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

Milo R, Hou JH, Springer M, Brenner MP, Kirschner MW
The relationship between evolutionary and physiological variation in hemoglobin.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16998-7003.
Physiological and evolutionary adaptations operate at very different time scales. Nevertheless, there are reasons to believe there should be a strong relationship between the two, as together they modify the phenotype. Physiological adaptations change phenotype by altering certain microscopic parameters; evolutionary adaptation can either alter genetically these same parameters or others to achieve distinct or similar ends. Although qualitative discussions of this relationship abound, there has been very little quantitative analysis. Here, we use the hemoglobin molecule as a model system to quantify the relationship between physiological and evolutionary adaptations. We compare measurements of oxygen saturation curves of 25 mammals with those of human hemoglobin under a wide range of physiological conditions. We fit the data sets to the Monod-Wyman-Changeux model to extract microscopic parameters. Our analysis demonstrates that physiological and evolutionary change act on different parameters. The main parameter that changes in the physiology of hemoglobin is relatively constant in evolution, whereas the main parameter that changes in the evolution of hemoglobin is relatively constant in physiology. This orthogonality suggests continued selection for physiological adaptability and hints at a role for this adaptability in evolutionary change. [Abstract/Link to Full Text]

Tse CY, Lee CL, Sullivan J, Garnsey SM, Dell GS, Fabiani M, Gratton G
Imaging cortical dynamics of language processing with the event-related optical signal.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17157-62.
Language processing involves the rapid interaction of multiple brain regions. The study of its neurophysiological bases would therefore benefit from neuroimaging techniques combining both good spatial and good temporal resolution. Here we use the event-related optical signal (EROS), a recently developed imaging method, to reveal rapid interactions between left superior/middle temporal cortices (S/MTC) and inferior frontal cortices (IFC) during the processing of semantically or syntactically anomalous sentences. Participants were presented with sentences of these types intermixed with nonanomalous control sentences and were required to judge their acceptability. ERPs were recorded simultaneously with EROS and showed the typical activities that are elicited when processing anomalous stimuli: the N400 and the P600 for semantic and syntactic anomalies, respectively. The EROS response to semantically anomalous words showed increased activity in the S/MTC (corresponding in time with the N400), followed by IFC activity. Syntactically anomalous words evoked a similar sequence, with a temporal-lobe EROS response (corresponding in time with the P600), followed by frontal activity. However, the S/MTC activity corresponding to a semantic anomaly was more ventral than that corresponding to a syntactic anomaly. These data suggest that activation related to anomaly processing in sentences proceeds from temporal to frontal brain regions for both semantic and syntactic anomalies. This first EROS study investigating language processing shows that EROS can be used to image rapid interactions across cortical areas. [Abstract/Link to Full Text]

Miao J, Wang Z, Provencher H, Muir B, Dahiya S, Carney E, Leong CO, Sgroi DC, Orsulic S
HOXB13 promotes ovarian cancer progression.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17093-8.
Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53(-/-) mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer. [Abstract/Link to Full Text]

Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, Lidov HG, Kang PB, North KN, Mitrani-Rosenbaum S, Flanigan KM, Neely LA, Whitney D, Beggs AH, Kohane IS, Kunkel LM
Distinctive patterns of microRNA expression in primary muscular disorders.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17016-21.
The primary muscle disorders are a diverse group of diseases caused by various defective structural proteins, abnormal signaling molecules, enzymes and proteins involved in posttranslational modifications, and other mechanisms. Although there is increasing clarification of the primary aberrant cellular processes responsible for these conditions, the decisive factors involved in the secondary pathogenic cascades are still mainly obscure. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs regulated during the degenerative process of muscle to gain insight into the specific regulation of genes that are disrupted in pathological muscle conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major muscular disorders in humans [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis]. Although five miRNAs were found to be consistently regulated in almost all samples analyzed, pointing to possible involvement of a common regulatory mechanism, others were dysregulated only in one disease and not at all in the other disorders. Functional correlation between the predicted targets of these miRNAs and mRNA expression demonstrated tight posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy. Together with direct mRNA-miRNA predicted interactions demonstrated in DMD, some of which are involved in known secondary response functions and others that are involved in muscle regeneration, these findings suggest an important role of miRNAs in specific physiological pathways underlying the disease pathology. [Abstract/Link to Full Text]

Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS
Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17069-74.
Cancer patients treated with antiangiogenic multitargeted receptor tyrosine kinase (RTK) inhibitors show increased levels of plasma VEGF and placental growth factor and decreased levels of soluble VEGF receptor-2, thus implicating these overall changes as a possible class effect of such drugs and raising the possibility of their exploitation as surrogate biomarkers for pharmacodynamic drug activity/exposure and patient benefit. A postulated mechanism for these changes is that they are tumor-dependent, resulting from drug-induced decreases in vascular function, increases in tumor hypoxia, and changes in hypoxia-regulated genes. However, here we report that an identical pattern of change is observed in normal nontumor-bearing mice treated with SU11248/sunitinib, a small-molecule inhibitor of VEGF and PDGF RTKs. The changes were dose-dependent, plateaued after 4 days of consecutive treatment, reversed after discontinuation of therapy, and correlated with antitumor activity. Altered protein expression was found in a broad variety of tissues, and dose-dependent elevations were observed of several plasma proteins previously unassociated with this class of inhibitor, including G-CSF, SDF-1alpha, SCF, and osteopontin. Our results suggest that observed sunitinib-induced molecular plasma changes, including those both directly and indirectly targeted by drug, represent a systemic tumor-independent response to therapy and may correlate with the most efficacious antitumor doses, potentially having utility for defining the optimal biologic dose range for this drug class but not as predictive markers of tumor response or clinical benefit. They may also be relevant to drug-associated toxicities, drug resistance, and observed rapid tumor (re)growth seen after cessation of therapy. [Abstract/Link to Full Text]

Stull MA, Pai V, Vomachka AJ, Marshall AM, Jacob GA, Horseman ND
Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16708-13.
Homeostatic control of volume within the alveolar spaces of the mammary gland has been proposed to involve a feedback system mediated by serotonin signaling. In this article, we describe some of the mechanisms underlying this feedback based on studies of a human normal mammary epithelial cell line (MCF10A) and mouse mammary epithelium. Mammary serotonin was elevated during lactation and after injection of 5-hydroxytryptophan (5-HTP). The genes encoding the serotonin reuptake transporter (SERT) and the type 7 serotonin receptor (5-HT(7)) were expressed in human and mouse mammary epithelial cells, and serotonin caused a concentration-dependent increase of cAMP in MCF10A cells. Mouse and human mammary epithelial cells formed polarized membranes, in which tight junction activity was monitored. Treatment of mammary epithelial membranes with serotonin receptor antagonists increased their transepithelial electrical resistance (TEER). Antagonist and agonist effects on TEER were mediated by receptors on the basolateral face of the membranes. Our results suggest a process in which serotonin accumulates in the interstitial fluid surrounding the mammary secretory epithelium and is detected by 5-HT(7) receptors, whereupon milk secretion is inhibited. One mechanism responsible for this process is serotonin-mediated opening of tight junctions, which dissipates the transepithelial gradients necessary for milk secretion. [Abstract/Link to Full Text]

Park EA, Macalpine DM, Orr-Weaver TL
Drosophila follicle cell amplicons as models for metazoan DNA replication: a cyclinE mutant exhibits increased replication fork elongation.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16739-46.
Gene clusters amplified in the ovarian follicle cells of Drosophila serve as powerful models for metazoan DNA replication. In response to developmental signals, specific genomic regions undergo amplification by repeated firing of replication origins and bidirectional movement of replication forks for approximately 50 kb in each direction. Previous work focused on initiation of amplification, defining replication origins, establishing the role of the prereplication complex and origin recognition complex (ORC), and uncovering regulatory functions for the Myb, E2F1, and Rb transcription factors. Here, we exploit follicle cell amplification to investigate the control of DNA replication fork progression and termination, poorly understood processes in metazoans. We identified a mutant in which, during gene amplification, the replication forks move twice as far from the origin compared with wild type. This phenotype is the result of an amino acid substitution mutation in the cyclinE gene, cyclinE(1f36). The rate of oogenesis is normal in cyclinE(1f36)/cyclinE(Pz8) mutant ovaries, indicating that increased replication fork progression is due to increased replication fork speed, possibly from increased processivity. The increased amplification domains observed in the mutant imply that there are not replication fork barriers preventing replication forks from progressing beyond the normal 100-kb amplified region. These results reveal a previously unrecognized role for CyclinE in controlling replication fork movement. [Abstract/Link to Full Text]

Bennett-Guerrero E, Veldman TH, Doctor A, Telen MJ, Ortel TL, Reid TS, Mulherin MA, Zhu H, Buck RD, Califf RM, McMahon TJ
Evolution of adverse changes in stored RBCs.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17063-8.
Recent studies have underscored questions about the balance of risk and benefit of RBC transfusion. A better understanding of the nature and timing of molecular and functional changes in stored RBCs may provide strategies to improve the balance of benefit and risk of RBC transfusion. We analyzed changes occurring during RBC storage focusing on RBC deformability, RBC-dependent vasoregulatory function, and S-nitrosohemoglobin (SNO-Hb), through which hemoglobin (Hb) O(2) desaturation is coupled to regional increases in blood flow in vivo (hypoxic vasodilation). Five hundred ml of blood from each of 15 healthy volunteers was processed into leukofiltered, additive solution 3-exposed RBCs and stored at 1-6 degrees C according to AABB standards. Blood was subjected to 26 assays at 0, 3, 8, 24 and 96 h, and at 1, 2, 3, 4, and 6 weeks. RBC SNO-Hb decreased rapidly (1.2 x 10(-4) at 3 h vs. 6.5 x 10(-4) (fresh) mol S-nitrosothiol (SNO)/mol Hb tetramer (P = 0.032, mercuric-displaced photolysis-chemiluminescence assay), and remained low over the 42-day period. The decline was corroborated by using the carbon monoxide-saturated copper-cysteine assay [3.0 x 10(-5) at 3 h vs. 9.0 x 10(-5) (fresh) mol SNO/mol Hb]. In parallel, vasodilation by stored RBCs was significantly depressed. RBC deformability assayed at a physiological shear stress decreased gradually over the 42-day period (P < 0.001). Time courses vary for several storage-induced defects that might account for recent observations linking blood transfusion with adverse outcomes. Of clinical concern is that SNO levels, and their physiological correlate, RBC-dependent vasodilation, become depressed soon after collection, suggesting that even "fresh" blood may have developed adverse biological characteristics. [Abstract/Link to Full Text]

Zhang D, Liu ZX, Choi CS, Tian L, Kibbey R, Dong J, Cline GW, Wood PA, Shulman GI
Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17075-80.
Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a primary or acquired defect in this process. To determine whether primary defects in mitochondrial beta-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an approximately 40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an approximately 50% decrease in Akt2 activation. These changes were associated with increased PKCepsilon activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKCepsilon activation, and hepatic insulin resistance. [Abstract/Link to Full Text]

Lemus L, Hern�ndez A, Luna R, Zainos A, N�cher V, Romo R
Neural correlates of a postponed decision report.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17174-9.
Depending on environmental demands, a decision based on a sensory evaluation may be either immediately reported or postponed for later report. If postponed, the decision must be held in memory. But what exactly is stored by the underlying memory circuits, the final decision itself or the sensory information that led to it? Here, we report that, during a postponed decision report period, the activity of medial premotor cortex neurons encodes both the result of the sensory evaluation that corresponds to the monkey's possible choices and past sensory information on which the decision is based. These responses could switch back and forth with remarkable flexibility across the postponed decision report period. Moreover, these responses covaried with the animal's decision report. We propose that maintaining in working memory the original stimulus information on which the decision is based could serve to continuously update the postponed decision report in this task. [Abstract/Link to Full Text]

DiFiglia M, Sena-Esteves M, Chase K, Sapp E, Pfister E, Sass M, Yoder J, Reeves P, Pandey RK, Rajeev KG, Manoharan M, Sah DW, Zamore PD, Aronin N
Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17204-9.
Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat in the huntingtin (Htt) gene. HD is autosomal dominant and, in theory, amenable to therapeutic RNA silencing. We introduced cholesterol-conjugated small interfering RNA duplexes (cc-siRNA) targeting human Htt mRNA (siRNA-Htt) into mouse striata that also received adeno-associated virus containing either expanded (100 CAG) or wild-type (18 CAG) Htt cDNA encoding huntingtin (Htt) 1-400. Adeno-associated virus delivery to striatum and overlying cortex of the mutant Htt gene, but not the wild type, produced neuropathology and motor deficits. Treatment with cc-siRNA-Htt in mice with mutant Htt prolonged survival of striatal neurons, reduced neuropil aggregates, diminished inclusion size, and lowered the frequency of clasping and footslips on balance beam. cc-siRNA-Htt was designed to target human wild-type and mutant Htt and decreased levels of both in the striatum. Our findings indicate that a single administration into the adult striatum of an siRNA targeting Htt can silence mutant Htt, attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model of HD. [Abstract/Link to Full Text]

Stewart GS, Stankovic T, Byrd PJ, Wechsler T, Miller ES, Huissoon A, Drayson MT, West SC, Elledge SJ, Taylor AM
RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16910-5.
Cellular DNA double-strand break-repair pathways have evolved to protect the integrity of the genome from a continual barrage of potentially detrimental insults. Inherited mutations in genes that control this process result in an inability to properly repair DNA damage, ultimately leading to developmental defects and also cancer predisposition. Here, we describe a patient with a previously undescribed syndrome, which we have termed RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties), whose cells lack an ability to recruit 53BP1 to sites of DNA double-strand breaks. As a consequence, cells derived from this patient exhibit a hypersensitivity to ionizing radiation, cell cycle checkpoint abnormalities, and impaired end-joining in the recombined switch regions. Sequencing of TP53BP1 and other genes known to regulate ionizing radiation-induced 53BP1 foci formation in this patient failed to detect any mutations. Therefore, these data indicate the existence of a DNA double-strand break-repair protein that functions upstream of 53BP1 and contributes to the normal development of the human immune system. [Abstract/Link to Full Text]

Eveleigh ES, McCann KS, McCarthy PC, Pollock SJ, Lucarotti CJ, Morin B, McDougall GA, Strongman DB, Huber JT, Umbanhowar J, Faria LD
Fluctuations in density of an outbreak species drive diversity cascades in food webs.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16976-81.
Patterns in food-web structure have frequently been examined in static food webs, but few studies have attempted to delineate patterns that materialize in food webs under nonequilibrium conditions. Here, using one of nature's classical nonequilibrium systems as the food-web database, we test the major assumptions of recent advances in food-web theory. We show that a complex web of interactions between insect herbivores and their natural enemies displays significant architectural flexibility over a large fluctuation in the natural abundance of the major herbivore, the spruce budworm (Choristoneura fumiferana). Importantly, this flexibility operates precisely in the manner predicted by recent foraging-based food-web theories: higher-order mobile generalists respond rapidly in time and space by converging on areas of increasing prey abundance. This "birdfeeder effect" operates such that increasing budworm densities correspond to a cascade of increasing diversity and food-web complexity. Thus, by integrating foraging theory with food-web ecology and analyzing a long-term, natural data set coupled with manipulative field experiments, we are able to show that food-web structure varies in a predictable manner. Furthermore, both recent food-web theory and longstanding foraging theory suggest that this very same food-web flexibility ought to be a potent stabilizing mechanism. Interestingly, we find that this food-web flexibility tends to be greater in heterogeneous than in homogeneous forest plots. Because our results provide a plausible mechanism for boreal forest effects on populations of forest insect pests, they have implications for forest and pest management practices. [Abstract/Link to Full Text]

