RLH-033, a novel, potent and selective ligand for the sigma 1 recognition site

RLH-033 [2-(4-phenylpiperidinyl)ethyl 1-(4-nitrophenyl)cyclopentanecarboxylate HCl] is a rationally designed ligand that was synthesized and evaluated for its binding affinities at sigma 1 and sigma 2 sites in guinea pig brain. RLH-033 has high affinity (Ki = 50 pM) for sigma 1 sites labeled by [3H](+)-pentazocine, while it was over 2000-fold less affinity at sigma 2 sites labeled by [3H]1,3-di(2-tolyl)guanidine (DTG) in the presence of 500 nM (+)-pentazocine (Ki = 105 nM). Unlike its potent sigma activity, the compound has little affinity for dopamine D1 (Ki = 2.9 microM), D2 (Ki = 0.35 microM), muscarinic M1 (Ki = 0.88 microM) or M2 (Ki = 1.7 microM) receptors, and none at all for N-methyl-D-aspartate, phencyclidine and opioid receptors. Thus, RLH-033 is the most potent sigma 1 ligand reported to date, and its very high affinity suggests it may be a useful radioligand to characterize the pharmacology of sigma 1 recognition sites.     

Contrasting patterns of regulation of the antioxidant selenoproteins, thioredoxin reductase, and glutathione peroxidase, in cancer cells

There is strong evidence that selenium protects against certain human cancers, but the underlying mechanism is unknown. Glutathione peroxidase (GPX1) and thioredoxin reductase (TR), the most abundant antioxidant selenium-containing proteins in mammals, have been implicated in this protection. We analyzed the expression of TR and GPX1 in the following model cancer systems: (1) liver tumors in TGFalpha/c-myc transgenic mice; (2) human prostate cell lines from normal and cancer tissues; and (3) p53-induced apoptosis in a human colon cancer cell line. TR was induced while GPX1 was repressed in malignancies relative to controls in transgenic mice and prostate cell lines. In the colon cell line, p53 expression resulted in elevated GPX1, but repressed TR. The data indicate that TR and GPX1 are regulated in a contrasting manner in the cancer systems tested and reveal the p53-dependent regulation of selenoprotein expression. The data suggest that additional studies on selenoprotein regulation in different cancers are required to evaluate future implementation of selenium as a dietary supplement in individuals at risk for developing certain cancers.     

Effect of epinephrine on muscle glycogenolysis during exercise in trained men

To test the hypothesis that an elevation in circulating epinephrine increases intramuscular glycogen utilization, six endurance-trained men performed two 40-min cycling trials at 71 +/- 2% of peak oxygen uptake in 20-22 degrees C conditions. On the first occasion, subjects were infused with saline throughout exercise (Con). One week later, after determination of plasma epinephrine levels in Con, subjects performed the second trial (Epi) with an epinephrine infusion, which resulted in a twofold higher (P < 0.01) plasma epinephrine concentration in Epi compared with Con. Although oxygen uptake was not different when the two trials were compared, respiratory exchange ratio was higher throughout exercise in Epi compared with Con (0.93 +/- 0.01 vs. 0.89 +/- 0.01; P < 0.05). Muscle glycogen concentration was not different when the trials were compared preexercise, but the postexercise value was lower (P < 0.01) in Epi compared with Con. Thus net muscle glycogen utilization was greater during exercise with epinephrine infusion (224 +/- 37 vs. 303 +/- 30 mmol/kg for Con and Epi, respectively; P < 0.01). In addition, both muscle and plasma lactate and plasma glucose concentrations were higher (P < 0.05) in Epi compared with Con. These data indicate that intramuscular glycogen utilization, glycolysis, and carbohydrate oxidation are augmented by elevated epinephrine during submaximal exercise in trained men.     

Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects

OBJECTIVES: To estimate the efficacy of dietary advice to lower blood total cholesterol concentration in free-living subjects and to investigate the efficacy of different dietary recommendations. DESIGN: Systematic overview of 19 randomised controlled trials including 28 comparisons. SUBJECTS: Free-living subjects. INTERVENTIONS: Individualised dietary advice to modify fat intake. MAIN OUTCOME MEASURE: Percentage difference in blood total cholesterol concentration between the intervention and control groups. RESULTS: The percentage reduction in blood total cholesterol attributable to dietary advice after at least six months of intervention was 5.3% (95% confidence interval 4.7% to 5.9%). Including both short and long duration studies, the effect was 8.5% at 3 months and 5.5% at 12 months. Diets equivalent to the step 2 diet of the American Heart Association were of similar efficacy to diets that aimed to lower total fat intake or to raise the polyunsaturated to saturated fatty acid ratio. These diets were moderately more effective than the step 1 diet of the American Heart Association (6.1% v 3.0% reduction in blood total cholesterol concentration; P<0.0001). On the basis of reported food intake, the targets for dietary change were seldom achieved. The observed reductions in blood total cholesterol concentrations in the individual trials were consistent with those predicted from dietary intake on the basis of the Keys equation. CONCLUSIONS: Individualised dietary advice for reducing cholesterol concentration is modestly effective in free-living subjects. More intensive diets achieve a greater reduction in serum cholesterol concentration. Failure to comply fully with dietary recommendations is the likely explanation for this limited efficacy.     

