odds of left ventricular hypertrophy is reduced by a negative test, were calculated. RESULTS: 21 studies and data on 5608 patients were analysed. The median prevalence of left ventricular hypertrophy was 33% (interquartile range 23-41%) in primary care settings (10 studies) and 65% (37-81%) in secondary care settings (11 studies). The median negative likelihood ratio was similar across electrocardiographic indexes, ranging from 0.85 (range 0.34-1.03) for the Romhilt-Estes score (with threshold > or =4 points) to 0.91 (0.70-1.01) for the Gubner index. Using the Romhilt-Estes score in primary care, a negative electrocardiogram result would reduce the typical pre-test probability from 33% to 31%. In secondary care the typical pre-test probability of 65% would be reduced to 63%. CONCLUSION: Electrocardiographic criteria should not be used to rule out left ventricular hypertrophy in patients with hypertension. [Abstract/Link to Full Text]

Bourdillon PJ
QRS voltage criteria can be useful.
BMJ. 2007 Oct 20;335(7624):787. [Abstract/Link to Full Text]

Vanezis AP, Bhopal R
Ethnicity is relevant.
BMJ. 2007 Oct 20;335(7624):787. [Abstract/Link to Full Text]

Nielsen OW, Sajadieh A
Diagnosing left ventricular hypertrophy in arterial hypertension.
BMJ. 2007 Oct 6;335(7622):681-2. [Abstract/Link to Full Text]

Conen D, Ridker PM, Buring JE, Glynn RJ
Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study.
BMJ. 2007 Sep 1;335(7617):432.
OBJECTIVE: To compare cardiovascular risk among women with high normal blood pressure (130-9/85-9 mm Hg) against those with normal blood pressure (120-9/75-84 mm Hg) and those with baseline hypertension. DESIGN: Prospective cohort study. SETTING: Women's health study, United States. PARTICIPANTS: 39 322 initially healthy women classified into four categories according to self reported baseline blood pressure and followed for a median of 10.2 years. MAIN OUTCOME MEASURES: Time to cardiovascular death, myocardial infarction, or stroke (major cardiovascular event-primary end point); progression to hypertension. RESULTS: 982 (2.5%) women developed a major cardiovascular event, and 8686 (30.1%) women without baseline hypertension progressed to hypertension. The age adjusted event rate for the primary end point was 1.6/1000 person years among women with normal blood pressure, 2.9/1000 person years among those with high normal blood pressure, and 4.3/1000 person years among those with baseline hypertension. Compared with women with high normal blood pressure (reference group), those with normal blood pressure had a lower risk of a major cardiovascular event (adjusted hazard ratio 0.61, 95% confidence interval 0.48 to 0.76) and of incident hypertension (0.42, 0.40 to 0.44). The hazard ratio for a major cardiovascular event in women with baseline hypertension was 1.30 (1.08 to 1.57). Women who progressed to hypertension (reference group) during the first 48 months of the study had a higher cardiovascular risk than those who remained normotensive (adjusted hazard ratio 0.64, 0.50 to 0.81). Women with high normal blood pressure at baseline who progressed to hypertension (reference group) had similar outcome rates to women with baseline hypertension (adjusted hazard ratio 1.17, 0.88 to 1.55). CONCLUSION: The cardiovascular risk of women with high normal blood pressure is higher than that of women with normal blood pressure. The cardiovascular risk of women who progress to hypertension is increased shortly after a diagnosis of hypertension has been made. TRIAL REGISTRATION: Clinical trials NCT00000479 [ClinicalTrials.gov]. [Abstract/Link to Full Text]

Nash IS
Reassessing normal blood pressure.
BMJ. 2007 Sep 1;335(7617):408-9. [Abstract/Link to Full Text]

Foster NE, Thomas E, Barlas P, Hill JC, Young J, Mason E, Hay EM
Acupuncture as an adjunct to exercise based physiotherapy for osteoarthritis of the knee: randomised controlled trial.
BMJ. 2007 Sep 1;335(7617):436.
OBJECTIVE: To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee. DESIGN: Multicentre, randomised controlled trial. SETTING: 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midlands, United Kingdom. PARTICIPANTS: 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis. INTERVENTIONS: Advice and exercise (n=116), advice and exercise plus true acupuncture (n=117), and advice and exercise plus non-penetrating acupuncture (n=119). MAIN OUTCOME MEASURES: The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months. Secondary outcomes included function, pain intensity, and unpleasantness of pain at two weeks, six weeks, six months, and 12 months. RESULTS: Follow-up rate at six months was 94%. The mean (SD) baseline pain score was 9.2 (3.8). At six months mean reductions in pain were 2.28 (3.8) for advice and exercise, 2.32 (3.6) for advice and exercise plus true acupuncture, and 2.53 (4.2) for advice and exercise plus non-penetrating acupuncture. Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 (95% confidence interval -1.0 to 0.9) for advice and exercise plus true acupuncture and 0.25 (-0.8 to 1.3) for advice and exercise plus non-penetrating acupuncture. Similar non-significant differences were seen at other follow-up points. Compared with advice and exercise alone there were small, statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture. CONCLUSION: The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores. Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups, making it unlikely that this was due to acupuncture needling effects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88597683 [controlled-trials.com] . [Abstract/Link to Full Text]

Herbert R, Fransen M
Management of chronic knee pain.
BMJ. 2007 Oct 20;335(7624):786. [Abstract/Link to Full Text]

Canani RB, Cirillo P, Terrin G, Cesarano L, Spagnuolo MI, De Vincenzo A, Albano F, Passariello A, De Marco G, Manguso F, Guarino A
Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations.
BMJ. 2007 Aug 18;335(7615):340.
OBJECTIVE: To compare the efficacy of five probiotic preparations recommended to parents in the treatment of acute diarrhoea in children. Design Randomised controlled clinical trial in collaboration with family paediatricians over 12 months. SETTING: Primary care. PARTICIPANTS: Children aged 3-36 months visiting a family paediatrician for acute diarrhoea. INTERVENTION: Children's parents were randomly assigned to receive written instructions to purchase a specific probiotic product: oral rehydration solution (control group); Lactobacillus rhamnosus strain GG; Saccharomyces boulardii; Bacillus clausii; mix of L delbrueckii var bulgaricus, Streptococcus thermophilus, L acidophilus, and Bifidobacterium bifidum; or Enterococcus faecium SF68. MAIN OUTCOME MEASURES: Primary outcomes were duration of diarrhoea and daily number and consistency of stools. Secondary outcomes were duration of vomiting and fever and rate of admission to hospital. Safety and tolerance were also recorded. RESULTS: 571 children were allocated to intervention. Median duration of diarrhoea was significantly shorter (P<0.001) in children who received L rhamnosus strain GG (78.5 hours) and the mix of four bacterial strains (70.0 hours) than in children who received oral rehydration solution alone (115.0 hours). One day after the first probiotic administration, the daily number of stools was significantly lower (P<0.001) in children who received L rhamnosus strain GG and in those who received the probiotic mix than in the other groups. The remaining preparations did not affect primary outcomes. Secondary outcomes were similar in all groups. CONCLUSIONS: Not all commercially available probiotic preparations are effective in children with acute diarrhoea. Paediatricians should choose bacterial preparations based on effectiveness data. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN56067537 [controlled-trials.com]. [Abstract/Link to Full Text]

Pawitan JA
Probiotics in children: Consider microbial cause.
BMJ. 2007 Sep 1;335(7617):414. [Abstract/Link to Full Text]

Whittaker PJ
Probiotics in children: All nutritional supplements should be classified as drugs.
BMJ. 2007 Sep 1;335(7617):414. [Abstract/Link to Full Text]

Fitzmaurice DA, Hobbs FD, Jowett S, Mant J, Murray ET, Holder R, Raftery JP, Bryan S, Davies M, Lip GY, Allan TF
Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomised controlled trial.
BMJ. 2007 Aug 25;335(7616):383.
OBJECTIVES: To assess whether screening improves the detection of atrial fibrillation (cluster randomisation) and to compare systematic and opportunistic screening. DESIGN: Multicentred cluster randomised controlled trial, with subsidiary trial embedded within the intervention arm. SETTING: 50 primary care centres in England, with further individual randomisation of patients in the intervention practices. PARTICIPANTS: 14,802 patients aged 65 or over in 25 intervention and 25 control practices. INTERVENTIONS: Patients in intervention practices were randomly allocated to systematic screening (invitation for electrocardiography) or opportunistic screening (pulse taking and invitation for electrocardiography if the pulse was irregular). Screening took place over 12 months in each practice from October 2001 to February 2003. No active screening took place in control practices. MAIN OUTCOME MEASURE: Newly identified atrial fibrillation. RESULTS: The detection rate of new cases of atrial fibrillation was 1.63% a year in the intervention practices and 1.04% in control practices (difference 0.59%, 95% confidence interval 0.20% to 0.98%). Systematic and opportunistic screening detected similar numbers of new cases (1.62% v 1.64%, difference 0.02%, -0.5% to 0.5%). CONCLUSION: Active screening for atrial fibrillation detects additional cases over current practice. The preferred method of screening in patients aged 65 or over in primary care is opportunistic pulse taking with follow-up electrocardiography. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19633732 [controlled-trials.com]. [Abstract/Link to Full Text]

van Weert HC
Diagnosing atrial fibrillation in general practice.
BMJ. 2007 Aug 25;335(7616):355-6. [Abstract/Link to Full Text]

Su LL, Chong YS, Chan YH, Chan YS, Fok D, Tun KT, Ng FS, Rauff M
Antenatal education and postnatal support strategies for improving rates of exclusive breast feeding: randomised controlled trial.
BMJ. 2007 Sep 22;335(7620):596.
OBJECTIVE: To investigate whether antenatal breast feeding education alone or postnatal lactation support alone improves rates of exclusive breast feeding compared with routine hospital care. DESIGN: Randomised controlled trial. SETTING: A tertiary hospital in Singapore. PARTICIPANTS: 450 women with uncomplicated pregnancies. MAIN OUTCOME MEASURES: Primary outcomes were rates of exclusive breast feeding at discharge from hospital and two weeks, six weeks, three months, and six months after delivery. Secondary outcomes were rates of any breast feeding. RESULTS: Compared with women who received routine care, women in the postnatal support group were more likely to breastfeed exclusively at two weeks (relative risk 1.82, 95% confidence interval 1.14 to 2.90), six weeks (1.85, 1.11 to 3.09), three months (1.87, 1.03 to 3.41), and six months (2.12, 1.03 to 4.37) postnatally. Women receiving antenatal education were more likely to breast feed exclusively at six weeks (1.73, 1.04 to 2.90), three months (1.92, 1.07 to 3.48), and six months (2.16, 1.05 to 4.43) postnatally. The numbers needed to treat to achieve one woman exclusively breast feeding at six months were 11 (6 to 80) for postnatal support and 10 (6 to 60) for antenatal education. Women who received postnatal support were more likely to exclusively or predominantly breast feed two weeks after delivery compared with women who received antenatal education (1.53, 1.01 to 2.31). The rate of any breastfeeding six weeks after delivery was also higher in the postnatal support group compared with women who received routine care (1.16, 1.02 to 1.31). CONCLUSIONS: Antenatal breast feeding education and postnatal lactation support, as single interventions based in hospital both significantly improve rates of exclusive breast feeding up to six months after delivery. Postnatal support was marginally more effective than antenatal education. TRIAL REGISTRATION: Clinical Trials NCT00270920 [ClinicalTrials.gov]. [Abstract/Link to Full Text]

Quigley MA
Increasing exclusive breast feeding.
BMJ. 2007 Sep 22;335(7620):574-5. [Abstract/Link to Full Text]

Rona RJ, Fear NT, Hull L, Greenberg N, Earnshaw M, Hotopf M, Wessely S
Mental health consequences of overstretch in the UK armed forces: first phase of a cohort study.
BMJ. 2007 Sep 22;335(7620):603.
OBJECTIVE: To assess the relation between frequency and duration of deployment of UK armed forces personnel on mental health. DESIGN: First phase of a cohort study. SETTING: UK armed forces personnel. PARTICIPANTS: Operational history in past three years of a randomly chosen stratified sample of 5547 regulars with experience of deployment. MAIN OUTCOME MEASURES: Psychological distress (general health questionnaire-12), caseness for post-traumatic stress disorder, physical symptoms, and alcohol use (alcohol use disorders identification test). RESULTS: Personnel who were deployed for 13 months or more in the past three years were more likely to fulfil the criteria for post-traumatic stress disorder (odds ratio 1.55, 95% confidence interval 1.07 to 2.32), show caseness on the general health questionnaire (1.35, 1.10 to 1.63), and have multiple physical symptoms (1.49, 1.19 to 1.87). A significant association was found between duration of deployment and severe alcohol problems. Exposure to combat partly accounted for these associations. The associations between number of deployments in the past three years and mental disorders were less consistent than those related to duration of deployment. Post-traumatic stress disorder was also associated with a mismatch between expectations about the duration of deployment and the reality. CONCLUSIONS: A clear and explicit policy on the duration of each deployment of armed forces personnel may reduce the risk of post-traumatic stress disorder. An association was found between deployment for more than a year in the past three years and mental health that might be explained by exposure to combat. [Abstract/Link to Full Text]

Ursano RJ, Benedek DM, Engel CC
Mental illness in deployed soldiers.
BMJ. 2007 Sep 22;335(7620):571-2. [Abstract/Link to Full Text]

Chung A, Perera R, Brueggemann AB, Elamin AE, Harnden A, Mayon-White R, Smith S, Crook DW, Mant D
Effect of antibiotic prescribing on antibiotic resistance in individual children in primary care: prospective cohort study.
BMJ. 2007 Sep 1;335(7617):429.
OBJECTIVE: To assess the effect of community prescribing of an antibiotic for acute respiratory infection on the prevalence of antibiotic resistant bacteria in an individual child. STUDY DESIGN: Observational cohort study with follow-up at two and 12 weeks. SETTING: General practices in Oxfordshire. PARTICIPANTS: 119 children with acute respiratory tract infection, of whom 71 received a beta lactam antibiotic. MAIN OUTCOME MEASURES: Antibiotic resistance was assessed by the geometric mean minimum inhibitory concentration (MIC) for ampicillin and presence of the ICEHin1056 resistance element in up to four isolates of Haemophilus species recovered from throat swabs at recruitment, two weeks, and 12 weeks. RESULTS: Prescribing amoxicillin to a child in general practice more than triples the mean minimum inhibitory concentration for ampicillin (9.2 microg/ml v 2.7 microg/ml, P=0.005) and doubles the risk of isolation of Haemophilus isolates possessing homologues of ICEHin1056 (67% v 36%; relative risk 1.9, 95% confidence interval 1.2 to 2.9) two weeks later. Although this increase is transient (by 12 weeks ampicillin resistance had fallen close to baseline), it is in the context of recovery of the element from 35% of children with Haemophilus isolates at recruitment and from 83% (76% to 89%) at some point in the study. CONCLUSION: The short term effect of amoxicillin prescribed in primary care is transitory in the individual child but sufficient to sustain a high level of antibiotic resistance in the population. [Abstract/Link to Full Text]

Del Mar C
Prescribing antibiotics in primary care.
BMJ. 2007 Sep 1;335(7617):407-8. [Abstract/Link to Full Text]

Roberts TE, Robinson S, Barton PM, Bryan S, McCarthy A, Macleod J, Egger M, Low N
Cost effectiveness of home based population screening for Chlamydia trachomatis in the UK: economic evaluation of chlamydia screening studies (ClaSS) project.
BMJ. 2007 Aug 11;335(7614):291.
OBJECTIVE: To investigate the cost effectiveness of screening for Chlamydia trachomatis compared with a policy of no organised screening in the United Kingdom. DESIGN: Economic evaluation using a transmission dynamic mathematical model. SETTING: Central and southwest England. PARTICIPANTS: Hypothetical population of 50,000 men and women, in which all those aged 16-24 years were invited to be screened each year. MAIN OUTCOME MEASURES: Cost effectiveness based on major outcomes averted, defined as pelvic inflammatory disease, ectopic pregnancy, infertility, or neonatal complications. RESULTS: The incremental cost per major outcome averted for a programme of screening women only (assuming eight years of screening) was 22,300 pounds (33,000 euros; $45,000) compared with no organised screening. For a programme screening both men and women, the incremental cost effectiveness ratio was approximately 28,900 pounds. Pelvic inflammatory disease leading to hospital admission was the most frequently averted major outcome. The model was highly sensitive to the incidence of major outcomes and to uptake of screening. When both were increased the cost effectiveness ratio fell to 6200 pound per major outcome averted for screening women only. CONCLUSIONS: Proactive register based screening for chlamydia is not cost effective if the uptake of screening and incidence of complications are based on contemporary empirical studies, which show lower rates than commonly assumed. These data are relevant to discussions about the cost effectiveness of the opportunistic model of chlamydia screening being introduced in England. [Abstract/Link to Full Text]

Underhill K, Montgomery P, Operario D
Sexual abstinence only programmes to prevent HIV infection in high income countries: systematic review.
BMJ. 2007 Aug 4;335(7613):248.
OBJECTIVE: To assess the effects of sexual abstinence only programmes for HIV prevention among participants in high income countries. DESIGN: Systematic review. DATA SOURCES: 30 electronic databases without linguistic or geographical restrictions to February 2007, contacts with experts, hand searching, and cross referencing. REVIEW METHODS: Two reviewers independently applied inclusion criteria and extracted data, resolving disagreements by consensus and referral to a third reviewer. Randomised and quasirandomised controlled trials of abstinence only programmes in any high income country were included. Programmes aimed to prevent HIV only or both pregnancy and HIV. Trials evaluated biological outcomes (incidence of HIV, sexually transmitted infection, pregnancy) or behavioural outcomes (incidence or frequency of unprotected vaginal, anal, or oral sex; incidence or frequency of any vaginal, anal, or oral sex; number of partners; condom use; sexual initiation). RESULTS: The search identified 13 trials enrolling about 15,940 US youths. All outcomes were self reported. Compared with various controls, no programme affected incidence of unprotected vaginal sex, number of partners, condom use, or sexual initiation. One trial observed adverse effects at short term follow-up (sexually transmitted infections, frequency of sex) and long term follow-up (sexually transmitted infections, pregnancy) compared with usual care, but findings were offset by trials with non-significant results. Another trial observed a protective effect on incidence of vaginal sex compared with usual care, but this was limited to short term follow-up and countered by trials with non-significant findings. Heterogeneity prevented meta-analysis. CONCLUSION: Programmes that exclusively encourage abstinence from sex do not seem to affect the risk of HIV infection in high income countries, as measured by self reported biological and behavioural outcomes. [Abstract/Link to Full Text]

Hawes SE, Sow PS, Kiviat NB
Is there a role for abstinence only programmes for HIV prevention in high income countries?
BMJ. 2007 Aug 4;335(7613):217-8. [Abstract/Link to Full Text]

MacLennan CA, Liu MK, White SA, van Oosterhout JJ, Simukonda F, Bwanali J, Moore MJ, Zijlstra EE, Drayson MT, Molyneux ME
Diagnostic accuracy and clinical utility of a simplified low cost method of counting CD4 cells with flow cytometry in Malawi: diagnostic accuracy study.
BMJ. 2007 Jul 28;335(7612):190.
OBJECTIVES: To assess the diagnostic accuracy and clinical utility of a simplified low cost method for measuring absolute and percentage CD4 counts with flow cytometry. DESIGN: A CD4 counting method (Blantyre count) using a CD4 and CD45 antibody combination with reduced blood and reagent volumes. Diagnostic accuracy was assessed by measuring agreement of the index test with two other assays (TruCount and FACSCount). Clinical utility was investigated by comparing CD4 counts with the new assay with WHO clinical staging in patients with HIV. SETTING: Research laboratories and antiretroviral therapy clinic at a medical school and large government hospital in southern Malawi. PARTICIPANTS: Assay comparisons were performed on consecutive blood samples sent for CD4 counting from 129 patients with HIV. Comparison of CD4 count with staging was conducted on 253 consecutive new patients attending the antiretroviral therapy clinic. MAIN OUTCOME MEASURES: Limits of agreement with 95% confidence intervals between index test and reference standards. RESULTS: The limits of agreement for Blantyre count and TruCount were excellent (cell count -48.9 to 27.0 x10(9)/l for absolute counts in the CD4 range <400x10(9)/l and -2.42% to 2.37% for CD4 percentage). The assay was affordable with reagent costs per test of $0.44 ( pound0.22, euro0.33) for both absolute count and CD4 percentage, and $0.11 for CD4 percentage alone. Of 193 patients with clinical stage I or II disease, who were ineligible for antiretroviral therapy by clinical staging criteria, 73 (38%) had CD4 counts <200x10(9)/l. By contrast, 12 (20%) of 60 patients with stage III or IV disease had CD4 counts >350x10(9)/l. CONCLUSIONS: This simplified method of counting CD4 cells with flow cytometry has good agreement with established commercial assays, is affordable for routine clinical use in Africa, and could improve clinical decision making in patients with HIV. [Abstract/Link to Full Text]

Madhivanan P, Krupp K
Technological challenges in diagnosis and management of HIV infection in resource limited settings.
BMJ. 2007 Jul 28;335(7612):165-6. [Abstract/Link to Full Text]

Potter S, Govindarajulu S, Shere M, Braddon F, Curran G, Greenwood R, Sahu AK, Cawthorn SJ
Referral patterns, cancer diagnoses, and waiting times after introduction of two week wait rule for breast cancer: prospective cohort study.
BMJ. 2007 Aug 11;335(7614):288.
OBJECTIVE: To investigate the long term impact of the two week wait rule for breast cancer on referral patterns, cancer diagnoses, and waiting times. DESIGN: Prospective cohort study. SETTING: A specialist breast clinic in a teaching hospital in Bristol. PARTICIPANTS: All patients referred to breast clinic from primary care between 1999 and 2005. MAIN OUTCOME MEASURES: Number, route, and outcome of referrals from primary care and waiting times for urgent and routine appointments. RESULTS: The annual number of referrals increased by 9% over the seven years from 3499 in 1999 to 3821 in 2005. Routine referrals decreased by 24% (from 1748 to 1331), but two week wait referrals increased by 42% (from 1751 to 2490) during this time. The percentage of patients diagnosed with cancer in the two week wait group decreased from 12.8% (224/1751) in 1999 to 7.7% (191/2490) in 2005 (P<0.001), while the number of cancers detected in the "routine" group increased from 2.5% (43/1748) to 5.3% (70/1331) (P<0.001) over the same period. About 27% (70/261) of people with cancer are currently referred in the non-urgent group. Waiting times for routine referrals have increased with time. CONCLUSION: The two week wait rule for breast cancer is failing patients. The number of cancers detected in the two week wait population is decreasing, and an unacceptable proportion is now being referred via the routine route. If breast cancer services are to be improved, the two week wait rule should be reviewed urgently. [Abstract/Link to Full Text]

