Protective effect of fenugreek (Trigonella foenum graecum) seeds in experimental ethanol toxicity

The study investigates the effect of aqueous extract of fenugreek seeds (Trigonella foenum graecum) on lipid peroxidation and antioxidant status in experimental ethanol toxicity in rats. The ability of the seed extract to prevent iron-induced lipid peroxidation in vitro was also investigated. Ethanol feeding for 60 days resulted in significant increases in the activities of serum aspartate transaminase, alanine transaminase and alkaline phosphatase. The levels of serum lipid hydroperoxides and thiobarbituric acid reactive substances in liver and brain were also significantly elevated. Significantly lower activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and glutathione reductase were observed in liver and brain accompanied by depletion in glutathione, ascorbic acid and alpha-tocopherol concentrations. Activity of Ca(2+) ATPase in brain was significantly lowered. Simultaneous administration of aqueous extract of fenugreek seeds with ethanol prevented the enzymatic leakage and the rise in lipid peroxidation and enhanced the antioxidant potential. The seeds exhibited appreciable antioxidant property in vitro which was comparable with that of reduced glutathione and alpha-tocopherol. Further, histopathological examination of liver and brain revealed that, aqueous extract of fenugreek seeds could offer a significant protection against ethanol toxicity.     

Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme

Despite the most aggressive medical and surgical treatments, glioblastoma multiforme remains incurable with a median survival of <1 year. We investigated the antitumor potential of a novel viral agent, an attenuated strain of measles virus (MV), derived from the Edmonston vaccine lineage, genetically engineered to produce carcinoembryonic antigen (CEA). CEA production as the virus replicates can serve as a marker of viral gene expression. Infection of a variety of glioblastoma cell lines including U87, U118, and U251 at MOIs 0.1, 1, and 10 resulted in significant cytopathic effect consisting of excessive syncycial formation and massive cell death at 72-96 h from infection. terminal deoxynucleotidyltransferase-mediated nick end labeling assays demonstrated the mechanism of cell death to be predominantly apoptotic. The efficacy of this approach in vivo was examined in BALB/c nude mice by using both s.c. and intracranial orthotopic U87 tumor models. In the s.c. U87 model, mice with established xenografts were treated with a total dose of 8 x 10(7) plaque forming units of MV-CEA, administered i.v. Mice treated with UV light inactivated MV, and untreated mice with established U87 tumors were used as controls. There was statistically significant regression of s.c. tumors (P < 0.001) and prolongation of survival (P = 0.007) in MV-CEA treated animals compared with the two control groups. In the intracranial orthotopic U87 model, there was significant regression of intracranial U87 tumors treated with intratumoral administration of MV-CEA at a total dose of 1.8 x 10(6) plaque forming units as assessed by magnetic resonance image (P = 0.002), and statistically significant prolongation of survival as compared with mice that received UV-inactivated virus and untreated mice (P = 0.02). Histological examination of brains of MV-CEA-treated animals revealed complete regression of the tumor with the presence of a residual glial scar and reactive changes, mainly presence of hemosiderin-laden macrophages. In addition, CEA levels in the peripheral blood in both the s.c. and orthotopic models increased before tumor regression, indicating viral gene expression, and returned to normal when the tumors regressed. Ifnar(ko) CD46 Ge transgenic mice, susceptible to MV infection, were used to assess central nervous system toxicity of MV-CEA. Intracranial administration of MV-CEA into the caudate nucleus of Ifnar(ko) CD46 Ge did not result in clinical neurotoxicity. Pathologic examination demonstrated limited microglial infiltration surrounding the injection site. In summary, MV-CEA has potent antitumor activity against gliomas in vitro, as well as in both s.c. and orthotopic U87 animal models. Monitoring CEA levels in the serum can serve as a low-risk method of detecting viral gene expression during treatment, and could allow dose optimization and individualization of treatment.     

Occult spinal dysraphism: evidence-based diagnosis and treatment

This article reviews the scientific evidence behind the diagnostic tools available for the appropriate workup and management of patients with occult spinal dysraphism (OSD). The diagnostic tools include the use of detailed history and physical examination, plain films, ultrasound, MR imaging, and neurophysiologic tests. In addition, the article discusses the epidemiology of the most common causes of OSD in children, which will allow physicians caring for children to develop a pretest probability of disease and make a more educated decision as to when additional diagnostic testing is required.     

Protective role of vitamin E, 2-deoxy-D-glucose, and taurine on perchloroethylene induced alterations in ATPases

Perchloroethylene (PER) administered by oral gavage for 15 consecutive days, at a dose of 3000 mg/kg body wt. decreased the activities of Na+, K(+)-ATPase and Mg(2+)-ATPase with an increase in the activity of Ca(2+)-ATPase. It also decreased RBC and platelet counts but the WBC count was found to be increased. An investigation of the relative importance of the modulators, vitamin E, 2-deoxy-D-glucose (2DG) and taurine in rendering protection to tissues against PER induced membrane damage was performed. PER administered mice were subjected to vitamin E (400 mg/kg body wt/day), 2DG (500 mg/kg body wt/day by i.p.) and taurine (100 mg/kg body wt/day) administration for 15 days to study their individual effect on ATPase and on certain hematological parameters. Vitamin E, 2DG and taurine treated mice showed a marked reversal of these metabolic changes related to membrane damage caused by PER. These results suggest that PER induced membrane damage may be associated with energy metabolism and hemolysis, which can be effectively prevented by these modulators.     

Disseminated nocardiosis in a bone marrow transplant recipient with chronic GVHD

We describe a case of disseminated nocardiosis in a 53-year-old male allogeneic marrow recipient with chronic GVHD, 15 years post BMT. Six months prior to admission he was treated for recurrent chronic GVHD with corticosteroids with a good response. He deteriorated subsequently while still on steroids requiring admission for fever, anorexia, weight loss, productive cough and progressive dyspnoea. On admission he had multiple nodular lesions on chest roentgenogram and subsequently grew Nocardia farcinica in blood culture. N. farcinica is rare post BMT, has a high mortality, is resistant to various antibiotics and needs prolonged antimicrobial therapy. We report the successful management of our patient with single agent trimethoprim-sulphamethoxazole.     

Dependence of insulin secretion from permeabilized pancreatic beta-cells on the activation of Ca(2+)/calmodulin-dependent protein kinase II. A re-evaluation of inhibitor studies

Previous studies utilizing inhibitors of the Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II) to address the role of this enzyme in insulin secretion have produced contradictory results. In the current study, these inconsistencies have been addressed by evaluating the effect of various CaM kinase II inhibitors to decrease Ca(2+)-induced insulin secretion from permeabilized beta-cells. KN-93 (2-[N-(2-hydroxyethyl)-N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlo rocinnamyl)-N-methylbenzylamine) markedly inhibited both CaM kinase II activation and insulin secretion in parallel in alpha-toxin-permeabilized beta-cells. These effects were specific since they were not mimicked by the inactive analog, KN-92 (2-[N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methy lbenzylamine). In contrast, KN-62 (1-[N, O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine) , while reported to be similar to KN-93 with respect to mechanism of action, did not inhibit Ca(2+)-induced activation of CaM kinase II or insulin secretion in these cell preparations. All three agents suppressed Ca(2+) influx in intact beta-cells induced by depolarization in the presence of elevated extracellular potassium although to different extents. The synthetic peptide inhibitors of CaM kinase II, [Ala(286)]CaMK 281-302 and AIP (autocamtide-2-related inhibitory peptide), strongly inhibited Ca(2+)-induced insulin secretion from electropermeabilized islets, an effect that also correlated with an equivalent inhibition of CaM kinase II activation. This re-evaluation (i) explains a lack of effect of KN-62 on insulin secretion from permeabilized cells based on its inability to inhibit CaM kinase II activation in these preparations; (ii) has revealed that CaM inhibitors, either chemical or peptide in nature, that are capable of preventing enzyme activation uniformly suppress Ca(2+)-sensitive insulin secretion; and (iii) cautions the use of KN-62/93/92 as selective inhibitors of CaM kinase II in intact cell studies. These observations reinforce the suggestion that CaM kinase II plays an important role in insulin exocytosis in the beta-cell.     

Surgery for medically intractable temporal lobe epilepsy during early life

PURPOSE: Temporal lobe epilepsy (TLE) in early life is often a catastrophic disorder with pharmacoresistant seizures and secondary neurological deterioration. there is little data available regarding epilepsy surgery performed in infants and young children and no prior study has focused on tle. METHODS: We analyzed the results of temporal resection for epilepsy as the primary indication in children less than age 5 years who had at least 2 years of follow-up. RESULTS: 20 children (14 males) were identified with a mean age at surgery of 26 months and a mean age at seizure onset of 12 months. Clinical presentation was diverse. Typical psychomotor seizures (n = 4; mean age at surgery 37 months) were followed by prominent motor changes (n = 7; 30 months) and were occasionally isolated (n = 3; 23 months). Epileptic spasms were noted in six patients and were frequently associated with lateralizing features. The interictal EEG was lateralizing in 15 patients and the ictal EEG was lateralizing in 18 patients. Brain MRI provided localizing value in 16 patients, ictal SPECT was concordant in 4/8 cases. Invasive EEG was employed in six cases. At mean follow-up of 5.5 years, 65% of the children were seizure-free and 15% had >90% seizure reduction. Morbidity included infection and hydrocephalus in one case and stroke-related hemiparesis in two cases. Cortical dysplasia was identified in eight children, tumors in eight including two DNET, two ganglioglioma, and four malignant tumors. Hippocampal sclerosis was present in four cases, always as dual pathology. CONCLUSION: TLE presents in early life with varied and severe manifestations. Excisional procedures in this age group are associated with favorable seizure reduction similar to older children and in adults.     

Disseminated Emmonsia pasteuriana infection in India: a case report and a review

We report here the first case of disseminated Emmonsia pasteuriana infection in a patient with AIDS in India. The patient presented with weight loss, dyspnoea, left‐sided chest pain and multiple non‐tender skin lesions over face and body for 3 months. Disseminated emmonsiosis was diagnosed on microscopic examination and fungal culture of skin biopsy and needle aspirate of lung consolidation. It was confirmed by sequencing internal transcribed spacer region of rDNA, beta tubulin, actin, and intein PRP8. The patient responded to amphotericin B and itraconazole therapy.     

OBG‐like ATPase 1 inhibition attenuates angiotensin II‐induced hypertrophic response in human ventricular myocytes via GSK‐3beta/beta‐catenin signalling

Obg‐like ATPase 1 (OLA1) that possesses both GTP and ATP hydrolyzing activities has been shown to be involved in translational regulation of cancer cell growth and survival. Also, GSK3β signalling has been implicated in cardiac development and disease. However, the role of OLA1 in pathological cardiac hypertrophy is unknown. We sought to understand the mechanism by which OLA1 regulates GSK3β‐β‐Catenin signalling and its functional significance in angiotensin‐II (ANG II)‐induced cardiac hypertrophic response. OLA1 function and its endogenous interaction with GSK3β/β‐catenin signalling in cultured human ventricular cardiomyocytes (AC16 cells) and mouse hearts (in vivo) was evaluated with/without ANG II‐stimulated hypertrophic response. ANG II administration in mice increases myocardial OLA1 protein expression with a corresponding increase in GSK3β phosphorylation and decrease in β‐Catenin phosphorylation. Cultured cardiomyocytes treated with ANG II show endogenous interaction between OLA1 and GSK3β, nuclear accumulation of β‐Catenin and significant increase in cell size and expression of hypertrophic marker genes such as atrial natriuretic factor (ANF; NPPA) and β‐myosin heavy chain (MYH7). Intriguingly, OLA1 inhibition attenuates the above hypertrophic response in cardiomyocytes. Taken together, our data suggest that OLA1 plays a detrimental role in hypertrophic response via GSK3β/β‐catenin signalling. Translation strategies to target OLA1 might potentially limit the underlying molecular derangements leading to left ventricular dysfunction in patients with maladaptive cardiac hypertrophy.