Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)--2',3'-dideoxycytidine (ddC): relevance to HIV-dementia

Human immunodeficiency virus dementia (HIVD) is the most common form of dementia occurring among young adults. In HIVD, neuronal cell loss occurs in the absence of neuronal infection. With the advent of highly active anti-retroviral therapy (HAART), the incidence of HIVD has drastically reduced, though prevalence of milder forms of HIVD continues to rise. Though these agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. Here we examine the possible role of NRTIs, in particular 2',3'-dideoxycytidine (ddC), in the neuropathology of HIVD. Synaptosomes and isolated mitochondria treated and incubated for 6 h with CSF-achievable concentrations of ddC, i.e., 6-11 ng/ml, were found to show a significant increase in oxidative stress with 40 nM ddC as measured by protein carbonyls and 3-nitrotyrosine (3NT), effects that were not observed in the more tolerable NRTI, 3TC. Protection against protein oxidation induced by ddC was observed when brain mitochondria were isolated from gerbils 1 h after injection i.p. with the brain accessible antioxidant and glutathione mimetic, tricyclodecan-9-yl-xanthogenate (D609). In addition, there is a significant reduction in the levels of anti-apoptotic protein Bcl-2 and a significant increase in cytochrome c release and also a significant increase in the expression of pro-apoptotic protein caspase-3 after mitochondria were treated with 40 nM ddC. The results reported here show that ddC at 40 nM can induce oxidative stress, cause the release of cytochrome c, and in addition, reduce the levels of anti-apoptotic proteins, increase the levels of pro-apoptotic proteins, thereby increasing the possibility for induction of apoptosis. These findings are consistent with the notion of a possible role of the NRTIs, and in particular, ddC, in the mechanisms involved in HIVD.     

The hemochromatosis protein HFE inhibits iron export from macrophages

Hereditary hemochromatosis (HH) is a disorder of iron metabolism caused by common mutations in the gene HFE. The HFE protein binds to transferrin receptor-1 (TfR1) in competition with transferrin, and in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively iron-deficient in HH. These latter observations suggest, paradoxically, that expression of wild-type HFE may lead to iron accumulation in these specialized cell types. Here we show that wild-type HFE protein raises cellular iron by inhibiting iron efflux from the monocytemacrophage cell line THP-1, and extend these results to macrophages derived from healthy individuals and HH patients. In addition, we find that the HH-associated mutant H41D has lost the ability to inhibit iron release despite binding to TfR1 as well as wild-type HFE. Finally, we show that the ability of HFE to block iron release is not competitively inhibited by transferrin. We conclude that HFE has two mutually exclusive functions, binding to TfR1 in competition with Tf, or inhibition of iron release.     

Failure of eruption of first permanent molar teeth: a diagnostic challenge

Ankylosis, mechanical and primary failure of eruption of molar teeth are rare and often difficult to distinguish between. All may have significant repercussions on the occlusion and successful management may involve invasive procedures. We present a case where an initial presentation characteristic of mechanical failure of eruption (ankylosis) of a first permanent molar tooth was excluded following a period of monitoring. Subsequent relief of crowding using a removable and then sectional fixed orthodontic appliance allowed spontaneous eruption of the tooth obviating the need for surgical intervention. This case highlights the utilisation of conservative treatment options until a diagnosis was confirmed to minimise the risk of iatrogenic damage and unnecessary treatment.     

Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia

Background  

Stroke is one of the leading causes of death worldwide and a major cause of morbidity and mortality in the United States of America. Brain ischemia-reperfusion (IR) triggers a complex series of biochemical events including inflammation. Leukotrienes derived from 5-lipoxygenase (5-LOX) cause inflammation and are thus involved in the pathobiology of stroke injury.     

Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats

6-Hydroxydopamine (6-OHDA) is one of the most widely used rat models for Parkinson's disease. There is ample evidence in the literature that 6-OHDA elicits its toxic manifestations through oxidant stress. In the present study, we evaluated the anti-parkinsonian effects of Withania somnifera extract, which has been reported to have potent anti-oxidant, anti-peroxidative and free radical quenching properties in various diseased conditions. Rats were pretreated with 100, 200 and 300 mg/kg b.w. of the W. somnifera extract orally for 3 weeks. On day 21, 2 microL of 6-OHDA (10 microg in 0.1% in ascorbic acid-saline) was infused into the right striatum while sham operated group received 2 microL of the vehicle. Three weeks after 6-OHDA injections, rats were tested for neurobehavioral activity and were killed 5 weeks after lesioning for the estimation of lipidperoxidation, reduced glutathione content, activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, catecholamine content, dopaminergic D2 receptor binding and tyrosine hydroxylase expression. W. somnifera extract was found to reverse all the parameters significantly in a dose-dependent manner. Thus, the study demonstrates that the extract of W. somnifera may be helpful in protecting the neuronal injury in Parkinson's disease.     

Evaluation of the adverse reactions of antiretroviral drug regimens in a tertiary care hospital

Objectives:

Antiretroviral toxicity is an increasingly important issue in the management of HIV-infected patients. The objective of our study was to evaluate the toxicity profile of currently used antiretroviral regimens and to compare these toxicities among males and females.

Materials and Methods:

A retrospective analysis with a one year follow-up was done at a tertiary care hospital by reviewing the record. Patients who were >18 years of age attending the hospital and were initiated an antiretroviral drug regimen were included in the analysis. Data regarding demographic details, medical history, details of human immunodeficiency virus (HIV) infection including most recent CD4 count, details of antiretroviral therapy (ART) collected from patient''s records. Adverse drug reactions were recorded by reviewing patient records.

Result:

A total of 99 patients were included in study. Among them, 71 (71.7%) were males and 28(28.3%) were females. Common adverse effects observed included anemia (58.6%), pruritus(23.2%), skin rash(18.2%), hypertriglyceridemia(15.2%), and hepatitis (60.6%), peripheral neuropathy (14.1%). Prevalence of skin rash was more in females than males, the difference being statistically significant. Pruritus was also commonly seen in females than males though the difference observed in our study is statistically insignificant. Hypertriglyceridemia was more in males compared to females, the difference is statistically significant.

Conclusion:

The most common adverse effects associated with currently used ART regimens are anemia, hepatic toxicity, itching, skin rash, elevated triglycerides, and peripheral neuropathy. Gender differences were seen mainly with skin rash, which was significantly more in females.KEY WORDS: Adverse effects, antiretroviral therapy, HIV     

Effect of Saffron (Crocus sativus) on neurobehavioral and neurochemical changes in cerebral ischemia in rats

The modifying effects of Crocus sativus (CS) stigma extract on neurobehavioral activities, malondialdehyde (MDA), reduced glutathione (GSH), glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase (SOD), catalase (CAT), and Na(+),K(+)-ATPase activities, and glutamate (Glu) and aspartate (Asp) content were examined in the middle cerebral artery (MCA) occlusion (MCAO) model of acute cerebral ischemia in rats. The right MCA of male Wistar rats was occluded for 2 hours using intraluminal 4-0 monofilament, and reperfusion was allowed for 22 hours. MCAO caused significant depletion in the contents of GSH and its dependent enzymes while significant elevation of MDA, Glu, and Asp. The activities of Na(+),K(+)-ATPase, SOD, and CAT were decreased significantly by MCAO. The neurobehavioral activities (grip strength, spontaneous motor activity, and motor coordination) were also decreased significantly in the MCAO group. All the alterations induced by ischemia were significantly attenuated by pretreatment of CS (100 mg/kg of body weight, p.o.) 7 days before the induction of MCAO and correlated well with histopathology by decreasing the neuronal cell death following MCAO and reperfusion. The present results may suggest the effectiveness of CS in focal ischemia most probably by virtue of its antioxidant property.     

Atrium of stone: A case of confined left atrial calcification without hemodynamic compromise

Dystrophic cardiac calcification is often associated with conditions causing systemic inflammation and when present, is usually extensive, often encompassing multiple cardiac chambers and valves. We present an unusual case of dystrophic left atrial calcification in the setting of end stage renal disease on hemodialysis diagnosed by echocardiography and computed tomography. Significant calcium deposition is confined within the walls of the left atrium with no involvement of the mitral valve, and no hemodynamic effects.