Crawford SM
Two week rule: Breast cancer experience has wider implications.
BMJ. 2007 Aug 25;335(7616):361. [Abstract/Link to Full Text]

Helm EJ, Nash E
Two week rule: Breast cancer growth rates favour abolition of rule.
BMJ. 2007 Aug 25;335(7616):361. [Abstract/Link to Full Text]

Burns T, Catty J, Dash M, Roberts C, Lockwood A, Marshall M
Use of intensive case management to reduce time in hospital in people with severe mental illness: systematic review and meta-regression.
BMJ. 2007 Aug 18;335(7615):336.
OBJECTIVES: To explain why clinical trials of intensive case management for people with severe mental illness show such inconsistent effects on the use of hospital care. DESIGN: Systematic review with meta-regression techniques applied to data from randomised controlled trials. DATA SOURCES: Cochrane central register of controlled trials, CINAHL, Embase, Medline, and PsychINFO databases from inception to January 2007. Additional anonymised data on patients were obtained for multicentre trials. REVIEW METHODS: Included trials examined intensive case management compared with standard care or low intensity case management for people with severe mental illness living in the community. We used a fidelity scale to rate adherence to the model of assertive community treatment. Multicentre trials were disaggregated into individual centres with fidelity data specific for each centre. A multivariate meta-regression used mean days per month in hospital as the dependent variable. RESULTS: We identified 1335 abstracts with a total of 5961 participants. Of these, 49 were eligible and 29 provided appropriate data. Trials with high hospital use at baseline (before the trial) or in the control group were more likely to find that intensive case management reduced the use of hospital care (coefficient -0.23, 95% confidence interval -0.36 to -0.09, for hospital use at baseline; -0.44, -0.57 to -0.31, for hospital use in control groups). Case management teams organised according to the model of assertive community treatment were more likely to reduce the use of hospital care (coefficient -0.31, -0.59 to -0.03), but this finding was less robust in sensitivity analyses and was not found for staffing levels recommended for assertive community treatment. CONCLUSIONS: Intensive case management works best when participants tend to use a lot of hospital care and less well when they do not. When hospital use is high, intensive case management can reduce it, but it is less successful when hospital use is already low. The benefits of intensive case management might be marginal in settings that have already achieved low rates of bed use, and team organisation is more important than the details of staffing. It might not be necessary to apply the full model of assertive community treatment to achieve reductions in inpatient care. [Abstract/Link to Full Text]

Killaspy H
Assertive community treatment in psychiatry.
BMJ. 2007 Aug 18;335(7615):311-2. [Abstract/Link to Full Text]

Palfreyman S, Nelson EA, Michaels JA
Dressings for venous leg ulcers: systematic review and meta-analysis.
BMJ. 2007 Aug 4;335(7613):244.
OBJECTIVE: To review the evidence of effectiveness of dressings applied to venous leg ulcers. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Hand searches of journals and searches of electronic databases, conference proceedings, and bibliographies up to April 2006; contacts with dressing manufacturers for unpublished studies. STUDIES REVIEWED: All randomised controlled trials that evaluated dressings applied to venous leg ulcers were eligible for inclusion. Data from eligible studies were extracted and summarised independently by two reviewers using a data extraction sheet. Methodological quality was assessed independently by two reviewers. RESULTS: The search strategy identified 254 studies; 42 of these fulfilled the inclusion criteria. Hydrocolloids were no more effective than simple low adherent dressings used beneath compression (eight trials; relative risk for healing with hydrocolloid 1.02, 95% confidence interval 0.83 to 1.28). For other comparisons, insufficient evidence was available to allow firm conclusions to be drawn. None of the dressing comparisons showed evidence that a particular class of dressing healed more ulcers. Some differences existed between dressings in terms of subjective outcome measures and ulcer healing rates. The results were not affected by the size or quality of trials or the unit of randomisation. Insufficient data were available to allow conclusions to be drawn about the relative cost effectiveness of different dressings. CONCLUSIONS: The type of dressing applied beneath compression was not shown to affect ulcer healing. The results of the meta-analysis showed that applying hydrocolloid dressings beneath compression produced no benefit in terms of ulcer healing compared with applying simple low adherent dressings. No conclusive recommendations can be made as to which type of dressing is most cost effective. Decisions on which dressing to apply should be based on the local costs of dressings and the preferences of the practitioner or patient. [Abstract/Link to Full Text]

No type of dressing stands out as best for leg ulcers.
J Fam Pract. 2007 Nov;56(11):892. [Abstract/Link to Full Text]

Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith SK, DeStavola BL, Rose S, Dowell A, Wilkes HC, Darbyshire JH, Meade TW
Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women.
BMJ. 2007 Aug 4;335(7613):239.
OBJECTIVE: To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy). DESIGN: Multicentre, randomised, placebo controlled, double blind trial. SETTING: General practices in UK (384), Australia (91), and New Zealand (24). PARTICIPANTS: Postmenopausal women aged 50-69 years at randomisation. At early closure of the trial, 56,583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22,300) started treatment. INTERVENTIONS: Oestrogen only therapy (conjugated equine oestrogens 0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of treatment planned. MAIN OUTCOME MEASURES: Primary outcomes: major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes: other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life. RESULTS: The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women years) in those enrolled, after the publication of early results from the women's health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n=2196) was compared with placebo (n=2189), there was a significant increase in the number of major cardiovascular events (7 v 0, P=0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no significant differences. CONCLUSIONS: Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause. The results are consistent with the findings of the women's health initiative study and secondary prevention studies. Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause, when the effect may be different. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 63718836. [Abstract/Link to Full Text]

Roberts H
Hormone replacement therapy comes full circle.
BMJ. 2007 Aug 4;335(7613):219-20. [Abstract/Link to Full Text]

Watts G
Commentary: Liquid automation refreshes Dr Papanicolaou.
BMJ. 2007 Jul 7;335(7609):35-6. [Abstract/Link to Full Text]

Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, May M, Brindle P
Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study.
BMJ. 2007 Jul 21;335(7611):136.
OBJECTIVE: To derive a new cardiovascular disease risk score (QRISK) for the United Kingdom and to validate its performance against the established Framingham cardiovascular disease algorithm and a newly developed Scottish score (ASSIGN). DESIGN: Prospective open cohort study using routinely collected data from general practice. SETTING: UK practices contributing to the QRESEARCH database. PARTICIPANTS: The derivation cohort consisted of 1.28 million patients, aged 35-74 years, registered at 318 practices between 1 January 1995 and 1 April 2007 and who were free of diabetes and existing cardiovascular disease. The validation cohort consisted of 0.61 million patients from 160 practices. MAIN OUTCOME MEASURES: First recorded diagnosis of cardiovascular disease (incident diagnosis between 1 January 1995 and 1 April 2007): myocardial infarction, coronary heart disease, stroke, and transient ischaemic attacks. Risk factors were age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol to high density lipoprotein, body mass index, family history of coronary heart disease in first degree relative aged less than 60, area measure of deprivation, and existing treatment with antihypertensive agent. RESULTS: A cardiovascular disease risk algorithm (QRISK) was developed in the derivation cohort. In the validation cohort the observed 10 year risk of a cardiovascular event was 6.60% (95% confidence interval 6.48% to 6.72%) in women and 9.28% (9.14% to 9.43%) in men. Overall the Framingham algorithm over-predicted cardiovascular disease risk at 10 years by 35%, ASSIGN by 36%, and QRISK by 0.4%. Measures of discrimination tended to be higher for QRISK than for the Framingham algorithm and it was better calibrated to the UK population than either the Framingham or ASSIGN models. Using QRISK 8.5% of patients aged 35-74 are at high risk (20% risk or higher over 10 years) compared with 13% when using the Framingham algorithm and 14% when using ASSIGN. Using QRISK 34% of women and 73% of men aged 64-75 would be at high risk compared with 24% and 86% according to the Framingham algorithm. UK estimates for 2005 based on QRISK give 3.2 million patients aged 35-74 at high risk, with the Framingham algorithm predicting 4.7 million and ASSIGN 5.1 million. Overall, 53 668 patients in the validation dataset (9% of the total) would be reclassified from high to low risk or vice versa using QRISK compared with the Framingham algorithm. CONCLUSION: QRISK performed at least as well as the Framingham model for discrimination and was better calibrated to the UK population than either the Framingham model or ASSIGN. QRISK is likely to provide more appropriate risk estimates to help identify high risk patients on the basis of age, sex, and social deprivation. It is therefore likely to be a more equitable tool to inform management decisions and help ensure treatments are directed towards those most likely to benefit. It includes additional variables which improve risk estimates for patients with a positive family history or those on antihypertensive treatment. However, since the validation was performed in a similar population to the population from which the algorithm was derived, it potentially has a "home advantage." Further validation in other populations is therefore required. [Abstract/Link to Full Text]

Bonneux L
Cardiovascular risk models.
BMJ. 2007 Jul 21;335(7611):107-8. [Abstract/Link to Full Text]

Montini G, Toffolo A, Zucchetta P, Dall'Amico R, Gobber D, Calderan A, Maschio F, Pavanello L, Molinari PP, Scorrano D, Zanchetta S, Cassar W, Brisotto P, Corsini A, Sartori S, Da Dalt L, Murer L, Zacchello G
Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial.
BMJ. 2007 Aug 25;335(7616):386.
OBJECTIVE: To compare the efficacy of oral antibiotic treatment alone with treatment started parenterally and completed orally in children with a first episode of acute pyelonephritis. DESIGN: Multicentre, randomised controlled, open labelled, parallel group, non-inferiority trial. SETTING: 28 paediatric units in north east Italy. PARTICIPANTS: 502 children aged 1 month to <7 years with clinical pyelonephritis. INTERVENTION: Oral co-amoxiclav (50 mg/kg/day in three doses for 10 days) or parenteral ceftriaxone (50 mg/kg/day in a single parenteral dose) for three days, followed by oral co-amoxiclav (50 mg/kg/day in three divided doses for seven days). Main outcomes measures Primary outcome was the rate of renal scarring. Secondary measures of efficacy were time to defervescence (<37 degrees C), reduction in inflammatory indices, and percentage with sterile urine after 72 hours. An exploratory subgroup analysis was conducted in the children in whom pyelonephritis was confirmed by dimercaptosuccinic acid (DMSA) scintigraphy within 10 days after study entry. RESULTS: Intention to treat analysis showed no significant differences between oral (n=244) and parenteral (n=258) treatment, both in the primary outcome (scarring scintigraphy at 12 months 27/197 (13.7%) v 36/203 (17.7%), difference in risk -4%, 95% confidence interval -11.1% to 3.1%) and secondary outcomes (time to defervescence 36.9 hours (SD 19.7) v 34.3 hours (SD 20), mean difference 2.6 (-0.9 to 6.0); white cell count 9.8x10(9)/l (SD 3.5) v 9.5x10(9)/l (SD 3.1), mean difference 0.3 (-0.3 to 0.9); percentage with sterile urine 185/186 v 203/204, risk difference -0.05% (-1.5% to 1.4%)). Similar results were found in the subgroup of 278 children with confirmed acute pyelonephritis on scintigraphy at study entry. CONCLUSIONS: Treatment with oral antibiotics is as effective as parenteral then oral treatment in the management of the first episode of clinical pyelonephritis in children. TRIAL REGISTRATION: Clinical Trials NCT00161330 [ClinicalTrials.gov]. [Abstract/Link to Full Text]

Watson AR
Management of urinary tract infection in children.
BMJ. 2007 Aug 25;335(7616):356-7. [Abstract/Link to Full Text]

Davey E, d'Assuncao J, Irwig L, Macaskill P, Chan SF, Richards A, Farnsworth A
Accuracy of reading liquid based cytology slides using the ThinPrep Imager compared with conventional cytology: prospective study.
BMJ. 2007 Jul 7;335(7609):31.
OBJECTIVE: To compare the accuracy of liquid based cytology using the computerised ThinPrep Imager with that of manually read conventional cytology. DESIGN: Prospective study. SETTING: Pathology laboratory in Sydney, Australia. PARTICIPANTS: 55,164 split sample pairs (liquid based sample collected after conventional sample from one collection) from consecutive samples of women choosing both types of cytology and whose specimens were examined between August 2004 and June 2005. MAIN OUTCOME MEASURES: Primary outcome was accuracy of slides for detecting squamous lesions. Secondary outcomes were rate of unsatisfactory slides, distribution of squamous cytological classifications, and accuracy of detecting glandular lesions. RESULTS: Fewer unsatisfactory slides were found for imager read cytology than for conventional cytology (1.8% v 3.1%; P<0.001). More slides were classified as abnormal by imager read cytology (7.4% v 6.0% overall and 2.8% v 2.2% for cervical intraepithelial neoplasia of grade 1 or higher). Among 550 patients in whom imager read cytology was cervical intraepithelial neoplasia grade 1 or higher and conventional cytology was less severe than grade 1, 133 of 380 biopsy samples taken were high grade histology. Among 294 patients in whom imager read cytology was less severe than cervical intraepithelial neoplasia grade 1 and conventional cytology was grade 1 or higher, 62 of 210 biopsy samples taken were high grade histology. Imager read cytology therefore detected 71 more cases of high grade histology than did conventional cytology, resulting from 170 more biopsies. Similar results were found when one pathologist reread the slides, masked to cytology results. CONCLUSION: The ThinPrep Imager detects 1.29 more cases of histological high grade squamous disease per 1000 women screened than conventional cytology, with cervical intraepithelial neoplasia grade 1 as the threshold for referral to colposcopy. More imager read slides than conventional slides were satisfactory for examination and more contained low grade cytological abnormalities. [Abstract/Link to Full Text]

Denton KJ
Liquid based cytology in cervical cancer screening.
BMJ. 2007 Jul 7;335(7609):1-2. [Abstract/Link to Full Text]

Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ
Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial.
BMJ. 2007 Jul 14;335(7610):80.
OBJECTIVE: To determine the efficacy of a probiotic drink containing Lactobacillus for the prevention of any diarrhoea associated with antibiotic use and that caused by Clostridium difficile. DESIGN: Randomised double blind placebo controlled study. PARTICIPANTS: 135 hospital patients (mean age 74) taking antibiotics. Exclusions included diarrhoea on admission, bowel pathology that could result in diarrhoea, antibiotic use in the previous four weeks, severe illness, immunosuppression, bowel surgery, artificial heart valves, and history of rheumatic heart disease or infective endocarditis. INTERVENTION: Consumption of a 100 g (97 ml) drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus twice a day during a course of antibiotics and for one week after the course finished. The placebo group received a longlife sterile milkshake. MAIN OUTCOME MEASURES: Primary outcome: occurrence of antibiotic associated diarrhoea. Secondary outcome: presence of C difficile toxin and diarrhoea. RESULTS: 7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (P=0.007). Logistic regression to control for other factors gave an odds ratio 0.25 (95% confidence interval 0.07 to 0.85) for use of the probiotic, with low albumin and sodium also increasing the risk of diarrhoea. The absolute risk reduction was 21.6% (6.6% to 36.6%), and the number needed to treat was 5 (3 to 15). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by C difficile (P=0.001). The absolute risk reduction was 17% (7% to 27%), and the number needed to treat was 6 (4 to 14). CONCLUSION: Consumption of a probiotic drink containing L casei, L bulgaricus, and S thermophilus can reduce the incidence of antibiotic associated diarrhoea and C difficile associated diarrhoea. This has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50. TRIAL REGISTRATION: National Research Register N0016106821. [Abstract/Link to Full Text]

Wilcox MH, Sandoe JA
Probiotics and diarrhea: Data are not widely applicable.
BMJ. 2007 Jul 28;335(7612):171. [Abstract/Link to Full Text]

Billyard T
Probiotics and diarrhea: No high risk antibiotics?
BMJ. 2007 Jul 28;335(7612):171. [Abstract/Link to Full Text]

Konfortov MB
Probiotics and diarrhea: No proton pump inhibitors?
BMJ. 2007 Jul 28;335(7612):171. [Abstract/Link to Full Text]

Mant J, Fitzmaurice DA, Hobbs FD, Jowett S, Murray ET, Holder R, Davies M, Lip GY
Accuracy of diagnosing atrial fibrillation on electrocardiogram by primary care practitioners and interpretative diagnostic software: analysis of data from screening for atrial fibrillation in the elderly (SAFE) trial.
BMJ. 2007 Aug 25;335(7616):380.
OBJECTIVE: To assess the accuracy of general practitioners, practice nurses, and interpretative software in the use of different types of electrocardiogram to diagnose atrial fibrillation. DESIGN: Prospective comparison with reference standard of assessment of electrocardiograms by two independent specialists. SETTING: 49 general practices in central England. PARTICIPANTS: 2595 patients aged 65 or over screened for atrial fibrillation as part of the screening for atrial fibrillation in the elderly (SAFE) study; 49 general practitioners and 49 practice nurses. INTERVENTIONS: All electrocardiograms were read with the Biolog interpretative software, and a random sample of 12 lead, limb lead, and single lead thoracic placement electrocardiograms were assessed by general practitioners and practice nurses independently of each other and of the Biolog assessment. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values. RESULTS: General practitioners detected 79 out of 99 cases of atrial fibrillation on a 12 lead electrocardiogram (sensitivity 80%, 95% confidence interval 71% to 87%) and misinterpreted 114 out of 1355 cases of sinus rhythm as atrial fibrillation (specificity 92%, 90% to 93%). Practice nurses detected a similar proportion of cases of atrial fibrillation (sensitivity 77%, 67% to 85%), but had a lower specificity (85%, 83% to 87%). The interpretative software was significantly more accurate, with a specificity of 99%, but missed 36 of 215 cases of atrial fibrillation (sensitivity 83%). Combining general practitioners' interpretation with the interpretative software led to a sensitivity of 92% and a specificity of 91%. Use of limb lead or single lead thoracic placement electrocardiograms resulted in some loss of specificity. CONCLUSIONS: Many primary care professionals cannot accurately detect atrial fibrillation on an electrocardiogram, and interpretative software is not sufficiently accurate to circumvent this problem, even when combined with interpretation by a general practitioner. Diagnosis of atrial fibrillation in the community needs to factor in the reading of electrocardiograms by appropriately trained people. [Abstract/Link to Full Text]

Cole TJ, Flegal KM, Nicholls D, Jackson AA
Body mass index cut offs to define thinness in children and adolescents: international survey.
BMJ. 2007 Jul 28;335(7612):194.
OBJECTIVE: To determine cut offs to define thinness in children and adolescents, based on body mass index at age 18 years. DESIGN: International survey of six large nationally representative cross sectional studies on growth. SETTING: Brazil, Great Britain, Hong Kong, the Netherlands, Singapore, and the United States. SUBJECTS: 97 876 males and 94 851 females from birth to 25 years. MAIN OUTCOME MEASURE: Body mass index (BMI, weight/height(2)). RESULTS: The World Health Organization defines grade 2 thinness in adults as BMI <17. This same cut off, applied to the six datasets at age 18 years, gave mean BMI close to a z score of -2 and 80% of the median. Thus it matches existing criteria for wasting in children based on weight for height. For each dataset, centile curves were drawn to pass through the cut off of BMI 17 at 18 years. The resulting curves were averaged to provide age and sex specific cut-off points from 2-18 years. Similar cut offs were derived based on BMI 16 and 18.5 at 18 years, together providing definitions of thinness grades 1, 2, and 3 in children and adolescents consistent with the WHO adult definitions. CONCLUSIONS: The proposed cut-off points should help to provide internationally comparable prevalence rates of thinness in children and adolescents. [Abstract/Link to Full Text]

Cameron N
Body mass index cut offs to define thinness in children and adolescents.
BMJ. 2007 Jul 28;335(7612):166-7. [Abstract/Link to Full Text]

Farmer A, Wade A, Goyder E, Yudkin P, French D, Craven A, Holman R, Kinmonth AL, Neil A
Impact of self monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial.
BMJ. 2007 Jul 21;335(7611):132.
OBJECTIVE: To determine whether self monitoring, alone or with instruction in incorporating the results into self care, is more effective than usual care in improving glycaemic control in non-insulin treated patients with type 2 diabetes. DESIGN: Three arm, open, parallel group randomised trial. SETTING: 48 general practices in Oxfordshire and South Yorkshire. PARTICIPANTS: 453 patients with non-insulin treated type 2 diabetes (mean age 65.7 years) for a median duration of three years and a mean haemoglobin A1c level of 7.5%. INTERVENTIONS: Standardised usual care with measurements of HbA1c every three months as the control group (n=152), blood glucose self monitoring with advice for patients to contact their doctor for interpretation of results, in addition to usual care (n=150), and blood glucose self monitoring with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (n=151). MAIN OUTCOME MEASURE: HbA1c level measured at 12 months. RESULTS: At 12 months the differences in HbA1c level between the three groups (adjusted for baseline HbA1c level) were not statistically significant (P=0.12). The difference in unadjusted mean change in HbA1c level from baseline to 12 months between the control and less intensive self monitoring groups was -0.14% (95% confidence interval -0.35% to 0.07%) and between the control and more intensive self monitoring groups was -0.17% (-0.37% to 0.03%). CONCLUSIONS: Evidence is not convincing of an effect of self monitoring blood glucose, with or without instruction in incorporating findings into self care, in improving glycaemic control compared with usual care in reasonably well controlled non-insulin treated patients with type 2 diabetes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47464659. [Abstract/Link to Full Text]

Moore A, Derry S, McGeogh G
Self monitoring in diabetes: Useful in which patients?
BMJ. 2007 Aug 11;335(7614):271; author reply 272. [Abstract/Link to Full Text]

Evans PD
Self monitoring in diabetes: Let me own my disease.
BMJ. 2007 Aug 11;335(7614):271; author reply 272. [Abstract/Link to Full Text]

Lister AJ
Self monitoring in diabetes: Education seems to work better.
BMJ. 2007 Aug 11;335(7614):271; author reply 272. [Abstract/Link to Full Text]

Heller SR
Self monitoring of blood glucose in type 2 diabetes.
BMJ. 2007 Jul 21;335(7611):105-6. [Abstract/Link to Full Text]

Do glucose monitors help type 2 patients with long-term control?
J Fam Pract. 2007 Oct;56(10):801. [Abstract/Link to Full Text]

