A physiological increase in maternal cortisol alters uteroplacental metabolism in the pregnant ewe.

KEY POINTS: Fetal nutrient supply is dependent, in part, upon the transport capacity and metabolism of the placenta. The stress hormone, cortisol, alters metabolism in the adult and fetus but it is not known whether cortisol in the pregnant mother affects metabolism of the placenta. In this study, when cortisol concentrations were raised in pregnant sheep by infusion, proportionately more of the glucose taken up by the uterus was consumed by the uteroplacental tissues while less was transferred to the fetus, despite an increased placental glucose transport capacity. Concomitantly, the uteroplacental tissues produced lactate at a greater rate. The results show that maternal cortisol concentrations regulate uteroplacental glycolytic metabolism, producing lactate for use in utero. Prolonged increases in placental lactate production induced by cortisol overexposure may contribute to the adverse effects of maternal stress on fetal wellbeing. ABSTRACT: Fetal nutrition is determined by maternal availability, placental transport and uteroplacental metabolism of carbohydrates. Cortisol affects maternal and fetal metabolism, but whether maternal cortisol concentrations within the physiological range regulate uteroplacental carbohydrate metabolism remains unknown. This study determined the effect of maternal cortisol infusion (1.2 mg kg-1  day-1 i.v. for 5 days, n = 20) on fetal glucose, lactate and oxygen supplies in pregnant ewes on day ∼130 of pregnancy (term = 145 days). Compared to saline infusion (n = 21), cortisol infusion increased maternal, but not fetal, plasma cortisol (P < 0.05). Cortisol infusion also raised maternal insulin, glucose and lactate concentrations, and blood pH, PCO2 and HCO3- concentration. Although total uterine glucose uptake determined by Fick's principle was unaffected, a greater proportion was consumed by the uteroplacental tissues, so net fetal glucose uptake was 29% lower in cortisol-infused than control ewes (P < 0.05). Concomitantly, uteroplacental lactate production was > 2-fold greater in cortisol- than saline-treated ewes (P < 0.05), although uteroplacental O2 consumption was unaffected by maternal treatment. Materno-fetal clearance of non-metabolizable [3 H]methyl-d-glucose and placental SLC2A8 (glucose transporter 8) gene expression were also greater with cortisol treatment. Fetal plasma glucose, lactate or α-amino nitrogen concentrations were unaffected by treatment although fetal plasma fructose and hepatic lactate dehydrogenase activity were greater in cortisol- than saline-treated ewes (P < 0.05). Fetal plasma insulin levels and body weight were also unaffected by maternal treatment. During stress, cortisol-dependent regulation of uteroplacental glycolysis may allow increased maternal control over fetal nutrition and metabolism. However, when maternal cortisol concentrations are raised chronically, prolonged elevation of uteroplacental lactate production may compromise fetal wellbeing.

Estimates on HCV disease burden worldwide - filling the gaps.

Hepatitis C is caused by infection with the hepatitis C virus (HCV) and represents a major global health burden. Persistent HCV infection can lead to progressive liver disease with the development of liver cirrhosis and hepatocellular carcinoma, possibly accounting for up to 0.5 million deaths every year. Treatment of HCV infection is undergoing a profound and radical change. As new treatments are extremely safe and effective, there are virtually no medical reasons to withhold therapy. Yet, the new therapies are expensive. As resources are limited, solid data to estimate the disease burden caused by HCV are urgently needed. Epidemiology data and disease burden analyses for 16 countries are presented. For almost all countries, the peak of HCV-related cirrhosis, hepatocellular carcinoma and liver-related death is a decade or more away. However, a surprising heterogeneity in country-specific HCV-associated disease burden exists. Also, HCV diagnosis and treatment uptake varied markedly between countries. A consistent finding was that a reduction of HCV liver-related mortality is dependent on access to therapy. Increasing efficacy of therapy alone with a constant numbers of treatments will not have a major impact on the HCV-related disease burden. The data presented here should inform public health policy and help drive advocacy for enhanced strategic investment and action. HCV kills patients, and the disease burden will continue to rise in most countries unless action is taken soon. Chronic HCV is a curable infection and a reversible liver disease. Fortunately, the tools to eliminate HCV are now available.

