Effects of resistive training and chromium picolinate on body composition and skeletal muscle size in older women

This study assessed the effect of resistive training (RT), with or without highdose chromium picolinate (Cr-pic) supplementation, on body composition and skeletal muscle size of older women. Seventeen sedentary women, age range 54-71 years, BMI 28.8 +/- 2.4 kg/m2, were randomly assigned (double-blind) to groups (Cr-pic, n = 9; Placebo, n = 8) that consumed either 924 micrograms Cr/d as Cr-pic or a low-Cr placebo (< 0.2 microgram Cr/d) during a 12-week RT program (2 day/week, 3 sets.exercise-1.d-1, 80% of 1 repetition maximum). Urinary chromium excretion was 60-fold higher in the Cr-pic group, compared to the Placebo group (p < .001), during the intervention. Resistive training increased maximal strength of the muscle groups trained by 8 to 34% (p < .001), and these responses were not influenced by Cr-pic supplementation. Percent body fat and fat-free mass were unchanged with RT in these weight-stable women, independent of Cr-pic supplementation. Type I and type II muscle fiber areas of the m. vastus lateralis were not changed over time and were not influenced by Cr-pic supplementation. These data demonstrate that high-dose Cr-pic supplementation did not increase maximal strength above that of resistive training alone in older women. Further, these data show that, under these experimental conditions, whole body composition and skeletal muscle size were not significantly changed due to resistive training and were not influenced by supplemental chromium picolinate.     

A study of P2X1 receptor function in murine megakaryocytes and human platelets reveals synergy with P2Y receptors

We have examined the role of ATP-dependent P2X(1) receptors in megakaryocytes (MKs) and platelets using receptor-deficient mice and selective agonists. Alpha,beta-meATP- and ATP- evoked ionotropic inward currents were absent in whole-cell recordings from MKs of P2X(1)(-/-) mice, demonstrating that the P2X receptor phenotype in MKs, and by inference, platelets, is due to expression of homomeric P2X(1) receptors. P2X(1) receptor deficiency had no effect on MK (CD 41) numbers or size distribution, showing that it is not essential for normal MK development. P2Y receptor-stimulated [Ca(2+)](i) responses were unaffected in MKs from P2X(1)(-/-) mice, however the inward cation current associated with Ca(2+) release was reduced by approximately 50%, suggesting an interaction between the membrane conductances activated by P2X(1) and P2Y receptors. Interaction between P2X(1) and P2Y receptors in human platelets was also examined using [Ca(2+)](i) recordings from cell suspensions. Alpha,beta-meATP (10 microM) evoked a rapid transient P2X(1) receptor-mediated increase in [Ca(2+)](i), whereas ADP-(10 microM) evoked P2Y receptor responses were slower, peaked at a higher level and remained elevated for longer periods. Co-application of alpha, beta-meATP and ADP resulted in marked acceleration and amplification of the peak [Ca(2+)](i) response. We conclude that ionotropic P2X(1) receptors may play a priming role in the subsequent activation of metabotropic P2Y receptors during platelet stimulation.     

Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats

In order to investigate the mechanism of kinin release leading to vascular symptoms in acute interstitial-oedematous pancreatitis, the novel, selective inhibitors of tissue kallikrein, (2S,2'R)-2-(2'-amino-3'-(4'-chlorophenyl)propanoylamino)-N-(3-guanidinopropyl)-3-(1-naphthyl)propanoamide (FE999024, CH-2856), and of plasma kallikrein, (2'S,2"R)-4-(2'-(2"(carboxymethylamino)-3"-cyclohexyl-propanoylamino)-3'-phenyl-propanoylamino)piperidine-1-carboxamidin (FE999026, CH-4215), were used in experimental caerulein-induced pancreatitis in rats. Oedema formation and plasma protein extravasation during the 2 h infusion of caerulein were inhibited in a dose-dependent manner by i.p. pretreatment with FE999024 (7-60 micromol kg(-1)) while FE999026 had no effect at the same doses. Haemoconcentration and hypovolaemia associated with the pancreatic oedema formation during pancreatitis were significantly attenuated by FE999024 at a dose of 20 micro mol kg(-1). The reduction in circulating plasma volume was not affected by FE999026. Accumulation of amylase and lipase in the pancreas was dose-dependently reduced by FE999024 while enzyme activities in the blood serum were increased by FE999024 at 60 micromol kg(-1) indicating improved enzyme removal from the tissue. Enzyme activities in the tissue and in the blood remained unaffected by FE999026. FE999024 (20 micromol kg(-1)) largely inhibited increased tissue kallikrein-like activity in the pancreas during acute pancreatitis and also strongly attenuated influx of plasma kallikrein into the tissue. FE999026 (20 micromol kg(-1)) significantly inhibited plasma kallikrein-like activity in the pancreas but had no effect on tissue kallikrein-like activity. In conclusion, vascular kinin-mediated symptoms observed during oedematous pancreatitis in the rat are caused by the action of tissue kallikrein in the pancreas whereas an involvement of plasma kallikrein seems to be unlikely.     