McDonald R, Harrison S, Checkland K, Campbell SM, Roland M
Impact of financial incentives on clinical autonomy and internal motivation in primary care: ethnographic study.
BMJ. 2007 Jun 30;334(7608):1357.
OBJECTIVE: To explore the impact of financial incentives for quality of care on practice organisation, clinical autonomy, and internal motivation of doctors and nurses working in primary care. DESIGN: Ethnographic case study. SETTING: Two English general practices. PARTICIPANTS: 12 general practitioners, nine nurses, four healthcare assistants, and four administrative staff. MAIN OUTCOME MEASURE: Observation of practices over a five month period after the introduction of financial incentives for quality of care introduced in the 2004 general practitioner contract. RESULTS: After the introduction of the quality and outcomes framework there was an increase in the use of templates to collect data on quality of care. New regimens of surveillance were adopted, with clinicians seen as "chasers" or the "chased," depending on their individual responsibility for delivering quality targets. Attitudes towards the contract were largely positive, although discontent was higher in the practice with a more intensive surveillance regimen. Nurses expressed more concern than doctors about changes to their clinical practice but also appreciated being given responsibility for delivering on targets in particular disease areas. Most doctors did not question the quality targets that existed at the time or the implications of the targets for their own clinical autonomy. CONCLUSIONS: Implementation of financial incentives for quality of care did not seem to have damaged the internal motivation of the general practitioners studied, although more concern was expressed by nurses. [Abstract/Link to Full Text]

Strong M, Radford J
Financial incentives and GPs: What about the impact on patient health?
BMJ. 2007 Jul 14;335(7610):60. [Abstract/Link to Full Text]

Bierman AS, Clark JP
Performance measurement and equity.
BMJ. 2007 Jun 30;334(7608):1333-4. [Abstract/Link to Full Text]

Wong MC, Chung JW, Wong TK
Effects of treatments for symptoms of painful diabetic neuropathy: systematic review.
BMJ. 2007 Jul 14;335(7610):87.
OBJECTIVE: To evaluate the effects of treatments for the symptoms of painful diabetic neuropathy. DESIGN: Systematic review. DATA SOURCES: Articles (English and full text) on double blind randomised trials found by searching with the key words anticonvulsant, antidepressant, non-steroidal anti-inflammatory drugs, tramadol, opioid, ion channel blocker, diabetic neuropathy, diabetic peripheral neuropathy, peripheral neuropathy, and neuropathy. The search included Medline, Embase, EMB reviews-AP Journal club, and the Cochrane central register of controlled trials. STUDY SELECTION: Randomised controlled trials comparing topically applied and orally administered drugs with a placebo in adults with painful diabetic neuropathy. DATA EXTRACTION: Data were extracted to examine quality of methods, characteristics of studies and patients, efficacy, and side effects. The primary outcome was dichotomous information for 50% or moderate reduction of pain. Secondary outcomes were 30% reduction of pain and withdrawals related to adverse events. RESULTS: Odds ratios were calculated for achievement of 30%, 50%, or moderate pain relief and for withdrawals related to adverse effects. Twenty five reports were included and seven were excluded. The 25 included reports compared anticonvulsants (n=1270), antidepressants (94), opioids (329), ion channel blockers (173), N-methyl-D-aspartate antagonist (14), duloxetine (805), capsaicin (277), and isosorbide dinitrate spray (22) with placebo. The odds ratios in terms of 50% pain relief were 5.33 (95% confidence interval 1.77 to 16.02) for traditional anticonvulsants, 3.25 (2.27 to 4.66) for newer generation anticonvulsants, and 22.24 (5.83 to 84.75) for tricylic antidepressants. The odds ratios in terms of withdrawals related to adverse events were 1.51 (0.33 to 6.96) for traditional anticonvulsants, 2.98 (1.75 to 5.07) for newer generation anticonvulsants, and 2.32 (0.59 to 9.69) for tricylic antidepressants. Insufficient dichotomous data were available to calculate the odds ratios for ion channel blockers. CONCLUSION: Anticonvulsants and antidepressants are still the most commonly used options to manage diabetic neuropathy. Oral tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants. Evidence of the long term effects of oral antidepressants and anticonvulsants is still lacking. Further studies are needed on opioids, N-methyl-D-aspartate antagonists, and ion channel blockers. [Abstract/Link to Full Text]

Tricyclics, capsaicin, and older anticonvulsants are best for neuropathy.
J Fam Pract. 2007 Oct;56(10):793. [Abstract/Link to Full Text]

Goodyer I, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, Breen S, Ford C, Barrett B, Leech A, Rothwell J, White L, Harrington R
Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial.
BMJ. 2007 Jul 21;335(7611):142.
OBJECTIVE: To determine whether a combination of a selective serotonin reuptake inhibitor (SSRIs) and cognitive behaviour therapy (CBT) together with clinical care is more effective in the short term than an SSRI and clinical care alone in adolescents with moderate to severe major depression. DESIGN: Pragmatic randomised controlled superiority trial. SETTING: 6 outpatient clinics in Manchester and Cambridge. PARTICIPANTS: 208 adolescents, aged 11-17, with moderate to severe major or probable major depression who had not responded to a brief initial intervention. Adolescents with suicidality, depressive psychosis, or conduct disorder were included. INTERVENTIONS: 103 adolescents received an SSRI and routine care; 105 received an SSRI, routine care, and CBT. The trial lasted 12 weeks, followed by a 16 week maintenance phase. MAIN OUTCOME MEASURES: Change in score on the Health of the Nation outcome scales for children and adolescents (primary outcome) from baseline with 12 weeks as the primary and 28 weeks as the follow-up end point. Secondary measures were change in scores on the mood and feelings questionnaire, the revised children's depression rating scale, the children's global assessment scale, and the clinical global impression improvement scale. RESULTS: At 12 weeks the treatment effect for the primary outcome was -0.64 (95% confidence interval -2.54 to 1.26, P=0.50). In a longitudinal analysis, there was no difference in effectiveness of treatment for the primary (average treatment effect 0.001, -1.52 to 1.52, P=0.99) or secondary outcome measures. On average there was a decrease in suicidal thoughts and self harm. There was no evidence of a protective effect of cognitive behaviour therapy on suicidal thinking or action. By 28 weeks, 57% were much or very much improved with 20% remaining unimproved. CONCLUSIONS: For adolescents with moderate to severe major depression there is no evidence that the combination of CBT plus an SSRI in the presence of routine clinical care contributes to an improved outcome by 28 weeks compared with the provision of routine clinical care plus an SSRI alone. TRIAL REGISTRATION: Current Controlled Trials ISRCNT 83809224. [Abstract/Link to Full Text]

Jureidini JN
Depression in adolescents: Study was not a trial of antidepressants.
BMJ. 2007 Aug 4;335(7613):221; author reply 221. [Abstract/Link to Full Text]

Hazell P
Depression in adolescents.
BMJ. 2007 Jul 21;335(7611):106-7. [Abstract/Link to Full Text]

Collins R, Burch J, Cranny G, Aguiar-Ib��ez R, Craig D, Wright K, Berry E, Gough M, Kleijnen J, Westwood M
Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: systematic review.
BMJ. 2007 Jun 16;334(7606):1257.
OBJECTIVES: To determine the diagnostic accuracy of duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography, alone or in combination, for the assessment of lower limb peripheral arterial disease; to evaluate the impact of these assessment methods on management of patients and outcomes; and to evaluate the evidence regarding attitudes of patients to these technologies and summarise available data on adverse events. DESIGN: Systematic review. METHODS: Searches of 11 electronic databases (to April 2005), six journals, and reference lists of included papers for relevant studies. Two reviewers independently selected studies, extracted data, and assessed quality. Diagnostic accuracy studies were assessed for quality with the QUADAS checklist. RESULTS: 107 studies met the inclusion criteria; 58 studies provided data on diagnostic accuracy, one on outcomes in patients, four on attitudes of patients, and 44 on adverse events. Quality assessment highlighted limitations in the methods and quality of reporting. Most of the included studies reported results by arterial segment, rather than by limb or by patient, which does not account for the clustering of segments within patients, so specificities may be overstated. For the detection of stenosis of 50% or more in a lower limb vessel, contrast enhanced magnetic resonance angiography had the highest diagnostic accuracy with a median sensitivity of 95% (range 92-99.5%) and median specificity of 97% (64-99%). The results were 91% (89-99%) and 91% (83-97%) for computed tomography angiography and 88% (80-98%) and 96% (89-99%) for duplex ultrasonography. A controlled trial reported no significant differences in outcomes in patients after treatment plans based on duplex ultrasonography alone or conventional contrast angiography alone, though in 22% of patients supplementary contrast angiography was needed to form a treatment plan. The limited evidence available suggested that patients preferred magnetic resonance angiography (with or without contrast) to contrast angiography, with half expressing no preference between magnetic resonance angiography or duplex ultrasonography (among patients with no contraindications for magnetic resonance angiography, such as claustrophobia). Where data on adverse events were available, magnetic resonance angiography was associated with the highest proportion of adverse events, but these were mild. The most severe adverse events, although rare, were mainly associated with contrast angiography. CONCLUSIONS: Contrast enhanced magnetic resonance angiography seems to be more specific than computed tomography angiography (that is, better at ruling out stenosis over 50%) and more sensitive than duplex ultrasonography (that is, better at ruling in stenosis over 50%) and was generally preferred by patients over contrast angiography. Computed tomography angiography was also preferred by patients over contrast angiography; no data on patients' preference between duplex ultrasonography and contrast angiography were available. Where available, contrast enhanced magnetic resonance angiography might be a viable alternative to contrast angiography. [Abstract/Link to Full Text]

Bradbury AW, Adam DJ
Diagnosis of peripheral arterial disease of the lower limb.
BMJ. 2007 Jun 16;334(7606):1229-30. [Abstract/Link to Full Text]

Thomson PC, Collidge TA, Mark PB, Traynor JP
Gadolinium contrast may be risky in kidney disease.
BMJ. 2007 Jun 30;334(7608):1335-6. [Abstract/Link to Full Text]

Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt KR
Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial.
BMJ. 2007 Jul 14;335(7610):83.
OBJECTIVE: To determine whether recurrence of leg ulcers may be prevented by surgical correction of superficial venous reflux in addition to compression. DESIGN: Randomised controlled trial. SETTING: Specialist nurse led leg ulcer clinics in three UK vascular centres. PARTICIPANTS: 500 patients (500 legs) with open or recently healed leg ulcers and superficial venous reflux. INTERVENTIONS: Compression alone or compression plus saphenous surgery. MAIN OUTCOME MEASURES: Primary outcomes were ulcer healing and ulcer recurrence. The secondary outcome was ulcer free time. RESULTS: Ulcer healing rates at three years were 89% for the compression group and 93% for the compression plus surgery group (P=0.73, log rank test). Rates of ulcer recurrence at four years were 56% for the compression group and 31% for the compression plus surgery group (P<0.01). For patients with isolated superficial reflux, recurrence rates at four years were 51% for the compression group and 27% for the compress plus surgery group (P<0.01). For patients who had superficial with segmental deep reflux, recurrence rates at three years were 52% for the compression group and 24% for the compression plus surgery group (P=0.04). For patients with superficial and total deep reflux, recurrence rates at three years were 46% for the compression group and 32% for the compression plus surgery group (P=0.33). Patients in the compression plus surgery group experienced a greater proportion of ulcer free time after three years compared with patients in the compression group (78% v 71%; P=0.007, Mann-Whitney U test). CONCLUSION: Surgical correction of superficial venous reflux in addition to compression bandaging does not improve ulcer healing but reduces the recurrence of ulcers at four years and results in a greater proportion of ulcer free time. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07549334 [controlled-trials.com]. [Abstract/Link to Full Text]

Recent Articles in CMAJ : Canadian Medical Association Journal

Vyvey M
Mzungu.
CMAJ. 2007 Oct 23;177(9):1018-9. [Abstract/Link to Full Text]

Wakabi W
US$58 million grant to fight yellow fever in Africa.
CMAJ. 2007 Oct 23;177(9):1017. [Abstract/Link to Full Text]

Wakabi W
"Homophobia is fuelling the AIDS epidemic in Africa".
CMAJ. 2007 Oct 23;177(9):1017. [Abstract/Link to Full Text]

Sharma SP
Building health services in the world's poorest nations.
CMAJ. 2007 Oct 23;177(9):1016. [Abstract/Link to Full Text]

Bagchi S
Faster malaria testing.
CMAJ. 2007 Oct 23;177(9):1016. [Abstract/Link to Full Text]

Eggertson L
Shelter from the mental storm.
CMAJ. 2007 Oct 23;177(9):1015. [Abstract/Link to Full Text]

Silversides A
The North "like Darfur".
CMAJ. 2007 Oct 23;177(9):1013-4. [Abstract/Link to Full Text]

Attaran A
Global poverty is ours to reject.
CMAJ. 2007 Oct 23;177(9):999-1000, 1003-4. [Abstract/Link to Full Text]

Kopala M
Reefer madness.
CMAJ. 2007 Oct 9;177(8):988. [Abstract/Link to Full Text]

Yeates N
Health Canada's new standards on conflict of interest.
CMAJ. 2007 Oct 9;177(8):900; author reply 900. [Abstract/Link to Full Text]

Kondro W
US proposes more stringent conflict-of-interest rules.
CMAJ. 2007 May 22;176(11):1571-2. [Abstract/Link to Full Text]

Goodwin J
Whose responsibility is it?
CMAJ. 2007 Oct 9;177(8):900-1. [Abstract/Link to Full Text]

Bliss M
Contrary history: socialized medicine and Canada's decline.
CMAJ. 2007 Jul 17;177(2):224. [Abstract/Link to Full Text]

Richman VV
Analyzing the risks of cesarean delivery.
CMAJ. 2007 Oct 9;177(8):899. [Abstract/Link to Full Text]

Liu S, Liston RM, Joseph KS, Heaman M, Sauve R, Kramer MS
Maternal mortality and severe morbidity associated with low-risk planned cesarean delivery versus planned vaginal delivery at term.
CMAJ. 2007 Feb 13;176(4):455-60.
BACKGROUND: The rate of elective primary cesarean delivery continues to rise, owing in part to the widespread perception that the procedure is of little or no risk to healthy women. METHODS: Using the Canadian Institute for Health Information's Discharge Abstract Database, we carried out a retrospective population-based cohort study of all women in Canada (excluding Quebec and Manitoba) who delivered from April 1991 through March 2005. Healthy women who underwent a primary cesarean delivery for breech presentation constituted a surrogate "planned cesarean group" considered to have undergone low-risk elective cesarean delivery, for comparison with an otherwise similar group of women who had planned to deliver vaginally. RESULTS: The planned cesarean group comprised 46,766 women v. 2,292,420 in the planned vaginal delivery group; overall rates of severe morbidity for the entire 14-year period were 27.3 and 9.0, respectively, per 1000 deliveries. The planned cesarean group had increased postpartum risks of cardiac arrest (adjusted odds ratio [OR] 5.1, 95% confidence interval [CI] 4.1-6.3), wound hematoma (OR 5.1, 95% CI 4.6-5.5), hysterectomy (OR 3.2, 95% CI 2.2-4.8), major puerperal infection (OR 3.0, 95% CI 2.7-3.4), anesthetic complications (OR 2.3, 95% CI 2.0-2.6), venous thromboembolism (OR 2.2, 95% CI 1.5-3.2) and hemorrhage requiring hysterectomy (OR 2.1, 95% CI 1.2-3.8), and stayed in hospital longer (adjusted mean difference 1.47 d, 95% CI 1.46-1.49 d) than those in the planned vaginal delivery group, but a lower risk of hemorrhage requiring blood transfusion (OR 0.4, 95% CI 0.2-0.8). Absolute risk increases in severe maternal morbidity rates were low (e.g., for postpartum cardiac arrest, the increase with planned cesarean delivery was 1.6 per 1000 deliveries, 95% CI 1.2-2.1). The difference in the rate of in-hospital maternal death between the 2 groups was nonsignificant (p = 0.87). INTERPRETATION: Although the absolute difference is small, the risks of severe maternal morbidity associated with planned cesarean delivery are higher than those associated with planned vaginal delivery. These risks should be considered by women contemplating an elective cesarean delivery and by their physicians. [Abstract/Link to Full Text]

Main C
Treatment of septic arthritis.
CMAJ. 2007 Oct 9;177(8):899; author reply 899-900. [Abstract/Link to Full Text]

Kherani RB, Shojania K
Septic arthritis in patients with pre-existing inflammatory arthritis.
CMAJ. 2007 May 22;176(11):1605-8. [Abstract/Link to Full Text]

Arnold SR
Revenge of the killer microbe.
CMAJ. 2007 Oct 9;177(8):895-6. [Abstract/Link to Full Text]

Cadieux G, Tamblyn R, Dauphinee D, Libman M
Predictors of inappropriate antibiotic prescribing among primary care physicians.
CMAJ. 2007 Oct 9;177(8):877-83.
BACKGROUND: Inappropriate use of antibiotics promotes antibiotic resistance. Little is known about physician characteristics that may be associated with inappropriate antibiotic prescribing. Our objective was to assess whether physician knowledge, time in practice, place of training and practice volume explain the differences in antibiotic prescribing among physicians. METHODS: A historical cohort of 852 primary care physicians in Quebec who became certified between 1990 and 1993 was followed for their first 6-9 years of practice (1990-1998). We evaluated whether inappropriate antibiotic prescribing had occurred during the study period (1990-1998) for viral (prescription of antibiotics) and bacterial (prescription of second-or third-line antibiotics given orally) infections. We used logistic regression to estimate the independent contributions of time in practice, practice volume, place of medical training and scores on licensure examinations. Physician sex and visit setting were controlled for, as were patient age, sex, education, income and geographic area of residence. RESULTS: A total of 104 230 patients who received a diagnosis of a viral infection and 65 304 who received a diagnosis of a bacterial infection were included in our study. International medical graduates were more likely than University of Montr�al graduates to prescribe antibiotics for viral respiratory infections (risk ratio [RR] 1.78, 95% confidence interval [CI] 1.30-2.44). Inappropriate antibiotic prescribing increased with time in practice. Physicians with a high practice volume were more likely than those with low practice volume to prescribe antibiotics for viral respiratory infections (RR 1.27, 95% CI 1.09-1.48) and to prescribe second-and third-line antibiotics as first-line treatment (RR 1.20, 95% CI 1.06-1.37). Physician scores on licensure examinations were not predictive of inappropriate antibiotic prescribing. INTERPRETATION: International medical graduates, physicians with high-volume practices and those who were in practice longer were more likely to prescribe antibiotics inappropriately. Developing effective interventions will require increased knowledge of the mechanisms that underlie these predictors of inappropriate antibiotic prescribing. [Abstract/Link to Full Text]

Cranney A
Is there a new role for angiotensin-converting-enzyme inhibitors in elderly patients?
CMAJ. 2007 Oct 9;177(8):891-2. [Abstract/Link to Full Text]

Sumukadas D, Witham MD, Struthers AD, McMurdo ME
Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial.
CMAJ. 2007 Oct 9;177(8):867-74.
BACKGROUND: Physical function and exercise capacity decline with age and are a major source of disability in older people. Recent evidence suggests a potential role for the renin-angiotensin system in modulating muscle function. We sought to examine the effect of the angiotensin-converting-enzyme (ACE) inhibitor perindopril on physical function in elderly people with functional impairment who had no heart failure or left ventricular systolic dysfunction. METHODS: In this double-blind randomized controlled trial, participants aged 65 years and older who had problems with mobility or functional impairment were randomly assigned to receive either perindopril or placebo for 20 weeks. The primary outcome was the change in the 6-minute walking distance over the 20 weeks. Secondary outcomes were changes in muscle function, daily activity levels, self-reported function and health-related quality of life. RESULTS: A total of 130 participants were enrolled in the study (mean age 78.7, standard deviation 7.7 years); 95 completed the trial. At 20 weeks, the mean 6-minute walking distance was significantly improved in the perindopril group relative to the placebo group (mean between-group difference 31.4 m, 95% confidence interval [CI] 10.8 to 51.9 m; p = 0.003). There was a significant impact on health-related quality of life: although the mean score for part 1 of the EQ-5D questionnaire deteriorated over time in the placebo group, quality of life was maintained in the perindopril group, for a between-group difference of 0.09 (p = 0.046). There were no significant differences between the 2 groups in the other outcomes. INTERPRETATION: Use of the ACE inhibitor perindopril improved exercise capacity in functionally impaired elderly people who had no heart failure and maintained health-related quality of life. The degree of improvement was equivalent to that reported after 6 months of exercise training. (International Standard Randomised Controlled Trial Register no. ISRCTN67679521). [Abstract/Link to Full Text]

Alter DA
Therapeutic lifestyle and disease-management interventions: pushing the scientific envelope.
CMAJ. 2007 Oct 9;177(8):887-9. [Abstract/Link to Full Text]

Wister A, Loewen N, Kennedy-Symonds H, McGowan B, McCoy B, Singer J
One-year follow-up of a therapeutic lifestyle intervention targeting cardiovascular disease risk.
CMAJ. 2007 Oct 9;177(8):859-65.
BACKGROUND: In this study, we tested the efficacy of a low-intensity lifestyle intervention aimed at reducing the risk of cardiovascular disease among mid-life individuals. METHODS: We conducted a randomized controlled trial in which participants were randomly assigned either to receive a health report card with counselling (from a Telehealth nurse) on smoking, exercise, nutrition and stress or to receive usual care. The patients were divided into 2 groups on the basis of risk: the primary prevention group, with a Framingham risk score of 10% or higher (intervention, n = 157; control, n = 158), and the secondary prevention group, who had a diagnosis of coronary artery disease (intervention, n = 153; control, n = 143). The primary outcome was a change in the Framingham global risk score between baseline and 1-year follow-up. Data were analyzed separately for the 2 prevention groups using an intention-to-treat analysis controlling for covariates. RESULTS: Within the primary prevention group, there were statistically significant changes for the treatment group relative to the controls, from baseline to year 1, in Framingham score (intervention, -3.10 [95% confidence interval (CI) -3.98 to -2.22]; control, -1.30 [95% CI -2.18 to -0.42]; p < 0.01) and scores for total cholesterol (intervention, -0.41 [95% CI -0.59 to -0.23]; control, -0.14 [95% CI -0.32 to 0.04]; p < 0.05), systolic blood pressure (intervention, -7.49 [95% CI -9.97 to -5.01]; control, -3.58 [95% CI -6.08 to -1.08]; p < 0.05), nutrition level (intervention, 0.30 [95% CI 0.13 to 0.47]; control, -0.05 [95% CI -0.22 to 0.12]; p < 0.01), and health confidence (intervention, 0.20 [95% CI 0.09 to 0.31]; control, 0.04 [95% CI -0.07 to 0.15]; p < 0.05), with adjustment for covariates. No significant changes in outcome variables were found for the secondary prevention group. INTERPRETATION: We found evidence for the efficacy of an intervention addressing multiple risk factors for primary prevention at 1 year using Framingham risk score report cards and telephone counselling. (Requirement for clinical trial registration waived [enrolment completed before requirement became applicable].). [Abstract/Link to Full Text]

Di Stefani A, Orlandi A, Chimenti S, Bianchi L
Phrynoderma: a cutaneous sign of an inadequate diet.
CMAJ. 2007 Oct 9;177(8):855-6. [Abstract/Link to Full Text]

Parkins MD, Fonseca K, Peets AD, Laupland KB, Shamseddin K, Gill MJ
A potentially preventable case of serious influenza infection in a pregnant patient.
CMAJ. 2007 Oct 9;177(8):851-3. [Abstract/Link to Full Text]

Baerlocher MO
Fertility rates and gross national incomes per capita.
CMAJ. 2007 Oct 9;177(8):846. [Abstract/Link to Full Text]

Kondro W
Exit interview with Dr. Alan Bernstein.
CMAJ. 2007 Oct 9;177(8):844-5. [Abstract/Link to Full Text]

Lett D
Vaccine autism link discounted, but effect of "study" is unknown.
CMAJ. 2007 Oct 9;177(8):841. [Abstract/Link to Full Text]

Brooks J
US Medicare will stop paying for preventable errors.
CMAJ. 2007 Oct 9;177(8):841-2. [Abstract/Link to Full Text]

Stanbrook MB, H�bert PC
Getting serious about Canadian health research.
CMAJ. 2007 Oct 9;177(8):825, 827. [Abstract/Link to Full Text]

Kondro W
Troubled Afghan hospital needs Canadian SWAT team.
CMAJ. 2007 Oct 9;177(8):837-9. [Abstract/Link to Full Text]

Cassels A
W is for Wilbert's wee willy (which tends to go off prematurely).
CMAJ. 2007 Sep 25;177(7):816. [Abstract/Link to Full Text]

Singh AE, Sutherland K, Lee B, Robinson JL, Wong T
Early congenital syphilis.
CMAJ. 2007 Sep 25;177(7):752. [Abstract/Link to Full Text]

Schultz BK
Methylphenidate use and divorce.
CMAJ. 2007 Sep 25;177(7):751; author reply 751. [Abstract/Link to Full Text]

Strohschein LA
Prevalence of methylphenidate use among Canadian children following parental divorce.
CMAJ. 2007 Jun 5;176(12):1711-4.
BACKGROUND: Evidence suggests that children living in single-parent or step-parent households are more likely than children in households with 2 biological parents to be prescribed methylphenidate. I conducted a study of prospective data to investigate parental divorce as a predictor of methylphenidate use. METHODS: I used data for children who participated in the National Longitudinal Survey of Children and Youth from 1994 to 2000. The sample was restricted to children who remained in the survey in 2000 and who, at initial interview, lived in a household with 2 biological parents (n = 4784). A generalized estimating equation model was used to compare the odds ratios of methylphenidate use among children whose parents obtained a divorce between 1994 and 2000 relative to children whose parents remained married during this period. RESULTS: Between 1994 and 2000, 633 children (13.2%) experienced the divorce of their parents. The proportion of children who received methylphenidate at any time between 1994 and 2000 was 3.3% among those whose parents remained married and 6.1% among those whose parents divorced during this period. After adjustment for age of the mother and sex and age of the child, I found that methylphenidate use was significantly higher among children whose parents subsequently divorced than among those whose parents remained married (odds ratio 1.82, 95% confidence interval 1.01-3.33). INTERPRETATION: The increased risk of children receiving a prescription for methylphenidate in the period following parental divorce raises questions about the causal links in this association. Future research is needed to replicate these findings and to investigate possible explanations. [Abstract/Link to Full Text]

Hegele RA, Al-Attar SA, Rutt BK
Obstructive sleep apnea in 2 women with familial partial lipodystrophy due to a heterozygous LMNA R482Q mutation.
CMAJ. 2007 Sep 25;177(7):743-5. [Abstract/Link to Full Text]

Pittler MH, Brown EM, Ernst E
Static magnets for reducing pain: systematic review and meta-analysis of randomized trials.
CMAJ. 2007 Sep 25;177(7):736-42.
BACKGROUND: Static magnets are marketed with claims of effectiveness for reducing pain, although evidence of scientific principles or biological mechanisms to support such claims is limited. We performed a systematic review and meta-analysis to assess the clinical evidence from randomized trials of static magnets for treating pain. METHODS: Systematic literature searches were conducted from inception to March 2007 for the following data sources: MEDLINE, EMBASE, AMED (Allied and Complementary Medicine Database), CINAHL, Scopus, the Cochrane Library and the UK National Research Register. All randomized clinical trials of static magnets for treating pain from any cause were considered. Trials were included only if they involved a placebo control or a weak magnet as the control, with pain as an outcome measure. The mean change in pain, as measured on a 100-mm visual analogue scale, was defined as the primary outcome and was used to assess the difference between static magnets and placebo. RESULTS: Twenty-nine potentially relevant trials were identified. Nine randomized placebo-controlled trials assessing pain with a visual analogue scale were included in the main meta-analysis; analysis of these trials suggested no significant difference in pain reduction (weighted mean difference [on a 100-mm visual analogue scale] 2.1 mm, 95% confidence interval -1.8 to 5.9 mm, p = 0.29). This result was corroborated by sensitivity analyses excluding trials of acute effects and conditions other than musculoskeletal conditions. Analysis of trials that assessed pain with different scales suggested significant heterogeneity among the trials, which means that pooling these data is unreliable. INTERPRETATION: The evidence does not support the use of static magnets for pain relief, and therefore magnets cannot be recommended as an effective treatment. For osteoarthritis, the evidence is insufficient to exclude a clinically important benefit, which creates an opportunity for further investigation. [Abstract/Link to Full Text]

Weir E, Mitchell J, Reballato S, Fortuna D
Raw milk and the protection of public health.
CMAJ. 2007 Sep 25;177(7):721-3. [Abstract/Link to Full Text]

Szakacs TA, MacPherson P, Sinclair BJ, Gill BD, McCarthy AE
Nosocomial myiasis in a Canadian intensive care unit.
CMAJ. 2007 Sep 25;177(7):719-20. [Abstract/Link to Full Text]

Bhat M, Dawson D
Wheezes, blisters, bumps and runs: multisystem manifestations of a Crohn's disease flare-up.
CMAJ. 2007 Sep 25;177(7):715-8. [Abstract/Link to Full Text]

Baerlocher MO
Differences in the proportion of boys and girls enrolled in primary school.
CMAJ. 2007 Sep 25;177(7):712. [Abstract/Link to Full Text]

Hendricks A
Matters of trust.
CMAJ. 2007 Sep 25;177(7):710. [Abstract/Link to Full Text]

Silversides A
Interface of private and public faces proposed cord blood bank.
CMAJ. 2007 Sep 25;177(7):705-6. [Abstract/Link to Full Text]

Sibley R
When healers become killers: the doctor as terrorist.
CMAJ. 2007 Sep 11;177(6):688. [Abstract/Link to Full Text]

Armstrong EJ
Reed Elsevier's arms business.
CMAJ. 2007 Sep 11;177(6):606. [Abstract/Link to Full Text]

Palepu A
Open Medicine and open access.
CMAJ. 2007 Sep 11;177(6):606. [Abstract/Link to Full Text]

Stanbrook MB, Flegel K, Sibbald B, Wooltorton E, McDonald N, Attaran A, H�bert PC
Congratulations to our colleagues at Open Medicine.
CMAJ. 2007 Jul 3;177(1):59-61. [Abstract/Link to Full Text]

Bernstein A
Stepping down from CIHR.
CMAJ. 2007 Sep 11;177(6):605-6; discussion 606. [Abstract/Link to Full Text]

Kondro W
Bernstein bails presidency.
CMAJ. 2007 Jul 31;177(3):241. [Abstract/Link to Full Text]

Holub BJ
Treating hypertriglyceridemia.
CMAJ. 2007 Sep 11;177(6):604; author reply 604-5. [Abstract/Link to Full Text]

Yuan G, Al-Shali KZ, Hegele RA
Hypertriglyceridemia: its etiology, effects and treatment.
CMAJ. 2007 Apr 10;176(8):1113-20.
Elevated plasma triglyceride concentration is a common biochemical finding, but the evidence for the benefit of treating this lipid disturbance remains less robust than that for treating elevated low-density lipoprotein-cholesterol. Part of the difficulty in the provision of specific recommendations has been the frequent coexistence of elevated triglycerides with other conditions that affect cardiovascular disease risk, such as depressed high-density lipoprotein-cholesterol, obesity, metabolic syndrome, proinflammatory and prothrombotic biomarkers, and type 2 diabetes. Recent investigations of outcomes of cardiovascular disease when medications are used to reduce triglyceride levels suggest that, although a net benefit probably exists, both relative and absolute risk reductions seem underwhelming when compared with the benefit of reducing low-density lipoprotein-cholesterol levels with treatment. However, the totality of evidence suggests that elevated triglyceride levels likely contribute independently to increased risk of cardiovascular disease, although there is no consensus about appropriate target levels. Furthermore, severe hypertriglyceridemia is associated with an increased risk of acute pancreatitis, irrespective of its effect on risk of cardiovascular disease. We review the causes and classification of elevated triglyceride levels, the clinical manifestations of primary hypertriglyceridemia and the management of patients with elevated triglyceride levels. [Abstract/Link to Full Text]

R�ggla G, Fasan M, Kapiotis S
Treating hypertriglyceridemia.
CMAJ. 2007 Sep 11;177(6):603; author reply 604-5. [Abstract/Link to Full Text]

Recent Articles in The Journal of Clinical Investigation

McAulay KA, Higgins CD, Macsween KF, Lake A, Jarrett RF, Robertson FL, Williams H, Crawford DH
HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection.
J Clin Invest. 2007 Oct;117(10):3042-8.
Infectious mononucleosis (IM) is an immunopathological disease caused by EBV that occurs in young adults and is a risk factor for Hodgkin lymphoma (HL). An association between EBV-positive HL and genetic markers in the HLA class I locus has been identified, indicating that genetic differences in the HLA class I locus may alter disease phenotypes associated with EBV infection. To further determine whether HLA class I alleles may affect development of EBV-associated diseases, we analyzed 2 microsatellite markers and 2 SNPs located near the HLA class I locus in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM. Specific alleles of the 2 SNPs were also significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients possessing the associated microsatellite allele had fewer lymphocytes and increased neutrophils relative to IM patients lacking the allele. These patients also displayed higher EBV titers and milder IM symptoms. The results of this study indicate that HLA class I polymorphisms may predispose patients to development of IM upon primary EBV infection, suggesting that genetic variation in T cell responses can influence the nature of primary EBV infection and the level of viral persistence. [Abstract/Link to Full Text]

Farrell PJ
Role for HLA in susceptibility to infectious mononucleosis.
J Clin Invest. 2007 Oct;117(10):2756-8.
Factors involved in determining whether infectious mononucleosis occurs after primary EBV infection may include age, dose of virus received, and various genetic markers. A study by McAulay and colleagues reported in this issue of the JCI shows that the presence of certain HLA class I alleles correlates with the incidence and severity of infectious mononucleosis. These same HLA alleles are also risk factors for EBV-associated Hodgkin lymphoma (HL), supporting recent epidemiology that indicates that a history of infectious mononucleosis predisposes to HL. Recent studies suggest that an EBV vaccine might help to prevent infectious mononucleosis, and further development of this should now be considered. [Abstract/Link to Full Text]

Gelderman KA, Hultqvist M, Pizzolla A, Zhao M, Nandakumar KS, Mattsson R, Holmdahl R
Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species.
J Clin Invest. 2007 Oct;117(10):3020-8.
Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell-independent anti-collagen antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis. [Abstract/Link to Full Text]

Yanagi S, Kishimoto H, Kawahara K, Sasaki T, Sasaki M, Nishio M, Yajima N, Hamada K, Horie Y, Kubo H, Whitsett JA, Mak TW, Nakano T, Nakazato M, Suzuki A
Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice.
J Clin Invest. 2007 Oct;117(10):2929-40.
PTEN is a tumor suppressor gene mutated in many human cancers. We generated a bronchioalveolar epithelium-specific null mutation of Pten in mice [SP-C-rtTA/(tetO)(7)-Cre/Pten(flox/flox) (SOPten(flox/flox)) mice] that was under the control of doxycycline. Ninety percent of SOPten(flox/flox) mice that received doxycycline in utero [SOPten(flox/flox)(E10-16) mice] died of hypoxia soon after birth. Surviving SOPten(flox/flox)(E10-16) mice and mice that received doxycycline postnatally [SOPten(flox/flox)(P21-27) mice] developed spontaneous lung adenocarcinomas. Urethane treatment accelerated number and size of lung tumors developing in SOPten(flox/flox) mice of both ages. Histological and biochemical examinations of the lungs of SOPten(flox/flox)(E10-16) mice revealed hyperplasia of bronchioalveolar epithelial cells and myofibroblast precursors, enlarged alveolar epithelial cells, and impaired production of surfactant proteins. Numbers of bronchioalveolar stem cells (BASCs), putative initiators of lung adenocarcinomas, were increased. Lungs of SOPten(flox/flox)(E10-16) mice showed increased expression of Spry2, which inhibits the maturation of alveolar epithelial cells. Levels of Akt, c-Myc, Bcl-2, and Shh were also elevated in SOPten(flox/flox)(E10-16) and SOPten(flox/flox)(P21-27) lungs. Furthermore, K-ras was frequently mutated in adenocarcinomas observed in SOPten(flox/flox)(P21-27) lungs. These results indicate that Pten is essential for both normal lung morphogenesis and the prevention of lung carcinogenesis, possibly because this tumor suppressor is required for BASC homeostasis. [Abstract/Link to Full Text]

Combadi�re C, Feumi C, Raoul W, Keller N, Rod�ro M, P�zard A, Lavalette S, Houssier M, Jonet L, Picard E, Debr� P, Sirinyan M, Deterre P, Ferroukhi T, Cohen SY, Chauvaud D, Jeanny JC, Chemtob S, Behar-Cohen F, Sennlaub F
CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration.
J Clin Invest. 2007 Oct;117(10):2920-8.
The role of retinal microglial cells (MCs) in age-related macular degeneration (AMD) is unclear. Here we demonstrated that all retinal MCs express CX3C chemokine receptor 1 (CX3CR1) and that homozygosity for the CX3CR1 M280 allele, which is associated with impaired cell migration, increases the risk of AMD. In humans with AMD, MCs accumulated in the subretinal space at sites of retinal degeneration and choroidal neovascularization (CNV). In CX3CR1-deficient mice, MCs accumulated subretinally with age and albino background and after laser impact preceding retinal degeneration. Raising the albino mice in the dark prevented both events. The appearance of lipid-bloated subretinal MCs was drusen-like on funduscopy of senescent mice, and CX3CR1-dependent MC accumulation was associated with an exacerbation of experimental CNV. These results show that CX3CR1-dependent accumulation of subretinal MCs evokes cardinal features of AMD. These findings reveal what we believe to be a novel pathogenic process with important implications for the development of new therapies for AMD. [Abstract/Link to Full Text]

Chen J, Connor KM, Smith LE
Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration.
J Clin Invest. 2007 Oct;117(10):2758-62.
Age-related macular degeneration (AMD), the most common cause of blindness in the elderly, is characterized by degeneration of the macula and can lead to loss of fine color vision. Alterations in inflammatory and immune system pathways, which arise from genetic differences, predispose individuals to AMD. Yet the mechanism of disease progression with respect to inflammation is not fully understood. In this issue of the JCI, the study by Combadi�re and colleagues shows that CX3C chemokine receptor 1-deficient (CX3CR1-deficient) mice have abnormal microglia that accumulate beneath the retina and contribute to the progression of AMD. [Abstract/Link to Full Text]

Morioka T, Asilmaz E, Hu J, Dishinger JF, Kurpad AJ, Elias CF, Li H, Elmquist JK, Kennedy RT, Kulkarni RN
Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice.
J Clin Invest. 2007 Oct;117(10):2860-8.
Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on beta cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater beta cell mass secondary to increased beta cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 beta cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes. [Abstract/Link to Full Text]

Niswender KD, Magnuson MA
Obesity and the beta cell: lessons from leptin.
J Clin Invest. 2007 Oct;117(10):2753-6.
In this issue of the JCI, Morioka et al. report on mice with a whole-pancreas knockout of the leptin receptor that exhibit improved glucose tolerance due to enhanced insulin secretion . At first glance, their findings are very different from those reported in another recent study in which beta cell-specific and hypothalamic knockout of the same gene caused obesity and impaired beta cell function. The differences, which are understandable when one considers the body weights of the animals studied, provide new insight into the links among insulin, leptin action, and beta cell function. [Abstract/Link to Full Text]

Diwan A, Krenz M, Syed FM, Wansapura J, Ren X, Koesters AG, Li H, Kirshenbaum LA, Hahn HS, Robbins J, Jones WK, Dorn GW
Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice.
J Clin Invest. 2007 Oct;117(10):2825-33.
Following myocardial infarction, nonischemic myocyte death results in infarct expansion, myocardial loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes ventricular remodeling in the mouse, despite having no effect on early or late infarct size. We evaluated the effects of ablating Bnip3 on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia/reperfusion (IR) injury in mice. Immediately following IR, no significant differences were observed between Bnip3(-/-) and WT mice. However, at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium, and at 3 weeks after IR, Bnip3(-/-) mice exhibited preserved LV systolic performance, diminished LV dilation, and decreased ventricular sphericalization. These results suggest myocardial salvage by inhibition of apoptosis. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice, causing progressive LV dilation and diminished systolic function. Conditional Bnip3 overexpression prior to coronary ligation increased apoptosis and infarct size. These studies identify postischemic apoptosis by myocardial Bnip3 as a major determinant of ventricular remodeling in the infarcted heart, suggesting that Bnip3 may be an attractive therapeutic target. [Abstract/Link to Full Text]

Whelan RS, Mani K, Kitsis RN
Nipping at cardiac remodeling.
J Clin Invest. 2007 Oct;117(10):2751-3.
Much of the mortality following myocardial infarction results from remodeling of the heart after the acute ischemic event. Cardiomyocyte apoptosis has been thought to play a key role in this remodeling process. In this issue of the JCI, Diwan and colleagues present evidence that Bnip3, a proapoptotic Bcl2 family protein, mediates cardiac enlargement, reshaping, and dysfunction in mice without influencing infarct size. [Abstract/Link to Full Text]

Nissen LJ, Cao R, Hedlund EM, Wang Z, Zhao X, Wetterskog D, Funa K, Br�kenhielm E, Cao Y
Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis.
J Clin Invest. 2007 Oct;117(10):2766-77.
Tumors produce multiple growth factors, but little is known about the interplay between various angiogenic factors in promoting tumor angiogenesis, growth, and metastasis. Here we show that 2 angiogenic factors frequently upregulated in tumors, PDGF-BB and FGF2, synergistically promote tumor angiogenesis and pulmonary metastasis. Simultaneous overexpression of PDGF-BB and FGF2 in murine fibrosarcomas led to the formation of high-density primitive vascular plexuses, which were poorly coated with pericytes and VSMCs. Surprisingly, overexpression of PDGF-BB alone in tumor cells resulted in dissociation of VSMCs from tumor vessels and decreased recruitment of pericytes. In the absence of FGF2, capillary ECs lacked response to PDGF-BB. However, FGF2 triggers PDGFR-alpha and -beta expression at the transcriptional level in ECs, which acquire hyperresponsiveness to PDGF-BB. Similarly, PDGF-BB-treated VSMCs become responsive to FGF2 stimulation via upregulation of FGF receptor 1 (FGFR1) promoter activity. These findings demonstrate that PDGF-BB and FGF2 reciprocally increase their EC and mural cell responses, leading to disorganized neovascularization and metastasis. Our data suggest that intervention of this non-VEGF reciprocal interaction loop for the tumor vasculature could be an important therapeutic target for the treatment of cancer and metastasis. [Abstract/Link to Full Text]

Arbiser JL
Why targeted therapy hasn't worked in advanced cancer.
J Clin Invest. 2007 Oct;117(10):2762-5.
In this issue of the JCI, Nissen et al. report that a reciprocal interaction exists between the growth factors FGF2 and PDGF-BB, causing tumors to exhibit increased angiogenesis and metastatic potential. Both FGF2 and PDGF-BB signal through tyrosine kinase receptors, which have been the target of tyrosine kinase inhibitors for cancer therapies. These inhibitors are usually small molecules that inhibit the kinase activity of a receptor or nonreceptor tyrosine kinase, preventing downstream signaling. The results of this study shed light on why tyrosine kinase inhibitors have been useful for the treatment of only a small number of advanced cancers. Currently, a major focus of pharmaceutical companies is to develop ever more potent and specific tyrosine kinases. The results presented here suggest that this approach may not be successful. [Abstract/Link to Full Text]

Sun S, Schiller JH, Spinola M, Minna JD
New molecularly targeted therapies for lung cancer.
J Clin Invest. 2007 Oct;117(10):2740-50.
Lung cancer is the leading cause of cancer death worldwide. The disease is particularly difficult to detect, and patients often present at an advanced stage. Current treatments have limited effectiveness, and unfortunately, the prognosis remains poor. Recent insights into the molecular pathogenesis and biologic behavior of lung cancer have led to the development of rationally designed methods of early detection, prevention, and treatment of this disease. This article will review the important clinical implications of these advances, with a focus on new molecularly targeted therapies currently in development. [Abstract/Link to Full Text]

Honey K
Translating medical science around the world.
J Clin Invest. 2007 Oct;117(10):2737. [Abstract/Link to Full Text]

Wilson MS, Elnekave E, Mentink-Kane MM, Hodges MG, Pesce JT, Ramalingam TR, Thompson RW, Kamanaka M, Flavell RA, Keane-Myers A, Cheever AW, Wynn TA
IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice.
J Clin Invest. 2007 Oct;117(10):2941-51.
Development of persistent Th2 responses in asthma and chronic helminth infections are a major health concern. IL-10 has been identified as a critical regulator of Th2 immunity, but mechanisms for controlling Th2 effector function remain unclear. IL-10 also has paradoxical effects on Th2-associated pathology, with IL-10 deficiency resulting in increased Th2-driven inflammation but also reduced airway hyperreactivity (AHR), mucus hypersecretion, and fibrosis. We demonstrate that increased IL-13 receptor alpha 2 (IL-13Ralpha2) expression is responsible for the reduced AHR, mucus production, and fibrosis in BALB/c IL-10(-/-) mice. Using models of allergic asthma and chronic helminth infection, we demonstrate that IL-10 and IL-13Ralpha2 coordinately suppress Th2-mediated inflammation and pathology, respectively. Although IL-10 was identified as the dominant antiinflammatory mediator, studies with double IL-10/IL-13Ralpha2-deficient mice illustrate an indispensable role for IL-13Ralpha2 in the suppression of AHR, mucus production, and fibrosis. Thus, IL-10 and IL-13Ralpha2 are both required to control chronic Th2-driven pathological responses. [Abstract/Link to Full Text]

Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM, Howles PN, Morgan DA, Benoit SC, Szanto I, Schrott B, Sch�rmann A, Joost HG, Hammond C, Hui DY, Woods SC, Rahmouni K, Butler AA, Farooqi IS, O'Rahilly S, Rohner-Jeanrenaud F, Tsch�p MH
The central melanocortin system directly controls peripheral lipid metabolism.
J Clin Invest. 2007 Nov;117(11):3475-88.
Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity. [Abstract/Link to Full Text]

Maron JL, Johnson KL, Slonim D, Lai CQ, Ramoni M, Alterovitz G, Jarrah Z, Yang Z, Bianchi DW
Gene expression analysis in pregnant women and their infants identifies unique fetal biomarkers that circulate in maternal blood.
J Clin Invest. 2007 Oct;117(10):3007-19.
The discovery of fetal mRNA transcripts in the maternal circulation holds great promise for noninvasive prenatal diagnosis. To identify potential fetal biomarkers, we studied whole blood and plasma gene transcripts that were common to 9 term pregnant women and their newborns but absent or reduced in the mothers postpartum. RNA was isolated from peripheral or umbilical blood and hybridized to gene expression arrays. Gene expression, paired Student's t test, and pathway analyses were performed. In whole blood, 157 gene transcripts met statistical significance. These fetal biomarkers included 27 developmental genes, 5 sensory perception genes, and 22 genes involved in neonatal physiology. Transcripts were predominantly expressed or restricted to the fetus, the embryo, or the neonate. Real-time RT-PCR amplification confirmed the presence of specific gene transcripts; SNP analysis demonstrated the presence of 3 fetal transcripts in maternal antepartum blood. Comparison of whole blood and plasma samples from the same pregnant woman suggested that placental genes are more easily detected in plasma. We conclude that fetal and placental mRNA circulates in the blood of pregnant women. Transcriptional analysis of maternal whole blood identifies a unique set of biologically diverse fetal genes and has a multitude of clinical applications. [Abstract/Link to Full Text]

Cho SR, Benraiss A, Chmielnicki E, Samdani A, Economides A, Goldman SA
Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease.
J Clin Invest. 2007 Oct;117(10):2889-902.
Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU(+)betaIII-tubulin(+) neurons, which developed as DARPP-32(+) and GABAergic medium spiny neurons that expressed either enkephalin or substance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease. [Abstract/Link to Full Text]

Zhao B, Song J, Chow WN, St Clair RW, Rudel LL, Ghosh S
Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr mice.
J Clin Invest. 2007 Oct;117(10):2983-92.
Accumulation of cholesteryl esters (CEs) in macrophage foam cells, central to atherosclerotic plaque formation, occurs as a result of imbalance between the cholesterol influx and efflux pathways. While the uptake, or influx, of modified lipoproteins is largely unregulated, extracellular acceptor-mediated free cholesterol (FC) efflux is rate limited by the intracellular hydrolysis of CE. We previously identified and cloned a neutral CE hydrolase (CEH) from human macrophages and demonstrated its role in cellular CE mobilization. In the present study, we examined the hypothesis that macrophage-specific overexpression of CEH in atherosclerosis-susceptible Ldlr(-/-) mice will result in reduction of diet-induced atherosclerosis. Transgenic mice overexpressing this CEH specifically in the macrophages (driven by scavenger receptor promoter/enhancer) were developed and crossed into the Ldlr(-/-) background (Ldlr(-/-)CEHTg mice). Macrophage-specific overexpression of CEH led to a significant reduction in the lesion area and cholesterol content of high-fat, high-cholesterol diet-induced atherosclerotic lesions. The lesions from Ldlr(-/-)CEHTg mice did not have increased FC, were less necrotic, and contained significantly higher numbers of viable macrophage foam cells. Higher CEH-mediated FC efflux resulted in enhanced flux of FC from macrophages to gall bladder bile and feces in vivo. These studies demonstrate that by enhancing cholesterol efflux and reverse cholesterol transport, macrophage-specific overexpression of CEH is antiatherogenic. [Abstract/Link to Full Text]

Russo V, Cipponi A, Raccosta L, Rainelli C, Fontana R, Maggioni D, Lunghi F, Mukenge S, Ciceri F, Bregni M, Bordignon C, Traversari C
Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity.
J Clin Invest. 2007 Oct;117(10):3087-96.
The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of tyrosinase-related protein 2-transduced (TRP-2-transduced) lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice. Analysis of the mechanism responsible for the induction of such an immune response allowed us to demonstrate that cross-presentation of the antigen mediated by the CD11c(+)CD8alpha(+) DC subset had occurred. Furthermore, we demonstrated in vivo and in vitro that DCs had undergone activation upon phagocytosis of genetically modified lymphocytes, a process mediated by a cell-to-cell contact mechanism independent of CD40 triggering. Targeting and activation of secondary lymphoid organ-resident DCs endowed antigen-specific T cells with full effector functions, which ultimately increased tumor growth control and animal survival in a therapeutic tumor setting. We conclude that the use of transduced lymphocytes represents an efficient method for the in vivo loading of tumor-associated antigens on DCs. [Abstract/Link to Full Text]

Mutlu GM, Green D, Bellmeyer A, Baker CM, Burgess Z, Rajamannan N, Christman JW, Foiles N, Kamp DW, Ghio AJ, Chandel NS, Dean DA, Sznajder JI, Budinger GR
Ambient particulate matter accelerates coagulation via an IL-6-dependent pathway.
J Clin Invest. 2007 Oct;117(10):2952-61.
The mechanisms by which exposure to particulate matter increases the risk of cardiovascular events are not known. Recent human and animal data suggest that particulate matter may induce alterations in hemostatic factors. In this study we determined the mechanisms by which particulate matter might accelerate thrombosis. We found that mice treated with a dose of well characterized particulate matter of less than 10 microM in diameter exhibited a shortened bleeding time, decreased prothrombin and partial thromboplastin times (decreased plasma clotting times), increased levels of fibrinogen, and increased activity of factor II, VIII, and X. This prothrombotic tendency was associated with increased generation of intravascular thrombin, an acceleration of arterial thrombosis, and an increase in bronchoalveolar fluid concentration of the prothrombotic cytokine IL-6. Knockout mice lacking IL-6 were protected against particulate matter-induced intravascular thrombin formation and the acceleration of arterial thrombosis. Depletion of macrophages by the intratracheal administration of liposomal clodronate attenuated particulate matter-induced IL-6 production and the resultant prothrombotic tendency. Our findings suggest that exposure to particulate matter triggers IL-6 production by alveolar macrophages, resulting in reduced clotting times, intravascular thrombin formation, and accelerated arterial thrombosis. These results provide a potential mechanism linking ambient particulate matter exposure and thrombotic events. [Abstract/Link to Full Text]

Mizugishi K, Li C, Olivera A, Bielawski J, Bielawska A, Deng CX, Proia RL
Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice.
J Clin Invest. 2007 Oct;117(10):2993-3006.
Uterine decidualization, a process that occurs in response to embryo implantation, is critical for embryonic survival and thus is a key event for successful pregnancy. Here we show that the sphingolipid metabolic pathway is highly activated in the deciduum during pregnancy and disturbance of the pathway by disruption of sphingosine kinase (Sphk) genes causes defective decidualization with severely compromised uterine blood vessels, leading to early pregnancy loss. Sphk-deficient female mice (Sphk1(-/-)Sphk2(+/-)) exhibited both an enormous accumulation of dihydrosphingosine and sphingosine and a reduction in phosphatidylethanolamine levels in pregnant uteri. These mice also revealed increased cell death in decidual cells, decreased cell proliferation in undifferentiated stromal cells, and massive breakage of decidual blood vessels, leading to uterine hemorrhage and early embryonic lethality. Thus, sphingolipid metabolism regulates proper uterine decidualization and blood vessel stability. Our findings also suggest that disturbance in sphingolipid metabolism may be considered as a cause of pregnancy loss in humans. [Abstract/Link to Full Text]

Zhang J, Park SI, Artime MC, Summy JM, Shah AN, Bomser JA, Dorfleutner A, Flynn DC, Gallick GE
AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts.
J Clin Invest. 2007 Oct;117(10):2962-73.
The actin filament-associated protein AFAP-110 is an actin cross-linking protein first identified as a substrate of the viral oncogene v-Src. AFAP-110 regulates actin cytoskeleton integrity but also functions as an adaptor protein that affects crosstalk between Src and PKC. Here we investigated the roles of AFAP-110 in the tumorigenic process of prostate carcinoma. Using immunohistochemistry of human tissue arrays, we found that AFAP-110 was absent or expressed at very low levels in normal prostatic epithelium and benign prostatic hyperplasia but significantly increased in prostate carcinomas. The level of AFAP-110 in carcinomas correlated with the Gleason scores. Downregulation of AFAP-110 in PC3 prostate cancer cells inhibited cell proliferation in vitro and tumorigenicity and growth in orthotopic nude mouse models. Furthermore, downmodulation of AFAP-110 resulted in decreased cell-matrix adhesion and cell migration, defective focal adhesions, and reduced integrin beta1 expression. Reintroduction of avian AFAP-110 or a mutant disabling its interaction with Src restored these properties. However, expression of an AFAP-110 lacking the PKC-interacting domain failed to restore properties of parental cells. Thus, increased expression of AFAP-110 is associated with progressive stages of prostate cancer and is critical for tumorigenic growth, in part by regulating focal contacts in a PKC-dependent mechanism. [Abstract/Link to Full Text]

Seguchi O, Takashima S, Yamazaki S, Asakura M, Asano Y, Shintani Y, Wakeno M, Minamino T, Kondo H, Furukawa H, Nakamaru K, Naito A, Takahashi T, Ohtsuka T, Kawakami K, Isomura T, Kitamura S, Tomoike H, Mochizuki N, Kitakaze M
A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart.
J Clin Invest. 2007 Oct;117(10):2812-24.
Marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing human myocardium. Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC2v), which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development. Integrated cDNA expression analysis of failing human myocardia uncovered a novel protein kinase, cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v. Expression levels of cardiac-MLCK were well correlated with the pulmonary arterial pressure of patients with heart failure. In cultured cardiomyocytes, knockdown of cardiac-MLCK by specific siRNAs decreased MLC2v phosphorylation and impaired epinephrine-induced activation of sarcomere reassembly. To further clarify the physiologic roles of cardiac-MLCK in vivo, we cloned the zebrafish ortholog z-cardiac-MLCK. Knockdown of z-cardiac-MLCK expression using morpholino antisense oligonucleotides resulted in dilated cardiac ventricles and immature sarcomere structures. These results suggest a significant role for cardiac-MLCK in cardiogenesis. [Abstract/Link to Full Text]

Groshong JS, Spencer MJ, Bhattacharyya BJ, Kudryashova E, Vohra BP, Zayas R, Wollmann RL, Miller RJ, Gomez CM
Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome.
J Clin Invest. 2007 Oct;117(10):2903-12.
The slow-channel myasthenic syndrome (SCS) is a hereditary disorder of the acetylcholine receptor (AChR) of the neuromuscular junction (NMJ) that leads to prolonged AChR channel opening, Ca(2+) overload, and degeneration of the NMJ. We used an SCS transgenic mouse model to investigate the role of the calcium-activated protease calpain in the pathogenesis of synaptic dysfunction in SCS. Cleavage of a fluorogenic calpain substrate was increased at the NMJ of dissociated muscle fibers. Inhibition of calpain using a calpastatin (CS) transgene improved strength and neuromuscular transmission. CS caused a 2-fold increase in the frequency of miniature endplate currents (MEPCs) and an increase in NMJ size, but MEPC amplitudes remained reduced. Persistent degeneration of the NMJ was associated with localized activation of the non-calpain protease caspase-3. This study suggests that calpain may act presynaptically to impair NMJ function in SCS but further reveals a role for other cysteine proteases whose inhibition may be of additional therapeutic benefit in SCS and other excitotoxic disorders. [Abstract/Link to Full Text]

Schenk M, Bouchon A, Seibold F, Mueller C
TREM-1--expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases.
J Clin Invest. 2007 Oct;117(10):3097-106.
Triggering receptor expressed on myeloid cells-1 (TREM-1) potently amplifies acute inflammatory responses by enhancing degranulation and secretion of proinflammatory mediators. Here we demonstrate that TREM-1 is also crucially involved in chronic inflammatory bowel diseases (IBD). Myeloid cells of the normal intestine generally lack TREM-1 expression. In experimental mouse models of colitis and in patients with IBD, however, TREM-1 expression in the intestine was upregulated and correlated with disease activity. TREM-1 significantly enhanced the secretion of relevant proinflammatory mediators in intestinal macrophages from IBD patients. Blocking TREM-1 by the administration of an antagonistic peptide substantially attenuated clinical course and histopathological alterations in experimental mouse models of colitis. This effect was also seen when the antagonistic peptide was administered only after the first appearance of clinical signs of colitis. Hence, TREM-1-mediated amplification of inflammation contributes not only to the exacerbation of acute inflammatory disorders but also to the perpetuation of chronic inflammatory disorders. Furthermore, interfering with TREM-1 engagement leads to the simultaneous reduction of production and secretion of a variety of pro-inflammatory mediators such as TNF, IL-6, IL-8 (CXCL8), MCP-1 (CCL2), and IL-1beta. Therefore, TREM-1 may also represent an attractive target for the treatment of chronic inflammatory disorders. [Abstract/Link to Full Text]

Wu H, Chen G, Wyburn KR, Yin J, Bertolino P, Eris JM, Alexander SI, Sharland AF, Chadban SJ
TLR4 activation mediates kidney ischemia/reperfusion injury.
J Clin Invest. 2007 Oct;117(10):2847-59.
Ischemia/reperfusion injury (IRI) may activate innate immunity through the engagement of TLRs by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Using a mouse model of kidney IRI, we demonstrated a significant increase in TLR4 expression by tubular epithelial cells (TECs) and infiltrating leukocytes within the kidney following ischemia. TLR4 signaling through the MyD88-dependent pathway was required for the full development of kidney IRI, as both TLR4(-/-) and MyD88(-/-) mice were protected against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. In vitro, WT kidney TECs produced proinflammatory cytokines and chemokines and underwent apoptosis after ischemia. These effects were attenuated in TLR4(-/-) and MyD88(-/-) TECs. In addition, we demonstrated upregulation of the endogenous ligands high-mobility group box 1 (HMGB1), hyaluronan, and biglycan, providing circumstantial evidence that one or more of these ligands may be the source of TLR4 activation. To determine the relative contribution of TLR4 expression by parenchymal cells or leukocytes to kidney damage during IRI, we generated chimeric mice. TLR4(-/-) mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with TLR4(-/-) BM, suggesting that TLR4 signaling in intrinsic kidney cells plays the dominant role in mediating kidney damage. [Abstract/Link to Full Text]

Marden JJ, Harraz MM, Williams AJ, Nelson K, Luo M, Paulson H, Engelhardt JF
Redox modifier genes in amyotrophic lateral sclerosis in mice.
J Clin Invest. 2007 Oct;117(10):2913-9.
Amyotrophic lateral sclerosis (ALS), one of the most common adult-onset neurodegenerative diseases, has no known cure. Enhanced redox stress and inflammation have been associated with the pathoprogression of ALS through a poorly defined mechanism. Here we determined that dysregulated redox stress in ALS mice caused by NADPH oxidases Nox1 and Nox2 significantly influenced the progression of motor neuron disease caused by mutant SOD1(G93A) expression. Deletion of either Nox gene significantly slowed disease progression and improved survival. However, 50% survival rates were enhanced significantly more by Nox2 deletion than by Nox1 deletion. Interestingly, female ALS mice containing only 1 active X-linked Nox1 or Nox2 gene also had significantly delayed disease onset, but showed normal disease progression rates. Nox activity in spinal cords from Nox2 heterozygous female ALS mice was approximately 50% that of WT female ALS mice, suggesting that random X-inactivation was not influenced by Nox2 gene deletion. Hence, chimerism with respect to Nox-expressing cells in the spinal cord significantly delayed onset of motor neuron disease in ALS. These studies define what we believe to be new modifier gene targets for treatment of ALS. [Abstract/Link to Full Text]

Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman AH
Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice.
J Clin Invest. 2007 Oct;117(10):2974-82.
T lymphocyte responses promote proatherogenic inflammatory events, which are influenced by costimulatory molecules of the B7 family. Effects of negative regulatory members of the B7 family on atherosclerosis have not been described. Programmed death-ligand 1 (PD-L1) and PD-L2 are B7 family members expressed on several cell types, which inhibit T cell activation via binding to programmed death-1 (PD-1) on T cells. In order to test whether the PD-1/PD-L pathway regulates proatherogenic T cell responses, we compared atherosclerotic lesion burden and phenotype in hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice and LDLR(-/-) controls. PD-L1/2 deficiency led to significantly increased atherosclerotic burden throughout the aorta and increased numbers of lesional CD4(+) and CD8(+) T cells. Compared with controls, PD-L1/2(-/-)LDLR(-/-) mice had iliac lymphadenopathy and increased numbers of activated CD4(+) T cells. Serum levels of TNF-alpha were higher in PD-L1/2(-/-)LDLR(-/-) mice than in controls. PD-L1/2-deficient APCs were more effective than control APCs in activating CD4(+) T cells in vitro, with or without cholesterol loading. Freshly isolated APCs from hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice stimulated greater T cell responses than did APCs from hypercholesterolemic controls. Our findings indicate that the PD-1/PD-L pathway has an important role in downregulating proatherogenic T cell response and atherosclerosis by limiting APC-dependent T cell activation. [Abstract/Link to Full Text]

Choi JY, Joo NS, Krouse ME, Wu JV, Robbins RC, Ianowski JP, Hanrahan JW, Wine JJ
Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis.
J Clin Invest. 2007 Oct;117(10):3118-27.
Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological cascade that is incompletely understood. Airway glands, which produce most airway mucus, do so in response to both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). CF glands fail to secrete mucus in response to VIP, but do so in response to ACh. Because vagal cholinergic pathways still elicit strong gland mucus secretion in CF subjects, it is unclear whether VIP-stimulated, CFTR-dependent gland secretion participates in innate defense. It was recently hypothesized that airway intrinsic neurons, which express abundant VIP and ACh, are normally active and stimulate low-level gland mucus secretion that is a component of innate mucosal defenses. Here we show that low levels of VIP and ACh produced significant mucus secretion in human glands via strong synergistic interactions; synergy was lost in glands of CF patients. VIP/ACh synergy also existed in pig glands, where it was CFTR dependent, mediated by both Cl(-) and HCO(3) (-), and clotrimazole sensitive. Loss of "housekeeping" gland mucus secretion in CF, in combination with demonstrated defects in surface epithelia, may play a role in the vulnerability of CF airways to bacterial infections. [Abstract/Link to Full Text]

Recent Articles in Medical Science Monitor : International Medical Journal of Experimental and Clinical Research

Korres SG, Balatsouras DG, Lyra C, Kandiloros D, Ferekidis E
A comparison of automated auditory brainstem responses and transiently evoked otoacoustic emissions for universal newborn hearing screening.
Med Sci Monit. 2006 Jun;12(6):CR260-3.
BACKGROUND: The aim of this study was to compare the performance of automated auditory brainstem responses (a-ABR) and automated transiently evoked otoacoustic emissions (a-TEOAEs). MATERIAL/METHODS: A prospective, case-control study in a group of newborns was performed in a maternity hospital carrying out universal newborn hearing screening. Two groups of full-term newborns were examined. The first group included 50 newborns (100 ears) who underwent: 1) a-TEOAEs, 2) a-ABR, and 3) transiently evoked otoacoustic emissions (TEOAEs). The second group consisted of the same number of newborns who underwent identical testing, but in a different order: 1) a-ABR, 2) a-TEOAEs, and 3) TEOAEs. All a-TEOAE and a-ABR testing was performed using the AccuScreen device and all standard TEOAE testing was performed using the ILO88. The pass-fail results of each method were recorded and compared. RESULTS: a-ABR yielded lower referral rates than the otoacoustic emission tests, but the differences were not statistically significant. Comparison between the two groups of study showed higher "pass" rates in the second group, indicating an order effect. CONCLUSIONS: Either method might be useful in universal newborn hearing screening. However, the lower referral rate obtained by a-ABR and its potential to recognize infants at risk for auditory neuropathy and central pathology should be considered. [Abstract/Link to Full Text]

Aytacoglu BN, Ozcan C, Sucu N, Gorur K, Doven O, Camdeviren H, K�se N, Dikmengil M
Hearing loss in patients undergoing coronary artery bypass grafting with or without extracorporeal circulation.
Med Sci Monit. 2006 Jun;12(6):CR253-9.
BACKGROUND: Our aim was to investigate the differences in postoperative hearing thresholds in patients undergoing coronary artery bypass grafting with (Group I, n=20) or without (Group II, n=17) extracorporeal circulation. MATERIAL/METHODS: 37 patients undergoing coronary artery bypass grafting with or without extracorporeal circulation were prospectively evaluated in terms of hearing threshold changes with the intention of documenting hearing losses postoperatively. The t-test for two independent variables was used for statistical analysis. RESULTS: Hearing threshold changes were detected in 9 Group I patients (45%) and 3 Group II patients (17.65%). The difference between the two groups was statistically significant (p=0.0426). CONCLUSIONS: Postoperative hearing threshold changes, not necessarily revealed by clinical examinations, are encountered after coronary artery bypass grafting operations. Extracorporeal circulation usage seems to bring an additional risk in terms of hearing loss. [Abstract/Link to Full Text]