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels.

Virtual reality training for radiotherapy becomes a reality.

A report in 2007 to the UK Government identified a crisis in England for training staff and students for the radiotherapy treatment of cancer. The Hull authors have developed an immersive life size virtual environment of a radiotherapy treatment room, known as VERT, to address this problem. VERT provides the trainee with models, simulation, enhanced visualization and training aids for treatment of virtual patients in a virtual treatment room. In 2007 immersive VERT systems for radiotherapy training were established for training purposes at the University Aarhus Hospital (Denmark) and the Birmingham City University (UK). This paper reports on early evaluations of VERT by these two institutions.

Physics-based virtual environment for training core skills in vascular interventional radiological procedures.

Recent years have seen a significant increase in the use of Interventional Radiology (IR) as an alternative to open surgery. A large number of IR procedures commences with needle puncture of a vessel to insert guidewires and catheters: these clinical skills are acquired by all radiologists during training on patients, associated with some discomfort and occasionally, complications. While some visual skills can be acquired using models such as the ones used in surgery, these have limitations for IR which relies heavily on a sense of touch. Both patients and trainees would benefit from a virtual environment (VE) conveying touch sensation to realistically mimic procedures. The authors are developing a high fidelity VE providing a validated alternative to the traditional apprenticeship model used for teaching the core skills. The current version of the CRaIVE simulator combines home made software, haptic devices and commercial equipments.

Phospholipid metabolism in stimulated human platelets. Changes in phosphatidylinositol, phosphatidic acid, and lysophospholipids.

Endogenous phospholipid metabolism in stimulated human platelets was studied by phosphorus assay of major and minor components following separation by two-dimensional thin-layer chromatography. This procedure obviated the use of radioactive labels. Extensive changes were found in quantities of phosphatidylinositol (PI) and phosphatidic acid (PA) as a consequence of thrombin or collagen stimulation. Thrombin addition was followed by rapid alterations in the amount of endogenous PI and PA. The decrease in PI was not precisely reciprocated by an increase in PA when thrombin was the stimulus. This apparent discrepancy could be explained by removal of a transient intermediate in PI metabolism, such as diglyceride, formed by PI-specific phospholipase C (Rittenhouse-Simmons, S., J. Clin. Invest.63: 580-587, 1979). Diglyceride would be unavailable for PA formation by diglyceride kinase, if hydrolyzed by diglyceride lipase (Bell, R. L., D. A. Kennerly, N. Stanford, and P. W. Majerus. Proc. Natl. Acad. Sci. U. S. A.76: 3238-3241, 1979) to yield arachidonate for prostaglandin endoperoxide formation. Thrombin-treated platelets also accumulated lysophospho-glycerides. Specifically, lysophosphatidyl ethanolamines accumulated within 15s following thrombin addition. Fatty acid and aldehyde analysis indicated phospholipase A(2) activity, with an apparent preference for diacyl ethanolamine phosphoglycerides. In the case of collagen, these changes occurred concomitantly with aggregation and consumption of oxygen for prostaglandin endoperoxide formation.THESE STUDIES OF ENDOGENOUS PHOSPHOLIPID METABOLISM PROVIDE INFORMATION SUPPORTING THE EXISTENCE OF TWO PREVIOUSLY POSTULATED PATHWAYS FOR LIBERATION OF ARACHIDONIC ACID FROM PLATELET PHOSPHOLIPIDS: (a) the combined action of PI-specific phospholipase C plus diglyceride lipase yielding arachidonate derived from PI; and (b) a phospholipase A(2) acting primarily on diacyl ethanolamine phosphoglyceride.

