Association of markers of insulin and glucose control with subsequent colorectal cancer risk.

We evaluated the association of plasma insulin and other markers of insulin and glucose control with subsequent colorectal cancer. Incident colon (n = 132) and rectal (n = 41) cancer cases and matched controls (n = 346) were identified between baseline in 1989 and 2000 among participants in a community-based cohort in Washington County, Maryland. Circulating markers of insulin and glucose control were measured in baseline blood samples. Body mass index (BMI) and use of medications to treat diabetes mellitus were self-reported at baseline. Conditional logistic regression was used to estimate matched odds ratios (ORs). Compared with the lowest fourth, participants with insulin concentrations in the highest fourth were not at an increased risk of colorectal cancer [OR, 0.78; 95% confidence interval (CI), 0.45-1.35; P(trend) = 0.24]. Similarly, no associations were observed for the ratio of total cholesterol:HDL-cholesterol, triglycerides, and insulin-like growth factor binding protein 1. However, those in the highest fourth of glycosylated hemoglobin (HbA(1c)) level had a slightly increased risk of colorectal cancer (OR, 1.57; 95% CI, 0.94-2.60; P(trend) = 0.02). The OR of colorectal cancer was 1.70 (95% CI, 1.01-2.86; P(trend) = 0.08) comparing BMI >/=30 kg/m(2) to <25 kg/m(2). The OR of colorectal cancer was 2.43 (95% CI, 1.10-5.38) for the use of medications to treat diabetes. The associations of higher HbA(1c), higher BMI, and the use of medications to treat diabetes, with colorectal cancer lend support to the hypothesis that perturbations in insulin and glucose control may influence colorectal carcinogenesis. It is possible that HbA(1c), BMI, and the use of medications to treat diabetes, as a surrogate for protracted or severe type 2 diabetes mellitus, may have been better time-averaged indicators of hyperinsulinemia and hyperglycemia than the plasma markers that were measured once prediagnostically in a nonfasting population.     

Parvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here, we show that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a proapoptotic protein, mitochondrial anchored protein ligase (MAPL), selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood.     

Group II metabotropic glutamate receptors in the striatum of non-human primates: dysregulation following chronic cocaine self-administration

The purpose of this study was to investigate the possible effects of a treadmill training program on regeneration in young (3-month-old) and mature (13-month-old) rats with sciatic nerve crush using functional, electrophysiological, and morphometric analyses. When compared to both the young and mature untrained injury groups, those groups that underwent a treadmill training showed improved sensorimotor function evaluated by narrow beam test (p < 0.04 and p < 0.001, respectively), while muscle action potential amplitude was only greater in the young group (p < 0.02). The treadmill training program was able to reduce myelinated fiber density in the young group (p < 0.001), which appeared to increase after nerve injury (poly-innervation), but decreased with training, which means that the innervation became more functional. The data indicate that treadmill training is able to promote functional, electrophysiological and morphological recovery in young animals. However, in mature animals, improvement was only seen in terms of functional recovery.     

The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model

T cell Ig mucin 1 (TIM-1) plays an important role in regulating immune responses in autoimmune and asthma models, and it is expressed on both Th1 and Th2 cells. Using an antagonistic TIM-1-specific antibody, we studied the role of TIM-1 in alloimmunity. A short course of TIM-1-specific antibody monotherapy prolonged survival of fully MHC-mismatched vascularized mouse cardiac allografts. This prolongation was associated with inhibition of alloreactive Th1 responses and preservation of Th2 responses. TIM-1-specific antibody treatment was more effective in Th1-type cytokine-deficient Stat4(-/-) recipients as compared with Th2-type cytokine-deficient Stat6(-/-) recipients. Subtherapeutic doses of rapamycin plus TIM-1-specific antibody resulted in allograft acceptance and prevented the development of chronic allograft vasculopathy. Allograft survival via this treatment was accompanied by a Th1- to Th2-type cytokine switch. Depletion of natural Tregs abrogated the graft-protecting effect of the TIM-1-specific antibody. Importantly, CD4(+)CD25(+) Tregs obtained from long-term survivors had enhanced regulatory activity as compared with naive CD4(+)CD25(+) Tregs. Consistent with this, TIM-1-specific antibody treatment both preserved Tregs and prevented the expansion of alloreactive effector Th1 cells in an alloreactive TCR transgenic adoptive transfer model. These studies define previously unknown functions of TIM-1 in regulating alloimmune responses in vivo and may provide a novel approach to promoting transplantation tolerance.