A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus

Aims/hypothesis Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type I diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). Methods In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria >= 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria Results The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p=0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p=0.57), but a trend towards interaction with sex (p=0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p=0.03). Conclusions/interpretation CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements

Predicting Weight Outcomes in Preadolescence: The Role of Toddlers? Self-regulation Skills and the Temperament Dimension of Pleasure

Objective To investigate the role of toddlers? self-regulation skills and temperament in predicting weight outcomes in preadolescence. Method Participants for this study included 195 children (114 girls) obtained from three different cohorts participating in a larger ongoing longitudinal study. At 2 years of age, participants participated in several laboratory tasks designed to assess their self-regulation abilities, including emotion regulation, sustained attention, and delay of gratification, while parents filled out a temperament questionnaire to assess toddlers? pleasure expression. Height and weight measures were collected when children were 4, 5, 7, and 10 years of age. Children also filled out a body image and eating questionnaire at the 10 year visit. Results Self-regulation skills in toddlers were associated with both BMI development, pediatric obesity, and body image/eating concerns. The temperament dimension of pleasure was also associated with BMI development and pediatric obesity but not body image/eating concerns. Conclusion Self-regulation difficulties across domains as well as temperament based pleasure in toddlers represented significant individual risk factors for the development of pediatric obesity eight years later. Early self-regulation difficulties also contributed to body image and eating concerns that typically accompanied overweight children. The mechanisms by which early self-regulation skills and temperament based pleasure may contribute to the development of pediatric obesity and associated weight concerns are discussed

Optimal Control of Saccades by Spatial-Temporal Activity Patterns in the Monkey Superior Colliculus

A major challenge in computational neurobiology is to understand how populations of noisy, broadly-tuned neurons produce accurate goal-directed actions such as saccades. Saccades are high-velocity eye movements that have stereotyped, nonlinear kinematics; their duration increases with amplitude, while peak eye-velocity saturates for large saccades. Recent theories suggest that these characteristics reflect a deliberate strategy that optimizes a speed-accuracy tradeoff in the presence of signal-dependent noise in the neural control signals. Here we argue that the midbrain superior colliculus (SC), a key sensorimotor interface that contains a topographically-organized map of saccade vectors, is in an ideal position to implement such an optimization principle. Most models attribute the nonlinear saccade kinematics to saturation in the brainstem pulse generator downstream from the SC. However, there is little data to support this assumption. We now present new neurophysiological evidence for an alternative scheme, which proposes that these properties reside in the spatial-temporal dynamics of SC activity. As predicted by this scheme, we found a remarkably systematic organization in the burst properties of saccade-related neurons along the rostral-to-caudal (i.e., amplitude-coding) dimension of the SC motor map: peak firing-rates systematically decrease for cells encoding larger saccades, while burst durations and skewness increase, suggesting that this spatial gradient underlies the increase in duration and skewness of the eye velocity profiles with amplitude. We also show that all neurons in the recruited population synchronize their burst profiles, indicating that the burst-timing of each cell is determined by the planned saccade vector in which it participates, rather than by its anatomical location. Together with the observation that saccade-related SC cells indeed show signal-dependent noise, this precisely tuned organization of SC burst activity strongly supports the notion of an optimal motor-control principle embedded in the SC motor map as it fully accounts for the straight trajectories and kinematic nonlinearity of saccades

Folic acid supplementation in postmenopausal women with hot flushes: phase III randomised double-blind placebo-controlled trial

Objective To assess whether folic acid supplementation ameliorates hot flushes. Design Double-blind, placebo-controlled randomised trial. Setting Nine hospitals in England. Population Postmenopausal women experiencing ≥50 hot flushes weekly. Methods Women (n = 164) were randomly assigned in a 1:1 ratio to receive folic acid 5 mg tablet or placebo daily for 12 weeks. Participants recorded frequency and severity of hot flushes in a Sloan Diary daily and completed Greene Climacteric and Utian Quality of Life (UQoL) Scales at 4-week intervals. Main outcome measures The change in daily Hot Flush Score at week 12 from randomisation based on Sloan Diary Composite Score B calculation. Results Data of 143 (87%) women were available for the primary outcome. The mean change (SD) in Hot Flush Score at week 12 was −6.98 (10.30) and −4.57 (9.46) for folic acid and placebo group, respectively. The difference between groups in the mean change was −2.41 (95% CI −5.68 to 0.87) (P = 0.149) and in the adjusted mean change −2.61 (95% CI −5.72 to 0.49) (P = 0.098). Analysis of secondary outcomes indicated an increased benefit in the folic acid group regarding changes in total and emotional UQoL scores at week 8 when compared with placebo. The difference in the mean change from baseline was 5.22 (95% CI 1.16–9.28) and 1.88 (95% CI 0.23–3.52) for total and emotional score, respectively. Conclusions The study was not able to demonstrate that folic acid had a statistically significant greater benefit in reducing Hot Flush Score over 12 weeks in postmenopausal women when compared with placebo. Tweetable abstract Folic acid may ameliorate hot flushes in postmenopausal women but confirmation is required from a larger study

