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

Kobayashi T, Ogo Y, Itai RN, Nakanishi H, Takahashi M, Mori S, Nishizawa NK
The transcription factor IDEF1 regulates the response to and tolerance of iron deficiency in plants.
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19150-5.
Iron is essential for most living organisms and is often the major limiting nutrient for normal growth. Plants induce iron utilization systems under conditions of low iron availability, but the molecular mechanisms of gene regulation under iron deficiency remain largely unknown. We identified the rice transcription factor IDEF1, which specifically binds the iron deficiency-responsive cis-acting element IDE1. IDEF1 belongs to an uncharacterized branch of the plant-specific transcription factor family ABI3/VP1 and exhibits the sequence recognition property of efficiently binding to the CATGC sequence within IDE1. IDEF1 transcripts are constitutively present in rice roots and leaves. Transgenic tobacco plants expressing IDEF1 under the control of the constitutive cauliflower mosaic virus 35S promoter transactivate IDE1-mediated expression only in iron-deficient roots. Transgenic rice plants expressing an introduced IDEF1 exhibit substantial tolerance to iron deficiency in both hydroponic culture and calcareous soil. IDEF1 overexpression leads to the enhanced expression of the iron deficiency-induced transcription factor gene OsIRO2, suggesting the presence of a sequential gene regulatory network. These findings reveal cis element/trans factor interactions that are functionally linked to the iron deficiency response. Manipulation of IDEF1 also provides another approach for producing crops tolerant of iron deficiency to enhance food and biomass production in calcareous soils. [Abstract/Link to Full Text]

Funderburg N, Lederman MM, Feng Z, Drage MG, Jadlowsky J, Harding CV, Weinberg A, Sieg SF
Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18631-5.
There is increasing evidence that innate and adaptive immune responses are intimately linked. This linkage is in part mediated through the recognition of conserved microbial products by Toll-like receptors (TLRs). Detection of microbial products by TLRs can result in induction of inflammatory cytokines and activation of professional antigen-presenting cells, thereby enhancing adaptive immune responses. Here, we show that human beta-defensin-3 (hBD-3), an innate antimicrobial peptide, can induce expression of the costimulatory molecules CD80, CD86, and CD40, on monocytes and myeloid dendritic cells in a TLR-dependent manner. Activation of monocytes by hBD-3 is mediated by interaction with TLRs 1 and 2, resulting in signaling that requires myeloid differentiating factor 88 and results in IL-1 receptor-associated kinase-1 phosphorylation. In studies with HEK cells engineered to express various TLRs, we show that activation of NF-kappaB by hBD-3 depends on the expression of both TLR1 and TLR2. Thus, human TLR signaling is not restricted to recognition of microbial patterns but also can be initiated by host-derived peptides such as hBD-3. [Abstract/Link to Full Text]

Rogers LD, Foster LJ
The dynamic phagosomal proteome and the contribution of the endoplasmic reticulum.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18520-5.
Macrophages use phagocytosis to control the spread of pathogens in the body, to clear apoptotic cells, and to aid in tissue remodeling. The phagosomal membrane is traditionally thought to originate from the plasmalemma and then go through a series of maturation steps involving sequential fusion with endosomal compartments, leading to the formation of a phagolysosome. A recent model suggests that the endoplasmic reticulum (ER) is involved in the maturation as well. Here we use stable isotope labeling and multiple quantitative proteomic approaches to follow the dynamic composition of the maturing phagosome in RAW 264.7 macrophage cells to a greater depth and higher temporal resolution than was previously possible. Analysis of the results suggests that the traditional model of a linear sequence of fusion events with different compartments is more complex or variable than previously thought. By concomitantly measuring the degree to which each component is enriched on phagosomes, our data argue that the amount of ER involved in phagocytosis is much less than predicted by the model of ER-mediated phagocytosis. [Abstract/Link to Full Text]

Wolfrum S, Teupser D, Tan M, Chen KY, Breslow JL
The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappaB target genes.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18601-6.
Up-regulation of inflammatory responses is considered a driving force of atherosclerotic lesion development. One key regulator of inflammation is the A20 (also called TNF-alpha-induced protein 3 or Tnfaip3) gene, which is responsible for NF-kappaB termination and maps to an atherosclerosis susceptibility locus revealed by quantitative trait locus-mapping studies at mouse proximal chromosome 10. In the current study, we examined the role of A20 in atherosclerotic lesion development. At the aortic root lesion size was found to be increased in C57BL/6 (BG) apolipoprotein E-deficient (ApoE(-/-)) mice haploinsufficient for A20, compared with B6 ApoE(-/-) controls that expressed A20 normally (60% in males and 23% in females; P < 0.001 and P < 0.05, respectively). In contrast, lesion size was found to be decreased in F(1) (B6 x FVB/N) mice overexpressing A20 by virtue of containing an A20 BAC transgene compared with nontransgenic controls (30% in males, P < 0.001, and 17% in females, P = 0.02). The increase in lesions in the A20 haploinsufficient mice correlated with increased expression of proatherosclerotic NF-kappaB target genes, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and macrophage-colony-stimulating factor, and elevated plasma levels of NF-kappaB-driven cytokines. These findings suggest that A20 diminishes atherosclerosis by decreasing NF-kappaB activity, thereby modulating the proinflammatory state associated with lesion development. [Abstract/Link to Full Text]

Wang T, Zeng J, Lowe CB, Sellers RG, Salama SR, Yang M, Burgess SM, Brachmann RK, Haussler D
Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18613-8.
The evolutionary forces that establish and hone target gene networks of transcription factors are largely unknown. Transposition of retroelements may play a role, but its global importance, beyond a few well described examples for isolated genes, is not clear. We report that LTR class I endogenous retrovirus (ERV) retroelements impact considerably the transcriptional network of human tumor suppressor protein p53. A total of 1,509 of approximately 319,000 human ERV LTR regions have a near-perfect p53 DNA binding site. The LTR10 and MER61 families are particularly enriched for copies with a p53 site. These ERV families are primate-specific and transposed actively near the time when the New World and Old World monkey lineages split. Other mammalian species lack these p53 response elements. Analysis of published genomewide ChIP data for p53 indicates that more than one-third of identified p53 binding sites are accounted for by ERV copies with a p53 site. ChIP and expression studies for individual genes indicate that human ERV p53 sites are likely part of the p53 transcriptional program and direct regulation of p53 target genes. These results demonstrate how retroelements can significantly shape the regulatory network of a transcription factor in a species-specific manner. [Abstract/Link to Full Text]

Atanasiu D, Whitbeck JC, Cairns TM, Reilly B, Cohen GH, Eisenberg RJ
Bimolecular complementation reveals that glycoproteins gB and gH/gL of herpes simplex virus interact with each other during cell fusion.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18718-23.
Herpes simplex virus entry into cells requires four glycoproteins, gB, gD, gH, and gL. Binding of gD to one of its receptors triggers steps requiring the core fusion proteins, gB and the gH/gL heterodimer. There is evidence that gH/gL initiates hemifusion of cells, but whether this complex interacts physically with gB to cause complete fusion is unknown. We used bimolecular complementation (BiMC) of enhanced yellow fluorescent protein (EYFP) to detect glycoprotein interactions during cell-cell fusion. The N- or C-terminal half of EYFP was fused to the C terminus of gD, gB, and gH to form six chimeric proteins (Dn, Dc, Bn, Bc, Hn, and Hc). BiMC was detected by confocal microscopy. Receptor-bearing (C10) cells cotransfected with Dn and Bc or Dn, Hc, and untagged gL exhibited EYFP fluorescence, indicative of interactions between gD and gB and between gD and gH/gL. EYFP complementation did not occur in cells transfected with gL, Bc, and Hn. However, when gD was coexpressed with these other three proteins, cell-cell fusion occurred and the syncytia exhibited bright EYFP fluorescence. To separate glycoprotein expression from fusion, we transfected C10 cells with gL, Bc, and Hn for 20 h and then added soluble gD to trigger fusion. We detected fluorescent syncytia within 10 min, and both their number and size increased with exposure time to gD. Thus, when gD binds its receptor, the core fusion machinery is triggered to form a multiprotein complex as a step in fusion and possibly virus entry. [Abstract/Link to Full Text]

Zhang L, Wang L, Kao YT, Qiu W, Yang Y, Okobiah O, Zhong D
Mapping hydration dynamics around a protein surface.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18461-6.
Protein surface hydration is fundamental to its structure and activity. We report here the direct mapping of global hydration dynamics around a protein in its native and molten globular states, using a tryptophan scan by site-specific mutations. With 16 tryptophan mutants and in 29 different positions and states, we observed two robust, distinct water dynamics in the hydration layer on a few ( approximately 1-8 ps) and tens to hundreds of picoseconds ( approximately 20-200 ps), representing the initial local relaxation and subsequent collective network restructuring, respectively. Both time scales are strongly correlated with protein's structural and chemical properties. These results reveal the intimate relationship between hydration dynamics and protein fluctuations and such biologically relevant water-protein interactions fluctuate on picosecond time scales. [Abstract/Link to Full Text]

Sohn EJ, Rojas-Pierce M, Pan S, Carter C, Serrano-Mislata A, Madueño F, Rojo E, Surpin M, Raikhel NV
The shoot meristem identity gene TFL1 is involved in flower development and trafficking to the protein storage vacuole.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18801-6.
Plants are unique in their ability to store proteins in specialized protein storage vacuoles (PSVs) within seeds and vegetative tissues. Although plants use PSV proteins during germination, before photosynthesis is fully functional, the roles of PSVs in adult vegetative tissues are not understood. Trafficking pathways to PSVs and lytic vacuoles appear to be distinct. Lytic vacuoles are analogous evolutionarily to yeast and mammalian lysosomes. However, it is unclear whether trafficking to PSVs has any analogy to pathways in yeast or mammals, nor is PSV ultrastructure known in Arabidopsis vegetative tissue. Therefore, alternative approaches are required to identify components of this pathway. Here, we show that an Arabidopsis thaliana mutant that disrupts PSV trafficking identified TERMINAL FLOWER 1 (TFL1), a shoot meristem identity gene. The tfl1-19/mtv5 (for "modified traffic to the vacuole") mutant is specifically defective in trafficking of proteins to the PSV. TFL1 localizes to endomembrane compartments and colocalizes with the putative delta-subunit of the AP-3 adapter complex. Our results suggest a developmental role for the PSV in vegetative tissues. [Abstract/Link to Full Text]

Huang H, Chen Y, Ye J
Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18666-70.
Hepatitis C virus (HCV) is a single-stranded positive-sense RNA virus of the Flaviviridae family. HCV-infected hepatocytes are known to produce reactive oxygen species (ROS), which initiate lipid peroxidation, a reaction that converts polyunsaturated fatty acids, such as arachidonate, into reactive carbonyls that inactivate proteins. To study the effect of lipid peroxidation on HCV replication, we administered arachidonate to Huh7 cells that harbor an HCV replicon (Huh7-K2040 cells). After incubation in medium supplemented with arachidonate but deprived of lipid-soluble antioxidants, the cellular amount of malondialdehyde (MDA), a product of lipid peroxidation, increased markedly in Huh7-K2040 cells but not in parental Huh7 cells that do not harbor an HCV replicon. This increase was followed by a sharp reduction (>95%) in HCV RNA. Both of these events were prevented when cells were treated with vitamin E, a lipid-soluble antioxidant. After prolonged incubation of Huh7-K2040 cells with arachidonate in the absence of lipid-soluble antioxidants, the amount of MDA decreased after the reduction in the amount of HCV RNA. Thus, in the presence of arachidonate and in the absence of lipid-soluble antioxidants, HCV replication induces lipid peroxidation that reduces the amount of HCV RNA. Our results provide a mechanism for the previous observation that polyunsaturated fatty acids inhibit HCV replication [Kapadia SB, Chisari FV (2005) Proc Natl Acad Sci USA 102:2561-2566], and they suggest that these agents may be effective in inhibiting HCV replication in vivo. [Abstract/Link to Full Text]

Sorg C, Riedl V, Mühlau M, Calhoun VD, Eichele T, Läer L, Drzezga A, Förstl H, Kurz A, Zimmer C, Wohlschläger AM
Selective changes of resting-state networks in individuals at risk for Alzheimer's disease.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18760-5.
Alzheimer's disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n = 16) and patients with amnestic mild cognitive impairment (aMCI) (n = 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of resting-state fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs. [Abstract/Link to Full Text]

Omberg L, Golub GH, Alter O
A tensor higher-order singular value decomposition for integrative analysis of DNA microarray data from different studies.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18371-6.
We describe the use of a higher-order singular value decomposition (HOSVD) in transforming a data tensor of genes x "x-settings," that is, different settings of the experimental variable x x "y-settings," which tabulates DNA microarray data from different studies, to a "core tensor" of "eigenarrays" x "x-eigengenes" x "y-eigengenes." Reformulating this multilinear HOSVD such that it decomposes the data tensor into a linear superposition of all outer products of an eigenarray, an x- and a y-eigengene, that is, rank-1 "subtensors," we define the significance of each subtensor in terms of the fraction of the overall information in the data tensor that it captures. We illustrate this HOSVD with an integration of genome-scale mRNA expression data from three yeast cell cycle time courses, two of which are under exposure to either hydrogen peroxide or menadione. We find that significant subtensors represent independent biological programs or experimental phenomena. The picture that emerges suggests that the conserved genes YKU70, MRE11, AIF1, and ZWF1, and the processes of retrotransposition, apoptosis, and the oxidative pentose phosphate pathway that these genes are involved in, may play significant, yet previously unrecognized, roles in the differential effects of hydrogen peroxide and menadione on cell cycle progression. A genome-scale correlation between DNA replication initiation and RNA transcription, which is equivalent to a recently discovered correlation and might be due to a previously unknown mechanism of regulation, is independently uncovered. [Abstract/Link to Full Text]

Palacios-Callender M, Hollis V, Mitchison M, Frakich N, Unitt D, Moncada S
Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: a possible explanation for hypoxic vasodilation.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18508-13.
One of the many routes proposed for the cellular inactivation of endogenous nitric oxide (NO) is by the cytochrome c oxidase of the mitochondrial respiratory chain. We have studied this possibility in human embryonic kidney cells engineered to generate controlled amounts of NO. We have used visible light spectroscopy to monitor continuously the redox state of cytochrome c oxidase in an oxygen-tight chamber, at the same time as which we measure cell respiration and the concentrations of oxygen and NO. Pharmacological manipulation of cytochrome c oxidase indicates that this enzyme, when it is in turnover and in its oxidized state, inactivates physiological amounts of NO, thus regulating its intra- and extracellular concentrations. This inactivation is prevented by blocking the enzyme with inhibitors, including NO. Furthermore, when cells generating low concentrations of NO respire toward hypoxia, the redox state of cytochrome c oxidase changes from oxidized to reduced, leading to a decrease in NO inactivation. The resultant increase in NO concentration could explain hypoxic vasodilation. [Abstract/Link to Full Text]

Jones LM, Fontanini A, Sadacca BF, Miller P, Katz DB
Natural stimuli evoke dynamic sequences of states in sensory cortical ensembles.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18772-7.
Although temporal coding is a frequent topic of neurophysiology research, trial-to-trial variability in temporal codes is typically dismissed as noise and thought to play no role in sensory function. Here, we show that much of this supposed "noise" faithfully reflects stimulus-related processes carried out in coherent neural networks. Cortical neurons responded to sensory stimuli by progressing through sequences of states, identifiable only in examinations of simultaneously recorded ensembles. The specific times at which ensembles transitioned from state to state varied from trial to trial, but the state sequences were reliable and stimulus-specific. Thus, the characterization of ensemble responses in terms of state sequences captured facets of sensory processing that are missing from, and obscured in, other analyses. This work provides evidence that sensory neurons act as parts of a systems-level dynamic process, the nature of which can best be appreciated through observation of distributed ensembles. [Abstract/Link to Full Text]

Resnik ER, Herron JM, Lyu SC, Cornfield DN
Developmental regulation of hypoxia-inducible factor 1 and prolyl-hydroxylases in pulmonary vascular smooth muscle cells.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18789-94.
The transcriptional machinery involved in the transition of an infant from intrauterine to air-breathing life is developmentally regulated, as the fetus and adult manifest differential genetic expression. The low oxygen (O(2)) environment of the mammalian fetus and the increase in O(2) tension that occurs at birth may account for the developmentally regulated alterations in gene expression. We tested the hypothesis that hypoxia-inducible factor 1 (HIF-1) expression, an O(2)-sensitive transcription factor, is developmentally regulated. We found that in fetal pulmonary artery (PA) smooth muscle cells (SMC), fetal HIF-1 protein levels were O(2)-insensitive, whereas in adult PA SMC, hypoxia increased HIF-1 protein expression. Surprisingly, hypoxia increased HIF-1 mRNA expression in fetal, but not in adult, PA SMC. HIF-1 degradation and transcriptional activity is contingent on prolyl- and asparagyl-hydroxylases. To determine whether developmental differences in O(2) sensitivity or expression of these enzymes accounts for the divergence of HIF-1 sensitivity between fetus and adult, we studied the expression of the three most well characterized prolyl-hydroxylases, PHD1, PHD2, and PHD3, and the expression of regulators of HIF-1 transcriptional activity, asparagyl-hydroxylase, factor inhibiting HIF, and the oncogenic factor, CITED2 (CREB-binding protein/p300 interacting transactivator with ED-rich tail). We found that, as in the case of HIF-1, these genes are differentially regulated in the fetus, enabling the mammalian fetus to thrive in the low O(2) tension intrauterine environment even while rendering a newborn infant uniquely well adapted to respond to the acute increase in O(2) tension that occurs at birth. [Abstract/Link to Full Text]

Cloern JE, Jassby AD, Thompson JK, Hieb KA
A cold phase of the East Pacific triggers new phytoplankton blooms in San Francisco Bay.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18561-5.
Ecological observations sustained over decades often reveal abrupt changes in biological communities that signal altered ecosystem states. We report a large shift in the biological communities of San Francisco Bay, first detected as increasing phytoplankton biomass and occurrences of new seasonal blooms that began in 1999. This phytoplankton increase is paradoxical because it occurred in an era of decreasing wastewater nutrient inputs and reduced nitrogen and phosphorus concentrations, contrary to the guiding paradigm that algal biomass in estuaries increases in proportion to nutrient inputs from their watersheds. Coincidental changes included sharp declines in the abundance of bivalve mollusks, the key phytoplankton consumers in this estuary, and record high abundances of several bivalve predators: Bay shrimp, English sole, and Dungeness crab. The phytoplankton increase is consistent with a trophic cascade resulting from heightened predation on bivalves and suppression of their filtration control on phytoplankton growth. These community changes in San Francisco Bay across three trophic levels followed a state change in the California Current System characterized by increased upwelling intensity, amplified primary production, and strengthened southerly flows. These diagnostic features of the East Pacific "cold phase" lead to strong recruitment and immigration of juvenile flatfish and crustaceans into estuaries where they feed and develop. This study, built from three decades of observation, reveals a previously unrecognized mechanism of ocean-estuary connectivity. Interdecadal oceanic regime changes can propagate into estuaries, altering their community structure and efficiency of transforming land-derived nutrients into algal biomass. [Abstract/Link to Full Text]

Cheng S, Logan BE
Sustainable and efficient biohydrogen production via electrohydrogenesis.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18871-3.
Hydrogen gas has tremendous potential as an environmentally acceptable energy carrier for vehicles, but most hydrogen is generated from nonrenewable fossil fuels such as natural gas. Here, we show that efficient and sustainable hydrogen production is possible from any type of biodegradable organic matter by electrohydrogenesis. In this process, protons and electrons released by exoelectrogenic bacteria in specially designed reactors (based on modifying microbial fuel cells) are catalyzed to form hydrogen gas through the addition of a small voltage to the circuit. By improving the materials and reactor architecture, hydrogen gas was produced at yields of 2.01-3.95 mol/mol (50-99% of the theoretical maximum) at applied voltages of 0.2 to 0.8 V using acetic acid, a typical dead-end product of glucose or cellulose fermentation. At an applied voltage of 0.6 V, the overall energy efficiency of the process was 288% based solely on electricity applied, and 82% when the heat of combustion of acetic acid was included in the energy balance, at a gas production rate of 1.1 m(3) of H(2) per cubic meter of reactor per day. Direct high-yield hydrogen gas production was further demonstrated by using glucose, several volatile acids (acetic, butyric, lactic, propionic, and valeric), and cellulose at maximum stoichiometric yields of 54-91% and overall energy efficiencies of 64-82%. This electrohydrogenic process thus provides a highly efficient route for producing hydrogen gas from renewable and carbon-neutral biomass resources. [Abstract/Link to Full Text]

Xu J, Saunders CW, Hu P, Grant RA, Boekhout T, Kuramae EE, Kronstad JW, Deangelis YM, Reeder NL, Johnstone KR, Leland M, Fieno AM, Begley WM, Sun Y, Lacey MP, Chaudhary T, Keough T, Chu L, Sears R, Yuan B, Dawson TL
Dandruff-associated Malassezia genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18730-5.
Fungi in the genus Malassezia are ubiquitous skin residents of humans and other warm-blooded animals. Malassezia are involved in disorders including dandruff and seborrheic dermatitis, which together affect >50% of humans. Despite the importance of Malassezia in common skin diseases, remarkably little is known at the molecular level. We describe the genome, secretory proteome, and expression of selected genes of Malassezia globosa. Further, we report a comparative survey of the genome and secretory proteome of Malassezia restricta, a close relative implicated in similar skin disorders. Adaptation to the skin environment and associated pathogenicity may be due to unique metabolic limitations and capabilities. For example, the lipid dependence of M. globosa can be explained by the apparent absence of a fatty acid synthase gene. The inability to synthesize fatty acids may be complemented by the presence of multiple secreted lipases to aid in harvesting host lipids. In addition, an abundance of genes encoding secreted hydrolases (e.g., lipases, phospholipases, aspartyl proteases, and acid sphingomyelinases) was found in the M. globosa genome. In contrast, the phylogenetically closely related plant pathogen Ustilago maydis encodes a different arsenal of extracellular hydrolases with more copies of glycosyl hydrolase genes. M. globosa shares a similar arsenal of extracellular hydrolases with the phylogenetically distant human pathogen, Candida albicans, which occupies a similar niche, indicating the importance of host-specific adaptation. The M. globosa genome sequence also revealed the presence of mating-type genes, providing an indication that Malassezia may be capable of sex. [Abstract/Link to Full Text]

