Additional pathways of S-conjugate formation during interaction of 4-nitrosophenetole with glutathione.

The rapid reactions of nitrosoarenes with cellular SH groups have proved to be main metabolic conversions during detoxication. Interactions of the phenacetin metabolite 4-nitrosophenetole with glutathione have been investigated in detail during the last years, revealing a complex pattern of products depending on the stoichiometry of the reactants and reaction conditions. Eight metabolites have been identified hitherto, and the present work extends this medley by six additional products. Three metastable sulfenamides, 4-ethoxy-2,N-bis(glutathion-S-yl)-aniline, N4-(glutathion-S-yl)-4-amino-4'-ethoxydiphenylamine, and N-(glutathion-S-yl)-4-aminophenol, as well as the N-sulfenylquinonimine N-(glutathion-S-yl)-1,4-benzoquinonimine were characterized by chemical reactivity, chromatographic behavior, UV/vis absorption, 1H NMR, and FAB-MS data. The structure of the sulfenamide 2,N4-bis(glutathion-S-yl)-4-amino-4'-ethoxydiphenylamine could not be proved unequivocally, but is strongly suggested due to the chemical reactivity, chromatographic behavior, and UV/vis absorption of the compound. Finally, traces of 4-aminophenol were detected. A reaction scheme is presented explaining the formation of all identified metabolites via a central sulfenamide cation. Molecular orbital calculations for this sulfenamide cation have been performed, corroborating the proposed reaction mechanisms on the basis of Klopman's generalized perturbation theory.

HIV-1 disease progression and AIDS-defining disorders in rural Uganda.

BACKGROUND: The majority of people infected with HIV-1 live in Africa, yet little is known about the natural history of the disease in that continent. We studied survival times, disease progression, and AIDS-defining disorders, according to the proposed WHO staging system, in a population-based, rural cohort in Uganda. METHODS: In 1990 we recruited a random sample of people already infected with HIV-1 (as prevalent cases) detected during the initial survey round of a general-population study to form a natural-history cohort. Individuals from the general-population cohort who seroconverted between 1990 and 1995 (incident cases) were also invited to enroll. Participants were seen routinely every 3 months and when they were III. FINDINGS: By the end of 1995, 93 prevalent cases and 86 incident cases had been enrolled. Four patients in the prevalent group were in stage 4 (AIDS) at the initial visit. During the next 5 years, 37 prevalent cases progressed to AIDS. Seven incident cases progressed to AIDS and the cumulative progression to AIDS at 1, 3, and 5 years after seroconversion was 2%, 6%, and 22%, respectively. The cumulative probability of AIDS at 4 years from entering stages 1, 2, and 3 was 11%, 33%, and 58%, respectively. There were 47 deaths among prevalent cases and seven among incident cases during follow-up. The cumulative mortality 4 years after patients entered stages 1, 2, 3, and 4 was 9%, 33%, 56%, and 86%, respectively. The median survival after the onset of AIDS was 9.3 months. INTERPRETATION: Our results are important for the setting of priorities and rationalisation of treatment availability in countries with poor resources. We found that progression rates to AIDS are similar to those in developed countries for homosexual cohorts and greater than for cohorts infected by other modes of transmission. However, we have found that the rates of all-cause mortality are much higher and the progression times to death are shorter than in developed countries.

PIP: The authors studied AIDS-defining disorders, disease progression, and survival times in cohorts of HIV-infected people in a rural region of Uganda. A random sample of people already infected with HIV-1 was recruited in 1990. The subjects had been detected during the initial survey round of a general-population study to form a natural-history cohort. Individuals from the general-population cohort who seroconverted between 1990 and 1995 were also invited to enroll in the study. Participants were seen routinely every 3 months and when they were ill. By the end of 1995, 93 prevalent cases and 86 incident cases had been enrolled. Four patients in the prevalent group were in World Health Organization-defined stage 4 HIV disease, AIDS, at the initial visit. Over the next 5 years, 37 prevalent cases progressed to AIDS. Seven incident cases progressed to AIDS and the cumulative progression to AIDS at 1, 3, and 5 years after seroconversion was 2%, 6%, and 22%, respectively. The cumulative probability of AIDS at 4 years from entering stages 1, 2, and 3 was 11%, 33%, and 58%, respectively. There were 47 deaths among prevalent cases and seven among incident cases during follow-up. The cumulative mortality 4 years after patients entered stages 1, 2, 3, and 4 was 9%, 33%, 56%, and 86%, respectively. The median survival duration after the onset of AIDS was 9.3 months.

