Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing ‘depression-like’ shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = −3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997–1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10−4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men

Child Fitness and Father’s BMI Are Important Factors in Childhood Obesity: A School Based Cross-Sectional Study

BACKGROUND: This study examines obesity and factors associated with obesity in children aged 11-13 years in the UK. METHODS: 1147 children from ten secondary schools participated in a health survey that included blood samples, fitness test and anthropometric measures. Factors associated with obesity were examined using multilevel logistic regression. FINDINGS: Of the children examined (490 male; 657 female) a third were overweight, 1 in 6 had elevated blood pressure, more than 1 in 10 had high cholesterol, 58% consumed more fat than recommended, whilst 37% were classified as unfit. Children in deprived areas had a higher proportion of risk factors; for example, they had higher blood pressure (20% (deprived) compared to 11% (non-deprived), difference: 9.0% (95%CI: 4.7%-13.4%)). Obesity is associated with risk factors for heart disease and diabetes. Maintaining fitness is associated with a reduction in the risk factors for heart disease (high blood pressure and cholesterol) but not on risk factors for diabetes (insulin levels). In order of importance, the main risk factors for childhood obesity are being unfit, having an obese father, and being large at birth. CONCLUSION: The high proportion of children with risk factors suggests future interventions need to focus on community and policy change to shift the population norm rather than targeting the behaviour of high risk individuals. Interventions need to focus on mothers' lifestyle in pregnancy, fathers' health, as well as promoting fitness among children. Obesity was not associated with deprivation. Therefore, strategies should be adopted in both deprived and non deprived areas

Comparison of pain, cortisol levels, and psychological distress in women undergoing surgical termination of pregnancy under local anaesthesia versus intravenous sedation

<p>Abstract</p> <p>Background</p> <p>The weight of evidence suggests that women who freely choose to terminate a pregnancy are unlikely to experience significant mental health risks, however some studies have documented psychological distress in the form of posttraumatic stress disorder and depression in the aftermath of termination. Choice of anaesthetic has been suggested as a determinant of outcome. This study compared the effects of local anaesthesia and intravenous sedation, administered for elective surgical termination, on outcomes of pain, cortisol, and psychological distress.</p> <p>Methods</p> <p>155 women were recruited from a private abortion clinic and state hospital (mean age: 25.4 ± 6.1 years) and assessed on various symptom domains, using both clinician-administered interviews and self-report measures just prior to termination, immediately post-procedure, and at 1 month and 3 months post-procedure. Morning salivary cortisol assays were collected prior to anaesthesia and termination.</p> <p>Results</p> <p>The group who received local anaesthetic demonstrated higher baseline cortisol levels (mean = 4.7 vs 0.2), more dissociative symptoms immediately post-termination (mean = 14.7 vs 7.3), and higher levels of pain before (mean = 4.9 vs 3.0) and during the procedure (mean = 8.0 vs 4.4). However, in the longer-term (1 and 3 months), there were no significant differences in pain, psychological outcomes (PTSD, depression, self-esteem, state anxiety), or disability between the groups. More than 65% of the variance in PTSD symptoms at 3 months could be explained by baseline PTSD symptom severity and disability, and post-termination dissociative symptoms. Of interest was the finding that pre-procedural cortisol levels were positively correlated with PTSD symptoms at both 1 and 3 months.</p> <p>Conclusion</p> <p>High rates of PTSD characterise women who have undergone surgical abortions (almost one fifth of the sample meet criteria for PTSD), with women who receive local anaesthetic experiencing more severe acute reactions. The choice of anesthetic, however, does not appear to impact on longer-term psychiatric outcomes or functional status.</p

Vitamin D Receptor Gene Polymorphisms Modify Cardiometabolic Response to Vitamin D Supplementation in T2DM Patients