Zag�lski O, Jurkiewicz D
Functional evaluation of the vestibular organ in infants with risk factors for hearing loss occurring in the perinatal period.
Med Sci Monit. 2006 Jun;12(6):CR248-52.
BACKGROUND: Asphyxia at birth, low birth weight and low birth age constitute risk factors for inner ear damage in the perinatal period. Caloric stimulation is one of the most reliable diagnostic tools for vestibular testing in infants. Recording of vestibular-evoked myogenic potentials (VEMPs) evaluates the otolith organ and its pathways. Potentials reflecting the integrity of sacculo-collic reflex pathways are recorded on the surface of the neck muscles. The purpose of our study was to evaluate vestibular function in the discussed group of infants. MATERIAL/METHODS: 72 infants aged 3 months were examined: 40 healthy controls and 32 infants (17 girls, 15 boys) with risk factors for hearing loss occurring in the perinatal period. RESULTS: No reaction to caloric stimulation was elicited from 6 examined ears, no VEMPs were recorded from 6 ears, profound sensorineural hearing loss was diagnosed in 4 ears. The VEMP measurements did not differ between the groups. Profound sensorineural hearing loss occurred most frequently in infants with very low Apgar scores, responses to caloric stimulation were weakened in subjects with low Apgar scores. The response of the horizontal semicircular canals was more frequently abnormal than that of the otolith organs. CONCLUSIONS: The vestibular organ functions were frequently impaired in this group of infants, but the damage was rarely complete. Infants' vestibular organs should be routinely diagnosed. [Abstract/Link to Full Text]

Cengiz O, Kocer B, S�rmeli S, Santicky MJ, Soran A
Are pretreatment serum albumin and cholesterol levels prognostic tools in patients with colorectal carcinoma?
Med Sci Monit. 2006 Jun;12(6):CR240-7.
BACKGROUND: The purpose of this study was to determine if pretreatment serum albumin and cholesterol levels are prognostic factors in patients with colorectal carcinomas. MATERIAL/METHODS: Ninety-nine patients with colorectal carcinoma were included in this study. Retrospective data analysis included the clinicopathological parameters of age and gender; emergent surgical intervention; stage at presentation; tumor location, size, and differentiation; lymph node metastases; lymphatic, venous and perineural invasion; preoperative serum albumin, cholesterol, hemoglobin, and CEA levels; the presence of preoperative and postoperative metastases; and tumor recurrence. RESULTS: Low levels of serum albumin, advanced TNM stage, presence of venous invasion, and high CEA levels were independently correlated with prognosis in multivariate analysis. Advanced stage and low levels of serum cholesterol were found to be a statistically significant parameter for disease free survival. Mean serum albumin levels were found to be decreased in patients with advanced stage, which correlated with increased tumor burden. Although not statistically significant for cholesterol levels, the patients with low serum albumin and low cholesterol levels had shorter overall survival than patients with normal serum albumin and normal cholesterol levels. CONCLUSIONS: These results suggest that a preoperative low level of serum albumin can be an indicator for the malignant potential of the tumor and represents an unfavorable prognosis for patients with colorectal carcinoma. [Abstract/Link to Full Text]

Geier DA, Geier MR
An assessment of downward trends in neurodevelopmental disorders in the United States following removal of Thimerosal from childhood vaccines.
Med Sci Monit. 2006 Jun;12(6):CR231-9.
BACKGROUND: The US is in the midst of an epidemic of neurodevelopmental disorders (NDs). Thimerosal is an ethylmercury-containing compound added to some childhood vaccines. Several previous epidemiological studies conducted in the US have associated Thimerosal-containing vaccine (TCV) administration with NDs. MATERIAL/METHODS: An ecological study was undertaken to evaluate NDs reported to the Vaccine Adverse Event Reporting System (VAERS) from 1991 through 2004 by date of receipt and by date of vaccine administration. The NDs examined included autism, mental retardation, and speech disorders. Statistical trend analysis was employed to evaluate the effects of removal of Thimerosal on the proportion of NDs reported to VAERS. RESULTS: There was a peak in the proportion of ND reports received by VAERS in 2001-2002 and in the proportion of ND reports by date of vaccine administration in 1998. There were significant reductions in the proportion of NDs reported to VAERS as Thimerosal was begun to be removed from childhood vaccines in the US from mid-1999 onwards. CONCLUSIONS: The present study provides the first epidemiological evidence showing that as Thimerosal was removed from childhood vaccines, the number of NDs has decreased in the US. The analysis techniques utilized attempted to minimize chance or bias/confounding. Additional research should be conducted to further evaluate the relationship between TCVs and NDs. This is especially true because the handling of vaccine safety data from the National Immunization Program of the CDC has been called into question by the Institute of Medicine of the National Academy of Sciences in 2005. [Abstract/Link to Full Text]

Aksen F, Akdag MZ, Ketani A, Yokus B, Kaya A, Dasdag S
Effect of 50-Hz 1-mT magnetic field on the uterus and ovaries of rats (electron microscopy evaluation).
Med Sci Monit. 2006 Jun;12(6):BR215-20.
BACKGROUND: The aim of this study was to investigate the effect of extremely low frequency magnetic fields (ELFMF) on the uterus and ovary of rats. MATERIAL/METHODS: Forty-eight female Wistar albino rats were divided into two groups, one for 50 and the other for 100 days of exposure. Each group was further divided into two groups, one sham exposed (n=12) and the other the experimental group (n=12). The experimental rats were exposed to 50-Hz 1-mT ELFMF for three hours/day for 50 or 100 days. The sham groups of rats were kept under the same circumstances without applying ELFMF. Electron microscopic examination was performed to evaluate the ovaries and uterus. RESULTS: Ultrastructural dissolution, decrease in cell organelles, cavities in cells, heterochromative appearance, and typical structural loss of the nucleus were observed in germinal epithelial cells of the rat ovaries in the 50-days ELFMF exposure group. Ultrastructural alterations in germinal epithelium and tunica albuginea of ovaries, irregularity in nucleus and nucleolus, increase in lipid vacuoles of cell cytoplasm and reduction in organelles were observed in rat ovaries in the 100-days ELFMF exposure group. Similar alterations were observed in uterus. Malondialdehyde concentration (MDA) of the ovaries and uterus increased in rats of the two exposure groups (p<0.001). CONCLUSIONS: The results of the study showed that 50 and 100 days of exposure to a 1-mT ELFMF can cause alterations at the cellular level and in MDA concentration. [Abstract/Link to Full Text]

Meus J, Brylinski M, Piwowar M, Piwowar P, Wi?niowski Z, Stefaniak J, Konieczny L, Sur�wka G, Roterman I
A tabular approach to the sequence-to-structure relation in proteins (tetrapeptide representation) for de novo protein design.
Med Sci Monit. 2006 Jun;12(6):BR208-14.
BACKGROUND: Experimental observations classify the protein-folding process as a multi-step event. The backbone conformation has been experimentally recognized as responsible for the early-stage structural forms of a polypeptide. The sequence-to-structure and structure-to-sequence relation is critical for predicting protein structure. A contingency table representing this relation for tetrapeptides in their early-stage is presented. Their correlation seems to be essential in protein-folding simulation. MATERIAL/METHODS: The polypeptide chains of all the proteins in the Protein Data Bank were transformed into their early-stage structural forms. The tetrapeptide was selected as the structural unit. Tetrapetide sequences and structures were expressed by letter codes. The transformation of a contingency table of any size (here: 160,000x2401) to a 2x2 table performed for each non-zero cell of the original table allowed calculation of the rho-coefficient measuring the strength of the relation. RESULTS: High values of the rho-coefficient extracted sequences of strong structural determinability and structures of high sequence selectivity. The web-site program to calculate the rho-coefficient ranking list was constructed to enable applying this method to any problem of contingency table analysis. CONCLUSIONS: The results revealed sequence-to-structure (and vice versa) correlation in early-stage folding. Surprisingly, the irregular structural forms of loops and bends appeared to be highly determined. Comparison of these results with another method based on information entropy revealed high accordance. The method oriented on interpretation of a large contingency table seems very useful especially for large-scale microarray analysis, a very popular technique in the post-genomic era. [Abstract/Link to Full Text]

Bayat M, Chelcheraghi F, Piryaei A, Rakhshan M, Mohseniefar Z, Rezaie F, Bayat M, Shemshadi H, Sadeghi Y
The effect of 30-day pretreatment with pentoxifylline on the survival of a random skin flap in the rat: an ultrastructural and biomechanical evaluation.
Med Sci Monit. 2006 Jun;12(6):BR201-7.
BACKGROUND: The aim of this study was to clarify the histological, ultrastructural and biomechanical effects of pentoxifylline (PTX) on the survival of random skin flaps (RSFs) in rats. MATERIAL/METHODS: Thirty male rats were randomly divided into experimental, sham and control groups. The experimental group received PTX 20 mg/kg/day, and the sham group received saline. A 20x70-mm RSF was made 30 days after the commencement of treatment for the three groups. PTX and saline were continued postoperatively for 7 days in the experimental and sham groups, respectively. On the seventh postoperative day, the surviving parts of the flaps were determined and examined through light and transmission electron microscopes. The wounds (incisions) on the margins of the flaps were evaluated histologically and biomechanically. RESULTS: Analysis of variance showed that, in the experimental group, the mean of the surviving parts of the RSFs, fibroblast proliferation, collagen organization and granulation tissue of the wounds was significantly higher than in the sham and control groups (P=0.007, P=0.001, P=0.041, P=0.000, respectively). There were swollen mitochondria in the endothelium of the blood vessels of the surviving flap parts in the control and sham groups, whereas in the experimental group the mitochondria were normal. CONCLUSIONS: Thirty days of pretreatment of RSFs with PTX significantly increased the survival of the flaps. PTX appeared to have healed wounds and reversed ultrastructural changes resulting from hypoxia in the blood vessel endothelium of the flaps. [Abstract/Link to Full Text]

Mantione KJ, Kim C, Stefano GB
Morphine regulates gill ciliary activity via coupling to nitric oxide release in a bivalve mollusk: opiate receptor expression in gill tissues.
Med Sci Monit. 2006 Jun;12(6):BR195-200.
BACKGROUND: Invertebrates express opiate receptors and synthesize opiate alkaloids such as morphine and morphine-6beta-glucuronide. Most of this work has been demonstrated in immune and neural tissues of various invertebrates. We hypothesized that morphinergic signaling may also take place in Mytilus edulis gill since they are innervated, in part, with dopamine nerves. MATERIAL/METHODS: Ciliary activity from excised gills was evaluated via stroboscopic synchronization of metachronal wave formation before and after drug exposure. Nitric oxide was determined in real-time via an amperometric probe following drug application. Real-time RT-PCR was performed on excised gill tissue to confirm the presence of the mu opiate receptor transcript. RESULTS: Incubation of M. Edulis excised gill filaments reveal spontaneously lateral cilia beating in a metachronal wave of about 600 beats per minute, which was significantly decreased by morphine in a concentration dependent and naloxone reversible manner. Exposure of the spontaneously beating cilia to SNAP, a nitric oxide donor, also diminished the beating rate in a concentration dependent manner. Exposing the cilia to L-NAME blocked the morphine induced cilio-inhibition, demonstrating that morphine was working to inhibit the cilia via NO. Furthermore, the gill tissue contained mu opiate receptor transcripts, which was mu3 in nature. CONCLUSIONS: As in mammals, opiate signaling is not confined to neural tissues. This report demonstrates the occurrence of opiate signaling for the first time in an invertebrate's respiratory tissue. [Abstract/Link to Full Text]

Franca R, Spadari S, Maga G
APOBEC deaminases as cellular antiviral factors: a novel natural host defense mechanism.
Med Sci Monit. 2006 May;12(5):RA92-8.
The APOBEC (acronym for apolipoprotein B editing catalytic polypeptide) family of cytidine deaminases are widely distributed in the biological world and play a central role in diverse enzymatic pathways. Members of this family (APOBEC3G and APOBEC3F) have been recently shown to be able to restrict HIV-1 replication in physiologically relevant target cells (macrophages, lymphocytes), presumably by triggering extensive deamination of the viral RNA/DNA replication intermediates. This natural antiretroviral host defense mechanism is counteracted by the HIV-1 protein Vif, which is able to target APOBECs to degrade. The so-called "Vif/APOBEC3G paradigm" has been confirmed by a growing literature. However, evidence arising from recent studies has expanded this view, showing that the replication of other viruses is also restricted by APOBEC family members and suggesting antiviral mechanism(s) of action unrelated to the catalytic activity of these proteins. Furthermore, evolutionary investigations on primates have shown that APOBEC3 gene expansion might be related to an ancient adaptive selection to prevent endogenous genetic instability, indicating an additional ancient protective role of APOBECs. This article is aimed at broadening the current knowledge about the antiviral activity of the APOBEC members and to highlight the notion that their role(s) might be more general than previously anticipated. [Abstract/Link to Full Text]

Sprott DE, Spangenberg ER, Knuff DC, Devezer B
Self-prediction and patient health: influencing health-related behaviors through self-prophecy.
Med Sci Monit. 2006 May;12(5):RA85-91.
People asked to make a self-prediction about a socially normative behavior are significantly more likely (than a comparable control group) to perform the behavior in a manner consistent with social norms. Making a behavioral self-prediction has been demonstrated to increase attendance to a health club, consumption of healthy snacks, and commitment to a health and fitness assessment. Empirical evidence indicates that this self-prophecy effect is due to dissonance-based motivation generated by the prediction request. In this article, we present self-prediction as a practical and effective tool that health care professionals can use to favorably influence a variety of health-related, patient behaviors. Previous studies on health behaviors are aggregated using meta-analytical techniques to determine the magnitude of self-prediction effects on health-related behaviors. To account for potential errors of exclusion in our analysis, a file drawer analysis is also conducted. Our analysis suggests that self-prophecy manifests as a small- to medium- effect size when used in the context of modifying health-related behaviors. Providing support for the robustness of this effect, our file drawer analysis indicated that 270 further studies with null results would be needed to negate our conclusions regarding the effect. Based on previous research and findings of the current meta-analysis, we are confident that health care professionals can effectively employ self-prediction as a method for promoting healthier behaviors and lifestyles among their patients. Implications for medical practice and allied health fields, as well as areas of future research, are identified. [Abstract/Link to Full Text]

Das UN
Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule.
Med Sci Monit. 2006 May;12(5):RA79-84.
Pyruvic acid, an intermediate metabolite of glucose, an effective scavenger of reactive oxygen species (ROS), inhibits tumor necrosis factor-alpha production and NF-kappaB signaling pathways, reduces circulating levels of HMGB1 (high mobility group B1), decreases COX-2 (cyclo-oxygenase-2), iNOS (inducible nitric oxide synthase), and IL-6 (interleukin-6) mRNA expression in liver, ileal mucosa, and colonic mucosa in animal models with endotoxemia. These studies suggest that pyruvate has potent anti-oxidant and anti-inflammatory actions. Insulin influences the production of pyruvate by its action on glucose metabolism and pyruvate is an insulin secretagogue. This suggests that in metabolic syndrome X, obesity, hypertension, diabetes mellitus, and cancer (where insulin resistance is common due to enhanced TNF-alpha production) pyruvate plays a role. This may have relevance to the use of glucose-insulin-potassium regimen in these clinical conditions, sepsis, and cancer. [Abstract/Link to Full Text]

Belo MT, Selig L, Luiz RR, Hanson C, Luna AL, Teixeira EG, Trajman A
Choosing incentives to stimulate tuberculosis treatment compliance in a poor county in Rio de Janeiro state, Brazil.
Med Sci Monit. 2006 May;12(5):PH1-5.
BACKGROUND: Tuberculosis (TB) treatment default is a major constraint of TB control, resulting in continued disease transmission and possibly the emergence of multidrug resistance. Marginalized populations may abandon treatment before being cured. The objective of this study was to evaluate the socioeconomic status (SES) of TB patients and identify potential incentives for improving treatment compliance by SES. MATERIAL AND METHODS: A cross-sectional survey was conducted in a public health unit in Duque de Caxias, a county with one of the lowest per capita incomes in Rio de Janeiro state. From November 2003 to March 2004, 305 TB patients answered an anonymous questionnaire on socio-demographic aspects, household items and family income, history of previous treatment default, and on incentives for improving treatment adherence. Incentives were classified as economic, administrative, health service support, and habits, and scored as fundamental (3), important (2), desirable (1), or irrelevant (0). RESULTS: Health service support incentives had the highest scores overall. The aggregate economic incentive score correlated with SES (r = -0.191, p = 0.001). Among the 20% poorest patients, 16.7% had a previous history of default vs. 1.6% among the wealthiest (p = 0.004). Patients with a history of treatment default were significantly more likely to choose health service support incentives than other patients (r = -0.263, p = 0.039). CONCLUSIONS: Professional commitment will be needed to effect the necessary changes in health service support. Financial support for food and transportation subsidies may be required to improve treatment compliance among the poorest TB patients, i.e. those most likely to have previously defaulted from treatment. [Abstract/Link to Full Text]

Najjar DM, Awwad ST, Zein WM, Haddad WF
Assessment of the corneal endothelium in acute ultraviolet keratitis.
Med Sci Monit. 2006 May;12(5):MT23-5.
BACKGROUND: The purpose of this prospective case-control study was to investigate whether exposure to ultraviolet (UV) light produces detectable damage to the corneal endothelium in patients presenting with acute UV keratitis. MATERIAL/METHODS: Non-contact specular microscopy was performed on 20 consecutive patients who presented to our clinic from July 2000 to July 2002 with acute UV keratitis and similarly on 20 age-matched healthy controls. Both the coefficient of variation in mean cell size (CV) and the mean cell density (CD) were compared in these two groups using the Student t-test. RESULTS: Mean age was 28.6 years in the study group and 28.4 years in the control group. The mean CD in the patient group was 2609.6 (SD = 103.47) and in the control group 2632.87 (SD = 117.05). No statistically significant difference was found between the mean CDs in these two groups (p = 0.93). The mean CV in the patient group was 46.7 (SD = 4.40) and in the control group 45.4 (SD = 5.60). Similarly, there was no statistically significant difference between the mean CVs in these two groups (p = 0.85). CONCLUSIONS: UV light exposure does not seem to have a direct immediate effect on the corneal endothelium in humans with acute UV keratitis. Whether UV light produces cumulative and/or longer-term damage requires further studies with a larger number of patients and a longer follow-up time. [Abstract/Link to Full Text]

Fraguas D, Kirchoff D
Pharmacogenetics of antipsychotic-induced weight gain.
Med Sci Monit. 2006 May;12(5):LE6-7. [Abstract/Link to Full Text]

Bishop JR, Ellingrod VL, Moline J, Miller D
Pilot study of the G-protein beta3 subunit gene (C825T) polymorphism and clinical response to olanzapine or olanzapine-related weight gain in persons with schizophrenia.
Med Sci Monit. 2006 Feb;12(2):BR47-50.
BACKGROUND: Despite advances in schizophrenia treatment, nearly 30% of patients do not respond to atypical antipsychotic agents, such as olanzapine. Furthermore, 30-60% of patients will gain significant weight during the course of olanzapine therapy. Little research has been done to investigate the relationship between antipsychotic treatment outcomes and genetic variability in second messengers coupled to serotonin (5HT) receptors. The purpose of this investigation was examine associations between the second messenger G-Protein Beta3 Subunit Gene (GNB3) C825T polymorphism and olanzapine response and weight gain treatment. MATERIAL/METHODS: We conducted a pharmacogenetic association study to examine GNB3 genotypes in relation to olanzapine clinical response (as measured by the Brief Psychiatric Rating Scale or Scale for the Assessment of Negative Symptoms) or weight gain. Subjects included forty-two individuals meeting DSM-IV criteria for schizophrenia that started olanzapine, were titrated to a fixed dose for 6 weeks, and subsequently genotyped for this investigation. RESULTS: No statistically significant associations existed between our outcome variables and GNB3 genotypes. However we did observe trends suggesting a potential relationship between the TT genotype, response, and weight gain that warrant further investigation. CONCLUSIONS: Preliminary results showed no statistical relationship between the C825T polymorphism and olanzapine response or weight gain. Numerical differences in outcome measures between the TT vs. CT/CC genotype groups indicate that G-protein second messenger systems variability coupled to primary targets of atypical antipsychotics may relate to clinical outcomes in persons with schizophrenia and that future research in this area is warranted. [Abstract/Link to Full Text]

Westall FC
Integrating theories of the etiology of Crohn's disease on the etiology of Crohn's disease: questioning the hypotheses. William M. Chamberlin, Saleh A. Naser Med Sci Monit, 2006; 12(2): RA27-33.
Med Sci Monit. 2006 May;12(5):LE5-6. [Abstract/Link to Full Text]

Chamberlin WM, Naser SA
Integrating theories of the etiology of Crohn's disease. On the etiology of Crohn's disease: questioning the hypotheses.
Med Sci Monit. 2006 Feb;12(2):RA27-33.
The most prominent theory describes the Crohn's Syndrome as a dysregulated, inappropriate immune response to otherwise innocuous bowel flora in a genetically susceptible host. The autoimmune theory assumes that a specific infectious agent does not exist. Data from mouse models, impairment of the mucosal epithelial barrier and the influence of gut flora are used to support the autoimmune theory. Critics claim that the dysregulated immune responses are not the primary disorder but secondary to an underlying infection. Two other theories are also consistent with the same data. The immunodeficiency theory hypothesizes that defects in innate immunity leading to compensatory immune processes underlie the Crohn's phenotype and suggests that therapy should stimulate immunity rather than suppress it. The mycobacterial theory proposes that Mycobacterium avium subspecies paratuberculosis is one of the causes of the Crohn's Disease syndrome. Mycobacterial molecules dysregulate immune signaling pathways as part of the organisms'evolved survival strategy. If MAP were to initiate the dysregulated immune response then the necessity to hypothesize that commensal gut flora provide the antigenic stimulus would be moot. Commensal bacteria would be relegated to a secondary role of modifying the immune response rather than occupying the central role of providing the initiating antigens. Critics claim that MAP is merely a secondary invader. The three theories differ primarily by emphasizing different aspects of the same overall process. [Abstract/Link to Full Text]

Hurreiz H, Hussain I, Hamo I
Urachal fistula presenting as umbilical sepsis: a rare case in an adult male.
Med Sci Monit. 2006 May;12(5):CS44-7.
BACKGROUND: Urachal anomalies are rare normally presenting during childhood. They are difficult to diagnose and surgical treatment is always needed to prevent recurrence. CASE REPORT: A 28 year old male presented with a red tender umbilical swelling that was confused with an umbilical hernia. The correct diagnosis of a urachal fistula was reached after performing a CT scan. The patient was initially treated with oral antibiotics and complete surgical excision of the fistulous tract was carried out at a later stage after controlling the infection. CONCLUSIONS: Staged resection is the treatment of choice in urachal anomalies associated with sepsis. Surgical excision of the urachal remnant is necessary to prevent recurrence. [Abstract/Link to Full Text]