An HIV-1 natural history cohort and survival times in rural Uganda.

OBJECTIVE: To describe a population-based rural cohort of HIV-1-seropositive and seronegative individuals established in 1990 in south-west Uganda, and determine survival times in the cohort. DESIGN: Prospective cohort study. METHODS: Participants were recruited from a large population study, and invited to attend a clinic every 3 months. They were seen by clinicians who administered detailed medical questionnaires and undertook a physical examination. RESULTS: By the end of 1995, 390 (79%) of the 491 people asked to enrol in the natural history cohort (NHC) had done so. Ninety-three were prevalent cases of HIV infection detected during the initial survey round of the general population cohort in 1989/1990, 66 were subsequent incident cases, 177 were age-matched HIV-negative controls and 54 were HIV-negative spouses of HIV-positive individuals. Twenty participants seroconverted in the NHC. The age-standardized mortality rates per 1000 person-years for the prevalent, incident, and negative cases were 156.5 [95% confidence interval (CI), 115.8-211.4], 35.0 (95% CI, 16.4 75.0) and 13.5 (95% CI, 7.3-25.1), respectively. The median survival time from enrolment to death for the prevalent cases was 4.5 years (95% CI, 3.5- > 5.2); > 5.4 years from seroconversion for the incident cases; and > 5.2 years from enrolment for the HIV-negative cases. The 5-year cumulative survival for prevalents, incidents and HIV-negative participants was 46%, 83% and 94%, respectively. CONCLUSIONS: We have described an NHC of HIV-positive and HIV-negative participants which is representative of the general population. The NHC was established over 5 years ago; it is continuing and we are maintaining good compliance rates. Survival probabilities in the cohort were lower than most other reported studies.

PIP: To enhance understanding of the natural history of HIV-1 infection among the general population in Africa, a population-based cohort of HIV-prevalent (n = 93) and HIV-incident (n = 66) cases, HIV-negative controls (n = 177), and seronegative partners of HIV-positive cases (n = 54) was recruited in rural southwest Uganda. Between 1990 and 1995, 1353 people-years (PY) of observation were achieved. There were 20 seroconversions during this period. The median duration from enrollment to seroconversion were 25 months for negative controls and 6 months for negative discordants. Of the 64 deaths over the 5-year study period, 54 involved HIV-infected subjects. The age-standardized mortality rates for the prevalent, incident, and negatives per 1000 PY of observation were 156.5 (95% confidence interval [CI], 115.8-211.4), 35.0 (95% CI, 17.4-75.0), and 13.5 (95% CI, 7.3-25.1), respectively. There were no significant differences in the gender-specific mortality rates per 1000 PY in males (48.9) and females (45.7). The median ages at death of prevalent, incident, and negative participants were 33, 53, and 53 years, respectively. The median survival times from enrollment to death were 4.5 years for prevalent cases, over 5.4 years for incident cases, and over 5.2 years for HIV-negative cases. At 5 years, the cumulative survival probabilities for prevalent, incident, and negative cases were 46%, 83%, and 94%, respectively, considerably lower than those reported in other studies. Follow-up of the cohort will continue, and future papers will address the clinical manifestations and other parameters of disease progression.

Incidence of HIV-1 infection in adults and socio-demographic characteristics of seroconverters in a rural population in Uganda: 1990-1994.