Hernandez JM, Feller A, Morohashi K, Frame K, Grotewold E
The basic helix loop helix domain of maize R links transcriptional regulation and histone modifications by recruitment of an EMSY-related factor.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17222-7.
The control of anthocyanin accumulation in maize by the cooperation of the basic helix-loop-helix (bHLH) protein R with the MYB transcription factor C1 provides one of the best examples of plant combinatorial transcriptional control. Establishing the function of the bHLH domain of R has remained elusive, and so far no proteins that interact with this conserved domain have been identified. We show here that the bHLH domain of R is dispensable for the activation of transiently expressed genes yet is essential for the activation of the endogenous genes in their normal chromatin environment. The activation of A1, one of the anthocyanin biosynthetic genes, is associated with increased acetylation of histone 3 (H3) at K9/K14 in the promoter region to which the C1/R complex binds. We identified R-interacting factor 1 (RIF1) as a nuclear, AGENET domain-containing EMSY-like protein that specifically interacts with the bHLH region of R. Knockdown experiments show that RIF1 is necessary for the activation of the endogenous promoters but not of transiently expressed genes. ChIP experiments established that RIF1 is tethered to the regulatory region of the A1 promoter by the C1/R complex. Together, these findings describe a function for the bHLH domain of R in linking transcriptional regulation with chromatin functions by the recruitment of an EMSY-related factor. [Abstract/Link to Full Text]

Scherthan H, Wang H, Adelfalk C, White EJ, Cowan C, Cande WZ, Kaback DB
Chromosome mobility during meiotic prophase in Saccharomyces cerevisiae.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16934-9.
In many organisms, a synaptonemal complex (SC) intimately connects each pair of homologous chromosomes during much of the first meiotic prophase and is thought to play a role in regulating recombination. In the yeast Saccharomyces cerevisiae, the central element of each SC contains Zip1, a protein orthologous to mammalian SYCP1. To study the dynamics of SCs in living meiotic cells, a functional ZIP1::GFP fusion was introduced into yeast and analyzed by fluorescence video microscopy. During pachytene, SCs exhibited dramatic and continuous movement throughout the nucleus, traversing relatively large distances while twisting, folding, and unfolding. Chromosomal movements were accompanied by changes in the shape of the nucleus, and all movements were reversibly inhibited by the actin antagonist Latrunculin B. Normal movement required the NDJ1 gene, which encodes a meiosis-specific telomere protein needed for the attachment of telomeres to the nuclear periphery and for normal kinetics of recombination and meiosis. These results show that SC movements involve telomere attachment to the nuclear periphery and are actin-dependent and suggest these movements could facilitate completion of meiotic recombination. [Abstract/Link to Full Text]

Samuel MA, Wang H, Siddharthan V, Morrey JD, Diamond MS
Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17140-5.
West Nile virus (WNV) has emerged as a significant cause of epidemic viral encephalitis and flaccid limb paralysis, yet the mechanism by which it enters the CNS remains uncertain. We used compartmentalized neuron cultures to demonstrate that WNV spreads in both retrograde and anterograde directions via axonal transport. Transneuronal spread of WNV required axonal release of viral particles and was blocked by addition of a therapeutic neutralizing antibody. To test the physiologic significance of axonal transport in vivo, we directly inoculated the sciatic nerve of hamsters with WNV. Intrasciatic infection resulted in paralysis of the hind limb ipsilateral but not contralateral to the injection site. Limb paralysis was blocked either by surgical transection of the sciatic nerve or treatment with the therapeutic neutralizing antibody. Collectively, these studies establish that WNV undergoes bidirectional spread in neurons and that axonal transport promotes viral entry into the CNS and acute limb paralysis. Moreover, antibody therapeutics directly inhibit transneuronal spread of WNV infection and prevent the development of paralysis in vivo. [Abstract/Link to Full Text]

Lane MC, Alteri CJ, Smith SN, Mobley HL
Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16669-74.
Uropathogenic Escherichia coli (UPEC) cause most uncomplicated urinary tract infections (UTIs) in humans. Because UTIs are considered to occur in an ascending manner, flagellum-mediated motility has been suggested to contribute to virulence by enabling UPEC to disseminate to the upper urinary tract. Previous studies from our laboratory and others have demonstrated a modest yet important role for flagella during ascending UTI. To better understand the role of flagella in vivo, we used biophotonic imaging to monitor UPEC infection and temporospatial flagellin gene expression during ascending UTI. Using em7-lux (constitutive) and fliC-lux transcriptional fusions, we show that flagellin expression by UPEC coincides with ascension of the ureters and colonization of the kidney. The patterns of fliC luminescence observed in vitro and in vivo were also validated by comparative quantitative PCR. Because fliC expression appeared coincident during ascension, we reassessed the contribution of fliC to ascending UTI using a low-dose intraurethral model of ascending UTI. Although wild-type UPEC were able to establish infection in the bladder and kidneys by 6 hours postinoculation, fliC mutant bacteria were able to colonize the bladder but were significantly attenuated in the kidneys at this early time point. By 48 hours postinoculation, the fliC mutant bacteria were attenuated in the bladder and kidneys and were not detectable in the spleen. These data provide compelling evidence that wild-type UPEC express flagellin and presumably utilize flagellum-mediated motility during UTI to ascend to the upper urinary tract and disseminate within the host. [Abstract/Link to Full Text]

Ghaffari R, Aranyosi AJ, Freeman DM
Longitudinally propagating traveling waves of the mammalian tectorial membrane.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16510-5.
Sound-evoked vibrations transmitted into the mammalian cochlea produce traveling waves that provide the mechanical tuning necessary for spectral decomposition of sound. These traveling waves of motion that have been observed to propagate longitudinally along the basilar membrane (BM) ultimately stimulate the mechano-sensory receptors. The tectorial membrane (TM) plays a key role in this process, but its mechanical function remains unclear. Here we show that the TM supports traveling waves that are an intrinsic feature of its visco-elastic structure. Radial forces applied at audio frequencies (2-20 kHz) to isolated TM segments generate longitudinally propagating waves on the TM with velocities similar to those of the BM traveling wave near its best frequency place. We compute the dynamic shear storage modulus and shear viscosity of the TM from the propagation velocity of the waves and show that segments of the TM from the basal turn are stiffer than apical segments are. Analysis of loading effects of hair bundle stiffness, the limbal attachment of the TM, and viscous damping in the subtectorial space suggests that TM traveling waves can occur in vivo. Our results show the presence of a traveling wave mechanism through the TM that can functionally couple a significant longitudinal extent of the cochlea and may interact with the BM wave to greatly enhance cochlear sensitivity and tuning. [Abstract/Link to Full Text]

Waldherr M, Neumann ID
Centrally released oxytocin mediates mating-induced anxiolysis in male rats.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16681-4.
Sexual activity and mating are accompanied by a high level of arousal, whereas anecdotal and experimental evidence demonstrate that sedation and calmness are common phenomena in the postcoital period in humans. These remarkable behavioral consequences of sexual activity contribute to a general feeling of well being, but underlying neurobiological mechanisms are largely unknown. Here, we demonstrate that sexual activity and mating with a receptive female reduce the level of anxiety and increase risk-taking behavior in male rats for several hours. The neuropeptide oxytocin has been shown to exert multiple functions in male and female reproduction, and to play a key role in the regulation of emotionality after its peripheral and central release, respectively. In the present study, we reveal that oxytocin is released within the brain, specifically within the hypothalamic paraventricular nucleus, of male rats during mating with a receptive female. Furthermore, blockade of the activated brain oxytocin system by central administration of an oxytocin receptor antagonist immediately after mating prevents the anxiolytic effect of mating, while having no effect in nonmated males. These findings provide direct evidence for an essential role of an activated brain oxytocin system mediating the anxiolytic effect of mating in males. [Abstract/Link to Full Text]

Wisler JW, DeWire SM, Whalen EJ, Violin JD, Drake MT, Ahn S, Shenoy SK, Lefkowitz RJ
A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62.
For many years, beta-adrenergic receptor antagonists (beta-blockers or betaAR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, beta-adrenergic receptor antagonists have been found to provide survival benefits in patients suffering from heart failure, although the efficacy of different beta-blockers varies widely in this condition. One drug, carvedilol, a nonsubtype-selective betaAR antagonist, has proven particularly effective in the treatment of heart failure, although the mechanism(s) responsible for this are controversial. Here, we report that among 16 clinically relevant betaAR antagonists, carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in beta2 adrenergic receptor (beta2AR)-expressing HEK-293 cells, carvedilol has inverse efficacy for stimulating G(s)-dependent adenylyl cyclase but, nonetheless, stimulates (i) phosphorylation of the receptor's cytoplasmic tail on previously documented G protein-coupled receptor kinase sites; (ii) recruitment of beta-arrestin to the beta2AR; (iii) receptor internalization; and (iv) activation of extracellular regulated kinase 1/2 (ERK 1/2), which is maintained in the G protein-uncoupled mutant beta2AR(T68F,Y132G,Y219A) (beta2AR(TYY)) and abolished by beta-arrestin2 siRNA. Taken together, these data indicate that carvedilol is able to stabilize a receptor conformation which, although uncoupled from G(s), is nonetheless able to stimulate beta-arrestin-mediated signaling. We hypothesize that such signaling may contribute to the special efficacy of carvedilol in the treatment of heart failure and may serve as a prototype for a new generation of therapeutic beta2AR ligands. [Abstract/Link to Full Text]

Li W, Frank J
Transfer RNA in the hybrid P/E state: correlating molecular dynamics simulations with cryo-EM data.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16540-5.
Transfer RNA (tRNA) transiently occupies the hybrid P/E state (P/E-tRNA) when mRNA-tRNA are translocated in the ribosome. In this study, we characterize the structure of P/E-tRNA and its interactions with the ribosome by correlating the results from molecular dynamics simulations on free tRNA with the cryo-EM map of P/E-tRNA. In our approach, we show that the cryo-EM map may be interpreted as a conformational average. Along the molecular dynamics trajectories (44 ns, 18 ns, and 18 ns), some of the snapshots prove to be quite close to the observed density. In a representative structure, the CCA (3') arm is uniquely twisted, and the anticodon stem loop is kinked at the junctions to both the anticodon loop and the D stem. In addition, the map shows that the P/E-tRNA is no longer bound to helix H69 of 23S rRNA and is flexible, and the conformations of helices H68 and h44 of 16S rRNA differ from those in the x-ray structure. Thus, our study presents structural and dynamic information on the P/E-tRNA and characterizes its interactions with the translocating ribosome. [Abstract/Link to Full Text]

Wu J, Zhang S, Meng Q, Cao H, Li Z, Li X, Shi S, Kim DH, Bi L, Turro NJ, Ju J
3'-O-modified nucleotides as reversible terminators for pyrosequencing.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16462-7.
Pyrosequencing is a method used to sequence DNA by detecting the pyrophosphate (PPi) group that is generated when a nucleotide is incorporated into the growing DNA strand in polymerase reaction. However, this method has an inherent difficulty in accurately deciphering the homopolymeric regions of the DNA templates. We report here the development of a method to solve this problem by using nucleotide reversible terminators. These nucleotide analogues are modified with a reversible chemical moiety capping the 3'-OH group to temporarily terminate the polymerase reaction. In this way, only one nucleotide is incorporated into the growing DNA strand even in homopolymeric regions. After detection of the PPi for sequence determination, the 3'-OH of the primer extension products is regenerated through different deprotection methods. Using an allyl or a 2-nitrobenzyl group as the reversible moiety to cap the 3'-OH of the four nucleotides, we have synthesized two sets of 3'-O-modified nucleotides, 3'-O-allyl-dNTPs and 3'-O-(2-nitrobenzyl)-dNTPs as reversible terminators for pyrosequencing. The capping moiety on the 3'-OH of the DNA extension product is efficiently removed after PPi detection by either a chemical method or photolysis. To sequence DNA, templates containing homopolymeric regions are immobilized on Sepharose beads, and then extension-signal detection-deprotection cycles are conducted by using the nucleotide reversible terminators on the DNA beads to unambiguously decipher the sequence of DNA templates. Our results establish that this reversible-terminator-pyrosequencing approach can be potentially developed into a powerful methodology to accurately determine DNA sequences. [Abstract/Link to Full Text]

Beisel C, Buness A, Roustan-Espinosa IM, Koch B, Schmitt S, Haas SA, Hild M, Katsuyama T, Paro R
Comparing active and repressed expression states of genes controlled by the Polycomb/Trithorax group proteins.
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16615-20.
Drosophila Polycomb group (PcG) and Trithorax group (TrxG) proteins are responsible for the maintenance of stable transcription patterns of many developmental regulators, such as the homeotic genes. We have used ChIP-on-chip to compare the distribution of several PcG/TrxG proteins, as well as histone modifications in active and repressed genes across the two homeotic complexes ANT-C and BX-C. Our data indicate the colocalization of the Polycomb repressive complex 1 (PRC1) with Trx and the DNA binding protein Pleiohomeotic (Pho) at discrete sequence elements as well as significant chromatin assembly differences in active and inactive regions. Trx binds to the promoters of active genes and noncoding transcripts. Most strikingly, in the active state, Pho covers extended chromatin domains over many kilobases. This feature of Pho, observed on many polytene chromosome puffs, reflects a previously undescribed function. At the hsp70 gene, we demonstrate in mutants that Pho is required for transcriptional recovery after heat shock. Besides its presumptive function in recruiting PcG complexes to their site of action, our results now uncover that Pho plays an additional role in the repression of already induced genes. [Abstract/Link to Full Text]

Schwegmann A, Guler R, Cutler AJ, Arendse B, Horsnell WG, Flemming A, Kottmann AH, Ryan G, Hide W, Leitges M, Seoighe C, Brombacher F
Protein kinase C delta is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16251-6.
Activation of macrophages and subsequent "killing" effector functions against infectious pathogens are essential for the establishment of protective immunity. NF-IL6 is a transcription factor downstream of IFN-gamma and TNF in the macrophage activation pathway required for bacterial killing. Comparison of microarray expression profiles of Listeria monocytogenes (LM)-infected macrophages from WT and NF-IL6-deficient mice enabled us to identify candidate genes downstream of NF-IL6 involved in the unknown pathways of LM killing independent of reactive oxygen intermediates and reactive nitrogen intermediates. One differentially expressed gene, PKCdelta, had higher mRNA levels in the LM-infected NF-IL6-deficient macrophages as compared with WT. To define the role of PKCdelta during listeriosis, we infected PKCdelta-deficient mice with LM. PKCdelta-deficient mice were highly susceptible to LM infection with increased bacterial burden and enhanced histopathology despite enhanced NF-IL6 mRNA expression. Subsequent studies in PKCdelta-deficient macrophages demonstrated that, despite elevated levels of proinflammatory cytokines and NO production, increased escape of LM from the phagosome into the cytoplasm and uncontrolled bacterial growth occurred. Taken together these data identified PKCdelta as a critical factor for confinement of LM within macrophage phagosomes. [Abstract/Link to Full Text]

Sarid L, Bruno R, Sakmann B, Segev I, Feldmeyer D
Modeling a layer 4-to-layer 2/3 module of a single column in rat neocortex: interweaving in vitro and in vivo experimental observations.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16353-8.
We report a step in constructing an in silico model of a neocortical column, focusing on the synaptic connection between layer 4 (L4) spiny neurons and L2/3 pyramidal cells in rat barrel cortex. It is based first on a detailed morphological and functional characterization of synaptically connected pairs of L4-L2/3 neurons from in vitro recordings and second, on in vivo recordings of voltage responses of L2/3 pyramidal cells to current pulses and to whisker deflection. In vitro data and a detailed compartmental model of L2/3 pyramidal cells enabled us to extract their specific membrane resistivity ( approximately 16,000 ohms x cm(2)) and capacitance ( approximately 0.8 microF/cm(2)) and the spatial distribution of L4-L2/3 synaptic contacts. The average peak conductance per L4 synaptic contact is 0.26 nS for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and 0.2 nS for NMDA receptors. The in vivo voltage response for current steps was then used to calibrate the model for in vivo conditions in the Down state. Consequently, the effect of a single whisker deflection was modeled by converging, on average, 350 +/- 20 L4 axons onto the modeled L2/3 pyramidal cell. Based on values of synaptic conductance, the spatial distribution of L4 synapses on L2/3 dendrites, and the average in vivo spiking probability of L4 spiny neurons, the model predicts that the feed-forward L4-L2/3 connection on its own does not fire the L2/3 neuron. With a broader distribution in the number of L4 neurons or with slight synchrony among them, the L2/3 model does spike with low probability. [Abstract/Link to Full Text]