3D visualization and open planning platform in virtual fluoroscopy.

Typically virtual fluoroscopy systems display the tracked instruments as a projected shadow on a number of 2D x-ray images completely missing the depth information of the third dimension. This paper describes an extra tool for 3D reconstruction in virtual fluoroscopy which is useful to clarify the position of instruments or anatomy and can be used in planning and assessing surgical procedure without further x-ray images. Two examples are given: displaced subtrochanteric fracture and slipped upper femoral epiphysis is presented.

Immersive visualization with automated collision detection for radiotherapy treatment planning.

Intensity modulated radiotherapy (IMRT) is a technique for treating cancer tumours using external delivery of radiation. To create a treatment plan the directions of the external radiation beams (typically 5 to 9) need to be specified. Normally the beams are all coplanar due to the added complexity of planning and patient set-up for non-coplanar beams. RTStar provides a virtual environment of a radiotherapy (RT) treatment room that provides a range of views and visualizations that aid a treatment planner to choose non-coplanar beam directions efficiently. RTStar also automatically warns the planner when a collision would occur during patient set-up. A study was conducted on 8 prostate IMRT cancer patients using RTStar to create RT plans using non-coplanar beams. The study demonstrated that these IMRT prostate plans with non-coplanar beams had a dosimetric advantage over their coplanar conterparts.

Factors affecting targeting using the computer assisted orthopaedic surgery system (CAOSS).

An advantage of CAOS over traditional surgery is improved precision of implant position and trajectories in 3D space. However, the implementation of these trajectories often adds an extra step to the operation that increases operative time and requires extra training. This paper reports a study of variation in time-to-task and learning curve in performing a standard task of targeting in 3D space using Hull's CAOSS. It shows that time-to-task can be reduced by replacing a 3D targeting task with multiple independent 2D targeting tasks whilst potentially reducing targeting error. Based on this better understanding of targeting a novel jig was developed for performing dynamic hip Screw (DHS) insertion using CAOSS that would provide improved targeting performance by the surgeon.

Distribution of CD4+ T lymphocytes at diagnosis of acquired immunodeficiency syndrome-defining and other human immunodeficiency virus-related illnesses. The Adult and Adolescent Spectrum of HIV Disease Project Group.

BACKGROUND: Depletion of circulating CD4+ T lymphocytes among persons infected with the human immunodeficiency virus (HIV) is associated with increased risk for development of opportunistic, life-threatening diseases and death. METHODS: To describe the levels of CD4+ T lymphocytes at which acquired immunodeficiency syndrome (AIDS)-defining and other illnesses initially occur, we analyzed data from an ongoing survey of medical records of 18,062 HIV-infected patients who received medical care between January 1990 and August 1993 in more than 100 clinics, hospitals, and private practices in 10 US cities. We report the median and upper 80th percentile CD4+ T-lymphocyte counts at diagnosis. RESULTS: We found that AIDS-defining conditions first occurred in HIV-infected patients with CD4+ T-lymphocyte counts below 0.20 x 10(9)/L (200/microL) for 80% of diagnoses. Similarly, AIDS-defining diseases occurred at counts below 0.05 x 10(9)/L for 50% of diagnoses. Exceptions to both criteria were invasive cervical cancer and pulmonary tuberculosis. Non-AIDS-defining illnesses with which 80% of patients were diagnosed at CD4+ T-lymphocyte counts below 0.20 x 10(9)/L were bacterial sepsis and retinopathy (excluding cytomegalovirus). CONCLUSION: Our observations support the need for continued CD4+ cell count monitoring below a level of 0.20 x 10(9)/L as a guide to diagnosis and medical management of HIV-infected persons.

The expanding regional diversity of the acquired immunodeficiency syndrome epidemic in the United States.

