Evidence that a Panel of Neurodegeneration Biomarkers Predicts Vasospasm, Infarction, and Outcome in Aneurysmal Subarachnoid Hemorrhage

Biomarkers for neurodegeneration could be early prognostic measures of brain damage and dysfunction in aneurysmal subarachnoid hemorrhage (aSAH) with clinical and medical applications. Recently, we developed a new panel of neurodegeneration biomarkers, and report here on their relationships with pathophysiological complications and outcomes following severe aSAH. Fourteen patients provided serial cerebrospinal fluid samples for up to 10 days and were evaluated by ultrasonography, angiography, magnetic resonance imaging, and clinical examination. Functional outcomes were assessed at hospital discharge and 6–9 months thereafter. Eight biomarkers for acute brain damage were quantified: calpain-derived α-spectrin N- and C-terminal fragments (CCSntf and CCSctf), hypophosphorylated neurofilament H

Collaborative review of pilot projects to inform policy: A methodological remedy for pilotitis?

BACKGROUND In rural health and other health service development contexts, there is frustration with a reliance on pilot projects as a means of informing policy and service innovation. There is also an emerging recognition that existing research methods do not draw lessons from the failed sustainability that characterises many of these pilots and demonstration projects. DISCUSSION: This article describes critical aspects of the methodology of a successful collaborative, multi-method, systematic synthesis of exemplary primary health care pilot projects in rural and remote Australia, which synthesised principles from a number of pilot projects to inform policy makers and planners. Hallmarks of the method were: the nature of the source materials for the research, the subsequent research engagement with the actual pilot projects, the extent of collaboration throughout the study with end-users from policy and planning arenas, and the attention to procedural quality. SUMMARY: The methodology, while time consuming, has resulted in applied, policy-relevant findings, and evidence of consideration by policy-makers

Evaluation of SLC11A1 as an inflammatory bowel disease candidate gene

BACKGROUND: Significant evidence suggests that a promoter polymorphism withinthe gene SLC11A1 is involved in susceptibility to both autoimmune and infectious disorders. The aim of this study was to evaluate whether SLC11A1 has a role in the susceptibility to inflammatory bowel disease (IBD) by characterizing a promoter polymorphism within the gene and two short tandem repeat (STR) markers in genetic proximity to SLC11A1. METHODS: The studied population consisted of 484 Caucasians with IBD, 144 population controls, and 348 non-IBD-affected first-degree relatives of IBD patients. IBD subjects were re-categorized at the sub-disease phenotypic level to characterize possible SLC11A1 genotype-phenotype correlations. Polymorphic markers were amplified from germline DNA and typed using gel electrophoresis. Genotype-phenotype correlations were defined using case-control, haplotype, and family-based association studies. RESULTS: This study did not provide compelling evidence for SLC11A1 disease association; most significantly, there was no apparent evidence of SLC11A1 promoter allele association in the studied Crohn's disease population. CONCLUSION: Our results therefore refute previous studies that have shown SLC11A1 promoter polymorphisms are involved in susceptibility to this form of IBD

Heregulin β1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells

Introduction Resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies is an emerging clinical problem. The efficacy of anti-EGFR therapies can be influenced by the presence of heregulins (HRGs), which can bind erbB3/4 receptors and can activate alternative signalling pathways. In the present study we have examined whether HRG signalling can circumvent EGFR blockade in an EGFR-positive tamoxifen-resistant MCF-7 (Tam-R) breast cancer cell line. Methods Tam-R cells, incubated with the selective EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839), were exposed to HRGβ1 and the effects on erbB receptor dimerization profiles and on activation of associated downstream signalling components were assessed by immunoprecipitation, western blotting and immunocytochemistry. The effects of HRGβ1 on gefitinib-treated Tam-R cell growth and invasion were also examined, and HRGβ1 expression levels were assessed in breast cancer tissue by immunohistochemistry to address the potential clinical relevance of such a resistance mechanism. Results In Tam-R cells, HRGβ1 promoted erbB3/erbB2 and erbB3/EGFR heterodimerization, promoted ERK1/2 and AKT pathway activation and increased cell proliferation and invasion. Gefitinib prevented HRGβ1-driven erbB3/EGFR heterodimerization, ERK1/2 activation and Tam-R cell proliferation, but HRGβ1-driven erbB3/erbB2 heterodimerization, AKT activation and Tam-R cell invasion were maintained. A combination of gefitinib and the phosphatidylinositol 3-kinase inhibitor LY294002 effectively blocked HRGβ1-mediated intracellular signalling activity, growth and invasion in Tam-R cells. Similarly, targeting erbB2 with trastuzumab in combination with gefitinib in Tam-R cells reduced HRGβ1-induced erbB2 and ERK1/2 activity; however, HRGβ1-driven AKT activity and cell growth were maintained while cell invasion was significantly enhanced with this combination. In clinical tissue all samples demonstrated cytoplasmic tumour epithelial HRGβ1 protein staining, with expression correlating with EGFR positivity and activation of both AKT and ERK1/2. Conclusion HRGβ1 can overcome the inhibitory effects of gefitinib on cell growth and invasion in Tam-R cells through promotion of erbB3/erbB2 heterodimerization and activation of the phosphatidylinositol 3-kinase/AKT signalling pathway. This may have implications for the effectiveness of anti-EGFR therapies in breast cancer as HRGβ1 is enriched in many EGFR-positive breast tumours

Reducing corruption in a Mexican medical school: impact assessment across two cross-sectional surveys