BACKGROUND: To evaluate HIV-1 incidence among adults and socio-demographic risk factors in a rural population in Uganda, a prospective cohort study was carried out. METHODS: All consenting adult residents in a cluster of 15 neighbouring villages of the Masaka District of south-west Uganda have been participating in annual socio-demographic and serological surveys since November 1989. Those who had a negative serostatus when they were first tested and had at least one serostatus assessment during the 4 years of follow-up (1990-1994) have been evaluated for HIV-1 seroconversion. Incidence rates have been calculated per 1000 person-years of observation and socio-demographic characteristics assessed for association with recent seroconversion. RESULTS: At the baseline survey, of 4175 adults with assessable serostatus (79% of all censused adults), 342 (8.2%) were seropositive. During 12588.2 person-years of follow-up 89 seroconversions were identified corresponding to an incidence rate of 7.1 (95% CI: 5.6-8.5). Overall rates were highest in females aged 20-24 years (15.2) and in males aged 20-44 years (11.6). There was a significant interaction between age and sex; the ratio of the rate in females to that in males decreased from 3.3:1 to 0.5:1 with increasing age. Rates for males aged > or = 20 years were four times higher than those for younger males. Other significant socio-demographic correlates with risk included not belonging to the majority tribe, non-Muslim religion and length of stay on compound of less than 10 years. Incidence rates did not show any clear trends with time. CONCLUSION: These findings further emphasize the need for targeted interventions.

Verbal autopsy as a tool for diagnosing HIV-related adult deaths in rural Uganda.

BACKGROUND: In general, information on the causes of adult deaths in developing countries is scarce. More specifically, relatively little is known about the effect of HIV-1 associated disease on adult mortality in general populations. In this study we have used a verbal autopsy technique to ascertain whether adult deaths were associated with HIV-1 in a rural population with a prevalence of HIV-1 infection of 8%, and used HIV-1 antibody status to validate the verbal autopsy findings. METHODS: All adult deaths in the population cohort that occurred between December 1990 and November 1993 were identified through a monthly death registration system. Approximately 2 months after death, a relative of the deceased was interviewed by a trained nurse, and questionnaires were assessed by at least two independent clinicians; all were unaware of the HIV serostatus of the deceased. RESULTS: A total of 155 adult deaths was assessed, i.e. 53% of all recorded adult deaths. Of those assessed half were HIV-1 positive. In all 47% of deaths were classified as HIV-related. The overall specificity and positive predictive value of the verbal autopsy tool were both 92%; in those aged 13-44 years (83 adults) the corresponding values were 85% and 95% respectively. The verbal autopsy estimated HIV-1 attributable mortality fraction was similar to the calculated fraction based on prospective data. CONCLUSIONS: The results of this study suggest that verbal autopsy studies may assist in providing data on HIV-associated mortality in general populations and may be useful as surveillance tools.

PIP: The verbal autopsy technique represents a means for increasing the accuracy of acquired immunodeficiency syndrome (AIDS)-related mortality statistics in sub-Saharan Africa, where many deaths occur at home. A structured interview, adapted to local disease perceptions, is administered by lay personnel to relatives or friends of the deceased. This technique was evaluated in a rural area of Uganda's Masaka district with a human immunodeficiency virus (HIV)-1 seroprevalence rate of 8%. All adult deaths occurring in the 15 index villages from December 1990 to November 1993 were identified through a monthly village-based death registration system. A nurse paid an initial condolence visit to the bereaved family and returned about two months later with the questionnaire. Interviews were conducted with families or friends of 155 (53%) of the 293 adult deaths for which HIV serostatus was known. At least two clinicians unaware of serostatus results assessed each questionnaire and indicated the likely causes of death. There was agreement on whether the death was or was not HIV-related in 141 (91%) of these deaths. The 14 cases with discordant assessments were reviewed by a third clinician. Overall, 73 (47%) of deaths were attributed to HIV-related causes. Using HIV serostatus as a standard of comparison, the overall specificity and predictive value of the verbal autopsy were both 92%. These findings suggest that the method can be relied upon to estimate HIV-associated mortality in populations with a relatively high HIV prevalence.

HIV-1 infection in a Ugandan town on the trans-African highway: prevalence and risk factors.