Yatime L, Mechulam Y, Blanquet S, Schmitt E
Structure of an archaeal heterotrimeric initiation factor 2 reveals a nucleotide state between the GTP and the GDP states.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18445-50.
Initiation of translation in eukaryotes and in archaea involves eukaryotic/archaeal initiation factor (e/aIF)1 and the heterotrimeric initiation factor e/aIF2. In its GTP-bound form, e/aIF2 provides the initiation complex with Met-tRNA(i)(Met). After recognition of the start codon by initiator tRNA, e/aIF1 leaves the complex. Finally, e/aIF2, now in a GDP-bound form, loses affinity for Met-tRNA(i)(Met) and dissociates from the ribosome. Here, we report a 3D structure of an aIF2 heterotrimer from the archeon Sulfolobus solfataricus obtained in the presence of GDP. Our report highlights how the two-switch regions involved in formation of the tRNA-binding site on subunit gamma exchange conformational information with alpha and beta. The zinc-binding domain of beta lies close to the guanine nucleotide and directly contacts the switch 1 region. As a result, switch 1 adopts a not yet described conformation. Moreover, unexpectedly for a GDP-bound state, switch 2 has the "ON" conformation. The stability of these conformations is accounted for by a ligand, most probably a phosphate ion, bound near the nucleotide binding site. The structure suggests that this GDP-inorganic phosphate (Pi) bound state of aIF2 may be proficient for tRNA binding. Recently, it has been proposed that dissociation of eIF2 from the initiation complex is closely coupled to that of Pi from eIF2gamma upon start codon recognition. The nucleotide state of aIF2 shown here is indicative of a similar mechanism in archaea. Finally, we consider the possibility that release of Pi takes place after e/aIF2gamma has been informed of e/aIF1 dissociation by e/aIF2beta. [Abstract/Link to Full Text]

Rudge JS, Holash J, Hylton D, Russell M, Jiang S, Leidich R, Papadopoulos N, Pyles EA, Torri A, Wiegand SJ, Thurston G, Stahl N, Yancopoulos GD
Inaugural Article: VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18363-70.
VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in the efficacious range. [Abstract/Link to Full Text]

Baum P, Zewail AH
Attosecond electron pulses for 4D diffraction and microscopy.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18409-14.
In this contribution, we consider the advancement of ultrafast electron diffraction and microscopy to cover the attosecond time domain. The concept is centered on the compression of femtosecond electron packets to trains of 15-attosecond pulses by the use of the ponderomotive force in synthesized gratings of optical fields. Such attosecond electron pulses are significantly shorter than those achievable with extreme UV light sources near 25 nm ( approximately 50 eV) and have the potential for applications in the visualization of ultrafast electron dynamics, especially of atomic structures, clusters of atoms, and some materials. [Abstract/Link to Full Text]

Senoo-Matsuda N, Johnston LA
Soluble factors mediate competitive and cooperative interactions between cells expressing different levels of Drosophila Myc.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18543-8.
When neighboring cells in the developing Drosophila wing express different levels of the transcription factor, dMyc, competitive interactions can occur. Cells with more dMyc proliferate and ultimately overpopulate the wing, whereas cells with less dMyc die, thereby preventing wing overgrowth. How cells sense dMyc activity differences between themselves and the nature of the process leading to changes in growth and survival during competition remain unknown. We have developed a cell culture-based assay by using Drosophila S2 cells to investigate the mechanism of cell competition. We find that in vitro coculture of S2 cells that express different levels of dMyc leads to cellular interactions that recapitulate many aspects of cell competition in the developing wing. Our data indicate that both cell populations in the cocultures participate in and are required for the competitive process by releasing soluble factors into the medium. We demonstrate that the response of naive cells to medium conditioned with competitive cocultures depends on their potential to express dMyc: Cells that can express high levels of dMyc gain a survival advantage and proliferate faster, whereas cells with lower dMyc levels are instructed to die. We suggest that the ability of cells to perceive and respond to local differences in Myc activity is a cooperative mechanism that could contribute to growth regulation and developmental plasticity in organs and tissues during normal development and regeneration. [Abstract/Link to Full Text]

De Silva FS, Lewis W, Berglund P, Koonin EV, Moss B
Poxvirus DNA primase.
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18724-9.
Poxviruses are large enveloped viruses that replicate in the cytoplasm of vertebrate or invertebrate cells. At least six virus-encoded proteins are required for synthesis and processing of the double-stranded DNA genome of vaccinia virus, the prototype member of the family. One of these proteins, D5, is an NTPase that contains an N-terminal archaeoeukaryotic primase domain and a C-terminal superfamily III helicase domain. Here we report that individual conserved aspartic acid residues in the predicted primase active site were required for in vivo complementation of infectious virus formation as well as genome and plasmid replication. Furthermore, purified recombinant D5 protein synthesized oligoribonucleotides in vitro. Incorporation of label from [alpha-(32)P]CTP or [alpha-(32)P]UTP into a RNase-sensitive and DNase-resistant product was demonstrated by using single-stranded circular bacteriophage DNA templates and depended on ATP or GTP and a divalent cation. Mutagenesis studies showed that the primase and NTPase activities of the recombinant D5 protein could be independently inactivated. Highly conserved orthologs of D5 are present in all poxviruses that have been sequenced, and more diverged orthologs are found in members of all other families of nucleocytoplasmic large DNA viruses. These viral primases may have roles in initiation of DNA replication or lagging-strand synthesis and represent potential therapeutic targets. [Abstract/Link to Full Text]

Kinney AL
National scientific facilities and their science impact on nonbiomedical research.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):17943-7.
The "h index" proposed by Hirsch [Hirsch JE (2005) Proc Natl Acad Sci USA 102:16569-16573] is a good indicator of the impact of a scientist's research and has the advantage of being objective. When evaluating departments, institutions, or laboratories, the importance of the h index can be further enhanced when it is properly calibrated for the size of the group. Particularly acute is the issue of federally funded facilities whose number of actively publishing scientists frequently dwarfs that of academic departments. Recently, Molinari and Molinari [Molinari JF, Molinari A (2008) Scientometrics, in press] developed a methodology that shows that the h index has a universal growth rate for large numbers of papers, allowing for meaningful comparisons between institutions. An additional challenge when comparing large institutions is that fields have distinct internal cultures, with different typical rates of publication and citation; biology is more highly cited than physics, for example. For this reason, the present study has focused on the physical sciences, engineering, and technology and has excluded biomedical research. Comparisons between individual disciplines are reported here to provide a framework. Generally, it was found that the universal growth rate of Molinari and Molinari holds well across the categories considered, testifying to the robustness of both their growth law and our results. The goal here is to set the highest standard of comparison for federal investment in science. Comparisons are made of the nation's preeminent private and public institutions. We find that many among the national science facilities compare favorably in research impact with the nation's leading universities. [Abstract/Link to Full Text]

Li Y, Beisson F, Koo AJ, Molina I, Pollard M, Ohlrogge J
Identification of acyltransferases required for cutin biosynthesis and production of cutin with suberin-like monomers.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18339-44.
Cutin and suberin are the two major lipid-based polymers of plants. Cutin is the structural polymer of the epidermal cuticle, the waterproof layer covering primary aerial organs and which is often the structure first encountered by phytopathogens. Suberin contributes to the control of diffusion of water and solutes across internal root tissues and in periderms. The enzymes responsible for assembly of the cutin polymer are largely unknown. We have identified two Arabidopsis acyltransferases essential for cutin biosynthesis, glycerol-3-phosphate acyltransferase (GPAT) 4 and GPAT8. Double knockouts gpat4/gpat8 were strongly reduced in cutin and were less resistant to desiccation and to infection by the fungus Alternaria brassicicola. They also showed striking defects in stomata structure including a lack of cuticular ledges between guard cells, highlighting the importance of cutin in stomatal biology. Overexpression of GPAT4 or GPAT8 in Arabidopsis increased the content of C16 and C18 cutin monomers in leaves and stems by 80%. In order to modify cutin composition, the acyltransferase GPAT5 and the cytochrome P450-dependent fatty acyl oxidase CYP86A1, two enzymes associated with suberin biosynthesis, were overexpressed. When both enzymes were overexpressed together the epidermal polyesters accumulated new C20 and C22 omega-hydroxyacids and alpha,omega-diacids typical of suberin, and the fine structure and water-barrier function of the cuticle were altered. These results identify GPATs as partners of fatty acyl oxidases in lipid polyester synthesis and indicate that their cooverexpression provides a strategy to probe the role of cutin composition and quantity in the function of plant cuticles. [Abstract/Link to Full Text]

den Elzen MG, van Vuuren DP
Peaking profiles for achieving long-term temperature targets with more likelihood at lower costs.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):17931-6.
How can dangerous interference with the climate system be avoided? Science can help decision-makers answer this political question. Earlier publications have focused on the probability of keeping global mean temperature change below certain thresholds by stabilizing greenhouse gas concentrations at particular levels. We compare the results of such "stabilization profiles" with a set of "peaking profiles" that reduce emissions further after stabilization and thus result in a concentration peak. Given the inertia in the climate system, stabilization profiles lead to ongoing warming beyond 2100 until the temperature reaches equilibrium. This warming partly can be prevented for peaking profiles. In this way, these profiles can increase the likelihood of achieving temperature thresholds by 10-20% compared with the likelihood for the associated stabilization profiles. Because the additional mitigation efforts and thus costs for peaking profiles lie mainly beyond 2100, peaking profiles achieving temperature thresholds with the same likelihood as the original stabilization profile, but at considerably lower cost (up to 40%), can be identified. The magnitude of the cost reductions depends on the assumptions on discounting. Peaking profiles and overshoot profiles with a limited overshoot may, in particular, play an important role in making more ambitious climate targets feasible. [Abstract/Link to Full Text]

Vespa L, Warrington RT, Mokros P, Siroky J, Shippen DE
ATM regulates the length of individual telomere tracts in Arabidopsis.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18145-50.
Telomeres have the paradoxical ability of protecting linear chromosome ends from DNA damage sensors by using these same proteins as essential components of their maintenance machinery. We have previously shown that the absence of ataxia telangiectasia mutated (ATM), a central regulator of the DNA damage response, accelerates the onset of genome instability in telomerase-deficient Arabidopsis, without increasing the rate of bulk telomere shortening. Here, we examine individual telomere tracts through successive plant generations using both fluorescence situ in hybridization (FISH) and primer extension telomere repeat amplification (PETRA). Unexpectedly, we found that the onset of profound developmental defects and abundant end-to-end chromosome fusions in fifth generation (G(5)) atm tert mutants required the presence of only one critically shortened telomere. Parent progeny analysis revealed that the short telomere arose as a consequence of an unusually large telomere rapid deletion (TRD) event. The most dramatic TRD was detected in atm tert mutants that had undergone meiosis. Notably, in contrast to TRD, alternative lengthening of telomeres (ALT) was suppressed in the absence of ATM. Finally, we show that size differences between telomeres on homologous chromosome ends are greater for atm tert than tert plants. Altogether, these findings suggest a dual role for ATM in regulating telomere size by promoting elongation of short telomeres and by preventing the accumulation of cells that harbor large telomere deletions. [Abstract/Link to Full Text]

Silver SJ, Hagen JW, Okamura K, Perrimon N, Lai EC
Functional screening identifies miR-315 as a potent activator of Wingless signaling.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18151-6.
The existence of vast regulatory networks mediated by microRNAs (miRNAs) suggests broad potential for miRNA dysfunction to contribute to disease. However, relatively few miRNA-target interactions are likely to make detectable contributions to phenotype, and effective strategies to identify these few interactions are currently wanting. We hypothesized that signaling cascades represent critical points of susceptibility to miRNA dysfunction, and we developed a strategy to test this theory by using quantitative cell-based screens. Here we report a screen for miRNAs that affect the Wingless (Wg) pathway, a conserved pathway that regulates growth and tissue specification. This process identified ectopic miR-315 as a potent and specific activator of Wg signaling, an activity that we corroborated in transgenic animals. This miR-315 activity was mediated by direct inhibition of Axin and Notum, which encode essential, negatively acting components of the Wg pathway. Genetic interaction tests substantiated both of these genes as key functional targets of miR-315. The ability of ectopic miR-315 to activate Wg signaling was not a trivial consequence of predicted miRNA-target relationships because other miRNAs with conserved sites in the Axin 3' UTR neither activated Wg outputs nor inhibited an Axin sensor. In summary, activity-based screening can selectively identify miRNAs whose deregulation can lead to interpretable phenotypic consequences. [Abstract/Link to Full Text]

Pereira A, Ribeiro S, Wiest M, Moore LC, Pantoja J, Lin SC, Nicolelis MA
Processing of tactile information by the hippocampus.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18286-91.
The ability to detect unusual events occurring in the environment is essential for survival. Several studies have pointed to the hippocampus as a key brain structure in novelty detection, a claim substantiated by its wide access to sensory information through the entorhinal cortex and also distinct aspects of its intrinsic circuitry. Novelty detection is implemented by an associative match-mismatch algorithm involving the CA1 and CA3 hippocampal subfields that compares the stream of sensory inputs received by CA1 to the stored representation of spatiotemporal sequences in CA3. In some rodents, including the rat, the highly sensitive facial whiskers are responsible for providing accurate tactile information about nearby objects. Surprisingly, however, not much is known about how inputs from the whiskers reach CA1 and how they are processed therein. Using concurrent multielectrode neuronal recordings and chemical inactivation in behaving rats, we show that trigeminal inputs from the whiskers reach the CA1 region through thalamic and cortical relays associated with discriminative touch. Ensembles of hippocampal neurons also carry precise information about stimulus identity when recorded during performance in an aperture-discrimination task using the whiskers. We also found broad similarities between tactile responses of trigeminal stations and the hippocampus during different vigilance states (wake and sleep). Taken together, our results show that tactile information associated with fine whisker discrimination is readily available to the hippocampus for dynamic updating of spatial maps. [Abstract/Link to Full Text]

Haass FA, Jonikas M, Walter P, Weissman JS, Jan YN, Jan LY, Schuldiner M
Identification of yeast proteins necessary for cell-surface function of a potassium channel.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18079-84.
Inwardly rectifying potassium (Kir) channels form gates in the cell membrane that regulate the flow of K(+) ions into and out of the cell, thereby influencing the membrane potential and electrical signaling of many cell types, including neurons and cardiomyocytes. Kir-channel function depends on other cellular proteins that aid in the folding of channel subunits, assembly into tetrameric complexes, trafficking of quality-controlled channels to the plasma membrane, and regulation of channel activity at the cell surface. We used the yeast Saccharomyces cerevisiae as a model system to identify proteins necessary for the functional expression of a mammalian Kir channel at the cell surface. A screen of 376 yeast strains, each lacking one nonessential protein localized to the early secretory pathway, identified seven deletion strains in which functional expression of the Kir channel at the plasma membrane was impaired. Six deletions were of genes with known functions in trafficking and lipid biosynthesis (sur4Delta, csg2Delta, erv14Delta, emp24Delta, erv25Delta, and bst1Delta), and one deletion was of an uncharacterized gene (yil039wDelta). We provide genetic and functional evidence that Yil039wp, a conserved, phosphoesterase domain-containing protein, which we named "trafficking of Emp24p/Erv25p-dependent cargo disrupted 1" (Ted1p), acts together with Emp24p/Erv25p in cargo exit from the endoplasmic reticulum (ER). The seven yeast proteins identified in our screen likely impact Kir-channel functional expression at the level of vesicle budding from the ER and/or the local lipid environment at the plasma membrane. [Abstract/Link to Full Text]

Xu H, Delling M, Li L, Dong X, Clapham DE
Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18321-6.
Transient receptor potential (TRP) genes of the mucolipin subfamily (TRPML1-3 and MCOLN1-3) are presumed to encode ion channel proteins of intracellular endosomes and lysosomes. Mutations in human TRPML1 (mucolipin 1/MCOLN1) result in mucolipidosis type IV, a severe inherited neurodegenerative disease associated with defective lysosomal biogenesis and trafficking. A mutation in mouse TRPML3 (A419P; TRPML3(Va)) results in the varitint-waddler (Va) phenotype. Va mice are deaf, exhibit circling behavior due to vestibular defects, and have variegated/dilute coat color as a result of pigmentation defects. Prior electrophysiological studies of presumed TRPML plasma membrane channels are contradictory and inconsistent with known TRP channel properties. Here, we report that the Va mutation produces a gain-of-function that allows TRPML1 and TRPML3 to be measured and identified as inwardly rectifying, proton-impermeant, Ca(2+)-permeant cation channels. TRPML3 is highly expressed in normal melanocytes. Melanocyte markers are lost in the Va mouse, suggesting that their variegated and hypopigmented fur is caused by severe alteration of melanocyte function or cell death. TRPML3(Va) expression in melanocyte cell lines results in high resting Ca(2+) levels, rounded, poorly adherent cells, and loss of membrane integrity. We conclude that the Va phenotype is caused by mutation-induced TRPML3 gain-of-function, resulting in cell death. [Abstract/Link to Full Text]

Recent Articles in BMJ: British Medical Journal

Magee LA, von Dadelszen P
Pre-eclampsia and increased cardiovascular risk.
BMJ. 2007 Nov 10;335(7627):945-6. [Abstract/Link to Full Text]

Thachil JV
Pre-eclampsia is an inflammatory disorder.
BMJ. 2007 Nov 24;335(7629):1059. [Abstract/Link to Full Text]

Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Davey Smith G, Romundstad PR
Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study.
BMJ. 2007 Nov 10;335(7627):978.
OBJECTIVE: To examine the effect of cardiovascular risk factors before pregnancy on risk of pre-eclampsia. DESIGN: Population based prospective study. SETTING: Linkage between a Norwegian population based study (Nord-Trøndelag health study, HUNT-2) and Norway's medical birth registry. PARTICIPANTS: 3494 women who gave birth after participating in the Nord-Trøndelag health study at baseline; of whom 133 (3.8%) delivered after a pre-eclamptic pregnancy. MAIN OUTCOME MEASURE: Odds ratio of developing pre-eclampsia. RESULTS: After adjustment for smoking; previous pre-eclampsia; parity; maternal age, education, and socioeconomic position; and duration between baseline measurements and delivery, positive associations were found between prepregnancy serum levels of triglycerides, cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and blood pressure and risk of pre-eclampsia. The odds ratio of developing pre-eclampsia for women with baseline systolic blood pressures greater than 130 mm Hg (highest fifth) was 7.3 (95% confidence interval 3.1 to 17.2) compared with women with systolic blood pressures less than 111 mm Hg (lowest fifth). Similar results were found for nulliparous and parous women. Women who used oral contraceptives at baseline had half the risk of pre-eclampsia compared with never or former users (0.5, 0.3 to 0.9). CONCLUSION: Women with cardiovascular risk factors may be predisposed to pre-eclampsia. [Abstract/Link to Full Text]

Wildman MJ, Sanderson C, Groves J, Reeves BC, Ayres J, Harrison D, Young D, Rowan K
Implications of prognostic pessimism in patients with chronic obstructive pulmonary disease (COPD) or asthma admitted to intensive care in the UK within the COPD and asthma outcome study (CAOS): multicentre observational cohort study.
BMJ. 2007 Dec 1;335(7630):1132.
OBJECTIVE: To determine whether clinicians' prognoses in patients with severe acute exacerbations of obstructive lung disease admitted to intensive care match observed outcomes in terms of survival. DESIGN: Prospective cohort study. SETTING: 92 intensive care units and three respiratory high dependency units in the United Kingdom. PARTICIPANTS: 832 patients aged 45 years and older with breathlessness, respiratory failure, or change in mental status because of an exacerbation of COPD, asthma, or a combination of the two. MAIN OUTCOME MEASURES: Outcome predicted by clinicians. Observed survival at 180 days. RESULTS: 517 patients (62%) survived to 180 days. Clinicians' prognoses were pessimistic, with a mean predicted survival of 49% at 180 days. For the fifth of patients with the poorest prognosis according to the clinician, the predicted survival rate was 10% and the actual rate was 40%. Information from a database covering 74% of intensive care units in the UK suggested no material difference between units that participated and those that did not. Patients recruited were similar to those not recruited in the same units. CONCLUSIONS: Because decisions on whether to admit patients with COPD or asthma to intensive care for intubation depend on clinicians' prognoses, some patients who might otherwise survive are probably being denied admission because of unwarranted prognostic pessimism. [Abstract/Link to Full Text]

Rubin GJ, Page L, Morgan O, Pinder RJ, Riley P, Hatch S, Maguire H, Catchpole M, Simpson J, Wessely S
Public information needs after the poisoning of Alexander Litvinenko with polonium-210 in London: cross sectional telephone survey and qualitative analysis.
BMJ. 2007 Dec 1;335(7630):1143.
OBJECTIVES: To identify public perceptions of the risk to health after the poisoning of Alexander Litvinenko with polonium-210 (210Po) in London and to assess the impact of public health communications. DESIGN: Cross sectional telephone survey and qualitative interviews. SETTING: London, United Kingdom. PARTICIPANTS: 1000 people completed the cross sectional survey and 86 potentially exposed people completed the qualitative interviews. MAIN OUTCOME MEASURES: Perception of risk to personal health after the 210Po incident. Qualitative interviews were analysed with an emphasis on information needs. RESULTS: 11.7% of the survey sample (n=117) perceived their health to be at risk. Aside from personal variables the main predictors of perceived risk to health were believing that the incident was related to terrorism (odds ratio 2.7, 95% confidence interval 1.5 to 4.6) rather than to espionage, that it was targeted at the wider public rather than one person (5.9, 3.2 to 10.9), and that it could affect people who had not been in the contaminated area (3.2, 2.1 to 5.1). Participants in the qualitative interviews were generally satisfied with the information they had received, although they would have preferred more information about their individual risk of exposure, the results of their urine tests, and the health implications of the incident. CONCLUSIONS: Perceptions of the public that the 210Po incident in London in 2006 was related to espionage helped to reassure them that the risks to personal health were low. In the event of future incidents it is important to ensure that detailed, comprehensible information about the risks of any exposure is available. [Abstract/Link to Full Text]

Wilson IB, Landon BE, Marsden PV, Hirschhorn LR, McInnes K, Ding L, Cleary PD
Correlations among measures of quality in HIV care in the United States: cross sectional study.
BMJ. 2007 Nov 24;335(7629):1085.
OBJECTIVE: To determine whether a selected set of indicators can represent a single overall quality construct. DESIGN: Cross sectional study of data abstracted during an evaluation of an initiative to improve quality of care for people with HIV. SETTING: 69 sites in 30 states. DATA SOURCES: Medical records of 9020 patients. MAIN OUTCOME MEASURES: Adjusted performance rates at site level for eight measures of quality of care specific to HIV and a site level summary performance score (the number of measures for which the site was in the top quarter of the distribution). RESULTS: Of 28 site level correlations between measures, two were greater than 0.40, two were between 0.30 and 0.39, four were between 0.20 and 0.29, and the 20 remaining were all less than 0.20. One site was in the top quarter for seven measures, but no sites were in the top quarter for six or eight of the measures. Across the eight quality measures, sites were in the top quarter no more often than predicted by a chance (binomial) distribution. CONCLUSIONS: The quality suggested by one measured indicator cannot necessarily be generalised to unmeasured indicators, even if this might be expected for clinical or other reasons. [Abstract/Link to Full Text]

Agins BD, Holden MM
Defining a high performance healthcare organisation.
BMJ. 2007 Nov 24;335(7629):1055-6. [Abstract/Link to Full Text]

