An age-period-cohort analysis of 50,875 AIDS cases among injecting drug users in Europe

BACKGROUND: The long average incubation time from HIV infection to AIDS makes it difficult to estimate recent HIV transmission from AIDS incidence data. Age-period-cohort (APC) analysis can separate out the effects of age, calendar time and birth cohort to provide a clearer picture of transmission trends. METHODS: AIDS incidence data from 1981 to 1994 among intravenous drug users (IDU) for 12 Western European countries were used. Yearly incidences per 100,000 population or 100,000 person-years were calculated by age at diagnosis and 5-year birth cohort (1950-1954, 1955-1959, 1960-1964, 1965-1969 and 1970-1974), and corrected for reporting delay. Incidence patterns were compared between birth cohorts and countries. RESULTS: For most countries the impact was greatest on the cohort born 1960-1964. Comparing incidence patterns in the 1965-1969 to 1960-1964 cohorts suggest the epidemic has plateaued at low to intermediate levels in Austria, Greece and the North-Western European countries, and at high levels in France, Italy and Switzerland. For most countries transmission amongst the 1970-1974 as compared to the 1965-1969 cohorts could not be assessed due to small numbers and short follow-up time. In Spain the epidemic was uncontrolled with a high incidence among recent birth cohorts. In Portugal the epidemic was still at an early and expanding phase. CONCLUSIONS: The APC analysis revealed large country differences in the dynamics of the HIV/AIDS epidemic among IDU. Full interpretation of these differences is dependent on information from other sources about the local public health response and trends in drug injecting behaviours. Earlier introduction of the virus and higher prevalence of injecting drug use may explain some of the generally higher incidence in Southern European countries, but the larger part of it is most likely explained by local characteristics of drug users, such as younger age and more frequent sharing of needles and syringes, and a less effective public health response.     

Agonist-induced GTPgamma35S binding mediated by human 5-HT(2C) receptors expressed in human embryonic kidney 293 cells

The 5-HT(2C) receptor as heterologously expressed in various mammalian cells mediates inositol 1,4,5-triphosphate (IP(3)) signal by activating G(q/11) subtypes of G proteins, but minimally promotes agonist-induced GTPgamma35S binding in membranes due to slow GTP turnover rates of the G proteins. Here we discovered robust (over 200%) agonist-induced GTPgamma35S binding mediated by the human receptor expressed in human embryonic kidney (HEK) 293 cells, and investigated its pharmacology. Agonists concentration-dependently increased GTPgamma35S binding in isolated membranes, which was competitively blocked by antagonists. Intrinsic efficacies of agonists from GTPgamma35S binding were comparable to those from IP(3) measurement. Pertussis toxin treatment largely blocked serotonin-induced GTPgamma35S binding, serotonin high affinity sites by 70% without altering the total binding sites, and reduced IP(3) release by 40%. GTPgamma35S-bound Galpha subunits from serotonin-activated membranes were mainly Galpha(i), judging from immobilization studies with various Galpha-specific antibodies. Inhibition of forskolin-stimulated cAMP formation, however, was not observed. Apparently, the 5-HT(2C) receptor-mediated GTPgamma35S binding is a unique phenotype observed in HEK293 cells, reflecting its coupling to pertussis toxin-sensitive G(i) subtypes, which contribute to the IP(3) signal, along with pertussis toxin-insensitive G(q/11) subtypes.     

N-Substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D(2) antagonists/5-HT(1A) partial agonists with potential as atypical antipsychotic agents.

A series of N-substituted 1-(2,3-dihydro-1, 4-benzodioxin-2-yl)methylamine derivatives with D(2) antagonist/5-HT(1A) partial agonist activity has been prepared as potential atypical antipsychotic agents. Optimization of in vitro receptor binding activity and in vivo activity in rodent models of psychosis has led to compound 24, which showed good affinities for human D(2), D(3), and 5-HT(1A) receptors but significantly less affinity for human alpha(1) adrenoceptors and rat H(1) and muscarinic receptors. In rodents, 24 showed functional D(2)-like antagonism and 5-HT(1A) partial agonism. After oral dosing, 24 showed good activity in rodent antipsychotic tests and very little potential to cause extrapyramidal side effects (EPS), as measured by its ability to induce catalepsy in rats only at very high doses. In the light of this promising profile of activity, 24 has been selected for clinical investigation as a novel antipsychotic agent with a predicted low propensity to cause EPS.     

An examination of ALDH2 genotypes, alcohol metabolism and the flushing response in Native Americans

OBJECTIVE: The study was designed to examine the relationship between aldehyde dehydrogenase (ALDH2) genotype and the flushing response in a population of Native Americans. METHOD: Objective measures of the flushing response were obtained by monitoring skin temperature, heart rate, blood pressure, as well as blood alcohol concentrations, in flushing and nonflushing Native Americans (n = 105) as well as in Oriental (n = 15) and white (n = 15) control subjects following a dose of alcohol (0.2 or 0.4 gm/kg). ALDH genotypes were determined via polymerase chain reaction followed by hybridization to 32P or biotin-labeled allele-specific oligonucleotide probes. RESULTS: There were no ALDH2 mutations detectable in Native Americans reporting the flushing response, nor any objective evidence of an Oriental-like response to alcohol. The rate of alcohol metabolism was shown to be the same among whites, Native flushers and Native nonflushers. CONCLUSIONS: The results demonstrate that the flushing reaction experienced by Native Americans appears to be milder and less unpleasant than the "Oriental" flushing reaction, with little effect on drinking frequency and amount. In addition, the flushing is not mediated by the ALDH2 mutation or elevated blood acetaldehyde. A critical analysis of the discrepancies in the literature regarding alcohol metabolism in Native Americans is provided.     

HIV vaccine research continues despite setbacks

New agents for treating asthma and allergic disease are now under development. From Arris Pharmaceutical comes recombinant neutral endopeptidase (rNEP), ^* an agent that may prove effective as prophylaxis against symptomatic episodes in patients with moderate-to-severe asthma. A group of compounds known as tryptase inhibitors may also be of use in inflammatory diseases such as asthma, as preclinical studies have shown that they can prevent airway inflammation in sheep. In addition, Tanox Biosystems is developing therapies that target immunoglobulin E (IgE), which is a key mediator of atopic allergic disease. News of recent progress with these agents was presented at an IBC USA conference on Asthma [ Philadelphia, US; October 1995 ].     

A new method of STR interpretation using inferential logic -development of a criminal intelligence database

Abstract A short tandem repeat (STR) system consisting of seven multiplexed loci has recently been introduced in the UK to support a National strategy to create large DNA databases for criminal intelligence purposes. The process uses automated sequencers, employing dye-labelled primers. Identification of tetrameric loci such as HUMTH01 are straightforward. Sizing windows are estimated by running a series of control allelic ladders on several gels and unknown samples are designated if they fall within a defined window. However, utilisation of complex STRs (eg. D21 S 11) characteristically have common variants which differ by just 2 bp. In addition, rare alleles are encountered which may differ by just 1 by from a common variant. To assist with the identification of alleles, we have introduced a series of allelic ladders, so that direct comparisons with unknown samples can be made on the same gel. To designate an allele, it should be within 0.5 by of an allelic ladder marker. Not all alleles (in particular rare alleles) can be included within an allelic ladder, however their expected positions can be easily calculated by reference to existing alleles in the ladder. Measurement of band shift is also a useful diagnostic tool. A series of guidelines are described to enable reliable allelic identification. These guidelines can be converted into computer programmes, which form the basis of an expert system.     

Access Technique for Retroperitoneoscopy

Purpose

The access technique for retroperitoneoscopy is not well established, and differs from transperitoneal laparoscopic access in 3 key aspects: 1) location and technique of primary trocar placement, 2) optimal positioning of the balloon dilator and 3) technique for safe placement of secondary ports. Our method of obtaining retroperitoneoscopic access addresses these issues.

Materials and Methods

A total of 37 patients underwent retroperitoneoscopic surgery of the kidney and upper ureter.

Results

Our technique facilitates balloon placement within Gerota's fascia, minimizes peritoneal injury and optimizes port placement during retroperitoneoscopic surgery.

Conclusions

Although our success rate for placing the balloon within Gerota's fascia has improved, additional experience is required to achieve subfascial balloon placement more consistently.     

Attenuation of voluntary ethanol consumption by dopamine-beta-hydroxylase inhibition (FLA-57): mediated by changes in aversion, reinforcement or both

The dopamine-beta-hydroxylase inhibitor, FLA-57, was reported by several investigators to reduce voluntary ethanol consumption in rats. The nature of the effect of FLA-57 on this behavior had been attributed to its involvement in both the mediation of positive reinforcing and aversive processes. In the present study, the capacity of FLA-57 to induce a conditioned taste aversion (CTA) in both a forward and a "nominally backward conditioning" paradigms was investigated. This was done in an attempt to assess the possible contribution of a FLA-57-induced CTA to the previously observed reduction in ethanol intake in several drinking studies. Furthermore, the ability of FLA-57 to induce a CTA in a nonnovel situation, where the taste of the presented solution (ethanol or saccharin) was familiar to the animals, was also assessed. The inclusion of these specific conditions was necessitated by the attempt to create conditions similar to those prevalent in drinking studies. We found that FLA-57, in both conditioning paradigms, induced a significant CTA. Animals, naive and experienced with the taste of ethanol or saccharin, exhibited a CTA following the administration of FLA-57. However, the magnitude and rate of extinction of the observed CTAs did not resemble those observed in studies on the effects of FLA-57 on ethanol intake. The results of this study suggest that while it is possible that FLA-57 exerts its effect on ethanol intake, at least in part, through an aversive mechanism, such a mechanism is unlikely to be the exclusive process through which ethanol ingestion is attenuated.