Age-related oxidative decline of mitochondrial functions in rat brain is prevented by long term oral antioxidant supplementation

A combination of antioxidants (N-acetyl cysteine, α-lipoic acid, and α-tocopherol) was selected for long term oral supplementation study in rats for protective effects on age-related mitochondrial alterations in the brain. Four groups of rats were chosen: young control (6–7 months); aged rats (22–24 months); aged rats (22–24 months) on daily antioxidant supplementation from 18 month onwards and young rats (6–7 months) on daily antioxidant supplementation from 2 month onwards. The brain mitochondrial functional parameters, status of antioxidant enzymes and accumulation of oxidative damage markers were measured in the four groups of rats. A significant decrease in complex IV activity and a loss of transmembrane potential and phosphorylation capacity along with an increased accumulation of oxidative damage markers and compromised antioxidant enzyme status were noticed in aged rat brain mitochondria as compared to that in young controls, but in aged rats supplemented with oral antioxidants the mitochondrial alterations were largely prevented. Antioxidant supplementation in young rats had no effect on mitochondrial parameters investigated in this study. The results have implications in biochemical and functional deficits of brain during aging as well as in neurodegenerative disorders.     

Red cell and platelet‐derived microparticles are increased in G6PD‐deficient subjects

In response to oxidative stress and during apoptosis, cells often shed microparticles (MPs), submicron elements carrying phosphatidylserine and protein antigens. Glucose‐6‐phosphate dehydrogenase (G6PD)‐deficient cells are extremely sensitive to oxidative damage that may lead to the formation of MPs. To determine whether G6PD deficiency alters membrane phospholipid asymmetry and increases MPs production, we determined the concentrations and cellular origins of MPs in G6PD‐deficient individuals using flow cytometry. G6PD‐deficient individuals showed an increase in circulating MPs concentrations as compared with G6PD‐normal individuals [1051/μL (865–2532/μL) vs. 258/μL (235–575/μL), P < 0.01]. MPs concentrations were significantly increased with the severity of G6PD deficiency. Median MPs concentrations from individuals with severe G6PD deficiency, and individuals with moderate G6PD deficiency were 2567/μL (1216–2532/μL) and 984/μL (685–2107/μL), respectively (P < 0.01). Importantly, G6PD enzymatic activity was significantly correlated with MPs concentrations with r² = 0.731. MPs found in G6PD deficiency individuals were largely derived from red blood cells (RBCs) (45%) and platelets (30%). Additionally, Atomic Force Microscopy was used to study the morphology and measures the diameter of MPs found in G6PD‐deficient individuals. The mean (SD) width and height of RMPs were 0. 41 (0.18) and 2.04 (0.14) μm, respectively. Together, these results indicate that MP concentration is significantly correlated with G6PD enzymatic activity and is increased in G6PD‐deficient as compared with G6PD‐normal individuals. Our data also provide an evidence for an alteration in cell membrane associated with a decreased in G6PD activity. However, the significance of MPs in G6PD deficiency needs further clarification.     

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.     

The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation

Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan-Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pancreas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates.     

Role of mangiferin on biochemical alterations and antioxidant status in isoproterenol-induced myocardial infarction in rats

The current study dealt with the protective role of mangiferin, a polyphenol from Mangifera indica Linn. (Anacardiaceae), on isoproterenol (ISPH)-induced myocardial infarction (MI) in rats through its antioxidative mechanism. Subcutaneous injection of ISPH (200 mg/kg body weight in 1 ml saline) to rats for 2 consecutive days caused myocardial damage in rat heart, which was determined by the increased activity of serum lactate dehydrogenase (LDH) and creatine phosphokinase isoenzymes (CK-MB), increased uric acid level and reduced plasma iron binding capacity. The protective role of mangiferin was analyzed by triphenyl tetrazolium chloride (TTC) test used for macroscopic enzyme mapping assay of the ischemic myocardium. The heart tissue antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase and glutathione reductase activities, non-enzymic antioxidants such as cerruloplasmin, Vitamin C, Vitamin E and glutathione levels were altered in MI rats. Upon pretreatment with mangiferin (100 mg/kg body weight suspended in 2 ml of dimethyl sulphoxide) given intraperitoneally for 28 days to MI rats protected the above-mentioned parameters to fall from the normal levels. Activities of heart tissue enzymic antioxidants and serum non-enzymic antioxidants levels rose significantly upon mangiferin administration as compared to ISPH-induced MI rats. From the present study it is concluded that mangiferin exerts a beneficial effect against ISPH-induced MI due to its antioxidant potential, which regulated the tissues defense system against cardiac damage.     

L-carnitine in beta thalassemia

This study was conducted to determine L-carnitine levels in regularly transfused and chelated beta thalassemia patients (n=40; mean age, 17.5±5.0 years).Ten age matched controls were also studied. The mean L-carnitine level in thalassemic patients was 23.71±7.3 μM as compared to control 29.26±2.37μM (P<0.0001). Mean Carnitine was significantly lower (P=0.037) in those with ferritin greater than 2000ng/dL (22.80±6.97μM) in comparison to those with ferritin less than 2000ng/dL (30.1±7.77μM). Although Carnitine levels in non vegetarians was higher (26.91 ±8.4μM) than in vegetarians (22.34±6.55μM), this difference was not statistically significant (P=0.072). We conclude that L-carnitine levels were found to be lower in thalassemics as compared to age matched controls.     

Misidentification of Mycobacterium peregrinum, the causal organism of a case of bacteremia and automatic implantable cardioverter defibrillator-associated infection, due to its unusual acid-fast staining characteristics

We report an unusual case of Mycobacterium peregrinum bacteremia and infection of an automatic implantable cardioverter defibrillator that was originally misidentified as a Nocardia sp. due, in part, to its partially acid-fast staining characteristic, morphology, and odor. The misdiagnosis had a direct effect on patient care, though the patient was subsequently successfully treated.     

A study of twins--in search of an optimal age for delivery

The question regarding the optimal age of delivery in twins remains unanswered. A prospective observational study was carried out in the gynaecology and obstetrics department of RG Kar Medical College and Hospital, Kolkata during 2008-2009 to arrive at a logical conclusion to this question. The objective of this study was to evaluate the optimal timing of delivery in twins and compare the perinatal outcome in these babies by dividing them into 3 groups: 34 weeks to 35 weeks 6 days, 36 weeks to 37 weeks 6 days and >38 weeks. Perinatal outcome was also compared between different modes of delivery. Few maternal complications like pre-eclampsia, anaemia, premature rupture of membrane, preterm labour and antepartum haemorrhage were also evaluated.     

Estrogen and progesterone receptor status in breast cancer: effect of oral contraceptive pills and hormone replacement therapy

BACKGROUND: Higher incidence of hormone receptor positive breast cancer (BC) in White women compared to Blacks and Asians is attributed to different inherent biology. Many of our patients have estrogen receptor (ER) and progesterone receptor (PR) negative tumors. We tried to explore if this is related to low frequency of oral contraceptive pills (OCP) and hormone replacement therapy (HRT) intake. SETTING: Breast Unit, Department of Surgical Oncology, Tertiary Care Hospital, India. METHODS: Records of female BC patients classified as 'Users' of OCP/HRT for minimum of 1 year and age, stage, histopathology matched 'Non-users' were reviewed retrospectively from January 1990 to October 2006. RESULTS: Analysis of 150 evaluable 'Users' (58/122 premenopausal, 92/178 postmenopausal) and 150 matched 'Non-users' revealed 128 (42.67%) patients had ER and PR-negative, 157 (52.33%) ER and PR-positive, 12(4%) ER-positive/PR-negative, 3(1%) ER-negative/PR-positive tumor. Significantly more ER-positive tumor was found in both premenopausal [62.07% versus 39.06%, p=0.0184, odd's ratio (OR) 2.5527 and 95% confidence interval (CI) 1.2297-5.2993] and postmenopausal (63.04% versus 40.7%, p=0.0046, OR 2.4857 and 95% CI 1.3593-4.5455) 'Users' compared to 'Non-users', respectively. Grade III tumors were significantly less in premenopausal (p=0.0041) and postmenopausal (p=0.0012) 'Users'. CONCLUSIONS: These observations suggest that a low incidence of hormone receptor positivity in our patients could be partly due to low prevalence of OCP/HRT intake.