Michalopoulos A, Falagas ME
Multi-systemic methicillin resistant Staphylococcus aureus (MRSA) community-acquired infection.
Med Sci Monit. 2006 May;12(5):CS39-43.
BACKGROUND: An alarming increase of the incidence of community-acquired infections due to methicillin resistant Staphylococcus aureus (MRSA) has been noted in several countries during the recent years. CASE REPORT: We present the case of a 64-year-old male who complained of fever, shortness of breath, productive cough, and mild low back pain. The patient was diagnosed to have severe community-acquired pneumonia caused by methicillin resistant Staphylococcus aureus. Due to the severity of his respiratory symptoms and the history of back injury, the mild low back pain did not receive the appropriate attention. It became clear later that the back pain was caused by an extra-pulmonary focus of the MRSA infection. CONCLUSIONS: Staphylococcus aureus has been reported to be the cause of considerably different proportions of patients with community-acquired pneumonia in studies from various parts of the world. Our case emphasizes the occasionally multi-systemic manifestations of community-acquired MRSA infections and the difficulties in their control. [Abstract/Link to Full Text]

Alici S, Kaya S, Izmirli M, Tuncer I, Do?an E, Ozbek H, Sayarlioglu H
Analysis of survival factors in patients with advanced-stage gastric adenocarcinoma.
Med Sci Monit. 2006 May;12(5):CR221-9.
BACKGROUND: Prognosis in patients with gastric cancer is determined by the tumor itself, as well as certain patient-related factors. MATERIAL/METHODS: In this study, 138 patients with high-grade gastric adenocarcinoma who were admitted to our hospital between September 1999 and April 2002 were retrospectively evaluated in terms of the effects of clinicopathological parameters and treatment approaches on survival by single and multiple variable analyses. Patients histopathologically diagnosed as having gastric adenocarcinomas with stage IV M0 (without distant organ metastasis) or stage IV M1, (with distant organ metastasis) were included in the study. RESULTS: Overall median survival time was 3.1 months and three-year survival rate was 8%. With single variable analysis, body mass index (BMI), clinical stage, surgery, type of surgery, and serum level of albumin were significant prognostic factors related to overall median survival time. Gender, clinical stage, surgery, type of surgery, hemoglobin concentration, and serum level of albumin were found to be significant prognostic factors related to survival without progression (p < 0.05). No surgical treatment, palliative surgery (compared with radical surgery), and BMI below 20 were found to be the statistically significant poor prognostic factors related to survival in multiple variable analysis. In terms of both overall survival and survival without progression, performing surgery or not was statistically the most significant independent prognostic factor. CONCLUSIONS: No surgical treatment, palliative surgery instead of radical surgery, and BMI below 20 on first admission were determined as poor prognostic factors related to survival in patients with high-grade gastric adenocarcinoma. [Abstract/Link to Full Text]

Swiatkowska-Stodulska R, Bakowska A, Drobi?ska-Jurowiecka A
Interleukin-8 in the blood serum of patients with alcoholic liver disease.
Med Sci Monit. 2006 May;12(5):CR215-20.
BACKGROUND: The influence of the immune system on the development of alcoholic liver disease has recently been the object of attention. However, the connection between alcohol consumption, altered immune response, and development of changes in the liver has not been fully explained. The aim of the present study was to evaluate serum IL-8 concentration in patients with chronic alcoholic liver disease. MATERIAL/METHODS: 85 patients with different types of ALD and 35 healthy subjects were enrolled in the study. Serum IL-8 concentration was evaluated with the ELISA immunoenzymatic method. IL-8 in liver tissue was measured by the indirect immunofluorescence method. RESULTS: There was a significant correlation between IL-8 concentration and AST, ALP, GGT, total bilirubin and albumin levels in blood serum. A significantly higher concentration of IL-8 was seen in all the groups of ALD patients. The highest values were found in patients with chronic alcoholic hepatitis, and the lowest in those with fatty liver. Significantly higher values were found in patients with ascites or encephalopathy in comparison to those without any features of portal hypertension and/or insufficiency of the liver cells. A high concentration of the tested cytokine is a disadvantageous prognostic factor in patients with ALD. CONCLUSIONS: IL-8 appears to be an important factor in liver pathology in patients with ALD, especially in the development of the inflammatory process. [Abstract/Link to Full Text]

Piwowar A, Knapik-Kordecka M, Fus I, Warwas M
Urinary activities of cathepsin B, N-acetyl-beta-D-glucosaminidase, and albuminuria in patients with type 2 diabetes mellitus.
Med Sci Monit. 2006 May;12(5):CR210-4.
BACKGROUND: The proximal kidney tubule contains a large number of lysosomes involved in the breakdown of intracellular as well as reabsorbed proteins. When tubular protein reabsorption is overburdened or when there is tubular cell damage, higher urinary excretion of lysosomal enzymes, e.g. cathepsins and N-acetyl-beta-D-glucosaminidase (NAG), can be found. We compared urinary cathepsin B (CB) activity with NAG in diabetic patients. MATERIAL/METHODS: Using fluorogenic substrates, urinary and plasma CB and NAG activities in 130 type 2 diabetic patients with varying stages of albuminuria and 42 control subjects were determined. Early morning urine samples were used. RESULTS: In the patients, only higher values of plasma NAG were found. In urine, CB and NAG activities increased progressively from normoalbuminuria, through microalbuminuria to macroalbuminuria group. The normoalbuminuria group had both enzyme activities higher than healthy controls. Urine CB activity in the patients also increased gradually to tertiles of urinary NAG. Only urinary CB activity was significantly associated with glycemic state. The correlation was stronger in the patients with poor glycemic control. The plasma/urine ratios for both CB and NAG decreased in the patients compared with controls. CONCLUSIONS: Determination of urinary CB activity might be useful as a non-invasive surrogate marker of incipient nephropathy. [Abstract/Link to Full Text]

Kamalipour H, Mowla A, Saadi MH, Davari HR, Kamali K
Determination of the incidence and severity of hoarseness after cardiac surgery.
Med Sci Monit. 2006 May;12(5):CR206-9.
BACKGROUND: The aim of the study was to determine the incidence and severity of hoarseness and vocal cord dysfunction in 200 patients undergoing open heart surgery in Shiraz-Iran. MATERIAL/ METHODS: This study involved prospective evaluation of 200 patients who underwent open heart surgery during the year 2003 in Shiraz University hospitals. All patients received the same standard anesthetic technique. In post-operative course, all patients were electively ventilated for variable periods depending on several factors, at least until the morning after surgery. All patients underwent direct laryngoscopy immediately after extubation by the otolaryngologist, and the existence and grade of hoarseness was evaluated on a four-point scale 6 and 12 hours after extubation. RESULTS: Two hundred patients, 64.5% male and 35.5% female, with a mean age of 56.7 (S.D. = 5.2) were evaluated. CABG was performed most frequently and the mean duration of cold perfusion was 122 minutes (S.D. = 15). CVP insertion, endotracheal intubation, sternotomy, and hypothermia were performed in all patients. Hoarseness was found to be present in 17% of patients; all but one were rated to be grade one on the four-point scale. However, laryngoscopy did not reveal anything specific. CONCLUSIONS: The incidence of hoarseness in this study was 17%; similar series reported as high as 32%. Vocal cord dysfunction never occurred in our study and hoarseness probably resulted from intubation trauma. Although we found no case of nerve injury and cord dysfunction, vocal cord palsy as a rare cause of respiratory insufficiency in chest and neck surgeries must never be overlooked. [Abstract/Link to Full Text]

Bozcuk H, Artac M, Kara A, Ozdogan M, Sualp Y, Topcu Z, Karaagacli A, Yildiz M, Savas B
Does music exposure during chemotherapy improve quality of life in early breast cancer patients? A pilot study.
Med Sci Monit. 2006 May;12(5):CR200-5.
BACKGROUND: Adjuvant chemotherapy is associated with poor quality of life (qol) in breast cancer patients. We tested the effect of listening to music during chemotherapy on quality of life in these patients. MATERIAL/METHODS: We tested in a prospective cohort the changes in qol scores as assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and the influence of listening to non-preferred music at the chemotherapy unit on these parameters in a mixed linear model by repeated measures analysis of variance (RMANOVA). RESULTS: For the whole cohort, musical intervention was not associated with a change in any dimension of quality of life. However; the music effect significantly interacted with patient age; patients > 45 years old had improved insomnia and appetite loss scores after musical intervention (F = 6.76, P = 0.019 and F = 11.22, P = 0.004, respectively). CONCLUSIONS: Our results show that brief, non-preferred music exposure at the time of chemotherapy administration does not improve quality of life in patients with early breast cancer. Nonetheless, there is still a possibility that a subgroup will benefit from this approach as suggested by the interaction of the music effect with patient age. [Abstract/Link to Full Text]

Ko GT, Tsang PC, Chan HC
A 10-week Tai-Chi program improved the blood pressure, lipid profile and SF-36 scores in Hong Kong Chinese women.
Med Sci Monit. 2006 May;12(5):CR196-9.
BACKGROUND: Physical activity is associated with a better longevity and reduced morbidity. In addition, exercise has a mood-elevating effect, which improves self-esteem. Tai-Chi is a traditional Chinese aerobic exercise. We aimed to assess the short-term effects of Tai-Chi on the clinical parameters and health-related quality of life (QOL) in Hong Kong Chinese. MATERIAL/METHODS: Twenty Chinese healthy female subjects were recruited. There were 2 Tai-Chi sessions per week for 10 weeks. Each session lasted for one hour. Health-related QOL was assessed with SF-36 questionnaire. RESULTS: Of the 20 subjects, their mean age was 40.8 +/- 5.9 years (median 42.5 years, range 30-50 years). At the end of the study, systolic blood pressure, total cholesterol and low-density lipoprotein cholesterol levels significantly reduced (114 +/- 9 to 108 +/- 9 mmHg, p = 0.012; 4.7 +/- 0.8 to 4.4 +/- 0.5 mmol/L, p = 0.020 and 2.7 +/- 0.6 to 2.2 +/- 0.5 mmol/L, p = 0.001, respectively). Among all SF-36 items, Vitality and Mental Health significantly improved after the 10-week Tai-Chi program (64.9 +/- 8.1 to 68.4 +/- 6.6, p = 0.038 and 64.4 +/- 6.9 to 69.1 +/- 1.4, p = 0.003, respectively). CONCLUSIONS: A 10-week Tai-Chi exercise program improved systolic blood pressure, lipid profiles and some of the parameters of health-related QOL in Hong Kong Chinese women. Tai-Chi is likely to be a useful choice of physical activity. We need a larger study that covers a wider range of populations to confirm our results. [Abstract/Link to Full Text]

Scardovi AB, De Maria R, Colettat C, Aspromonte N, Perna S, Infusino T, D'Errigo P, Rosato S, Greggi M, Di Giacomo T, Riccio R, Cec V
Brain natriuretic peptide is a reliable indicator of ventilatory abnormalities during cardiopulmonary exercise test in heart failure patients.
Med Sci Monit. 2006 May;12(5):CR191-5.
BACKGROUND: Whether brain natriuretic peptide (BNP), a neurohormone marker of ventricular dysfunction, correlates with an enhanced ventilatory response (EVR) during cardiopulmonary exercise test, a well-known predictor of prognosis, in systolic heart failure (HF) is currently unknown. MATERIAL/METHODS: Resting BNP was measured in 134 consecutive stable outpatients aged 69 +/- 11 years with mild to moderate HF and LV ejection fraction (LVEF) < 40% who performed a maximal exercise test. EVR was assessed as the slope of the relation between minute ventilation and carbon dioxide production (VE/VCO2 slope) > or = 35. RESULTS: LVEF averaged 33 +/- 7%, BNP 350 +/- 396 pg/ml, and the VE/VCO2 slope 36 +/- 8. Fifty-six of 123 patients (45%) had EVR. BNP correlated with VE/VCO2 slope (r = 0.453; p < 0.01). By multivariate logistic regression, plasma BNP was the only independent predictor of EVR (RR: 1.004 per unit increment, 95% CI: 1.002-1.006, p < 0.0001). A BNP > or = 160 pg/ml had 86% sensitivity, 67% specificity, and 76% overall accuracy for the prediction of EVR (chi square: 37.4, RR 12.2, 95% CI: 4.96-30.3, p < 0.0001, AUC 0.815 (95%CI. 0.738-0.892)). CONCLUSIONS: In systolic HF, plasma BNP is related to an enhanced ventilatory response to exercise and offers a simple and reliable alternative to the cardiopulmonary exercise test in patients with inability or contraindications to exercise. [Abstract/Link to Full Text]

Ince H, Kandemir E, Bagci C, Gulec M, Akyol O
The effect of caffeic acid phenethyl ester on short-term acute myocardial ischemia.
Med Sci Monit. 2006 May;12(5):BR187-93.
BACKGROUND: We previously showed that caffeic acid phenethyl ester (CAPE) attenuated NO production, reduced apoptosis, diminished serum CK and AST activities, and is cardio-protective in rat heart subjected to ischemia/reperfusion (I/R). We now studied the short-term cardio-protective effect of CAPE in an I/R rat heart model. MATERIAL/METHODS: Wistar rats were divided into four groups: (i) sham-operated, (ii) I/R, (iii) I/R+CAPE, and (iv) I/R+glutathione. CAPE (10 micromol/kg) was infused i.v. 10 min before occlusion of the left anterior descending coronary artery (8 min) followed by reperfusion (8 min). RESULTS: SOD (p < 0.010) and CAT (p < 0.014) activities were increased and GSH-Px (p < 0.019) activity decreased in the I/R group in cardiac tissues compared with the sham-operated group. There were no effects of CAPE on antioxidant enzyme activities after I/R. Glutathione administration led to decreased SOD activity (p < 0.024) and increased GSH-Px (p < 0.014) activity after I/R. The most prominent effects of CAPE were seen in XO and ADA activities, which were increased after I/R compared with the sham-operated group (p < 0.029 and p < 0.001, respectively). When CAPE was administered, XO and ADA activities were decreased compared with the I/R group (p < 0.045 and p < 0.001). ADA activity was also decreased in the I/R+glutathione group compared with the I/R group. No differences in basal heart rate or systolic or diastolic pressure were noted among the experimental groups. CONCLUSIONS: This study demonstrates that CAPE exerts cardio-protective effects in short-term I/R of rat heart. This protective effect may be mediated by a combination of decreased XO activity and direct antioxidant effects. [Abstract/Link to Full Text]

Nzeako BC, Al-Hashmi S
The effect of preservatives on the sterility of microorganisms introduced into different fruit juices.
Med Sci Monit. 2006 May;12(5):BR179-86.
BACKGROUND: The aim of this study was to investigate the degree of sterility of some fruit juices post manufacture and to determine how effective the preservatives in them aid the killing of some microorganisms introduced into them. MATERIAL/METHODS: Blackcurrant/raspberry, apple, guava, orange, mango, and mixed fruits were each checked for sterility by inoculating 100 microl separately in tryptone soy broth, Robertson's cooked meat, and Sabouraud broth and incubating for growth for 72 hours at 37 degrees C. Twenty-milliliter aliquots of each juice were subsequently kept in a 37 degrees C water bath and inoculated separately with S. aureus, P. aeruginosa, E. coli, and C. albicans. At predetermined time intervals, a 1:250 dilution of each juice with the individual organism was made and the dilutions were plated on blood and Sabouraud plates for viable counts. Each 1:250 dilution was then incubated along with the plates. The pH of each undiluted juice was determined. RESULT: All the juices were found to be sterile. The growth inhibition exhibited by each juice was bactericidal or bacteriostatic, fungicidal or fungistatic, depending on the type of juice. The p[H of the juices varied from 2.53-3.75. CONCLUSIONS: We found the juices to be bacteriologically free of organisms associated with food infection. Though the juices were sterile, they could allow the survival of some bacteria and yeasts if these gained access into them. We found the orange, blackcurrant/raspberry, and mango juices to be bactericidal and fungicidal, while pineapple, mixed fruit, and guava were fungistatic, though with varying bactericidal activities. [Abstract/Link to Full Text]

Wu M, Chen S, Wu X
Differences in cytochrome P450 2C19 (CYP2C19) expression in adjacent normal and tumor tissues in Chinese cancer patients.
Med Sci Monit. 2006 May;12(5):BR174-8.
BACKGROUND: Cytochrome P450 2C19 (CYP2C19) exhibits polymorphic expression in humans and deficiencies in its expression have been associated with a number of different cancers. Our aim was to determine if CYP2C19 mRNA and CYP2C19 enzyme protein expression differed between various tumors and normal tissue adjacent to the tumor tissue in Han Chinese cancer patients. MATERIALS AND METHODS: The level of CYP2C19 mRNA expression was examined in tumor and adjacent normal tissue from liver, colon, stomach, breast, esophagus, lung, uterus, brain, pancreas, ovary, kidney, and several cell lines by semi-quantitative RT-PCR Western immunoblots were also used to qualitatively assess CYP2C19 protein in the above tissues and cell lines. RESULTS: CYP2C19 mRNA was found only in normal livers, hepatic carcinomas, and hepatocarcinoma cell lines. The CYP2C19 mRNA was expressed at significantly higher levels in hepatocellular carcinomas (x +/- s: 3.72 +/- 1.21, n = 14) than in adjacent normal liver tissue (x +/- s: 1.79 +/- 0.33, n = 14, p = 0.000). CYP2C19 protein was also detected in hepatocarcinoma tissues, adjacent normal tissues, and the hepatocarcinoma cell lines HepG2, HepGA, and 7721 based on Western blotting methods. These results are in accordance with observations employing RT-PCR. CONCLUSIONS: CYP2C19 mRNA expression is highest in hepatocarcinoma tissue, moderate in adjacent normal liver tissue, and absent in other cancer tissues and their adjacent normal tissues. The significantly elevated expression of CYP2C19 mRNA in hepatocarcinoma indicates an association between the occurrence of hepatocarcinoma and the expression and/or turnover of CYP2C19 mRNA. [Abstract/Link to Full Text]

Nandi A, Chandil D, Lechesal R, Pryor SC, McLaughlin A, Bonventre JA, Flynnx K, Weeks BS
Bifenthrin causes neurite retraction in the absence of cell death: a model for pesticide associated neurodegeneration.
Med Sci Monit. 2006 May;12(5):BR169-73.
BACKGROUND: Bifenthrin is a synthetic pyrethroid insecticide derivative of naturally occurring pyrethrins from chrysanthemum flowers. Bifenthrin is considered relatively safe and therefore incorporated as the active ingredient in preparations sold over the counter for household use. Recent studies have raised concern that chronic exposure to pesticides in the home setting may increase the risk for neurodegenerative diseases. To address this concer, in the present study, bifenthrin is added to pre-differentiated PC12 and effect of bifenthrin on the retraction of existing neurites is observed a model for neurodegeneration. MATERIAL/METHODS: PC12 cells were differentiated with nerve growth factor for twenty-four hours and then treated with what was determined to be a sublethal dose of bifenthrin for up to an additional 48 hours. The percent of cells with neurites was assessed at various times before and after nerve growth factor treatment. Bifenthrin toxicity was determined using trypan blue exclusion. RESULTS: Bifenthrin was not toxic to PC12 cells at concentrations ranging from 1 x 10(-10) M to 1 x 10(-4) M. Twenty-four hours after nerve growth factor treatment, a maximum percent of cells had formed neurites and with a treatment of 1 x 10(-5) M bifenthrin, approximately 80% of these neurites retracted in within 12 additional hours and almost all neurites had retracted within 48 hours. Trypan exclusion showed that these cells were viable. CONCLUSIONS: These data show that bifenthrin can stimulate the retraction of neurites in the absence of frank toxicity. [Abstract/Link to Full Text]

Cain ML, Hester RL, Izevbigie EB
Ethanol abrogates angiotensin II-stimulated vascular smooth muscle cell growth.
Med Sci Monit. 2006 May;12(5):BR162-8.
BACKGROUND: Aberrant vascular smooth muscle cell (VSMC) proliferation is one of the etiological factors for hypertension and stroke. Angiotensin II (Ang II) and ethanol (EtOH) have been shown to modulate the proliferation of vascular smooth muscle cells (VSMCs) individually, but the combined effects of Ang II and EtOH on VSMC proliferative activities are unknown. The objective of this study was to determine the effects of EtOH, Ang II, and the combination of Ang II and EtOH on DNA synthesis, cell number, cyclic AMP (cAMP) production, and Mitogen-Activated Protein Kinase (MAPK) or (p44/42) activities in murine primary VSMCs. MATERIAL AND METHODS: Cell growth was determined by [3H] thymidine incorporation and confirmed by cell counts using a hemacytometer. Cyclic AMP assays were carried out using commercially available kits. MAPK activity was determined by immunoprecipitation studies using an ELK-1 fusion protein as a substrate. RESULTS: Ang II (10 microM) stimulated DNA synthesis by four-fold (P < 0.05), cAMP production by 50% (P < 0.05), and MAPK (p44/42) activities by more than seven-fold (P < 0.01). In contrast, EtOH (100 mM) had no significant effects on DNA synthesis, cell number, and cAMP production. Ethanol exacerbated cAMP production by several fold but inhibited MAPK activity and subsequent cell growth induced by Ang II. CONCLUSIONS:These results suggest that EtOH elicits a regulatory effect on the Ang II signaling pathway. [Abstract/Link to Full Text]

Zhu W, Mantione KJ, Casares FM, Cadet P, Kim JW, Bilfinger TV, Kream RM, Khalill S, Singh S, Stefano GB
Alcohol-, nicotine-, and cocaine-evoked release of morphine from invertebrate ganglia: model system for screening drugs of abuse.
Med Sci Monit. 2006 May;12(5):BR155-61.
BACKGROUND: Invertebrates express regulatory receptors, transporters, and channels responsive to established drugs of abuse, many of which mediate their effects through catecholamine pathways. We hypothesized that invertebrate neural systems may serve as models by which to evaluate the interactive pharmacological effects of these agents. MATERIAL AND METHODS: Ex vivo pharmacological trials determined the effects of saturating levels of ethanol on morphine levels in pooled Mytilus edulis ganglia via HPLC coupled to electrochemical detection and/or HPLC/RIA analyses. Additional trials evaluated the ability of ethanol, nicotine, and cocaine, to promote evoked release of 125I-labeled morphine from neural tissues, because intrinsically low levels of morphine did not allow direct quantification of its release. RESULTS: Incubation of pooled M. edulis pedal ganglia with 200 mM ethanol (approximately 1% ethanol v/v) resulted in a two-fold increase in morphine concentration at 15 min, return to baseline at 30 min, and a 50% decrease in morphine concentration at 60 min. Separate incubations of pooled M. edulis pedal ganglia and H. americanus nerve cord with ethanol, cocaine, and nicotine resulted in a statistically significant enhancement of 125I-trace labeled morphine release. CONCLUSIONS:The stimulatory effects of ethanol, nicotine, and cocaine on cellular expression and release of endogenous morphine suggest convergent mechanisms underlying the reinforcing and addictive properties for a variety of drugs of abuse. The evolutionary conservation of L-tyrosine as a common precursor to catecholamine and opiate/opioid signaling systems may define a functional triad involving endogenous morphine, dopamine, and other classes of addictive drugs. [Abstract/Link to Full Text]