Lozano-Garc�a Mdel S, Caballero M, Ortega B, Rodr�guez A, Sosa S
Tracing the effects of the Little Ice Age in the tropical lowlands of eastern Mesoamerica.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16200-3.
The causes of late-Holocene centennial to millennial scale climatic variability and the impact that such variability had on tropical ecosystems are still poorly understood. Here, we present a high-resolution, multiproxy record from lowland eastern Mesoamerica, studied to reconstruct climate and vegetation history during the last 2,000 years, in particular to evaluate the response of tropical vegetation to the cooling event of the Little Ice Age (LIA). Our data provide evidence that the densest tropical forest cover and the deepest lake of the last two millennia were coeval with the LIA, with two deep lake phases that follow the Sp�rer and Maunder minima in solar activity. The high tropical pollen accumulation rates limit LIA's winter cooling to a maximum of 2 degrees C. Tropical vegetation expansion during the LIA is best explained by a reduction in the extent of the dry season as a consequence of increased meridional flow leading to higher winter precipitation. These results highlight the importance of seasonal responses to climatic variability, a factor that could be of relevance when evaluating the impact of recent climate change. [Abstract/Link to Full Text]

Umeshima H, Hirano T, Kengaku M
Microtubule-based nuclear movement occurs independently of centrosome positioning in migrating neurons.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16182-7.
During neuronal migration in the developing brain, it is thought that the centrosome precedes the nucleus and provides a cue for nuclear migration along the microtubules. In time-lapse imaging studies of radially migrating granule cells in mouse cerebellar slices, we observed that the movements of the nucleus and centrosome appeared to occur independently of each other. The nucleus often migrated ahead of the centrosome during its saltatory movement, negating the supposed role of the centrosome in pulling the nucleus. The nucleus was associated with dynamic microtubules enveloping the entire nucleus and stable microtubules extending from the leading process to the anterior part of the nucleus. Neither of these perinuclear microtubules converged at the centrosome. Disruption or excess formation of stable microtubules attenuated nuclear migration, indicating that the configuration of stable microtubules is crucial for nuclear migration. The inhibition of LIS1 function, a regulator of a microtubule motor dynein, specifically blocks nuclear migration without affecting the coupling of the centrosome and microtubules in the leading process, suggesting that movements of the nucleus and centrosome are differentially regulated by dynein motor function. Thus, the nucleus moves along the microtubules independently of the position of the centrosome in migrating neurons. [Abstract/Link to Full Text]

Imamula K, Kon T, Ohkura R, Sutoh K
The coordination of cyclic microtubule association/dissociation and tail swing of cytoplasmic dynein.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16134-9.
The dynein motor domain is composed of a tail, head, and stalk and is thought to generate a force to microtubules by swinging the tail against the head during its ATPase cycle. For this "power stroke," dynein has to coordinate the tail swing with microtubule association/dissociation at the tip of the stalk. Although a detailed picture of the former process is emerging, the latter process remains to be elucidated. By using the single-headed recombinant motor domain of Dictyostelium cytoplasmic dynein, we address the questions of how the interaction of the motor domain with a microtubule is modulated by ATPase steps, how the two mechanical cycles (the microtubule association/dissociation and tail swing) are coordinated, and which ATPase site among the multiple sites in the motor domain regulates the coordination. Based on steady-state and pre-steady-state measurements, we demonstrate that the two mechanical cycles proceed synchronously at most of the intermediate states in the ATPase cycle: the motor domain in the poststroke state binds strongly to the microtubule with a K(d) of approximately 0.2 microM, whereas most of the motor domains in the prestroke state bind weakly to the microtubule with a K(d) of >10 microM. However, our results suggest that the timings of the microtubule affinity change and tail swing are staggered at the recovery stroke step in which the tail swings from the poststroke to the prestroke position. The ATPase site in the AAA1 module of the motor domain was found to be responsible for the coordination of these two mechanical processes. [Abstract/Link to Full Text]

Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, Pyecroft S, Woods GM, Belov K
Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16221-6.
A fatal transmissible tumor spread between individuals by biting has emerged in the Tasmanian devil (Sarcophilus harrisii), a carnivorous marsupial. Here we provide genetic evidence establishing that the tumor is clonal and therefore foreign to host devils. Thus, the disease is highly unusual because it is not just a tumor but also a tissue graft, passed between individuals without invoking an immune response. The MHC plays a key role in immune responses to both tumors and grafts. The most common mechanism of immune evasion by tumors is down-regulation of classical cell surface MHC molecules. Here we show that this mode of immune escape does not occur. However, because the tumor is a graft, it should still be recognized and rejected by the host's immune system due to foreign cell surface antigens. Mixed lymphocyte responses showed a lack of alloreactivity between lymphocytes of different individuals in the affected population, indicating a paucity of MHC diversity. This result was verified by genotyping, providing a conclusive link between a loss of MHC diversity and spread of a disease through a wild population. This novel disease arose as a direct result of loss of genetic diversity and the aggressive behavior of the host species. The neoplastic clone continues to spread although the population, and, without active disease control by removal of affected animals and the isolation of disease-free animals, the Tasmanian devil faces extinction. [Abstract/Link to Full Text]

Dietrich C, Swingley D, Werker JF
Native language governs interpretation of salient speech sound differences at 18 months.
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16027-31.
One of the first steps infants take in learning their native language is to discover its set of speech-sound categories. This early development is shown when infants begin to lose the ability to differentiate some of the speech sounds their language does not use, while retaining or improving discrimination of language-relevant sounds. However, this aspect of early phonological tuning is not sufficient for language learning. Children must also discover which of the phonetic cues that are used in their language serve to signal lexical distinctions. Phonetic variation that is readily discriminable to all children may indicate two different words in one language but only one word in another. Here, we provide evidence that the language background of 1.5-year-olds affects their interpretation of phonetic variation in word learning, and we show that young children interpret salient phonetic variation in language-specific ways. Three experiments with a total of 104 children compared Dutch- and English-learning 18-month-olds' responses to novel words varying in vowel duration or vowel quality. Dutch learners interpreted vowel duration as lexically contrastive, but English learners did not, in keeping with properties of Dutch and English. Both groups performed equivalently when differentiating words varying in vowel quality. Thus, at one and a half years, children's phonological knowledge already guides their interpretation of salient phonetic variation. We argue that early phonological learning is not just a matter of maintaining the ability to distinguish language-relevant phonetic cues. Learning also requires phonological interpretation at appropriate levels of linguistic analysis. [Abstract/Link to Full Text]

Recent Articles in BMJ: British Medical Journal

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]

Akhtar PC, Currie DB, Currie CE, Haw SJ
Changes in child exposure to environmental tobacco smoke (CHETS) study after implementation of smoke-free legislation in Scotland: national cross sectional survey.
BMJ. 2007 Sep 15;335(7619):545.
OBJECTIVE: To detect any change in exposure to secondhand smoke among primary schoolchildren after implementation of smoke-free legislation in Scotland in March 2006. DESIGN: Comparison of nationally representative, cross sectional, class based surveys carried out in the same schools before and after legislation. SETTING: Scotland. PARTICIPANTS: 2559 primary schoolchildren (primary 7; mean age 11.4 years) surveyed in January 2006 (before smoke-free legislation) and 2424 in January 2007 (after legislation). OUTCOME MEASURES: Salivary cotinine concentrations, reports of parental smoking, and exposure to tobacco smoke in public and private places before and after legislation. RESULTS: The geometric mean salivary cotinine concentration in non-smoking children fell from 0.36 (95% confidence interval 0.32 to 0.40) ng/ml to 0.22 (0.19 to 0.25) ng/ml after the introduction of smoke-free legislation in Scotland-a 39% reduction. The extent of the fall in cotinine concentration varied according to the number of parent figures in the home who smoked but was statistically significant only among pupils living in households in which neither parent figure smoked (51% fall, from 0.14 (0.13 to 0.16) ng/ml to 0.07 (0.06 to 0.08) ng/ml) and among pupils living in households in which only the father figure smoked (44% fall, from 0.57 (0.47 to 0.70) ng/ml to 0.32 (0.25 to 0.42) ng/ml). Little change occurred in reported exposure to secondhand smoke in pupils' own homes or in cars, but a small decrease in exposure in other people's homes was reported. Pupils reported lower exposure in cafes and restaurants and in public transport after legislation. CONCLUSIONS: The Scottish smoke-free legislation has reduced exposure to secondhand smoke among young people in Scotland, particularly among groups with lower exposure in the home. We found no evidence of increased secondhand smoke exposure in young people associated with displacement of parental smoking into the home. The Scottish smoke-free legislation has thus had a positive short term impact on young people's health, but further efforts are needed to promote both smoke-free homes and smoking cessation. [Abstract/Link to Full Text]

Haw SJ, Gruer L
Changes in exposure of adult non-smokers to secondhand smoke after implementation of smoke-free legislation in Scotland: national cross sectional survey.
BMJ. 2007 Sep 15;335(7619):549.
OBJECTIVE: To measure change in adult non-smokers' exposure to secondhand smoke in public and private places after smoke-free legislation was implemented in Scotland. DESIGN: Repeat cross sectional survey. SETTING: Scotland. PARTICIPANTS: Scottish adults, aged 18 to 74 years, recruited and interviewed in their homes. INTERVENTION: Comprehensive smoke-free legislation that prohibits smoking in virtually all enclosed public places and workplaces, including bars, restaurants, and cafes. OUTCOME MEASURES: Salivary cotinine, self reported exposure to smoke in public and private places, and self reported smoking restriction in homes and in cars. RESULTS: Overall, geometric mean cotinine concentrations in adult non-smokers fell by 39% (95% confidence interval 29% to 47%), from 0.43 ng/ml at baseline to 0.26 ng/ml after legislation (P<0.001). In non-smokers from non-smoking households, geometric mean cotinine concentrations fell by 49% (40% to 56%), from 0.35 ng/ml to 0.18 ng/ml (P<0.001). The 16% fall in cotinine concentrations in non-smokers from smoking households was not statistically significant. Reduction in exposure to secondhand smoke was associated with a reduction after legislation in reported exposure to secondhand smoke in public places (pubs, other workplaces, and public transport) but not in homes and cars. We found no evidence of displacement of smoking from public places into the home. CONCLUSIONS: Implementation of Scotland's smoke-free legislation has been accompanied within one year by a large reduction in exposure to secondhand smoke, which has been greatest in non-smokers living in non-smoking households. Non-smokers living in smoking households continue to have high levels of exposure to secondhand smoke. [Abstract/Link to Full Text]

Garvey JF, McElwaine P, Monaghan TS, McNicholas WT
Banning smoking: Confessions of an accordion cleaner.
BMJ. 2007 Sep 29;335(7621):630. [Abstract/Link to Full Text]

Eborall H, Davies R, Kinmonth AL, Griffin S, Lawton J
Patients' experiences of screening for type 2 diabetes: prospective qualitative study embedded in the ADDITION (Cambridge) randomised controlled trial.
BMJ. 2007 Sep 8;335(7618):490.
OBJECTIVES: To provide insight into factors that contribute to the anxiety reported in a quantitative study of the psychological effect of screening for type 2 diabetes. To explore expectations of and reactions to the screening experience of patients with positive, negative, and intermediate results. DESIGN: Prospective qualitative interview study of patients attending a screening programme for type 2 diabetes. SETTING: Seven general practices in the ADDITION (Cambridge) trial in the east of England. PARTICIPANTS: 23 participants (aged 50-69) attending different stages in the screening process. RESULTS: Participants' perceptions changed as they progressed through the screening programme; the stepwise process seemed to help them adjust psychologically. The first screening test was typically considered unimportant and was attended with no thought about its implications. By the final diagnostic test, type 2 diabetes was considered a strong possibility, albeit a "mild" form. After diagnosis, people with screen detected type 2 diabetes tended to downplay its importance and talked confidently about their plans to control it. Participants with intermediate results seemed uncertain about their diagnosis, and those who screened negative were largely unaware of their remaining high risk. CONCLUSIONS: This study helps in understanding the limited psychological impact of screening for type 2 diabetes quantified previously, in particular by the quantitative substudy of ADDITION (Cambridge). The findings have implications for implementing such a screening programme in terms of timing and content. [Abstract/Link to Full Text]

Stolk RP
Screening for diabetes.
BMJ. 2007 Sep 8;335(7618):457-8. [Abstract/Link to Full Text]

Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA
Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review.
BMJ. 2007 Sep 8;335(7618):497.
OBJECTIVE: To review the literature on the association between antidiabetic agents and morbidity and mortality in people with heart failure and diabetes. DESIGN: Systematic review and meta-analysis of controlled studies (randomised trials or cohort studies) evaluating antidiabetic agents and outcomes (death and admission to hospital) in patients with heart failure and diabetes. DATA SOURCES: Electronic databases, manual reference search, and contact with investigators. REVIEW METHODS: Two reviewers independently extracted data. Risk estimates for specific treatments were abstracted and pooled estimates derived by meta-analysis where appropriate. RESULTS: Eight studies were included. Three of four studies found that insulin use was associated with increased risk for all cause mortality (odds ratio 1.25, 95% confidence interval 1.03 to 1.51; 3.42, 1.40 to 8.37 in studies that did not adjust for diet and antidiabetic drugs; hazard ratio 1.66, 1.20 to 2.31; 0.96, 0.88 to 1.05 in the studies that did). Metformin was associated with significantly reduced all cause mortality in two studies (hazard ratio 0.86, 0.78 to 0.97) compared with other antidiabetic drugs and insulin; 0.70, 0.54 to 0.91 compared with sulfonylureas); a similar trend was seen in a third. Metformin was not associated with increased hospital admission for any cause or for heart failure specifically. In four studies, use of thiazolidinediones was associated with reduced all cause mortality (pooled odds ratio 0.83, 0.71 to 0.97, I2=52%, P=0.02). Thiazolidinediones were associated with increased risk of hospital admission for heart failure (pooled odds ratio 1.13 (1.04 to 1.22), I2=0%, P=0.004). The two studies of sulfonylureas had conflicting results, probably because of differences in comparator treatments. Important limitations were noted in all studies. CONCLUSION: Metformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies. [Abstract/Link to Full Text]

Snoek FJ
Self management of type 2 diabetes.
BMJ. 2007 Sep 8;335(7618):458-9. [Abstract/Link to Full Text]

Peel E, Douglas M, Lawton J
Self monitoring of blood glucose in type 2 diabetes: longitudinal qualitative study of patients' perspectives.
BMJ. 2007 Sep 8;335(7618):493.
OBJECTIVE: To explore views of patients with type 2 diabetes about self monitoring of blood glucose over time. DESIGN: Longitudinal, qualitative study. SETTING: Primary and secondary care settings across Lothian, Scotland. PARTICIPANTS: 18 patients with type 2 diabetes. MAIN OUTCOME MEASURES: Results from repeat in-depth interviews with patients over four years after clinical diagnosis. RESULTS: Analysis revealed three main themes-the role of health professionals, interpreting readings and managing high values, and the ongoing role of blood glucose self monitoring. Self monitoring decreased over time, and health professionals' behaviour seemed crucial in this: participants interpreted doctors' focus on levels of haemoglobin A(1c), and lack of perceived interest in meter readings, as indicating that self monitoring was not worth continuing. Some participants saw readings as a proxy measure of good and bad behaviour-with women especially, chastising themselves when readings were high. Some participants continued to find readings difficult to interpret, with uncertainty about how to respond to high readings. Reassurance and habit were key reasons for continuing. There was little indication that participants were using self monitoring to effect and maintain behaviour change. CONCLUSIONS: Clinical uncertainty about the efficacy and role of blood glucose self monitoring in patients with type 2 diabetes is mirrored in patients' own accounts. Patients tended not to act on their self monitoring results, in part because of a lack of education about the appropriate response to readings. Health professionals should be explicit about whether and when such patients should self monitor and how they should interpret and act upon the results, especially high readings. [Abstract/Link to Full Text]