BACKGROUND: The geographic spread of the human immunodeficiency virus (HIV) epidemic reflects multiple subepidemics in different regions and population groups. METHODS: To describe regional trends in the acquired immunodeficiency syndrome (AIDS) in the United States, we analyzed national surveillance data for persons with AIDS diagnosed from 1988 through 1991. RESULTS: Highest annual AIDS incidence rates were in the US territories (52.7 per 100,000) and the Northeast (27.7 per 100,000). The greatest percentage increases were in the US territories (68.8%), the South (60.1%), and the Midwest (52.4%). Men who have sex with men constituted the majority of AIDS cases nationally (54.6%), as well as in the Midwest (67.8%), the South (57.4%), and the West (75.3%). Among injecting drug users, the greatest rates of increase in AIDS cases were observed among blacks in the South. Although large increases in the number of persons with HIV transmitted through heterosexual contact were reported from almost all regions, the largest increase was in the South. CONCLUSION: High rates of increase in AIDS cases from the Midwest, South, and US territories probably reflect later entry of HIV into these regions compared with the earlier HIV epidemics in large metropolitan areas of the Northeast and West. In particular, because the South has the largest population of the regions, and sexually transmitted disease surveillance data suggest that substantial populations in the South are at risk, the marked increase in AIDS incidence in this region suggests that the major impact of the epidemic may yet be seen. The continuing spread of HIV and AIDS in different communities and regions demonstrates the need to expand preventive and therapeutic services.

Effect of influenza vaccination on disease progression among HIV-infected persons.

OBJECTIVE: To describe the effect of influenza vaccination on long-term change in CD4 count and HIV RNA level, and on progression to AIDS or death. DESIGN AND SETTING: A longitudinal medical record review set in 113 medical clinics in 10 United States cities. PATIENTS: A total of 36,050 HIV-infected persons aged > or = 13 years in care for HIV infection. MAIN OUTCOME MEASURES: Change in CD4 count and HIV RNA level at follow-up (3-12 months after vaccination); hazard ratios (HR) for association of influenza vaccine with progression from baseline CD4 or HIV RNA level to AIDS and to death. RESULTS: The median CD4 count among all persons decreased 28 cells/year during follow-up, with no difference in change in CD4 count between the 8007 (40%) vaccinated (median = 6 months, vaccine to follow-up CD4 count) and the 11,794 unvaccinated persons. In a viral load subanalysis, median HIV RNA level decreased 90 copies/ml per year among all persons during follow-up; decreases were not different between vaccinated and unvaccinated persons (median = 7 months, vaccine to follow-up HIV RNA level determination). Influenza vaccination was weakly associated with decreased risk of progression to clinical AIDS [HR 0.93; 95% confidence interval (CI), 0.87-0.99], but not associated with time to death (HR, 0.97; CI, 0.93-1.01). CONCLUSIONS: No negative long-term effect of influenza vaccination on CD4 counts, HIV RNA levels, or progression to AIDS or death was found in this HIV-infected population. These data suggest that physicians should not withhold influenza vaccine because of concerns about long-term detrimental effects of increased viral replication.

Changes in AIDS incidence for men who have sex with men, United States 1990-1995.

OBJECTIVES: To describe changes in AIDS incidence for men who have sex with men (MSM) from 1990 to 1995, by demographic and geographic groups. METHODS: We examined national AIDS surveillance data reported up to 30 September 1996, for men who received AIDS diagnoses in the years 1990-1995 and whose only reported risk behavior was sex with men. We evaluated trends in AIDS rates by estimating the incidence of clinical AIDS (AIDS defined by opportunistic illnesses), and report clinical AIDS incidence rates for MSM (AIDS rates) and proportional change in rates from 1990 to 1995. RESULTS: Clinical AIDS rates (MSM per 100,000 men per year) increased by 12% from 25.5% in 1990 to 28.5% in 1995. Significant variations in AIDS rates and 5-year changes in AIDS rates were observed in various subgroups of MSM. Five-year increases in AIDS rates were highest for American-Indian/Alaskan native (53%), black (45%), and Hispanic (23%) MSM; the only decrease occurred for white MSM (-2%). Incidence for black MSM increased from twofold (in 1990) to threefold (in 1995) the rate for white MSM. Large increases in AIDS rates were observed for MSM in rural areas (34%) and areas with 50,000 to 249,999 residents (34%) and for MSM aged over 60 years (32%). CONCLUSIONS: The high national AIDS rate for MSM continued to rise, but more slowly than earlier in the epidemic. Racial/ethnic minority MSM had consistently large increases in AIDS rates; AIDS rates decreased only slightly for white MSM. The AIDS epidemic among MSM is not homogenous, and AIDS rates continue to increase for minority MSM, and MSM living in rural areas. HIV prevention remains a high priority for all MSM, especially black and Hispanic MSM.

Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Adult/Adolescent Spectrum of Disease Group.

OBJECTIVE: To examine the effects of antiretroviral therapy (ART) and opportunistic illness chemoprophylaxis on the survival of persons with AIDS and survival time based on year of AIDS diagnosis. DESIGN: Longitudinal medical record review. SETTING: Ninety-three hospitals and clinics in nine cities in the USA. PATIENTS: We observed 19,565 persons with AIDS from 1990 through January 1998. INTERVENTIONS: Prescribed use of antiretroviral monotherapy, dual- and triple-combination therapies, primary prophylaxis against Pneumocystis carinii pneumonia and Mycobacterium avium complex, and pneumococcal vaccine. MAIN OUTCOME MEASURES: Time from AIDS diagnosis to death in the presence and absence of ART. Survival curves were compared of AIDS cases diagnosed during 1990-1992 and 1993-1995. RESULTS: Triple ART had the greatest effect on the risk of death [relative risk (RR), 0.15; 95% confidence limit (CL), 0.12, 0.17], followed by dual ART (RR, 0.24; 95% CL, 0.22, 0.26), and monotherapy (RR, 0.38; 95% CL, 0.36, 0.40). Risk of death was decreased among persons receiving Pneumocystis carinii pneumonia prophylaxis (RR, 0.79; 95% CL, 0.70, 0.89) and Mycobacterium avium complex prophylaxis (RR, 0.76; 95% CL, 0.68, 0.86). Median survival increased from 31 months [95% confidence interval (CI), 30-32 months] for AIDS cases diagnosed during 1990-1992 to 35 months (95% CI, 35-38 months) for cases diagnosed during 1993-1995. CONCLUSIONS: The risk of death was decreased for persons receiving triple ART compared with persons receiving dual therapy and persons receiving monotherapy. Increased use of ART and improved ART regimens probably contributed to prolonged survival of persons whose diagnosis was made during 1993-1995 compared with persons whose diagnosis was made during 1990-1992.

Surveillance of AIDS-defining conditions in the United States. Adult/Adolescent Spectrum of HIV Disease Project Group.

OBJECTIVE: To examine the reporting of AIDS-defining illnesses using two national surveillance systems. METHODS: Comparison of AIDS indicator diseases reported to the national AIDS reporting system (ARS) for AIDS cases diagnosed from January 1990-December 1992 among individuals aged > 13 years in 10 metropolitan areas, with that observed in the Adult/Adolescent Spectrum of HIV Disease (ASD) project, a surveillance project that monitors the clinical diagnoses of HIV-infected individuals receiving medical care. RESULTS: In the 10 metropolitan areas, 39,265 individuals with AIDS were reported to ARS, and 5969 with AIDS had medical record reviews as part of ASD. At initial AIDS diagnosis, the number of indicator diseases reported to ARS was almost identical to the number observed in ASD (mean number of diagnoses, ARS 1.3; ASD 1.2). However, ASD recorded a greater number of diagnoses over time than ARS (mean number of indicator diagnoses > 12 months after initial diagnosis, ASD 2.3; ARS 1.4). Conditions that typically occur late in the course of AIDS such as Mycobacterium avium infection and cytomegalovirus disease, were more frequently recorded by ASD than by ARS. CONCLUSION: ARS provides complete, population-based information on the frequency of AIDS-defining conditions at initial diagnosis. However, specialized surveillance projects such as ASD are needed to accurately describe subsequent AIDS-defining conditions.

