Extrasynaptic GABA Type A Receptors in the Mechanism of Action of Ethanol

The gamma-aminobutyric acid (GABA) Type A receptor (GABAA-R) mediates the majority of rapid inhibition in the central nervous system and is the site of action for many clinically used drugs. GABAA-R mediated inhibition can occur via the conventional mechanism - the transient activation of synaptic receptors i.e. phasic inhibition, or via continuous activation of extrasynaptic, high affinity receptors by low concentrations of ambient GABA, leading to "tonic" inhibition. The GABAA-R alpha4 subunit is expressed at high levels in the dentate gyrus and thalamus and when partnered with the delta subunit, it is suspected to contribute to tonic inhibition. In vitro studies have found that GABAA-Rs containing alpha4 and delta are highly sensitive to ethanol and to competitive GABAA-R agonists such as gaboxadol and muscimol. In light of these findings, the central hypothesis tested in this thesis was that extrasynaptic GABAA-Rs mediate the depressant effects of these drugs. To provide a model for understanding the precise role of alpha4 containing GABAA-Rs in drug action, mice were engineered to lack the alpha4 subunit by targeted disruption of the Gabra4 gene. alpha4 Subunit knockout mice were viable and superficially indistinguishable from wild-type mice. In electrophysiological recordings, alpha4 knockout mice showed a lack of tonic inhibition in dentate granule cells and thalamic relay neurons. alpha4 knockout mice were also less sensitive to the behavioral effects of gaboxadol and muscimol. However, alpha4 knockout mice did not differ in ethanol-induced changes in anxiety, locomotion, ataxia, coordination, analgesia, or thermoregulation. These data demonstrate that tonic inhibition in dentate granule cells and thalamic relay neurons is mediated by extrasynaptic GABAA-Rs containing the alpha4 subunit and that gaboxadol and muscimol likely achieve their effects via the activation of this GABAA-R subtype. These data also suggest that GABAA-Rs containing the alpha4 subunit are not necessary for many acute behavioral responses to ethanol

India and the International Crops Research Institute for the Semi-Arid Tropics: A Study of Their Collaboration in Agricultural Research

A study of the Indian Council for Agricultural Research (ICAR), its institutes, centers, and projects, and the impacts of their collaboration with ICRISAT in promoting Indian national research capacity and raising agricultural production in the semi arid and dry zones of the country. The study also addresses the roles and contributions of India's twenty three agricultural universities, and of the National Academy for Agricultural Research Management in education, training, and extension.Written by Ishwar Chandra Mahapatra, Dev Raj Bhumbla, and Shriniwas Dattatraya Bokil

Distribution, Composition Profiles and Source Identification of Polycyclic Aromatic Hydrocarbons in Roadside Soil of Delhi, India

Distribution, composition profiles and sources of polycyclic aromatic hydrocarbons (PAHs) were evaluated in roadside soils from Delhi, India. PAH determination was made by Sonication extraction and chromatographic clean-up with final analysis by high performance liquid chromatography with ultraviolet-diode array detector (HPLC-UV-DAD).The average concentration of ∑PAHs was 6838.6±3528.4 µg kg-1 and ranged between 81.6 to 45017.4 µg kg-1. Seven possible carcinogenic PAHs (7c-PAHs) accounted 67.4% to the total PAHs. Diagnostic ratios of individual PAHs and LMWPAHs to HMWPAHs ratio were calculated and applied to assess the possible sources of PAHs which, indicates the mixed pyrogenic activities such as petroleum, biomass and coal combustion are the main contributors. Although, concentrations of individual PAHs were lower than the guideline values but, the concentrations of some high molecular weight PAHs were higher at the locations in the vicinity of industrial areas and there is probable some risk to human health. Keywords: Polycyclic aromatic hydrocarbons (PAHs), HPLC-UV, roadside soil, diagnostic ratio, Indi

Profiles of gall bladder cancer reported in the hospital cancer registry of a Regional Cancer Center in the North-East India

Background: The incidence of gall bladder cancer (GBC) is very high in this part of the world and there is little information on the descriptive epidemiology of GBC from our population.Methods: A retrospective study on the data set of hospital cancer registry was analyzed. The data set consisted of patient information registered during the period of January 2011 to December 2012. The cases included for the present study were histologically confirmed and radiologically diagnosed cases of GBC. All the cases were retrospectively analyzed for gender, age, urban-rural residences, religion of patients and their educational levels. Descriptive statistics was calculated and Chi square test was done to see the significance differences among categories.Results: A total of 837 cases of GBC were registered, F:M was 2.33, median age in females and males was 54 and 50 years respectively, majority of cases in both the genders were seen in 50-59 years of age, 81.1% patients were from rural areas and 18.8% from urban areas, Chi square on comparison with other cancers showed p<0.05, and there was no major religious and educational pattern of GBC seen in our population.Conclusion: In our population females are at high risk especially past 40 years of age and rural population with its varied environmental, lifestyles and infective agents should be investigated for possible risk factor in the causation of GBC.

Value of urinary microalbumin test in cancer patients with borderline serum creatinine level

Background: Micralbuminuria (MA) is an early sign of incipient renal damage and cancer patients are at the risk of developing kidney diseases due to the use of nephrtoxic chemotherapeutic agents.Methods: A pilot study of urinary microalbumin on 41 patients with borderline serum creatinine was carried out at regional cancer centre of North-East India during the period from June to August 2014. The patients whose serum creatinine levels were between 1.2 mg/dl to 1.3 mg/dl were considered as borderline for the present study. The assays were performed with a dimension Rxl max random access biochemistry analyzer.Results: Out of 41 cases, 22 (53.6%) had MA, M:F = 1.75, 65 years 2 (9.0%) patients were detected with urinary microalbumin. Chi square test showed P = 0.695 (Fisher’s exact P value).  Conclusion: Testing of urinary microalbumin can be done in cancer patients with borderline serum creatinine level in order to identify patients at risk of developing kidney disease.