All adult residents (aged 13 years or more) of 154 randomly selected households in 3 urban and one semi-rural ward of a town in South West Uganda on the trans-African highway were invited to participate in a socio-demographic, behavioural and medical survey. An unambiguous HIV-1 serostatus was obtained for 389 (80%) adults. The overall sero-prevalence rate was 40.4%; all age groups except males aged 13-19 years had infection rates in excess of 20%. Rates above 50% were found in females aged 20-34 years and males aged 35-44 years. For females seropositivity rates increased steeply with increasing numbers of lifetime sexual partners up to a maximum of 3; in contrast, for males rates continued to increase with increasing numbers of partners. The risk of infection amongst those with only one reported partner was 17%. A high proportion of males (14%) and females (18%) reported a history of genital ulcer disease within the previous 6 months; on examination genital lesions were observed in 12% of all participants. Interventions with a single focus are unlikely to have much impact in such a situation and a strategy is suggested which includes 3 components, namely improved STD control, a reduction in partner change and an increase in condom utilization.

PIP: In mid-1991, in a Ugandan town on the trans-African highway, interviews were conducted with and blood specimens taken from 389 persons aged 13 to more than 45 years from 154 households to assess the prevalence of HIV-1 infection and to identify its risk factors. The overall HIV-1 prevalence rate stood at 40.4% (35.6% for men and 43.7% for women). The highest HIV-1 prevalence rates were among men aged 35-44 (56.7%) and women aged 20-24 and aged 25-34 (52.9% and 50.6%, respectively). The urban rate was higher than the semi-rural rate (44.1% vs. 25.6%; p 0.005). 65% of all households had at least one HIV-1 seropositive adult. Single adults had a lower HIV-1 seroprevalence rate than ever married adults (e.g., among men, 10.3% vs. 30.8-62.5%) (relative risk [RR] = 2.8; p 0.005). The Baganda ethnic group had the lowest rate, while the Rwandese group had the highest rate (35.8% vs. 59.2%; RR = 1.4). Education did not affect the prevalence rate. Employed persons were more likely to have HIV-1 infection than the unemployed (44.4% vs. 32.6%; p 0.05). The occupations with the highest HIV-1 infection rates were business person (56.2%) and bar attendant (50%). History of blood transfusion did not appear to be a risk factor for HIV-1 infection (28% vs. 41.3% for no history). 33 HIV-1 seropositive adults had never had sexual intercourse. Men were more likely to have had multiple sex partners than women (e.g., having at least 10 lifetime partners, 61% vs. 11%). Seropositivity rates increased greatly with rising numbers of lifetime sexual partners to a maximum of 3 for females, but it continued to rise for men. It increased for men as the number of contacts in the last month increased (p = 0.05 for trend). 14% of men and 18% of women had a genital ulcer disease in the last 6 months. These findings suggest a need for a three-pronged AIDS prevention strategy: improved sexually transmitted disease control, a reduction in partner change, and an increase in condom use.

Migration and AIDS.

PIP: A successful short-term solution to transmission of AIDS in Western Africa by migrants involves provision of accessible and acceptable basic health and social services to migrants at their destination. The aim is to establish a sense of security and community, which is a health requirement. When migrants are excluded from community life or victimized as carriers of HIV infections, they will be driven by basic survival needs and dysfunctional social organization, which results in the rapid spread of HIV. Closing borders and mass deportation may not be an option. The long-term solution is population policy, environmental protection, and economic development. The focus on mapping the spread of AIDS must shift to a consideration of the migrant social conditions that make them vulnerable to AIDS. The issue of migration and AIDS will be addressed at the First European Conference on Tropical Medicine in October 1995 in Hamburg, Germany. In Uganda, HIV seroprevalence rates ranged from 5.5% among the stable population to 12.4% among internal migrants moving between villages to 16.3% among migrants from other areas. A World Bank project is operating in Western Africa, which traces seasonal male migration from the Cameroon to Liberia, Senegal to Nigeria, and from the Sahel to the coast during dry seasons. National border rules may influence the routes but not the extent of migration. A major destination place is Cote d' Ivoire, which has 25% of total population comprised of migrants from other countries and one of the highest HIV prevalence rates in Western Africa. On plantations prostitutes are brought in. Each prostitute serves about 25 workers. The pattern of sexual mixing contributes to the high HIV rates. Female migration is smaller and usually concentrated in prostitution at place of destination. Illiteracy and poverty drive women migrants into the trade. Their frequent health problems are malaria, pelvic pain, menstrual irregularity, vaginal discharge, and genital sores. Drugs are bought on the streets or from friends and may be of questionable efficacy. Health services may be sought upon return to the home country.^ieng

Migration and HIV-1 seroprevalence in a rural Ugandan population.

OBJECTIVE: To study the association between change of residence and HIV-1 serostatus in a rural Ugandan population. DESIGN: A longitudinal cohort study. METHODS: As part of the annual surveillance of a population cohort of approximately 10,000 individuals in a rural subcounty of southwest Uganda, information has been collected for all adults on change of residence over a 3-year period and its association with HIV-1 serostatus. Sera were collected by a medical team during home visits. Antibody testing was performed at the Uganda Virus Research Institute using two independent enzyme immunoassay systems and Western blot when appropriate. RESULTS: At the fourth survey-round, age and sex-standardized seroprevalence rates were 7.9% overall; the rate was 5.5% for 2,129 adults who had not changed address since the first survey, 8.2% for 336 who moved within the village, 12.4% for 128 who moved to a neighbouring village, 11.5% for 1,130 who had left the area and 16.3% for 541 who had joined the study area during the previous 3 years (P << 0.001, 4 degrees of freedom). We also observed an inverse relationship between years lived at the present house at the time of the first survey and both seroprevalence and subsequent seroincidence rates. The reported numbers of lifetime sexual partners were higher in those who changed residence. CONCLUSION: Change of residence is strongly associated with an increased risk of HIV-1 infection in this rural population and is likely to be the result of more risky sexual behaviour among those who move. These findings have important implications for the design of AIDS control programmes and intervention studies.

PIP: A longitudinal cohort study was conducted in a rural subcounty of Masaka district, Uganda, to study the association between change of residence and HIV-1 serostatus. Information was collected for all adults with regard to change of residence over a three-year period. The association of change of residence was assessed through the analysis of blood sera collected by a medical team during home visits. At the fourth survey round, age and sex-standardized seroprevalence rates were 7.9% overall; 5.5% for 2129 adults who had not changed address since the first survey, 8.2% for 336 who moved within the village, 12.4% for 128 who moved to a neighboring village, 11.5% for 1130 who had left the area, and 16.3% for 541 who had joined the study area during the previous three years. An inverse relationship was observed between the years lived at the present house at the time of the first survey and both seroprevalence and subsequent seroincidence rates. The reported numbers of lifetime sexual partners were higher among individuals who changed residence.

Estimating the number of HIV transmissions through reused syringes and needles in the Mbeya Region, Tanzania.

OBJECTIVE: HIV infection attributable to medical injections is suspected to be low, although case-control studies have not provided definite results. This study aims to determine the number of HIV infections caused by the reuse of syringes and needles in the Mbeya Region, Tanzania. METHODS: The direct identification or detection of HIV in syringes and needles under field conditions was not appropriate, therefore a surrogate marker consisting of two components for possible HIV transmission was used: insufficient sterilization, and blood remaining from a previous patient. The assumption was that HIV infection can only occur if both markers are positive. Samples were collected in nine health-care facilities. All syringes and needles prepared for use in these facilities were collected without prior notification. The samples were rinsed and the resulting fluid was cultured for bacteria. Traces of blood were detected by urine stick test for haemoglobin volumes > 0.0015 microliters. RESULTS: Bacterial contamination was found in 32.8% of the total 1219 syringes and needles; 67% was caused by improper handling of the equipment after sterilization. Blood was detected in 12.5% of the samples. In the following three sampling strata, both contamination criteria were positive either on the syringe or the needle: wards/outpatient departments (OPD), 1.39%; laboratories, 7.45%; expanded programme on immunization (EPI), < 0.1%. We calculated that from 1.1 million patients injected in wards/OPD in any 1 year, fewer than 13 become infected, in laboratories fewer than 12 (160,000 blood-taking procedures), and less than one child in the EPI (850,000 vaccinations). CONCLUSION: With an established AIDS intervention programme supporting the health system, less than 0.4% of the total annual incidence of 4500-8500 is attributable to medical injections in the Mbeya Region.