Nitric oxide supports atrial function in sepsis: relevance to side effects of inhibitors in shock

The mechanisms underlying myocardial dysfunction in sepsis remain poorly understood. The theoretical benefits of nitric oxide synthase (NOS) inhibition in reversing the haemodynamic changes that characterise septic shock have not been supported by clinical trials, some of which have demonstrated detrimental myocardial effects. We have therefore assessed the effects of endotoxaemia on NOS enzyme expression as well as a number of functional responses of myocardial tissue from rats. Atrial tissue expressed high levels of mRNA for inducible (i) NOS and released increased levels of nitrite after animals were treated with endotoxin. In parallel, the inotropic response stimulated by isoprenaline was reduced in atria from endotoxin-treated animals, an effect that was reversed when endogenous release of NO was maximised. Our results suggest that myocardial contractility is maintained by NO production and that inhibitors may compromise cardiac output; this may explain the deleterious effects of NOS inhibition on cardiac function in clinical trials.     

Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation

Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincubation time-dependent, with K(I) and k(inact) values estimated at 9.9 microM and 0.16 min(-1), respectively. The observed loss of P450 3A4 activity was attenuated partially by glutathione (GSH), implying the involvement of a reactive metabolite(s) in the inactivation process. Subsequently, GSH adducts of raloxifene were identified in incubations with human liver microsomes; substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3'-position of the phenol ring, with the 7-glutathionyl derivative being most abundant based on LC/MS and NMR analyses. These adducts are postulated to derive from addition of GSH to raloxifene arene oxides followed by dehydration and aromatization. Alternatively, raloxifene may be oxidized to an extended quinone intermediate, which then is trapped by GSH conjugation. The bioactivation of raloxifene most likely is catalyzed by P450 3A4, since the formation of GSH adducts was almost abolished when liver microsomes were pretreated with ketoconazole or with an inhibitory anti-P450 3A4 IgG. The GSH adducts also were detected in incubations of raloxifene with rat or human hepatocytes, while the corresponding N-acetylcysteine adducts were identified in the bile and urine from rats treated orally with the drug at 5 mg/kg. Taken together, these data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity. The significance of these findings with respect to the clinical use of raloxifene remains to be determined.     

The effects of alprazolam and buspirone in light and moderate female social drinkers

Individuals who are moderate/heavy drinkers are at increased risk to abuse benzodiazepines and this risk is increased in women compared to men. However, no studies have determined whether female moderate drinkers (MD) show a differential response to the subjective and performance effects of benzodiazepines compared to female light drinkers (LD). Fourteen female MD who consumed an average of 36 drinks/month were compared to 14 female LD who consumed an average of 4.2 drinks/month. None of the participants had either a first- or second-degree family history of alcoholism. The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg) and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using a full range of performance measures and subjective-effects questionnaires. Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. There were few differences between LD and MD with respect to subjective response or performance impairment following either alprazolam or buspirone. Although MD reported greater ratings of Good Drug Effect and Drug Liking than LD, this was neither dose-related, nor specific to alprazolam. The results of the present study suggest that female MD without a family history of alcoholism experience the same level of performance impairment as female LD, although they tend to report greater positive subjective effects from alprazolam.     

Economic evaluation of vaccination programmes: a consensus statement focusing on viral hepatitis

The methods that have been used to estimate the clinical and economic impact of vaccination programmes are not always uniform, which makes it difficult to compare results between economic analyses. Furthermore, the relative efficiency of vaccination programmes can be sensitive to some of the more controversial aspects covered by general guidelines for the economic evaluation of healthcare programmes, such as discounting of health gains and the treatment of future unrelated costs. In view of this, we interpret some aspects of these guidelines with respect to vaccination and offer recommendations for future analyses. These recommendations include more transparency and validation, more careful choice of models (tailored to the infection and the target groups), more extensive sensitivity analyses, and for all economic evaluations (also nonvaccine related) to be in better accordance with general guidelines. We use these recommendations to interpret the evidence provided by economic evaluation applied to viral hepatitis vaccination. We conclude that universal hepatitis B vaccination (of neonates, infants or adolescents) seems to be the most optimal strategy worldwide, except in the few areas of very low endemicity, where the evidence to enable a choice between selective and universal vaccination remains inconclusive. While targeted hepatitis A vaccination seems economically unattractive, universal hepatitis A vaccination strategies have not yet been sufficiently investigated to draw general conclusions.