Chronic multisymptom illness affecting Air Force veterans of the Gulf War

CONTEXT: Gulf War (GW) veterans report nonspecific symptoms significantly more often than their nondeployed peers. However, no specific disorder has been identified, and the etiologic basis and clinical significance of their symptoms remain unclear. OBJECTIVES: To organize symptoms reported by US Air Force GW veterans into a case definition, to characterize clinical features, and to evaluate risk factors. DESIGN: Cross-sectional population survey of individual characteristics and symptoms and clinical evaluation (including a structured interview, the Medical Outcomes Study Short Form 36, psychiatric screening, physical examination, clinical laboratory tests, and serologic assays for antibodies against viruses, rickettsia, parasites, and bacteria) conducted in 1995. PARTICIPANTS AND SETTING: The cross-sectional questionnaire survey included 3723 currently active volunteers, irrespective of health status or GW participation, from 4 air force populations. The cross-sectional clinical evaluation included 158 GW veterans from one unit, irrespective of health status. MAIN OUTCOME MEASURES: Symptom-based case definition; case prevalence rate for GW veterans and nondeployed personnel; clinical and laboratory findings among veterans who met the case definition. RESULTS: We defined a case as having 1 or more chronic symptoms from at least 2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155 GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness was not associated with time or place of deployment or with duties during the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases, 86 (54%) mild-to-moderate cases, and 13 (8%) severe cases. Although no physical examination, laboratory, or serologic findings identified cases, veterans who met the case definition had significantly diminished functioning and well-being. CONCLUSIONS: Among currently active members of 4 Air Force populations, a chronic multisymptom condition was significantly associated with deployment to the GW. The condition was not associated with specific GW exposures and also affected nondeployed personnel.     

Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat

Peripherally administered or released substances that modulate memory storage, but do not freely enter the brain, may produce their effects on memory by activating peripheral receptors that send messages centrally through the vagus nerve. Indeed, vagus nerve stimulation enhances memory performance, although it is unclear whether this effect is due to the activation of vagal afferents or efferents. To eliminate the possible influence of descending fibers on memory storage processes, rats were implanted with cuff electrode/catheter systems along the left cervical vagus. Forty-eight hours following surgery, each animal received a 3. 0-microliter infusion (1.0 microliter/min) of either lidocaine hydrochloride (75.0 mM) or isotonic saline below the point of stimulation. Animals were then trained 10 min later on an inhibitory-avoidance task with a 0.75-mA, 1.0-s foot shock. Sham stimulation or vagus nerve stimulation (0.5-ms biphasic pulses; 20.0 Hz; 30 s; 0.2, 0.4, or 0.8 mA) was administered immediately after training. Memory, tested 24 h later, was enhanced by stimulation whether descending vagus nerve fibers were inactivated or not. Both lidocaine- and saline-infused groups showed an intensity-dependent, inverted-U-shaped pattern of retention performance, with the greatest effect observed for 0.4 mA (U = 9, p < .05, and U = 7, p < .01, respectively). Additionally, animals that received lidocaine infusions, but no vagus nerve stimulation, showed impaired memory compared to the performance of saline-infused control animals (U = 11, p < .05). Together, these findings suggest that vagal afferents carry messages about peripheral states that lead to the modulation of memory storage and that the memory-enhancing effect produced by vagus nerve stimulation is not mediated via the activation of vagal efferents.     

Localization of a C-terminal region of lambda2 protein in reovirus cores

The 144-kDa lambda2 protein is a structural component of mammalian reovirus particles and contains the guanylyltransferase activity involved in adding 5' caps to reovirus mRNAs. After incubation of reovirus T3D core particles at 52 degrees C, the lambda2 protein became sensitive to partial protease degradation. Sequential treatments with heat and chymotrypsin caused degradation of a C-terminal portion of lambda2, leaving a 120K core-associated fragment. The four other proteins in cores--lambda1, lambda3, mu2, and sigma2--were not affected by the treatment. Purified cores with cleaved lambda2 were subjected to transmission cryoelectron microscopy and image reconstruction. Reconstruction analysis demonstrated that a distinctive outer region of lambda2 was missing from the modified cores. The degraded region of lambda2 corresponded to the one that contacts the base of the sigma1 protein fiber in reovirus virions and infectious subvirion particles, suggesting that the sigma1-binding region of lambda2 is near its C terminus. Cores with cleaved lambda2 were shown to retain all activities required to transcribe and cap reovirus mRNAs, indicating that the C-terminal region of lambda2 is dispensable for those functions.