<p>Abstract</p> <p>Background</p> <p>Corruption pervades educational and other institutions worldwide and medical schools are not exempt. Empirical evidence about levels and types of corruption in medical schools is sparse. We conducted surveys in 2000 and 2007 in the medical school of the Autonomous University of Guerrero in Mexico to document student perceptions and experience of corruption and to support the medical school to take actions to tackle corruption.</p> <p>Methods</p> <p>In both 2000 and 2007 medical students completed a self-administered questionnaire in the classroom without the teacher present. The questionnaire asked about unofficial payments for admission to medical school, for passing an examination and for administrative procedures. We examined factors related to the experience of corruption in multivariate analysis. Focus groups of students discussed the quantitative findings.</p> <p>Results</p> <p>In 2000, 6% of 725 responding students had paid unofficially to obtain entry into the medical school; this proportion fell to 1.6% of the 436 respondents in 2007. In 2000, 15% of students reported having paid a bribe to pass an examination, not significantly different from the 18% who reported this in 2007. In 2007, students were significantly more likely to have bribed a teacher to pass an examination if they were in the fourth year, if they had been subjected to sexual harassment or political pressure, and if they had been in the university for five years or more. Students resented the need to make unofficial payments and suggested tackling the problem by disciplining corrupt teachers. The university administration made several changes to the system of admissions and examinations in the medical school, based on the findings of the 2000 survey.</p> <p>Conclusion</p> <p>The fall in the rate of bribery to enter the medical school was probably the result of the new admissions system instituted after the first survey. Further actions will be necessary to tackle the continuing presence of bribery to pass examinations and for administrative procedures. The social audit helped to draw attention to corruption and to stimulate actions to tackle it.</p

Effects of Aberrant Pax6 Gene Dosage on Mouse Corneal Pathophysiology and Corneal Epithelial Homeostasis

Background: Altered dosage of the transcription factor PAX6 causes multiple human eye pathophysiologies. PAX6(+/-) heterozygotes suffer from aniridia and aniridia-related keratopathy (ARK), a corneal deterioration that probably involves a limbal epithelial stem cell (LESC) deficiency. Heterozygous Pax6(+/Sey-Neu) (Pax6(+/-)) mice recapitulate the human disease and are a good model of ARK. Corneal pathologies also occur in other mouse Pax6 mutants and in PAX77(Tg/-) transgenics, which over-express Pax6 and model human PAX6 duplication. Methodology/Principal Findings: We used electron microscopy to investigate ocular defects in Pax6(+/-) heterozygotes (low Pax6 levels) and PAX77(Tg/-) transgenics (high Pax6 levels). As well as the well-documented epithelial defects, aberrant Pax6 dosage had profound effects on the corneal stroma and endothelium in both genotypes, including cellular vacuolation, similar to that reported for human macular corneal dystrophy. We used mosaic expression of an X-linked LacZ transgene in X-inactivation mosaic female (XLacZ(Tg/-)) mice to investigate corneal epithelial maintenance by LESC clones in Pax6(+/-) and PAX77(Tg/-) mosaic mice. PAX77(Tg/-) mosaics, over-expressing Pax6, produced normal corneal epithelial radial striped patterns (despite other corneal defects), suggesting that centripetal cell movement was unaffected. Moderately disrupted patterns in Pax6(+/-) mosaics were corrected by introducing the PAX77 transgene (in Pax6(+/-), PAX77(Tg/-) mosaics). Pax6(Leca4/+), XLacZ(Tg/-) mosaic mice (heterozygous for the Pax6(Leca4) missense mutation) showed more severely disrupted mosaic patterns. Corrected corneal epithelial stripe numbers (an indirect estimate of active LESC clone numbers) declined with age (between 15 and 30 weeks) in wild-type XLacZ(Tg/-) mosaics. In contrast, corrected stripe numbers were already low at 15 weeks in Pax6(+/-) and PAX77(Tg/-) mosaic corneas, suggesting Pax6 under-and over-expression both affect LESC clones. Conclusions/Significance: Pax6(+/-) and PAX77(Tg/-) genotypes have only relatively minor effects on LESC clone numbers but cause more severe corneal endothelial and stromal defects. This should prompt further investigations of the pathophysiology underlying human aniridia and ARK

GHQ increases among Scottish 15 year olds 1987–2006

BACKGROUND: Increases in a number of psychosocial disorders have been identified among Western youth in the second half of the Twentieth century. However findings are not consistent, trends are complex, and comparisons over time are hampered by methodological problems. METHODS: Data were drawn from three samples identical in respect of age (15 years), school year (final year of statutory schooling) and geographical location (the West of Scotland). Each sample was administered the 12-item General Health Questionnaire, a measure of self-report psychological distress, in 1987 (N = 505), 1999 (N = 2,196) and 2006 (N = 3,194). Analyses were conducted to examine changes in: GHQ 'caseness'; individual items; and factors, derived via confirmatory factor analysis representing (a) 'negative' and 'positive' items, and (b) 'anxiety and depression', 'loss of confidence or self-esteem' and 'anhedonia and social dysfunction'. RESULTS: Based on the standard (2/3) cut-off, 'caseness' rates in 1987, 1999 and 2006 were 12.7, 15.1 and 21.5% (males) and 18.8, 32.5 and 44.1% (females). Similar increases were observed with more stringent 'caseness' cut-offs. Examination of individual items showed some to have increased much more markedly over time than others. There were larger increases among females for all except two items and some evidence, among both genders, of steeper increases among 'negative' items compared with 'positive' ones. However, the differences in slope were very small compared with the overall increases in both types. CONCLUSIONS: Data from three samples identical in respect of age, school year and geographical location, show marked increases in GHQ-12 'caseness' among females between 1987 and 1999 and among both males and females between 1999 and 2006. Although slightly steeper increases in 'negative' items raise the possibility that endorsing such symptoms may have become more acceptable, these were small in comparison with increases in all dimensions of psychological distress. The next step is to identify causal explanations for the increases reported here

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies