IS BETA CELL DYSFUNCTION RESPONSIBLE FOR FLAT GLUCOSE TOLERANCE CURVE IN PRIMARY HYPOTHYROIDISM? (A HYPOTHESIS)

An intimate relationship between thyroid hormones and carbohydrate metabolism has long been recognised and oral glucose load produces flat glucose tolerance curve in patients with primary hypothyroidism. Although delayed glucose absorption was proposed to explain flat glucose tolerance curve exact mechanism remains to be elucidated. Hence this study was undertaken to assess glucose and insulin response to OGTT and IVGTT in 25 freshly detected cases of hypothyroidism and 25 healthy control. The cases were matched for sex, age, BMI, and waist hip ratio with controls. Cases and controls with past or family history of obesity, diabetes mellitus, or hypertension were excluded from study. The biochemical profile of the cases and controls was also comparable except for haemoglobin (11.2±0.31 vs 12.9±0.22 gm/dl)(p=0.0004). Serum cholesterol and triglyceride levels were higher in the cases but difference was not statistically significant Fasting plasma glucose level was significantly lower in hypothyroid patients (78±2.2 vs88±4.4 mg/dl, p=0.049). The oral glucose tolerance curve was flat with plasma glucose levels significantly lower at 30 minutes. The insulin levels during OGTT were found to be higher in the cases at all stages. There was loss of first phase insulin response to the glucose load during the IVGTT, which was blunted at all stages and the difference was statistically significant at 0 and 3 minutes. Loss of first phase insulin response to IV glucose suggests that there is evidence of beta-cell dysfunction. Patients with hypothyroidism were more insulin sensitive than control and insulin secretion was comparable with controls. Therefore flat glucose tolerance curve can be explained by absence of insulin priming effect leading to decreased glucose absorption followed by increased glucose disposal because of higher insulin levels following OGTT and increased glucose disposal caused by increased insulin sensitivity.KEY WORDS: Beta-cell function, Hypothyroidism, Insulin resistance, Insulin sensitivity     

Alteration of blood brain barrier permeability by T-2 toxin: Role of MMP-9 and inflammatory cytokines

T-2 toxin is a cytotoxic fungal secondary metabolite produced by different species of Fusarium such as F. sporotichioides, F. poae, F. equiseti, F. acuminatum etc. This class of mycotoxins causes a number of pathologies including nervous disorders, cardiovascular alterations, immunodepression and hemostatic derangements. In the present study, mechanism of T-2 toxin induced alteration of blood-brain barrier (BBB) permeability was assessed in terms of oxidative stress, gene expression of MMP-9, MMP-2 and their inhibitors TIMP-1 and TIMP-2, activation of inflammatory cytokines in both brain and peripheral tissue spleen. Gel zymography was used to show the activity of MMP-9 and MMP-2. The percutaneous exposure of 1 LD50 T2 toxin caused a reversible alteration in BBB permeability as observed by extravasation of Evans blue dye. Maximum dye level was observed on day 3 and reduced by day 7. A significant GSH depletion was observed on days 1 and 3. Brain ROS and lipid peroxidation levels increased significantly on 1 and 3 days and decreased by day 7. The SOD levels in brain showed significantly higher activity on 3 days (4-fold) and 7 days (5-fold) of toxin exposure compared to control. A similar trend was observed with catalase enzyme levels. The gene expression analysis of cNOS and iNOS showed varying levels of expression on different time points of post exposure. MMP-9 expression was significantly high on days 3 and 7 in brain with corresponding alteration in TIMP-1. MMP-2 and TIMP-2 showed no effect. Gene expression analysis of the inflammatory cytokines, IL-1α, IL-1β, IL-6 and TNF-α showed elevated levels on day 7 in brain. As spleen plays an important role in inflammatory response we analyzed MMP-9, MMP-2 and inflammatory cytokines in spleen. The MMP-9 was activated on day 7. MMP-2 activity was found to be elevated on 3 and 7 days and TIMP-2 mRNA level increased on 1 and 3 days in spleen. Inflammatory cytokines, IL-1 α, IL-1β, IL-6 and TNF-α showed elevated levels on days 1 and 3 in spleen indicating an early effect in spleen than in brain. In summary, the results of the study showed that the T-2 induced alteration in BBB permeability is mediated through oxidative stress, activation of MMP-9, and proinflammatory cytokines in brain as well as contribution from peripheral tissue spleen.     

Beating Heart versus Conventional Coronary Bypass Surgery: Our Experience

Background

Off-pump Coronary Artery Bypass (OPCAB) has become the standard surgical treatment of Coronary Artery Disease in most centres in India. It is clear from the current evidence that, in certain patients, OPCAB offers advantages over conventional Coronary Artery Bypass Grafting (CABG). Experience of this procedure in the Armed Forces is highlighted. Methods: Retrospective analysis of 200 nonrandomized consecutive patients taken up for OPCAB and 200 conventional CABG between Jan 2005 and Dec 2007 was done. The European system for cardiac operative risk evaluation (euroSCORE) was used in all patients. Perioperative morbidity and mortality was compared in the two groups.

Result

OPCAB was possible in 192 (96 %) out of 200 patients taken up for this procedure. Eight patients required cardiopulmonary bypass (CPB) to complete the revascularization. Incidence of reoperation for bleeding was 2.5% in OPCAB and 6% in CABG In the CABG group 2% patients developed severe bleeding complications, 3% required ventilation for more than 24 hour, 1% required renal replacement therapy, 1% had acute respiratory distress syndrome and 3.5% had neuro-psychiatric manifestations. Incidence of these complications in OPCAB patients was lower or NIL. Overall mortality in the OPCAB group was 1.5% and 2% in the CABG group. However only one patient out of 192 (0.5%) who underwent successful OPCAB died, while two patients out of eight who required conversion to CPB in this group died. Incidence of stroke, deep sternal infection and mortality was similar in both groups.

Conclusion

OPCAB is safe, effective and can be offered to more than 90% patients as the primary strategy for surgical myocardial revascularization. It has lower overall morbidity than conventional CABG Its main limitations are hemodynamic instability and inability to find a deeply embedded target vessel. Both these factors affect the outcome adversely making conventional CABG a better option in these situations.Key Words: Off-pump coronary artery bypass!, Coronary artery bypass     

Hepatoprotective efficacy of certain flavonoids against microcystin induced toxicity in mice

Toxic cyanobacteria (blue-green algae) water blooms have become a serious problem in several industrialized areas of the world. Microcystin-LR (MC-LR) is a cyanobacterial heptapeptide that represents acute and chronic hazards to animal and human health. Identification of suitable chemprotectants against microcystin is essential considering human health hazards. In the present study, we have evaluated the protective efficacy of three flavanoids namely quercetin (200 mg/kg), silybin (400 mg/kg), and morin (400 mg/kg)] pretreatment against microcystin toxicity (0.75 LD(50), 57.5 microg/kg) in mice. Various biochemical variables were measured to study the recovery profile of protected animals at 1- and 3-days post-toxin treatment. The serum alanine amino transferase (ALT) shows 17-fold increase in MC-LR treated animals compared with control group at 1 day. The silybin and quercetin group showed a decrease in level of ALT compared with MC-LR group but still higher than control group. No significant protection was observed with aspartate aminotransaminase (AST) and lactate dehydrogenase (LDH) levels in flavanoid-treated groups at 1-day post-treatment. But at 3 days, the serum levels of AST and ALT were normalized to control values, but the serum LDH levels were still significantly higher than the control group. No significant changes were observed in glutathione peroxidase and reduced glutathione levels at both 1- and 3-day postexposure. The catalase activity shows a significant decrease in quercetin-treated animals at 3-day postexposure. The protein phosphatase was significantly inhibited in MC-LR group compared to control. The silybin pretreated group showed recovery after 1 day. At 3 days, the PPAse activity was reversed to control values in all the flavanoid-treated groups. Immunoblotting analysis showed microcystin-PPAse adduct in liver tissues of toxin-treated as well as flavanoid-treated mice even after 3 days. The results of this study show that flavanoids, quercetin, silybin, and morin could reverse the hepatotoxic effects of MC-LR in vivo.