Tosevski J, Tosevski DL
Concealed female external genitals: possible morpho-psychological clue to unique emotional and cognitive evolutionary matrix of man.
Med Sci Monit. 2006 May;12(5):HY11-9.
Despite genetic similarities between man and other anthropoids, the cognitive abilities of man are distinct. Inaccessible and concealed external female genitals are one of the morphological characteristics distinguishing humans from other higher primates. External female sexual organs in subhuman primates are visible and accessible in the habitual quadrupedal and occasional bipedal posture, whereas these organs in the human female are inaccessible and concealed in any posture. A prospective consequence of gradual bipedalism of hominids during evolution was a shifting of the external female genitals in an anterior direction. In the completely bipedal Homo sapiens, this resulted in the vulvo-cryptic phenomenon, i.e. concealed female genitals in humans. The unique morphology of the human female pelvis served as an obstacle to easy access of the male in the process of copulation, necessitating the female's conscious decision for sexual intercourse. This circumstance might have created a psychological basis for female propellant psychosexual manipulation of the male as a natural consequence. Also, through the process of positive selection it could have formed a basis for linking reproductive success with the development of cognitive and emotional capacities. Female consent to copulation is a conscious and complex act that would be impossible without the involvement of highly developed emotional-cognitive and memoric brain systems. Thus the extraordinary evolutionary strategy might imply a teleological link between concealed female genitals and the emotional-cognitive characteristics of man, creating a permanent promoter of further development of emotional and cognitive brain systems with an impact on all domains of everyday life. [Abstract/Link to Full Text]

Polat M, Akil I, Yuksel H, Coskun S, Yilmaz D, Erguder I, Onag A
The effect of seasonal changes on blood pressure and urine specific gravity in children living in Mediterranean climate.
Med Sci Monit. 2006 Apr;12(4):CR186-90.
BACKGROUND: We aimed to evaluate the effects of seasonal changes on urinary specific gravity, blood pressure and urinary erythrocyte number in children living in Mediterranean climate. MATERIAL/METHODS: The study was conducted on 547 children who presented for routine follow up to healthy-child care department between January 1997 and December 2002. Age, sex, weight, height, blood pressure, urinary specific gravity and urinary erythrocyte number were recorded by retrospective evaluation of files. Then, the parameters during summer were compared with those during winter. Additionally, correlation between the blood pressure, urinary specific gravity and urinary erythrocyte number was assessed separately during summer and winter. RESULTS: Anthropometrical measurements and mean age of the patients in summer and winter groups were similar. There was no significant change in urinary specific gravity (p > 0,05), while systolic and diastolic blood pressures were significantly higher in winter (p = 0.031 and p = 0.028 respectively). Temperature and humidity levels did not change significantly among different years but mean air temperatures during summer positively correlated with time from 1997 till 2002 (r = 0.965, p = 0.002). Blood pressure and urinary specific gravity were not correlated to each other at any time. Contrarily, there was a positive correlation between urinary specific gravity and erythrocyte number in summer (p = 0.01). The number of children with hematuria and degree of hematuria did not differ significantly between summer and winter. CONCLUSIONS: Seasonal changes in Mediterranean climate do not lead to changes in hydration status or in urinary erythrocyte number in children. Therefore, the decrease in blood pressure during summer can not be attributed to the hydration status. [Abstract/Link to Full Text]

Taupin P
Derivation of embryonic stem cells for cellular therapy: challenges and new strategies.
Med Sci Monit. 2006 Apr;12(4):RA75-8.
Cellular therapy is the replacement of unhealthy or damaged cells or tissues by new ones. Embryonic stem (ES) cells are undifferentiated cells that can generate all the cell types of the body, and therefore hold the potential to cure a broad range of diseases and injuries, ranging from diabetes, liver and heart diseases, to neurological diseases, such as Alzheimer's and Parkinson's diseases. The derivation of human ES (hES) cells has been a major step toward bringing ES cell research to therapy. However, there are several challenges to the advent of ES cell research to therapy. Among them, the derivation of hES cell lines devoid of animal contaminants, the maintenance of their normal karyotypes, their potentials to form tumors upon grafting, and the derivation of isogenic hES cell lines. Stringent ethical and political guidelines are also limiting the use of human embryos for research, thereby limiting progress in ES cell research. Recently, several investigators have devised protocols to derive hES cells free of feeder layer and animal serum, reported that some established cell lines remain stable overtime, pre-differentiated ES cells in vitro to circumvent the risk of tumor formation, and derived ES cell lines without destroying embryos. In this manuscript, we will review and discuss these developments that may unlock ES cell research and therapy. [Abstract/Link to Full Text]

Dallas A, Vlassov AV
RNAi: a novel antisense technology and its therapeutic potential.
Med Sci Monit. 2006 Apr;12(4):RA67-74.
Antisense oligonucleotide agents induce the inhibition of target gene expression in a sequence-specific manner by exploiting the ability of oligonucleotides to bind to target RNAs via Watson-Crick hybridization. Once bound, the antisense agent either disables or induces the degradation of the target RNA. This technology may be used for therapeutic purposes, functional genomics, and target validation. There are three major categories of gene-silencing molecules: (1) antisense oligonucleotide derivatives that, depending on their type, recruit RNase H to cleave the target mRNA or inhibit translation by steric hindrance; (2) ribozymes and deoxyribozymes--catalytically active oligonucleotides that cause RNA cleavage; (3) small interfering double-stranded RNA molecules that induce RNA degradation through a natural gene-silencing pathway called RNA interference (RNAi). RNAi is the latest addition to the family of antisense technologies and has rapidly become the most widely used approach for gene knockdown because of its potency. In this mini-review, we introduce the RNAi effect, briefly compare it with existing antisense technologies, and discuss its therapeutic potential, focusing on recent animal studies and ongoing clinical trials. RNAi may provide new therapeutics for treating viral infections, neurodegenerative diseases, septic shock, macular degeneration, cancer, and other illnesses, although in vivo delivery of small interfering RNAs remains a significant obstacle. [Abstract/Link to Full Text]

Can M, Be?irbellioglu BA, Avci IY, Beker CM, Pahsa A
Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: a prospective study.
Med Sci Monit. 2006 Apr;12(4):PI19-22.
BACKGROUND: Interest to probiotics for the prevention and treatment of antibiotic-associated diarrhea is increasing gradually. The most promising seems to be Saccharomyces boulardii . Using a double-blind controlled study, we investigated the preventive effect of S. boulardii on the development of antibiotic-associated diarrhea in patients under antibiotherapy but not requiring intensive care therapy. MATERIAL/METHODS: All the patients were hospitalized at the Gulhane Military Medical Academy, Department of Infectious Diseases and Clinical Microbiology. S. boulardii was given twice daily during the course of antibiotic therapy and application was initiated in all patients as late as after 48 hours of antibiotic therapy. A total of 151 patients completed the study. RESULTS: The antibiotic-associated diarrhea development ratio in placebo group was 9% (7/78) and in the study group 1.4% (1/73) (p < 0.05). Stool samples from the patients with antibiotic-associated diarrhea were stored at -70 degrees C and Clostiridium difficile toxin A assay was performed using Enzyme Immune Assay as late as in seven days. C. difficile toxin A assay yielded positive results in two (2/7) stool samples from the patients with antibiotic-associated diarrhea in the placebo group and a negative result in the only patient who developed antibiotic-associated diarrhea in the study group. CONCLUSIONS: The results implied that prophylactic use of Saccharomyces boulardii resulted in reduced, with no serious side effects, antibiotic-associated diarrhea in hospitalized patients. [Abstract/Link to Full Text]

Antosik-Biernacka A, Peuskens H, De Hert M, Peuskens J, Sunaert S, Van Hecke P, Goraj B
Magnetization transfer imaging in chronic schizophrenia.
Med Sci Monit. 2006 Apr;12(4):MT17-21.
BACKGROUND: It has recently been suggested that new imaging methods such as magnetization transfer imaging (MTI) may play an important role in detecting subtle gray- and white-matter abnormalities in schizophrenia. The aim of the study was to investigate whether MTI, analyzed on a voxel-by-voxel basis, could identify areas of abnormal magnetization transfer ratio (MTR) in patients with schizophrenia. MATERIAL/METHODS: Twenty schizophrenic patients and 23 healthy controls matched for handedness and demographic variables underwent MTI and T1-weighted structural MRI in a 3-tesla scanner. Post-processing was performed with SPM99 and included co-registration of the MT-weighted and non-MT-weighted images, calculation of the MTR maps, spatial normalization, and smoothing. Differences in the MTR maps between groups were assessed using two-sample t-tests. Significant changes in MTR were detected at an individual voxel threshold of p < 0.05. RESULTS: Group comparisons revealed no significant MTR changes, although there was a trend towards MTR reduction in the left superior temporal gyrus, in the right occipital cortex, and left periventricular white matter in patients compared with controls prior to correction for multiple comparisons (p < 0.001, uncorrected). CONCLUSIONS: MTI and voxel-by-voxel statistical analysis used in the study failed to identify regions of significant MTR reductions in schizophrenic patients. Our results disagree with findings of widespread MTR abnormalities reported in recent literature. [Abstract/Link to Full Text]

Shah SS, McGowan JP, Klein RS, Converse PJ, Blum S, Gourevitch MN
Agreement between Mantoux skin testing and QuantiFERON-TB assay using dual mycobacterial antigens in current and former injection drug users.
Med Sci Monit. 2006 Apr;12(4):MT11-6.
BACKGROUND: Individuals infected with non-tuberculous mycobacteria may elicit false-positive reactions on tuberculin skin testing. The QuantiFERON-TB (QFT) assay utilizes tuberculin and M. avium antigens and, therefore, may be more specific for latent tuberculosis infection. The objective of this study was to investigate the agreement between the QFT and single and dual antigen skin testing for detecting latent M. tuberculosis and assess the impact of cross-reactions from latent infection with other mycobacteria in inner-city injection drug users, a population at high risk for tuberculosis. MATERIAL/METHODS: We studied the agreement of results from skin testing using tuberculin and purified protein derivative-Battey (PPD-B) with the QFT test using tuberculin and Mycobacterium avium sensitin (MAS) in 48 HIV-seronegative injection drug users. RESULTS: The agreement between skin testing and the QFT assay for tuberculin was 73% (kappa = 0.45) and for PPD-B/MAS was 63% (kappa = 0.12). Agreement between skin test tuberculin dominance (tuberculin reaction > or =5 mm greater than PPD-B) and QFT tuberculin dominance (proportional difference between MAS and tuberculin reaction of > or =10%) was 75% (kappa = 0.53). All subjects tuberculin dominant by skin test were also QFT positive for tuberculin. Agreement between skin test Battey dominance and QFT avium dominance was 83% (kappa = 0.12). CONCLUSIONS: Results from the QFT assay and skin testing demonstrated moderate concordance in identifying subjects with latent tuberculous infection, and use of dual antigens did not appreciably improve the agreement between the two methods. [Abstract/Link to Full Text]

Ortendahl M
Using framing effects in medical education and training to meet community needs.
Med Sci Monit. 2006 Apr;12(4):LE3. [Abstract/Link to Full Text]

Rabbani F, Shaikh BT, Mahmood Q, Khan KS, Israr SM, Memon Y
Medical education and training: responding to community needs.
Med Sci Monit. 2005 Oct;11(10):SR21-5.
At its inception in 1987, the Aga Khan University introduced the idea of community-based medical education in Pakistan, at a time when this model was being introduced and adapted internationally. Human resource development has been a major objective in the Department of Community Health Sciences (CHS). CHS has contributed to developing a medical curriculum that addresses the health needs of the community at large. This paper narrates the department's experience in working directly with under-served communities, leading to the development of specialized courses and degree programs. CHS emphasizes operational research and development of managerial skills among front-line public health professionals, in both the public and private sectors. Training is provided by people from diverse backgrounds, such as public health, community development, social sciences, law, epidemiology, economy, biostatistics, demography, theater, and film. The lessons we have learned show that the mode of training depends on the overall objectives of the program, the clients and the setting. However, in the spirit of the participatory approach, the recipients of the training must be involved during all stages so as to ensure the sustainability of the training program. Training must focus on the communities at the grass roots level or community based organizations, where the communities identify their own capacity and needs. Wide dissemination of training materials, courses and manuals is also useful to replicate successful experience. [Abstract/Link to Full Text]

McHugh JB, Fullen DR
Atypical compound nevus arising in mature cystic ovarian teratoma.
Med Sci Monit. 2006 Apr;12(4):CS34-7.
BACKGROUND: Mature cystic ovarian teratoma (MCOT) is the most common primary ovarian tumor. Rarely, MCOT may undergo malignant transformation. Melanoma arising primarily in MCOT is a rare event. Melanocytic nevi have also rarely been reported in MCOT. CASE REPORT: A 28 year-old female presented with a palpable, 4.6 cm, right pelvic mass on physical examination. Histologically, the cystic neoplasm demonstrated epidermis with numerous pilosebaceous units and respiratory-type epithelium (endoderm) surrounded by adipose tissue and cartilage (mesoderm). A 2.0 x 1.0 cm pigmented area corresponded to a nevus with architectural and cytologic features of the so-called "dysplastic nevus," including variable-sized nests of nevomelanocytes irregularly distributed on distorted rete ridges, bridging of nests between rete ridges, fibroplasia around rete ridges, and junctional shouldering beyond the dermal nevus. The nevomelanocytes demonstrated moderate cytologic atypia. Diagnostic criteria of melanoma were not identified. CONCLUSIONS: Herein, we report, to the best of our knowledge, the first case of an atypical ("dysplastic") nevus, arising in a MCOT. No features of melanoma were present and the patient is disease-free at one-year follow-up. Rarely, melanocytic nevi and melanomas arise from the ectodermal component of MCOTs. Moreover, melanomas may arise de novo or in association with a nevus. Distinction between a melanocytic nevus, as in our case, and a primary melanoma is critical for determining the patient's prognosis and need for additional therapy. As primary ovarian melanomas, like their skin counterpart, may arise from a precursor lesion, removal of a melanocytic nevus, such as this atypical nevus, could theoretically prevent melanoma transformation. [Abstract/Link to Full Text]

Imanieh MH, Mowla A, Zohouri D, Forootan HR, Karimi M
Spontaneous perforation of the common bile duct with eosinophilia in an 18-month-old girl: a case report and review of literature.
Med Sci Monit. 2006 Apr;12(4):CS31-3.
BACKGROUND: Spontaneous perforation of the common bile duct is a rare but important cause of jaundice in infancy, requiring prompt diagnosis and surgical intervention. First described in 1932, fewer than 150 cases have been reported to date. CASE REPORT: The report concerns a 18-month-old girl who developed mild jaundice, abdominal distension, and constipation three days prior to admission. On admission, ascites and hepatomegaly were detected and the complete blood count was normal, but on the 3rd, 4th, and 5th days of admission, the blood cell count revealed elevation of the eosinophil count to 16% of total WBC. Abdominal sonography showed a moderate amount of ascitic fluid and paracentesis demonstrated biliary ascites. Hepatobiliary scintigraphy suggested leakage of bile to the abdominal cavity. Exploratory laparotomy revealed clear bilious ascitic fluid and a ruptured common bile duct at the anterior wall of the junction of the cystic duct and the common bile duct. Three days after T-tube insertion and closure of the perforation, the eosinophil count returned normal. CONCLUSIONS: Perforation of the bile duct may be considered as one of the differential diagnoses of eosinophilia. This point makes our case a unique study, worthy of being reported. [Abstract/Link to Full Text]

Ochiai T, Washio H, Shiraiwa H, Takei M, Sawada S
Psoriatic onycho-pachydermo-periostitis successfully treated with low-dose methotrexate.
Med Sci Monit. 2006 Apr;12(4):CS27-30.
BACKGROUND: Psoriatic onycho-pachydermo-periostitis (POPP) is a rare manifestation of psoriatic arthritis that is often misdiagnosed as a nail infection. The treatment for POPP has not yet been established. CASE REPORT: We present a case of a 67-year-old man who had no psoriatic skin lesions with POPP, characterized by psoriatic nail changes, painful swelling of the distal soft tissues on the great toes and fingers, and enthesopathies of the involved terminal phalanges. The clinical nail and arthritic changes were improved with methotrexate treatment 4 mg weekly for 6 months. CONCLUSIONS: Methotrexate can be recommended as the first-choice therapeutic agent for patients with POPP. [Abstract/Link to Full Text]

Pawlak K, Pawlak D, My?liwiec M
Possible association between circulating vascular endothelial growth factor and oxidative stress markers in hemodialysis patients.
Med Sci Monit. 2006 Apr;12(4):CR181-5.
BACKGROUND: Vascular endothelial growth factor is involved in the process of atherogenesis. Increased oxidative stress has been reported in hemodialyzed patients, but its influence on vascular endothelial growth factor levels remains unknown. MATERIAL/METHODS: The levels of two oxidative stress markers, Cu/Zn superoxide dismutase and autoantibodies against oxidized LDL, and the level of vascular endothelial growth factor were measured in pre-dialysis samples of hemodialyzed patients with and without cardiovascular disease and in healthy controls. RESULTS: Vascular endothelial growth factor levels were significantly increased in both hemodialysis groups compared with controls (all p < 0.001), more so in patients with than those without cardiovascular disease (p < 0.05). Cu/Zn superoxide dismutase levels were elevated in both patient groups (all p < 0.001), whereas the levels of autoantibodies against oxidized LDL were increased only in the patients with cardiovascular disease (p < 0.05) compared with the controls. Vascular endothelial growth factor level positively correlated with Cu/Zn superoxide dismutase level (p < 0.01) and with the levels of autoantibodies against oxidized LDL (p < 0.05) in the whole hemodialysis group. CONCLUSIONS: Our data indicate for the first time a relationship between oxidative stress and VEGF levels in hemodialyzed patients, particularly in those with cardiovascular disease. This association may represent one of the mechanisms involved in the progression of atherosclerosis in this population. [Abstract/Link to Full Text]

Harirchian MH, Sahraian MA, Shirani A
Serum prolactin level in patients with multiple sclerosis: a case control study.
Med Sci Monit. 2006 Apr;12(4):CR177-80.
BACKGROUND: Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system and is considered to be multifactorial with an autoimmune component. Prolactin (PRL) is a neuroendocrine peptide with potent immunomodulatory properties. Hyperprolactinemia enhances several autoimmune disorders and may play a role in the pathogenesis of MS. The aim of this study was to compare serum PRL levels in MS patients with those of healthy controls. MATERIAL/METHODS: There were 43 patients with definite MS and 43 sex- and age-matched healthy controls. Conditions leading to a rise in PRL, such as pregnancy, lactation, and specific underlying diseases and drugs, were excluded. PRL levels were measured in fasting blood samples. For the MS group, disease duration and subtype, clinical manifestations, and expanded disability status scores (EDSS) were also recorded. RESULTS: There were no significant differences in serum PRL levels between the case and control groups in both women and men (376.78+/-231.11 mIU/l in female patients with MS vs. 364.19+/-202.55 mIU/l in female controls, 266.00+/-200.83 mIU/l in male patients with MS vs. 197.25+/-65.25 mIU/l in male controls). We also found no significant relationship between PRL and disease activity, disease duration, and EDSS. CONCLUSIONS: Our findings do not support the hypothesis that MS patients are in a hyperprolactinemic state. However, further studies in more homogenous MS subgroups are needed. [Abstract/Link to Full Text]

Pola?ska J, Jarosz-Chobot P
Maternal age at delivery and order of birth are risk factors for type 1 diabetes mellitus in Upper Silesia, Poland.
Med Sci Monit. 2006 Apr;12(4):CR173-6.
BACKGROUND: Parental age and birth order as risk factors for childhood type 1 diabetes mellitus were investigated using data from the Regional Diabetic Center for Upper Silesia, Poland, in a population-based study of 398 children with type 1 DM aged 0-14 years born between 1979-1996. MATERIAL/METHODS: Noting differences in the proportions of children of different birth order between cases and controls, the data were stratified by birth order. For each stratum, odds ratios and their 95% confidence intervals were calculated to assess risks related to the mother's age. The homogeneity of the odds ratios related to the mother's age between strata was evaluated by the Mantel-Haenszel method. Risks related to mother's age and birth order were also estimated jointly by multivariable logistic regression. RESULTS: Decreased risk in later children compared with firstborns was noted. Increased maternal age was found to be a risk factor for type 1 DM. An increase in the mother's age by one year increases the risk of the child being affected by type 1 DM 1.07 times, and children born as the nth in the family are 1.59 times less exposed to the same risk than those born as the (n-1)th. CONCLUSIONS: Children of different birth order have different risks of being affected by type 1 DM. Increased maternal age at the time of delivery is a risk factor for type 1 DM in Upper Silesia, Poland. To avoid bias in estimating risks, the mother's age and child's sequence number should be analyzed jointly. [Abstract/Link to Full Text]

BaHammam A
Sleep quality of patients with acute myocardial infarction outside the CCU environment: a preliminary study.
Med Sci Monit. 2006 Apr;12(4):CR168-72.
BACKGROUND: Environmental factors have been implicated as major causes of sleep disruption in patients in critical care units, including coronary care units (CCU). We hypothesized that myocardial infarction may disturb sleep architecture regardless of the surrounding environmental factors. MATERIAL/METHODS: Twenty consecutive patients with a first-ever acute myocardial infarction (AMI) who were not on sedation or ionotropes underwent a full polysomnography (PSG) in our sleep disorders center, away from the CCU environment, within three days of AMI, with a follow-up PSG performed six months later. During patient stay in the CCU, each resided in a single room in which normal light-dark exposure was maintained. RESULTS: The 20 patients with AMI consisted of 18 males and 2 females, of a mean +/-SE age of 51.1+/-1.7 years. Compared with the follow-up PSG, the initial PSG revealed significant increases in arousal index, spontaneous arousal index, wake time, and REM latency and significant reductions in sleep efficiency and REM sleep. CONCLUSIONS: Patients with AMI have altered sleep architecture, despite controlling for common sleep-disrupting environmental factors. Future research should explore other possible etiologies of sleep disruption in patients with AMI, including the underlying infarction itself and its associated physiological and inflammatory changes. [Abstract/Link to Full Text]