Seroprevalence and incidence of sexually transmitted diseases in a rural Ugandan population.

The aim of the study was to determine in a rural population the age- and sex-specific prevalence and incidence rates of serological reactivity of 5 common sexually transmitted diseases (STDs) and their association with HIV-1 antibody status. Of the adult population of two villages (529 adults aged 15 years or more) 294 provided an adequate blood specimen both on enrollment and at 12 months. The sera were tested at 3 collaborating laboratories for antibodies against HIV-1, Treponema pallidum, Haemophilus ducreyi, Chlamydia trachomatis and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). A sample of 45 children were tested for HSV-1 and HSV-2. Seroprevalence rates in adults on enrollment were 7.8% for HIV-1, 10.8% for active syphilis, 10.4% for H. ducreyi, 66.0% for C. trachomatis, 91.2% for HSV-1 and 67.9% for HSV-2. Males were significantly more likely than females to be seropositive for H. ducreyi (15.6% versus 6.6%), but less likely to be HSV-2 antibody positive (57.0% versus 74.4%). Reactivity to H. ducreyi, C. trachomatis and HSV-2 rose with increasing age. In contrast, active syphilis showed no age trend. All STDs tended to be more common in those HIV-1 seropositive. Incidence rates over the 12 months were nil for HIV-1, 0.5% for syphilis, 1.2% for H. ducreyi, 11.3% for C. trachomatis, and 16.7% for HSV-2. The results of this exploratory study indicate that all STDs included are common in this rural population. The high HSV-2 prevalence rate among adolescents suggests that HSV-2 may be an important risk factor for HIV-1 infection.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: A seroprevalence survey conducted in rural Uganda revealed a high potential for interaction between sexually transmitted diseases (STDs) such as herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV). Venous blood samples were collected at baseline and one year later from 294 randomly selected adults aged 15 years or over from two neighboring villages. At baseline, 23 (7.8%) adults were HIV-positive; no seroconversion occurred during the one-year study period. STD prevalence rates were 10.8% for syphilis, 10.4% for Hemophilus ducreyi, 66.0% for Chlamydia trachomatis, and 91.2% for HSV-1 and 67.9% for HSV-2. More females (74.4%) than males (57.0%) were HSV-2 antibody-positive. Reactivity to H. ducreyi, C. trachomatis, and HSV-2 rose with increasing age, but there was no such trend for syphilis. HIV prevalence rates were 0.0% among those with no serologic evidence of previous STDs, 2.6% among those with one or two prior STDs, and 20.0% among those with three or four STD markers. Of particular concern was the high rate of HSV-2 prevalence among adolescents (85% among females aged 20-24 years and 82% in males aged 25-29 years). It is suggested that age-specific HSV-2 seroprevalence can provide an accurate marker of premarital sexual activity among Ugandan adolescents since it lacks the potential for bias associated with self-reporting in this population.

Two-year HIV-1-associated mortality in a Ugandan rural population.

The mortality in 15 villages in South-West Uganda was studied in relation to HIV infection. After a population census, serum samples were tested for antibodies to HIV-1. Deaths were ascertained over 2 years. Unequivocal HIV-1 serology results were available for 9389 individuals. The prevalence of infection was 4.8% for all ages and 8.2% for adults (aged 13 or more). 198 deaths were recorded during 15,725 person years of observation. Mortality among seronegative adults was 7.7 per 1000 and among seropositive adults 115.9 per 1000. The excess annual death rate associated with HIV-1 infection was 5.3 per 1000 and in adults 7.9 per 1000. Highest excess mortality was 16.9 per 1000 in the age group 25-34. Among adults, half of all deaths and among those aged 13-44 over 80% of deaths were attributable to HIV-1 infection. These results show the strong impact that HIV-1 infection is having on mortality in a rural area of Uganda where the overall HIV-1 adult prevalence rate is below 10%--a rate lower than in many other parts of East Africa.

Risk factors for HIV-1 infection in adults in a rural Ugandan community: a case-control study.

OBJECTIVE: To study in depth sexual history and sexual behaviour variables as risk factors for HIV-1 infection in a rural Ugandan population. METHODS: Following a socioeconomic and serological survey of a rural population in Masaka District, south-west Uganda, 233 randomly selected HIV-1-positive cases and 233 negative controls matched on age and village of residence, were invited in October 1990 to participate in a case-control study. A total of 132 cases and 161 controls attended for in-depth investigation including an interview about sexual behaviour. RESULTS: The factor most strongly associated with increased risk of infection was a greater number of lifetime sexual partners, with odds ratios (OR) of 2.1 and 4.9 for those reporting 4-10 and 11 or more partners, respectively, compared with those reporting less than four partners. Having only one sexual partner did not provide complete protection, a total of seven (one male, six female) subjects reporting only one sexual partner were HIV-1-positive. Other significant factors were a history of genital ulcers [OR, 2.9; 95% confidence intervals (CI), 1.0-9.1) and not being a Muslim (OR, 5.4; 95% CI, 1.8-16.5) suggesting a possible protective effect of circumcision. There was a suggestion that those who married within the last 7 years (OR, 2.4; 95% CI, 0.9-6.1) and men exposed to menstrual blood (OR, 5.7; 95% CI, 0.7-49.8) were at an increased risk of HIV-1 infection. CONCLUSIONS: These results confirm the predominant role of sexual behaviour in the HIV-1 epidemic. Of particular concern is the observation of HIV-1 infection among those reporting only one partner. Where HIV-1 infection is widely distributed in the general population, risk reduction strategies should, in addition to the promotion of partner reduction, place strong emphasis on safe-sex techniques.

HIV-1 incidence and HIV-1-associated mortality in a rural Ugandan population cohort.

OBJECTIVE: To determine the incidence of HIV-1 infection and HIV-1-associated mortality in a rural Ugandan population. DESIGN: A prospective cohort study. METHODS: A cohort consisting of the population (de jure census 9820) of a cluster of 15 villages in Masaka District, south-west Uganda was enrolled between 1989 and 1990 through a demographic and medical survey. The HIV-1 seroprevalence rate was 4.8% for all ages combined and 8.2% for those aged 13 years or more. The survey was repeated after 1 year. RESULTS: The 1-year HIV-1 incidence rate among adults was 1% [9.2 per 1000 person-years of observation; 95% confidence interval (CI), 5.5-12.9). A total of 84 deaths were observed. In adults, half of all deaths (31 out of 60) were in HIV-1-seropositive individuals. The age-adjusted overall mortality rate ratio for HIV-positive adults compared with HIV-negatives was 20.8 (95% CI, 12.0-35.7). In the 13-44 age group the corresponding rate ratios for men, women and both sexes combined were 16.3, 108.9 and 58.7, respectively. The HIV-attributable mortality fractions, i.e., the proportion of deaths that would have been avoided in the absence of HIV, were 44, 50 and 89% for adult men, adult women and adults aged 25-34 years (both sexes combined), respectively. The 1-year progression to death among HIV-1-seropositive adults was 10.3%. CONCLUSION: These results demonstrate the profound impact that the HIV-1 epidemic has on adult mortality in a rural area of Uganda where the HIV-1 prevalence and incidence rates in adults are 8 and 1%, respectively.

General and HIV-1-associated morbidity in a rural Ugandan community.

OBJECTIVES: The AIDS epidemic in sub-Saharan Africa affects whole communities, adding to the already high burden of morbidity. Reports of AIDS cases are usually from hospital attenders, often diagnosed using the World Health Organization (WHO) clinical case definition. Little is known about the extent of HIV-associated morbidity in the general population. The objectives of this study were to describe the prevalence of (1) markers of general morbidity and (2) the criteria of the WHO clinical case definition for AIDS and (3) to determine the association between these markers and HIV-1 serostatus in a rural Ugandan community. METHODS: A survey was conducted among the adult population (aged > or = 13 years) of 15 neighbouring villages in Masaka District, south-west Uganda. The survey included medical history, physical examination and testing for HIV-1 antibodies. RESULTS: The HIV-1 seroprevalence among 4175 out of 5278 (79%) eligible adults was 8.2%. Current health problems were reported by 57.6% of adults, with increased rates in HIV-1-positive subjects, women and older people. Five of the 10 most common complaints showed significant associations with HIV-1 status, as did reported genital ulcer and vaginal discharge. The crude HIV-1 attributable disease burden in the population was 1.2% for current illness, 4.3% for previous serious illness and 9.9% for illness leading to hospital admission. Overall, 11 (3.3%) of the HIV-1-positive and nine (0.2%) of the HIV-1-negative subjects had AIDS as defined by the clinical case definition. The positive and negative predictive values and specificity were 55.0, 92.0%, and 99.8%, respectively. CONCLUSIONS: Against a background of high general morbidity, we observed a relatively small population attribution of HIV-1-associated morbidity. The results indicate that the clinical AIDS case definition may provide a useful tool for population surveys.