Socioeconomic status and prostate cancer incidence and mortality rates among the diverse population of California

The racial/ethnic disparities in prostate cancer rates are well documented, with the highest incidence and mortality rates observed among African-Americans followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders. Whether socioeconomic status (SES) can account for these differences in risk has been investigated in previous studies, but with conflicting results. Furthermore, previous studies have focused primarily on the differences between African-Americans and non-Hispanic Whites, and little is known for Hispanics and Asian/Pacific Islanders. To further investigate the relationship between SES and prostate cancer among African-Americans, non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders, we conducted a large population-based cross-sectional study of 98,484 incident prostate cancer cases and 8,997 prostate cancer deaths from California. Data were abstracted from the California Cancer Registry, a population-based surveillance, epidemiology, and end results (SEER) registry. Each prostate cancer case and death was assigned a multidimensional neighborhood-SES index using the 2000 US Census data. SES quintile-specific prostate cancer incidence and mortality rates and rate ratios were estimated using SEER*Stat for each race/ethnicity categorized into 10-year age groups. For prostate cancer incidence, we observed higher levels of SES to be significantly associated with increased risk of disease [SES Q1 vs. Q5: relative risk (RR) = 1.28; 95% confidence interval (CI): 1.25–1.30]. Among younger men (45–64 years), African-Americans had the highest incidence rates followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders for all SES levels. Yet, among older men (75–84 years) Hispanics, following African-Americans, displayed the second highest incidence rates of prostate cancer. For prostate cancer deaths, higher levels of SES were associated with lower mortality rates of prostate cancer deaths (SES Q1 vs. Q5: RR = 0.88; 95% CI: 0.92–0.94). African-Americans had a twofold to fivefold increased risk of prostate cancer deaths in comparison to non-Hispanic Whites across all levels of SES. Our findings suggest that SES alone cannot account for the greater burden of prostate cancer among African-American men. In addition, incidence and mortality rates of prostate cancer display different age and racial/ethnic patterns across gradients of SES

Rapid Cellular Turnover in Adipose Tissue

It was recently shown that cellular turnover occurs within the human adipocyte population. Through three independent experimental approaches — dilution of an inducible histone 2B-green fluorescent protein (H2BGFP), labeling with the cell cycle marker Ki67 and incorporation of BrdU — we characterized the degree of cellular turnover in murine adipose tissue. We observed rapid turnover of the adipocyte population, finding that 4.8% of preadipocytes are replicating at any time and that between 1–5% of adipocytes are replaced each day. In light of these findings, we suggest that adipose tissue turnover represents a possible new avenue of therapeutic intervention against obesity

Bone mineral density measurement and osteoporosis treatment after a fragility fracture in older adults: regional variation and determinants of use in Quebec

