The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam.

The fear-potentiated startle paradigm has been characterized for drugs that act via ionotropic (NMDA and AMPA/kainate receptor) glutamate receptor mechanisms. Previous studies have shown that the potent systemically active mGlu2/3 receptor agonist, LY354740, effectively reduced the expression of fear-potentiated startle responses in rats. The present study examined the effects of LY354740 in a pre- versus post-fear conditioning paradigm and compared the effects to diazepam. Diazepam (0.3, 0.6, and 1.0 mg/kg ip) attenuated both pre- and post-fear conditioning startle responses in a dose-related manner. In contrast, LY354740 (0.03, 0.3, and 3.0 mg/kg ip) did not disrupt preconditioning startle responses at doses that attenuated post-fear conditioning responses. The benzodiazepine antagonist, flumazenil, at a dose (2 mg/kg sc) that did not alter fear-potentiated startle per se, selectively reversed suppression of fear responses to diazepam (0.6 mg/kg ip) while not affecting fear suppression induced by LY354740 (0.3 mg/kg ip). At a dose of 1 mg/kg ip, the mGlu2/3 receptor antagonist, LY341495, did not disrupt fear-enhanced startle per se, but completely reversed the postconditioning anxiolytic effects of LY354740 in this model. This dose of LY341495 had no effect on fear suppression by diazepam. These results demonstrate that fear suppression by diazepam and LY354740 involves different neuronal mechanisms. While diazepam acts via the facilitation of GABAergic transmission, LY354740 induces its actions via the glutamatergic system, specifically mGlu2/3 receptor activation. Furthermore, in contrast to disruption of fear conditioning as well as fear suppression by diazepam, LY354740 had selective effects on fear expression, suggesting anxiolytic actions without the associated memory impairment.

Prediction of dietary flavonol consumption from fasting plasma concentration or urinary excretion.

OBJECTIVES: to predict flavonols content of the habitual diets of free-living subjects from urine and plasma concentrations of flavonols. DESIGN: Ten type 2 diabetic patients (five male, five female), mean age 60 (s.e.m. 7) y and BMI 30.2 (s.e.m. 3.5) kg/m2 were treated in a random crossover design for a 2 week period on either a low flavonoid diet or on the same diet supplemented at one of two high flavonols levels (total 77.3 or 110.4 mg/day) provided by supplements of 1500 ml tea daily and 400 g fried white onion in olive oil with and without tomato ketchup and herbs. SETTING: Glasgow Royal Infirmary, University of Glasgow, Scotland. MAIN OUTCOME MEASURES: Fasting plasma concentration, urine concentration and 24 h excretion of quercetin, isorhamnetin, kaempferol and myricetin. RESULTS: Plasma flavonol concentration (r=0.750, P=0.001), 24 h urine concentration (r=0.847, P=0.001) and 24 h urine excretion (r=0.728, P=<0.001) were all highly significantly related to dietary intake and gave similar estimates of intakes. Fasting plasma flavonols concentrations on habitual diets ranged from 0 to 43.7 ng/ml mean. Regression equations were constricted: total flavonols intake r=0.74, P<0.001 and quercetin intake r=0.744, P<0. 001. From these equations, flavonol intakes from habitual diets were estimated at 17-50, mean 35 mg/day. Of this, 91% was from quercetin. CONCLUSIONS: Dietary flavonols are absorbed and appear in plasma and urine as potential biomarkers in concentrations related quantitatively to intake. Estimation of dietary intake from plasma or urine concentrations appears possible. SPONSORSHIP: Rank Prize Funds and Rank Foundation of the Department of Human Nutrition; Ministry of Health and Medical Education, IR Iran. European Journal of Clinical Nutrition (2000) 54, 143-149

Dietary flavonols protect diabetic human lymphocytes against oxidative damage to DNA.

