Histopathology of veins after intravenous lorazepam and RO 21-3981.

A previously established rat model has been utilized to demonstrate that an acute inflammatory response occurs after high intravenous doses of lorazepam. This occurs only with high concentrations of drug equivalent to 20 times the normal clinical dosage in man. In contract, water soluble RO 21-3981 produces no vascular pathology in any dosage evaluated. It appears that propylene glycol may play a role in the pathogenesis of the intravascular injury observed.     

Regulated hydrogen peroxide production by Duox in human airway epithelial cells

Hydrogen peroxide (H(2)O(2)) is found in exhaled breath and is produced by airway epithelia. In addition, H(2)O(2) is a necessary substrate for the airway lactoperoxidase (LPO) anti-infection system. To investigate the source of H(2)O(2) produced by airway epithelia, PCR was used to screen nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression in human airway epithelia redifferentiated at the air-liquid interface (ALI) and demonstrated the presence of Duox1 and 2. Western blots of culture extracts indicated strong expression of Duox, and immunohistochemistry of human tracheal sections localized the protein to the apical portion of epithelial cells. Apical H(2)O(2) production was stimulated by 100 microM ATP or 1 microM thapsigargin, but not 100 microM ADP. Diphenyleneiodonium, an NADPH oxidase inhibitor, and dimethylthiourea, a reactive oxygen species scavenger, both inhibited this stimulation. ATP did not stimulate the basolateral H(2)O(2) production by ALI cultures. ATP and thapsigargin increased intracellular Ca(2+) with kinetics similar to increasing H(2)O(2) production, and thus consistent with the expected Ca(2+) sensitivity of Duox. These data suggest that Duox is the major NADPH oxidase expressed in airway epithelia and therefore a contributor of H(2)O(2) production in the airway lumen. In addition, the data suggest that extracellular H(2)O(2) production may be regulated by stimuli that raise intracellular Ca(2+).     

Association of ambulatory blood pressure and dietary caffeine in adolescents

BACKGROUND: Although relatively little is known about the responsible factors, there is an increased prevalence of essential hypertension in youth. Our previous research using casual blood pressure (BP) suggests a role for caffeine intake. The objective of this study was to assess the association between caffeine intake and ambulatory BP patterns among adolescents and to replicate our previous findings that compared caffeine intake to BP values obtained at a single time point. METHODS: Eighty-two African-American and non-Hispanic white adolescents (15 to 19 years old) with normal systolic BP selected foods and beverages for a 4-day sodium-controlled diet. Subjects were stratified into three groups based on the amount of caffeine in these foods. Ambulatory BP measures (24-h) were recorded during 1 day of the 4-day diet. The effects of ethnicity, caffeine, and the interaction of ethnicity and caffeine on BP were assessed for daytime and nighttime hours controlling for gender and body mass index. RESULTS: The level of dietary caffeine was positively associated with daytime systolic BP (F(2,76) = 3.1, P = .05, partial R(2) = 0.07) and daytime diastolic BP (F = 3.53(2,76), P = .03, partial R(2) = 0.07). Caffeine's effect on systolic BP was most pronounced for African-American subjects. These results replicated our earlier findings. There was no association between caffeine intake and nighttime BP. CONCLUSIONS: This investigation replicates and extends our previous findings that caffeine consumption impacts the BP of adolescents, during the daytime when sympathetic nervous system responses dominate BP control. Controlled studies that examine the pressor effects of caffeine intake at levels typical of the dietary patterns of today's adolescents are needed.     

Risk of birth defects associated with nelfinavir exposure during pregnancy

OBJECTIVE: The objective of this study was to examine the human teratogenic risk of the protease inhibitor, nelfinavir mesylate, used to treat human immunodeficiency virus. METHODS: This study used a subset of data from the Antiretroviral Pregnancy Registry, which was designed to monitor prenatal exposures to antiretroviral therapy and detect a potential increase in the risk of birth defects. The registry uses a prospective exposure-registration cohort design. All records of pregnant women exposed to nelfinavir, used alone or in combination, were extracted and analyzed. The prevalence of birth defects was compared with the Centers for Disease Control and Prevention's (CDC) population-based surveillance system. RESULTS: Through July 2002, the registry had monitored 915 live births exposed to nelfinavir. Among 301 first-trimester exposures, there were 9 birth defects, for a prevalence of 3% (95% confidence interval 1.4, 5.6). This rate is not significantly different from the CDC's system, which had a prevalence of 3.1 per 100 live births (95% confidence interval 3.1, 3.2; P =.99). There was no consistent pattern among reported birth defects. CONCLUSION: Adequate numbers of first-trimester exposures to nelfinavir have been monitored to detect a 2-fold increase in the prevalence of overall birth defects. No such increases have been detected when compared with the CDC rate. However, the numbers are not sufficient to detect any increased rate of specific defects. Although nelfinavir should only be used in pregnancy if the benefits outweigh the potential risks, the findings from this study should provide some assurance. LEVEL OF EVIDENCE: III     

Innate murine B cells produce anti-disialosyl antibodies reactive with Campylobacter jejuni LPS and gangliosides that are polyreactive and encoded by a restricted set of unmutated V genes

In Guillain-Barré syndrome following Campylobacter enteritis, anti-lipopolysaccharide antibodies cross-react with neural gangliosides, thereby precipitating autoimmune neuropathy. We examined the properties of 15 murine anti-LPS/ganglioside mAbs specific for NeuAc(alpha2-8)NeuAc-Gal disialosyl epitopes. Many mAbs displayed features of an innate B cell origin including polyreactivity (13/15), hybridoma CD5 mRNA expression (5/15), predominance of IgM (9/15) or IgG3 (3/6) isotype, low affinity, and utilisation of unmutated VH and VL VDJ rearrangements. Antibody specificity resided in highly selective V gene usage, with 6/15 mAbs being encoded by the VH7183.3b gene. These data indicate that neuropathogenic antiganglioside autoantibodies can arise from the natural autoantibody repertoire.     

Risk factors for suicide in blacks and whites: an analysis of data from the 1993 National Mortality Followback Survey

OBJECTIVE: Data on risk factors for suicide in blacks in the United States are needed, given the dramatic increase in the black suicide rate from 1980 to 1997. The 1993 National Mortality Followback Survey represented an unprecedented opportunity to identify risk factors for suicide in blacks and to determine whether race differences (black versus white) in risk factors exist. METHOD: Multiple logistic regression analyses were used to compare cases of suicide (150 suicides in blacks and 1,279 suicides in whites) with cases of accidental deaths (737 cases in blacks and 3,458 cases in whites). Predictors of interest were 18 items tapping four domains: antisocial behavior, substance use/abuse, depressive symptoms, and psychotic symptoms. RESULTS: Four items distinguished suicides from accidental deaths in both black and whites: death ideation, suicidal ideation, bizarre behavior, and making violent threats. Items in two of the four domains discriminated risk for suicide in whites more strongly than in blacks: reports of community complaints and problem drinking. No variable conferred greater risk for suicide in blacks than in whites. CONCLUSIONS: The current study underscores the need for examination of race differences in risk factors for suicide. It is also essential to examine variables that were unavailable in the National Mortality Followback Survey data set, particularly racism, perceived discrimination, and feelings of alienation from the dominant culture.