Correlation between ABO blood groups and various cancers in the north eastern region of India: a retrospective observational study

Background: Numerous studies have documented the association of the ABO blood groups with the occurrence of cancers. Aim was to find out an association of ABO blood groups and various cancers in the North Eastern region of India.Methods: The study was a retrospective observational study that included 1000 cases and 1000 controls. The data included the ABO blood typing of the selected cancer sites which were head and neck, esophagus, stomach, breast, cervix, and ovary. Patients who attended blood bank of regional cancer center with requisition for blood transfusion from 2014 to 2016 were included. The control group was healthy blood donors. Chi square test was used to assess the difference among the compared groups. Risk was calculated by regression analysis. P value <0.05 was considered as statistically significant at 95% confidence interval.Results: Out of 1000 cases and 1000 controls, O blood group were seen in 377 (37.7%) and 395 (39.5%) cases and control, respectively. Significant reduced odds ratio (OR) in non O blood groups for head and neck, esophagus, stomach, and breast was observed. In case of carcinoma cervix, OR for B group was 1.5 (P=0.05), and for blood group A OR=2.2 (P=0.02) was seen in carcinoma ovary.Conclusions: In the studied population, patients with O blood group are at an increased risk of developing head and neck, esophagus, stomach, and breast cancers

Rosai-Dorfman disease in a child with involvement of extra-nodal wrist joint

Rosai-Dorfman Disease (RDD) is a benign condition primarily affecting the lymph nodes. The term sinus histiocytosis with massive lymphadenopathy was first used. There may be extra-nodal presentation of RDD with or without constitutional symptoms. A 10-year-old boy presented with massive bilateral cervical lymphadenopathy which mimicked the diagnosis of lymphoma. We describe here a case of RDD in a child with extra-nodal bone involvement of the wrist joint, its diagnosis by histopathological examination supported by immunohistochemistry and consequent initial management

GABA(A )receptor γ2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines

BACKGROUND: Gamma-aminobutyric acid type A receptors (GABA(A)-Rs) are the major inhibitory receptors in the mammalian brain and are modulated by a number of sedative/hypnotic drugs including benzodiazepines and anesthetics. The significance of specific GABA(A)-Rs subunits with respect to behavior and in vivo drug responses is incompletely understood. The γ2 subunit is highly expressed throughout the brain. Global γ2 knockout mice are insensitive to the hypnotic effects of diazepam and die perinatally. Heterozygous γ2 global knockout mice are viable and have increased anxiety-like behaviors. To further investigate the role of the γ2 subunit in behavior and whole animal drug action, we used gene targeting to create a novel mouse line with attenuated γ2 expression, i.e., γ2 knockdown mice. RESULTS: Knockdown mice were created by inserting a neomycin resistance cassette into intron 8 of the γ2 gene. Knockdown mice, on average, showed a 65% reduction of γ2 subunit mRNA compared to controls; however γ2 gene expression was highly variable in these mice, ranging from 10–95% of normal. Immunohistochemical studies demonstrated that γ2 protein levels were also variably reduced. Pharmacological studies using autoradiography on frozen brain sections demonstrated that binding of the benzodiazepine site ligand Ro15-4513 was decreased in mutant mice compared to controls. Behaviorally, knockdown mice displayed enhanced anxiety-like behaviors on the elevated plus maze and forced novelty exploration tests. Surprisingly, mutant mice had an unaltered response to hypnotic doses of the benzodiazepine site ligands diazepam, midazolam and zolpidem as well as ethanol and pentobarbital. Lastly, we demonstrated that the γ2 knockdown mouse line can be used to create γ2 global knockout mice by crossing to a general deleter cre-expressing mouse line. CONCLUSION: We conclude that: 1) insertion of a neomycin resistance gene into intron 8 of the γ2 gene variably reduced the amount of γ2, and that 2) attenuated expression of γ2 increased anxiety-like behaviors but did not lead to differences in the hypnotic response to benzodiazepine site ligands. This suggests that reduced synaptic inhibition can lead to a phenotype of increased anxiety-like behavior. In contrast, normal drug effects can be maintained despite a dramatic reduction in GABA(A)-R targets

Ultrasound guided fine needle aspiration cytology of gall bladder mass and mural thickening: a radio-pathological correlation

Background: Carcinoma of the gall bladder (GB) is the commonest malignancy of the biliary tract. Ultrasound (US) guided Fine Needle Aspiration Cytology (FNAC) plays a major role in early detection of malignancy in a suspicious GB lesion. The aim of this study was to evaluate the safety and diagnostic accuracy of US guided FNAC in detection of GB malignancy, to find the association of gall stones with GB malignancy, to study the ultrasound pattern of GB malignant mass and demographic profile of the disease in North eastern India.Methods: The study was conducted retrospectively in Dr. B. Borooah Cancer Institute, Guwahati from January 2016 to December 2017. A total number of 173 patients suspected to have GB malignancy were subjected to US guided FNAC.Results: Total 161 patients were positive for malignancy with significant female majority. There were 124 female (77.02%) and 37 males (22.98%) in the range of 29 to 82 years. Male female ratio was 1:3.5. One was diagnosed as xanthogranulomatous cholecystitis and another was chronic cholecystitis. FNAC remained inconclusive in 2 patients. There was no major procedure related complication. Adenocarcinoma was the most common malignancy found in 146 patients (98.68%). Cholelithiasis was associated in 88.19% of malignant lesions.Conclusions: US-guided FNAC is a safe, highly accurate and reliable procedure for early detection of GB malignancy