Strander B, Andersson-Ellström A, Milsom I, Sparén P
Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study.
BMJ. 2007 Nov 24;335(7629):1077.
OBJECTIVE: To study the long term risk of invasive cancer of the cervix or vagina after treatment for cervical intraepithelial neoplasia grade 3. DESIGN: Prospective cohort study. SETTING: Swedish cancer registry. PARTICIPANTS: All women in Sweden with severe dysplasia or cervical carcinoma in situ (equivalent to cervical intraepithelial neoplasia grade 3) treated during 1958-2002 (n=132,493) contributing 2,315,724 woman years. MAIN OUTCOME MEASURES: Standardised incidence ratios with risk of cancer in the Swedish general female population as reference, and relative risks in multivariable log-linear regression model, with internal references. RESULTS: Women with previous cervical intraepithelial neoplasia grade 3 had an increased risk of invasive cervical cancer compared with the general female population (standardised incidence ratio 2.34, 95% confidence interval 2.18 to 2.50). The increased risk showed a decreasing trend with time since diagnosis for women treated later than 1970 but the risk was still increased after 25 years. An effect of age was found, with an accentuated increase in risk for women aged more than 50. The excess risk for cervical cancer associated with previous cervical intraepithelial neoplasia grade 3 has steadily increased since 1958. For vaginal cancer the standardised incidence ratio was 6.82 (5.61 to 8.21) but this decreased to 2.65 after 25 years. Adjustments in the multivariable log-linear regression model did not substantially alter these results. CONCLUSIONS: Women previously treated for cervical intraepithelial neoplasia grade 3 are at an increased risk of developing invasive cervical cancer and vaginal cancer. This risk has increased since the 1960s and is accentuated in women aged more than 50. The risk is still increased 25 years after treatment. [Abstract/Link to Full Text]

Ronco G, Sideri MG, Ciatto S
Cervical intraepithelial neoplasia and higher long term risk of cancer.
BMJ. 2007 Nov 24;335(7629):1053-4. [Abstract/Link to Full Text]

Bleich SN, Cutler DM, Adams AS, Lozano R, Murray CJ
Impact of insurance and supply of health professionals on coverage of treatment for hypertension in Mexico: population based study.
BMJ. 2007 Oct 27;335(7625):875.
OBJECTIVE: To examine the independent and combined contributions of insurance status and supply of health professionals on coverage of antihypertensive treatment among adults in Mexico. DESIGN: Population based study. SETTING: Mexico. PARTICIPANTS: 4032 hypertensive adults (2967 uninsured and 1065 insured): 1065 uninsured adults matched with 1065 adults insured through Seguro Popular, a programme to expand health insurance coverage to uninsured people in Mexico. MAIN OUTCOME MEASURES: Coverage of antihypertensive treatment and coverage of antihypertensive treatment with control of blood pressure. RESULTS: Rates of treatment for hypertension varied by insurance status and supply of health professionals. Hypertensive adults insured through Seguro Popular had a significantly higher probability of receiving antihypertensive treatment (odds ratio 1.50, 95% confidence interval 1.27 to 1.78) and receiving antihypertensive treatment with control of blood pressure (1.35, 1.00 to 1.82). Greater supply of health professionals in areas with coverage through Seguro Popular was a significant predictor of antihypertensive treatment after adjusting for covariates (1.49, 1.00 to 2.20). CONCLUSIONS: Expansion of healthcare coverage to uninsured people in Mexico was associated with greater use of antihypertensive treatment and blood pressure control, particularly in areas with a greater supply of health professionals. [Abstract/Link to Full Text]

Tumwine JK
Equitable access to health care.
BMJ. 2007 Oct 27;335(7625):833-4. [Abstract/Link to Full Text]

Huf G, Coutinho ES, Adams CE
Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine.
BMJ. 2007 Oct 27;335(7625):869.
OBJECTIVE: To determine whether haloperidol alone results in swifter and safer tranquillisation and sedation than haloperidol plus promethazine. DESIGN: Pragmatic randomised open trial (January-July 2004). SETTING: Psychiatric emergency room, Rio de Janeiro, Brazil. PARTICIPANTS: 316 patients who needed urgent intramuscular sedation because of agitation, dangerous behaviour, or both. INTERVENTIONS: Open treatment with intramuscular haloperidol 5-10 mg or intramuscular haloperidol 5-10 mg plus intramuscular promethazine up to 50 mg; doses were at the discretion of the prescribing clinician. MAIN OUTCOME MEASURES: The primary outcome was proportion tranquil or asleep by 20 minutes. Secondary outcomes were asleep by 20 minutes; tranquil or asleep by 40, 60, and 120 minutes; physically restrained or given additional drugs within 2 hours; severe adverse events; another episode of agitation or aggression; additional visit from the doctor during the subsequent 24 hours; overall antipsychotic load in the first 24 hours; and still in hospital after 2 weeks. RESULTS: Primary outcome data were available for 311 (98.4%) people, 77% of whom were thought to have a psychotic illness. Patients allocated haloperidol plus promethazine were more likely to be tranquil or asleep by 20 minutes than those who received intramuscular haloperidol alone (relative risk 1.30, 95% confidence interval 1.10 to 1.55; number needed to treat 6, 95% confidence interval 4 to 16; P=0.002). No differences were found after 20 minutes. However, 10 cases of acute dystonia occurred, all in the haloperidol alone group. CONCLUSIONS: Haloperidol plus promethazine is a better option than haloperidol alone in terms of speed of onset of action and safety. Enough data are now available to change guidelines that continue to recommend treatments that leave people exposed to longer periods of aggression than necessary and patients vulnerable to distressing and unsafe adverse effects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83261243 [controlled-trials.com]. [Abstract/Link to Full Text]

Andrade C
Rapid tranquillisation in emergency psychiatric settings.
BMJ. 2007 Oct 27;335(7625):835-6. [Abstract/Link to Full Text]

Raveendran NS, Tharyan P, Alexander J, Adams CE
Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine.
BMJ. 2007 Oct 27;335(7625):865.
OBJECTIVE: To compare the effect of intramuscular olanzapine with intramuscular haloperidol plus promethazine on rapid tranquillisation of agitated or violent people with mental illness. DESIGN: Pragmatic, allocation concealed, randomised controlled trial. SETTING: Emergency services of a general hospital psychiatry department in Vellore, south India. PARTICIPANTS: 300 adults with agitated or violent behaviour as a result of mental illness; 150 randomised to intramuscular olanzapine and 150 randomised to intramuscular haloperidol plus promethazine. INTERVENTIONS: Open treatment with intramuscular olanzapine or intramuscular haloperidol plus promethazine. MAIN OUTCOME MEASURES: Primary outcome was proportion of patients who were tranquil or asleep at 15 minutes and 240 minutes. Secondary outcomes were proportion of patients who were tranquil, asleep, restrained, absconding, or clinically improved at 15, 30, 60, 120, and 240 minutes; additional medical interventions and adverse effects over four hours; and compliance with oral drugs and adverse effects over two weeks. RESULTS: Of 300 people randomised to receive either intramuscular olanzapine or intramuscular haloperidol plus promethazine, follow-up data were available for primary outcomes for 298 (99%). Both treatments resulted in similar proportions of people being tranquil or asleep at 15 minutes (olanzapine 131/150 (87%), haloperidol plus promethazine 136/150 (91%); relative risk 0.96, 95% confidence interval 0.34 to 1.47) and 240 minutes (olanzapine 144/150 (96%), haloperidol plus promethazine 145/150 (97%); relative risk 0.99, 0.95 to 1.03). However, more people given olanzapine than those given haloperidol plus promethazine required additional drugs over four hours (65/150 (43%) v 31/150 (21%); relative risk 2.07, 1.43 to 2.97). Adverse effects were uncommon with both treatments. CONCLUSIONS: Intramuscular olanzapine and intramuscular haloperidol plus promethazine were effective at rapidly tranquillising or sedating agitated or violent patients with mental illness but the combination resulted in fewer additional medical interventions within four hours of intervention. TRIAL REGISTRATION: Clinical trials NCT00455234 [ClinicalTrials.gov]. [Abstract/Link to Full Text]

Biai S, Rodrigues A, Gomes M, Ribeiro I, Sodemann M, Alves F, Aaby P
Reduced in-hospital mortality after improved management of children under 5 years admitted to hospital with malaria: randomised trial.
BMJ. 2007 Oct 27;335(7625):862.
OBJECTIVE: To test whether strict implementation of a standardised protocol for the management of malaria and provision of a financial incentive for health workers reduced mortality. DESIGN: Randomised controlled intervention trial. SETTING: Paediatric ward at the national hospital in Guinea-Bissau. All children admitted to hospital with severe malaria received free drug kits. PARTICIPANTS: 951 children aged 3 months to 5 years admitted to hospital with a diagnosis of malaria randomised to normal or intervention wards. INTERVENTIONS: Before the start of the study, all personnel were trained in the use of the standardised guidelines for the management of malaria, including strict follow-up procedures. Nurses and doctors were randomised to work on intervention or control wards. Personnel in the intervention ward received a small financial incentive ($50 (25 pounds sterling; 35 euros)/month for nurses and $160 for doctors) and their compliance with standard case management was closely monitored. MAIN OUTCOME MEASURES: In-hospital mortality and cumulative mortality within 4 weeks of hospital admission. RESULTS: In-hospital mortality was 5% for the intervention group and 10% in the control group (risk ratio 0.48, 95% confidence interval 0.29 to 0.79). The effect may have been stronger in patients with positive malaria slides (0.36, 0.16 to 0.80). Cumulative mortality 4 weeks after discharge was also lower in the intervention group (0.61, 0.40 to 0.95). CONCLUSIONS: Supervising healthcare workers to adhere to a standardised treatment protocol was associated with greatly reduced in-hospital mortality. Financial incentives may be important for the dedication and compliance of staff members. TRIAL REGISTRATION: Clinical Trials NCT00465777 [ClinicalTrials.gov]. [Abstract/Link to Full Text]

Pakenham-Walsh N
Health in an unequal world: What about the needs of health workers in developing countries?
BMJ. 2007 Nov 10;335(7627):954. [Abstract/Link to Full Text]

Dorling D, Mitchell R, Pearce J
The global impact of income inequality on health by age: an observational study.
BMJ. 2007 Oct 27;335(7625):873.
OBJECTIVES: To explore whether the apparent impact of income inequality on health, which has been shown for wealthier nations, is replicated worldwide, and whether the impact varies by age. DESIGN: Observational study. SETTING: 126 countries of the world for which complete data on income inequality and mortality by age and sex were available around the year 2002 (including 94.4% of world human population). DATA SOURCES: Data on mortality were from the World Health Organization and income data were taken from the annual reports of the United Nations Development Programme. MAIN OUTCOME MEASURES: Mortality in 5-year age bands for each sex by income inequality and income level. RESULTS: At ages 15-29 and 25-39 variations in income inequality seem more closely correlated with mortality worldwide than do variations in material wealth. This relation is especially strong among the poorest countries in Africa. Mortality is higher for a given level of overall income in more unequal nations. CONCLUSIONS: Income inequality seems to have an influence worldwide, especially for younger adults. Social inequality seems to have a universal negative impact on health. [Abstract/Link to Full Text]

Petersen I, Johnson AM, Islam A, Duckworth G, Livermore DM, Hayward AC
Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database.
BMJ. 2007 Nov 10;335(7627):982.
OBJECTIVE: To determine the extent to which antibiotics reduce the risk of serious complications after common respiratory tract infections. DESIGN: Retrospective cohort study. SETTING: UK primary care practices contributing to the general practice research database. DATA SOURCE: 3.36 million episodes of respiratory tract infection. MAIN OUTCOME MEASURES: Risk of serious complications in treated and untreated patients in the month after diagnosis: mastoiditis after otitis media, quinsy after sore throat, and pneumonia after upper respiratory tract infection and chest infection. Number of patients needed to treat to prevent one complication. RESULTS: Serious complications were rare after upper respiratory tract infections, sore throat, and otitis media, and the number needed to treat was over 4000. The risk of pneumonia after chest infection was high, particularly in elderly people, and was substantially reduced by antibiotic use, with a number needed to treat of 39 for those aged > or =65 and 96-119 in younger age groups. CONCLUSION: Antibiotics are not justified to reduce the risk of serious complications for upper respiratory tract infection, sore throat, or otitis media. Antibiotics substantially reduce the risk of pneumonia after chest infection, particularly in elderly people in whom the risk is highest. [Abstract/Link to Full Text]

Coenen S, Goossens H
Antibiotics for respiratory tract infections in primary care.
BMJ. 2007 Nov 10;335(7627):946-7. [Abstract/Link to Full Text]

Hill N, Lenglet A, Arnéz AM, Carneiro I
Plant based insect repellent and insecticide treated bed nets to protect against malaria in areas of early evening biting vectors: double blind randomised placebo controlled clinical trial in the Bolivian Amazon.
BMJ. 2007 Nov 17;335(7628):1023.
OBJECTIVE: To determine the effectiveness in reducing malaria of combining an insect repellent with insecticide treated bed nets compared with the nets alone in an area where vector mosquitoes feed in the early evening. DESIGN: A double blind, placebo controlled cluster-randomised clinical study. SETTING: Rural villages and peri-urban districts in the Bolivian Amazon. PARTICIPANTS: 4008 individuals in 860 households. INTERVENTIONS: All individuals slept under treated nets; one group also used a plant based insect repellent each evening, a second group used placebo. MAIN OUTCOME MEASURE: Episodes of Plasmodium falciparum or P vivax malaria confirmed by rapid diagnostic test or blood slide, respectively. RESULTS: We analysed 15,174 person months at risk and found a highly significant 80% reduction in episodes of P vivax in the group that used treated nets and repellent (incidence rate ratio 0.20, 95% confidence interval 0.11 to 0.38, P<0.001). Numbers of P falciparum cases during the study were small and, after adjustment for age, an 82% protective effect was observed, although this was not significant (0.18, 0.02 to 1.40, P=0.10). Reported episodes of fever with any cause were reduced by 58% in the group that used repellent (0.42, 0.31 to 0.56, P<0.001). CONCLUSIONS: Insect repellents can provide protection against malaria. In areas where vectors feed in the early evening, effectiveness of treated nets can be significantly increased by using repellent between dusk and bedtime. This has important implications in malaria vector control programmes outside Africa and shows that the combined use of treated nets and insect repellents, as advocated for most tourists travelling to high risk areas, is fully justified. REGISTRATION: NCT 00144716. [Abstract/Link to Full Text]

Roberts DR
Preventing malaria in endemic areas.
BMJ. 2007 Nov 17;335(7628):1001-2. [Abstract/Link to Full Text]

Lam SK, Owen A
Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials.
BMJ. 2007 Nov 3;335(7626):925.
OBJECTIVE: To review the evidence base from randomised controlled trials of combined cardiac resynchronisation therapy and implantable cardioverter defibrillator therapy in left ventricular impairment and symptomatic heart failure. DESIGN: Bayesian network meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases up to June 2006. REVIEW METHODS: Two reviewers independently assessed trial eligibility and quality. Included trials compared cardiac resynchronisation therapy, implantable cardioverter defibrillator therapy, combined resynchronisation and implantable defibrillator therapy, and medical therapy alone, in patients with impaired left ventricular systolic function. Bayesian random effects network models were used to examine overall number of deaths. RESULTS: 12 studies including 1636 events in 8307 patients were identified. Combined cardiac resynchronisation and implantable cardioverter defibrillator therapy reduced the number of deaths by one third compared with medical therapy alone (odds ratio 0.57, 95% credible interval 0.40 to 0.80) but did not further improve survival when compared with implantable defibrillator therapy (0.82, 0.57 to 1.18) or resynchronisation (0.85, 0.60 to 1.22) therapy alone. CONCLUSION: Evidence from randomised controlled trials is insufficient to show the superiority of combined cardiac resynchronisation and implantable cardioverter defibrillator therapy over cardiac resynchronisation therapy alone in patients with left ventricular impairment. [Abstract/Link to Full Text]

McAlister FA
Device therapy in heart failure.
BMJ. 2007 Nov 3;335(7626):895-6. [Abstract/Link to Full Text]

James J, Thomas P, Kerr D
Preventing childhood obesity: two year follow-up results from the Christchurch obesity prevention programme in schools (CHOPPS).
BMJ. 2007 Oct 13;335(7623):762.
OBJECTIVE: To assess the long term effects of an obesity prevention programme in schools. DESIGN: Longitudinal results after a cluster randomised controlled trial. SETTING: Schools in southwest England. PARTICIPANTS: Of the original sample of 644 children aged 7-11, 511 children were tracked and measurements were obtained from 434 children three years after baseline. INTERVENTION: The intervention was conducted over one school year, with four sessions of focused education promoting a healthy diet and discouraging the consumption of carbonated drinks. MAIN OUTCOME MEASURES: Anthropometric measures of height, weight, and waist circumference. Body mass index (BMI) converted to z scores (SD scores) and to centile values with growth reference curves. Waist circumference was also converted to z scores (SD scores). RESULTS: At three years after baseline the age and sex specific BMI z scores (SD scores) had increased in the control group by 0.10 (SD 0.53) but decreased in the intervention group by -0.01 (SD 0.58), with a mean difference of 0.10 (95% confidence interval -0.00 to 0.21, P=0.06). The prevalence of overweight increased in both the intervention and control group at three years and the significant difference between the groups seen at 12 months was no longer evident. The BMI increased in the control group by 2.14 (SD 1.64) and the intervention group by 1.88 (SD 1.71), with mean difference of 0.26 (-0.07 to 0.58, P= 0.12). The waist circumference increased in both groups after three years with a mean difference of 0.09 (-0.06 to 0.26, P=0.25). CONCLUSIONS: These longitudinal results show that after a simple year long intervention the difference in prevalence of overweight in children seen at 12 months was not sustained at three years. [Abstract/Link to Full Text]

Veerman JL, Barendregt JJ
Preventing childhood obesity: Too early to ditch the campaign.
BMJ. 2007 Oct 27;335(7625):841. [Abstract/Link to Full Text]

Chong EW, Wong TY, Kreis AJ, Simpson JA, Guymer RH
Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis.
BMJ. 2007 Oct 13;335(7623):755.
OBJECTIVE: To evaluate the effectiveness of dietary antioxidants in the primary prevention of age related macular degeneration (AMD). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Search of seven databases without limits on year or language of publication, and retrieval of references in pertinent reviews and articles. METHODS: Two reviewers independently searched the databases and selected the studies, using standardised criteria. Randomised clinical trials and prospective cohort studies were included. Of the 4192 abstracts initially identified, 12 studies (nine prospective cohort studies and three randomised clinical trials) met the selection criteria and were included. Data extraction and study quality evaluation were independently reviewed, using standardised criteria. Results were pooled quantitatively using meta-analytic methods. RESULTS: The nine prospective cohort studies included 149 203 people, with 1878 incident cases of early AMD. The antioxidants investigated differed across studies, and not all studies contributed to the meta-analysis of each antioxidant. Pooled results from prospective cohort studies indicated that vitamin A, vitamin C, vitamin E, zinc, lutein, zeaxanthin, alpha carotene, beta carotene, beta cryptoxanthin, and lycopene have little or no effect in the primary prevention of early AMD. The three randomised clinical trials did not show that antioxidant supplements prevented early AMD. CONCLUSIONS: There is insufficient evidence to support the role of dietary antioxidants, including the use of dietary antioxidant supplements, for the primary prevention of early AMD. [Abstract/Link to Full Text]

Evans J
Primary prevention of age related macular degeneration.
BMJ. 2007 Oct 13;335(7623):729. [Abstract/Link to Full Text]

Mason S, Knowles E, Colwell B, Dixon S, Wardrope J, Gorringe R, Snooks H, Perrin J, Nicholl J
Effectiveness of paramedic practitioners in attending 999 calls from elderly people in the community: cluster randomised controlled trial.
BMJ. 2007 Nov 3;335(7626):919.
OBJECTIVE: To evaluate the benefits of paramedic practitioners assessing and, when possible, treating older people in the community after minor injury or illness. Paramedic practitioners have been trained with extended skills to assess, treat, and discharge older patients with minor acute conditions in the community. DESIGN: Cluster randomised controlled trial involving 56 clusters. Weeks were randomised to the paramedic practitioner service being active (intervention) or inactive (control) when the standard 999 service was available. SETTING: A large urban area in England. PARTICIPANTS: 3018 patients aged over 60 who called the emergency services (n=1549 intervention, n=1469 control). MAIN OUTCOME MEASURES: Emergency department attendance or hospital admission between 0 and 28 days; interval from time of call to time of discharge; patients' satisfaction with the service received. RESULTS: Overall, patients in the intervention group were less likely to attend an emergency department (relative risk 0.72, 95% confidence interval 0.68 to 0.75) or require hospital admission within 28 days (0.87, 0.81 to 0.94) and experienced a shorter total episode time (235 v 278 minutes, 95% confidence interval for difference -60 minutes to -25 minutes). Patients in the intervention group were more likely to report being highly satisfied with their healthcare episode (relative risk 1.16, 1.09 to 1.23). There was no significant difference in 28 day mortality (0.87, 0.63 to 1.21). CONCLUSIONS: Paramedics with extended skills can provide a clinically effective alternative to standard ambulance transfer and treatment in an emergency department for elderly patients with acute minor conditions. TRIAL REGISTRATION: ISRCTN27796329 [controlled-trials.com]. [Abstract/Link to Full Text]

Woollard M
Paramedic practitioners and emergency admissions.
BMJ. 2007 Nov 3;335(7626):893-4. [Abstract/Link to Full Text]

Loosemore M, Knowles CH, Whyte GP
Amateur boxing and risk of chronic traumatic brain injury: systematic review of observational studies.
BMJ. 2007 Oct 20;335(7624):809.
OBJECTIVE: To evaluate the risk of chronic traumatic brain injury from amateur boxing. SETTING: Secondary research performed by combination of sport physicians and clinical academics. DESIGN, DATA SOURCES, AND METHODS: Systematic review of observational studies in which chronic traumatic brain injury was defined as any abnormality on clinical neurological examination, psychometric testing, neuroimaging studies, and electroencephalography. Studies were identified through database (1950 to date) and bibliographic searches without language restrictions. Two reviewers extracted study characteristics, quality, and data, with adherence to a protocol developed from a widely recommended method for systematic review of observational studies (MOOSE). RESULTS: 36 papers had relevant extractable data (from a detailed evaluation of 93 studies of 943 identified from the initial search). Quality of evidence was generally poor. The best quality studies were those with a cohort design and those that used psychometric tests. These yielded the most negative results: only four of 17 (24%) better quality studies found any indication of chronic traumatic brain injury in a minority of boxers studied. CONCLUSION: There is no strong evidence to associate chronic traumatic brain injury with amateur boxing. [Abstract/Link to Full Text]

McCrory P
Boxing and the risk of chronic brain injury.
BMJ. 2007 Oct 20;335(7624):781-2. [Abstract/Link to Full Text]