Eborall HC, Griffin SJ, Prevost AT, Kinmonth AL, French DP, Sutton S
Psychological impact of screening for type 2 diabetes: controlled trial and comparative study embedded in the ADDITION (Cambridge) randomised controlled trial.
BMJ. 2007 Sep 8;335(7618):486.
OBJECTIVE: To quantify the psychological impact of primary care based stepwise screening for type 2 diabetes. DESIGN: Controlled trial and comparative study embedded in a randomised controlled trial. SETTING: 15 practices (10 screening, five control) in the ADDITION (Cambridge) trial in the east of England. PARTICIPANTS: 7380 adults (aged 40-69) in the top fourth for risk of having undiagnosed type 2 diabetes (6416 invited for screening, 964 controls). INTERVENTIONS: Invited for screening for type 2 diabetes or not invited (controls), incorporating a comparative study of subgroups of screening attenders. Attenders completed questionnaires after a random blood glucose test and at 3-6 months and 12-15 months later. Controls were sent questionnaires at corresponding time points. Non-attenders were sent questionnaires at 3-6 months and 12-15 months. MAIN OUTCOME MEASURES: State anxiety (Spielberger state anxiety inventory), anxiety and depression (hospital anxiety and depression scale), worry about diabetes, and self rated health. RESULTS: No significant differences were found between the screening and control participants at any time-for example, difference in means (95% confidence intervals) for state anxiety after the initial blood glucose test was -0.53, -2.60 to 1.54, at 3-6 months was 1.51 (-0.17 to 3.20), and at 12-15 months was 0.57, -1.11 to 2.24. After the initial test, compared with participants who screened negative, those who screened positive reported significantly poorer general health (difference in means -0.19, -0.25 to -0.13), higher state anxiety (0.93, -0.02 to 1.88), higher depression (0.32, 0.08 to 0.56), and higher worry about diabetes (0.25, 0.09 to 0.41), although effect sizes were small. Small but significant trends were found for self rated health across the screening subgroups at 3-6 months (P=0.047) and for worry about diabetes across the screen negative groups at 3-6 months and 12-15 months (P=0.001). CONCLUSIONS: Screening for type 2 diabetes has limited psychological impact on patients. Implementing a national screening programme based on the stepwise screening procedure used in the ADDITION (Cambridge) trial is unlikely to have significant consequences for patients' psychological health. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99175498 [controlled-trials.com]. [Abstract/Link to Full Text]

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

Fazel M
Why I'm a reluctant rapid responder.
BMJ. 2004 Feb 14;328(7436):413. [Abstract/Link to Full Text]

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

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

Parmar MS
Joy of rapid responses. Don't take points raised in open and free discussion personally.
BMJ. 2004 Mar 13;328(7440):644-5. [Abstract/Link to Full Text]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Recent Articles in CMAJ : Canadian Medical Association Journal

Dubois J, Rypens F, Garel L, David M, Lacroix J, Gauvin F
Incidence of deep vein thrombosis related to peripherally inserted central catheters in children and adolescents.
CMAJ. 2007 Nov 6;177(10):1185-90.
BACKGROUND: Peripherally inserted central catheters (PICC) in children and adolescents are being used with increasing frequency. We sought to determine the incidence and characterize risk factors of deep vein thrombosis associated with peripherally inserted central catheters in a pediatric population. METHODS: We conducted a prospective study involving consecutive patients referred to the radiology department of a tertiary care university-affiliated hospital for insertion of a peripherally inserted central catheter. We included patients aged 18 years or less who weighed more than 2.5 kg and had a peripherally inserted central catheter successfully inserted in his or her arm between June 2004 and November 2005. The primary outcome was the occurrence of partial or complete deep vein thrombosis evaluated by clinical examination, ultrasonography and venous angiography. RESULTS: A total of 214 patients (101 girls, 113 boys) were included in the study. Partial or complete deep vein thrombosis occurred in 20 patients, for an incidence of 93.5 per 1000 patients and 3.85 per 1000 catheter-days. Only 1 of the cases was symptomatic. In the univariable analyses, the only variable significantly associated with deep vein thrombosis was the presence of factor II mutation G20210A (odds ratio 7.08, 95% confidence interval 1.11-45.15, p = 0.04), a genetic mutation that increases the risk of a blood clot and that was present in 5 (2.3%) of the 214 patients. INTERPRETATION: The incidence of deep vein thrombosis related to peripherally inserted central catheters in our study was lower than the incidence related to centrally inserted venous catheters described in the pediatric literature (11%-50%). [Abstract/Link to Full Text]

Leith M
Reconsidering survival.
CMAJ. 2007 Oct 23;177(9):1148. [Abstract/Link to Full Text]

Jorens PG
Accuracy of point-of-care measurements.
CMAJ. 2007 Oct 23;177(9):1070. [Abstract/Link to Full Text]

Brindley PG, Butler MS, Cembrowski G, Brindley DN
Falsely elevated point-of-care lactate measurement after ingestion of ethylene glycol.
CMAJ. 2007 Apr 10;176(8):1097-9.
BACKGROUND: A patient presented with severe acidosis and a point-of-care lactate measurement of 42 mmol/L. Mesenteric ischemia was suspected, with a potential need for laparotomy; however, plasma lactate measurements were below 4 mmol/L. Ethylene glycol ingestion was subsequently diagnosed. We therefore wished to determine why discrepancies in lactate measurements occur and whether this "lactate gap" could be clinically useful. METHODS: We phlebotomized blood, added various concentrations of metabolites of ethylene glycol, and tested the resulting samples with the 5 most common lactate analyzers. RESULTS: With the Radiometer 700 point-of-care analyzer, glycolate addition resulted in an artifactual, massive lactate elevation, even at low glycolate concentrations. Another major ethylene glycol metabolite, glyoxylate (but not oxalate or formate), caused similar elevations. The i-STAT and Bayer point-of-care analyzers and the Beckman and Vitros laboratory analyzers reported minimal lactate elevations. Lactate gap was determined by comparing the Radiometer result with the corresponding result from any of the other analyzers. INTERPRETATION: We demonstrated how inappropriate laparotomy or delayed therapy might occur if clinicians are unaware of this phenomenon or have access to only a single analyzer. We also showed that lactate gap can be exploited to expedite treatment, diagnose late ethylene-glycol ingestion and terminate dialysis. By comparing lactate results from the iSTAT or Bayer devices with that from the Radiometer, ethylene-glycol ingestion can be diagnosed at the point of care. This can expedite diagnosis and treatment by hours, compared with waiting for laboratory results for plasma ethylene glycol. [Abstract/Link to Full Text]

Behroozi D
Screening men for osteoporosis.
CMAJ. 2007 Oct 23;177(9):1069; author reply 1069-70. [Abstract/Link to Full Text]

Brown JP, Josse RG
2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.
CMAJ. 2002 Nov 12;167(10 Suppl):S1-34.
OBJECTIVE: To revise and expand the 1996 Osteoporosis Society of Canada clinical practice guidelines for the management of osteoporosis, incorporating recent advances in diagnosis, prevention and management of osteoporosis, and to identify and assess the evidence supporting the recommendations. OPTIONS: All aspects of osteoporosis care and its fracture complications - including classification, diagnosis, management and methods for screening, as well as prevention and reducing fracture risk - were reviewed, revised as required and expressed as a set of recommendations. OUTCOMES: Strategies for identifying and evaluating those at high risk; the use of bone mineral density and biochemical markers in diagnosis and assessing response to management; recommendations regarding nutrition and physical activity; and the selection of pharmacologic therapy for the prevention and management of osteoporosis in men and women and for osteoporosis resulting from glucocorticoid treatment. EVIDENCE: All recommendations were developed using a justifiable and reproducible process involving an explicit method for the evaluation and citation of supporting evidence. VALUES: All recommendations were reviewed by members of the Scientific Advisory Council of the Osteoporosis Society of Canada, an expert steering committee and others, including family physicians, dietitians, therapists and representatives of various medical specialties involved in osteoporosis care (geriatric medicine, rheumatology, endocrinology, obstetrics and gynecology, nephrology, radiology) as well as methodologists from across Canada. Benefits, harm and costs: Earlier diagnosis and prevention of fractures should decrease the medical, social and economic burdens of this disease. RECOMMENDATIONS: This document outlines detailed recommendations pertaining to all aspects of osteoporosis. Strategies for identifying those at increased risk (i.e., those with at least one major or 2 minor risk factors) and screening with central dual-energy x-ray absorptiometry at age 65 years are recommended. Bisphosphonates and raloxifene are first-line therapies in the prevention and treatment of postmenopausal osteoporosis. Estrogen and progestin/progesterone is a first-line therapy in the prevention and a second-line therapy in the treatment of postmenopausal osteoporosis. Nasal calcitonin is a second-line therapy in the treatment of postmenopausal osteoporosis. Although not yet approved for use in Canada, hPTH(1-34) is expected to be a first-line treatment for postmenopausal women with severe osteoporosis. Ipriflavone, vitamin K and fluoride are not recommended. Bisphosphonates are the first-line therapy for the prevention and treatment of osteoporosis in patients requiring prolonged glucocorticoid therapy and for men with osteoporosis. Nasal or parenteral calcitonin is a first-line treatment for pain associated with acute vertebral fractures. Impact-type exercise and age-appropriate calcium and vitamin D intake are recommended for the prevention of osteoporosis. VALIDATION: All recommendations were graded according to the strength of the evidence; where the evidence was insufficient and recommendations were based on consensus opinion alone, this is indicated. These guidelines are viewed as a work in progress and will be updated periodically in response to advances in this field. [Abstract/Link to Full Text]

Khan AA, Hodsman AB, Papaioannou A, Kendler D, Brown JP, Olszynski WP
Management of osteoporosis in men: an update and case example.
CMAJ. 2007 Jan 30;176(3):345-8.
In 2002, Osteoporosis Canada published clinical practice guidelines for the diagnosis and management of osteoporosis. The current paper supplements that guideline and provides a review and synthesis of the current literature on the diagnosis and management of osteoporosis in men. [Abstract/Link to Full Text]

Turnbull J, Muckle W, Masters C
Homelessness and health.
CMAJ. 2007 Oct 23;177(9):1065-6. [Abstract/Link to Full Text]

Butler-Jones D
The health of the public is the foundation of prosperity: the work of the Public Health Agency of Canada at home and around the world.
CMAJ. 2007 Oct 23;177(9):1063-4. [Abstract/Link to Full Text]

Jha P, Chen Z
Poverty and chronic diseases in Asia: challenges and opportunities.
CMAJ. 2007 Oct 23;177(9):1059-62. [Abstract/Link to Full Text]

Paige CJ
The future of health research is hanging in the balance.
CMAJ. 2007 Oct 23;177(9):1057-8. [Abstract/Link to Full Text]

Clark DR, McGrath PJ, MacDonald N
Members' of Parliament knowledge of and attitudes toward health research and funding.
CMAJ. 2007 Oct 23;177(9):1045-51.
BACKGROUND: Establishment of the Canadian Institutes of Health Research (CIHR) in 2000 resulted in increased funding for health research in Canada. Since 2001, the number of proposals submitted to CIHR that, following peer review, are judged to be of scientific merit to warrant funding, has grown by 77%. But many of these proposals do not receive funding because of budget constraints. Given the role of Members of Parliament in setting government funding priorities, we surveyed Members of Parliament about their knowledge of and attitudes toward health research, health research funding and CIHR. METHODS: All Members of Parliament were invited to participate, or to designate a senior aide to participate, in a 15-minute survey of knowledge of and attitudes toward health research, health research funding and CIHR. Interviews were conducted between July 15, 2006, and Dec. 20, 2006. Responses were analyzed by party affiliation, region and years of service as a Member of Parliament. RESULTS: A total of 101 of 308 Members of Parliament or their designated senior aides participated in the survey. Almost one-third of respondents were senior aides. Most of the respondents (84%) were aware of CIHR, but 32% knew nothing about its role. Participants believed that health research is a critical component of a strong health care system and that it is underfunded. Overall, 78% felt that the percentage of total government spending directed to health research funding was too low; 85% felt the same way about the percentage of government health care spending directed to health research. Fifty-four percent believed that the federal government should provide both funding and guidelines for health research, and 66% believed that the business sector should be the primary source of health research funding. Participants (57%) most frequently defined health research as study into cures or treatments of disease, and 22% of participants were aware that CIHR is the main federal government funding organization for health research. Participants perceived health research to be a low priority for Canadian voters (mean ranking 3.8/10, with 1 being unimportant and 10 being extremely important [SD 1.85]). INTERPRETATION: Our results highlight significant knowledge gaps among Members of Parliament regarding health research. Many of these knowledge gaps will need to be addressed if health research is to become a priority. [Abstract/Link to Full Text]

Foley RN
Mortality trends among Canadian patients receiving dialysis.
CMAJ. 2007 Oct 23;177(9):1055-6. [Abstract/Link to Full Text]

Jassal SV, Trpeski L, Zhu N, Fenton S, Hemmelgarn B
Changes in survival among elderly patients initiating dialysis from 1990 to 1999.
CMAJ. 2007 Oct 23;177(9):1033-8.
BACKGROUND: Over the past decade, there has been a steep rise in the number of people with complex medical problems who require dialysis. We sought to determine the life expectancy of elderly patients after starting dialysis and to identify changes in survival rates over time. METHODS: All patients aged 65 years or older who began dialysis in Canada between 1990 and 1999 were identified from the Canadian Organ Replacement Register. We used Cox proportional hazards models to examine the effect that the period during which dialysis was initiated (era 1, 1990-1994; era 2, 1995-1999) had on patient survival, after adjusting for diabetes, sex and comorbidity. Patients were followed from initiation of dialysis until death, transplantation, loss to follow-up or study end (Dec. 31, 2004). RESULTS: A total of 14,512 patients aged 65 years or older started dialysis between 1990 and 1999. The proportion of these patients who were 75 years or older at the start of dialysis increased from 32.7% in era 1 (1990-1994) to 40.0% in era 2 (1995-1999). Despite increased comorbidity over the 2 study periods, the unadjusted 1-, 3- and 5-year survival rates among patients aged 65-74 years at dialysis initiation rose from 74.4%, 44.9% and 25.8% in era 1 to 78.1%, 51.5% and 33.5% in era 2. The respective survival rates among those aged 75 or more at dialysis initiation increased from 67.2%, 32.3% and 14.2% in era 1 to 69.0%, 36.7% and 20.3% in era 2. This survival advantage persisted after adjustment for diabetes, sex and comorbidity in both age groups (65-74 years: hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.72- 0.81; 75 years or more: HR 0.86, 95% CI 0.80-0.92). INTERPRETATION: Survival after dialysis initiation among elderly patients has improved from 1990 to 1999, despite an increasing burden of comorbidity. Physicians may find these data useful when discussing prognosis with elderly patients who are initiating dialysis. [Abstract/Link to Full Text]

Tonelli M, Manns B, Culleton B, Klarenbach S, Hemmelgarn B, Wiebe N, Gill JS
Association between proximity to the attending nephrologist and mortality among patients receiving hemodialysis.
CMAJ. 2007 Oct 23;177(9):1039-44.
BACKGROUND: Many Canadian patients who receive hemodialysis live far from their attending nephrologist, which may affect clinical outcomes. We investigated whether patients receiving hemodialysis who live farther from their attending nephrologist are more likely to die than those who live closer. METHODS: We studied a random sample of 18,722 patients who began hemodialysis between 1990 and 2000 in Canada. We calculated the distance between each patient's residence location at the start of dialysis and the practice location of their attending nephrologist. We used Cox proportional hazards models to examine the adjusted relation between distance and clinical outcomes (death from all causes, infectious causes and cardiovascular causes) over a follow-up period of up to 14 years. RESULTS: During the follow-up period (median 2.5 yr, interquartile range 1.0-4.7 yr), 11,582 (62%) patients died. Compared with patients who lived within 50 km of their nephrologist, the adjusted hazard ratio of death among those who lived 50.1-150 km away was 1.06 (95% confidence interval [CI] 1.01-1.12), 1.13 (95% CI 1.04-1.22) for those who lived 150.1-300 km away and 1.13 (95% CI 1.03-1.24) for those who lived more than 300 km from their nephrologist (p for trend < 0.001). The risk of death from infectious causes increased with greater distance from the attending nephrologist (p for trend < 0.001). The risk of death from cardiovascular causes did not increase with distance from the attending nephrologist (p for trend = 0.21). Compared with patients who lived within 50 km of their nephrologist, the adjusted hazard ratio of death among those who lived more than 300 km away was 1.75 (95% CI 1.32-2.32) for infectious causes and 0.93 (95% CI 0.79-1.09) for cardiovascular causes. Conclusions: Mortality associated with hemodialysis was greater among patients who lived farther from their attending nephrologist, as compared with those who lived closer. This was especially evident for death from infectious causes. [Abstract/Link to Full Text]