BACKGROUND: Osteoporosis (OP) is a skeletal disorder characterized by reduced bone strength and predisposition to increased risk of fracture, with consequent increased risk of morbidity and mortality. It is therefore an important public health problem. International and Canadian associations have issued clinical guidelines for the diagnosis and treatment of OP. In this study, we identified potential predictors of bone mineral density (BMD) testing and OP treatment, which include place of residence. METHODS: Our study was a retrospective population-based cohort study using data from the Quebec Health Insurance Board. The studied population consisted of all individuals 65 years and older for whom a physician claimed a consultation for a low velocity vertebral, hip, wrist, or humerus fracture in 1999 and 2000. Individuals were considered to have undergone BMD testing if there was a claim for such a procedure within two years following a fracture. They were considered to have received an OP treatment if there was at least one claim to Quebec's health insurance plan (RAMQ) for OP treatment within one year following a fracture. We performed descriptive analyses and logistic regressions by gender. Predictors included age, site of fracture, social status, comorbidity index, prior BMD testing, prior OP treatment, long-term glucocorticoid use, and physical distance to BMD device. RESULTS: The cohort, 77% of which was female, consisted of 25,852 individuals with fragility fractures. BMD testing and OP treatment rates were low and gender dependent (BMD: men 4.6%; women 13.1%; OP treatment: men 9.9%; women 29.7%). There was an obvious regional variation, particularly in BMD testing, ranging from 0 to 16%. Logistic regressions demonstrate that individuals living in long term care facilities received less BMD testing. Patients who had suffered from vertebral fractures, or who had received prior OP treatment or BMD testing, regardless of gender, subsequently received more BMD testing and OP treatments. Furthermore, increasing the distance between a patient's residence and BMD facility precluded likelihood of BMD testing. CONCLUSION: BMD testing rate was extremely low but not completely explained by reduced physical access; gender, age, social status, prior BMD testing and OP treatment were all important predictors for future BMD testing and OP treatment

Delay-Induced Transient Increase and Heterogeneity in Gene Expression in Negatively Auto-Regulated Gene Circuits

A generic feature in all intracellular biochemical processes is the time required to complete the whole sequence of reactions to yield any observable quantity-from gene expression to circadian rhythms. This widespread phenomenon points towards the importance of time delay in biological functions. Theoretically time delay is known to be the source of instability, and has been attributed to lead to oscillations or transient dynamics in several biological functions. Negative feedback loops, common in biochemical pathways, have been shown to provide stability and withstand considerable variations and random perturbations of biochemical parameters. The interaction of these two opposing factors-of instability and homeostasis-are features that are widespread in intracellular processes. To test the effect of these divergent forces in the dynamics of gene expression, we have designed and constructed simple negatively auto-regulated gene circuits consisting of a basic regulator and transcriptional repressor module, and compared it with one, which has delayed repression. We show, both theoretically and experimentally, that delayed repression induces transient increase and heterogeneity in gene expression before the gain of stability effected by the negative feedback. This design, therefore, seems to be suitable for conferring both stability and variability in cells required for adaptive response to a noisy environment

Association of a Deletion of GSTT2B with an Altered Risk of Oesophageal Squamous Cell Carcinoma in a South African Population: A Case-Control Study

Polymorphisms in the Glutathione S-transferase genes are associated with altered risks in many cancers, but their role in oesophageal cancer is unclear. Recently a 37-kb deletion polymorphism of GSTT2B that reduces expression of GSTT2 has been described. We evaluated the influence of the GSTT1 and GSTT2B deletion polymorphisms, and the GSTP1 Ile105Val polymorphism (rs1695) on susceptibility to oesophageal squamous cell carcinoma (OSCC) in the Black and Mixed Ancestry populations of South Africa.The GSTT1, GSTT2B and GSTP1 variants were genotyped in 562 OSCC cases and 907 controls, and tested for association with OSCC and for interaction with smoking and alcohol consumption. Linkage disequilibrium (LD) between the deletions at GSTT1 and GSTT2B was determined, and the haplotypes tested for association with OSCC. Neither the GSTT1 deletion nor the GSTP1 Ile105Val polymorphism was associated with OSCC risk in the Black or Mixed Ancestry populations. The GSTT2B deletion was not associated with OSCC risk in the Black population, but was associated with reduced risk of OSCC in the Mixed Ancestry population (OR=0.71; 95% CI 0.57-0.90, p=0.004). Case-only analysis showed no interaction between the GST polymorphisms and smoking or alcohol consumption. LD between the neighboring GSTT1 and GSTT2B deletions was low in both populations (r(2)(Black)=0.04; r(2)(MxA)=0.07), thus these deletions should be assessed independently for effects on disease risk.Although there was no association between the GSTT1 deletion polymorphism or the GSTP1 Ile105Val polymorphism with OSCC, our results suggest that the presence of the recently described GSTT2B deletion may have a protective effect on the risk of OSCC in the Mixed Ancestry South African population. This is the first report of the contribution of the GSTT2B deletion to cancer risk