Identification of TUB as a novel candidate gene influencing body weight in humans

Previously, we identified a locus on 11p influencing obesity in families with type 2 diabetes. Based on mouse studies, we selected TUB as a functional candidate gene and performed association studies to determine whether this controls obesity. We analyzed the genotypes of 13 single nucleotide polymorphisms (SNPs) around TUB in 492 unrelated type 2 diabetic patients with known BMI values. One SNP (rs1528133) was found to have a significant effect on BMI (1.54 kg/m(2), P = 0.006). This association was confirmed in a population enriched for type 2 diabetes, using 750 individuals who were not selected for type 2 diabetes. Two SNPs in linkage disequilibrium with rs1528133 and mapping to the 3' end of TUB, rs2272382, and rs2272383 also affected BMI by 1.3 kg/m2 (P = 0.016 and P = 0.010, respectively). Combined analysis confirmed this association (P = 0.005 and P = 0.002, respectively). Moreover, comparing 349 obese subjects (BMI >30 kg/m(2)) from the combined cohort with 289 normal subjects (BMI <25 kg/m(2)) revealed that the protective alleles have a lower frequency in obese subjects (odds ratio 1.32 [95% CI 1.04-1.67], P = 0.022). Altogether, data from the tubby mouse as well as these data suggest that TUB could be an important factor in controlling the central regulation of body weight in humans

Self-reported work productivity in people with multiple sclerosis and its association with mental and physical health

Purpose This study aimed to identify mental health, physical health, demographic and disease characteristics relating to work productivity in people with multiple sclerosis (MS). Methods In this cross-sectional study, 236 employed people with MS (median age = 42 years, 78.8% female) underwent neurological and neuropsychological assessments. Additionally, they completed questionnaires inquiring about work productivity (presenteeism: reduced productivity while working, and absenteeism: loss of productivity due to absence from work), mental and physical health, demographic and disease characteristics. Multiple linear and logistic regression analyses were performed with presenteeism and absenteeism as dependent variables, respectively. Results A model with mental and physical health factors significantly predicted presenteeism F(11,202) = 11.33, p < 0.001, R-2 = 0.38; a higher cognitive (p < 0.001) and physical impact (p = 0.042) of fatigue were associated with more presenteeism. A model with only mental health factors significantly predicted absenteeism; chi(2)(11)=37.72, p < 0.001, with R-2 = 0.27 (Nagelkerke) and R-2 = 0.16 (Cox and Snell). Specifically, we observed that more symptoms of depression (p = 0.041) and a higher cognitive impact of fatigue (p = 0.011) were significantly associated with more absenteeism. Conclusions In people with MS, both cognitive and physical impact of fatigue are positively related to presenteeism, while symptoms of depression and cognitive impact of fatigue are positively related to absenteeism.Neurological Motor Disorder

Self-reported occupational functioning in persons with relapsing-remitting multiple sclerosis: does personality matter?

Health and self-regulatio

SIRP alpha on Mouse B1 Cells Restricts Lymphoid Tissue Migration and Natural Antibody Production

The inhibitory immunoreceptor SIRPα is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRPα on B1 lymphocytes, a subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPαΔCYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective, we investigated the involvement of SIRPα signaling in atherosclerosis development. Bone marrow (SIRPαΔCYT>LDLR−/−) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRPα as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRPα as a potential therapeutic target in atherosclerosis

Has the Rate of CD4 Cell Count Decline before Initiation of Antiretroviral Therapy Changed over the Course of the Dutch HIV Epidemic among MSM?

Introduction:Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline.Methods:Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Algemeen letterkundig lexicon

Definities van termen in verband met de Nederlandse letterkunde en haar studie

Tumor-Infiltrating Lymphocytes in Low-Risk Patients With Breast Cancer Treated With Single-Dose Preoperative Partial Breast Irradiation

Contains fulltext : 232805.pdf (Publisher’s version ) (Open Access)PURPOSE: Preoperative partial breast irradiation (PBI) has the potential to induce tumor regression. We evaluated the differences in the numbers of preirradiation tumor infiltrating lymphocytes (TILs) between responders and nonresponders after preoperative PBI in low-risk patients with breast cancer. Furthermore, we evaluated the change in number of TILs before and after irradiation. METHODS AND MATERIALS: In the prospective ABLATIVE study, low-risk patients with breast cancer underwent treatment with single-dose preoperative PBI (20 Gy) to the tumor and breast-conserving surgery after 6 or 8 months. In the preirradiation diagnostic biopsy and postirradiation resection specimen, numbers of TILs in 3 square regions of 450 x 450 mum were counted manually. TILs were visualized with CD3, CD4, and CD8 immunohistochemistry. Differences in numbers of preirradiation TILs between responders and nonresponders were tested using Mann-Whitney U test. Responders were defined as pathologic complete or near-complete response, and nonresponders were defined "as all other response." Changes in numbers of TILs after preoperative PBI was evaluated with the Wilcoxon signed rank test. RESULTS: Preirradiation tissue was available from 28 patients, postirradiation tissue from 29 patients, resulting in 22 pairs of preirradiation and postirradiation tissue. In these 35 patients, 15 had pathologic complete response (43%), 11 had a near-complete response (31%), 7 had a partial response (20%), and 2 had stable disease (6%). The median numbers of CD3(+) TILs, CD4(+) TILs, and CD8(+) TILs in the preirradiation tumor tissue were 49 (interquartile range [IQR], 36-80), 45 (IQR, 28-57), and 19 (IQR, 8-35), respectively. The number of preirradiation TILs did not differ significantly between responders and nonresponders. The median numbers of CD3(+) TILs, CD4(+) TILs, and CD8(+) TILs in postirradiation tumor tissue were 17 (IQR, 13-31), 26 (IQR, 16-35), and 7 (IQR, 5-11), respectively. CONCLUSIONS: After preoperative PBI in this limited cohort, the number of TILs in tumor tissue decreased. No differences in numbers of preirradiation TILs between responders and nonresponders were observed