MacDonald N, Weir E, Langley JM
Influenza and the influenza vaccine.
CMAJ. 2007 Oct 23;177(9):1028. [Abstract/Link to Full Text]

Strebel BM, Ross S
Chronic post-thoracotomy pain syndrome.
CMAJ. 2007 Oct 23;177(9):1027. [Abstract/Link to Full Text]

Moutzouris DA, Soloukides A, Peppas C, Hadjiconstantinou V
Xanthogranulomatous pyelonephritis.
CMAJ. 2007 Oct 23;177(9):1027. [Abstract/Link to Full Text]

Koulaouzidis A, Bhat S, Gopal K
Retroperitoneal fibrosis.
CMAJ. 2007 Oct 23;177(9):1027. [Abstract/Link to Full Text]

Langley JM
Release of the statement on influenza for the 2007 2008 season from the National Advisory Committee on Immunization.
CMAJ. 2007 Oct 23;177(9):1025-6. [Abstract/Link to Full Text]

Kondro W
Odd numbers: food banks and liposuction.
CMAJ. 2007 Oct 23;177(9):1022. [Abstract/Link to Full Text]

Bryden L
Getting involved: donating time, money and expertise to global health.
CMAJ. 2007 Oct 23;177(9):1020-1. [Abstract/Link to Full Text]

Lai W
Measles.
CMAJ. 2007 Oct 23;177(9):1019. [Abstract/Link to Full Text]

Kovesi T
Qallunaat.
CMAJ. 2007 Oct 23;177(9):1018. [Abstract/Link to Full Text]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Recent Articles in The Journal of Clinical Investigation

Li HH, Willis MS, Lockyer P, Miller N, McDonough H, Glass DJ, Patterson C
Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins.
J Clin Invest. 2007 Nov;117(11):3211-23.
Cardiac hypertrophy is a major cause of human morbidity and mortality. Although much is known about the pathways that promote hypertrophic responses, mechanisms that antagonize these pathways have not been as clearly defined. Atrogin-1, also known as muscle atrophy F-box, is an F-box protein that inhibits pathologic cardiac hypertrophy by participating in a ubiquitin ligase complex that triggers degradation of calcineurin, a factor involved in promotion of pathologic hypertrophy. Here we demonstrated that atrogin-1 also disrupted Akt-dependent pathways responsible for physiologic cardiac hypertrophy. Our results indicate that atrogin-1 does not affect the activity of Akt itself, but serves as a coactivator for members of the Forkhead family of transcription factors that function downstream of Akt. This coactivator function of atrogin-1 was dependent on its ubiquitin ligase activity and the deposition of polyubiquitin chains on lysine 63 of Foxo1 and Foxo3a. Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype. These experiments define a role for lysine 63-linked ubiquitin chains in transcriptional coactivation and demonstrate that atrogin-1 uses this mechanism to disrupt physiologic cardiac hypertrophic signaling through its effects on Forkhead transcription factors. [Abstract/Link to Full Text]

Burlingham WJ, Love RB, Jankowska-Gan E, Haynes LD, Xu Q, Bobadilla JL, Meyer KC, Hayney MS, Braun RK, Greenspan DS, Gopalakrishnan B, Cai J, Brand DD, Yoshida S, Cummings OW, Wilkes DS
IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants.
J Clin Invest. 2007 Nov;117(11):3498-506.
Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture's syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration. [Abstract/Link to Full Text]

Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM
Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.
J Clin Invest. 2007 Nov;117(11):3393-402.
Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD. [Abstract/Link to Full Text]

Thorne SH, Hwang TH, O'Gorman WE, Bartlett DL, Sei S, Kanji F, Brown C, Werier J, Cho JH, Lee DE, Wang Y, Bell J, Kirn DH
Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963.
J Clin Invest. 2007 Nov;117(11):3350-8.
Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing. [Abstract/Link to Full Text]

Araya J, Cambier S, Markovics JA, Wolters P, Jablons D, Hill A, Finkbeiner W, Jones K, Broaddus VC, Sheppard D, Barzcak A, Xiao Y, Erle DJ, Nishimura SL
Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients.
J Clin Invest. 2007 Nov;117(11):3551-62.
Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1beta, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-beta activation in amplifying SM and driving IL-1beta-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin alpha(v)beta(8), which is the major mediator of airway fibroblast TGF-beta activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-beta as a potential therapeutic target for COPD. [Abstract/Link to Full Text]

Grosse J, Braun A, Varga-Szabo D, Beyersdorf N, Schneider B, Zeitlmann L, Hanke P, Schropp P, M�hlstedt S, Zorn C, Huber M, Schmittwolf C, Jagla W, Yu P, Kerkau T, Schulze H, Nehls M, Nieswandt B
An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice.
J Clin Invest. 2007 Nov;117(11):3540-50.
Changes in cytoplasmic Ca2+ levels regulate a variety of fundamental cellular functions in virtually all cells. In nonexcitable cells, a major pathway of Ca2+ entry involves receptor-mediated depletion of intracellular Ca2+ stores followed by the activation of store-operated calcium channels in the plasma membrane. We have established a mouse line expressing an activating EF hand motif mutant of stromal interaction molecule 1 (Stim1), an ER receptor recently identified as the Ca2+ sensor responsible for activation of Ca2+ release-activated (CRAC) channels in T cells, whose function in mammalian physiology is not well understood. Mice expressing mutant Stim1 had macrothrombocytopenia and an associated bleeding disorder. Basal intracellular Ca2+ levels were increased in platelets, which resulted in a preactivation state, a selective unresponsiveness to immunoreceptor tyrosine activation motif-coupled agonists, and increased platelet consumption. In contrast, basal Ca2+ levels, but not receptor-mediated responses, were affected in mutant T cells. These findings identify Stim1 as a central regulator of platelet function and suggest a cell type-specific activation or composition of the CRAC complex. [Abstract/Link to Full Text]

Luo J, Ho PP, Buckwalter MS, Hsu T, Lee LY, Zhang H, Kim DK, Kim SJ, Gambhir SS, Steinman L, Wyss-Coray T
Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis.
J Clin Invest. 2007 Nov;117(11):3306-15.
Autoimmune encephalomyelitis, a mouse model for multiple sclerosis, is characterized by the activation of immune cells, demyelination of axons in the CNS, and paralysis. We found that TGF-beta1 synthesis in glial cells and TGF-beta-induced signaling in the CNS were activated several days before the onset of paralysis in mice with autoimmune encephalomyelitis. While early production of TGF-beta1 was observed in glial cells TGF-beta signaling was activated in neurons and later in infiltrating T cells in inflammatory lesions. Systemic treatment with a pharmacological inhibitor of TGF-beta signaling ameliorated the paralytic disease and reduced the accumulation of pathogenic T cells and expression of IL-6 in the CNS. Priming of peripheral T cells was not altered, nor was the generation of TH17 cells, indicating that this effect was directed within the brain, yet affected the immune system. These results suggest that early production of TGF-beta1 in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation, providing a rare example of the brain modulating the immune system. Importantly, inhibition of TGF-beta signaling may have benefits in the treatment of the acute phase of autoimmune CNS inflammation. [Abstract/Link to Full Text]

Noubade R, Milligan G, Zachary JF, Blankenhorn EP, del Rio R, Rincon M, Teuscher C
Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-gamma production in mice.
J Clin Invest. 2007 Nov;117(11):3507-18.
Histamine receptor H1 (H1R) is a susceptibility gene in both experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune orchitis (EAO), 2 classical T cell-mediated models of organ-specific autoimmune disease. Here we showed that expression of H1R in naive CD4+ T cells was required for maximal IFN-gamma production but was dispensable for proliferation. Moreover, H1R signaling at the time of TCR ligation was required for activation of p38 MAPK, a known regulator of IFN-gamma expression. Importantly, selective reexpression of H1R in CD4+ T cells fully complemented both the IFN-gamma production and the EAE susceptibility of H1R-deficient mice. These data suggest that the presence of H1R in CD4+ T cells and its interaction with histamine regulates early TCR signals that lead to Th1 differentiation and autoimmune disease. [Abstract/Link to Full Text]

Li J, Sejas DP, Zhang X, Qiu Y, Nattamai KJ, Rani R, Rathbun KR, Geiger H, Williams DA, Bagby GC, Pang Q
TNF-alpha induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells.
J Clin Invest. 2007 Nov;117(11):3283-95.
The molecular pathogenesis of the myeloid leukemias that frequently occur in patients with Fanconi anemia (FA) is not well defined. Hematopoietic stem cells bearing inactivating mutations of FA complementation group C (FANCC) are genetically unstable and hypersensitive to apoptotic cytokine cues including IFN-gamma and TNF-alpha, but neoplastic stem cell clones that arise frequently in vivo are resistant to these cytokines. Reasoning that the combination of genetic instability and cytokine hypersensitivity might create an environment supporting the emergence of leukemic stem cells, we tested the leukemia-promoting effects of TNF-alpha in murine stem cells. TNF-alpha exposure initially profoundly inhibited the growth of Fancc-/- stem cells. However, longer-term exposure of these cells promoted the outgrowth of cytogenetically abnormal clones that, upon transplantation into congenic WT mice, led to acute myelogenous leukemia. TNF-alpha induced ROS-dependent genetic instability in Fancc-/- but not in WT cells. The leukemic clones were TNF-alpha resistant but retained their characteristic hypersensitivity to mitomycin C and exhibited high levels of chromosomal instability. Expression of FANCC cDNA in Fancc-/- stem cells protected them from TNF-alpha-induced clonal evolution. We conclude that TNF-alpha exposure creates an environment in which somatically mutated preleukemic stem cell clones are selected and from which unaltered TNF-alpha-hypersensitive Fancc-/- stem cells are purged. [Abstract/Link to Full Text]

Hofmann SM, Zhou L, Perez-Tilve D, Greer T, Grant E, Wancata L, Thomas A, Pfluger PT, Basford JE, Gilham D, Herz J, Tsch�p MH, Hui DY
Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice.
J Clin Invest. 2007 Nov;117(11):3271-82.
Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure. [Abstract/Link to Full Text]

Ling C, Poulsen P, Simonsson S, R�nn T, Holmkvist J, Almgren P, Hagert P, Nilsson E, Mabey AG, Nilsson P, Vaag A, Groop L
Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle.
J Clin Invest. 2007 Nov;117(11):3427-35.
Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance. [Abstract/Link to Full Text]

Matushansky I, Hernando E, Socci ND, Mills JE, Matos TA, Edgar MA, Singer S, Maki RG, Cordon-Cardo C
Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway.
J Clin Invest. 2007 Nov;117(11):3248-57.
Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. We present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, we show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/beta-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, we illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Our results provide mechanistic insights regarding the cell of origin of MFH, establish what we believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas. [Abstract/Link to Full Text]

Xicohtencatl-Cortes J, Monteiro-Neto V, Ledesma MA, Jordan DM, Francetic O, Kaper JB, Puente JL, Gir�n JA
Intestinal adherence associated with type IV pili of enterohemorrhagic Escherichia coli O157:H7.
J Clin Invest. 2007 Nov;117(11):3519-29.
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes hemorrhagic colitis and hemolytic uremic syndrome (HUS) by colonizing the gut mucosa and producing Shiga toxins (Stx). The only factor clearly demonstrated to play a role in EHEC adherence to intestinal epithelial cells is intimin, which binds host cell integrins and nucleolin, as well as a receptor (Tir) that it injects into the host cell. Here we report that EHEC O157:H7 produces adhesive type IV pili, which we term hemorrhagic coli pilus (HCP), composed of a 19-kDa pilin subunit (HcpA) that is encoded by the hcpA chromosomal gene. HCP were observed as bundles of fibers greater than 10 microm in length that formed physical bridges between bacteria adhering to human and bovine host cells. Sera of HUS patients, but not healthy individuals, recognized HcpA, suggesting that the pili are produced in vivo during EHEC infections. Inactivation of the hcpA gene in EHEC EDL933 resulted in significantly reduced adherence to cultured human intestinal and bovine renal epithelial cells and to porcine and bovine gut explants. An escN mutant, which is unable to translocate Tir, adhered less than the hcpA mutant, suggesting that adherence mediated by intimin-Tir interactions is a prelude to HCP-mediated adherence. An hcpA and stx1,2 triple mutant and an hcpA mutant had similar levels of adherence to bovine and human epithelial cells while a stx1,2 double mutant had only a minor defect in adherence, indicating that HCP-mediated adherence and cytotoxicity are independent events. Our data establish that EHEC O157:H7 HCP are intestinal colonization factors that are likely to contribute to the pathogenic potential of this food-borne pathogen. [Abstract/Link to Full Text]

Ornatowski W, Poschet JF, Perkett E, Taylor-Cousar JL, Deretic V
Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity.
J Clin Invest. 2007 Nov;117(11):3489-97.
Progressive pulmonary disease and infections with Pseudomonas aeruginosa remain an intractable problem in cystic fibrosis (CF). At the cellular level, CF is characterized by organellar hyperacidification, which results in altered protein and lipid glycosylation. Altered pH of the trans-Golgi network (TGN) may further disrupt the protein processing and packaging that occurs in this organelle. Here we measured activity of the major TGN endoprotease furin and demonstrated a marked upregulation in human CF cells. Increased furin activity was linked to elevated production in CF of the immunosuppressive and tissue remodeling cytokine TGF-beta and its downstream effects, including macrophage deactivation and augmented collagen secretion by epithelial cells. As furin is responsible for the proteolytic processing of a range of endogenous and exogenous substrates including growth factors and bacterial toxins, we determined that elevated furin-dependent activation of exotoxin A caused increased cell death in CF respiratory epithelial cells compared with genetically matched CF transmembrane conductance regulator-corrected cells. Thus elevated furin levels in CF respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. These data suggest that the use of furin inhibitors may represent a strategy for pharmacotherapy in CF. [Abstract/Link to Full Text]

Gevaert T, Vriens J, Segal A, Everaerts W, Roskams T, Talavera K, Owsianik G, Liedtke W, Daelemans D, Dewachter I, Van Leuven F, Voets T, De Ridder D, Nilius B
Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.
J Clin Invest. 2007 Nov;117(11):3453-62.
Here we provide evidence for a critical role of the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) in normal bladder function. Immunofluorescence demonstrated TRPV4 expression in mouse and rat urothelium and vascular endothelium, but not in other cell types of the bladder. Intracellular Ca2+ measurements on urothelial cells isolated from mice revealed a TRPV4-dependent response to the selective TRPV4 agonist 4alpha-phorbol 12,13-didecanoate and to hypotonic cell swelling. Behavioral studies demonstrated that TRPV4-/- mice manifest an incontinent phenotype but show normal exploratory activity and anxiety-related behavior. Cystometric experiments revealed that TRPV4-/- mice exhibit a lower frequency of voiding contractions as well as a higher frequency of nonvoiding contractions. Additionally, the amplitude of the spontaneous contractions in explanted bladder strips from TRPV4-/- mice was significantly reduced. Finally, a decreased intravesical stretch-evoked ATP release was found in isolated whole bladders from TRPV4-/- mice. These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure. [Abstract/Link to Full Text]

Brilot F, Strowig T, Roberts SM, Arrey F, M�nz C
NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Ralpha.
J Clin Invest. 2007 Nov;117(11):3316-29.
DCs activate NK cells during innate immune responses to viral infections. However, the composition and kinetics of the immunological synapse mediating this interaction are largely unknown. Here, we report the rapid formation of an immunological synapse between human resting NK cells and mature DCs. Although inhibitory NK cell receptors were polarized to this synapse, where they are known to protect mature DCs from NK cell lysis, the NK cell also received activation signals that induced mobilization of intracellular calcium and CD69 upregulation. The high-affinity component of the receptor for IL-15, IL-15Ralpha, accumulated at the synapse center on NK cells, and blocking of IL-15Ralpha increased NK cell apoptosis and diminished NK cell survival during their interaction with DCs. Furthermore, IL-15Ralpha-deficient NK cells, obtained from donors with a history of infectious mononucleosis, showed diminished survival in culture with DCs. Synapse formation was required for IL-15Ralpha-mediated NK cell survival, because synapse disruption by adhesion molecule blocking decreased DC-induced NK cell survival. These results identify what we believe to be a novel regulatory NK cell synapse with hallmarks of spatially separated inhibitory and activating interactions at its center. We suggest that this synapse formation enables optimal NK cell activation by DCs during innate immune responses. [Abstract/Link to Full Text]

Bianchi F, Nuciforo P, Vecchi M, Bernard L, Tizzoni L, Marchetti A, Buttitta F, Felicioni L, Nicassio F, Di Fiore PP
Survival prediction of stage I lung adenocarcinomas by expression of 10 genes.
J Clin Invest. 2007 Nov;117(11):3436-44.
Adenocarcinoma is the predominant histological subtype of lung cancer, the leading cause of cancer deaths in the world. At stage I, the tumor is cured by surgery alone in about 60% of cases. Markers are needed to stratify patients by prognostic outcomes and may help in devising more effective therapies for poor prognosis patients. To achieve this goal, we used an integrated strategy combining meta-analysis of published lung cancer microarray data with expression profiling from an experimental model. The resulting 80-gene model was tested on an independent cohort of patients using RT-PCR, resulting in a 10-gene predictive model that exhibited a prognostic accuracy of approximately 75% in stage I lung adenocarcinoma when tested on 2 additional independent cohorts. Thus, we have identified a predictive signature of limited size that can be analyzed by RT-PCR, a technology that is easy to implement in clinical laboratories. [Abstract/Link to Full Text]

Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, Borisenko V, Feirt N, Podgrabinska S, Shiraishi K, Chawengsaksophak K, Rossant J, Accili D, Skobe M, Kitajewski J
Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression.
J Clin Invest. 2007 Nov;117(11):3369-82.
The Notch family of cell surface receptors and its ligands are highly conserved proteins that regulate cell fate determination, including those involved in mammalian vascular development. We report that Notch induces VEGFR-3 expression in vitro in human endothelial cells and in vivo in mice. In vitro, Notch in complex with the DNA-binding protein CBF-1/suppressor of hairless/Lag1 (CSL) bound the VEGFR-3 promoter and transactivated VEGFR-3 specifically in endothelial cells. Through induction of VEGFR-3, Notch increased endothelial cell responsiveness to VEGF-C, promoting endothelial cell survival and morphological changes. In vivo, VEGFR-3 was upregulated in endothelial cells with active Notch signaling. Mice heterozygous for null alleles of both Notch1 and VEGFR-3 had significantly reduced viability and displayed midgestational vascular patterning defects analogous to Notch1 nullizygous embryos. We found that Notch1 and Notch4 were expressed in normal and tumor lymphatic endothelial cells and that Notch1 was activated in lymphatic endothelium of invasive mammary micropapillary carcinomas. These results demonstrate that Notch1 and VEGFR-3 interact genetically, that Notch directly induces VEGFR-3 in blood endothelial cells to regulate vascular development, and that Notch may function in tumor lymphangiogenesis. [Abstract/Link to Full Text]

Graham DB, Robertson CM, Bautista J, Mascarenhas F, Diacovo MJ, Montgrain V, Lam SK, Cremasco V, Dunne WM, Faccio R, Coopersmith CM, Swat W
Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCgamma2 signaling axis in mice.
J Clin Invest. 2007 Nov;117(11):3445-52.
Oxidative burst, a critical antimicrobial mechanism of neutrophils, involves the rapid generation and release of reactive oxygen intermediates (ROIs) by the NADPH oxidase complex. Genetic mutations in an NADPH oxidase subunit, gp91 (also referred to as NOX2), are associated with chronic granulomatous disease (CGD), which is characterized by recurrent and life-threatening microbial infections. To combat such infections, ROIs are produced by neutrophils after stimulation by integrin-dependent adhesion to the ECM in conjunction with stimulation from inflammatory mediators, or microbial components containing pathogen-associated molecular patterns. In this report, we provide genetic evidence that both the Vav family of Rho GTPase guanine nucleotide exchange factors (GEFs) and phospholipase C-gamma2 (PLC-gamma2) are critical mediators of adhesion-dependent ROI production by neutrophils in mice. We also demonstrated that Vav was critically required for neutrophil-dependent host defense against systemic infection by Staphylococcus aureus and Pseudomonas aeruginosa, 2 common pathogens associated with fatal cases of hospital-acquired pneumonia. We identified a molecular pathway in which Vav GEFs linked integrin-mediated signaling with PLC-gamma2 activation, release of intracellular Ca2+ cations, and generation of diacylglycerol to control assembly of the NADPH oxidase complex and ROI production by neutrophils. Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav. [Abstract/Link to Full Text]

Sun J, Sukhova GK, Yang M, Wolters PJ, MacFarlane LA, Libby P, Sun C, Zhang Y, Liu J, Ennis TL, Knispel R, Xiong W, Thompson RW, Baxter BT, Shi GP
Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice.
J Clin Invest. 2007 Nov;117(11):3359-68.
Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell-deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. KitW-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3+ T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-gamma. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow-derived mast cells from WT or TNF-alpha-/- mice, but not from IL-6-/- or IFN-gamma-/- mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-gamma, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms. [Abstract/Link to Full Text]

Salvati E, Leonetti C, Rizzo A, Scarsella M, Mottolese M, Galati R, Sperduti I, Stevens MF, D'Incalci M, Blasco M, Chiorino G, Bauwens S, Horard B, Gilson E, Stoppacciaro A, Zupi G, Biroccio A
Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect.
J Clin Invest. 2007 Nov;117(11):3236-47.
Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors gamma-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy. [Abstract/Link to Full Text]

Zinnanti WJ, Lazovic J, Housman C, LaNoue K, O'Callaghan JP, Simpson I, Woontner M, Goodman SI, Connor JR, Jacobs RE, Cheng KC
Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.
J Clin Invest. 2007 Nov;117(11):3258-70.
Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I. [Abstract/Link to Full Text]

Flick MJ, LaJeunesse CM, Talmage KE, Witte DP, Palumbo JS, Pinkerton MD, Thornton S, Degen JL
Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif.
J Clin Invest. 2007 Nov;117(11):3224-35.
Fibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib-) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin alphaMbeta2 binding motif (Fibgamma390-396A) or the alphaIIbbeta3 platelet integrin-binding motif (FibgammaDelta5), were challenged with collagen-induced arthritis (CIA). Fib- mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibgamma390-396A mice, which retain full clotting function. In contrast, arthritis in FibgammaDelta5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib- and Fibgamma390-396A mice with CIA displayed reduced local expression of TNF-alpha, IL-1beta, and IL-6, which suggests that alphaMbeta2-mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-alpha expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to alphaMbeta2-mediated inflammatory processes. [Abstract/Link to Full Text]

Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ, Neubauer N, Hu J, Mootha VK, Kim YB, Kulkarni RN, Shulman GI, Spiegelman BM
Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk.
J Clin Invest. 2007 Nov;117(11):3463-74.
The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1alpha and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1alpha expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1alpha knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic beta cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1alpha in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets. [Abstract/Link to Full Text]

Liu S, Suragani RN, Wang F, Han A, Zhao W, Andrews NC, Chen JJ
The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation.
J Clin Invest. 2007 Nov;117(11):3296-305.
Heme-regulated eIF2alpha kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and beta-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri-/- mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri-/- mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri-/- mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri-/- macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation. [Abstract/Link to Full Text]

Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, Anders R, Netto G, Getnet D, Bruno TC, Goldberg MV, Pardoll DM, Drake CG
LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
J Clin Invest. 2007 Nov;117(11):3383-92.
Lymphocyte activation gene-3 (LAG-3) is a cell-surface molecule with diverse biologic effects on T cell function. We recently showed that LAG-3 signaling is important in CD4+ regulatory T cell suppression of autoimmune responses. Here, we demonstrate that LAG-3 maintains tolerance to self and tumor antigens via direct effects on CD8+ T cells using 2 murine systems. Naive CD8+ T cells express low levels of LAG-3, and expression increases upon antigen stimulation. Our data show increased levels of LAG-3 protein on antigen-specific CD8+ T cells within antigen-expressing organs or tumors. In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene resulted in increased accumulation and effector function of antigen-specific CD8+ T cells within organs and tumors that express their cognate antigen. Most notably, combining LAG-3 blockade with specific antitumor vaccination resulted in a significant increase in activated CD8+ T cells in the tumor and disruption of the tumor parenchyma. A major component of this effect was CD4 independent and required LAG-3 expression by CD8+ T cells. Taken together, these data demonstrate a direct role for LAG-3 on CD8+ T cells and suggest that LAG-3 blockade may be a potential cancer treatment. [Abstract/Link to Full Text]

Fauci AS
A view from Washington through the eyes of an AAP physician-scientist: 2007 Association of American Physicians George M. Kober Medal.
J Clin Invest. 2007 Oct;117(10):3136-9. [Abstract/Link to Full Text]

Gallin JI
Introduction of Anthony S. Fauci, MD: 2007 Association of American Physicians George M. Kober Medal.
J Clin Invest. 2007 Oct;117(10):3131-5. [Abstract/Link to Full Text]

Ausiello D
Science education and communication: AAP Presidential Address.
J Clin Invest. 2007 Oct;117(10):3128-30. [Abstract/Link to Full Text]

Arjona A, Foellmer HG, Town T, Leng L, McDonald C, Wang T, Wong SJ, Montgomery RR, Fikrig E, Bucala R
Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion.
J Clin Invest. 2007 Oct;117(10):3059-66.
The flavivirus West Nile virus (WNV) is an emerging pathogen that causes life-threatening encephalitis in susceptible individuals. We investigated the role of the proinflammatory cytokine macrophage migration inhibitory factor (MIF), which is an upstream mediator of innate immunity, in WNV immunopathogenesis. We found that patients suffering from acute WNV infection presented with increased MIF levels in plasma and in cerebrospinal fluid. MIF expression also was induced in WNV-infected mice. Remarkably, abrogation of MIF action by 3 distinct approaches (antibody blockade, small molecule pharmacologic inhibition, and genetic deletion) rendered mice more resistant to WNV lethality. Mif(-/-) mice showed a reduced viral load and inflammatory response in the brain when compared with wild-type mice. Our results also indicate that MIF favors viral neuroinvasion by compromising the integrity of the blood-brain barrier. In conclusion, the data obtained from this study provide direct evidence for the involvement of MIF in viral pathogenesis and suggest that pharmacotherapeutic approaches targeting MIF may hold promise for the treatment of WNV encephalitis. [Abstract/Link to Full Text]

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

Shahin GM, van der Heijden GJ, Kelder JC, Boulaksil M, Knaepen PJ, Six AJ
Long-term follow-up of mitral valve repair: a single-center experience.
Med Sci Monit. 2006 Jul;12(7):CR308-14.
BACKGROUND: Our aim was to conduct a long-term follow-up of patients after mitral valve repair for incompetence. We identified determinants for mortality and compared mortality with standardized mortality rates of the Dutch population. MATERIAL/METHODS: We included in this single-center retrospective study 119 patients operated from March 1976 to February 1981. Patients with previous mitral valve surgery, isolated mitral stenosis, and congenital heart disease were excluded. Routine echocardiography was performed every 6 to 12 months. The cumulative probability of survival was calculated (Kaplan-Meier). The variables that statistically significantly associated with mortality were selected for multivariate analysis. Maximum follow-up was 27 years and complete in 98%. Mean age was 49.4 years, and 55% were preoperatively in New York Heart Association (NYHA) class III. Concomitant cardiac procedures were performed in 49%. RESULTS: The 30-day postoperative mortality was 6.7% and the 20-year overall mortality was 63%. The standardized mortality rate was 30%, which was based on survival rates of the general Dutch population. In 27 cases (22.7%), re-operation was performed. Independent predictors for mortality were, after univariate and multivariate analysis, concomitant coronary artery bypass grafting (p=0.002), renal impairment (p=0.027), age above 60 years (p=0.05), and ejection fraction<or=40% (p=0.05). CONCLUSIONS: The observed mortality exceeded the expected mortality. Concomitant coronary artery bypass grafting, renal impairment, age above 60 years, and reduced left ventricular function were independent predictors of mortality in patients with surgical repair for mitral valve regurgitation. [Abstract/Link to Full Text]

Federici L, Klouche K, Amigues L, Kanouni T, Lopez-Martinez E, Latry P, Beraud JJ, Rossi JF
Outcome and prognosis of severe thrombotic microangiopathies treated by plasma exchange.
Med Sci Monit. 2006 Jul;12(7):CR302-7.
BACKGROUND: Plasma exchange (PE) therapy has dramatically improved the outcome of thrombotic microangiopathies (TMA) in adults. However, resistance to PE, which indicates a poor prognosis, is observed in 1/3 of patients and remains not fully understood. We evaluated in this study the survival and the long-term outcome of severe TMA treated by PE and identified the predictive factors of resistance to PE and of mortality. MATERIAL/METHODS: Records of adults with severe TMA treated by PE were reviewed. Clinical and biological data, therapeutic delay to PE, plasma volume exchange per procedure, and number of PE sessions were collected. Mortality was assessed at one month and at one-year follow-up. All data were analyzed and compared between survived/deceased and between responder/non-responder patients. RESULTS: Nineteen females and six males were included. Mean age (+/-SD) was 46.8+/-16.3 years, Glasgow coma score 11+/-3, and Sequential Organ Failure Assessment (SOFA) score 5.8+/-2.8. Nineteen patients partially or fully responded to PE. Twenty patients were alive at one month and 19 at one year. The response to PE was the single discriminating parameter between survivors and non-survivors. A longer delay of PE and a neoplastic cause of TMA were significantly higher in the non-responders. CONCLUSIONS: Severe TMA treated by PE had a fair prognosis, with a survival rate at 76% after one year of follow-up. Unresponsiveness to PE was the only predictive factor of mortality; a neoplastic etiology of TMA and a longer therapeutic delay of PE were predictive of resistance to PE. [Abstract/Link to Full Text]

Petrofsky JS, Lohman E, Lee S, de la Cuesta Z, Labial L, Iouciulescu R, Moseley B, Korson R, Al Malty A
The influence of alterations in room temperature on skin blood flow during contrast baths in patients with diabetes.
Med Sci Monit. 2006 Jul;12(7):CR290-5.
BACKGROUND: Contrast baths (CB) have been used for over two thousand years. But it only was recently that CB were shown to improve limb circulation to a greater extent than that which can be seen after continuous exposure to a warm, constant temperature, bath. However, other studies show that this type of response to temperature can be impaired if the sympathetic nervous system applies vasoconstriction to the blood vessels. Therefore the purpose of the present investigation was to examine the relationship between sympathetic outflow on the magnitude of the change of blood flow (BF) during contrast baths in controls and with people diabetes. Sympathetic vasoconstriction activity was altered by global heating. MATERIAL/METHODS: Fourteen patients with type 2 diabetes were compared to 14 age-matched controls. BF was measured during 16 minutes of serial contrast baths of the foot following 3 minutes of warm water and 1 min of cold immersion at 2 different room temperatures, 19 and 32 deg C. RESULTS: When subjects were exposed to global heating (warm room) there is a greater response to CB than when subjects were initially in a cooler room. However, for both temperatures, subjects with diabetes had a response that was over 50% less than that seen in control subjects. CONCLUSIONS: Removing sympathetic vasoconstrictor tone by global heating benefits subjects with diabetes and control subjects in their response to CB. For subjects with diabetes, global heating may be necessary to increase blood flow to acceptable levels for effective therapy. [Abstract/Link to Full Text]

Lowe JC, Yellin J, Honeyman-Lowe G
Female fibromyalgia patients: lower resting metabolic rates than matched healthy controls.
Med Sci Monit. 2006 Jul;12(7):CR282-9.
BACKGROUND: Many features of fibromyalgia and hypothyroidism are virtually the same, and thyroid hormone treatment trials have reduced or eliminated fibromyalgia symptoms. These findings led the authors to test the hypothesis that fibromyalgia patients are hypometabolic compared to matched controls. MATERIAL/METHODS: Resting metabolic rate (RMR) was measured by indirect calorimetry and body composition by bioelectrical impedance for 15 fibromyalgia patients and 15 healthy matched controls. Measured resting metabolic rate (mRMR) was compared to percentages of predicted RMR (pRMR) by fat-free weight (FFW) (Sterling-Passmore: SP) and by sex, age, height, and weight (Harris-Benedict: HB). RESULTS: Patients had a lower mRMR (4,306.31+/-1077.66 kJ vs 5,411.59+/-695.95 kJ, p=0.0028) and lower percentages of pRMRs (SP: -28.42+/-15.82% vs -6.83+/-12.55%, p<0.0001. HB: -29.20+/-17.43% vs -9.13+/-9.51%, p=0.0008). Whereas FFW, age, weight, and body mass index (BMI) best accounted for variability in controls' RMRs, age and fat weight (FW) did for patients. In the patient group, TSH level accounted for 28% of the variance in pain distribution, and free T3 (FT3) accounted for 30% of the variance in pressure-pain threshold. CONCLUSIONS: Patients had lower mRMR and percentages of pRMRs. The lower RMRs were not due to calorie restriction or low FFW. Patients' normal FFW argues against low physical activity as the mechanism. TSH, FT4, and FT3 levels did not correlate with RMRs in either group. This does not rule out inadequate thyroid hormone regulation because studies show these laboratory values do not reliably predict RMR. [Abstract/Link to Full Text]

Petrofsky JS, Cuneo M, Lee S, Johnson E, Lohman E
Correlation between gait and balance in people with and without Type 2 diabetes in normal and subdued light.
Med Sci Monit. 2006 Jul;12(7):CR273-81.
BACKGROUND: Balance and gait are both impaired in people with diabetes but no study has examined both in the same subjects in people either with or even without diabetes or related these to room lighting. MATERIAL/METHODS: Twelve subjects with type 2 diabetes (D) and 15 age-matched controls (C) were examined under conditions of full light, eyes closed (no light) and low light (5 candle power). Balance was assessed during standing by a computerized posturography device. Gait was analyzed during the initiation of movement, while walking at uniform speed and during turns of 0.66 meters diameter through accelerometers, foot contact sensors and the electomyogram recorded from the gastrocnemius and tibialus anterior muscles. RESULTS: Subjects with diabetes had poorer balance during standing in diminished light compared to full light and no light conditions. When the room light was dimmed, sway during standing increased by an average of 25% in D. Control subjects did not have different sway with diminished light compared to the other lighting conditions. Gait was slower, circumduction greater and muscle use greater in D than C. There was a significant negative correlation between balance and gait; the worse the balance, the slower and poorer the gait for both groups of subjects (p<0.05), impaired balance accounting for 70% of the deviation in gait in D whereas it only accounted for 52% in C. CONCLUSIONS: Balance and gait are related in people with and without diabetes. Diabetes causes balance and gait to both be impaired compared to C. [Abstract/Link to Full Text]

Jezierska A, Olszewski WP, Pietruszkiewicz J, Olszewski W, Matysiak W, Motyl T
Activated Leukocyte Cell Adhesion Molecule (ALCAM) is associated with suppression of breast cancer cells invasion.
Med Sci Monit. 2006 Jul;12(7):BR245-56.
BACKGROUND: Activated Leukocyte Cell Adhesion Molecule (ALCAM) is expressed in different kinds of normal and neoplastic tissues. Data on the tissue distribution of ALCAM suggest that this protein is involved in tumor progression and metastasis. The lack of available data on ALCAM protein expression in breast cancer prompted us to undertake a study on the involvement of this adhesion molecule in tumor development. MATERIAL/METHODS: The expressions of ALCAM and reference biomarkers were examined in 56 breast cancer specimens by laser scanning cytometry and confocal microscopy. The results were related to clinical and pathological parameters, i.e. histological grade, tumor diameter, lymph node involvement, NPI, steroid receptor (estrogen, ER, and progesterone, PgR) expression, and HER2/neu over-expression. RESULTS: High levels of ALCAM significantly correlated with small tumor diameter (p=0.009), low tumor grade (p=0.001), and the presence of progesterone (p=0.009) and estrogen (p=0.006) receptors. Declining ALCAM concentrations correlated with HER2/neu gene amplification, inasmuch as the obtained p value, 0.065, was very close to the established statistical significance level of p=0.05. The ALCAM/MMP-2 ratio was significantly higher in cancer cases characterized by small tumor size (p=0.04) and low tumor grade (p=0.022). CONCLUSIONS: Analysis of ALCAM expression in relation to other molecular biomarkers revealed that ALCAM expression and the ALCAM/MMP-2 ratio are more promising indicators of breast cancer progression than MMP-2, E-cadherin, and alpha-catenin. Low ALCAM concentration correlated with an aggressive tumor phenotype, which supports the view that this adhesion molecule is a tumor suppressor marker with prognostic significance. [Abstract/Link to Full Text]

Ahmadi K, McCruden AB
Androgen binding site in J111 cell line.
Med Sci Monit. 2006 Jul;12(7):BR239-44.
BACKGROUND: The finding of sex steroid receptor protein in non classical reproductive tissues suggested the possibility that sex steroids may have a relevance to the immune system. MATERIAL/METHODS: The J111 cells were maintained in RPMI 1640 complete medium at 37 degrees C in 5% CO2 in air. Cells were resuspended at 1x10(6) cells in 0.2 ml complete medium in 1.5 ml eppendorf tubes. A single saturating concentration 1x10(-9) M of [3H]5alpha-DHT was added to the cells suspension. Unlabelled steroids (5alpha-DHT, 17-beta estradiol, or the synthetic glucocorticoid triamcinolone acetonid) were added over the range 1x10(-8) to 1x10(-9) M. Duplicate tubes were incubated at 37 degrees C for 1h. For autoradiography, the supernatant was discarded and the pellet resuspended in 0.2 ml medium. For binding assay, Labeled cells were separated from unbound steroid by immunomagnetic bead using anti-CD68 antibody. RESULTS: In autoradiography, a population of approximately 96% of J111 cells that contain receptors for androgen has been demonstrated. The results of immunomagnetic showed that binding identified in the J111 cells was modest selective towards androgenic compounds. Schatchard analysis of data showed the KD value of 2.5x10(-9) M and the number of receptor in each cell was found to be 257+/-1. Little competition was seen from 17 beta estradiol or the synthetic glucocorticoid triamcinolone acetonid. CONCLUSIONS: These data indicate that androgen binding in J111 cells is of modest affinity and specific, due to the inability of 100-fold molar excess of estradiol to displace bound [3H]-5alphaDHT. [Abstract/Link to Full Text]

Baysallar M, Aydogan H, Kilic A, Kucukkaraaslan A, Senses Z, Doganci L
Evaluation of the BacT/ALERT and BACTEC 9240 automated blood culture systems for growth time of Brucella species in a Turkish tertiary hospital.
Med Sci Monit. 2006 Jul;12(7):BR235-8.
BACKGROUND: The isolation of Brucella species from blood may be achieved by using classic culture techniques, but detection of the organism is difficult due to its slow growth. The time-to-detection of Brucella can take up to 30 days using the Castaneda blood culture method. Automated blood culture systems have reduced the growth time of Brucella. MATERIAL/METHODS: In this report we would like to contribute our experience on detection time in the isolation of Brucella species from 33,039 blood culture sets using BacT/ALERT between 1995 and 2000 (13 isolates) and thereafter using both the BACTEC and BacT/ALERT systems (17 isolates). RESULTS: Thirty Brucella spp. (17 by both systems and 13 by BacT/ALERT only) were isolated from 33,039 blood culture sets between 1995 and 2002. Brucellae were recovered between 1.8 and 3.7 days (mean: 2.5 days) in the BacT/ALERT blood culture system and between 2.1 and 3.8 days (mean: 2.8 days) in BACTEC 9240 system. CONCLUSIONS: We concluded that the mean time-to-detection could be <or=3 days, which is considered rapid enough for starting appropriate evidence-based treatment in an endemic setting. [Abstract/Link to Full Text]

Tvrd�k D, Dundr P, Pov�sil C, Pytl�k R, Plankov� M
Up-regulation of p21WAF1 expression is mediated by Sp1/Sp3 transcription factors in TGFbeta1-arrested malignant B cells.
Med Sci Monit. 2006 Jul;12(7):BR227-34.
BACKGROUND: TGFbeta1 has a profound effect on the growth of various mammalian cell types, including B lymphocytes. The inhibitory action of TGFbeta1 is mediated by deactivation of the cell cycle machinery. Several feedback-sensitive pathways determine whether the cells are stopped in G1 phase or allowed to leave G1 phase and enter S phase. Cell cycle-associated molecules, e.g. cyclin-dependent kinase inhibitors (CKIs), may become targets for the inhibitory signaling pathways induced by TGFbeta1. MATERIAL/METHODS: Our experimental DoHH2 cell line model was derived from a patient with malignant non-Hodgkin's lymphoma of follicular origin. The effect of TGFbeta1 on cell cycle progression was studied by flow cytometry. We examined the effect of TGFbeta1 on the expression of p21WAF1 by immunoblotting and RT-PCR. The binding activity of transcription factors to the p21 gene promoter was determined by gel mobility shift assay (GMSA). RESULTS: Our results showed that TGFbeta1 treatment increased the number of cells arrested in G0/G1 phase compared with untreated control cells. Moreover, we found that p21WAF1 expression was significantly up-regulated on the protein level after TGFbeta1 treatment. Similarly to the protein level, the expression of p21 mRNA was increased in TGFbeta1-treated cells. We further examined the binding activity of the Sp family of transcription factors to examine their role in p21WAF1 up-regulation. CONCLUSIONS: The results indicated that p21WAF1 over-expression in TGFbeta1-arrested malignant B cells is mediated by binding of Sp1/Sp3 transcription factors to the (-92/-71), (-77/-58), and (-65/-45) elements of the promoter region of the p21 gene. [Abstract/Link to Full Text]

Shimanuki S, Nagasawa T, Nishizawa N
Plasma HDL subfraction levels increase in rats fed proso-millet protein concentrate.
Med Sci Monit. 2006 Jul;12(7):BR221-6.
BACKGROUND: Millet has been consumed as human food in the countries of Asia and Africa. We reported previously the effects of dietary protein concentrates from proso millet (Panicum miliaceum L.) on plasma levels of high-density lipoprotein HDL cholesterol. Of note is that of these HDL subfractions, HDL2 particles may have the more strongly protective effect against the risk of coronary heart disease than HDL3. However, it is unclear how dietary millet protein affects plasma levels of HDL subfractions. MATERIAL/METHODS: We examined the effect of feeding of proso-millet protein concentrate (PMPC) for 21 days on plasma levels of HDL cholesterol, HDL subfractions and lecithin: cholesterol acyltransferase (LCAT) activities in rats. RESULTS: Results showed a clear elevation of plasma levels of HDL cholesterol (p<0.05) without an increase in low density lipoprotein cholesterol levels and enhancement of LCAT activities (p<0.06) by the intake of a PMPC diet compared with a casein diet. This increase in HDL cholesterol levels was substantially due to the elevation of HDL2 subfractions (p<0.05). CONCLUSIONS: PMPC could have a beneficial effect on cardiovascular disease because HDL2 subfractions may have the more strongly protective effect against the risk of coronary heart disease. [Abstract/Link to Full Text]

Jenicek M
How to read, understand, and write 'Discussion' sections in medical articles. An exercise in critical thinking.
Med Sci Monit. 2006 Jun;12(6):SR28-36.
Writing and reading 'Discussion' sections in medical articles require a procedure as exact and structured as that involved in raising questions, choosing materials and methods and producing results for a health research study. The medical article as a whole can be considered an exercise in modern argumentation and its 'Discussion' section, a systematic critical appraisal of a path from theses to conclusions. The methodology of modern critical thinking applies perfectly to article writing, reading, and understanding. Structuring the 'Discussion' section as a review of argumentation benefits more than the study and its authors. It allows the reader to grasp the real relevance and validity of the study and its usability for his or her decision-making in clinical and community care, research and health policies and program proposal, implementation, and evaluation. [Abstract/Link to Full Text]

Glattard E, Muller A, Aunis D, Metz-Boutigue MH, Stefano GB, Goumon Y
Rethinking the opiate system? Morphine and morphine-6-glucuronide as new endocrine and neuroendocrine mediators.
Med Sci Monit. 2006 Jun;12(6):SR25-7.
Since the 80s, intrigued by presence of morphine precursors in some mammalian cells, different laboratories were able to characterize morphine and morphine precursors in animal tissues. Endogenous morphine studies continued during 90s and this alkaloid was successfully characterized from more organs and fluids of vertebrates, including brain, adrenal gland, heart, cerebrospinal fluid and urine. Then, in the last three years a high rate of publications dealing with this topic emerged, leading to a better understanding of the endogenous morphine system. In this regard, this article comment all the new data recently collected on this rising subject and replace the morphine and its derivative, morphine-6-glucuronide, in the mammalian physiology. [Abstract/Link to Full Text]

Das UN
Can perinatal supplementation of long-chain polyunsaturated fatty acids prevent atopy, bronchial asthma and other inflammatory conditions?
Med Sci Monit. 2006 Jun;12(6):RA99-111.
I suggest that perinatal supplementation of long-chain polyunsaturated fatty acids (LCPUFAs) protects against the development of childhood and adult life eczema, atopy, bronchial asthma and other inflammatory conditions. LCPUFAs modulate T(H)1 and T(H)2 cell generation and their cytokine production such that the balance is tilted more towards the production of anti-inflammatory cytokines. In addition, LCPUFAs form precursors to anti-inflammatory products such as resolvins, lipoxins, and aspirin-triggered 15 epimer LXs (ATLs), nitric oxide, prostaglandin E1 and prostacyclin (PGI2) that suppress inflammatory process and enhance healing of tissue injury with little or no loss of function. These beneficial actions of LCPUFAs explain the protective effect of exclusive breast-feeding against eczema and other childhood allergies, and decreased incidence of several other inflammatory conditions in adult life since human breast milk contains substantial amounts of these long-chain polyunsaturated fatty acids. [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]

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

Tursi A, Giorgetti GM, Brandimarte G, Elisei W, Aiello F
Beclomethasone dipropionate for the treatment of mild-to-moderate Crohn's disease: an open-label, budesonide-controlled, randomized study.
Med Sci Monit. 2006 Jun;12(6):PI29-32.
BACKGROUND: Budesonide is a steroid with low systemic effect and high effectiveness in the treatment of Crohn's Disease (CD). Beclomethasone dipropionate (BDP) is also a steroid with the same systemic effects, but it has been never investigated in CD. MATERIAL/METHODS: To evaluate the effectiveness and tolerability of BDP versus budesonide in treating CD, we enrolled 30 consecutive patients affected by mild-to-moderate non-fistulizing, non-obstructive Crohn's disease (CDAI < or = 250) (13 M and 17 F, mean age: 33.4 years, range: 16-71 years) in whom this diagnosis was made for the first time. The patients were randomly treated for 8 weeks with budesonide 9 mg/day (group A, 15 patients) or with BDP 10 mg/day (group B, 15 patients). RESULTS: Of group A patients, 13/14 (on intention to treat (i-t-t): 86.67%) showed response to budesonide and 10/14 (on i-t-t.: 66.66%) were in remission after 8 weeks of treatment. In group B patients, 10/14 (on i-t-t: 66.66%) showed response to BDP and 8/14 (on i-t-t: 53.33%) were in remission after 8 weeks of treatment (p<0.001). Budesonide was also faster in the time to obtain symptomatic remission (p=n.s.) and was better in improving IBDQL (p<0.05). Regarding side effects, two group A patients (6.66%) and three group B patients (10%) experienced mild-to-moderate side effects which were transitory and did not require any specific treatment or stopping the treatment. CONCLUSIONS: BDP seems to be less effective than budesonide in treating CD, probably due to better the pharmacokinetic properties of budesonide. [Abstract/Link to Full Text]