Legg L, Drummond A, Leonardi-Bee J, Gladman JR, Corr S, Donkervoort M, Edmans J, Gilbertson L, Jongbloed L, Logan P, Sackley C, Walker M, Langhorne P
Occupational therapy for patients with problems in personal activities of daily living after stroke: systematic review of randomised trials.
BMJ. 2007 Nov 3;335(7626):922.
OBJECTIVE: To determine whether occupational therapy focused specifically on personal activities of daily living improves recovery for patients after stroke. DESIGN: Systematic review and meta-analysis. DATA SOURCES: The Cochrane stroke group trials register, the Cochrane central register of controlled trials, Medline, Embase, CINAHL, PsycLIT, AMED, Wilson Social Sciences Abstracts, Science Citation Index, Social Science Citation, Arts and Humanities Citation Index, Dissertations Abstracts register, Occupational Therapy Research Index, scanning reference lists, personal communication with authors, and hand searching. REVIEW METHODS: Trials were included if they evaluated the effect of occupational therapy focused on practice of personal activities of daily living or where performance in such activities was the target of the occupational therapy intervention in a stroke population. Original data were sought from trialists. Two reviewers independently reviewed each trial for methodological quality. Disagreements were resolved by consensus. RESULTS: Nine randomised controlled trials including 1258 participants met the inclusion criteria. Occupational therapy delivered to patients after stroke and targeted towards personal activities of daily living increased performance scores (standardised mean difference 0.18, 95% confidence interval 0.04 to 0.32, P=0.01) and reduced the risk of poor outcome (death, deterioration or dependency in personal activities of daily living) (odds ratio 0.67, 95% confidence interval 0.51 to 0.87, P=0.003). For every 100 people who received occupational therapy focused on personal activities of daily living, 11 (95% confidence interval 7 to 30) would be spared a poor outcome. CONCLUSIONS: Occupational therapy focused on improving personal activities of daily living after stroke can improve performance and reduce the risk of deterioration in these abilities. Focused occupational therapy should be available to everyone who has had a stroke. [Abstract/Link to Full Text]

McPherson KM, Ellis-Hill C
Occupational therapy after stroke.
BMJ. 2007 Nov 3;335(7626):894-5. [Abstract/Link to Full Text]

van Sluijs EM, McMinn AM, Griffin SJ
Effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials.
BMJ. 2007 Oct 6;335(7622):703.
OBJECTIVE: To review the published literature on the effectiveness of interventions to promote physical activity in children and adolescents. DESIGN: Systematic review. DATA SOURCES: Literature search using PubMed, SCOPUS, Psychlit, Ovid Medline, Sportdiscus, and Embase up to December 2006. Review methods Two independent reviewers assessed studies against the following inclusion criteria: controlled trial, comparison of intervention to promote physical activity with no intervention control condition, participants younger than 18 years, and reported statistical analyses of a physical activity outcome measure. Levels of evidence, accounting for methodological quality, were assessed for three types of intervention, five settings, and three target populations. RESULTS: The literature search identified 57 studies: 33 aimed at children and 24 at adolescents. Twenty four studies were of high methodological quality, including 13 studies in children. Interventions that were found to be effective achieved increases ranging from an additional 2.6 minutes of physical education related physical activity to 283 minutes per week of overall physical activity. Among children, limited evidence for an effect was found for interventions targeting children from low socioeconomic populations, and environmental interventions. Strong evidence was found that school based interventions with involvement of the family or community and multicomponent interventions can increase physical activity in adolescents. CONCLUSION: Some evidence was found for potentially effective strategies to increase children's levels of physical activity. For adolescents, multicomponent interventions and interventions that included both school and family or community involvement have the potential to make important differences to levels of physical activity and should be promoted. A lack of high quality evaluations hampers conclusions concerning effectiveness, especially among children. [Abstract/Link to Full Text]

Giles-Corti B, Salmon J
Encouraging children and adolescents to be more active.
BMJ. 2007 Oct 6;335(7622):677-8. [Abstract/Link to Full Text]

Westaby S, Archer N, Manning N, Adwani S, Grebenik C, Ormerod O, Pillai R, Wilson N
Comparison of hospital episode statistics and central cardiac audit database in public reporting of congenital heart surgery mortality.
BMJ. 2007 Oct 13;335(7623):759.
OBJECTIVE: To verify or refute the value of hospital episode statistics (HES) in determining 30 day mortality after open congenital cardiac surgery in infants nationally in comparison with central cardiac audit database (CCAD) information. DESIGN: External review of paediatric cardiac surgical outcomes in England (HES) and all UK units (CCAD), as derived from each database. SETTING: Congenital heart surgery centres in the United Kingdom. DATA SOURCES: HES for congenital heart surgery and corresponding information from CCAD for the period 1 April 2000 to 31 March 2002. HES was restricted to the 11 English centres; CCAD covered all 13 UK centres. MAIN OUTCOME MEASURE: Mortality within 30 days of open heart surgery in infants aged under 12 months. RESULTS: In a direct comparison for the years when data from the 11 English centres were available from both databases, HES omitted between 5% and 38% of infants operated on in each centre. A median 40% (range 0-73%) shortfall occurred in identification of deaths by HES. As a result, mean 30 day mortality was underestimated at 4% by HES as compared with 8% for CCAD. In CCAD, between 1% and 23% of outcomes were missing in nine of 11 English centres used in the comparison (predominantly those for overseas patients). Accordingly, CCAD mortality could also be underestimated. Oxford provided the most complete dataset to HES, including all deaths recorded by CCAD. From three years of CCAD, Oxford's infant mortality from open cardiac surgery (10%) was not statistically different from the mean for all 13 UK centres (8%), in marked contrast to the conclusions drawn from HES for two of those years. CONCLUSIONS: Hospital episode statistics are unsatisfactory for the assessment of activity and outcomes in congenital heart surgery. The central cardiac audit database is more accurate and complete, but further work is needed to achieve fully comprehensive risk stratified mortality data. Given unresolved limitations in data quality, commercial organisations should reconsider placing centre specific or surgeon specific mortality data in the public domain. [Abstract/Link to Full Text]

Singleton S
Data sources and performance measurement.
BMJ. 2007 Oct 13;335(7623):730. [Abstract/Link to Full Text]

Westaby S, Archer N, Wilson N
Surgical mortality: Media attack.
BMJ. 2007 Oct 27;335(7625):839; author reply 839-40. [Abstract/Link to Full Text]

Aylin P, Bottle A, Elliott P, Jarman B
Surgical mortality: Hospital episode statistics v central cardiac audit database.
BMJ. 2007 Oct 27;335(7625):839; author reply 839-40. [Abstract/Link to Full Text]

Minns Lowe CJ, Barker KL, Dewey M, Sackley CM
Effectiveness of physiotherapy exercise after knee arthroplasty for osteoarthritis: systematic review and meta-analysis of randomised controlled trials.
BMJ. 2007 Oct 20;335(7624):812.
OBJECTIVE: To evaluate the effectiveness of physiotherapy exercise after elective primary total knee arthroplasty in patients with osteoarthritis. DESIGN: Systematic review. DATA SOURCES: Database searches: AMED, CINAHL, Embase, King's Fund, Medline, Cochrane library (Cochrane reviews, Cochrane central register of controlled trials, DARE), PEDro, Department of Health national research register. Hand searches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings. Review methods Randomised controlled trials were reviewed if they included a physiotherapy exercise intervention compared with usual or standard physiotherapy care, or compared two types of exercise physiotherapy interventions meeting the review criteria, after discharge from hospital after elective primary total knee arthroplasty for osteoarthritis. OUTCOME MEASURES: Functional activities of daily living, walking, quality of life, muscle strength, and range of motion in the knee joint. Trial quality was extensively evaluated. Narrative synthesis plus meta-analyses with fixed effect models, weighted mean differences, standardised effect sizes, and tests for heterogeneity. RESULTS: Six trials were identified, five of which were suitable for inclusion in meta-analyses. There was a small to moderate standardised effect size (0.33, 95% confidence interval 0.07 to 0.58) in favour of functional exercise for function three to four months postoperatively. There were also small to moderate weighted mean differences of 2.9 (0.61 to 5.2) for range of joint motion and 1.66 (-1 to 4.3) for quality of life in favour of functional exercise three to four months postoperatively. Benefits of treatment were no longer evident at one year. CONCLUSIONS: Interventions including physiotherapy functional exercises after discharge result in short term benefit after elective primary total knee arthroplasty. Effect sizes are small to moderate, with no long term benefit. [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]

Goodacre S, Cross E, Lewis C, Nicholl J, Capewell S
Effectiveness and safety of chest pain assessment to prevent emergency admissions: ESCAPE cluster randomised trial.
BMJ. 2007 Sep 29;335(7621):659.
OBJECTIVE: To determine whether introducing chest pain unit care reduces emergency admissions without increasing reattendances and admissions over the next 30 days. DESIGN: Cluster randomised before and after intervention trial. SETTING: 14 diverse acute hospitals in the United Kingdom. PARTICIPANTS: Patients attending the emergency department with acute chest pain during the year before and the year after the intervention started. INTERVENTION: Establishment of chest pain unit care compared with continuation of routine care. MAIN OUTCOME MEASURES: Proportion of chest pain attendances resulting in admission; reattendances and admissions over the next 30 days; daily emergency medical admissions (all causes); and proportion of emergency department attendances with chest pain. RESULTS: The introduction of chest pain unit care was associated with weak evidence of an increase in emergency department attendances with chest pain (16% v 3.5%; P=0.08); no change in the proportion of chest pain attendances resulting in admission (odds ratio 0.998, 95% confidence interval 0.940 to 1.059; P=0.945); small increases in the proportion reattending (odds ratio 1.10, 1.00 to 1.21; P=0.036) or being admitted (1.30, 0.97 to 1.74; P=0.083) over the next 30 days; and evidence of increased daily medical admissions (1.7 per day, 95% confidence interval 0.8 to 2.5; P<0.001). However, this last finding was highly sensitive to changes in the method used to handle missing data. CONCLUSION: The introduction of chest pain unit care did not reduce the proportion of patients with chest pain admitted and may have been associated with increased emergency department attendances with chest pain. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55318418. [Abstract/Link to Full Text]

Clancy M
Effectiveness of chest pain units.
BMJ. 2007 Sep 29;335(7621):623-4. [Abstract/Link to Full Text]

Leitch A, McGinness P, Wallbridge D
Calculate the QT interval in patients taking drugs for dementia.
BMJ. 2007 Sep 15;335(7619):557. [Abstract/Link to Full Text]

Wald DS, Bestwick JP, Wald NJ
Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis.
BMJ. 2007 Sep 22;335(7620):599.
OBJECTIVE: To develop a population screening strategy for familial hypercholesterolaemia. DESIGN: Meta-analysis of published data on total and low density lipoprotein (LDL) cholesterol in people with and without familial hypercholesterolaemia according to age. Thirteen studies reporting on 1907 cases and 16 221 controls were used in the analysis. Included studies had at least 10 cases and controls with data on the distribution of cholesterol in affected and unaffected individuals. MAIN OUTCOME MEASURES: Detection rates (sensitivity) for specified false positive rates (0.1%, 0.5%, and 1%) in newborns and in age groups 1-9, 10-19, 20-39, 40-59, and > or =60 years. RESULTS: Serum cholesterol concentration discriminated best between people with and without familial hypercholesterolaemia at ages 1-9, when the detection rates with total cholesterol were 88%, 94%, and 96% for false positive rates of 0.1%, 0.5%, and 1%. The results were similar with LDL cholesterol. Screening newborns was much less effective. Once an affected child is identified, measurement of cholesterol would detect about 96% of parents with the disorder, using the simple rule that the parent with the higher serum cholesterol concentration is the affected parent. CONCLUSIONS: The proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously. [Abstract/Link to Full Text]

Hadfield GS, Humphries SE
Familial hypercholesterolaemia: Cascade testing is tried and tested and cost effective.
BMJ. 2007 Oct 6;335(7622):683. [Abstract/Link to Full Text]

Hopcroft KA
Familial hypercholesterolaemia: Child-parent screening may have adverse psychological effects.
BMJ. 2007 Oct 6;335(7622):683. [Abstract/Link to Full Text]

Calonge N, Guirguis-Blake J
Screening for familial hypercholesterolaemia.
BMJ. 2007 Sep 22;335(7620):573-4. [Abstract/Link to Full Text]

Stewart CE, Stephens DA, Fielder AR, Moseley MJ
Objectively monitored patching regimens for treatment of amblyopia: randomised trial.
BMJ. 2007 Oct 6;335(7622):707.
OBJECTIVES: To compare visual outcome in response to two prescribed rates of occlusion (six hours a day and 12 hours a day). DESIGN: Unmasked randomised trial. SETTING: Research clinics in two London hospitals. PARTICIPANTS: 97 children with a confirmed diagnosis of amblyopia associated with strabismus, anisometropia, or both. INTERVENTIONS: 18 week period of wearing glasses (refractive adaptation) followed by occlusion prescribed ("patching") for six or 12 hours a day. MAIN OUTCOME MEASURES: Visual acuity measured by logMAR letter recognition; objectively monitored rate of occlusion (hours a day). RESULTS: The mean age of children at study entry was 5.6 (SD 1.5) years. Ninety were eligible for occlusion but 10 dropped out in this phase, leaving 80 children who were randomised to a prescribed dose rate of six (n=40) or 12 (n=40) hours a day. The mean change in visual acuity of the amblyopic eye was not significantly different (P=0.64) between the two groups (0.26 (95% confidence interval 0.21 to 0.31) log units in six hour group; 0.24 (0.19 to 0.29) log units in 12 hour group). The mean dose rates (hours a day) actually received, however, were also not significantly different (4.2 (3.7 to 4.7) in six hour group v 6.2 (5.1 to 7.3) in 12 hour group; P=0.06). The visual outcome was similar for those children who received three to six hours a day or more than six to 12 hours a day, but significantly better than that in children who received less than three hours a day. Children aged under 4 required significantly less occlusion than older children. Visual outcome was not influenced by type of amblyopia. CONCLUSIONS: Substantial (six hours a day) and maximal (12 hours a day) prescribed occlusion results in similar visual outcome. On average, the occlusion dose received in the maximal group was only 50% more than in the substantial group and in both groups was much less than that prescribed. Younger children required the least occlusion. TRIALS REGISTRATION: Clinical Trials NCT00274664. [Abstract/Link to Full Text]

Lempert P
Occlusion studies are ambiguous.
BMJ. 2007 Oct 27;335(7625):842. [Abstract/Link to Full Text]

Loudon SE, Simonsz HJ
Occlusion therapy for amblyopia.
BMJ. 2007 Oct 6;335(7622):678-9. [Abstract/Link to Full Text]

Kramer MS, Matush L, Vanilovich I, Platt R, Bogdanovich N, Sevkovskaya Z, Dzikovich I, Shishko G, Mazer B
Effect of prolonged and exclusive breast feeding on risk of allergy and asthma: cluster randomised trial.
BMJ. 2007 Oct 20;335(7624):815.
OBJECTIVE: To assess whether exclusive and prolonged breast feeding reduces the risk of childhood asthma and allergy by age 6.5 years. DESIGN: Cluster randomised trial. SETTING: 31 Belarussian maternity hospitals and their affiliated polyclinics. PARTICIPANTS: A total of 17,046 mother-infant pairs were enrolled, of whom 13,889 (81.5%) were followed up at age 6.5 years. INTERVENTION: Breastfeeding promotion intervention modelled on the WHO/UNICEF baby friendly hospital initiative. MAIN OUTCOME MEASURES: International study of asthma and allergies in childhood (ISAAC) questionnaire and skin prick tests of five inhalant antigens. RESULTS: The experimental intervention led to a large increase in exclusive breast feeding at 3 months (44.3% v 6.4%; P<0.001) and a significantly higher prevalence of any breast feeding at all ages up to and including 12 months. The experimental group had no reduction in risks of allergic symptoms and diagnoses or positive skin prick tests. In fact, after exclusion of six sites (three experimental and three control) with suspiciously high rates of positive skin prick tests, risks were significantly increased in the experimental group for four of the five antigens. CONCLUSIONS: These results do not support a protective effect of prolonged and exclusive breast feeding on asthma or allergy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37687716 [controlled-trials.com]. [Abstract/Link to Full Text]

Silvers KM, Epton MJ, Frampton CM
Allergy after breast feeding: Study was not designed to test the hypothesis.
BMJ. 2007 Nov 3;335(7626):899. [Abstract/Link to Full Text]

Gahagan S
Breast feeding and the risk of allergy and asthma.
BMJ. 2007 Oct 20;335(7624):782-3. [Abstract/Link to Full Text]

Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ
Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study.
BMJ. 2007 Sep 29;335(7621):651.
OBJECTIVE: To examine the absolute risks or benefits on cancer associated with oral contraception, using incident data. DESIGN: Inception cohort study. SETTING: Royal College of General Practitioners' oral contraception study. PARTICIPANTS: Directly standardised data from the Royal College of General Practitioners' oral contraception study. MAIN OUTCOME MEASURES: Adjusted relative risks between never and ever users of oral contraceptives for different types of cancer, main gynaecological cancers combined, and any cancer. Standardisation variables were age, smoking, parity, social class, and (for the general practitioner observation dataset) hormone replacement therapy. Subgroup analyses examined whether the relative risks changed with user characteristics, duration of oral contraception usage, and time since last use of oral contraception. RESULTS: The main dataset contained about 339,000 woman years of observation for never users and 744,000 woman years for ever users. Compared with never users ever users had statistically significant lower rates of cancers of the large bowel or rectum, uterine body, and ovaries, tumours of unknown site, and other malignancies; main gynaecological cancers combined; and any cancer. The relative risk for any cancer in the smaller general practitioner observation dataset was not significantly reduced. Statistically significant trends of increasing risk of cervical and central nervous system or pituitary cancer, and decreasing risk of uterine body and ovarian malignancies, were seen with increasing duration of oral contraceptive use. Reduced relative risk estimates were observed for ovarian and uterine body cancer many years after stopping oral contraception, although some were not statistically significant. The estimated absolute rate reduction of any cancer among ever users was 45 or 10 per 100,000 woman years, depending on whether the main or general practitioner observation dataset was used. CONCLUSION: In this UK cohort, oral contraception was not associated with an overall increased risk of cancer; indeed it may even produce a net public health gain. The balance of cancer risks and benefits, however, may vary internationally, depending on patterns of oral contraception usage and the incidence of different cancers. [Abstract/Link to Full Text]

Meirik O, Farley TM
Risk of cancer and the oral contraceptive pill.
BMJ. 2007 Sep 29;335(7621):621-2. [Abstract/Link to Full Text]

Colbourn TE, Asseburg C, Bojke L, Philips Z, Welton NJ, Claxton K, Ades AE, Gilbert RE
Preventive strategies for group B streptococcal and other bacterial infections in early infancy: cost effectiveness and value of information analyses.
BMJ. 2007 Sep 29;335(7621):655.
OBJECTIVE: To determine the cost effectiveness of strategies for preventing neonatal infection with group B streptococci and other bacteria in the UK and the value of further information from research. DESIGN: Use of a decision model to compare the cost effectiveness of prenatal testing for group B streptococcal infection (by polymerase chain reaction or culture), prepartum antibiotic treatment (intravenous penicillin or oral erythromycin), and vaccination during pregnancy (not yet available) for serious bacterial infection in early infancy across 12 maternal risk groups. Model parameters were estimated using multi-parameter evidence synthesis to incorporate all relevant data inputs. DATA SOURCES: 32 systematic reviews were conducted: 14 integrated results from published studies, 24 involved analyses of primary datasets, and five included expert opinion. Main outcomes measures Healthcare costs per quality adjusted life year (QALY) gained. RESULTS: Current best practice (to treat only high risk women without prior testing for infection) and universal testing by culture or polymerase chain reaction were not cost effective options. Immediate extension of current best practice to treat all women with preterm and high risk term deliveries without testing (11% treated) would result in substantial net benefits. Currently, addition of culture testing for low risk term women, while treating all preterm and high risk term women, would be the most cost effective option (21% treated). If available in the future, vaccination combined with treating all preterm and high risk term women and no testing for low risk women would probably be marginally more cost effective and would limit antibiotic exposure to 11% of women. The value of information is highest (67m pounds sterling) if vaccination is included as an option. CONCLUSIONS: Extension of current best practice to treat all women with preterm and high risk term deliveries is readily achievable and would be beneficial. The choice between adding culture testing for low risk women or vaccination for all should be informed by further research. Trials to evaluate vaccine efficacy should be prioritised. [Abstract/Link to Full Text]

Briggs AH
New methods of analysing cost effectiveness.
BMJ. 2007 Sep 29;335(7621):622-3. [Abstract/Link to Full Text]

Phillips R, Amos A, Ritchie D, Cunningham-Burley S, Martin C
Smoking in the home after the smoke-free legislation in Scotland: qualitative study.
BMJ. 2007 Sep 15;335(7619):553.
OBJECTIVE: To explore the accounts of smokers and non-smokers (who live with smokers) of smoking in their homes and cars after the Scottish smoke-free legislation; to examine the reported impact of the legislation on smoking in the home; and to consider the implications for future initiatives aimed at reducing children's exposure to secondhand smoke in the home. DESIGN AND SETTING: A qualitative cross sectional study involving semistructured interviews conducted across Scotland shortly after the implementation of the legislation on 26 March 2006. PARTICIPANTS: A purposively selected sample of 50 adults (aged 18-75) drawn from all socioeconomic groups, included smokers living with smokers, smokers living with non-smokers, and non-smokers living with smokers. RESULTS: Passive smoking was a well recognised term. Respondents had varied understandings of the risks of secondhand smoke, with a few rejecting evidence of such risks. Children, however, were perceived as vulnerable. Most reported that they restricted smoking in their homes, with a range of restrictions across social classes and home smoking profiles. Spatial, relational, health, and aesthetic factors influenced the development of restrictions. Children and grandchildren were important considerations in the development and modification of restrictions. Other strategies were also used to militate against secondhand smoke, such as opening windows. The meaning of the home as somewhere private and social identity were important underlying factors. Respondents reported greater restrictions on smoking in their cars. There were diverse views on the smoke-free legislation. Few thought it had influenced their smoking in the home, and none thought it had affected how they restricted smoking in their homes. CONCLUSIONS: These data suggest two normative discourses around smoking in the home. The first relates to acceptable social identity as a hospitable person who is not anti-smoker. The second relates to moral identity as a caring parent or grandparent. Awareness of the risks of secondhand smoke, despite ambivalence about health messages and the fluidity of smoking restrictions, provides clear opportunities for public health initiatives to support people attain smoke-free homes. [Abstract/Link to Full Text]

Chapman S
The future of smoke-free legislation.
BMJ. 2007 Sep 15;335(7619):521-2. [Abstract/Link to Full Text]

Recent Articles in CMAJ : Canadian Medical Association Journal

Howell E
Gairdner winners honoured at Toronto symposium.
CMAJ. 2007 Dec 4;177(12):1489-90. [Abstract/Link to Full Text]

Dunleavy N
Searching for solutions to the North's quiet epidemic.
CMAJ. 2007 Dec 4;177(12):1488. [Abstract/Link to Full Text]

Howell E
Prescribing patterns drive up health care costs.
CMAJ. 2007 Dec 4;177(12):1487. [Abstract/Link to Full Text]

Bagchi S
India moves to improve black fever tracking.
CMAJ. 2007 Dec 4;177(12):1486. [Abstract/Link to Full Text]

Brooks JR
Ideological chasms divide US presidential hopefuls.
CMAJ. 2007 Dec 4;177(12):1484-6. [Abstract/Link to Full Text]

Kennedy G
Food for all.
CMAJ. 2007 Dec 4;177(12):1473, 1475. [Abstract/Link to Full Text]

Attaran A, Walker RB
Pharmaprix ou Pharmabraconnage?
CMAJ. 2007 Nov 30; [Abstract/Link to Full Text]

Attaran A, Walker RB
Shoppers Drug Mart or Poachers Drug Mart?
CMAJ. 2007 Nov 26; [Abstract/Link to Full Text]

Sibley R
In search of trust.
CMAJ. 2007 Nov 20;177(11):1464. [Abstract/Link to Full Text]

Desapriya E, Pike I, Scime G, Subzwari S
The safety of older drivers.
CMAJ. 2007 Nov 20;177(11):1392. [Abstract/Link to Full Text]

Warburton DE, Bredin SS, Gledhill N, Jamnik V, McKenzie DC, Shephard R
Personal trainers for obese patients.
CMAJ. 2007 Nov 20;177(11):1391. [Abstract/Link to Full Text]

Mascitelli L, Pezzetta F
Diabetes and osteoporotic fractures.
CMAJ. 2007 Nov 20;177(11):1391-2. [Abstract/Link to Full Text]

Wilson K
The Krever Commission--10 years later.
CMAJ. 2007 Nov 20;177(11):1387-9. [Abstract/Link to Full Text]

Rosser W, Schultz K
Promoting continuity of care should be integral to any health care system.
CMAJ. 2007 Nov 20;177(11):1385-6. [Abstract/Link to Full Text]

How J, Tabah R
Explaining the increasing incidence of differentiated thyroid cancer.
CMAJ. 2007 Nov 20;177(11):1383-4. [Abstract/Link to Full Text]

Le Foll B, George TP
Treatment of tobacco dependence: integrating recent progress into practice.
CMAJ. 2007 Nov 20;177(11):1373-80.
Tobacco use is one of the leading preventable causes of death in developed countries. Adoption of approaches that have demonstrated efficacy to improve the treatment of tobacco dependence are critical to reduce the health consequences of tobacco use. We summarize the latest epidemiologic data on tobacco use, the mechanisms that underlie tobacco dependence, and advances in pharmacotherapy and nonpharmacologic interventions available for the treatment of tobacco dependence. Specifically, we discuss the use of nicotine replacement therapy, bupropion and varenicline in primary care settings. [Abstract/Link to Full Text]

Juurlink DN, Park-Wyllie LY, Kapral MK
The effect of publication on Internet-based solicitation of personal-injury litigants.
CMAJ. 2007 Nov 20;177(11):1369-70.
Serious adverse drug events can prompt personal-injury lawsuits. However, the extent to which biomedical publication regarding drug-induced harm can influence the legal process has not been well characterized. Using an advanced Google search strategy, we determined the number of Internet "hits" for websites soliciting plaintiffs for medicolegal action before and after publication of a study that highlighted the risk of dysglycemia among patients taking the antibiotic gatifloxacin. We found that early online release and print publication were associated with an immediate and sustained increase in the number of websites soliciting plaintiffs for legal action. [Abstract/Link to Full Text]

Ionescu-Ittu R, McCusker J, Ciampi A, Vadeboncoeur AM, Roberge D, Larouche D, Verdon J, Pineault R
Continuity of primary care and emergency department utilization among elderly people.
CMAJ. 2007 Nov 20;177(11):1362-8.
BACKGROUND: People aged 65 years or more represent a growing group of emergency department users. We investigated whether characteristics of primary care (accessibility and continuity) are associated with emergency department use by elderly people in both urban and rural areas. METHODS: We conducted a cross-sectional study using information for a random sample of 95,173 people aged 65 years or more drawn from provincial administrative databases in Quebec for 2000 and 2001. We obtained data on the patients' age, sex, comorbidity, rate of emergency department use (number of days on which a visit was made to an emergency department per 1000 days at risk [i.e., alive and not in hospital] during the 2-year study period), use of hospital and ambulatory physician services, residence (urban v. rural), socioeconomic status, access (physician: population ratio, presence of primary physician) and continuity of primary care. RESULTS: After adjusting for age, sex and comorbidity, we found that an increased rate of emergency department use was associated with lack of a primary physician (adjusted rate ratio [RR] 1.45, 95% confidence interval [CI] 1.41-1.49) and low or medium (v. high) levels of continuity of care with a primary physician (adjusted RR 1.46, 95% CI 1.44-1.48, and 1.27, 95% CI 1.25-1.29, respectively). Other significant predictors of increased use of emergency department services were residence in a rural area, low socioeconomic status and residence in a region with a higher physician:population ratio. Among the patients who had a primary physician, continuity of care had a stronger protective effect in urban than in rural areas. INTERPRETATION: Having a primary physician and greater continuity of care with this physician are factors associated with decreased emergency department use by elderly people, particularly those living in urban areas. [Abstract/Link to Full Text]

Kent WD, Hall SF, Isotalo PA, Houlden RL, George RL, Groome PA
Increased incidence of differentiated thyroid carcinoma and detection of subclinical disease.
CMAJ. 2007 Nov 20;177(11):1357-61.
BACKGROUND: Recent reports from North America and Europe have documented an annual increase in the incidence of differentiated thyroid carcinoma. We sought to investigate the relation between rates of detection, tumour size, age and sex. METHODS: Using the Ontario Cancer Registry, we identified 7422 cases of differentiated thyroid carcinoma diagnosed from Jan. 1, 1990, to Dec. 31, 2001. We obtained pathology reports for a random 10% of the 7422 patients for each year of the study period. The sample represented all Cancer Care Ontario regions. We compared the size of the patients' tumours by year, sex and age. RESULTS: As expected, the incidence of differentiated thyroid carcinoma increased over the 12-year period. A significantly higher number of small (< or = 2 cm), nonpalpable tumours were resected in 2001 than in 1990 (p = 0.001). The incidence of tumours 2-4 cm in diameter remained stable. When we examined differences in tumour detection rates by age and sex, we observed a disproportionate increase in the number of small tumours detected among women and among patients older than 45 years. INTERPRETATION: Our findings suggest that more frequent use of medical imaging has led to an increased detection rate of small, subclinical tumours, which in turn accounts for the higher incidence of differentiated thyroid carcinoma. This suggests that we need to re-evaluate our understanding of the trends in thyroid cancer incidence. [Abstract/Link to Full Text]

Siegrist CA
Autoimmune diseases after adolescent or adult immunization: what should we expect?
CMAJ. 2007 Nov 20;177(11):1352-4. [Abstract/Link to Full Text]

Lim R, Peddle M
Penetrating pharyngeal injury in an infant.
CMAJ. 2007 Nov 20;177(11):1351-2. [Abstract/Link to Full Text]

Baerlocher MO
Adult literacy rates in African and Eastern Mediterranean countries.
CMAJ. 2007 Nov 20;177(11):1347. [Abstract/Link to Full Text]

Jassam J
Unprohibited crimes.
CMAJ. 2007 Nov 20;177(11):1345. [Abstract/Link to Full Text]

Bagchi S
Arsenic threat reaching global dimensions.
CMAJ. 2007 Nov 20;177(11):1344-5. [Abstract/Link to Full Text]

Jones D
Alberta to limit self-regulation.
CMAJ. 2007 Nov 20;177(11):1342. [Abstract/Link to Full Text]

Silversides A
Slouching toward disclosure.
CMAJ. 2007 Nov 20;177(11):1342-3. [Abstract/Link to Full Text]

O'Neil P
China's doctors signal retreat on organ harvest.
CMAJ. 2007 Nov 20;177(11):1341. [Abstract/Link to Full Text]

Jones D
On-the-job training.
CMAJ. 2007 Nov 20;177(11):1341-2. [Abstract/Link to Full Text]

Jones D
Health authority bans physician shadowing.
CMAJ. 2007 Nov 20;177(11):1339-40. [Abstract/Link to Full Text]

Straus S, Stelfox T
Whose life is it anyway? Capacity and consent in Canada.
CMAJ. 2007 Nov 20;177(11):1329, 1331. [Abstract/Link to Full Text]

Recent Articles in The Journal of Clinical Investigation

Demetri GD
Structural reengineering of imatinib to decrease cardiac risk in cancer therapy.
J Clin Invest. 2007 Dec;117(12):3650-3.
Imatinib, a selective, small-molecule tyrosine kinase inhibitor, has life-saving clinical activity in certain cancers, but questions have been raised about the potential for cardiac toxicity through inhibition of its target, ABL kinase. In this issue of the JCI, Fernández et al. describe a novel method by which the ABL-inhibitory activity of imatinib was deleted by modifying its chemical structure (see the related article beginning on page 4044). The anticancer activity of the reengineered agent, called WBZ_4, was instead preserved against gastrointestinal stromal tumors in both in vitro and in vivo models via inhibition of KIT tyrosine kinase, and the desired safety was demonstrated with less cardiotoxicity of WBZ_4 compared with imatinib via the inhibition of JNK. The study shows that structural reengineering of a kinase-inhibitory drug to improve tolerability while preserving efficacy is feasible. [Abstract/Link to Full Text]

Tononi G, Cirelli C
Staying awake puts pressure on brain arousal systems.
J Clin Invest. 2007 Dec;117(12):3648-50.
Many brain centers are involved in keeping us awake. One example is the recently discovered hypocretin system located in the posterior hypothalamus. In this issue of the JCI, Rao et al. show that, in mice, synapses targeting hypocretin neurons become stronger when wakefulness is prolonged beyond its physiological duration (see the related article beginning on page 4022). This increase in synaptic strength may be one of the mechanisms that help us to stay awake when we are sleep deprived, but it may also represent one of the signals telling the brain that it is time to sleep. [Abstract/Link to Full Text]

Contreras AG, Briscoe DM
Every allograft needs a silver lining.
J Clin Invest. 2007 Dec 3;117(12):3645-3648.
The development of chronic allograft rejection is based on the hypothesis that cumulative, time-dependent tissue injury eventually leads to a fibrotic response. In this issue of the JCI, Babu and colleagues found that alloimmune-mediated microvascular loss precedes tissue damage in murine orthotopic tracheal allografts (see the related article beginning on page 3774). The concept that injury to the endothelium may precede airway fibrosis suggests that interventions to maintain vascular integrity may be important, especially in the case of lung transplantation. Further, for all solid organ allografts, it is possible that the key to long-term allograft survival is physiological vascular repair at early times following transplantation. [Abstract/Link to Full Text]

Bour-Jordan H, Bluestone JA
B cell depletion: a novel therapy for autoimmune diabetes?
J Clin Invest. 2007 Dec;117(12):3642-5.
Autoimmune diabetes is believed to be mediated primarily by T cells. However, B cells have been implicated in the pathogenesis of the disease in NOD mice. Although preclinical studies have been limited by the absence of anti-CD20 reagents that can induce B cell depletion in mice, a clinical trial using the B cell-depleting anti-CD20 monoclonal antibody rituximab (Rituxan) is underway in type 1 diabetes patients. In this issue of the JCI, Hu et al. describe the generation of transgenic NOD mice that express human CD20 on B cells (see the related article beginning on page 3857). They show that anti-CD20 therapy induces B cell depletion in these mice and offers some level of protection against diabetes. Although many questions remain unanswered, this mouse model represents the first opportunity to evaluate the potential value of rituximab as a novel therapy for autoimmune diabetes. [Abstract/Link to Full Text]

Grimm D, Kay MA
Therapeutic application of RNAi: is mRNA targeting finally ready for prime time?
J Clin Invest. 2007 Dec;117(12):3633-41.
With unprecedented speed, RNA interference (RNAi) has advanced from its basic discovery in lower organisms to becoming a powerful genetic tool and perhaps our single most promising biotherapeutic for a wide array of diseases. Numerous studies document RNAi efficacy in laboratory animals, and the first clinical trials are underway and thus far suggest that RNAi is safe to use in humans. Yet substantial hurdles have also surfaced and must be surmounted before therapeutic RNAi applications can become a standard therapy. Here we review the most critical roadblocks and concerns for clinical RNAi transition, delivery, and safety. We highlight emerging solutions and concurrently discuss novel therapeutic RNAi-based concepts. The current rapid advances create realistic optimism that the establishment of RNAi as a new and potent clinical modality in humans is near. [Abstract/Link to Full Text]

Akhtar S, Benter IF
Nonviral delivery of synthetic siRNAs in vivo.
J Clin Invest. 2007 Dec;117(12):3623-32.
Sequence-specific gene silencing using small interfering RNA (siRNA) is a Nobel prize-winning technology that is now being evaluated in clinical trials as a potentially novel therapeutic strategy. This article provides an overview of the major pharmaceutical challenges facing siRNA therapeutics, focusing on the delivery strategies for synthetic siRNA duplexes in vivo, as this remains one of the most important issues to be resolved. This article also highlights the importance of understanding the genocompatibility/toxicogenomics of siRNA delivery reagents in terms of their impact on gene-silencing activity and specificity. Collectively, this information is essential for the selection of optimally acting siRNA delivery system combinations for the many proposed applications of RNA interference. [Abstract/Link to Full Text]

Corey DR
Chemical modification: the key to clinical application of RNA interference?
J Clin Invest. 2007 Dec;117(12):3615-22.
RNA interference provides a potent and specific method for controlling gene expression in human cells. To translate this potential into a broad new family of therapeutics, it is necessary to optimize the efficacy of the RNA-based drugs. As discussed in this Review, it might be possible to achieve this optimization using chemical modifications that improve their in vivo stability, cellular delivery, biodistribution, pharmacokinetics, potency, and specificity. [Abstract/Link to Full Text]

Gewirtz AM
On future's doorstep: RNA interference and the pharmacopeia of tomorrow.
J Clin Invest. 2007 Dec;117(12):3612-4.
Small molecules and antibodies have revolutionized the treatment of malignant diseases and appear promising for the treatment of many others. Nonetheless, there are many candidate therapeutic targets that are not amenable to attack by the current generation of targeted therapies, and in a small but growing number of patients, resistance to initially successful treatments evolves. This Review Series on the medicinal promise of posttranscriptional gene silencing with small interfering RNA and other molecules capable of inducing RNA interference (RNAi) is motivated by the hypothesis that effectors of RNAi can be developed into effective drugs for treating malignancies as well as many other types of disease. As this Review Series points out, there is still much to do, but many in the field now hope that the time has finally arrived when "antisense" therapies will finally come of age and fulfill their promise as the magic bullets of the 21st century. [Abstract/Link to Full Text]

Drenth JP, Waxman SG
Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders.
J Clin Invest. 2007 Dec 3;117(12):3603-3609.
The voltage-gated sodium-channel type IX alpha subunit, known as Na(v)1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Na(v)1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Na(v)1.7 in pain sensation in humans. [Abstract/Link to Full Text]

Neill US
How to write a scientific masterpiece.
J Clin Invest. 2007 Dec;117(12):3599-602.
I've been asked several times to give talks about various aspects of the scientific publishing enterprise, and sometimes to comment specifically on how to write a manuscript that will have maximal impact. While many in my audiences have felt that my presentations are designed for students and trainees, I hope everyone listens, as sometimes even established scientists are prone to making mistakes. I hope here to outline a few pointers that will help your manuscripts skate through the submission and peer review process. Some points may be elementary, but all bear repeating. [Abstract/Link to Full Text]

Honey K
Protection against malaria a real possibility.
J Clin Invest. 2007 Dec;117(12):3596. [Abstract/Link to Full Text]

Belguise K, Sonenshein GE
PKCtheta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor alpha synthesis.
J Clin Invest. 2007 Dec 3;117(12):4009-4021.
The vast majority of primary human breast cancer tissues display aberrant nuclear NF-kappaB c-Rel expression. A causal role for c-Rel in mammary tumorigenesis has been demonstrated using a c-Rel transgenic mouse model; however, tumors developed with a long latency, suggesting a second event is needed to trigger tumorigenesis. Here we show that c-Rel activity in the mammary gland is repressed by estrogen receptor alpha (ERalpha) signaling, and we identify an epigenetic mechanism in breast cancer mediated by activation of what we believe is a novel PKCtheta-Akt pathway that leads to downregulation of ERalpha synthesis and derepression of c-Rel. ERalpha levels were lower in c-Rel-induced mammary tumors compared with normal mammary gland tissue. PKCtheta induced c-Rel activity and target gene expression and promoted growth of c-Rel- and c-RelxCK2alpha-driven mouse mammary tumor-derived cell lines. RNA expression levels of PKCtheta and c-Rel target genes were inversely correlated with ERalpha levels in human breast cancer specimens. PKCtheta activated Akt, thereby inactivating forkhead box O protein 3a (FOXO3a) and leading to decreased synthesis of its target genes, ERalpha and p27(Kip1). Thus we have shown that activation of PKCtheta inhibits the FOXO3a/ERalpha/p27(Kip1) axis that normally maintains an epithelial cell phenotype and induces c-Rel target genes, thereby promoting proliferation, survival, and more invasive breast cancer. [Abstract/Link to Full Text]

Panicot-Dubois L, Thomas GM, Furie BC, Furie B, Lombardo D, Dubois C
Bile salt-dependent lipase interacts with platelet CXCR4 and modulates thrombus formation in mice and humans.
J Clin Invest. 2007 Dec;117(12):3708-19.
Bile salt-dependent lipase (BSDL) is an enzyme involved in the duodenal hydrolysis and absorption of cholesteryl esters. Although some BSDL is transported to blood, the role of circulating BSDL is unknown. Here, we demonstrate that BSDL is stored in platelets and released upon platelet activation. Because BSDL contains a region that is structurally homologous to the V3 loop of HIV-1, which binds to CXC chemokine receptor 4 (CXCR4), we hypothesized that BSDL might bind to CXCR4 present on platelets. In human platelets in vitro, both BSDL and a peptide corresponding to its V3-like loop induced calcium mobilization and enhanced thrombin-mediated platelet aggregation, spreading, and activated alpha(IIb)beta(3) levels. These effects were abolished by CXCR4 inhibition. BSDL also increased the production of prostacyclin by human endothelial cells. In a mouse thrombosis model, BSDL accumulated at sites of vessel wall injury. When CXCR4 was antagonized, the accumulation of BSDL was inhibited and thrombus size was reduced. In BSDL(-/-) mice, calcium mobilization in platelets and thrombus formation were attenuated and tail bleeding times were increased in comparison with those of wild-type mice. We conclude that BSDL plays a role in optimal platelet activation and thrombus formation by interacting with CXCR4 on platelets. [Abstract/Link to Full Text]

Hu K, Wu C, Mars WM, Liu Y
Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor-related protein 1-mediated integrin signaling.
J Clin Invest. 2007 Dec;117(12):3821-32.
The activation of interstitial fibroblasts to become alpha-SMA-positive myofibroblasts is an essential step in the evolution of chronic kidney fibrosis, as myofibroblasts are responsible for the production and deposition of the ECM components that are a hallmark of the disease. Here we describe a signaling pathway that leads to this activation. Tissue-type plasminogen activator (tPA) promoted TGF-beta1-mediated alpha-SMA and type I collagen expression in rat kidney interstitial fibroblasts. This fibrogenic effect was independent of its protease activity but required its membrane receptor, the LDL receptor-related protein 1 (LRP-1). In rat kidney fibroblasts, tPA induced rapid LRP-1 tyrosine phosphorylation and enhanced beta1 integrin recruitment by facilitating the LRP-1/beta1 integrin complex formation. Blockade or knockdown of beta1 integrin abolished type I collagen and alpha-SMA expression. Furthermore, inhibition of the integrin-linked kinase (ILK), a downstream effector of beta1 integrin, or disruption of beta1 integrin/ILK engagement, abrogated the tPA action, whereas ectopic expression of ILK mimicked tPA in promoting myofibroblast activation. In murine renal interstitium after obstructive injury, tPA and alpha-SMA colocalized with LRP-1, and tPA deficiency reduced LRP-1/beta1 integrin interaction and myofibroblast activation. These findings show that tPA induces LRP-1 tyrosine phosphorylation, which in turn facilitates the LRP-1-mediated recruitment of beta1 integrin and downstream ILK signaling, thereby leading to myofibroblast activation. This study implicates tPA as a fibrogenic cytokine that promotes the progression of kidney fibrosis. [Abstract/Link to Full Text]

Burkart EM, Sambandam N, Han X, Gross RW, Courtois M, Gierasch CM, Shoghi K, Welch MJ, Kelly DP
Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart.
J Clin Invest. 2007 Dec;117(12):3930-9.
In the diabetic heart, chronic activation of the PPARalpha pathway drives excessive fatty acid (FA) oxidation, lipid accumulation, reduced glucose utilization, and cardiomyopathy. The related nuclear receptor, PPARbeta/delta, is also highly expressed in the heart, yet its function has not been fully delineated. To address its role in myocardial metabolism, we generated transgenic mice with cardiac-specific expression of PPARbeta/delta, driven by the myosin heavy chain (MHC-PPARbeta/delta mice). In striking contrast to MHC-PPARalpha mice, MHC-PPARbeta/delta mice had increased myocardial glucose utilization, did not accumulate myocardial lipid, and had normal cardiac function. Consistent with these observed metabolic phenotypes, we found that expression of genes involved in cellular FA transport were activated by PPARalpha but not by PPARbeta/delta. Conversely, cardiac glucose transport and glycolytic genes were activated in MHC-PPARbeta/delta mice, but repressed in MHC-PPARalpha mice. In reporter assays, we showed that PPARbeta/delta and PPARalpha exerted differential transcriptional control of the GLUT4 promoter, which may explain the observed isotype-specific effects on glucose uptake. Furthermore, myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPARbeta/delta mice compared with control or MHC-PPARalpha mice, consistent with an increased capacity for myocardial glucose utilization. These results demonstrate that PPARalpha and PPARbeta/delta drive distinct cardiac metabolic regulatory programs and identify PPARbeta/delta as a potential target for metabolic modulation therapy aimed at cardiac dysfunction caused by diabetes and ischemia. [Abstract/Link to Full Text]

Castelo-Branco M, Mendes M, Sebastião AR, Reis A, Soares M, Saraiva J, Bernardes R, Flores R, Pérez-Jurado L, Silva E
Visual phenotype in Williams-Beuren syndrome challenges magnocellular theories explaining human neurodevelopmental visual cortical disorders.
J Clin Invest. 2007 Dec 3;117(12):3720-3729.
Williams-Beuren syndrome (WBS), a neurodevelopmental genetic disorder whose manifestations include visuospatial impairment, provides a unique model to link genetically determined loss of neural cell populations at different levels of the nervous system with neural circuits and visual behavior. Given that several of the genes deleted in WBS are also involved in eye development and the differentiation of retinal layers, we examined the retinal phenotype in WBS patients and its functional relation to global motion perception. We discovered a low-level visual phenotype characterized by decreased retinal thickness, abnormal optic disk concavity, and impaired visual responses in WBS patients compared with age-matched controls by using electrophysiology, confocal and coherence in vivo imaging with cellular resolution, and psychophysics. These mechanisms of impairment are related to the magnocellular pathway, which is involved in the detection of temporal changes in the visual scene. Low-level magnocellular performance did not predict high-level deficits in the integration of motion and 3D information at higher levels, thereby demonstrating independent mechanisms of dysfunction in WBS that will require remediation strategies different from those used in other visuospatial disorders. These findings challenge neurodevelopmental theories that explain cortical deficits based on low-level magnocellular impairment, such as regarding dyslexia. [Abstract/Link to Full Text]

Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH
Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition.
J Clin Invest. 2007 Dec 3;117(12):3810-3820.
Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT. [Abstract/Link to Full Text]

Jurisicova A, Taniuchi A, Li H, Shang Y, Antenos M, Detmar J, Xu J, Matikainen T, Benito Hernández A, Nunez G, Casper RF
Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri.
J Clin Invest. 2007 Dec 3;117(12):3971-3978.
Maternal smoking during pregnancy is associated with a variety of adverse neonatal outcomes including altered reproductive performance. Herein we provide molecular evidence for a pathway involved in the elimination of the female germline due to prepregnancy and/or lactational exposure to polycyclic aromatic hydrocarbons (PAHs), environmental toxicants found in cigarette smoke. We show that ovaries of offspring born to mice exposed to PAHs contained only a third of the ovarian follicle pool compared with offspring of unexposed female mice. Activation of the cell death pathway in immature follicles of exposed females was mediated by the aryl hydrocarbon receptor (Ahr), as ovarian reserve was fully rescued by maternal cotreatment with the Ahr antagonist, resveratrol, or by inactivation of the Ahr gene. Furthermore, in response to PAHs, Ahr-mediated activation of the harakiri, BCL2 interacting protein (contains only BH3 domain), was necessary for execution of cell death. This pathway appeared to be conserved between mouse and human, as xenotransplanted human ovarian cortex exposed to PAHs responded by activation of the identical cell death cascade. Our data indicate that maternal exposure to PAHs prior to pregnancy and/or during lactation compromises ovarian reserve of female offspring, raising the concern about the transgenerational impact of maternal smoking on ovarian function in the human. [Abstract/Link to Full Text]

Tan SY, Rosenthal J, Zhao XQ, Francis RJ, Chatterjee B, Sabol SL, Linask KL, Bracero L, Connelly PS, Daniels MP, Yu Q, Omran H, Leatherbury L, Lo CW
Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia.
J Clin Invest. 2007 Dec 3;117(12):3742-3752.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder associated with ciliary defects and situs inversus totalis, the complete mirror image reversal of internal organ situs (positioning). A variable incidence of heterotaxy, or irregular organ situs, also has been reported in PCD patients, but it is not known whether this is elicited by the PCD-causing genetic lesion. We studied a mouse model of PCD with a recessive mutation in Dnahc5, a dynein gene commonly mutated in PCD. Analysis of homozygous mutant embryos from 18 litters yielded 25% with normal organ situs, 35% with situs inversus totalis, and 40% with heterotaxy. Embryos with heterotaxy had complex structural heart defects that included discordant atrioventricular and ventricular outflow situs and atrial/pulmonary isomerisms. Variable combinations of a distinct set of cardiovascular anomalies were observed, including superior-inferior ventricles, great artery alignment defects, and interrupted inferior vena cava with azygos continuation. The surprisingly high incidence of heterotaxy led us to evaluate the diagnosis of PCD. PCD was confirmed by EM, which revealed missing outer dynein arms in the respiratory cilia. Ciliary dyskinesia was observed by videomicroscopy. These findings show that Dnahc5 is required for the specification of left-right asymmetry and suggest that the PCD-causing Dnahc5 mutation may also be associated with heterotaxy. [Abstract/Link to Full Text]

Shing DC, Trubia M, Marchesi F, Radaelli E, Belloni E, Tapinassi C, Scanziani E, Mecucci C, Crescenzi B, Lahortiga I, Odero MD, Zardo G, Gruszka A, Minucci S, Di Fiore PP, Pelicci PG
Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice.
J Clin Invest. 2007 Dec 3;117(12):3696-3707.
Transgenic expression of the abnormal products of acute myeloid leukemia-associated (AML-associated) primary chromosomal translocations in hematopoietic stem/progenitor cells initiates leukemogenesis in mice, yet additional mutations are needed for leukemia development. We report here aberrant expression of PR domain containing 16 (PRDM16) in AML cells with either translocations of 1p36 or normal karyotype. These carried, respectively, relatively high prevalence of mutations in the TP53 tumor suppressor gene and in the nucleophosmin (NPM) gene, which regulates p53. Two protein isoforms are expressed from PRDM16, which differ in the presence or absence of the PR domain. Overexpression of the short isoform, sPRDM16, in mouse bone marrow induced AML with full penetrance, but only in the absence of p53. The mouse leukemias were characterized by multilineage cellular abnormalities and megakaryocyte dysplasia, a common feature of human AMLs with 1p36 translocations or NPM mutations. Overexpression of sPRDM16 increased the pool of HSCs in vivo, and in vitro blocked myeloid differentiation and prolonged progenitor life span. Loss of p53 augmented the effects of sPRDM16 on stem cell number and induced immortalization of progenitors. Thus, overexpression of sPRDM16 induces abnormal growth of stem cells and progenitors and cooperates with disruption of the p53 pathway in the induction of myeloid leukemia. [Abstract/Link to Full Text]

Suliman HB, Carraway MS, Ali AS, Reynolds CM, Welty-Wolf KE, Piantadosi CA
The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.
J Clin Invest. 2007 Dec;117(12):3730-41.
The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis. [Abstract/Link to Full Text]

Lin SW, Hensley SE, Tatsis N, Lasaro MO, Ertl HC
Recombinant adeno-associated virus vectors induce functionally impaired transgene product-specific CD8 T cells in mice.
J Clin Invest. 2007 Dec;117(12):3958-70.
Recombinant adeno-associated virus (rAAV) vectors were used in human trials as carriers of vaccines for HIV-1 after encouraging preclinical results. However, the clinical trials yielded disappointing results. Here we demonstrated that in mice, rAAV vectors expressing the gene encoding HIV-1 gag stimulated gag-specific CD8(+) T cells, but these T cells failed to expand after a booster immunization with a replication-defective adenoviral (Ad) vector also expressing gag. We tested rAAV vectors of different serotypes expressing HIV-1 gag for induction of transgene product-specific CD8(+) T cells and found that the immunoinhibitory effect of rAAV priming observed with different AAV serotypes was transgene product specific, was independent of the interval between prime and boost, and extended to boosts with vaccine modalities other than Ad vectors. rAAV vector-induced CD8(+) T cells proliferated poorly, produced low levels of IFN-gamma in response to gag stimulation, and upregulated immunoinhibitory molecules. These T cells did not protect efficiently against challenge with a surrogate pathogen. Finally, we showed that the impaired proliferative capacity of the T cells was caused by persistence of the antigen-encoding rAAV vectors and could be reversed by placing the CD8(+) T cells in an antigen-free environment. Our data suggest that rAAV vectors induce functionally impaired T cells and could dampen the immune response to a natural infection. [Abstract/Link to Full Text]

Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA
Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy.
J Clin Invest. 2007 Dec;117(12):3952-7.
In myotonic dystrophy (dystrophia myotonica [DM]), an increase in the excitability of skeletal muscle leads to repetitive action potentials, stiffness, and delayed relaxation. This constellation of features, collectively known as myotonia, is associated with abnormal alternative splicing of the muscle-specific chloride channel (ClC-1) and reduced conductance of chloride ions in the sarcolemma. However, the mechanistic basis of the chloride channelopathy and its relationship to the development of myotonia are uncertain. Here we show that a morpholino antisense oligonucleotide (AON) targeting the 3' splice site of ClC-1 exon 7a reversed the defect of ClC-1 alternative splicing in 2 mouse models of DM. By repressing the inclusion of this exon, the AON restored the full-length reading frame in ClC-1 mRNA, upregulated the level of ClC-1 mRNA, increased the expression of ClC-1 protein in the surface membrane, normalized muscle ClC-1 current density and deactivation kinetics, and eliminated myotonic discharges. These observations indicate that the myotonia and chloride channelopathy observed in DM both result from abnormal alternative splicing of ClC-1 and that antisense-induced exon skipping offers a powerful method for correcting alternative splicing defects in DM. [Abstract/Link to Full Text]

Liu T, Chung MJ, Ullenbruch M, Yu H, Jin H, Hu B, Choi YY, Ishikawa F, Phan SH
Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice.
J Clin Invest. 2007 Dec;117(12):3800-9.
In addition to its well-known expression in the germline and in cells of certain cancers, telomerase activity is induced in lung fibrosis, although its role in this process is unknown. To identify the pathogenetic importance of telomerase in lung fibrosis, we examined the effects of telomerase reverse transcriptase (TERT) deficiency in a murine model of pulmonary injury. TERT-deficient mice showed significantly reduced lung fibrosis following bleomycin (BLM) insult. This was accompanied by a significant reduction in expression of lung alpha-SMA, a marker of myofibroblast differentiation. Furthermore, lung fibroblasts isolated from BLM-treated TERT-deficient mice showed significantly decreased proliferation and increased apoptosis rates compared with cells isolated from control mice. Transplantation of WT BM into TERT-deficient mice restored BLM-induced lung telomerase activity and fibrosis to WT levels. Conversely, transplantation of BM from TERT-deficient mice into WT recipients resulted in reduced telomerase activity and fibrosis. These findings suggest that induction of telomerase in injured lungs may be caused by BM-derived cells, which appear to play an important role in pulmonary fibrosis. Moreover, TERT induction is associated with increased survival of lung fibroblasts, which favors the development of fibrosis instead of injury resolution. [Abstract/Link to Full Text]

Vijay-Kumar M, Sanders CJ, Taylor RT, Kumar A, Aitken JD, Sitaraman SV, Neish AS, Uematsu S, Akira S, Williams IR, Gewirtz AT
Deletion of TLR5 results in spontaneous colitis in mice.
J Clin Invest. 2007 Dec;117(12):3909-21.
Activation of TLRs by bacterial products results in rapid activation of genes encoding products designed to protect the host from perturbing microbes. In the intestine, which is colonized by a large and diverse population of commensal bacteria, TLR signaling may not function in a simple on/off mode. Here, we show that the flagellin receptor TLR5 has an essential and nonredundant role in protecting the gut from enteric microbes. Mice lacking TLR5 (TLR5KO mice) developed spontaneous colitis, as assessed by well-defined clinical, serologic, and histopathologic indicators of this disorder. Compared with WT littermates, TLR5KO mice that had not yet developed robust colitis exhibited decreased intestinal expression of TLR5-regulated host defense genes despite having an increased bacterial burden in the colon. In contrast, such TLR5KO mice displayed markedly increased colonic expression of hematopoietic-derived proinflammatory cytokines, suggesting that elevated levels of bacterial products may result in activation of other TLRs that drive colitis in TLR5KO mice. In accordance, deletion of TLR4 rescued the colitis of TLR5KO mice in that mice lacking both TLR4 and TLR5 also had elevated bacterial loads in the colon but lacked immunological, histopathological, and clinical evidence of colitis. That an engineered innate immune deficiency ultimately results in spontaneous intestinal inflammation supports the notion that an innate immune deficiency might underlie some instances of inflammatory bowel disease. [Abstract/Link to Full Text]

Bu HF, Zuo XL, Wang X, Ensslin MA, Koti V, Hsueh W, Raymond AS, Shur BD, Tan XD
Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium.
J Clin Invest. 2007 Dec 3;117(12):3673-3683.
Milk fat globule-EGF factor 8 (MFG-E8)/lactadherin participates in several cell surface-mediated regulatory events. Although its mRNA is present in the gut, the physiological roles of MFG-E8 in the intestinal mucosa have not been explored. Here we show that MFG-E8 was expressed in intestinal lamina propria macrophages from mice. Using a wound-healing assay, MFG-E8 was shown to promote the migration of intestinal epithelial cells through a PKCepsilon-dependent mechanism. MFG-E8 bound to phosphatidylserine and triggered reorientation of the actin cytoskeleton in intestinal epithelial cells at the wound edge. Depleting MFG-E8 in mice by administration of anti-MFG-E8 antibody or targeted deletion of the MFG-E8 gene resulted in a slowing of enterocyte migration along the crypt-villus axis and focal mucosal injury. Moreover, in septic mice, intestinal MFG-E8 expression was downregulated, which correlated with intestinal injury, interrupted enterocyte migration, and impaired restitution. Treatment with recombinant MFG-E8 restored enterocyte migration, whereas deletion of MFG-E8 impeded mucosal healing in mice with sepsis. These results suggest that a decrease in intestinal MFG-E8 impairs intestinal mucosal repair in sepsis. Together, our data indicate that MFG-E8 plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing and suggest that recombinant MFG-E8 may be beneficial for the treatment of bowel injuries. [Abstract/Link to Full Text]

Zuo T, Liu R, Zhang H, Chang X, Liu Y, Wang L, Zheng P, Liu Y
FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2.
J Clin Invest. 2007 Dec;117(12):3765-73.
S-phase kinase-associated protein 2 (SKP2) is a component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex. Overexpression of SKP2 results in cell cycle dysregulation and carcinogenesis; however, the genetic lesions that cause this upregulation are poorly understood. We recently demonstrated that forkhead box P3 (FOXP3) is an X-linked breast cancer suppressor and an important repressor of the oncogene ERBB2/HER2. Since FOXP3 suppresses tumor growth regardless of whether the tumors overexpress ERBB2/HER2, additional FOXP3 targets may be involved in its tumor suppressor activity. Here, we show that mammary carcinomas from mice heterozygous for a Foxp3 mutation exhibited increased Skp2 expression. Ectopic expression of FOXP3 in mouse mammary cancer cells repressed SKP2 expression with a corresponding increase in p27 and polyploidy. Conversely, siRNA silencing of the FOXP3 gene in human mammary epithelial cells increased SKP2 expression. We also show that Foxp3 directly interacted with and repressed the Skp2 promoter. Moreover, the analysis of over 200 primary breast cancer samples revealed an inverse correlation between FOXP3 and SKP2 levels. Finally, we demonstrated that downregulation of SKP2 was critical for FOXP3-mediated growth inhibition in breast cancer cells that do not overexpress ERBB2/HER2. Our data provide genetic, biochemical, and functional evidence that FOXP3 is a novel transcriptional repressor for the oncogene SKP2. [Abstract/Link to Full Text]

Petermann KB, Rozenberg GI, Zedek D, Groben P, McKinnon K, Buehler C, Kim WY, Shields JM, Penland S, Bear JE, Thomas NE, Serody JS, Sharpless NE
CD200 is induced by ERK and is a potential therapeutic target in melanoma.
J Clin Invest. 2007 Dec 3;117(12):3922-3929.
Immune-mediated antitumor responses occur in patients with metastatic melanoma (MM), and therapies designed to augment such responses are clinically beneficial. Despite the immunogenicity of melanoma, immunomodulatory therapies fail in the majority of patients with MM. An inability of DCs to sufficiently activate effector cells may, in part, underlie this failure of the antitumor response seen in most patients. In this work, we show that mutation of N-RAS or B-RAF, signature genetic lesions present in most MMs, potently induced the expression of cell-surface CD200, a repressor of DC function. Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. CD200 mRNA expression correlated with progression and was higher in melanoma than in other solid tumors or acute leukemia. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect. These data indicate that in addition to its effects on growth, survival, and motility, ERK activation in MM attenuates a host antitumor immune response, implicating CD200 and its interaction with the CD200 receptor as a potential therapeutic target for MM. [Abstract/Link to Full Text]

Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, Schnyder B, Akira S, Quesniaux VF, Lagente V, Ryffel B, Couillin I
IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice.
J Clin Invest. 2007 Dec;117(12):3786-99.
The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis. [Abstract/Link to Full Text]

Yvan-Charvet L, Ranalletta M, Wang N, Han S, Terasaka N, Li R, Welch C, Tall AR
Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice.
J Clin Invest. 2007 Dec;117(12):3900-8.
HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediated sterol efflux in this disease process, we transplanted BM from Abca1(-/-)Abcg1(-/-) mice into LDL receptor-deficient mice and administered a high-cholesterol diet. Compared with control and single-KO BM recipients, Abca1(-/-)Abcg1(-/-) BM recipients showed accelerated atherosclerosis and extensive infiltration of the myocardium and spleen with macrophage foam cells. In experiments with isolated macrophages, combined ABCA1 and ABCG1 deficiency resulted in impaired cholesterol efflux to HDL or apoA-1, profoundly decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines. In addition, these cells showed increased apoptosis when challenged with free cholesterol or oxidized LDL loading. These results suggest that the combined effects of ABCA1 and ABCG1 in mediating macrophage sterol efflux are central to the antiatherogenic properties of HDL. [Abstract/Link to Full Text]

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

Talar-Wojnarowska R, Malecka-Panas E
Molecular pathogenesis of pancreatic adenocarcinoma: potential clinical implications.
Med Sci Monit. 2006 Sep;12(9):RA186-93.
Despite scientific efforts and significant progress in understanding the basic cellular event in pancreatic adenocarcinoma (PA), survival rates have not changed much during the last 20 years. Prognosis in pancreatic cancer remains unsatisfactory due to its late clinical presentation, low surgical resectability rates, and resistance to chemotherapy. Novel therapeutic strategies are needed in order to improve the prognosis of patients with PA. Improvement of our knowledge of the molecular biology of pancreatic cancer may have important clinical implications in pancreatic cancer risk assessment, early diagnosis, and management. In human pancreatic cancer, a specific sequence of oncogene and tumor suppressor gene alterations is observed, including K-ras, HER-2/neu, p16, p53, and DPC4. The prevalence of these genetic alterations rises with increasing severity of dysplasia of the ductal mucosal lesions. Drugs that target these molecular abnormalities hold great promise for PA treatment in the near future. The focus of this review is to evaluate the gene mutations in pancreatic cancer, with emphasis on those studies that are most important to the clinical practice. Our review also summarizes current aspects of PA treatment and the differential diagnosis of pancreatic cancer and chronic pancreatitis. [Abstract/Link to Full Text]

Wang X, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C
Mouse models of neointimal hyperplasia: techniques and applications.
Med Sci Monit. 2006 Sep;12(9):RA177-85.
Neointimal hyperplasia is a major cause of the failure in vascular reconstructive procedures such as angioplasty, vascular stenting, small caliber vascular graft, and vein graft. However, the underlying molecular mechanisms are not yet fully understood. The study of neointimal hyperplasia has relied heavily on the use of experimental animal models. Recent development in gene manipulation techniques in mice offers a unique opportunity to unravel the molecular basis of the neointimal response at the genetic level, which is critical to develop new strategies to prevent human neointimal hyperplasia. Several mouse models for studying neointimal hyperplasia have recently been established including blood-flow cessation, mechanical injury, and vein bypass graft. In an attempt to elaborate these models, this review highlights the characteristics, advantages, disadvantages, and applications of these mouse models in vascular disease. In addition, the difference between mouse models and human lesions is discussed. Thus, this review provides updated information and helps vascular surgeons and other vascular biologists in selecting appropriate mouse models for their research on neointimal hyperplasia. [Abstract/Link to Full Text]

Sato H, Akabayashi A, Kai I
Appraisal of the policymaking process in Japan for gene therapy: results of national surveys of academic societies, hospitals, and medical schools.
Med Sci Monit. 2006 Sep;12(9):PH7-15.
BACKGROUND: Since 1993, government agencies in Japan have introduced a series of guidelines for gene therapy clinical trials. Appraisals of these guidelines were obtained from academic societies, institutional review boards (IRBs) of hospitals, and ethics committees (ECs) at medical schools nationwide. MATERIAL/METHODS: Using data from a large-scale national opinion survey, this study evaluates the experts' appraisals of the contents of these official guidelines in Japan and the process of their development. RESULTS: 26.3% of the respondents from academic societies and 39.3% of those from university ECs gave positive appraisals of the speediness of the decision process for the 1994 guidelines. Appraisals of speediness improved for the 2002 guidelines. Concerning the clarity of the 1994 guidelines, the proportion of positive appraisals was slightly smaller than negative appraisals among academic societies and hospital IRBs, though the majority of university ECs gave positive ratings. The 2002 guidelines were appraised significantly more positively than the 1994 guidelines. Information received after the decision was consistently rated better than the information before the decision. All groups reported that the opinions of patients and those of citizens were less adequately considered than were the opinions of experts. A majority of respondents rated information disclosure as important for future agendas. CONCLUSIONS: Clarity of the guidelines could be improved by revision. More information disclosure was considered desirable, especially information available before decisions are made. Incorporation of patients and citizens in policymaking is an important future goal. [Abstract/Link to Full Text]

Banerjee B
Topical honey application vs. acyclovir for the treatment of recurrent herpes simplex lesions.
Med Sci Monit. 2006 Sep;12(9):LE18. [Abstract/Link to Full Text]

Al-Waili NS
Topical honey application vs. acyclovir for the treatment of recurrent herpes simplex lesions.
Med Sci Monit. 2004 Aug;10(8):MT94-8.
BACKGROUND: The objective of this research was to investigate the effect of the topical application of honey on recurrent attacks of herpes lesions, labial and genital, as compared to acyclovir cream. MATERIAL/METHODS: Sixteen adult patients with a history of recurrent attacks of herpetic lesions, 8 labial and 8 genital, were treated by topical application of honey for one attack and acyclovir cream for another attack. RESULTS: For labial herpes, the mean duration of attacks and pain, occurrence of crusting, and mean healing time with honey treatment were 35%, 39%, 28% and 43% better, respectively, than with acyclovir treatment. For genital herpes, the mean duration of attacks and pain, occurrence of crusting, and mean healing time with honey treatment were 53%, 50%, 49% and 59% better, respectively, than with acyclovir. Two cases of labial herpes and one case of genital herpes remitted completely with the use of honey. The lesions crusted in 3 patients with labial herpes and in 4 patients with genital herpes. With acyclovir treatment, none of the attacks remitted, and all the lesions, labial and genital, developed crust. No side effects were observed with repeated applications of honey, whereas 3 patients developed local itching with acyclovir. CONCLUSIONS: Topical honey application is safe and effective in the management of the signs and symptoms of recurrent lesions from labial and genital herpes. [Abstract/Link to Full Text]

Rafael H
Hypothalamic ischemia and metabolic syndrome.
Med Sci Monit. 2006 Sep;12(9):LE17-8. [Abstract/Link to Full Text]

Be?towski J
Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity?
Med Sci Monit. 2006 Jun;12(6):RA112-9.
Recent studies suggest that adipose tissue hormones ("adipokines") are involved in the pathogenesis of various complications of obesity, including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Apelin and visfatin are two recently described adipokines, although they are also synthesized outside adipose tissue. Apelin exists in at least three forms, consisting of 13, 17, or 36 amino acids, all originating from a common 77-amino-acid precursor. In the cardiovascular system, apelin elicits endothelium-dependent, nitric oxide-mediated vasorelaxation and reduces arterial blood pressure. In addition, apelin demonstrates potent and long-lasting positive inotropic activity which is preserved even in injured myocardium and is not accompanied by myocardial hypertrophy. Apelin synthesis in adipocytes is stimulated by insulin, and plasma apelin level markedly increases in obesity associated with insulin resistance and hyperinsulinemia. In addition to regulating cardiovascular function, apelin inhibits water intake and vasopressin production. Visfatin, previously recognized as a pre-B cell colony-enhancing factor (PBEF), is abundantly expressed in visceral adipose tissue and is upregulated in some, but not all, animal models of obesity. Preliminary studies suggest that plasma visfatin concentration is also increased in humans with abdominal obesity and/or type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from insulin and exerts hypoglycemic effect by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissues. Thus, apelin and visfatin are unique among adipose tissue hormones in that they are upregulated in the obese state and both exert primarily beneficial effects. [Abstract/Link to Full Text]

Stefano GB, Fricchione GL, Esch T
Relaxation: molecular and physiological significance.
Med Sci Monit. 2006 Sep;12(9):HY21-31.
There appears to be a molecular process for relaxation. Given this, we attempt to demonstrate this phenomenon based on established molecular and physiological processes in light of our current understanding of central and peripheral nervous system mechanisms. Central to our hypothesis is the significance of norepinephrine, nitric oxide, dopamine and morphine signaling both in the central and peripheral nervous system. We find that nitric oxide and morphine control catecholamine processes on many levels, including synthesis, release and actions. We conclude that enough scientific information exists to support these phenotmena as actual physical processes that can be harnessed to provide better patient care. [Abstract/Link to Full Text]

Buyukcelik A, Bulent Y, Utkan G, Icli F, Sanlidilek U, Akbulut H
Thrombosis of the pulmonary artery in a patient with mucinous adenocarcinoma.
Med Sci Monit. 2006 Sep;12(9):CS90-3.
BACKGROUND: The increased tendency to thromboembolism in cancer patient has been recognized for a long time. However, arterial thromboembolism and thrombosis of the pulinonary artery have rarely been reported. Pulmonary thromboembolism is usually a complication of peripheral venous thrombosis. CASE REPORT: Here we report on a 62-year-old female patient who presented with pulmonary artery thrombosis anti peritonitis carcinomatosa. Computed tomography of the thorax and digital subtraction angiography of both pulmonary arteries revealed multiple filling defects in virtually all the lobes of the right lung, in the mid-zone of the left lung, and a gross filling defect in the right main pulmoinary artery. These findings suggested that the thrombosis in the right pulmonary artery was primary rather than an embolus. No venotis thrombos is in the vena cava, pelvic veins, or any of the lower extremity veins was documented. CONCLUSIONS: Although thrombosis of the pulmonary artery is rarely seen in cancer patients, it is usually fatal and needs urgent intervention to save the patient's life. [Abstract/Link to Full Text]

Kazakos K, Chatzipapaso C, Xarchas KC, Mantatzis M, Tilkeridis K, Galanis V, Verettas DA
Knee osteonecrosis due to lead poisoning: case report and review of the literature.
Med Sci Monit. 2006 Sep;12(9):CS85-9.
BACKGROUND: Though rare, a relationship between toxic heavy-metal accumulation and bone necrosis exists. CASE REPORT: A 28-year-old man suffered from chronic bilateral knee pain accompanied by muscle fibrillations and night cramps. On examiniation he presented tenderness and mild quadriceps muscle atrophy, but unaffected range of movement, sensation, and tendon reflexes and no effuision. He also complained of blurred vision, lethargy, and tremor. CONCLUSIONS: On the basis of these data it appeared that these infarcts were attributable to lead poisoning. This situation has not been described in the knee region, but finrther clarification of a possible causal relationship between toxic trace element concentration and idiopathic bone necrosis appears necessary. [Abstract/Link to Full Text]

Stahl CE, Borlongan CV, Szerlip M, Szerlip H
No pain, no gain--exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra.
Med Sci Monit. 2006 Sep;12(9):CS81-4.
BACKGROUND: We describe a rare case of severe rhabdomyolysis provoked by ingestion of a performance-enhancer herbal supplement containing ephedra. CASE REPORT: A healthy 21-year-old Army soldier complained of "complete muscle failure" after collapsing at the end of Army Physical Fitness Test. The patient was found to be tachycardic and hypotensive, but his vital signs quickly stabilized after receiving sodium chloride in the ambulance. Physical examination of the patient, including a thorough neuromuscular exam, was unremarkable. Urine tested positive for myoglobin. Initial creatinine kinase was 426 U/L, which increased to a maximum creatinine kinase of 241,418 ti/IL by hospital day 6. The patient also developed acute renal failure secondary to pigment-induced actute tubular necrosis. He was treated with bicarbonate-containing fluid. The patient's creatinine kinase and renal function had normalized at one month follow-up. A muscle biopsy was negative for underlying neuromuscular disease. His past medical history was only notable for the patient having taken 2 tablets of an herbal supplement containing ephedra every day for a month leading to his physical fitness test. CONCLUSIONS: Rhabdomvolvsis and myoglobinuric renal failure associated with ephedra use are a very uncommion occurrence, but a significant clinical event that should be closely monitored due to rampant use by young adults of ephedra-containing dietary supplements. [Abstract/Link to Full Text]

Bajestan MN, Radvar M, Afshari JT, Naseh MR, Arab HR
Interleukin-6 production by cultured peripheral blood monocytes before and after stimulation by E. coli lipopolysaccharide in Iranian patients with aggressive periodontitis.
Med Sci Monit. 2006 Sep;12(9):CR393-6.
BACKGROUND: It has been suggested that hyper-responsiveness of monocytes to the products of dental plaque, especially the endotoxin of Gram-negative bacteria and the secretion of high levels of pro-inflammatory cytokines, may have a role in the pathogenesis of aggressive periodontitis (AP). To investigate this possibility, IL-6 production by cultured peripheral blood monocytes before and after stimulation by E. coli lipopolysaccharide (LPS) in AP patients was evaluated. MATERIAL/METHODS: Fifteen patients with AP were compared with 15 periodontally healthy controls in a case control study. Monocytes were obtained from peripheral blood samples and cultured. The reaction of monocytes was studied by their IL-6 production using ELISA before and six hours after stimulation by 0.1 microg/ml E. col. LPS. The Wilcoxon and Mann-Whitney U tests were used to compare the groups. RESULTS: There was no significant difference in IL-6 production levels before LPS stimulation between patients and controls. Upon LPS stimulation, IL-6 levels increased in both the patient and control groups compared with their IL-6 levels before stimulation. IL-6 production after LPS stimulation in the patients was higher than controls, but this was not statistically significant. However, the increase in IL-6 production as a result of LPS stimulation was significantly higher in patients than in controls. CONCLUSIONS: Increased monocyte responsiveness may play a potential role in the pathogenesis of AP. However, whether this is an intrinsic characteristic of the monocyte/macrophage cells of AP patients or just a priming effect as a result of the periodontal disease remains to be investigated. [Abstract/Link to Full Text]

Klopocka M, Budzy?ski J, Swiatkowski M, Pulkowski G, Meder A
Differences in esophageal corpus motility in patients with pathological and non-pathological gastroesophageal reflux.
Med Sci Monit. 2006 Sep;12(9):CR387-92.
BACKGROUND: First- and second-order esophageal contractions are important factors responsible for esophageal clearance of refluxed gastric content. The aim of this study was to estimate the influence of acid reflux on second-order esophageal peristalsis. MATERIAL/METHODS: Simultaneous 24-h esophageal pH-metry and 24-h motility monitoring was performed in 213 patients with non-cardiac chest pain. Pathological gastroesophageal acid reflux (pGER) was defined as pH <4 for more than 4.5% of the total monitoring time. RESULTS: The group of pGER patients (n=65, 31%) had a lower percentage of complete and effective peristalsis, a higher percentage of incomplete peristalsis, and a lower mean contraction amplitude than the group of patients with normal esophageal acid exposure (nGER). Analysis of motility parameters in three periods, i.e. during acid reflux and 2 min before and 10 min after episodes (second-order peristalsis), showed that the pGER group had a lower percentage of effective peristalsis (20.6 +/- 13.3 vs. 29.6 +/- 16.2%, p = 0.002) and a higher percentage of ineffective peristalsis both during and after acid reflux, a lower mean contraction amplitude (56.5 +/- 30.3 vs. 70.0 +/- 32.8 mmHg, p=0.025), and a lower contraction frequency during acid reflux (1.6 +/- 0.7 vs. 2.6 +/- 3.1/min, p=0.001) and 10 min after (1.9 +/- 1.9 vs. 20.6 +/- 30.2/min, p=0.002), which indicated a lack of esophageal peristalsis acceleration after acid reflux in the pGER group. CONCLUSIONS: (1) pGER patients had ineffective esophageal peristalsis more frequently than nGER patients. (2) Impaired second-order peristalsis in pGER patients may be an important factor determining prolonged exposure of the esophageal mucosa to gastric content in addition to lower esophageal sphincter function. [Abstract/Link to Full Text]

Jaleel F, Jaleel A, Aftab J, Rahman MA
Leptin and blood lipid levels in postmenopausal diabetic women with and without complication of ischemic heart disease.
Med Sci Monit. 2006 Sep;12(9):CR382-6.
BACKGROUND: Recent studies have provided evidence that leptin has significant effects on vascular development and repair. The aim was to determine the levels of leptin and lipid profile in diabetic postmenopausal women with and without the complication of ischemic heart disease and to develop correlation between them. Moreover, the relationship between leptin levels and extent of ischemic changes were determined. MATERIAL/METHODS: One hundred twenty postmenopausal subjects between the ages of 45 and 60 years were included in the study. They were divided into three groups of forty subjects each. The first group comprised normal healthy controls, the second diabetic type 2 patients with no history of ischemic heart disease (I1ID), and the third diabetic patients with IHD. Serum leptin levels were determined by a Kit obtained from DRG and samples were analyzed on ELISA. Fasting and random blood glucose was determined by the glucose oxidase method, cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol were also determined by kits obtained from Merck. RESULTS: The results show that leptin and serum lipid levels increased significantly in diabetic patients with IHD compared with diabetic patients without IHD as well as normal subjects. Moreover; the sertum leptin level increased significantly in the diabetic patients with IHD who had positive findings in myocardial perfusion scan compared with those having negative findings. CONCLUSIONS: Hyperleptinemia in diabetic patients shows that leptin contributes to the development of cardiovascular disease in diabetic patients. [Abstract/Link to Full Text]

Karabulut AB, Atambay M, Karaman U, Kilic E, Yazar S, Saraymen R, Daldal N
House dust-mites: effect on antioxidant enzyme activities.
Med Sci Monit. 2006 Sep;12(9):CR378-81.
BACKGROUND: House dust-mites are potent allergens of the indoor environment and are common inhabitants of houses worldwide. Free radicals are constantly produced by cells, mostly as reactive oxygen species. Once produced, free radicals are removed by antioxidant defenses, including the enzymes SOD, GPx, and CAT. MATERIAL/METHODS: The aim was to describe the importance of the antioxidant enzymes SOD, GPx, and CAT co-acting in hunan cells against toxic reactive oxygen species and their relationship with pathophysiological processes in stubjects who have dust-mites in their homes. RESULTS: The activities of erythrocyte GPx and SOD in skin-test-positive (dust-mite-positive/negative) patients were significantly lower than those in dust-mite- and skin-test-negative controls (p < 0.05). Among the skin-test-positive patients, SOD activity was found to be lower in dust-mite-positive than in dust-mite-negative patients (p < 0.05). There was not a statistically significant difference between the CAT levels of skin-test-positive (dust-mite-positive/negative) patients and dust-mite- and skin-test-negative controls (p > 0.05). CONCLUSIONS: This study clearly shows that dust-mite depresses the activities of SOD, GPx, and, to a small extent, CAT; which influence cellular reducing capacity and consequently may increase asthma risk more than other allergens. [Abstract/Link to Full Text]

Modrzy?ski M, Zawisza E
Seasonal asymptomatic lower airway hyperresponsiveness in patients with allergic rhinitis.
Med Sci Monit. 2006 Sep;12(9):CR372-7.
BACKGROUND: Allergic rhinitis is considered a risk factor for bronchial asthma. It therefore seems essential to identify patients threatened with this disease in whom no disturbing bronchial symptoms have occurred. The study's aim was to evaluate the incidence of nonspecific bronchial hyperactivity based on exercise results in pollinosis patients. MATERIAL/ METHODS: The study group comprised 27 patients with seasonal allergic rhinitis allergic to tree pollens but without asthma symrptom. Exercise provocation tests were performed before, during, and after completion of the pollination period. During the pollination period, specific IgE (sIgE) and nasal eosinophilia were also determined. Twelve patients allergic to Artemisia pollen made up the control group. The results were also evaluated in relation to desensitization therapy. RESULTS: In the study group a pathological result of the provocation test was obtained in 1 patient (3.7%) before the pollination period, in 7 patients (25.9%) during, and in 4 patients (11.8%) after its completion. The subjects with a positive test result had higher levels of nasal eosinophilia, while there was no relation between the result and sIgE levels. Only one case of positive exercise challenge was identified among the desensitized patients. CONCLUSIONS: During the pollination period, nonspecific bronchial hyperreactivity develops in some patients with seasonal allergic rhinitis; it can be sustained for some time after the disappearance of pollens from the atmosphere and can he identified using an exercise challenge. Incidence of bronchial hyperreactivity in desensitized patients was lower than in those subjected to symptomatic treatment. [Abstract/Link to Full Text]

Ferekidis E, Nikolopoulos TP, Yiotakis J, Ferekidou E, Kandiloros D, Papadimitriou K, Tzangaroulakis A
Correlation of clinical and surgical findings to histological features (koilocytosis, papillary hyperplasia) suggesting papillomavirus involvement in the pathogenesis of cholesteatoma.
Med Sci Monit. 2006 Sep;12(9):CR368-71.
BACKGROUND: The clinical course of cholesteatoma is rather unpredictable, as some cases show aggressive development, while others have a mild, more 'benign' nature. The aim was to correlate the clinical course and surgical findings of cholesteatomas with histological features. MATERIAL/METHODS: The study included 45 patients with cholesteatoma, 29 of whom had surgically aggressive and 16 simple (not surgically aggressive) cholesteatoma. All patients underwent mastoid surgery and the cholesteatoma specimens were sent for histological examination. RESULTS: The clinical course of the cholesteatomas had a statistically significant association (p < 0.001) with the 'aggressiveness' found in surgery, suggesting that clinical history correlates well with surgical findings. All 29 specimens of patients with surgically aggressive cholesteatoma had characteristic papillary hyperplasia of the epithelium and marked koilocytosis, suggesting papillomavirus-incduced lesions. In contrast, none of the specimens of the 16 patients with simple (non-aggressive) cholesteatoma had papillary hyperplasia and there was no marked koilocytosis, as few koilocytes could occasionally be found. The difference was statistically significant (p < 0.001). In situ hybridization for human papillomnavirus (HPV) was performed in 14 specimens (7 each with aggressive and simple cholesteatomna). Positive staining was found in three aggressive cholesteatomas. All seven simple cholesteatomas were negative for HPV. CONCLUSIONS: The results of the present paper suggest that papillomaviruses may play an important role in the pathogenesis of cholesteatomas. Further studies with controls and the development of new methods to identify known and unknown types of papillomavirus are needed to explore their exact role. [Abstract/Link to Full Text]

Akhtar AJ, Shaheen MA, Zha J
Organic colonic lesions in patients with irritable bowel syndrome (IBS).
Med Sci Monit. 2006 Sep;12(9):CR363-7.
BACKGROUND: To determine whether IBS patients develop organic lesions compared to those without IBS, and to determine type and frequency of these organic colonic lesions. MATERIAL/METHODS: Retrospective review of medical records of 622 IBS patients, ages 19-91 years, over fifteen years that underwent colonoscopy for new gastrointestinal symptoms during the course of their illness. Records of 642 non-IBS patients, who had colonoscopy for gastrointestinal complaints, were reviewed retrospectively as a comparison group. We abstracted and analyzed data related to demographics, history, diagnosis of IBS, and type of colonic lesions reported in the colonoscopy reports. RESULTS: Of the 622 patients diagnosed with IBS, the median duration of the IBS was 11 years (range=1 to 62 years). Colonoscopy findings were normal in 301 patients (48.4%) in the IBS group and 301 patients (46.9%) in the non-IBS group. Among the IBS group, the common organic colonic lesions were hemorrhoids (21.1%) polyps (20.3%) and diverticuli (19%) and angiodysplasia (11.9%). Among the non-IBS group, the common organic colonic lesions were hemorrhoids (22.6%), polyps (22.4%), diverticuli (20.6%) and angiodysplasia (12.1%). There was no difference in the prevalence of organic colonic lesions among patients with or without IBS (p > 0.05). Adjusting for the demographic variables and the number of lesions, there were no differences between the groups (p > 0.05). CONCLUSIONS: IBS patients may also develop organic colonic lesions, thus colonoscopy, if indicated, should not be delayed in these patients because of the assumption that their symptoms are due to IBS alone. [Abstract/Link to Full Text]

Brunaud L, Kebebew E, Sebag F, Zarnegar R, Clark OH, Duh QY
Observation or laparoscopic adrenalectomy for adrenal incidentaloma? A surgical decision analysis.
Med Sci Monit. 2006 Sep;12(9):CR355-62.
BACKGROUND: The optimal strategy remains controversial for adrenal incidentaloma, 4 to 6 cm in size, nonfunctioning, and without malignant imaging characteristics. A decision analysis model was used to identify relevant variables for selecting the optimal management (observation versus adrenalectomy). MATERIAL/METHODS: Risk/benefit analysis in tertiary care center. The probabilities of each health outcome states were determined by a review of the literature from 1980 to 2002 (n=2844 patients); and from a retrospective review of experience at University of California San Francisco (UCSF). RESULTS: The baseline probabilities of morbidity after laparoscopic unilateral adrenalectomy and a new indication developing during initial observation (hypersecretion, size increase, malignancy) were 7.8% and 3.1%, respectively. We found observation to be the preferred approach when using baseline probabilities and utilities. Laparoscopic adrenalectomy becomes the preferred approach however if: (1) The morbidity rate from laparoscopic unilateral adrenalectomy is < 3.0%, 2) The probability of a new indication developing for adrenalectomy during observation is > 7.5%, 3) A patient's perspective of observation has a utility of lower than 98.6%, and (4) A patient views having a complication from adrenalectomy is not much deleterious (utility > 88.1%). CONCLUSIONS: This decision analysis model identifies the important variables for selecting the optimal management approach for adrenal incidentalomas. These results can be used to select the optimal management strategy based on individual patient preference and surgeon-specific complication rate. [Abstract/Link to Full Text]

Ergün Y, Ergün UG, Orhan FO, Küçük E
Co-administration of a nitric oxide synthase inhibitor and melatonin exerts an additive antidepressant-like effect in the mouse forced swim test.
Med Sci Monit. 2006 Sep;12(9):BR307-12.
BACKGROUND: The aim was to assess the combination therapy of nitric oxide synthase inhibitors and melatonin, since they had been separately shown to be as efficacious as conventional antidepressant drugs in pre-clinical antidepressant screening procedures. MATERIAL/METHODS: The Porsolt swim test was conducted to resemble the symptornatolog of major depressive disorder and an open-filed locomotor activity was also used. RESULTS: N(G)-nitro-L-arginine (L-NNA) at 3 mg/kg slightly, but not significantly, reduced the duration of immobility, and increasing the dose to 10 mg/kg was sufficient to attain a significant reduction. On the other hand, the maximal dose of L-NNA (30 mg/kg) was without effect, although a non-significant small increase was observed. The results obtained with L-NNA were in accorldance with a U-shape effect. While 3 mg/kg melatonin was ineffective, a statistically significant decrease in the duration of immobility was determined at the dose of 10 mg/kg. While the combination of ineffective doses (3 mg/kg, each) of L-NNA and melatonin revealed no further inhibition in the duration of immobility, the most effective doses (10 mg/kg, each) caused a more pronounced reduction when compared with those of each drug alone. None of the drugs used in the present study had any effects on locomotor activity over the dose range applied. CONCLUSIONS: The combination therapy with L-NNA and melatonin seems to have an additive effect and may be considered as a feasible candidate in attenuating the symptoms of major depressive disorder. [Abstract/Link to Full Text]

Shuangsuo D, Zhengguo Z, Yunru C, Xin Z, Baofeng W, Lichao Y, Yan'an C
Inhibition of the replication of hepatitis B virus in vitro by emodin.
Med Sci Monit. 2006 Sep;12(9):BR302-6.
BACKGROUND: Emodin (1, 3, 8-trihvdroxy-6-methylanthraquinone) is derived from herbal medicines and proved to have a strong antimicrobial activity. However, its anti-virus effects are less known. The aim of the present study was to investigate the effects of emodin, interferon alpha (IFNalpha), and lamivudine (3TC) on hepatitis B virus (HBV) in vitro. MATERIAL/METHODS: The human hepatoma G2.2.15 cell line stably expresses hepatitis B virus particles in culture. The cells were exposed to different concentrations of emodin, IFNa, and lamivudine triphosphate, respectively. MTT (methyl thiazolyl tetrazolium) assay was used to evaluate the cytotoxicity of the drugs and real-time PCR was applied to quantify extracellular HBV DNA. HIBsAg and HBeAg were assessed by enzyme-linked immurnosorbent assay (ELISA). RESULTS: The results showed that exposure of HepG2.2.15 cells to emodin resulted in a time- and concentration-dependent inhibition of HBV DNA replication and HBsAg secretion. After exposed to three different concentrations of emodin for 3, 6, and 9 days, the inhibition rates of extracellular HBV DNA, HBsAg, and HBeAg of each concentration decreased significantly (P < 0.05). After 9 days of treatment, the inhibition rates of extracellular HBV DNA of the different concentrations differed greatly (P < 0.001). IFNalpha and 3TC had similar inhibition results to HBV DNA replication to those previously found. CONCLUSIONS: These findings suggest that mnodin may prove to be a new modality to treat hepatitis B infection. [Abstract/Link to Full Text]

Zhu W, Mantione KJ, Casares FM, Sheehan MH, Kream RM, Stefano GB
Cholinergic regulation of endogenous morphine release from lobster nerve cord.
Med Sci Monit. 2006 Sep;12(9):BR295-301.
BACKGROUND: Invertebrate nervous systems are regulated by G-coupled protein receptors, chemical transporters, and ion channels responsive to established drugs of abuse including opiates, alcohol, psychostinulants, and nicotine. Thus, invertebrate nervous tissue preparations can be used as predictive model systems by which to evaluate underlying pharmacological mechanisms of addictive processes. MATERIAL/METHODS: Ex vivo pharmacological trials were used to determine the comparative effects of the nicotinic agonists and antagonists on the evoked release of labeled morphine from H. americanus nerve cord. The intrinsically low basal levels of endogenous morphine required that we utilize an ex vivo model system involving pre-labeling of intracellutlar opiate alkaloid pools with high specific activity 125I labeled morphine. RESULTS: Both nicotine and epibatidine promoted evoked release of 125I labeled morphine that is selectively linked to activation of invertebrate nicotinic receptors based on pharmacological inhibition by alpha bungarotoxin (alpha-BuTx). Epibatidine promoted release at concentrations 2-3 orders of magnitude higher than nicotine. Co-administration of nicotine (60 nM) and the pre-junctional ganglionic nicotinic antagonist hexamethonium (1 microM) produced a marked potentiation of 125I labeled morphine release; a pharmacological effect also observed for epibatidine (35 microM) co-administered with the competitive nicotinic antagonist chlorisondaminie at 1 microM. The stimulatory effects of ethanol to promote enhanced release of endogenous morphine were not affected by co-admninistration of alpha-BuTx at 1 microM. CONCLUSIONS: The stirmulatory effects of nicotine on cellular expression and release of endogenous morphine occurs via specific alpha-BuTx sensitive receptors, suggesting a novel mechanism underling the reinforcing and addictive properties of nicotine via endogenous morphine. [Abstract/Link to Full Text]

Tot T
The limited prognostic value of measuring and grading small invasive breast carcinomas: the whole sick lobe versus the details within it.
Med Sci Monit. 2006 Aug;12(8):RA170-5.
Although tumor size and grade are well-established prognostic parameters in unselected series or in advanced cases of invasive breast carcinoma, studying their prognostic value in small invasive carcinomas has generated variable results. The significance of these parameters was recently questioned in three large studies on invasive carcinomas less than 15 mm in size, in which neither grade nor size were found to be independent prognostic parameters. Two of these studies were carried out on material of our institution and evidenced the outstanding prognostic significance of a radiological parameter (presence of casting type microcalcifications) in these tumors, challenging the traditional approach in breast pathology in which conventional morphologic prognostic parameters are clearly insufficient to explain these results. In the present article we discuss the practical difficulties in measuring and grading invasive breast carcinomas to point out the disturbing lack of wide international consensus considering the optimal assessment of these parameters, contributing to discordant results in the reviewed studies. We also present the unifying concept of the theory of the sick lobe which, by shifting the focus from the debated details of measuring and grading towards the judgement of the pattern of tumoral growth, offers alternative morphologic prognostic parameters which fulfill the needs of a modern interdisciplinary approach to diagnosing small breast carcinomas. [Abstract/Link to Full Text]

Kanaan RA, Kanaan LA
Transforming growth factor beta1, bone connection.
Med Sci Monit. 2006 Aug;12(8):RA164-9.
Transforming Growth Factor beta1 (TGF beta1) exerts its functions both during embryogenesis, and in adult organism. TGF beta1 regulates cell proliferation, differentiation, motility and apoptosis. TGF beta1 is the most abundant growth factor in human bone. It is implicated in the pathogenesis of several bone diseases such as otosclerosis. During embryonic development, TGF beta1 plays a role in the migration of cells to the site of future skeletogenesis, the epithelial-mesenchymal interaction, and the formation of cellular condensations which dictates the general shape of the future skeletal elements. It also influences normal skeleton development by playing a critical role in inducing mesenchymal cell differentiation to either chondrocytes or osteoblasts. During Adult life, TGF beta1 has an influence on the maintenance of normal skeleton by playing a critical role on bone-forming cell namely, the osteoblast. TGF beta1 affects osteoblast differentiation, matrix formation, and mineralization. In MC3T3-E1 osteoblast-like cell line TGF beta1 inhibited the expression of the Runx2 and osteocalcin osteoblast differentiation markers. It interacts with many will known pathways in osteoblasts biology, such as Prostaglandin E2, Parathyroid hormone related peptide and Wnt-beta-catenin pathways. TGF beta1 exerts effects on osteocytes too. Treatment of pre-osteocytes with TGF alpha1 decreased cell death. Studied performed on osteoclast revealed that it inhibits both their proliferation and activity. This review briefly discusses the relation between this cytokine and the skeleton development and maintenance. [Abstract/Link to Full Text]

Tarnowski M, Sieron AL
Adult stem cells and their ability to differentiate.
Med Sci Monit. 2006 Aug;12(8):RA154-63.
This is a review of the current status of knowledge on adult stem cells as well as the criteria and evidence for their potential to transform into different cell types and cell lineages. Reports on stem cell sources, focusing on tissues from adult subjects, were also investigated. Numerous reports have been published on the search for early markers of both stem cells and the precursors of various cell lineages. The question is still open about the characteristics of the primary stem cell. The existing proofs and hypotheses have not yielded final solutions to this problem. From a practical point of view it is also crucial to find a minimal set of markers determining the phenotypes of the precursor cells of a particular cell lineage. Several lines of evidence seem to bring closer the day when we will be able to detect the right stem cell niche and successfully isolate precursor cells that are needed for the treatment of a particular disorder. Recent reports on cases of cancer in patients subjected to stem cell therapy are yet another controversial issue looked into in this review, although the pros and cons emerging from the results of published studies still do not provide satisfying evidence to fully understand this issue. [Abstract/Link to Full Text]

Jenicek M
Towards evidence-based critical thinking medicine? Uses of best evidence in flawless argumentations.
Med Sci Monit. 2006 Aug;12(8):RA149-53.
Uses of informal logic and critical thinking methodology are increasingly taught, learnt and advantageously applied in such diverse domains as law, the military, business, and education. Health sciences are also following this trend. However, production and critical appraisal of evidence as already practiced in Evidence-Based Medicine must be coupled with equally rigorous uses in order to ensure appropriate health problem understanding and decision-making. Making most proposals and decisions in medicine is the conclusion of an argumentation process that lies behind any communication between health professionals working with patients, performing research or sharing ideas about health problems, their interpretations and solutions with numerous stakeholders in public life. Modern critical thinking and decision making in medicine is not instantly mastered, but is instead a learnt experience as anything else in professional and social interactions. The modern argument as outlined, illustrated and applied to health problems in this essay is an extension of a previously established way of thinking in Evidence-Based Medicine. Ideally, health professionals, their patients and all other stakeholders should speak the same language and it is up to us to make this possible. Evidence and critical thinking - based medicine might be a solution. As modern critical thinkers, we are at the forefront and we must see to it that patients and professional and general communities benefit from this more so even than from other remarkable historical and current contributions to the well-being of those under our care. [Abstract/Link to Full Text]

Knapik M, Knapik P, Nadziakiewicz P, Misio?ek H, Saucha W, Walaszczyk M, Dyaczy?ska-Herman A
Comparison of remifentanil or fentanyl administration during isoflurane anesthesia for coronary artery bypass surgery.
Med Sci Monit. 2006 Aug;12(8):PI33-8.
BACKGROUND: The combination of inhalational agents with moderate doses of fentanyl is popular in cardiac anesthesia. Remifentanil is a new opioid metabolized by non-specific esterases. The aim of our study was to assess whether remifentanil may be superior to fentanyl during isoflurane anesthesia for coronary artery surgery. MATERIAL/METHODS: Forty patients aged 40-70 years with stable coronary artery disease were randomly allocated to two groups: remifentanil was used in 20 patients (group I) and fentanyl was used in 20 patients (group II). Induction of anesthesia was performed with remifentanil infusion (0.5 microg/kg/min) or a bolus dose of fentanyl (5 microg/kg) followed by a bolus of etomidate and pancuronium. Maintenance of anesthesia was provided by isoflurane and infusion of the study opioid, with the rate adjusted according to systolic blood pressure values. Hemodynamic parameters were registered before and after the induction of anesthesia, skin incision, sternotomy, aortic cannulation, termination of cardiopulmonary bypass, chest closure, and skin closure. RESULTS: Heart rate and mean arterial pressure values were significantly lower in the remifentanil group, while systemic vascular resistance was higher in the fentanyl group in the measurements taken before the initiation of cardiopulmonary bypass. No differences were found between groups in the values of mean pulmonary pressure, pulmonary artery wedge pressure and transpulmonary pressure gradient, central venous pressure, and cardiac index. CONCLUSIONS: Remifentanil is safe during inhalation anesthesia for coronary artery surgery and it appears to be more effective than fentanyl in blunting hemodynamic response before the initiation of cardiopulmonary bypass surgery. [Abstract/Link to Full Text]

Shafik A, El-Sibal O, Shafik I
Electro-orchidogram: a non-invasive diagnostic tool in testicular pathologies.
Med Sci Monit. 2006 Aug;12(8):MT51-5.
BACKGROUND: We investigated the hypothesis that the transcutaneous electro-orchidogram (EOG) can act as a diagnostic tool in testicular pathological conditions. MATERIAL/METHODS: Three electrodes were applied to the scrotal skin of 21 healthy volunteers (controls), 12 patients with acute epididymo-orchitis (EO), 8 with testicular torsion (TT), 10 with unilateral undescended testicle (UT), and 9 with testicular seminoma (TS). Recordings were performed before and 48 hours and 1, 3, and 6 months after treatment. Semen analysis was done 1, 3, and 6 months post-treatment. RESULTS: Recordings from healthy volunteers showed slow waves (SWs) with similar wave variables from the three electrodes of the same individual. Patients with EO exhibited increased SW variables (p<0.05) during acute stage, which normalized in 8 and diminished in 4 patients 1, 3, and 6 months after inflammatory process resolution. Post resolution, the 8 patients had normospermia and the 4 oligospermia. In TT, SWs were absent during torsion and after detorsion in 7 patients; SWs and semen normalized in 1 patient 6 months after detorsion. The UT showed absent SWs up to 6 months post-descent; semen remained oligospermic. Testicles with TS exhibited areas with SWs and silent areas. CONCLUSIONS: Testicles in the above pathological conditions showed electro-orchidographic changes associated with changes in semen character. Repeated EOG could demonstrate the progress of the pathological condition in the testicle. The non-invasive EOG may act as a diagnostic and follow-up tool in some testicular pathological conditions after further studies have been performed in this issue. [Abstract/Link to Full Text]

Malkov SV, Markelov VV, Barabanschikov BI, Polozov GY, Trushin MV
Is there any alternative to conventional anticancer treatment? Comments to: Trustworthy alteration and improvement in adjuvant treatment of colon cancer. Ali Harlak, Atilla Soran Med Sci Monit, 2006; 12(3): RA46-52.
Med Sci Monit. 2006 Aug;12(8):LE16. [Abstract/Link to Full Text]

Harlak A, Soran A
Trustworthy alteration and improvement in adjuvant treatment of colon cancer.
Med Sci Monit. 2006 Mar;12(3):RA46-52.
Colorectal cancer is the third most common cancer both in men and women in the United States. Advances in adjuvant treatment of colon cancer have came to consist of a succession of small improvements by large-scale clinical trials. The National Surgical Adjuvant Breast and Bowel Project (NSABP) colon trials reflect the exciting history of progress in adjuvant treatment of colon cancer. Since 1977, the NSABP has successfully designed and conducted seven large-scale prospective randomized clinical trials for colon cancers that has altered and improved the standard of care for patients with this disease. More than 5,000 physicians, nurses, and other medical professionals at nearly 200 medical sites from across the United States, Canada, Puerto Rico, Australia and New Zealand assist the NSABP in its mission to eliminate colorectal and breast cancers. These medical sites include several university hospitals and many other local medical centers that treat patients from a variety of social, and economic backgrounds contributed to the trials. The NSABP clinical trials are distinctive because of the large number of patients and elimination of social, cultural and economic influences. The ongoing trials of the NSABP should continue to provide information used to determine principals of neoadjuvant treatment for colon cancer. In this article we review seven prospective randomized clinical trials with their published results and discuss the combined analysis of the first four trials. [Abstract/Link to Full Text]

Tsalis K
Septic shock; current pathogenetic concepts from a clinical perspective. Adelais G. Tsiotou, George H. Sakorafas, George Anagnostopoulos, John Bramis Med Sci Monit, 2005; 11(3): RA76-85.
Med Sci Monit. 2006 Aug;12(8):LE15-6. [Abstract/Link to Full Text]

Tsiotou AG, Sakorafas GH, Anagnostopoulos G, Bramis J
Septic shock; current pathogenetic concepts from a clinical perspective.
Med Sci Monit. 2005 Mar;11(3):RA76-85.
Sepsis is an infection-induced syndrome characterized by a generalized inflammatory state and represents a frequent complication in the surgical patient. The normal reaction to infection involves a series of complex immunologic processes. A potent, complex immunologic cascade ensures a prompt protective response to microbial invasion in humans. Although activation of the immune system during microbial invasion is generally protective, septic shock develops in a number of patients as a consequence of excessive or poorly regulated immune response to the offending organism (Gram-negative or Gram-positive bacteria, fungi, viruses, or microbial toxins). This unbalanced reaction may harm the host through a maladaptive release of endogenously generated inflammatory compounds. Many mechanisms are involved in the pathogenesis of septic shock, including the release of cytokines, the activation of neutrophils, monocytes, and microvascular endothelial cells, as well as the activation of neuroendocrine reflexes and plasma protein cascade systems, such as the complement system, the intrinsic (contact system) and extrinsic pathways of coagulation, and the fibrinolytic system. In critically ill patients, the gastrointestinal tract plays a central role in the pathogenesis of septic shock. The potential for complementary and synergistic interaction of the different components in this cascade highlights the difficulty encountered in trying to identify a single means of altering the progression of sepsis and septic shock to multiple organ dysfunction syndrome (MODS) and multiple organ failure (MOF). [Abstract/Link to Full Text]

Lovisi GM
Post-traumatic stress disorder in Polish stroke patients who survived Nazi concentration camps.
Med Sci Monit. 2006 Aug;12(8):LE15. [Abstract/Link to Full Text]

Pachalska M, Grochmal-Bach B, MacQueen BD, Fra?czuk B
Post-traumatic stress disorder in Polish stroke patients who survived Nazi concentration camps.
Med Sci Monit. 2006 Apr;12(4):CR137-49.
BACKGROUND: Many persons who survived Nazi concentration camps are now in advanced age, so that rehabilitation centers in Poland are seeing increasing numbers of such patients, especially after strokes. In many cases, the process of rehabilitation is severely hampered by Post-Traumatic Stress Disorder (PTSD), while the neuropsychological consequences of the stroke itself often evoke traumatic memories and simultaneously disorganize or destroy the patient's previous coping mechanisms. The present study describes the program developed by the authors for concentration camp survivors in post-stroke rehabilitation, including the use of art therapy and specially prepared films to help the patients cope with PTSD. MATERIAL/METHODS: The experimental group (KL) consisted of 8 such patients (4 men, 4 women, average age 79.1+/-4.28) with mild post-stroke aphasia who went through the PTSD program, while the comparison group (C) included 8 post-stroke patients, matched for age and gender, who were not concentration camp survivors and showed no premorbid symptoms of PTSD. All subjects were tested at baseline and again 3 months later, using structured interview and observation, self-rating scales for three basic negative emotions (anger, anxiety and sadness) and the Frustration and Aggression Test for the Disabled. RESULTS: The results showed significant differences between the groups at baseline, while at follow-up the differences between groups had changed in both extent and distribution. CONCLUSIONS: Qualitative analysis of the results allows for some important observations about the etiology and course of PTSD in these persons. [Abstract/Link to Full Text]

Ford GP, Reardon DC
Prolonged unintended brain cooling may inhibit recovery from brain injuries: case study and literature review.
Med Sci Monit. 2006 Aug;12(8):CS74-9.
BACKGROUND: Tracheal intubation of comatose patients is common, but contrary to most standards for respiratory care, heated nebulizers are not always used. This deviation from recommendations appears to be widespread. CASE REPORT: In the case examined, a tracheotomized patient suffering from severe anoxic brain injury was unintentionally exposed to chilled air, 17 degrees C (63 degrees F) at the cannula, for a period of 31 months. A month after upper respiratory tract warming was restored the vegetative state lifted, as marked by the patient's ability to verbalize responses to questions. CONCLUSIONS: This clinical experience led us to a review of the literature. Among other findings, we learned that brain temperature is strongly affected by the temperature of arterial blood flow. Arterial blood, in turn, is strongly affected by the air temperature in the lungs. Experiments have shown that the introduction of colder air in the lungs will produce rapid cooling of at least some surface brain tissues. Chilled aortic blood is also more viscous and less efficient in transfer of oxygen. Hypothermia of brain tissue may significantly affect the endocrine system and neurochemistry. Through inferences from the literature, we also identify other possible effects. We hypothesize that intubated delivery of air into the lungs at a temperature significantly below body temperature, especially over a prolonged period, is likely to inhibit recovery and may even produce iatrogenic effects. We recommend the use of heated nebulizers. Research strategies are recommended. [Abstract/Link to Full Text]

Woszczyk D, Ko?odziej-Jasku?a A, Myka?a-Cie?la J, Bal A, ?abuzek K, Gasi?ska T
Focal lesions in the ultrasonographic examination of the spleen as a symptom of various disease statuses: literature survey and case descriptions.
Med Sci Monit. 2006 Aug;12(8):CS67-73.
BACKGROUND: Ultrasonography (US) is an easy and non-invasive technique of visualizing spleen. Thanks to its repeatability, it plays an important role in the diagnostics of, among others, developmental anomalies, such as supernumerary or lobated spleens, as well as focal lesions. It is also used in monitoring the size of the spleen and it considerably facilitates diagnosis after certain injuries. Thanks to the application of the Doppler method, it also facilitates the diagnostics of pathologies within the spleen's vessels. CASE REPORT: This paper presents six different cases of focal lesions in the spleen, including lesions in the course of histiocytosis, in the course of sarcoidosis, as well as isolated abscesses of the spleen. The authors also present the case of a spleen with numerous metastatic lesions, the case of a near-splenic cyst, and the case of asymptomatic focal lesions of unknown origin. In all the presented cases, the lesions were accidentally revealed during ultrasonographic examination, which was the starting point for further diagnostics. CONCLUSIONS: Though rare, morphologic lesions in the spleen should always be taken into consideration when performing a routine ultrasonographic examination of the abdominal cavity, and the organ itself should not be ignored. US is a widely available, noninvasive, and useful method for diagnosing splenic abnormalities, including focal changes. [Abstract/Link to Full Text]

Krecicki T, Liebhart J, Morawska-Kochman M, Liebhart E, Zato?ski M, Zalesska-Krecicka M
Corticosteroid-induced laryngeal disorders in asthma.
Med Sci Monit. 2006 Aug;12(8):CR351-4.
BACKGROUND: Inhaled corticosteroids have proven to be the most effective agent available in treating bronchial asthma, and such treatment is believed to be very safe. Concerns regarding side effects of inhaled corticosteroids usually focus on potential systemic effects, where local side effects are often overlooked. The purpose of this study was to analyze and assess the influence of inhaled corticosteroids on the vocal cords of patients treated for bronchial asthma. MATERIAL/METHODS: Fifty patients (mean age: 50 years, range: 22 to 83 years) suffering from asthma and receiving corticosteroidal inhaled agents entered in this study. All of the patients underwent detailed videoscopic examination of the larynx. None complained of any laryngeal disorders or dysfunction before the diagnosis of asthma. All of the patients were non-smokers. RESULTS: Significant changes in the laryngeal status were observed. Changes included atrophy of laryngeal mucosa, vocal fold atrophy, and vocal fold bowing. CONCLUSIONS: Damage to the larynx is an important factor in patients with asthma treated with inhaled corticosteroids, which elicit apoptosis of the epithelium. [Abstract/Link to Full Text]

Vecchioli-Scaldazza C, Morosetti C
Urodynamic findings in female patients with urinary incontinence with intrinsic sphincteric deficiency.
Med Sci Monit. 2006 Aug;12(8):CR345-50.
BACKGROUND: The aim of the study was to evaluate differences in urodynamic findings in women with urinary incontinence between subjects with or without intrinsic sphincter deficiency (ISD). MATERIAL/METHODS: Sixty consecutive female patients with a history and urodynamically confirmed diagnosis of pure urinary incontinence were evaluated. Patients were divided into two groups according to their abdominal Valsalva leak-point pressure (AVLPP) values using a cutoff of 60 cm H(2)O: group A patients with AVLPP </=60 cm H(2)O and group B patients with AVLPP >60 cm H(2)O. RESULTS: Qmax and Qave in group A were higher than in group B; flow time was significantly shorter in group A than in group B. PVR in group A was lower than in group B. In pressure flow study, all detrusor findings in group A had a pressure value lower than in group B. MUCP in patients with AVLPP </=60 cm H(2)O was significantly lower than in group B, but the degrees of specificity and sensitivity in group A and B were 90% and 43.3%, respectively. CONCLUSIONS: The results of this study confirm a more efficient bladder emptying in patients with AVLPP </=60 cm H(2)O. [Abstract/Link to Full Text]

Falagas ME, Bliziotis IA, Soteriades ES
A prospective study of services utilization of a hospital-based employee health clinic.
Med Sci Monit. 2006 Aug;12(8):CR341-4.
BACKGROUND: Little is known regarding the utilization of services of a hospital-based employee health clinic (EHC). MATERIAL/METHODS: We evaluated the utilization of services of the EHC of a tertiary hospital in Greece. Demographic and clinical data were prospectively collected and analyzed for all employees who visited the EHC during a 24-month period (01/06/2003-31/05/2005). RESULTS: A total of 939 primary and 55 follow-up visits were recorded. Of all 994 visits, 419 were made by nurses (42%), 270 by administrative staff (27%), and only 15 visits by physicians (1%). Only 5.6% of physicians used the EHC during the study period (14 out of 252 doctors) whereas 35.4% of the nurses (218 out of 615) visited the EHC at least once (p<0.001). Three hundred and one of the rest 544 employees (55.3%) visited the EHC, significantly more than physicians (p < 0.001) and nurses (p<0.001). The majority of employees who visited the clinic were females (78%), while the most common reason for consultation was periodic evaluation accounting for 108 visits (11%), followed by abdominal pain (99 visits, 10%), dizziness (48 visits, 5%), and respiratory tract infections (44 visits, 5%). A significant reduction in the number of visits was observed after the 9(th) month of the study, coinciding with a change in the worker's health insurance policy (p<0.001). CONCLUSIONS: Periodic evaluations, abdominal pain, dizziness, respiratory tract infections, and weakness/malaise cover the bulk of consultation visits of a hospital-based EHC. Physicians were the group of employees that visited the EHC less often. [Abstract/Link to Full Text]

Alexopoulos EC
Occupational health services in Greek hospitals.
Med Sci Monit. 2006 Oct;12(10):LE20-1. [Abstract/Link to Full Text]

Olszewska E, Chodynicki S, Chyczewski L, Rogowski M
Some markers of proliferative activity in cholesteatoma epithelium in adults.
Med Sci Monit. 2006 Aug;12(8):CR337-40.
BACKGROUND: The aim of this study was to determine the proliferative capacity in certain layers of the cholesteatoma epithelium and normal skin. MATERIAL/METHODS: Cholesteatoma and skin were obtained during ear surgical procedures. The number of PCNA- and Ki-67-positive cells were counted within each of three microscopic fields at a magnification of x400. Fourteen normal skin specimens collected from the retroauricular area were used as controls. RESULTS: The skin specimens were found to have a lower proliferative capacity than the cholesteatoma epithelium. This activity was mainly observed in the cell nuclei of the basal layer of the epidermis. The percentage of PCNA-positive cells was 23% in the epidermis and 45.7% in the cholesteatoma epithelium. Immunohistochemical investigation of the epidermis revealed 7% Ki-67-positive cells, mainly located in the basal layer of the epidermis. The presence of Ki-67 antigen in the cell nuclei was determined in the parabasal layer of the cholesteatoma epithelium and stroma. Ki-67-positive cells made up 22% of the cholesteatoma epithelium, compared with 7% in the skin. CONCLUSIONS: Proliferative activity is mainly observed in the basal and suprabasal layers of the cholesteatoma epithelium. The proliferative capacity of the cholesteatoma epithelium is different in the various areas of the epithelium and does not depend on its thickness. [Abstract/Link to Full Text]