Neurochemical mechanisms of nitroglycerin-induced neuronal activation in rat brain: a pharmacological investigation

Nitroglycerin is a nitric oxide donor which induces sustained expression of Fos protein, a marker of neuronal activation, in specific neuronal groups in the central nervous system. The mechanisms which underlie nitroglycerin-induced neuronal activation are elusive at this time, although a precise role has been suggested for the pool of neurons containing nitric oxide synthase as well as for catecholaminergic and peptidergic pathways. The aim of this study was to provide further details on the central effect of nitroglycerin by means of a pharmacological manipulation of nitroglycerin-induced neuronal activation with inhibitors of the nitric oxide synthase, modulators of the sympathetic drive and mediators of pain perception. Adult male Sprague-Dawley rats received L-NGnitro-arginine methyl ester, 7-nitro-indazole, ephedrine sulfate, indomethacin, capsaicin or vehicle before the subcutaneous injection of nitroglycerin (10 mg/kg b.w.). They were sacrificed 4 hr after nitroglycerin administration and brain sections were processed for immunocytochemical visualization of Fos. All the pharmacological treatments administered before injecting nitroglycerin selectively influenced Fos expression in the different brain nuclei. The data obtained suggest that nitroglycerin-induced neuronal activation is mediated by nociceptive and barosensitive mechanisms. Nitric oxide seems to represent the most important mediator of this phenomenon. The sympathetic system and prostaglandin synthesis are also likely to be involved.     

Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: The objective of this study was to evaluate the effects of daily dietary supplementation with 1.25 g or 2.5 g of docosahexaenoic (DHA), in the absence of eicosapentaenoic acid (EPA), on serum lipids and lipoproteins in persons with combined hyperlipidemia (CHL) [serum low-density lipoprotein cholesterol (LDL-C) 130 to 220 mg/dL and triglycerides 150 to 400 mg/dL]. METHODS: After a 6-week dietary stabilization period, subjects entered a 4-week single-blind placebo (vegetable oil) run-in phase. Those with adequate compliance during the the run-in were randomized into one of three parallel groups (placebo, 1.25, or 2.5 g/day DHA) for 6 weeks of treatment. Supplements were administered in a triglyceride form contained in gelatin capsules. Primary outcome measurements were plasma phospholipid DHA content, serum triglycerides, high-density lipoprotein cholesterol (HDL-C). LDL-C and non-HDL-C. RESULTS: The DHA content of plasma phospholipids increased dramatically (2 to 3 fold) in a dose-dependent manner. Significant (p < 0.05) changes were observed in serum triglycerides (17 to 21% reduction) and HDL-C (6% increase) which were of similar magnitude in both DHA groups. Non-HDL-C [+1.6 (NS) and +5.7% (p < 0.04)] and LDL-C [+9.3% (NS) and +13.6% (p < 0.001)] increased in the DHA treatment groups. All lipid effects reached an apparent steady state within the first 3 weeks of treatment. CONCLUSION: Dietary DHA, in the absence of EPA, can affect lipoprotein cholesterol and triglyceride levels in patients with combined hyperlipidemia. The desirable triglyceride and HDL-C changes were present at a dose which did not significantly increased non-HDL-C or LDL-C. These preliminary findings suggest that dietary supplementation with 1.25 g DHA/day, provided in a triglyceride form, may be an effective tool to aid in the management of hypertriglyceridemia.     

Delta9-tetrahydrocannabinol activates [Ca2+]i increases partly sensitive to capacitative store refilling

Delta9-tetrahydrocannabinol induces [Ca2+]i increases in DDT1MF-2 smooth muscle cells. Both Ca2+ entry and release from intracellular Ca2+ stores were concentration dependently activated. The Ca2+ entry component contributed most to the increases in [Ca2+]i. Stimulation with delta9-tetrahydrocannabinol after functional downregulation of intracellular Ca2+ stores by longterm thapsigargin treatment, still induced a major Ca2+ entry and a minor Ca2+ release component. Thapsigargin sensitive influx and release were selectively inhibited by the cannabinoid CB1 receptor antagonist SR141716A. No effects on [Ca2+]i were obtained after stimulation with the CB2 receptor agonist palmitoylethanolamide. This study is the first demonstration of (1) Ca2+ release from thapsigargin sensitive intracellular stores and capacitative Ca2+ entry via CB1 receptor stimulation and of (2) an additional delta9-tetrahydrocannabinol induced thapsigargin insensitive component, mainly representing Ca2+ influx which is neither mediated by CB1 nor CB2 receptor stimulation.     

A conducting salt-based amperometric biosensor for measurement of extracellular lactate accumulation in ischemic myocardium

In this paper, fabrication, characterization, and physiological application of a miniaturized amperometric lactate biosensor are described. The sensor is based on cross-linked lactate oxidase and tetrathiafulvalene-tetracyano-quinodimethane (TTF-TCNQ) charge transfer complex. The sensor was developed for continuous quantitative measurement of the lactate accumulation in ischemic myocardium under severe depletion of oxygen. The sensor was evaluated in vitro at an applied potential of 0.15 V vs Ag/AgCl; it proved to combine all the performance characteristics desired for the present application, such as proper response in absence of oxygen, good operational stability, good accuracy and precision (103.5 +/- 1.2%), adequate response time (t95% = 80 s), and wide linear dynamic range up to 27 mM (r = 0.9998) in N2-saturated solutions and at 37 degrees C. The prepared sensors (n = 12) showed sensitivity of 380 +/- 90 nA/mM, and a background current of 240 +/- 50 nA. The lower limit of detection is 0.4 +/- 0.15 mM with a S/N ratio equal to 3. Results obtained for direct lactate monitoring in ischemic rabbit papillary muscle under no-flow conditions and PO2 < 6 mm Hg are presented.     

Social phobia: long-term treatment outcome and prediction of response--a moclobemide study

In this open, prospective, structured, naturalistic study of the efficacy of long-term treatment in social phobia 93 consecutive outpatients suffering from severe generalized or circumscribed social phobia (median Liebowitz Social Anxiety Scale score 83) and a high degree of concomitant psychiatric disease were administered treatment with moclobemide (712 +/- 75 mg/day at steady state). Fifty-nine patients who responded (Clinical Global Impression for Change: very much/much improved) completed 2 years of treatment. Patients then entered a drug-free period of at least 1 month during which 88% of the patients deteriorated. In a further 2-year treatment period with moclobemide those patients who had deteriorated became responders again. Symptoms recurred in a substantial number of the patients at the end of the study when the dose was reduced and then discontinued. Post-study follow up at 6-24 months after study completion found that 63.2% of patients were almost asymptomatic or had only mild symptoms, 15.8% were off all treatment, 28.1% were back on moclobemide, 10.6% were taking another psychotropic drug and 8.8% were in psychotherapy. All previous non-responders to moclobemide and mostly alcohol abusers (36.9%), had moderate or severe social phobia and were off all treatment (13.3%), on psychotherapy (15.9%) or on another psychotropic drug (8.8%). Discriminant analysis correctly predicted outcome in 93.5% of all patients. Alcohol abuse was by far the strongest predictor of negative outcome. Coexisting generalized anxiety disorder and dysthymia were less potent in this regard, whereas high baseline Hamilton anxiety or depression scale scores, circumscribed social phobia, or social phobia unassociated with avoidant personality disorder were predictors of a positive outcome. In conclusion, severe social phobia can be successfully treated in the long-term but many patients may need medication or psychotherapy for many years. Treatment should start as early as possible because complications such as alcohol abuse make treatment difficult.     

Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery

This study assesses the reliability of a self-reported health questionnaire completed by 413 subjects aged 25-74 yr in the Erie County Periodontal Disease (ECPD) Study. Specific questions on general and oral health conditions were completed by each subject during a first visit and at a follow-up examination 2 yr later, and the two compared. Results showed that the overall measure of agreement between the two visits is substantial (average kappa, kappa = 0.80). Variation by gender and age were minimal. Questions regarding allergy to medications, oral treatment, reason for tooth extraction, health symptoms and history of systemic diseases exhibited high levels of agreement (kappa ranged from 0.71-0.90). Information on vitamin and mineral intake yielded kappa = 0.63. Oral conditions scored the lowest but were still acceptable (kappa = 0.57). These findings indicate that there were no significant discrepancies in self-reported responses to the health questionnaire used in the ECPD Study. Although the information provided by the subject may not be as accurate as compared to laboratory testing, it is nevertheless a reliable source of information which can be utilized cost-effectively in research studies.     