Zanetti R, Zoccola M, Mossotti R, Innocenti R, Loria DI, Rosso S
PTCA determination in human hair: reliability and analytical aspects.
Med Sci Monit. 2006 Jun;12(6):PI23-8.
BACKGROUND: In this study we analysed the reliability of HPLC determination of 2.3.5-pyrroletricarboxylic acid (PTCA). This product derives from oxidation of melanin in human hair, and is a good candidate as a risk marker for skin tumors. MATERIAL/METHODS: We determined PTCA in 100 melanoma cases and 100 controls, 21 replicates from six different reference hairs, two trace elements, and one reference sample (brown hair). RESULTS: Work-up procedures showed an almost perfect reproducibility with an Intraclass Correlation Coefficient (ICC) of 0.990. We noticed a low, detectable, but not statistically significant decrease in reproducibility proportional to the amount of PTCA. Agreement between determination following injection of the same solution in HPLC column was also high, with an overall ICC of 0.986. Simultaneous analysis of reproducibility showed a partial ICC for work-up (0.986), for injection (0.987), and an overall standardised ICC (0.975). The analysis of the two reference tracers in successive tests showed a weak, not statistically significant, decreasing linear drift, possibly due to various factors, such as aging of chemical solutions and HPLC columns. CONCLUSIONS: PTCA extracted from human hair through oxidation and determined with HPLC can be considered a reliable marker as a candidate for identifying persons at high risk for melanoma. [Abstract/Link to Full Text]

Sucu N, Karaca K, Yilmaz N, C�melekoglu U, Aytacoglu BN, Tamer L, Ozeren M, Dondas HA, O?uz Y, Ogenler O, Dikmengil M
Two stage EDTA anti-calcification method for bioprosthetic heart valve materials.
Med Sci Monit. 2006 Jun;12(6):MT33-8.
BACKGROUND: The aim of this study was to investigate the effect of two-stage EDTA treatment in diminishing calcific degeneration in bovine pericardial bioprosthetic heart valve material. MATERIAL/METHODS: Conventionally preserved pericardium specimens were divided into two groups. Group I (controls, n=18) pieces were first fixed in phosphate-buffered solution (PBS)+0.6% glutaraldehyde at +4 degrees C for 24 hours, then stored in PBS+0.2% glutaraldehyde at room temperature for 6 days. Group II (study group, n=18) pieces were treated with PBS containing 100 microg/ml ethylenediaminetetraacetic acid (EDTA) at +4 degrees C for 24 hours, then fixed in PBS+0.6% glutaraldehyde as was group I at +4 degrees C for 24 hours. After a second exposure to PBS containing 100 microg/ml EDTA at room temperature for 24 hours, they were stored in PBS+0.2% glutaraldehyde at room temperature for 4 days. Pericardial patches were inserted into the dorsal pouches of 18 juvenile male Wistar rats. After 7 weeks of implantation, all the pericardium pieces were harvested from sacrificed rats. The calcium content and biomechanical properties of the explanted tissues were evaluated and also examined histopathologically. RESULTS: The difference in the calcium content of the control and study groups was statistically significant. Biomechanical and histopathologic assessment also supported these findings. CONCLUSIONS: Application of two-stage EDTA was found to be useful in the attenuation of calcification in bioprosthetic heart valve materials with mildly increased durability. As calcification was reduced by approximately 50%, it can be considered for use with other agents as an adjuvant treatment. [Abstract/Link to Full Text]

Rozen P, Waked A, Vilkin A, Levi Z, Niv Y
Evaluation of a desk top instrument for the automated development and immunochemical quantification of fecal occult blood.
Med Sci Monit. 2006 Jun;12(6):MT27-32.
BACKGROUND: The guaiac fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is user dependent and not specific for human hemoglobin (Hb). The automated-developed, quantitative, immunochemical human Hb FOBT (I-FOBT) is specific, allows for quality control and selection of a suitable Hb level, with optimal sensitivity and specificity, for colonoscopy. MATERIAL/METHODS: We evaluated a desktop instrument, OC-MICRO (Eiken, Japan), which automatically develops and quantifies 50 fecal tests/hr for Hb; for ease of use, test reproducibility and stability and intra-patient daily I-FOBT variation; clinical evaluation included sensitivity and specificity for neoplasia in patients undergoing colonoscopy. RESULTS: Five hundred patients prepared 3 fecal tests which were quantified for Hb, I-FOBT samples were: (1) repeatedly re-examined; (2) stored at 4 degrees C or 20 degrees C or 28 degrees C and re-examined; (3) I-FOBT levels correlated with colonoscopic findings. Five I-FOBTs re-examined 6 times had no significant changes; 30 tests stored > or = 21 days had a decay/day of: 0.3%+/-0.4 at 4 degrees C (NS), 2.2%+/-1.7 at 20 degrees C (NS) and 3.7%+/-1.8 at 28 degrees C (P<0.05). Receiver operator characteristic curve analysis showed that at the 100 ng Hb/mL I-FOBT level 76.5% of CRCs and advanced adenomas were detected with a specificity of 95.3%. CONCLUSIONS: The instrument provided reproducible results and refrigerated I-FOBT samples were stable 21 days. An I-FOBT level can be chosen to provide optimal sensitivity and specificity for significant neoplasia. [Abstract/Link to Full Text]

Ozdemir O
Mast cells and the tumor-associated neoangiogenesis.
Med Sci Monit. 2006 Jun;12(6):LE9-11. [Abstract/Link to Full Text]

Nienartowicz A, Sobaniec-?otowska ME, Jarocka-Cyrta E, Lemancewicz D
Mast cells in neoangiogenesis.
Med Sci Monit. 2006 Mar;12(3):RA53-6.
Mast cells (MCs) always accompany connective tissue and are located in the proximity of lymphatic and blood vessels and nerve fibers. They are round or oval mononuclear cells with a diameter of 4-20 microm containing in their cytoplasm specific exocrine granules (storing neutral proteases) enclosed by a single membrane, whose presence is regarded as an index of the MC's static state. In view of their wide distribution in the organism, they play various roles in, for example, type I hypersensitivity reactions, chronic inflammatory processes, tissue reconstruction and wound healing, and pathological pulmonary fibrosis. They also play a role in angiogenesis, both in normal conditions during tissue regeneration and in pathological neoplastic states. The microcirculation provides building and nutritional substances to cancer cells and enables cancer spread via the blood. On the other hand, a tumor with good vascularization is more prone to penetration by cytostatics, which is why angiogenesis is a very important process in the course of neoplastic disease. Many authors indicate a close association between mast cells and angiogenesis. Some substances contained in the cytoplasm of these cells are potent stimulators of angiogenesis (tryptase, heparin), while others may inhibit it (protamine, platelet factor 4), and this conditions cancer growth and the development of the metastatic process. It is not known, however, what interactions occur between stimulants and inhibitors and what the proportional involvement of particular mediators in the formation of new vessels is. [Abstract/Link to Full Text]

Telles S, Visweswaraiah NK
Comments to: Health realization/innate health: can a quiet mind and a positive feeling state be accessible over the lifespan without stress-relief techniques?
Med Sci Monit. 2006 Jun;12(6):LE13. [Abstract/Link to Full Text]

Sedgeman JA
Health Realization/Innate Health: can a quiet mind and a positive feeling state be accessible over the lifespan without stress-relief techniques?
Med Sci Monit. 2005 Dec;11(12):HY47-52.
Health Realization/Innate Health (HR/IH) questions long-held assumptions about chronic stress, and challenges current definitions of both stress and resiliency. HR/IH sets forth principles that explain why the experience of psychological stress is not an effect of causal factors beyond people's control, but is an artifact of the energetic potential of the mind. HR/IH describes the "cognitive factor" in stress not as the content of people's thinking in response to stressors, but rather as a quality of the way people hold and use their thinking, referred to as state of mind. HR/IH hypothesizes that understanding principles that explain the nature and origin of thinking and experience offers a means to access innate protective processes that are healing and antibiosenescent reliably and consistently, without techniques. HR/IH suggests that the primary effort of mental health care could be to initiate life-long prevention of the state of chronic stress. In addition, HR/IH suggests that addressing mental well-being would have a broad impact on the incidence and course of the many physical illnesses that are known to be stress-related. The brief therapeutic interactions of HR/IH draw upon people's innate wisdom and recognition of the healthy perspective available to everyone. Anecdotal results suggest that people who gain insight into the principles that explain the nature of thought and experience and who realize how to re-access a natural, positive state of mind can and do experience sustained day-to-day peace of mind, wisdom and well-being, regardless of circumstances. HR/IH deserves rigorous scientific evaluation. [Abstract/Link to Full Text]

Gentili A, Iannella E, Giuntoli L, Baroncini S
System for predicting outcome and for clinical evaluation in sepsis and septic shock: could scores and biochemical markers be of greater help in the future?
Med Sci Monit. 2006 Jun;12(6):LE11-2. [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]

Zheng MH, Feng B, Lu AG, Li JW, Hu WG, Wang ML, Zang L, Dong F, Mao ZH, Peng YF, Jiang Y
Laparoscopic pancreaticoduodenectomy for ductal adenocarcinoma of common bile duct: a case report and literature review.
Med Sci Monit. 2006 Jun;12(6):CS57-60.
BACKGROUND: Minimal access techniques have gained wide acceptance in surgical practice, but the role of laparoscopic pancreaticoduodenectomy is still controversial. Laparoscopic pancreaticoduodenectomy has seldom been described. In this report, we assessed the feasibility and safety of laparoscopic pancreaticoduodenectomy for ductal adenocarcinoma of the common bile duct. CASE REPORT: According to imaging findings, a 71-year-old Chinese man was diagnosed with malignancy of the common bile duct, and successfully underwent laparoscopic pancreaticoduodenectomy in our center. The operation's safety, postoperative recovery, complications, oncological clearance, and short-term follow-up results of the patient are evaluated. No severe intraoperative or postoperative complications were observed. The operation time was 390 minutes, and the blood loss was about 50 ml; the flatus, time to resume early activity and hospital stay were 3, 4, and 30 days respectively. The patient remained well at a follow-up of 6 months. CONCLUSIONS: Laparoscopic pancreaticoduodenectomy can be performed feasibly and safely by surgeons with advanced laparoscopic skills, and could be considered for the treatment of common bile duct tumors. [Abstract/Link to Full Text]

Monterrubio Villar J, C�rdoba L�pez A, Macayo S�nchez AJ
Idiopathic eosinophilia associated with portal vein and massive thrombosis: successful thrombolysis with streptokinase.
Med Sci Monit. 2006 Jun;12(6):CS53-6.
BACKGROUND: Portal vein thrombosis in adults is usually related to cirrhosis. There are several possible therapies. including anticoagulation, transjugular intrahepatic portosystemic shunt, balloon dilatation, local and systemic fibrinolytics agents. Hypercoagulable states are also reported in association with this disease entity. Eosinophilia may activate platelets and promote thrombosis due to proteins contained in intracytoplasmic granules, such as eosinophil cationic protein and major basic protein. There is only one paper in the medical literature linking eosinophilia and portal vein thrombosis. CASE REPORT: We present here the case of a middle-age woman with idiopathic eosinophilia and acute portal vein thrombosis with massive venous thrombosis, involving the mesenteric, splenic, inferior cava, iliac and femoral veins, successfully treated with systemic streptokinase. CONCLUSIONS: Acute portal vein thrombosis with associated mesenteric and splenic vein thrombosis is a potentially lethal coagulation disorder that can be treated successfully with systemic streptokinase. [Abstract/Link to Full Text]

Ayantunde AA, Pinder E, Heath DI
Symptomatic pyloric pancreatic heterotopia: report of three cases and review of the literature.
Med Sci Monit. 2006 Jun;12(6):CS49-52.
BACKGROUND: Pancreatic heterotopia is a relatively common congenital anomaly which sometimes becomes symptomatic and mimics other upper gastrointestinal tract (GIT) pathologies. It is the presence of abnormally located pancreatic glandular tissue at sites with no structural or vascular contact with the main pancreas. It most often occurs in the proximal gastrointestinal tract. The hallmark of diagnosis is the presence of pancreatic tissue within another, anatomically different organ. CASE REPORT: We report three patients, I, II, and III, 48, 86, and 33 years of age, respectively, surgically treated for symptomatic heterotopic pancreas in the pylorus. A review of the literature on this pathology is hereby presented. Patients I and II had uneventful postoperative recovery, while patient III developed postoperative intra-abdominal sepsis due to leakage from the gastric suture line, which was treated with further surgery. Histology confirmed pancreatic heterotopia in all cases. All patients made full recovery and follow-up endoscopy showed no residual disease. CONCLUSIONS: Most pancreatic heterotopias are asymptomatic and require no treatment. This entity is extremely difficult to diagnose preoperatively as the cause of upper gastrointestinal tract symptoms and therefore requires a high index of suspicion. Symptomatic lesions should be excised, and this can be safely carried out by minimally invasive techniques depending on the size and the anatomical location. [Abstract/Link to Full Text]

Imarengiaye CO, Ande AB
Risk factors for blood transfusion during c-section in a tertiary hospital in Nigeria.
Med Sci Monit. 2006 Jun;12(6):CR269-72.
BACKGROUND: Blood and blood products are scarce in developing countries due to increasing demand and declining supply. Rational utilization of blood products is imperative and prompted this study, which identifies the risk factors for blood transfusion during C-sections in a tertiary hospital in Nigeria. MATERIAL/METHODS: This retrospective case-controlled study reviewed all C-sections in our hospital from January 1, 1998, to December 31, 2002. Clinical variables including demographic characteristics, surgical events, EBL, indication for transfusion, and the number of units transfused were recorded. RESULTS: A total of 1117 cesarean sections were performed within the study period. Sixty-three patients (5.6%) received blood transfusions. An unbooked patient was six times more likely to receive a blood transfusion during cesarean section than women who had had antenatal care (p<0.001). Grand-multiparous women were associated with intraoperative transfusion during cesarean section (p=0.004). Placental previa was significantly associated with transfusion during cesarean section (p=0.0002). Previous cesarean section was an associated factor for intraoperative transfusion at cesarean section (p=0.02). CONCLUSIONS: The factors associated with transfusion at cesarean section were lack of prenatal care, grand multiparity, previous cesarean section, and pregnancies complicated by placenta previa. These factors should be considered in the care of parturients for cesarean section, especially in developing countries. [Abstract/Link to Full Text]

Papachristou G, Plessas S, Sourlas J, Chronopoulos E, Levidiotis C, Pnevmaticos S
Cementless LCS rotating-platform knee arthroplasty in patients over 60 years without patella replacement: a mid-term clinical-outcome study.
Med Sci Monit. 2006 Jun;12(6):CR264-8.
BACKGROUND: The aim of this prospective paper is to present the results of a cementless LCS rotating-platform artificial knee design without resurfacing of the patella in patients over 60 years of age. MATERIAL/METHODS: In this prospective series, 234 patients were included with 251 knees. The LCS rotating-platform uncemented design was used in all cases, without replacement of the patella. Thirty-four patients were men and 200 were women. Two hundred three patients were suffering from osteoarthrosis (10 bilateral) and 31 patients (7 bilateral) from rheumatoid arthritis. Seventeen patients had a bilateral procedure. Prophylactic antibiotics and anticoagulants were also instituted to all patients. RESULTS: Forty-nine patients developed deep vein thrombosis and responded well to the applied conservative treatment. Overall results in the first 251 cementless cases at 2 to 9.8 years' follow-up (average: 5.7 years) were good to excellent in 94.4%, fair in 4.7%, and poor in 0.7%. Radiographs of the knees showed good bonding and no signs of radiolucency. The average clinical and functional Knee Society Ratings were 21.07 points and 30.95 points, respectively, preoperatively and 87.95 points and 78.56 points, respectively, at the final follow-up evaluation. CONCLUSIONS: With an average follow-up of 5.7 years, uncemented LCS rotating-platform knee joint arthroplasty without replacing the patella in patients over 60 years old was found to perform well, with encouraging clinical and radiological results and a survival rate of 98.1%. [Abstract/Link to Full Text]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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