Subbulaxmi Trikudanathan

Association of Female Reproductive Factors with Body Composition: The Framingham Heart Study

BACKGROUND Identifying reproductive risk factors in women offers a life course approach to obesity and cardiovascular disease prevention. The association of female reproductive factors with measures of regional body fat distribution has not been comprehensively studied. METHODS We examined the association of female reproductive factors (age at menarche, parity, age at natural menopause, menopausal status) in association with body composition data from women who participated in the Offspring and the Third Generation Framingham Heart Study cohorts. Visceral adipose tissue (VAT) and sc adipose tissue (SAT) were measured volumetrically by multidetector computerized tomography. We modeled the relationship between each fat depot and female reproductive factors after adjusting for various factors such as age, smoking status, alcohol intake, physical activity index, hormone replacement therapy, and menopausal status. RESULTS Earlier age at menarche was associated with increased body mass index (BMI), waist circumference (WC), VAT, and SAT (P < 0.0001). This association of earlier menarche with adiposity measures was attenuated after adjusting for BMI (all P > 0.70). We observed no association between parity and all parameters of adiposity measurements (all P > 0.24). Similarly, age at natural menopause was not associated with measures of body composition. Despite higher mean BMI among the post- (BMI 27.3 kg/m(2)) compared with the premenopausal women (BMI 25.9 kg/m(2)) in an age-matched analysis, mean VAT was not different between the two groups (P = 0.30). CONCLUSIONS Earlier menarche is associated with overall obesity but not with VAT or SAT after accounting for measures of generalized adiposity. Parity and menopausal age were not associated with adiposity measures. Although postmenopausal women had increased BMI, VAT, and SAT, the association was predominantly due to age.

Immune modulation by Lacto-N-fucopentaose III in experimental autoimmune encephalomyelitis

Parasitic infections frequently lead to immune deviation or suppression. However, the application of specific parasitic molecules in regulating autoimmune responses remains to be explored. Here we report on the immune modulatory function of Lacto-N-fucopentaose III (LNFPIII), a schistosome glycan, in an animal model for multiple sclerosis. We found that LNFPIII treatment significantly reduced the severity of experimental autoimmune encephalomyelitis (EAE) and CNS inflammation, and skewed peripheral immune response to a Th2 dominant profile. Inflammatory monocytes (IMCs) purified from LNFPIII-treated mice had increased expression of nitric oxide synthase 2, and mediated T cell suppression. LNFPIII treatment also significantly increased mRNA expression of arginase-1, aldehyde dehydrogenase 1 subfamily A2, indoleamine 2,3-dioxygenase and heme oxygenase 1 in splenic IMCs. Furthermore, LNFPIII treatment significantly reduced trafficking of dendritic cells across brain endothelium in vitro. In summary, our study demonstrates that LNFPIII glycan treatment suppresses EAE by modulating both innate and T cell immune response.

Comparison of Insulin Sensitivity Measures in South Asians

OBJECTIVE South Asians have increased visceral adiposity, insulin resistance and greater prevalence of type 2 diabetes and cardiovascular disease when compared to Caucasians of European origin. Surrogate markers of insulin resistance such as the composite insulin sensitivity (Matsuda) index correlate with glucose clamps in other populations, but ethnicity can affect these indices. We compared the Matsuda index, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and triglyceride/HDL ratio to insulin sensitivity derived from euglycemic clamps in healthy South Asians and Caucasians. MATERIALS/METHODS Twenty-three healthy South Asians and 18 Caucasians matched for age (mean±SE=33.6±2.1 vs. 36.0±3.0 years) and BMI (25.2±1.1 vs. 24.6±0.9 kg/m(2)) underwent 75 g oral glucose tolerance test (OGTT), 2-h euglycemic hyperinsulinemic clamp (240 pmol·m(-2)·min(-1)), fasting lipid profile, and anthropometric measures. RESULTS South Asians had higher fasting insulin (41±5 vs. 21±2 pmol/l; p=0.002) and lower HDL-C (1.25±0.06 vs. 1.56±0.10 mmol/l; p=0.010), but similar fasting glucose (5.0±0.1 vs. 4.9±0.1 mmol/l) levels vs. Caucasians. South Asians had significantly decreased measures of insulin sensitivity derived from both the euglycemic clamp (24.9±1.3 vs. 41.4±1.9 μmol·kg(-1)·min(-1); p<0.0001) and OGTT (Matsuda Index 7.60±0.99 vs. 13.60±1.79; p=0.004). The Matsuda index correlated highly with clamp insulin sensitivity in South Asians (r=0.50; p=0.014) and Caucasians (r=0.47; p=0.046). HOMA-IR, QUICKI, and triglyceride/HDL ratio correlated with clamp values in South Asians, but not in Caucasians. CONCLUSIONS In South Asians, Matsuda index, HOMA-IR, QUICKI, and triglyceride/HDL ratio offer simple and valid surrogate measures of insulin sensitivity that can be employed in larger clinical or epidemiological studies in this ethnic group.

Transplant tolerance through costimulation blockade - are we there yet?

Achieving a tolerant state specific to the transplanted graft without subjecting patients to the risks of non-specific immunosuppression is the goal of transplant immunologists. In spite of the success achieved with currently available immunosuppresive therapies over acute rejection, an ongoing T cell mediated alloimmune response still poses a major challenge to the health of an allograft through chronic rejection. Modulating these destructive alloresponses through T cell costimulation blockade is a promising area of interest. In this article, we review our current knowledge about the role of various positive and negative costimulatory pathways during an alloimmune response. The ultimate nature of that response depends on the complex interaction between these positive and negative costimulatory pathways. We discuss the progress that has been achieved so far, through targeting these individual pathways, their interaction with other costimulatory pathways and the currently available immunosuppressive agents in various organ transplant models.

Altered Adrenal Function and the Autonomic Nervous System

Publisher Summary This chapter focuses on altered adrenal function, the autonomic nervous system, and the influence of the autonomic nervous system on adrenocortical function. The adrenal gland consists of the outer cortex and the inner medulla. The adrenal cortex consists of the outer zona glomerulosa that secretes aldosterone which plays a major role in regulation of blood pressure, volume and potassium balance. Primary adrenal insufficiency results from destruction of the adrenal cortex. Autoimmune adrenalitis remains the predominant cause for primary adrenocortical dysfunction in the western world. The adrenal cortex and medulla appear to be interlaced with multiple areas of contact that are not separated by connective tissue or interstitial membranes. The most common symptoms include weakness, malaise, fatigue, weight loss, anorexia, and nausea. The distinctive clinical features of chronic primary adrenal insufficiency include hyperpigmentation and salt craving. The autonomic nervous system also may play a role in mediating the increased cardiovascular risk associated with aldosterone. It is indicated that aldosterone can centrally increase the sympathetic activity in the brain.

Anti-CD3 mAb treatment cures PDL1-/-.NOD mice of diabetes but precipitates fatal myocarditis.

Anti-CD3 mAb is an effective therapy that can reverse diabetes in NOD mice and has therapeutic potential in patients with type 1 diabetes (T1D). We administered anti-CD3 to PDL1-/-.NOD mice in order to determine whether this treatment would reverse the development of diabetes in these mice. Mice injected with anti-CD3 mAb neonatally were protected from T1D. However, all of these anti-CD3 mAb treated PDL1-/-.NOD mice developed a wasting disease between 12 and 20 weeks of age with sudden deterioration and weight loss, leading to death within 3-5 days of development of illness. Histology revealed severe inflammation in the heart and skeletal muscles. These results suggest that deficiency of PDL1 in NOD background has the potential to lead to immune-mediated tissue damage in organs other than the pancreas, but this cannot be appreciated in PDL1-/-.NOD mice as the mice develop T1D at an early age and die from diabetes prior to manifesting other autoimmune diseases.