Hormone replacement therapy and other potential treatments for dementias

The past decade has seen a substantial increase in the number of individuals affected by dementia. Dementia places a tremendous personal and economic burden on millions of patients and caregivers annually. Consequently, many scientists have been searching for a treatment for dementia to avoid the imminent public health crisis that will occur if this trend continues. Primary and secondary prevention studies, as well as animal research, demonstrate the potential for hormone replacement therapy (HRT) as an efficacious treatment for dementia. Recently, the Women's Health Initiative-Memory Study began the first randomized, longterm clinical trial to test the hypothesized role of HRT at the onset and in the progression of dementia in women. Researchers also are investigating the potential of other treatments for dementias, such as nonsteroidal anti-inflammatory drugs and free radical scavengers.     

Deletion mapping of two potential chromosome 14 tumor suppressor gene loci in ovarian carcinoma

Previous allelotyping studies of epithelial ovarian carcinoma suggest that loss of heterozygosity on chromosome 14q may be a common genetic alteration in this tumor type. The purpose of this study was to determine a precise frequency of chromosome 14q allelic loss in ovarian carcinomas and to define a minimal region(s) of deletion. Seventy-six ovarian carcinomas representative of the complete spectrum of grade, stage, and histological subtype were selected for PCR-based deletion mapping analysis using 15 highly polymorphic microsatellite markers spanning the length of this chromosome arm. Loss of heterozygosity was observed in 49% of the tumors studied, placing 14q among the most frequently affected chromosomal regions in ovarian cancer. Deletions were observed in all tumor grades and stages and in all histological subtypes except tumors of low malignant potential. Deletion of the entire chromosome arm was rare; the majority of tumors displayed partial losses, providing an informative basis for detailed deletion mapping. Two distinct minimal regions of deletion were delineated. One region was defined by markers D14S80 and D14S75 at 14q12-13, and the other region was defined by markers D14S65 and D14S267 at 14q32. These data implicate the involvement of two tumor suppressor genes on chromosome 14q in a substantial fraction of ovarian carcinomas.     

Angiotensin II receptor blockade in Syrian hamster (T0-2) cardiomyopathy does not affect microscopic cardiac material properties: implications for mechanisms of tissue remodeling

This study delineates the role of angiotensin II type I (AT1) receptor in the remodeling of Syrian cardiomyopathic hamsters. Twelve cardiomyopathic (T0-2) hamsters received L-158,809 treatment and libitum in their drinking water (27 micrograms/ml) and 9 cardiomyopathic and 9 normal FL-B hamsters received tap water from 1 to 4 months of age. Although pharmacologically effective with regard to complete suppression of the blood pressure response to angiotensin II infusion, L-158,809 did not diminish the progression or severity of cardiomyopathy. Heart weight/100 g body weight and left ventricular wall thickness adjusted for body weight of both L-158,809 and cardiomyopathic control hamsters did not differ and exceeded those of F1-B controls (p < 0.05). Myocardial material properties (e.g., stiffness and density) of cardiomyopathic hamsters treated with L-158,809 were not affected. Thus, the progression of fibrosis, calcification, and necrosis in T0-2 cardiomyopathic hamsters was not sensitive to AT1 receptor blockade.     

Adulthood functioning: the joint effects of parental alcoholism, gender and childhood socio-economic stress

The popular literature has publicized the adjustment difficulties of adult children of an alcohol-dependent parent (ACOAs); however, empirical studies do not provide consistent support. We examined the impact of parental alcoholism, degree of childhood socio-economic stress and gender on three broad categories of adulthood functioning (psychopathology, socio-economic attainment and marital stability). These effects were investigated with a heterogeneous sample of 400 men and 226 women participating in studies at the University of Michigan Alcohol Research Center. Parental alcoholism and childhood socio-economic stress exerted significant independent effects on most adulthood functioning measures. Men and women differed substantially only on socio-economic attainment measures, and effects of parental alcoholism and childhood economic stress on men and women were generally similar. For marital stability, parental alcoholism and childhood socio-economic stress interacted. These results suggest that researchers who study the impact of family history for alcoholism on psychological functioning should consider other aspects of the family of origin that promote wellbeing. In addition, results of this study point to the need for more research on gender differences, protective factors that promote good adjustment and outcome measures reflecting general life adaptation.