Diabetic patients have reduced antioxidant defenses and suffer from an increased risk of free radical-mediated diseases such as coronary heart disease. Epidemiological evidence has suggested that antioxidant dietary flavonoids may protect against heart disease, but a biological effect has yet to be demonstrated directly in humans. In this study, 10 stable type 2 diabetic patients were treated for 2 weeks on a low-flavonol diet and for 2 weeks on the same diet supplemented with 76-110 mg of flavonols (mostly quercetin) provided by 400 g of onions (and tomato sauce) and six cups of tea daily. Freshly collected lymphocytes were subjected to standard oxidative challenge with hydrogen peroxide, and DNA damage was measured by single-cell gel electrophoresis. Fasting plasma flavonol concentrations (measured by high-performance liquid chromatography) were 5.6 +/- 2.9 ng/ml on the low-flavonol diet and increased 12-fold to 72.1 +/- 15.8 ng/ml on the high-flavonol diet (P < 0.001). Oxidative damage to lymphocyte DNA was 220 +/- 12 on an arbitrary scale of 0-400 U on the low-flavonol diet and 192 +/- 14 on the high-flavonol diet (P = 0.037). This decrease was not accounted for by any change in the measurements of diabetic control (fasting plasma glucose or fructosamine) or by any change in the plasma levels of known antioxidants, including vitamin C, carotenoids, alpha-tocopherol, urate, albumin, and bilirubin. In conclusion, we have shown a biological effect of potential medical importance that appears to be associated with the absorption of dietary flavonols.

Doenças respiratórias: em busca da prevençäo / Respiratory disease's: searching the prevention

O Centro de Saúde 24 horas do Jardim Leonor, localiza-se na Zona Oeste de Londrina. O maior índice de morbidade, nessa comunidade, segundo a Oficina de Territorializaçäo, realizada em maio de 1994, säo as doenças respiratórias, o que representa 40 por cento dos diagnósticos diários. Frente a esta constataçäo, buscou-se identificar junto à comunidade, quais säo os problemas respiratórios mais frequentes, sintomas, causas e como elas lidam com essas doenças, objetivando aumentar o seu nível de informaçäo e a possibilidade de um maior cuidado com sua saúde. Foram entrevistados 468 pessoas entre crianças, jovens, adultos e idosos que frequentam a Unidade Básica do Jardim Leonor. Os dados revelaram que: Ivas, bronquite, pneumonia, amigdalite, asma, bronquite asmática, rinite, bronquiolite e bronquiectasia sä os problemas respiratórios apresentados pelos entrevistados. Ivas, bronquite e pneumonia säo as doenças frequentes na maioria das faixa etárias, exceto na de 50 anos ou mais onde asma é predominante sobre pneumonia. Bronquiolite e bronquiectasia estäo presentes apenas na faixa etária de 0-10 anos. Os dados foram devolvidos à Unidade Básica de Saúde (UBS) em uma reuniäo com a equipe e em outra com as mäes que têm seus filhos na Creche do Jardim Leonor. A reuniäo com as mäes teve por objetivos: informá-las sobre causas, sintomas e cuidados com as doenças respiratórias; alertá-las sobre os riscos da automedicaçäo; falar sobre plantas medicinais, como preparar e modo de usar

Creatine kinase. Modification of the working enzyme.

Protection against inhibition of creatine kinase by iodoacetamide is measured by the decrease in the rate constant for the inhibition reaction; A mixture of purified substrates at equilibrium protects quite strongly when all the components of the mixture are nearly saturating. The protection by substrates 'working' in the forward direction only (from creatine and MgATP) was measured by carrying out the experiment rapidly at low concentrations of the enzyme; by varying the concentration of substrate it was found that the amount of protection when the substrates of the forward reaction are saturating is about 80% (100% protection would imply a value of zero for the rate constant of the inhibition reaction). The effects of Ca2+ and Mg2+ are compared. It is already known that the complex creatine-NO3--MgADP, which is considered to be either a transition-state analogue or an analogue of an intermediate in the reaction pathway, protects fully against iodoacetamide, whereas creatine and MgADP alone, or together without NO3-, do not protect. This suggests that the degree of protection by the working enzyme represents the proportion of enzyme molecules that have a conformation complementary to a creatine-PO3-MgADP intermediate.