Influence of Adrenal Glands on the Modulation of Prolactin Gene Expression by the Endogenous Benzodiazepine Ligand Octadecaneuropeptide in the Male Rat Pituitary Gland

Recently, an 86-amino acid polypeptide with high affinity for diazepam binding sites, termed diazepam-binding inhibitor (DBI), has been found in the rat brain. DBI, as well as a peptide derived from DBI, the octadecaneuropeptide DBI[33–50] (ODN), interacts with the GABA_A receptor complex. To investigate the role of these endogenous ligands for GABA_A receptors on prolactin gene expression, we studied the effects of acute intracerebroventricular administration (4  h before sacrifice) of ODN on prolactin mRNA levels in the male rat. Because, in some neuropeptidergic systems, glucocorticoids play a role in the response to ODN, we also studied the influence of adrenal glands and the effect of dexamethasone administration in the response of prolactin gene expression to ODN. ODN injection produced an increase in prolactin mRNA levels. Adrenalectomy performed 5 days before sacrifice resulted in an increase in prolactin gene expression and also potentiated the stimulating effect of ODN. Because castration has been shown to decrease prolactin gene expression in the male rat, we used castrated and adrenalectomized animals to study the role of dexamethasone in the response of lactotrophs to ODN. In these steroid-deprived animals, dexamethasone treatment (for 4 days) decreased prolactin mRNA levels but did not modify the response to ODN. These data indicate that an endogenous neuropeptide interacting with the GABA_A receptor complex can stimulate prolactin gene expression and suggest that the adrenal glands may produce factor(s) capable of decreasing prolactin mRNA. On the other hand, it does not appear that glucocorticoid hormones play a role in the effect of ODN on lactotroph activity.     

Different acute effects of single-axis and multi-axis hand-arm vibration

Under laboratory conditions the effects of single-axis and multi-axis hand-arm vibration exposure on several strain parameters were tested in up to 20 male subjects. As parameters of these acute effects, the biodynamic vibration behavior of the hand-arm system, the electrical activity of the most affected muscle groups, the skin temperature, the vibration sensitivity of the fingertips, and the subjective vibration sensation were measured. When comparing simulated three-axis vibration exposure with single-axis vibration exposure, synergistic effects in the form of an increasing reaction could be found. It could be proven that the vector sum of the frequency-weighted acceleration in the three axes represents the acute effects better than does the weighted acceleration in the main axis alone. This summation has to take into account the relatively lower effects of vibration in the x- or y-direction compared with the z-direction. On the basis of the experimental results a new proposal for frequency weighting of the three different axes and an energetic summation procedure are derived. Application of this knowledge in the International Standard ISO 5349 is proposed.     

Atracurium and vecuronium interaction with gentamicin and tobramycin

Drug interactions between the aminoglycosides (tobramycin and gentamicin) and atracurium and vecuronium were studied prospectively in 44 patients. Twenty-two patients had therapeutic serum levels of tobramycin or gentamicin and 22 served as controls. Onset time, clinical duration, and time to spontaneous recovery of T4/T1 ratio of 0.70 after atracurium or vecuronium injection were measured. No statistically significant differences were found in onset time, but clinical duration and time to recovery were significantly longer in patients receiving tobramycin or gentamicin and paralyzed with vecuronium than for controls (P less than 0.01 for clinical duration and P less than 0.0005 for recovery). The neuromuscular block produced by atracurium was not significantly influenced by the presence of therapeutic serum levels of tobramycin or gentamicin. We conclude that for patients treated with these antibiotics, atracurium may present some advantages over vecuronium when a prolonged block is not desired.     

Evaluation of the Cobasbact automated antimicrobial susceptibility testing system

The Cobasbact is an automated system for use in the microbiological laboratory which is capable of performing antimicrobial susceptibility tests within five hours. The performance of the Cobasbact system was evaluated using 2000 non-fastidious, facultative and aerobic clinical bacterial isolates. The standard Kirby-Bauer disk diffusion test served as reference method. For gram-positive isolates, the rate of overall full and essential agreement between Cobasbact and reference antibiograms was 90 % and 95.5 % respectively, forEnterobacteriaceae 91 % and 95.5 % and forPseudomonas spp. 90% and 96 %. Reproducibility studies yielded an essential agreement rate of 98 %. On the basis of this preliminary evaluation it would seem that the Cobasbact system can rapidly produce reasonably accurate and reproducible results of antimicrobial susceptibility tests for gram-positive cocci,Enterobacteriaceae andPseudomonas spp.     

Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts

Repairing DNA damage is critical during embryogenesis because development involves sensitive periods of cell proliferation, and abnormal cell growth or death can result in malformations. Knockout mouse experiments have demonstrated that disruption of DNA repair genes results in embryolethality and structural defects. Studies using mid-organogenesis rat embryos showed that DNA repair genes were variably expressed. It is hypothesized that polymorphisms that alter the functionality of DNA repair enzymes may modify the risk of malformations. We conducted a case-control analysis to investigate the relationship between DNA repair gene polymorphisms and the risk of spina bifida and oral clefts. Newborn screening blood spot DNA was obtained for 250 cases (125 spina bifida, 125 oral clefts) identified by the California Birth Defects Monitoring Program, and 350 non-malformation controls identified from birth records. Six single nucleotide polymorphisms of five DNA repair genes representing three distinct repair pathways were interrogated including: XRCC1 (Arg399Gln), APE1 (Asp148Glu), XRCC3 (Thr241Met), hOGG1(Ser326Cys), XPD (Asp312Asn, Lys751Gln). Elevated or decreased odds ratios (OR, adjusted for race/ethnicity) for spina bifida were found for genotypes containing at least one copy of the variant allele for XPD [751Gln, OR = 1.62; 95% confidence interval (CI) = 1.05-2.50] and APE 148 (OR = 0.58; CI = 0.37-0.90). A decreased risk of oral clefts was found for XRCC3 (OR = 0.62; CI = 0.39-0.99) and hOGG1 (326 Cys/Cys, OR = 0.22; CI = 0.06-0.78). This study suggested that polymorphisms of DNA repair genes, representing different major repair pathways, may affect risk of two major birth defects. Future, larger studies, examining additional repair genes, birth defects, and interaction with exposures are recommended.     

The atheroprotective effect of 17beta-estradiol depends on complex interactions in adaptive immunity

Estradiol prevents fatty streak formation in chow-fed atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol. In the present work, we demonstrate that the reconstitution of ApoE(-/-)/RAG-2(-/-) with bone marrow from immunocompetent ApoE(-/-)/RAG-2(+/+) mice restores the protective effect of estradiol on fatty streak constitution. We extended this demonstration to the model of low-density lipoprotein receptor-deficient mice, establishing the obligatory role of mature lymphocytes in this process. We then investigated whether the protective effect of estradiol was mediated by a specific lymphocyte subpopulation by studying the hormonal effect on fatty streak constitution in recently developed models of ApoE(-/-) mice deficient in selective T-lymphocyte subsets (either TCRalphabeta+, CD4+, CD8+, or TCRgammadelta+ lymphocytes) or B lymphocytes. In all these specifically immunodeficient mice, estradiol administration to ovariectomized mice conferred protection as in immunocompetent ApoE(-/-) mice, clearly demonstrating that no single lymphocyte subpopulation was specifically required for this effect. These results point to additional lymphocyte-dependent mechanisms such as modulating the interactions among lymphocytes and between lymphocytes and endothelial and/or antigen-presenting cells.     

Voluntary HIV counseling and testing: experience among the sexually active population in Bangui,Central African Republic

OBJECTIVES: In July 1997, the National Reference Center for Sexually Transmitted Diseases of Bangui, Central African Republic (CAR), was expanded by the creation of an anonymous and voluntary counseling and testing (VCT) unit for HIV infection, the Anonymous Surveillance Unit (Unité de Dépistage Anonyme [UDA]). The goal of the UDA was to initiate and promote voluntary HIV testing in the general adult population of Bangui. We carried out an observational and comprehensive survey over a 4-year period to document and analyze the experience of VCT in the UDA, with special attention to risk factors associated with HIV infection. METHODS: All clients for VCT were given adequate pretest counseling by trained counselors focused on knowledge about HIV infection and sexually transmitted infections, individual risks of acquiring HIV, and anticipation of the client's attitude about test results. After consent was obtained, a blood sample was drawn and tested for HIV by two ELISAs in parallel. The client paid a standard cost of $1.20 at the initial visit. After a week, test results were given to the client during the posttest visit, at which time HIV-seropositive individuals received emotional support and were referred to specific social or medical structures. Seronegative clients received reinforcement of prevention messages and were asked to come back for serologic follow-up free of charge after 3 (M3) and 12 (M12) months. RESULTS: From July 1997 to March 2001, 5686 individuals aged 14 to 65 years (mean age, 27 years) had an initial visit for VCT (V1). Peaks of UDA visitation (250-450 clients) were observed on the annual AIDS Day in the CAR, at which time HIV serologic testing was offered free of charge. A total of 5060 (89%) clients came back for a second visit (V2) to receive test results. Among those, 18.3% were infected with HIV type 1. Multivariate analysis of risk factors demonstrated marked association of HIV seropositivity with age, female gender, widowed/divorced women, poor or low education level, occupations such as civil servants or merchants, presence of symptoms of sexually transmitted infections, and lack of systematic condom use. Single young women were at higher risk for HIV infection compared with men of the same age (OR = 7.7 for women aged 15-24 years, 95% CI: 4.0-14.0; OR = 2.8 for women aged 25-34 years, 95% CI: 1.7-4.5). Widowed women older than 44 years of age were more likely to be HIV-seropositive than men (OR = 10.0; 95% CI: 1.7-83.6). A total of 885 (21%) HIV-seronegative individuals returned for follow-up at 3 months (M3; 0.45% rate of seroconversion). Seventy-nine (9%) individuals returned at 12 months (M12), without any new cases of HIV infection. HIV-negative clients consulting at M3 and M12 showed a significant reduction in unprotected intercourse with occasional sexual partners. CONCLUSION: This experience demonstrates that VCT for HIV infection is feasible in Central Africa.     

Concentration and turnover of intraperitoneal hyaluronan during inflammation

Aseptic peritonitis was induced in rabbits by intraperitoneal injection of irritating agents, mainly starch suspensions. The inflammatory response was followed in the peritoneal lavage fluid by cell counts (average increase about 800-fold the first day) and hyaluronan concentration (average increase about 200-fold on the second and third days). The turnover rate of hyaluronan was studied by injecting tritium-labeled hyaluronan intraperitoneally and by following the appearance of tritiated water in serum. In control animals given trace amounts of hyaluronan, half-lives of 1–14 h were recorded. When the labeled polysaccharide had been mixed with 10 mg/ml of unlabeled hyaluronan, the half-life was approximately one day. Rabbits with ongoing peritonitis exhibited half-lives between 1 and 16 h. It was concluded that there was a large individual variation in uptake kinetics, that the removal process could be receptor mediated, and that the increase in intraperitoneal hyaluronan in peritonitis mainly was due to an increased production of the polysaccharide rather than a decreased rate of removal.     

Foscarnet salvage therapy efficacy is associated with the presence of thymidine-associated mutations (TAMs) in HIV-infected patients

BACKGROUND: Salvage therapy based on foscarnet plus a thymidine analog is effective in patients with advanced-stage HIV disease and viruses harbouring multiple drug-resistance mutations. OBJECTIVE: To identify viral genetic determinants associated with the virological efficacy of foscarnet salvage therapy. STUDY DESIGN: Thirteen patients received foscarnet at a fixed dose of 80mg/kg twice daily for 14 days, in combination with zidovudine or stavudine. RESULTS: The baseline median HIV viral load and CD4 cell count were 5.10log(10)copies/ml and 23cells/mm(3), respectively. Following foscarnet therapy, viral load fell by a median of 1.84log(10)copies/ml (range: -0.29 to -2.82), and by at least 1log(10)copies/ml in 11 patients, all of whom harboured viruses with at least three thymidine-associated mutations (TAMs). The two patients with smaller declines in viral load (<0.50log(10)copies/ml) harboured viruses with only one or zero TAMs. CONCLUSIONS: These findings corroborate, in vivo, the impact of TAMs on HIV susceptibility to foscarnet. The virological response to foscarnet salvage therapy in multiclass-experienced patients may thus differ according to the number of TAMs.