Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications.

Activation of cell surface death receptors by their cognate ligands triggers apoptosis. Several human death receptors (Fas, TNF-R1, TRAMP, DR4, DR5, DR6, EDA-R and NGF-R) have been identified. The most promising cytokine for anticancer therapy is TRAIL/APO-2L, which induces apoptosis in cancer cells by binding to death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. The cytotoxic activity of TRAIL is relatively selective to cancer cells compared to normal cells. Signaling by TRAIL and its receptors is tightly regulated process essential for key physiological functions in a variety of organs, as well as the maintenance of immune homeostasis. Despite early promising results, recent studies have identified several TRAIL-resistant cancer cells of various origins. Based on molecular analysis of death-receptor signaling pathways several new approaches have been developed to increase the efficacy of TRAIL. Resistance of cancer cells to TRAIL appears to occur through the modulation of various molecular targets. They may include differential expression of death receptors, constitutively active Akt and NFkappaB, overexpression of cFLIP and IAPs, mutations in Bax and Bak genes, and defects in the release of mitochondrial proteins in resistant cells. Conventional chemotherapeutic and chemopreventive drugs, and irradiation can sensitize TRAIL-resistant cells to undergo apoptosis. Thus, these agents enhance the therapeutic potential of TRAIL in TRAIL-sensitive cells and sensitize TRAIL-resistant cells. TRAIL and TRAIL-receptor antibodies may prove to be useful for cancer therapy, either alone or in association with conventional approaches such as chemotherapy or radiation therapy. This review discusses intracellular mechanisms of TRAIL resistance and various approaches that can be taken to sensitize TRAIL-resistant cancer cells.     

A three-year naturalistic follow-up of patients receiving clozapine: Report from India

INTRODUCTION: Clozapine is a first-line drug for treatment-resistant schizophrenia, but studies dealing with long-term outcome are lacking, so we decided to carry out such a study. METHODS: Patients with treatment-resistant schizophrenia who were recruited in an open-label study three years ago were re-evaluated using the same parameters: BPRS, PANSS and a side-effect rating checklist. RESULTS: Nineteen out of 25 patients who participated in the initial study were available for re-evaluation. Two patients had changed to conventional neuroleptic medication, and were excluded from the study. A significant reduction in psychopathology was observed in 85% of patients. An improvement in social functioning was evident, with seven patients pursuing a career independently, and another six working with their family members since being started on clozapine. All the patients were on clozapine monotherapy, and the average daily dose was 248.21 mg. No patient required hospitalization and there was no incidence of granulocytopenia. CONCLUSIONS: A significant improvement in the psychopathology and social functioning of patients was observed with much lower doses of clozapine than has been reported elsewhere. The doses used for maintenance were lower than those used in the acute phase of treatment. (Int J Psych Clin Pract 2002; 6: 167-171 )     

Injury to the oral mucosa by organophosphates without systemic toxicity: a rare case

We describe a case of multiple Zargar grade IIA ulcerations of the oral mucosa with no systemic toxicity in a patient after ingestion of an organophosphate. Serial debridement, control of superadded infections, and active physiotherapy were the mainstay of the treatment plan. We know of no other reported cases of poisoning by organophosphates that caused burns of the oral mucosa and no systemic toxicity.     

An evaluation of microleakage of various glass ionomer based restorative materials in deciduous and permanent teeth: An in vitro study

AimTo evaluate the microleakage of recently available glass ionomer based restorative materials (GC Fuji IX GP, GC Fuji VII, and Dyract) and compare their microleakage with the previously existing glass ionomer restorative materials (GC Fuji II LC) in primary and permanent teeth.MethodOne hundred and fifty (75 + 75) non-carious deciduous and permanent teeth were restored with glass ionomer based restorative materials after making class I cavities. Samples were subjected to thermocycling after storing in distilled water for 24 h. Two coats of nail polish were applied 1 mm short of restorative margins and samples sectioned buccolingually after storing in methylene blue dye for 24 h. Microleakage was assessed using stereomicroscope.ResultSignificant differences (P < 0.05) were found when inter group comparisons were done. Except when GC Fuji VII (Group III) was compared with GC Fuji II LC (Group II) and Dyract (Group IV), non-significant differences (P > 0.05) were observed. It was found that there was no statistically significant difference when the means of microleakage of primary teeth were compared with those of permanent teeth.ConclusionsGC Fuji IX GP showed maximum microleakage and GC Fuji VII showed least microleakage.     

Differences Between Dendritic Spines of Neurons of Different Regions of the Cerebral Cortex of the Garden Lizard, C. versicolor (Daudin)

The present study, based on neurohistological techniques (Golgi impregnation), focuses on the morphological and numerical changes in the dendritic spines of neuronal classes of the cerebral cortex in Calotes versicolor. The cerebral cortex in reptiles occupies the roof of the cerebral hemisphere and is divided into four regions viz. medial, dorsomedial, dorsal and lateral cortex. Using different characteristics such as criteria of location, dendritic tree pattern, dendritic spine covering and soma shape different neuronal types have been distinguished in the cell layer-II of medial, dorsomedial, dorsal and lateral cortex. The dendritic diameter, spine length and diameter of spine head show almost uniform pattern in all cortical regions except being slightly higher in case of the neurons of dorsomedial cortex. The multipolar and pyramidal neurons show higher dendritic diameter, spine length, spine head diameter and dendritic spine density in comparison to other neurons. The density of these neurons acts as the indicator of high or low activity of a particular region.     

Evaluation of quantitative variation of secondary metabolites in Bergenia ciliata （Haw.） using high performance thin layer chromatography

Dear Editor： Therapeutically active metabolite contents in a med- icinal plant vary in nature, which may impact on its therapeutic efficacy. Bergenia （Saxifragaceae） is an evergreen perennial herb widely distributed in Central and East Asia with about 30 species reported worldwide. It grows at a range of altitudes from the Khasia hills at 400 feet to the temperate Himalayas from Kashmir to Bhutan at 7,000-10,000 feet. Its distribution over a wide range of altitudinal zones makes it a good candidate for studying variations in its metabolic profiles under different climatic conditions. Bergenin （C-glycoside of 4-O-methyl gallic acid） has been identified as a potent active secondary metabolite in Bergenia and other therapeutically active constituents including, among others, gallic acid （3,4,5 trihydroxybenzoic acid）, （＋） catechin, and gallicin （Fig. 1）.