There is conflicting evidence on the favorable effects of vitamin D supplementation on metabolic profile in Type 2 diabetes mellitus (T2DM) patients and this might be due to genetic variations in vitamin D receptors (VDRs). Thus, we studied the metabolic effects of a 12-month vitamin D supplementation in T2DM patients according to VDR polymorphisms. A total of 204 T2DM subjects received 2000 IU vitamin D3 daily for 12 months. Serum 25(OH)D and metabolic profiles were measured at baseline and after 12 months. VDR polymorphisms (Taq-I, Bsm-I, Apa-I and Fok-I) were identified using TaqMan genotyping assays. Vitamin D supplementation significantly increased HOMA β-cell function (p = 0.003) as well as significantly decreased triglycerides, total and LDL-cholesterol (p < 0.001). The lowest increment in 25(OH)D levels was detected in patients with Fok-I CC genotypes (p < 0.0001). With vitamin D supplementation, Taq-I GG genotype carriers showed significant improvements in triglycerides, LDL- and total cholesterol, insulin, HbA1c and HOMA-IR (p < 0.005, 0.01, < 0.001, < 0.005, 0.03 and 0.01, respectively). Similarly, Bsm-I TT genotype carriers showed significant improvements in triglycerides (p = 0.01), insulin and HOMA-IR (p-values < 0.05). In conclusion, improvements in metabolic profile due to vitamin D supplementation is influenced by VDR polymorphisms, specifically for carriers of Taq-I GG and Bsm-I TT genotypes

Exploring the experiences and coping strategies of international medical students

<p>Abstract</p> <p>Background</p> <p>Few studies have addressed the challenges that international medical students face and there is a dearth of information on the behavioural strategies these students adopt to successfully progress through their academic program in the face of substantial difficulties of language barrier, curriculum overload, financial constraints and assessment tasks that require high proficiency in communication skills.</p> <p>Methods</p> <p>This study was designed primarily with the aim of enhancing understanding of the coping strategies, skill perceptions and knowledge of assessment expectations of international students as they progress through the third and fourth years of their medical degree at the School of Medicine, University of Tasmania, Australia.</p> <p>Results</p> <p>Survey, focus group discussion and individual interviews revealed that language barriers, communication skills, cultural differences, financial burdens, heavy workloads and discriminatory bottlenecks were key factors that hindered their adaptation to the Australian culture. Quantitative analyses of their examination results showed that there were highly significant (p < 0.001) variations between student performances in multiple choice questions, short answer questions and objective structured clinical examinations (70.3%, 49.7% & 61.7% respectively), indicating existence of communication issues.</p> <p>Conclusions</p> <p>Despite the challenges, these students have adopted commendable coping strategies and progressed through the course largely due to their high sense of responsibility towards their family, their focus on the goal of graduating as medical doctors and their support networks. It was concluded that faculty needs to provide both academic and moral support to their international medical students at three major intervention points, namely point of entry, mid way through the course and at the end of the course to enhance their coping skills and academic progression. Finally, appropriate recommendations were made.</p

Deletion of Forkhead Box M1 Transcription Factor from Respiratory Epithelial Cells Inhibits Pulmonary Tumorigenesis

The Forkhead Box m1 (Foxm1) protein is induced in a majority of human non-small cell lung cancers and its expression is associated with poor prognosis. However, specific requirements for the Foxm1 in each cell type of the cancer lesion remain unknown. The present study provides the first genetic evidence that the Foxm1 expression in respiratory epithelial cells is essential for lung tumorigenesis. Using transgenic mice, we demonstrated that conditional deletion of Foxm1 from lung epithelial cells (epFoxm1−/− mice) prior to tumor initiation caused a striking reduction in the number and size of lung tumors, induced by either urethane or 3-methylcholanthrene (MCA)/butylated hydroxytoluene (BHT). Decreased lung tumorigenesis in epFoxm1−/− mice was associated with diminished proliferation of tumor cells and reduced expression of Topoisomerase-2α (TOPO-2α), a critical regulator of tumor cell proliferation. Depletion of Foxm1 mRNA in cultured lung adenocarcinoma cells significantly decreased TOPO-2α mRNA and protein levels. Moreover, Foxm1 directly bound to and induced transcription of the mouse TOPO-2α promoter region, indicating that TOPO-2α is a direct target of Foxm1 in lung tumor cells. Finally, we demonstrated that a conditional deletion of Foxm1 in pre-existing lung tumors dramatically reduced tumor growth in the lung. Expression of Foxm1 in respiratory epithelial cells is critical for lung cancer formation and TOPO-2α expression in vivo, suggesting that Foxm1 is a promising target for anti-tumor therapy

Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism

Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders