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Background: Diabetes is global endemic rapidly increasing in both developed and developing countries and is a common secondary cause of hyperlipidaemia in T2DM patients. Diabetic- dyslipidemic patients exhibit atherogenic lipid profile, which greatly increases their CVD risk. Zinc, essential trace element, has significant function in energy metabolism and has been shown to serve a regulatory role in insulin signalling pathway and in supporting structural integrity of endothelial cells. A study designed to assess the plasma zinc status in t2 dm patients and to correlate zinc levels with lipid parameters, CVD markers as well as with glycemic status. Methods: The t2dm patients in the age group 30-60 years were randomly selected and were sub-grouped age wise, glycemic status-wise and diabetic duration-wise. Fasting Glucose, lipid parameters and zinc were estimated and atherogenic Index of Plasma (AIP), Atherogenic Coefficient (AC), and Cardiac Risk Ratio (CRR) were calculated. Results: The results shows levels of glucose, lipid parameters, AIP, AC and CRR are significantly elevated whereas the levels of HDLC and zinc are significantly lowered in t2dm patients and the rises as well as the fall in HDLC and zinc are proportional to glycemic status. Conclusion: It can be concluded from the present study that zinc levels are lower in t2dm patients and is reciprocally related to glycemic status as well as to the diabetic duration. Further the rise in CVD markers is directly proportional to the glycemic status but inversely related to CVD markers. Keywords: t2dm, CVD markers, glycemic status, zinc.

Severe symptomatic tricuspid regurgitation (TR) with right heart failure is associated with significant morbidity and mortality. Medical therapy is often ineffective and surgical correction is not feasible due to prohibitive perioperative risk. Transcatheter caval valve implantation (CAVI) is an evolving therapeutic option for this condition. It refers to the heterotopic placement of a valve into the inferior vena cava alone or with a second valve in the superior vena cava to restrict the backflow from the failing tricuspid valve. We hereby describe a patient with previous mitral valve surgery with chronic severe TR who underwent successful CAVI at our institute.

Background: Stroke is a major cause of morbidity and mortality in an aging population. In the elderly, ischemic stroke accounts for more than 80% of all stroke cases. Stroke is the second leading cause of disability after ischaemic heart disease (IHD) and is the sixth leading cause worldwide. The aim of this study was to evaluate the effects of clopidogrel and aspirin (combination therapy) and aspirin alone (monotherapy for Acute Ischemic Stroke patients. Material and Methods: This is a Prospective, non-randomized and observational study conducted in the Department of General Medicine, Subbaiah Institute of Medical Sciences, Shimoga among 70 acute ischemic stroke patients from January 2019 to September 2019. Clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or aspirin (75 mg per day for 90 days) group.Result: In our study, majority of patients were more than 60 years and least were less than 40 years in both the groups. Predominant were male than female in both the groups. An mRS of 3–6 at 90-day assessment occurred in 3 patients in the clopidogrel-aspirin group, and in 3 patients in the aspirin group (p=0.039). Poor quality of life at 90 days occurred in 1 patients in the clopidogrel aspirin group and in 2 in the aspirin group (p=0.081). Conclusions: For patients with acute Acute Ischemic Stroke, treatment with clopidogrel and aspirin provided significantly greater inhibition of platelet activity than aspirin alone. Thus, dual therapy can be safer and more effective in reducing ischemic stroke recurrence.

Background: Triglycerides (TG) are one of the major constituents of body fat and energy reservoir, which consist of an ester derived from glycerol and three free fatty acids. TG lipase, monoacylglycerol lipase, fatty acid synthase, and HMG-CoA reductase are some of the key enzymes related to TG metabolism, and their roles in colorectal cancer (CRC) initiation and progression are under investigation. Methods: The literature search was performed based on various published papers, mostly on triglyceride metabolism relevant to CRC in PubMed, Google Scholar and other search engines. The gene expression profiling of some of the TG metabolic pathway mediators was performed by transcriptomic and/or proteomic data from The Cancer Genome Atlas (TCGA) database using R program and cBioportal software. Results and Discussion: Accumulating pieces of evidence suggest that TG profiling may be used as a biomarker for the diagnosis and/or prognosis of CRC. Dysregulation of TG metabolism is associated with the initiation and progression of CRC. Most of the TG anabolic pathway mediators are overexpressed and/or overactivated during CRC tumorigenesis, while most TG catabolic pathway mediators are downregulated and/or inactivated based on literature search and correlated with TCGA data. Metabolic enzymes of TG and FAs metabolic pathways are involved in CRC tumor growth survival and metastasis. Conclusion: Overall studies from the previous literature and our TCGA data analysis demonstrated that the area of research on TG-associated lipid metabolic pathways holds great promise and warranted detailed investigations in this area for the implementation of novel preventive and therapeutic strategies against CRC.

Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. The initiation and progression of CRC is a multi-step process that proceeds via precursor lesions to carcinoma, with each stage characterized by its distinct molecular and tissue microenvironment changes. Precursor lesions of CRC, aberrant crypt foci, and adenoma exhibit drastic changes in genetic, transcriptomic, and proteomic profiles compared to normal tissue. The identification of these changes is essential and provides further validation as an initiator or promoter of CRC and, more so, as lesion-specific druggable molecular targets for the precision chemoprevention of CRC. Mutated/dysregulated signaling (adenomatous polyposis coli, β-catenin, epidermal growth factor receptor, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein53, Akt, etc.), inflammatory (cyclooxygenase-2, microsomal prostaglandin E synthase-1, inducible nitric oxide synthase, and other pro-inflammatory mediators), and metabolic/growth factor (fatty acid synthase, β-Hydroxy β-methylglutaryl-CoA reductase, and ornithine decarboxylase) related targets are some of the well-characterized molecular targets in the precision chemoprevention of CRC. In this review, we discuss precursor-lesion specific targets of CRC and the current status of pre-clinical studies regarding clinical interventions and combinations for better efficacy and safety toward future precision clinical chemoprevention. In addition, we provide a brief discussion on the usefulness of secondary precision chemopreventive targets for tertiary precision chemoprevention to improve the disease-free and overall survival of advanced stage CRC patients.

Background and Aim: Mechanisms of glioma progression are poorly understood. Upregulation of calcium-activated potassium channel subunit alpha-1 (KCNMA1), which encodes the α-subunit of maxi-calcium-activated potassium (BKCa) channels, is shown to be a novel mechanism for the malignant phenotype of brain tumor cells. The aim of this study was to establish the functional role of KCNMA1 in glioma biology. Materials and Methods: U-87-MG (U-87) cells were transfected to increase BKCa channel expression and activity. Glioma cell proliferation, invasiveness, and transendothelial migration were then measured. BKCa channels were blocked with iberiotoxin or short hairpin RNA (shRNA), which significantly inhibited K+ currents and growth of U-87 cells. It was tested whether KCNMA1 overexpression enhanced tumorogenecity in glioma xenograft mouse models by injecting wild-type and KCNMA1- overexpressing U87-MG cells. In parallel experiment, it was studied whether shRNA KCNMA1-expressing U-87 cells show attenuated glioma growth in mice. The study protocol was approved by the Institutional Animal Care and Use Committee, Mercer University (A0706007_01), Atlanta, GA, USA on July 20, 2007. Results: The effect of KCNMA1 overexpression in glioma growth as well as on associated cell biology functions such as proliferation, invasion, and migration was presented in this study. Messenger RNA and protein analyses revealed that KCNMA1 was amplified in 90% of high-grade gliomas and in high-grade glioma cell line U-87. In contrast, KCNMA1 amplification was not found in normal brain tissues. These data indicate that KCNMA1 plays critical role in glioma biology by interacting with several cellular processes. The data demonstrate that KCNMA1 amplification drives glioma cell proliferation and growth, which can be attenuated by its downregulation. Conclusion: KCNMA1 is a regulator of glioma cell proliferation and growth and thus qualifies as a promising diagnostic and therapeutic target in the treatment of glioma.

Background This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that has an impact on anticancer therapeutics delivery. We discussed latest breakthroughs in developing pharmaceutical strategies, including nanomedicines and delivering them across BTB for brain tumor management and treatment. Methods We performed an extensive literature search and highlighted important studies on the regulation of BTB permeability with respect to nanotech-based nanomedicines for targeted treatment of brain tumors. We have reviewed research articles that describe the development of specialized molecules and nanospheres, which carry payload of anticancer agents to brain tumor cells across the BBB/ BTB and avoid drug efflux systems. We highlighted research on the identification and development of targeted anti-cancer drug delivery to brain tumors. In addition, we discussed multimeric molecular therapeutics and nanomedicines that were encapsulated in nanospheres for treatment and monitoring of brain tumors. Results In this context, we quoted our research on large conductance calcium-activated potassium channels (BKCa) and ATP-dependent potassium channels (KATP) as portals of enhanced antineoplastic drugs delivery. We showed that several innovative drug delivery agents such as liposomes, polymeric nanoparticles, dendrimers and many such tools can be utilized to improve anticancer drugs and nanomedicines across the BTB to reach brain tumor cells. Conclusion This review might interest both academic and drug company scientists involved in drug delivery to brain tumors. We further seek to present evidence that BTB modulators can be clinically developed as combination drug or/ and as stand-alone anticancer drugs. Eventually, it is expected that unrelenting effort from the scientific community in developing novel drug delivery methods should increase the survival rate of brain tumor patients, which is dismally low presently.

This review focuses on the key issues raised during the International Coronary Congress (ICC) 2016. The left internal thoracic artery and the drug-eluting stents in relation to the left anterior descending artery re-vascularization have been compared and the role of Heart Team stressed upon. The current role of bilateral internal thoracic artery grafting is discussed. The importance of and tools for intra-operative assessment of graft patency have been outlined. The patency and related issues of saphenous vein grafts harvested using the no-touch technique has been discussed in detail. Following the discussion at ICC 2016 and review of literature, we conclude that left internal thoracic artery remains the best option for left anterior descending artery lesions and for left main and ostial or proximal left anterior descending artery lesions. The Heart Team should be approached for decision making. Bilateral internal thoracic artery usage should be encouraged especially in the Indian population which includes a higher proportion of younger patients with a particularly high prevalence of diabetes. Transit time flowmetry is a useful tool to confirm and assess whether intra-operative graft flow and saphenous vein grafts harvested with a no-touch technique have better patency than conventionally harvested vein grafts.

Inflammation is a key hallmark of many cancers and potent target for chemoprevention. Experimental and clinical intervention studies indicate strong cancer preventive efficacy of cyclooxygenase (COX)-2 inhibitors. Their use for chemoprevention is limited due to increased cardiovascular (CV) toxicities. Selective COX-2 inhibition diverts arachidonic acid to the 5-lipoxygenase (5-LOX) pathway resulting in accumulation of prothrombotic leukotrienes while depleting antithrombotic prostaglandin (PG)I2, leading to increased risk of CV events. To overcome side effects, balanced dual inhibitors targeting COX-2/5-LOX or microsomal PGE synthase (mPGES)-1/5-LOX enzymes are being developed for chemoprevention. In this study, the clinically advanced dual COX-2/5-LOX inhibitor, licofelone, and its glycine analogue (LFA-9), the mPGES-1/5-LOX dual inhibitor, were evaluated for colon cancer preventive efficacy in the FAP relevant PIRC rat model. In preclinical dose range finding and preliminary toxicity studies in F344 rats, dietary administration of licofelone Citation Format: Venkateshwar Madka, Nagendra S. Yarla, Gopal Pathuri, Yuting Zhang, Anh Bao, Nicole C. Stratton, Anil Singh, David L. McCormick, Altaf Mohammed, Shizuko Sei, Jennifer Fox, Chinthalapally V. Rao. Colon cancer preventive efficacy of licofelone and its analogue LFA-9 in PIRC rat model of FAP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB225.

We reviewed studies on biology of blood–brain tumor barrier (BTB) permeability regulation in brain tumors. Recent developments in molecular imaging probes using nanotechnology for functional imaging should improve the efficacy of targeted treatment of brain tumors. We reviewed studies of leading researchers who have identified and developed nanomedicines and nanoimaging agents. They have combined specialized molecules and nanospheres to carry pay load of anticancer or imaging agents across the blood–brain barrier or BTB brain tumors. Unique biomarkers on BTB for increased imaging agents’ and anticancer drug delivery to brain tumors were discussed. For instance, we targeted calcium-activated potassium channels (BKCa) and adenosine triphosphate (ATP)-sensitive potassium channels (KATP) for enhanced delivery of antineoplastic drugs and imaging agents. We also discussed nanomedicines and multimeric molecular imaging strategies, including development of peripheral benzodiazepine receptors ligand-PK11195 for better metastatic brain tumor detection. Such agents with flurophores or therapeutics encapsulated in nanospheres are useful in detection of brain tumors, treatment, and monitoring.

Sleep disturbances, as well as sleep-wake rhythm disturbances, are typical symptoms of Alzheimer's disease (AD) that may precede the other clinical signs of this neurodegenerative disease. Here, we describe clinical features of sleep disorders in AD and the relation between sleep disorders and both cognitive impairment and poor prognosis of the disease. There are difficulties of the diagnosis of sleep disorders based on sleep questionnaires, polysomnography or actigraphy in the AD patients. Typical disturbances of the neurophysiological sleep architecture in the course of the AD include deep sleep and paradoxical sleep deprivation. Among sleep disorders occurring in patients with AD, the most frequent disorders are sleep breathing disorders and restless legs syndrome. Sleep disorders may influence circadian fluctuations of the concentrations of amyloid-β in the interstitial brain fluid and in the cerebrovascular fluid related to the glymphatic brain system and production of the amyloid-β. There is accumulating evidence suggesting that disordered sleep contributes to cognitive decline and the development of AD pathology. In this mini-review, we highlight and discuss the association between sleep disorders and AD.

Background: We have previously reported our experience in primary arterial switch operation (ASO) in children more than six weeks with transposition of great arteries and intact ventricular septum (TGA/IVS). The upper age limit for performing an ASO in these children is not yet settled and reports regarding outcome of ASO in these children are few. In this prospective observational study, we report the midterm results of children with TGA-IVS older than six weeks undergoing primary ASO. Methods: A total of 109 children aged more than 6 weeks with median age of 60 days (range 42-3,000 days), with regressed left ventricle underwent primary ASO. Extracorporeal membrane oxygenation was used in 20% (22 of 109) of them; 90.8% (99 of 109) of children who survived were prospectively followed, with a mean follow-up of 28 months (range 18-84 months). Results: Two late deaths occurred, and survival in the remainder was estimated to be 98% at seven years. The incidence of aortic regurgitation (AR) was found to have a decreasing trend with freedom from AR approaching 100% by 34 months. The left ventricular shape and function returned to normal within one to three months following surgery. None of these children had any rhythm disturbances or evidence of myocardial ischemia. Conclusions: Primary ASO can be safely performed in children with regressed ventricle, irrespective of age with encouraging results. The midterm results of these children are comparable in terms of survival and freedom from complications associated with preserved ventricle.

Background: Psoriasis, a chronic skin complication been considered in the recent years by dermatologists as a systemic disease with multi organ abnormalities. Dyslipidemia commonly observed in psoriasis patients may result in cardiovascular complications hence a prompt routine cardiovascular risk evaluation is essential in these patients. A study was designed to assess plasma lipid profile as well as cardiovascular risk markers in psoriasis patients to find out the relationship between cardiovascular risk indicators and psoriasis disease severity.Methods: Study consists of 200 subjects including 100 psoriatics. These psoriatics were sub-grouped based on their increasing PASI score into four groups.Results: The results indicate a significant elevation in lipid parameters and in cadiac risk ratio, atherogenic index of plasma as well as atherogenic coefficient in psoriatics as compared to normal controls. Further a parallel raise has seen in these lipid parameters and risk indicators based on their increasing PASI score.Conclusions: It can be stated from the study results that psoriatics are more affected group for cardiovascular complications and a proper evaluation of cardiovascular risk indicators in these patients is essential in preventing development of cardiovascular risk. Further the risk indicators atherogenic index of plasma and atherogenic coefficient are more promising in evaluating cardiovascular risk in psoriases patients.

were considered and detailed history and general examination was done. Follow up was done to know the duration of the disease with treatment and with placebo. RESULTS: The study shows commonest age group affected to be 11-30 years, with male to female ratio of 2.1:1. The most common type was classical Pityriasis Rosea. Trunk and extremities were the most common sites of lesions. Most cases were seen during the cooler part of the year. The duration of the disease in placebo group was between 8 to 10 weeks, whereas in treatment group it was 4 to 6 weeks. CONCLUSION: The study concludes that Pityriasis Rosea is a self-limiting disease, more common in adolescent to adults with male preponderance, common in cooler part of the year. Erythromycin has reduced the total duration of the disease and signs and symptoms significantly, hence it is effective in Pityriasis Rosea.

OBJECTIVES: To study the incidence, clinical varieties, histopathological findings of PLE and to know its possible relationship to other cutaneous disorders and systemic diseases. METHODS: 70 patients of PMLE were considered and detailed general examination and biopsy of selected patients was done. Follow-up was done to know the prognosis of the patients. RESULTS: The study shows that females are more affected than males with a ratio of 1:2.33 and the maximum incidence in the age group of 11-20 years and minimum in the age group of 51-60 years. The most common form of PLE was papular variant and histopathologically hyperkeratosis and perivascular lymphocytic infiltration was observed in all the specimens. CONCLUSION: The study concludes that PMLE is photosensitive disorder, more common in childhood and adolescents with female preponderance and histopathologically shows non-specific dermatitis.

Introduction Despite considerable benefits associated with current drug-eluting stents, continued attention to the safety, efficacy, and deliverability of available drug-eluting stent has led to the development of newer stent. Methods This study was a single-centre, prospective, non-randomized, first-in-man study which included clinical follow-up data was collected at 1, 8 and 12 months after the procedure. The study included 105 patients with de novo native coronary artery lesions including multi-vessel disease treated with Supralimus-Core® stent. Repeat angiography was performed 8 months post-stent implantation. Results At quantitative coronary angiography 8-month luminal late loss was 0.39 ± 0.33 mm in-stent and 0.33 ± 0.35 mm in-segment. The incidence of any major adverse cardiac event at 30 days, 8 months and 12 months was 1 (1%), 6 (6%) and 7 (7%) respectively. Conclusion This study demonstrates that the Supralimus-Core® SES is a safe and effective treatment for patients with obstructive coronary artery disease. ClinicalTrials.gov ID: NCT00811616 .

Background and Aim: The overexpression and alternative splicing of calcium-activated potassium channel subunit alpha-1 (KCNMA1) that encodes large-conductance calcium-activated voltage-sensitive potassium (BKCa) channels are implicated in the development of human cancers. Dysfunctional angiogenesis in hypoxic tumors is a challenge to intravenous anticancer drug treatments. Hypoxic factors also lead to abnormal vascular functions posing hurdle for anticancer drug delivery to tumors. The aim of this study was to explore the role of BKCachannels in tumor angiogenesis, specifically with regard to release of vascular endothelial growth factor (VEGF). Materials and Methods: We subjected the glioma cells under hypoxia and normoxia and studied the expression and activity of BKCachannels in in vitro and in vivo tumor models. Then, we studied the proangiogenic factor, VEGF, in tumors and monitored the neoangiogenic process. The study protocol was approved by the Institutional Animal Care and Use Committee, Mercer University, Atlanta, GA, USA (approved No. A0706007_01) on July 20, 2007. Results: We presented in vivo and cell based in vitro experimental evidence on the direct and indirect interactions of BKCachannels with VEGF signaling. There was evidence that under hypoxia, glioma cells overexpressed KCNMA1 and increased VEGF secretion. By inhibiting KCNMA1, we showed that VEGF secretion was significantly reduced, thus potentially controlling angiogenesis, which has implications for vascular permeability and anticancer drug delivery. Moreover, there were differences in alternate splicing of KCNMA1 between normal and malignant cells under hypoxia and normoxia. Conclusion: We conclude that BKCachannels regulate hypoxia-induced angiogenesis. Therefore, serious effort is needed to better understand the molecular mechanisms of BKCachannelopathies triggering angiogenesis and progression of glioma. The modulators of BKCachannels could be viable in new anticancer therapeutics.

Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological, clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, naproxen, sulindac, celecoxib, and licofelone), statins and other natural agentsboth individually, and in combinations. Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.

Background: Acne is one of the most common inflammatory chronic skin diseases that affect teenagers and continues into adulthood. Self-medication is common among medical students. Hence this present study was undertaken to study the knowledge, attitude and practice of self-medication for acne among medical students.Methods: This cross-sectional study included medical students of the second phase and final phase (Part I and Part II). A pretested questionnaire was given to them which included questions on knowledge, attitude and practice about self-medication for acne.Results: Self-medication for acne was seen in 240 (77.4%) students out of 310 students. Mild nature of illness was the most common reason for self-medication for acne followed by privacy. Most common source of information was seniors/friends/family members. Most of the students felt that self-medication is part of self-care (48%). Clindamycin was the most common drug self-medicated for acne.Conclusions: Self-medication for acne is quite high among medical students. Self-medication is part of self-care so it should be encouraged for minor illness. But should be based on thorough knowledge and restricted to over the counter drugs.

Three cardo bisphenols containing decahydronaphthalene group viz., 4,4′-(octahydro-2(1H)-naphthylidene)bisphenol, 4,4′-(octahydro-2(1H)-naphthylidene)bis-3-methylphenol and 4,4′-(octahydro-2(1H)-naphthylidene)bis-3,5-dimethylphenol were synthesized starting from commercially available 2-naphthol and were utilized for synthesis of new aromatic polyesters by phase transfer-catalyzed interfacial polycondensation with isophthaloyl chloride, terephthaloyl chloride and a mixture of isophthaloyl chloride and terephthaloyl chloride (50:50 mol %). Inherent viscosities and number average molecular weights (Mn) of polyesters were in the range 0.35–0.84 dL/g and 13,300–48,500 (Gel Permeation Chromatography, polystyrene standard), respectively. Polyesters were readily soluble in organic solvents such as dichloromethane, chloroform, tetrahydrofuran, meta-cresol, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidinone at room temperature and could be cast into tough, transparent and flexible films from their chloroform solutions. Wide-angle X-ray diffraction measurements revealed the amorphous nature of polyesters. The glass transition temperature of polyesters was in the range 207–287 °C. The temperature at 10% weight loss (T10), determined from thermogravimetric analysis of polyesters, was in the range 425–460 °C indicating their good thermal stability.

Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to brain tumors. Previously we have shown that potassium channel agonists increased carboplatin and Her-2 neu antibody delivery in animal glioma models. Here, we studied whether potassium channel agonist increase TMZ and Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial tumor. The K(Ca) channel activity and expression was also evaluated in human glioma tissues. We administered NS-1619, calcium-dependent potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and Herceptin do not cross the BTB in significant amounts, however, NS-1619 co-infusion with [(14)C]-TMZ and Herceptin resulted in enhanced drug delivery to brain-tumor cells. The combination treatment of TMZ and Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit brain tumor patients by increasing anti-neoplastic agent's delivery to brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit brain tumor patients.

Several anticancer drugs are ineffective against brain tumor and do not impact patient survival because they fail to cross the blood-brain tumor barrier (BTB) effective levels. One such agent temozolomide is commonly used in brain tumor patients, which works better when combined with radiation or other anticancer agents. Likewise, trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2/neu over expressing gliomas may work well when combined with temozolomide. Nonetheless, both drugs do not cross the BTB to significantly impact patient survival. Beforehand we showed that potassium channel agonists when intracarotidly administered increased carboplatin and Her-2 antibody delivery in animal glioma models by triggering formation of brain vascular endothelial transcytotic vesicles. In this study, we investigated whether, intravenously administered, ATP-sensitive potassium channel (K(ATP)) activator (minoxidil sulfate; MS) increases temozolomide and Herceptin delivery to brain tumors to induce anti-tumor activity and increase survival in nude mice with Glioblastoma multiforme (GBM) cells. The results clearly demonstrate that when given intravenously temozolomide crosses BTB at a relatively low amount while Herceptin failed to cross the BTB. However, MS co-infusion with [(14)C]-temozolomide or fluorescently labeled-Herceptin resulted in improved and selective drug delivery to brain tumor. We also showed that combination treatment with temozolomide and Herceptin has enhanced anti-tumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with GBM when co-infused with MS. Therefore, brain tumor patients may be benefited when anti-neoplastic agent delivery is increased selectively to the brain tumors using KATP channel agonists.

Nearly 12.5 million new cancer cases are diagnosed worldwide each year. Although new treatments have been developed, most new anticancer drugs that are effective outside the brain have failed in clinical trials against brain tumours, in part due to poor penetration across the blood-brain barrier and the blood-brain tumour barrier. This review will discuss the challenges of drug delivery across the blood-brain barrier/blood-brain tumour barrier to cancer cells, as well as progress made so far. This will include a biochemical modulation strategy that transiently opens the barrier to increase anticancer drug delivery selectively to brain tumours. It will also briefly discuss a quantitative non-invasive method to measure permeability changes and tumour response to treatment in the human brain.

Background The blood-brain tumor barrier (BTB) significantly impedes delivery of most hydrophilic molecules to brain tumors. Several promising strategies, however, have been developed to overcome this problem. Methods We discuss several drug delivery methods to brain tumor, including intracerebroventricular, convection enhanced delivery, BBB/BTB disruption, and BTB permeability modulation, which was developed in our laboratory. Results Using immunolocalization, immunoblotting, and potentiometric studies, we found that brain tumor capillary endothelial cells overexpress certain unique protein markers that are absent or barely detectable in normal capillary endothelial cells. We biochemically modulated these markers to sustain and enhance drug delivery, including molecules of varying sizes, selectively to tumors in rat syngeneic and xenograft brain tumor models. We also demonstrated that the cellular mechanism for vasomodulator-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles that transport therapeutic molecules across the BTB. Conclusions Other methods to deliver drugs across the BTB are effective but have severe drawbacks. Our strategy targets BTB-specific proteins to increase antineoplastic drug delivery selectively to brain tumors with few or no side effects, thus increasing the possibility of improving brain tumor treatment.

The blood-brain tumor barrier (BTB) limits the delivery of therapeutic drugs to brain tumors. We demonstrate in a rat brain tumor (RG2) model an enhanced drug delivery to brain tumor following intracarotid infusion of bradykinin (BK), nitric oxide (NO) donors, or agonists of soluble guanylate cyclase (sGC) and calcium-dependent potassium (K(Ca)) channels. We modulated K(Ca) channels by specific agonists and agents that produce NO and cGMP in situ to obtain sustained enhancement of selective drug delivery to brain tumors. Intracarotid infusion of BK or 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) significantly enhanced BTB permeability (K(i)) to [(14)C]alpha-aminoisobutyric acid in the brain tumor area but not in normal brain tissue. The K(i) increase achieved by BK, NS-1619, NO donors, or the sGC activator 3-(5'-hydroxymethyl-2'furyl)-1-benzylindazole (YC-1) was significantly attenuated when coinfused with a K(Ca) channel antagonist, iberiotoxin. Immunoblot and immunolocalization studies demonstrate overexpression of K(Ca) channels in tumor cells and capillaries compared with normal brain. The potentiometric assays demonstrate the functional activity of K(Ca) channels in rat brain endothelial and glioma cells. Additionally, we show that BK and NS-1619 significantly increased the density of transport vesicles in the cytoplasm of brain tumor capillary endothelia and tumor cells. The cleft indices and cleft area indices in rat tumor capillaries were significantly higher than in normal brain capillaries, and BK infusion did not alter these indices. These data demonstrate that the cellular mechanism for K(Ca) channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport drugs across BTB. We conclude that K(Ca) channels serve as a convergence point in the biochemical regulation of BTB permeability.

Background:Alopecia areata (AA) is one of the common causes of localized hair loss among the patients attending the outpatient department. The objective of this study was to know the clinical and epidemiological profile of AA and to compare the efficacy of different topical treatment modalities in AA.Methods:100 patients of any age group and of both sexes presenting with AA to the dermatology outpatient department were included in this study. It was conducted as a randomized prospective study for a period of 12 weeks after taking an informed consent from the patient. After studying the clinical profile, patients were randomly distributed, excluding the age and sex bias into four treatment groups. Alopecia grading scale (AGS) was calculated at first visit and 12 weeks. Regrowth score (RGS) was calculated at 12 weeks. Treatment outcome in different groups were compared using mean AGS at 12 weeks and RGS.Results:Group A patients showed statistically significant clinical improvement when compared to all the other groups. Poorest response was seen in Group D. Intermediate response was seen in Group B and C patients.Conclusions:The study concluded that topical 0.05% betamethasone dipropionate is the most effective treatment modality in patients with patchy AA (having

Background: It is not surprising that patients hospitalized on nondermatology inpatient services are frequently found to have skin problems and present as a source of confusion for their admitting physicians. Aims and Objective: To analyse the reasons for dermatology referrals and its frequency, departments sending the referral and the impact on health care management.Methods: We conducted a study on 464 patient referrals over a 4‑year period. The demographic details, specialties requesting consultation, cause of referral, and dermatological advice have been recorded and analyzed.Results: Unspecified “skin rash” was the most common dermatologic condition for which skin referral was sought. The final diagnoses made by dermatologists revealed infections as most common skin disorder. Almost 48% of the patients referred as “skin rash” were diagnosed to be suffering from infectious disorders. The referring doctors could provide an accurate dermatological diagnosis only in 32% of cases.Conclusions: Most of the nondermatologists fail to diagnose common skin disorders. This reveals need for more trained dermatologists to combat this problem and more extensive dermatological training for the medical students.

The objective of this study was to investigate the effects of repeated, short-term ischemia on bradykinin-mediated permeability of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB). The mechanism by which bradykinin transiently opens the BTB, involves B2 receptors, Ca2+ flux, nitric oxide (NO) and cyclic GMP (cGMP). Since global and focal cerebral ischemia are known to increase levels of brain nitric oxide synthase (bNOS) and endothelial nitric oxide synthase (eNOS) we tested the hypothesis that bradykinin may increase the BTB permeability to a greater extent under ischemic rather than nonischemic conditions. The vertebral arteries in female Wistar rats were coagulated immediately after intracerebral implantation of RG2 glioma. Short-term ischemia was produced in some rats by a modification of the four-vessel occlusion procedure for incomplete forebrain ischemia, in which the common carotid arteries were clamped daily for 15 min on days 7, 8 and 9 after tumor implantation, after which reperfusion was allowed. On day 10 after tumor implantation, bradykinin (10 microg kg(-1) min(-1)) or phosphate-buffered saline (PBS) was infused for 15 min into the right carotid artery of anesthetized, sham-operated (nonischemic controls) and ischemic rats, followed by an intravenous bolus (100 microCi kg(-1)) each of [14C]-iodo-antipyrine (IAP), [14C]-dextran or [14C]-aminoisobutyric acid (AIB) to measure regional cerebral blood flow (rCBF), blood volume, or unidirectional transfer constant Ki, respectively, by quantitative autoradiography. A single 15-min ischemic episode significantly decreased rCBF in the tumor center (158.9 +/- 17.33 in control vs. 58.78 +/- 24.45 ml 100 g(-1) min(-1) in ischemic group; p0.01) and in the tumor periphery (106.82 +/- 7.34 in control vs. 70.55 +/- 26.66 ml 100 g(-1) min(-1) in ischemic group; p0.05). Respective mean blood volume in tumors (11.7 +/- 13.3, 12.7 +/- 14.0, and 13.3 +/- 14.5 microl g(-1)) from ischemic-PBS, nonischemic-bradykinin, and ischemic-bradykinin groups, respectively, was not significantly different; mean blood volume in normal brain (3.7, 3.1 and 3.8 microl g(-1)) was not significantly different among these groups either. Intracarotid infusion of bradykinin following repeated ischemia significantly increased mean Ki, as compared to bradykinin infusion in nonischemic controls, in both the tumor center (36.60 +/- 8.4 vs. 22.90 +/- 4.61 microl g(-1) min(-1), p0.05) and in tumor periphery (17.70 +/- 5.93 vs. 8.50 +/- 4.42 microl g(-1) min(-1), p0.05). Mean Ki values for tumor center and tumor periphery of ischemic rats receiving intracarotid bradykinin were 3-fold greater than those of nonischemic rats infused with PBS. Immunohistochemical and Western blot analyses showed that repeated, short-term ischemia significantly increased the levels of bNOS in tumor cells and eNOS in tumor capillaries, but neither induced iNOS nor affected B2 receptor levels in tumor cells in vivo, as compared with nonischemic controls. Taken together, these results demonstrate for the first time that repeated, short-term ischemia augments bradykinin-mediated opening of the BTB. We conclude that the elevated intratumoral levels of bNOS and eNOS may 'prime' the NO generating capacity of tumor cells. Consequently, increased de novo synthesis and a correspondingly elevated concentration of NO within the tumor, therefore, may be one mechanistic explanation for the significantly increased, bradykinin-mediated BTB opening under ischemic conditions, reported here.

Localization of B2 receptors in brain tumor cells and microvessel endothelial cells of the brain tumors was investigated to study the differential sensitivity of brain tumors to bradykinin. The present study shows that B2 receptor expression levels vary in cultured RG2, C6 and 9L glioma cells as well as in the intracerebral tumors established with these cell lines in rats. The double immunohistochemical data indicate that B2 receptors are localized to tumor cells and not to the tumor capillaries. Immunostaining and Western blot analysis for B2 receptor showed that the B2 receptor expression was in the order C6 > RG2 > 9L. The permeability studies on RG2, C6 and 9L tumors in rats showed that C6 tumor had the highest increase (178%) in Ki (unidirectional transport across blood-brain barrier (BBB)/blood-tumor barrier (BTB)), while 9L tumor had the least increase of Ki (35%) over the control group, following intracarotid infusion of bradykinin. We found a positive correlation (r = 0.965, p < 0.001) between B2 receptor levels and bradykinin-induced increase in BTB permeability. We conclude that B2 receptors are localized to tumor cells and not to normal or tumor capillary endothelial cells. C6 tumor with highest B2 receptor expression was most responsive to bradykinin, while RG2 and 9L tumors with lower B2 receptor expression level were less sensitive to bradykinin with regard to BTB permeability.

We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram (DSF). These results indicate that BCAL alone decreases GSH content and limits glutathione reductase (GR) activity, and these changes were enhanced by DSF pretreatment. Similar observations were recorded with DSF alone. GR activity (74.3 +/- 4.0 micromol min(-1) mg(-1) tissue; p0.001) and GSH content (1.23 +/- 0.06 micromol min(-1) g(-1) tissue; p0.001) was attenuated in rats subjected to synergistic effect of BCAL and DSF with a concomitant increase of GSSG (0.006 +/- 0.006 micromol min(-1) g(-1) tissue; p0.001). Recovery of GSH/GSSG level and GR activity during reperfusion following 30 min BCAL was considerably delayed (96 h) in the BCAL and DSF group as compared to the recovery time of 24 h in the group subjected to BCAL-reperfusion alone. Perturbation of GSH/GSSG homeostasis as a result of BCAL was augmented by DSF. These findings clearly demonstrate central nervous system oxidative stress due to a BCAL-DSF synergistic effect. Based on the results obtained with this model, we conclude that DSF increases brain oxidative stress and this may be detrimental to alcoholics who might drink and develop an acetaldehyde-induced hypotension while taking DSF.

S -Methyl N , N -diethylthiolcarbamate sulfoxide (DETC-MeSO) and sulfone (DETC-MeSO 2 ) both inhibit rat liver low K m aldehyde dehydrogenase (ALDH 2 ) in vitro and in vivo (Nagendra et al ., Biochem Pharmacol 47: 1465–1467, 1994). DETC-MeSO has been shown to be a metabolite of disulfiram, but DETC-MeSO 2 has not. Studies were carried out to further investigate the inhibition of ALDH 2 by DETC-MeSO and DETC-MeSO 2 . In an in vitro system containing hydrogen peroxide and horseradish peroxidase, the rate of DETC-MeSO oxidation corresponded to the rate of DETC-MeSO 2 formation. Carbamoylation of GSH by both DETC-MeSO and DETC-MeSO 2 was observed in a rat liver S 9 fraction. Carbamoylation of GSH was not observed in the presence of N -methylmaleimide. In in vitro studies, DETC-MeSO and DETC-MeSO 2 were equipotent ALDH 2 inhibitors when solubilized mitochondria were used, but DETC-MeSO was approximately four times more potent than DETC-MeSO 2 in intact mitochondria. In studies with rats, the dose (i.p. or oral) required to inhibit 50% ALDH 2 ( ed 50 ) was 3.5 mg/kg for DETC-MeSO and approximately 35 mg/kg for DETC-MeSO 2 , approximately a 10-fold difference. Furthermore, maximum ALDH 2 inhibition occurred 1 hr after DETC-MeSO administration, whereas maximal ALDH 2 inhibition occurred 8 hr after DETC-MeSO 2 dosing. DETC-MeSO is, therefore, not only a more potent ALDH 2 inhibitor than DETC-MeSO 2 in vivo , but also in vitro when intact mitochondria are utilized. The in vitro results thus support the in vivo findings. Since oxidation of DETC-MeSO can occur both enzymatically and non-enzymatically, it is possible that DETC-MeSO 2 is formed in vivo . DETC-MeSO 2 , however, is not as effective as DETC-MeSO in inhibiting ALDH 2 , probably because it has difficulty penetrating the mitochondrial membrane. Thus, even if DETC-MeSO 2 is formed in vivo from DETC-MeSO, it is the metabolite DETC-MeSO that is most likely responsible for the inhibition of ALDH 2 after disulfiram administration.

Necrotising fasciitis (NF) is a rare infection of the fascial planes, which is less common in head and neck, because of the rarity and higher vascularity in the region. We report a case of necrotising fasciitis in a 43-year-old man, arising from a dental infection treated successfully by early diagnosis, prompt surgical management, antibiotic therapy and adjunctive hyperbaric oxygen (HBO) therapy. The diagnosis of descending NF must always be considered in a patient who presents with a history of oropharyngeal infection with evidence of neck swelling, chest pain, and dyspnea or respiratory distress. Aggressive surgical debridement of all involved tissue along with intravenous antibiotic therapy should be initiated before aerobic and anaerobic cultures are obtained. HBO may also be of some benefit in the treatment of this potentially fatal infection.

Introduction: The inappropriate use of antibiotics has contributed to a worldwide problem of antimicrobial resistance. The objective of present study is to assess the most common microorganisms causing orofacial infections and their antimicrobial susceptibility to routinely used antibiotics in this part of India. Materials and Methods: Sixty eight patients with orofacial infection were selected on the basis of a series of predefined inclusion and exclusion criteria. Samples were collected under aseptic conditions and subjected to culture and antibiotic susceptibility testing. Descriptive statistics were provided. Results: A total of 64 aerobic and 87 anaerobic strains were isolated. The predominant bacteria were Streptococci viridans (64%), Prevotella (43%), Peptostreptococcus (26%), Porphyromonas (7%), and Fusobacterium (14%). The isolated strains seemed to be highly sensitive to the routinely used antibiotics such as amoxicillin - clavulanate and amoxicillin alone, clindamycin, and levofloxacin. In contrast, more resistance to erythromycin was observed. Conclusion: Amoxicillin still possesses powerful antimicrobial activity against major pathogens in orofacial odontogenic infections. Amoxicillin/clavulanate and clindamycin would also be advocated as being useful alternatives for the management of severe orofacial infections. However, the findings of this study indicate that erythromycin is of questionable benefit in the treatment of severe orofacial odontogenic infections.

Introduction: Pneumoperitoneum is a striking feature of hollow viscous perforation and may need of immediate surgical intervention. Blunt trauma chest with pneumoperitoneum without evidence of hollow viscous perforation is unusual and the condition is called spotaneous pneumoperitoneum. Case Presentation: A 29 year male presented to the emergency department after a road traffic accident with hypotension and respiratory distress. Clinically there was surgical emphysema associated with diminished breath sound over left half of the chest and multiple contusions over left hypochondrium and left flank. Bedside X- ray showed fracture of ribs on left side with pneumothorax and air under both the dome of diaphragm. Emergency tube thoracostomy done and respiratory symptoms improved. Further patient evaluated with Ultrasound abdomen and Computerized tomogram of abdomen. Dilated bowels, gross pneumoperitoneum with minimal fluid collection was noted. Diagnostic laparoscopy done to find out hollow viscous perforation or diaphragm injury but to the surprising hollow viscous and diaphragm found to be normal. Case Discussion: Pneumothorax and pnemoperitoneum with presence of abdominal contusions make the surgeon in dilemma for choosing conservative or therapeutic approach. Conclusion: Diagnostic laparoscopy with systemic exploration of abdominal organs and spaces will help in diagnosis and mandatory laparotomy may avoided.

Two bisphenols, viz., 4,4′-[1-(2-naphthalenyl)ethylidene]bisphenol and 4,4′-[1-(2-naphthalenyl) ethylidene]bis-3-methylphenol were prepared by condensation of commercially available 2-acetonaphthanone with phenol and o-cresol, respectively. A series of new aromatic polyesters containing pendent naphthyl units was synthesized by phase-transfer-catalyzed interfacial polycondensation of these bisphenols with isophthaloyl chloride, terephthaloyl chloride, and a mixture of isophthaloyl chloride/terephthaloyl chloride (50 : 50 mol %). Inherent viscosities of polyesters were in the range 0.83–1.76 dL g−1, while number average molecular weights (Mn) were in the range 61,000–235,000 g mol−1. Polyesters were readily soluble in organic solvents such as dichloromethane, chloroform, tetrahydrofuran, m-cresol, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidinone at room temperature. Tough, transparent, and flexible films were cast from a solution of polyesters in chloroform. X-Ray diffraction measurements displayed a broad halo at 2θ ≅ 19° indicating the amorphous nature of polyesters. Glass transition temperatures of polyesters were in the range 209–259°C. The temperature at 10% weight loss (T10), determined by TGA in nitrogen atmosphere, of polyesters was in the range 435–500°C indicating their good thermal stability. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Background The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BKCa) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming α-subunit of BKCa channels in breast cancer metastasis and invasion. Methods We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BKCa channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BKCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX). Results The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BKCa channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1. Conclusion Determining the relative abundance of BKCa channel expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy.

Human herpes virus 6 (HHV-6) has been implicated as a human pathogen in both normal and immunocompromised hosts. It has been associated with interstitial pneumonitis and bone marrow suppression after transplantation. We report here a case of fatal encephalitis in a bone marrow transplant recipient. This case illustrates the importance of considering HHV6 as an emerging pathogen in immunocompromised hosts.

Acamprosate (AC), N-acetyl-homotaurine, has recently been introduced for treating alcohol craving and reducing relapses in weaned alcoholics. AC may exert its action through the taurine system rather than the glutamatergic or GABAergic system. This conclusion is based on the observations that AC strongly inhibits the binding of taurine to taurine receptors while it has little effect on the binding of glutamate to glutamate receptors or muscimol to GABA(A) receptors. In addition, AC was found to be neurotoxic, at least in neuronal cultures, triggering neuronal damage at 1 mM. The underlying mechanism of AC-induced neuronal injury appears to be due to its action in increasing the intracellular calcium level, [Ca2+](i). Both AC-induced neurotoxicity and elevation of [Ca2+](i) can be prevented by taurine suggesting that AC may exert its effect through its antagonistic interaction with taurine receptors.