Identical twins discordant for multiple sclerosis have a shift in their T-cell receptor repertoires

CD4 T‐cells have an important role in the autoimmune response in multiple sclerosis (MS). We investigate the possibility that a shift occurs in the T‐cell receptor (TR) repertoire of identical twins discordant for MS. We compare the CDR3 spectratype distributions of 24 different TR V beta (TRBV) segments in naïve CD4 T‐cells from discordant MS twins and from healthy identical twins. We also compare the CDR3 spectratype distributions in unrelated healthy pairs, formed by combining members of different healthy twins, with the CDR3 spectratype distributions in unrelated pairs of MS patients and in unrelated pairs of their apparently healthy cotwins, formed by combining members of different discordant twins. We use the correlation coefficient (r‐value) as a measure of similarity of CDR3 spectratypes in each pair, and we test for the significance of the difference between r‐values from the different pairs. We observe that the r‐value for the CDR3 spectratype distributions among discordant twins differs significantly from the corresponding r‐value for the healthy twins for two TRBV segments. Further, the r‐values, for both the unrelated MS patient pairs and the unrelated pairs of their apparently healthy cotwins, differ significantly from the r‐values for healthy unrelated pairs of individuals. We conclude that both the MS patients and their apparently healthy cotwins have shifts in their CDR3 repertoires. Because we study naïve CD4 T‐cells, we postulate that CDR3 repertoire shifts precede MS and predispose to MS, but are unlikely to be sufficient to cause MS.     

Caffeic acid and protocatechuic acid modulate Nrf2 and inhibit Ehrlich ascites carcinomas in mice

Objective: To assess the nuclear factor-erythroid 2-related factor-2 (Nrf2) modulatory effect of caffeic acid and protocatechuic acid and determine the anti-tum...     

Purification and properties of hyaluronidase from Palamneus gravimanus (Indian black scorpion) venom.

Scorpion venoms are a rich source of enzymes. Some of the enzymes such as phospholipase A2, proteolytic enzymes and phosphodiesterase are well characterized. However, hyaluronidase has not been studied extensively. In this paper we describe the purification and characterization of hyaluronidase (Hyaluronate lyase, E.C.3.2.1.35) from the Palamneus gravimanus scorpion venom by a combination of gel filtration on Sephadex G-75 and ion-exchange chromatography on DEAE-cellulose. The optimal pH and temperature for its maximum activity of the isolated enzyme were 4.5 and 37 degrees C, respectively, and its K(m) was 47.61 microg/ml at 37 degrees C and its specific activity was 6411.7 +/- 117TRU/min per mg against 250 +/- 4.0 TRU/min per mg for the whole desiccated venom suggesting 25-fold purification. The molecular weight of the isolated enzyme was 52 +/- 1 kDa as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration chromatography on Sephadex G-75. The enzyme was stable for 30 days in the presence of NaCl; no loss of activity was observed up to 37 degrees degrees C and showed a sharp decrease in its activity at 40 degrees C. Heparin inhibited the enzyme activity.     

Biochemical and clinicopathological changes induced by Bungarus coeruleus venom in a rat model

Bungarus coeruleus, a common venomous snake allied to the cobra, is responsible for most envenomations in India. This study examines the pathological effects of B. caeruleus venom and the associated biochemical changes in a rat model. Increased serum aspartate aminotransferase (48%), creatine kinase (30%), and lactate dehydrogenase (6%) were detected after a sublethal dose of 25 microg/kg of B. caeruleus venom was injected intramuscularly into rats observed for 180 min. The venom induced hyperglycemia and increased serum alkaline phosphatase (55%) and urea (90%) concentrations, whereas cholesterol and triglycerides remained normal. Histopathological changes in the heart-hemorrhage, multifocal areas of myocardial fiber necrosis-and constriction of blood vessels in the kidney, with congested vessels, hemorrhage and necrosis of proximal tubules, liver congestion, and hemorrhage were found.     

Synthesis and Antimycobacterial Activity of a Novel Series of Isonicotinylhydrazide Derivatives

A novel series of 14 new isonicotinyl hydrazide derivatives 2a – g , 3a – g containing a 4‐thiazolidinone / 2‐azetidinone nucleus were synthesized by reacting N′‐substituted arylidene / heteroarylidene isonicotinyl hydrazide 1a – g with thioglycollic acid in the presence of dry benzene and with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly synthesized compounds were characterized on the basis of elemental analyses and spectral data (IR and ¹H‐NMR). All the title compounds were tested for their in‐vitro antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv using Alamar‐Blue susceptibility test, and the activity is expressed as the minimum inhibitory concentration (MIC) in μg/mL. Among the series, compounds 2b , 2g , 3b , and 3g displayed an encouraging antimycobacterial activity profile as compared to that of the reference drugs isoniazid / rifampicin.     

Aldehyde induced hypertension in rats: prevention by N-acetyl cysteine

Methylglyoxal, a highly reactive endogenous aldehyde is formed in the tissue of humans and animals as an intermediate of glucose and fructose metabolism. N-acetyl cysteine (NAC), an analogue of the dietary amino acid cysteine, binds aldehydes thus preventing their damaging effect on physiological proteins. We measured systolic blood pressure (SBP), platelet [Ca2+]i, circulating nitric oxide levels, tissue aldehyde conjugates and renal vascular changes in chronic methyglyoxal treated Wistar-Kyoto (WKY) rats and examined the effect of NAC in the diet on these parameters. Animals, age seven weeks, were divided into three groups of six animals each and were treated as follows: WKY-control (chow diet and normal drinking water); WKY-methylglyoxal (chow diet and methyglyoxal in drinking water); WKY-methyglyoxal + NAC (1.5% NAC in diet and methylglyoxal in drinking water) for the next 18 weeks. Methylgyoxal in drinking water was given at a concentration of 0.2% during weeks 0-5; 0.4%, weeks 6-10; and 0.8%, weeks 11-18. After 18 weeks systolic blood pressure, platelet [Ca2+]i and kidney aldehyde conjugates were significantly higher and serum nitric oxide levels lower in methylglyoxal treated rats. Methylglyoxal treated rats also showed smooth muscle cell hyperplasia in the small artery and arterioles of the kidney. N-acetyl cysteine, an aldehyde binding thiol compound, prevented these changes.     

Dietary lipoic acid supplementation prevents fructose-induced hypertension in rats

BACKGROUND AND AIMS: In fructose-induced hypertension in Wistar-Kyoto (WKY) rats, excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, alter membrane Ca2+ channels and increase cytosolic free calcium and blood pressure. The thiol compound N-acetyl cysteine prevents such hypertension by binding these aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of this work was to investigate whether dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound known to increase cysteine and glutathione, prevents this hypertension and its associated biochemical and histopathological changes. METHODS AND RESULTS: Starting at seven weeks of age, animals were divided into three groups of six animals each and treated as follows: control (normal diet and normal drinking water); fructose (normal diet and 4% fructose in drinking water); fructose + lipoic acid (diet supplemented with lipoic acid 500 mg/kg feed and 4% fructose in drinking water). After 14 weeks, systolic blood pressure, platelet [Ca2+]i, plasma glucose and insulin and kidney and aortic aldehyde conjugates were significantly higher in the fructose group. These also displayed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. CONCLUSION: Dietary alpha-lipoic acid supplementation in fructose-treated WKY rats may prevent their increase in systolic blood pressure by normalizing cytosolic [Ca2+], blood glucose and insulin, kidney and aortic aldehyde conjugates and preventing adverse renal vascular changes.     

Dietary vitamin B6 supplementation prevents ethanol-induced hypertension in rats

BACKGROUND AND AIMS: All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. Acetaldehyde has been shown to deplete vitamin B6 in chronic alcoholics. It also binds with sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing vascular cytosolic free calcium, peripheral vascular resistance and blood pressure. The aldehyde-binding thiol compound, N-acetyl cysteine, attenuates elevated blood pressure and associated adverse changes in ethanol-induced hypertensive rats. Vitamin B6 supplementation increases the level of endogenous cysteine. Aim of this work was thus to investigate whether a dietary supplementation of vitamin B6 can prevent ethanol-induced hypertension and associated changes in Wistar-Kyoto (WKY) rats. METHODS AND RESULTS: Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each. The control group received a normal vitamin B6 diet (regular chow) and normal drinking water, the ethanol group, the same diet plus 1% ethanol in the drinking water, and the ethanol + vitamin B6 group a high vitamin B6 diet (20 times normal diet) and 1% ethanol in the drinking water. After 14 weeks, systolic blood pressure, platelet [Ca2+]i and kidney and aortic aldehyde conjugate levels were significantly higher in the ethanol group. These rats also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin B6 supplementation prevented these changes. CONCLUSIONS: Dietary vitamin B6 supplementation prevented ethanol-induced hypertension and associated changes in WKY rats by normalizing tissue aldehyde conjugate levels.     

Accuracy of Intraoperative Epicardial Echocardiography in the Assessment of Surgical Repair of Congenital Heart Defects confirmed

Objective:

To determine the accuracy of epicardial echocardiography in detecting residual lesions after surgical repair of congenital heart defects. To determine the sensitivity, specificity, positive predictive valve, negative predictive valve, and false negative and false positive percentage of the same.

Materials and Methods:

One year hospital-based prospective study of epicardial echocardiography in patients undergoing cardiopulmonary bypass for surgical correction of congenital heart defects in children and adults.

Results:

Epicardial echocardiography was done in 158 patients. Residual lesions were detected in 38 patients by epicardial echocardiography. In 28 of these cases the residual lesions were significant. In 24 of them immediate reoperation was done with good outcome. Epicardial echo has high sensitivity, specificity, positive and negative predictive valve, in detecting residual lesion with congenital heart defects.

Conclusion:

Routine use of intraoperative epicardial echocardiography allows detection of majority of residual defects. It has high accuracy. There were no complications associated with use of epicardial echocardiography. The use of transesophageal echocardiography (TEE) can be avoided in small children and neonates undergoing cardiac surgery.