Consensus Conference on Platelet Transfusion, Royal College of Physicians of Edinburgh, 27-28 November 1997. Synopsis of background papers

The effects of 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxypheneth yl)-N-methylamino] ethane hydrochloride (KCB-328), in comparison with those of dofetilide, were studied on the action potentials (APs) of isolated guinea pig papillary muscles. KCB-328 (0.003-3 microM) concentration-dependently prolonged the AP duration at 90% repolarization (APD90) at 1- and 3-Hz pacing, and the concentration-response relations at 1 and 3 Hz resemble each other. Dofetilide (0.001-1 microM) also produced the concentration-dependent prolongation of APD90 but more pronouncedly at 1 than at 3 Hz, demonstrating the reverse frequency-dependent effect. KCB-328 at 0.03, 0.1, 0.3, and 1 microM increased APD90 by 11 +/- 1, 19 +/- 1, 25 +/- 1, and 29 +/- 1% at 3 Hz and by 9 +/- 1, 19 +/- 2, 27 +/- 2, and 33 +/- 2% at 1 Hz, respectively. Prolongation of the effective refractory period (ERP) by each drug is parallel to those of APD90 at each pacing frequency. KCB-328 modified neither the maximal velocity of depolarization, amplitude of AP, and resting membrane potential in the fast APs, nor any parameters of the slow APs. In a separate experiment, the effects of KCB-328 on the ERP of contractile response (ERPc) of excised guinea-pig papillary muscles also were studied at 1 and 3 Hz. KCB-328 (0.01-10 microM) lengthened the ERPc in a concentration-dependent and frequency-independent manner as in the electrophysiologic results. This frequency-independent ERPc prolongation by KCB-328 was not influenced by increased extracellular K+ concentration from 4 to 10 mM. These results suggest that KCB-328 might be a selective class III agent with effects that are relatively frequency independent.     

Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors

Previous studies indicate that the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR141716A), inhibits the anandamide- and delta9-tetrahydrocannabinol- (THC) induced hypotension and bradycardia in anesthetized rats with a potency similar to that observed for SR141716A antagonism of THC-induced neurobehavioral effects. To further test the role of CB1 receptors in the cardiovascular effects of cannabinoids, we examined two additional criteria for receptor-specific interactions: the rank order of potency of agonists and stereoselectivity. A series of cannabinoid analogs including the enantiomeric pair (-)-11-OH-delta9-THC dimethylheptyl (+)-11-OH-delta9-THC dimethylheptyl were evaluated for their effects on arterial blood pressure and heart rate in urethane anesthetized rats. Six analogs elicited pronounced and long lasting hypotension and bradycardia that were blocked by 3 mg/kg of SR141716A. The rank order of potency was (-)-11-OH-delta9-THC dimethylheptyl > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > THC > anandamide > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol, which correlated well with CB1 receptor affinity or analgesic potency (r = 0.96-0.99). There was no hypotension or bradycardia after palmitoylethanolamine or (+)-11-OH-delta9-THC dimethylheptyl. An initial pressor response was also observed with THC and anandamide, which was not antagonized by SR141716A. We conclude that the similar rank orders of potency, stereoselectivity and sensitivity to blockade by SR141716A indicate the involvement of CB1-like receptors in the hypotensive and bradycardic actions of cannabinoids, whereas the mechanism of the pressor effect of THC and anandamide remains unclear.     

