Increased expression of complement component C3 in the plasma of obese Zucker fa and LA/N fa(f) rats compared with their lean counterparts

OBJECTIVES: The objectives of this study were to determine whether there are differences in the electrophoretic profiles of plasma proteins from lean and obese rats and to identify a protein that was found to be more abundant in the plasma of obese rats. RESEARCH METHODS AND PROCEDURES: Plasma proteins from lean and obese Zucker fa and LA/N fa(f) rats were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The identity of a band that was differentially expressed was determined by amino acid sequencing and Western blot analysis. RESULTS: A band migrating approximately the same distance as the 116 kDa molecular weight marker was more prominent in plasma from obese rats than in plasma of lean rats. Partial sequencing of the peptide revealed that 17 of the first 18 amino acids at the amino terminus were identical with the corresponding residues in the alpha-chain of complement component C3. Western blot analysis confirmed the identity of the peptide as complement component C3. Complement C3 activity was measured using a hemolytic assay to determine whether there was a corresponding increase in the biological activity of this component in the serum of obese rats. Serum from obese rats was found to have 1.8 times as much complement component C3 activity as serum from lean rats. DISCUSSION: Elevated levels of complement C3 in genetically obese rats may be relevant because increased amounts of C3 could serve as a reservoir from which increased amounts of acylation stimulating protein, a cleavage product of complement C3, could be produced.     

Auditory behavior monitoring after bacterial meningitis. Case report

Bacterial meningitis is the main cause for acquired hearing loss. Nevertheless very little has been written about the development of the auditory behaviour either for improvement or for deterioration, after hospital release. The present study describes the case of a five month old boy with Haemophilus influenzae meningitis. Amongst various complications, a decrement in the auditory acuity was detected in the immediate evolution, with significant improvement later on by qualitative and quantitative tests.     

The activity of acid phosphatase and its isoenzymes in patients with food poisonings

Changes in the activity of acid phosphatase (AP) and its isoenzymes (tartrate-insensitive AP and formalin-insensitive AP) were investigated in patients with food poisoning in the course of the disease. The activity of AP and its isoenzymes in the serum started to grow in early convalescence and reached maximum in late convalescence. Total activity of AP in food toxic infections consists primarily of the activity of its platelet fraction. AP activity may serve as an additional criterion to predict vascular platelet involvement of hemostasis.     

Evidence for increased seizure susceptibility in rats exposed to cocaine in utero

The effect of (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105), a novel cognition enhancer, on adenylate cyclase activity was investigated in cultured neurons of the mouse cerebral cortex. NS-105 (10(-7) and 10(-6) M) inhibited forskolin-stimulated cyclic AMP formation, an action that was dependent on pertussis toxin-sensitive G proteins. Conversely, in pertussis toxin-pretreated neurons, NS-105 (10(-7)-10(-5) M) significantly enhanced the forskolin-stimulated cyclic AMP formation, and this action was completely reversed by cholera toxin. A metabotropic glutamate receptor agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3R-ACPD) produced similar bi-directional actions on the cyclic AMP formation. Both of these inhibitory and facilitatory actions of NS-105 and 1S, 3R-ACPD were blocked by L(+)-2-amino-3-phosphopropinoic acid (L-AP3). NS-105 (10(-6) M) and 1S, 3R-ACPD (10(-4) M) significantly enhanced isoproterenol- and adenosine-stimulated cyclic AMP formation. The enhancement of such Gs-coupled receptor agonists-stimulated cyclic AMP formation was also produced by quisqualate but not by L(+)-2-amino-4-phosphonobutanoate (L-AP4). The phosphoinositides hydrolysis was enhanced by 1S, 3R-ACPD (10(-4) M) but not by NS-105 (10(-6) M), however, 1S, 3R-ACPD-induced increase in phosphoinositides turnover was attenuated by NS-105. These findings suggest that NS-105 stimulates metabotropic glutamate receptor subclasses that are coupled both negatively and positively to adenylate cyclase, but it acts as an antagonist at the receptor subclasses that are linked to phosphoinositides hydrolysis.     

Antihypertensive agent moxonidine enhances muscle glucose transport in insulin-resistant rats

The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia--on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.     

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group

BACKGROUND: This double blind parallel group study assessed the acute antiemetic efficacy of four oral doses of dolasetron mesylate in cancer patients receiving their first course of intravenous chemotherapy with doxorubicin and/or cyclophosphamide. METHODS: Patients were randomized to receive 25, 50, 100, or 200 mg of dolasetron mesylate 30 minutes prior to chemotherapy and were monitored for nausea and emetic episodes for the next 24 hours. RESULTS: Three hundred and nineteen cancer patients at 32 sites completed the study. Most patients were female (81%); of this group, 69% had breast carcinoma. A highly statistically significant linear trend demonstrating improved response with higher doses was detected for complete response (no emetic episodes and no rescue medication) (P < 0.001), for complete plus major response (0-2 emetic episodes and no rescue medication) (P < 0.001), and for patient visual analog scale assessments of nausea (P = 0.001) and general satisfaction with antiemetic therapy (P = 0.001). No serious adverse events were noted. The most frequent adverse event was mild, self-limiting headache, which has been reported with other drugs in this class. CONCLUSIONS: Single oral doses of dolasetron mesylate were found to be effective in preventing acute emesis in cancer patients receiving moderately emetogenic chemotherapy.     

Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry

OBJECTIVE: To characterize changes of Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) that occur during the course of HIV infection by cytoplasmic cytokine staining on single cell level. DESIGN AND METHODS: Mitogen-stimulated PBMC from 16 healthy donors, 18 HIV-1-infected individuals without AIDS and 14 patients with AIDS were stained intracellularly with fluorescein-labelled MAb against interleukin (IL)-2, IL-4, IL-10 and interferon (IFN)-gamma. Additionally, co-staining of CD4+ T-cell, CD8+ T-cell, natural killer (NK) cell, B-cell and monocytic markers was performed. Fluorescence staining was analysed by three-colour flow-cytometry. RESULTS: A reduced percentage of IL-2 and IFN-gamma (Th1 type)-producing cells among CD4+ T cells from HIV-1-infected individuals could be demonstrated. There was a continuous decrease of IFN-gamma-producing CD4+ T cells in the course of HIV infection and a dramatic reduction of IL-2-expressing cells among CD4+ T cells in patients with AIDS. In contrast to Th1 cytokines, the frequency of Th2 cytokine expressing cells among CD4+ T cells increased in HIV-infected individuals. The maximum frequency of IL-4-expressing cells among CD4+ T cells was seen in HIV-infected individuals without AIDS, whereas the rate of IL-10-producing cells was highest in patients with AIDS. In HIV-infected individuals no significant proportion of Th0 cells expressing both Th1 and Th2 cytokines was detectable. In CD8+ T cells the percentage of IL-2 was expressing cells decreased continuously accompanied by a strong increase of the frequency of IFN-gamma-producing cells. CONCLUSION: The decreased percentage of cells expressing IL-2 and IFN-gamma in conjunction with an increased proportion of IL-4- and IL-10-producing cells among the CD4+ T cells in HIV-1-infected individuals demonstrate a Th1 to Th2 cytokine shift in the course of HIV infection on a single cell level. There was no evidence of a Th1 to Th0 cytokine shift. In addition to the loss of CD4+ T cells in HIV infection, the qualitative changes of Th1/Th2 cytokine expression may serve as a marker for progressive failure of cell-mediated immunity.     

B7 blockade prevents activation-induced cell death of thymocytes

Although both B7 and its counter-receptor CD28 are expressed in the thymus, the role of B7 in thymic selection is not clear. We investigated the role of B7 in intrathymic deletion of antigen-specific T cells using a TCR transgenic model specific for antigen ovalbumin (OVA) and H-2Ad. Intraperitoneal injection of OVA induced apoptosis of thymocytes and drastic reduction of thymocyte numbers. This was significantly inhibited by co-injection of CTLA-4-Ig which blocks B7 co-stimulation. Deletion of T cells in the thymus following i.p. injection of OVA was associated with T cell pre-activation as demonstrated by T cell proliferation and cytokine production. Injection of CTLA-4-Ig blocked all these activation events and rescued thymocytes from activation-induced cell death. These results demonstrate that B7 is required for the activation-induced cell death of MHC class II-restricted thymocytes in vivo.     

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. RESULTS: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. CONCLUSIONS: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.