Conformational studies of two histamine H2-receptor antagonistic phenylformamidines: mifentidine and its guanidinothiazole analogue DA 4643.

Two histamine H2-receptor antagonists of the phenylformamidine type, mifentidine (N-isopropyl-N'-(4-1H-imidazol-4-yl-phenyl) formamidine dihydrochloride; I) and DA 4643 (N-methyl-N'-(3-(2-guanidinothiazol-4-yl)-phenyl) formamidine dihydrochloride; II), have been investigated by experimental physico-chemical studies and theoretical conformational analysis. PKa determinations on the two molecules I and II show that these substances exist at physiological pH (7.4) predominantly as their monoprotonated forms at the formamidine moiety. Semiempirical quantum mechanical (MNDO, CNDO/2) and molecular mechanics (MMPI) calculations show a preference of the nearly planar conformations for I and of different low energy rotamers for II. The energy of these conformers is a function of two important torsion angles, one around the bond joining the imidazole, or the guanidinothiazole, and the phenyl ring and the other around the bond joining the phenyl ring and the formamidinium cation. When the distances between crucial parts present in I and II are considered, it results that the relatively higher flexibility of II allows accommodation of amidine pairs present in the latter at a distance similar to that found for correspondent pairs in the conformationally more restricted I. Conformational aspects of I and II are discussed with reference to a recently described conformation of cimetidine determined by X-ray method. A hypothesis of binding of H2-receptor antagonists of the phenylformamidine type is advanced with reference to electrostatic potential maps calculated for crucial part structures of I, II and cimetidine. The present work supports the hypothesis that both mifentidine and DA 4643 interact with the histamine H2-receptor at the same site, utilizing in the binding process the same, or closely similar, receptor structural features.

Conformational analysis of the antiulcer drug pirenzepine. X-ray investigations, molecular mechanics and quantum mechanical calculations and comparisons with structurally or pharmacologically related compounds.

The crystal structures of the antiulcer drug 5,11-dihydro-11-[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one dihydrochloride (pirenzepine dihydrochloride, L-S 519 CL 2, Gastrozepin) and its monoprotonated form (pirenzepine monohydrochloride, L-S 519 CL) were determined by X-ray analysis. Molecular mechanics (MMPI) and semiempirical quantum chemical (MNDO) calculations showed that the calculated minimum energy conformations of the tricycle and of the exocyclic amide group are in agreement with the crystal structures. The conformational energies of pirenzepine as a function of four important torsional angles were calculated using different semiempirical quantum chemical methods with the CNDO/2 (complete neglect of differential overlap)-, MNDO (modified neglect of diatomic overlap)- and PCILO (perturbative configuration interaction using localized orbitals)-approximations. The conformation of one local energy minimum corresponds closely to the crystal structure of pirenzepine monohydrochloride. This conformation has a spatial arrangement which is analogous to a single consistent conformation known from the literature of 24 anticholinergic agents determined from their crystal structures by a computer graphics analysis. On the other hand there are no structural relationships of any low energy conformation of pirenzepine to conformations of other classes of tricyclic compounds which could rationalize their antidepressant, neuroleptic or antihistaminic activity. This finding explains the absence of any central effect of pirenzepine following intracerebral application. The computational elucidation of the conformational requirements for the interaction with the muscarinic receptors may be helpful for the interpretation of the selectivity of pirenzepine within the muscarinic system.