Cost-effectiveness of chemoprophylaxis after occupational exposure to HIV

OBJECTIVES: To assess the economic efficiency of recent US Public Health Service recommendations for chemoprophylaxis with a combination of antiretroviral drugs following high-risk occupational exposure to human immunodeficiency virus (HIV). To provide a framework for evaluating the relative effectiveness and costs associated with candidate postexposure prophylaxis (PEP) regimens. METHODS: Standard techniques of cost-effectiveness and cost-utility analysis were used. The analysis compares the costs and consequences of a hypothetical, voluntary combination-drug PEP program consisting of counseling for all HIV-exposed health care workers, followed by chemoprophylaxis for those who elect it vs an alternative in which PEP is not offered. A societal perspective was adopted and a 5% discount rate was used. Hospital costs of recommended treatment regimens (zidovudine alone or in combination with lamivudine and indinavir) were used, following the dosing schedules recommended by the US Public Health Service. Estimates of lifetime treatment costs for HIV and acquired immunodeficiency syndrome were obtained from the literature. Because the effectiveness of combination PEP has not been established, the effectiveness of zidovudine PEP was used in the base-case analyses. MAIN OUTCOME MEASURES: Net PEP program costs, number of HIV infections averted, cost per HIV infection averted, and cost-utility ratio (net cost per discounted quality-adjusted life-year saved) for zidovudine, lamivudine, and indinavir combination PEP. Lower bounds on the effectiveness required for combination regimens to be considered incrementally cost saving, relative to zidovudine PEP alone, were calculated. Multiple sensitivity and threshold analyses were performed to assess the impact of uncertainty in key parameters. RESULTS: Under base-case assumptions, the net cost of a combination PEP program for a hypothetical cohort of 10,000 HIV-exposed health care workers is about $4.8 million. Nearly 18 HIV infections are prevented. The net cost per averted infection is just less than $400,000, which exceeds estimated lifetime HIV and acquired immunodeficiency syndrome treatment costs. Although combination PEP is not cost saving, the cost-utility ratio (about $37,000 per quality-adjusted life-year in the base case) is within the range conventionally considered cost-effective, provided that chemoprophylaxis is delivered in accordance with Public Health Service guidelines. Small incremental improvements in the effectiveness of PEP are associated with large overall societal savings. CONCLUSIONS: Under most reasonable assumptions, chemoprophylaxis with zidovudine, lamivudine, and indinavir following moderate- to high-risk occupational exposures is cost-effective for society. If combination PEP is minimally more effective than zidovudine PEP, then the added expense of including lamivudine and indinavir in the drug regimen is clearly justified.     

Synergistic neutralization of a chimeric SIV/HIV type 1 virus with combinations of human anti-HIV type 1 envelope monoclonal antibodies or hyperimmune globulins

A panel of 14 human IgG monoclonal antibodies (MAbs) specific for envelope antigens of the human immunodeficiency virus type 1 (HIV-1), 2 high-titer human anti-HIV-1 immunoglobulin (HIVIG) preparations, and 15 combinations of MAbs or MAb/HIVIG were tested for their ability to neutralize infection of cultured human T cells (MT-2) with a chimeric simian immunodeficiency virus (SHIV-vpu+), which expressed HIV-1 IIIB envelope antigens. Eleven MAbs and both HIVIGs were neutralizing. When used alone, the anti-CD4-binding site MAb b12, the anti-gp41 MAb 2F5, and the anti-gp120 MAb 2G12 were the most potent. When combination regimens involving two MAbs targeting different epitopes were tested, synergy was seen in all paired MAbs, except for one combination that revealed additive effects. The lowest effective antibody concentration for 50% viral neutralization (EC50) and EC90 were achieved with combinations of MAbs b12, 2F5, 2G12, and the anti-V3 MAb 694/98D. Depending on the combination regimen, the concentration of MAbs required to reach 90% virus neutralization was reduced approximately 2- to 25-fold as compared to the dose requirement of individual MAbs to produce the same effect. Synergy of the combination regimens implies that combinations of antibodies may have a role in passive immunoprophylaxis against HIV-1. The ability of SHIV to replicate in rhesus macaques will allow us to test such approaches in vivo.     

Bronchoscopy-associated Mycobacterium xenopi pseudoinfections

Mycobacterium xenopi typically accounts for less than 0.3% of all clinical mycobacterial isolates. Over a 37-mo period, 21 (35%) of 60 mycobacterial isolates from a Michigan hospital were identified as M. xenopi. Hospital, laboratory, and bronchoscopy records were reviewed to determine case characteristics, develop a case series, and calculate procedure-specific M. xenopi isolation rates. A case-control study was conducted to elucidate aspects of the bronchoscopy procedure associated with M. xenopi isolation. Bronchoscope cleaning procedures were reviewed, and hospital water systems were cultured. Four isolates were from three patients with disease attributable to M. xenopi. Of the other isolates, specimens obtained by bronchoscopy were more likely to yield M. xenopi than were specimens obtained by other routes (relative risk, 9.7; 95% confidence intervals, 3.2, 29.6). Bronchoscopes were disinfected in a 0.13% glutaraldehyde-phenate and tap-water bath and then were rinsed in tap water. Water from the hot water tank supplying this area yielded M. xenopi. Mycobacteria were cultured from bronchoscopes after disinfection. M. xenopi in the tap water appears to have contaminated the bronchoscopes during cleaning. Adequate disinfection of contaminated bronchoscopes and careful collection of specimens to avoid contamination with contaminated water are essential, both for limiting diagnostic confusion caused by mycobacterial pseudoinfections and for reducing risks of disease transmission.     

Personal social networks and HIV status among women on methadone

This objective of this study was to examine the association between a women's HIV status and specific (IDUs) characteristics of her social networks with respect to (1) number of injection drug users (2) number of drug partners and (3) number of HIV-positive contacts in her personal networks, after controlling for the respondent's demographic characteristics and drug use. Participants were recruited through posted announcements in three methadone clinics in Harlem, New York City. Individuals were considered eligible if they were enrolled as patients in one of the clinics for at least three months. A social network questionnaire modeled after the General Social Survey network section was developed by the investigators. Face-to-face interviews were conducted by trained interviewers and included demographics, drug use, self-reported HIV status of the woman and her network members, and the social network structures. Univariate analyses found that HIV-positive and HIV-negative women had different network profiles. HIV-positive women were more likely to associate with a higher number of current drug users, injection drug users, injection drug users who were HIV-positive, drug partners, drug partners who used injection drugs, and drug partners who were HIV-positive. Multivariate analyses indicated that HIV-positive respondents were more likely to associate with HIV-positive network members than their HIV-negative counterparts. The findings suggest that to better understand the spread of HIV among female drug users and to design more effective HIV/AIDS prevention programmes, efforts should move beyond focusing on individual attributes to address the contextual dynamics of social networks.     

Pigs fed cholesterol neonatally have increased cerebrum cholesterol as young adults

Sixty-eight female neonatal pigs selected for seven (Experiment 1) or eight (Experiment 2) generations for high (HG) or low (LG) plasma cholesterol were used to test the hypothesis that neonatal dietary cholesterol fed during the first 4 or 8 wk of postnatal life increases the cholesterol content of the cerebrum in young adulthood following free access to a high-fat (15%), high-cholesterol (0.5%) diet from 8 to 20 or 24 wk of age. Pigs were removed from their dams at 1 d of age and given free access to a sow-milk replacer diet containing 9.5% coconut fat and 0 or 0.5 % cholesterol. All pigs (except four HG and four LG pigs in Experiment 2, which were deprived of cholesterol throughout the study) were fed the high-fat, high-cholesterol diet from 8 wk to termination at 20 or 24 wk of age. Cerebrum weight and cholesterol concentration were higher in pigs fed cholesterol neonatally than in those deprived of cholesterol neonatally in both experiments, but weight and cholesterol concentration were unaffected by genetic line. Cholesterol concentrations in longissimus and semitendinosus muscles and in subcutaneous fat were unaffected by diet or genetic line. We conclude that dietary cholesterol deprivation during the first 4 to 8 wk of life in piglets is associated with lower cholesterol concentration and total content in the young adult cerebrum than in pigs supplemented with cholesterol in early life. These data support previous observations and suggest the possibility of a metabolic need for neonatal dietary cholesterol in normal brain development.     

Phylogenetic analysis of the Bunocotylinae dollfus, 1950 (Digenea: Hemiuridae)

We investigated the functional determinants of the cutaneous expression of elements of the hypothalamic-pituitary-adrenal axis. In the present work, the presence of adrenocorticotropin (ACTH) peptide in skin of C57/BL6 mouse was demonstrated by reversed-phase HPLC analysis combined with specific radioimmunoassay. ACTH concentration that was low in telogen, increased during anagen in two steps: a rapid phase in anagen I, and a slower rise that reached its peak in anagen VI. Immunofluorescence localized the ACTH antigen to the basal layer of epidermis, outer root sheath of hair follicle and subcutaneous muscle of anagen VI skin. At physiological plasma concentration (10-9 M), ACTH selectively stimulated DNA synthesis in dermis, while pharmacological doses (10-7-10-6 M) inhibited DNA synthesis in both dermis and epidermis. In conclusion, we suggest that local production of ACTH may represent a regulatory element in the control of skin functions including hair growth.