The epidemiology of HIV transmission among paid plasma donors, Mexico City, Mexico.

Screening of blood product donations for antibody to HIV began in Mexico in May 1986. From June to October 1986, the HIV cumulative seroprevalence increased from 6.3 to 9.2% in a commercial plasma collection center. Of the 281 people who donated the antibody-positive units, 62 (22.1%) had documented seroconversion during these 5 months. An epidemiologic study of 54 seropositive and 58 seronegative donors was carried out. The HIV serologic status did not change in any of these donors after repeat testing. Only 13.0% of the seropositives and 15.5% of the seronegatives had any of the known risk factors for AIDS. There was a direct relationship between frequency of plasma donation and the risk of being seropositive. A survey of employees disclosed the frequent re-use of disposable blood collection equipment. We conclude that HIV transmission had probably occurred in this plasma collection center.

PIP: This report provides the results of a study of plasma donor clients from records abstracted between June-October 1986. The purpose was to identify risk factors for HIV infection among donors at the National Center for Blood Transfusions. Screening for HIV among donors began in May 1986. 54 Seropositive donors were identified and located from 281 and 58 seronegative donors were randomly selected. 16 employees of the plasma collection center were locatable and also included in the study. The results were that seroprevalence increased between June-October from 6.3% to 9.2%. The total donations were 3201 of which 294 were seropositive. Of 281 seropositive clients, 62 (22%) had seroconversion (a prior seronegative donation). Seroconversions increased from 1.6% in July to 50% in October. On retesting of the 112 study participants, no change in status was found. The groups were similar and both groups had relatively low risk factors for (13% for HIV seropositive and 15.5% for HIV seronegative donors). The rate of seropositivity increased with the frequency of plasma donations from 19.6% for those donating 1-3 times/month to 88.9% for those donating 10 times/month. Of the 16 employees, 1 died who was HIV seropositive; 5 were directly involved in plasma collection and reported reuse of saline solution and intravenous tubing. The results lead the authors to suggest that HIV was transmitted in the collection process. Support for this suggestion comes from the number of seroconversions; the risk factors among the seropositive donors had no known risk factors. Although not statistically significant, male seropositive donors had greater contract with prostitutes in Mexico City, but prostitutes had shown in the past 2 years a seropositivity rate of 1%. More demonstrative evidence comes from the increased rate of seropositivity with frequency of donation, and the employee reports of reutilization of blood collection materials. Other studies have postulated plasma donor site risk. Regardless of the expense of intravenous equipment, it is suggested that the risk of HIV transmission precludes reuse of materials. At present, all blood is collected from volunteer donors with disposable equipment. Other countries need to assess the safety of blood donor centers, particularly with paid donors.

HIV testing patterns: where, why, and when were persons with AIDS tested for HIV?

OBJECTIVE: To describe the location of, primary reason for, and time between the first positive HIV test and AIDS diagnosis in a sample of persons with newly diagnosed AIDS. DESIGN: Interviews supplementing information routinely collected through AIDS case reporting. SETTING: Eleven US states and cities. PATIENTS: Persons with AIDS (2441) diagnosed between January 1990 and December 1992. MAIN OUTCOME MEASURES: Location of first positive HIV test, primary reason for testing, and time interval between first positive HIV test and AIDS diagnosis. RESULTS: Overall, persons were tested late in their course of HIV infection: 36% were tested for HIV within 2 months and 51% within 1 year of their AIDS diagnosis. Sixty-five per cent were HIV-tested in acute health-care settings: 33% in hospitals, 28% in physicians' offices, and 4% in emergency departments. Testing during hospitalization was most common among injecting drug users (43%) and persons infected through heterosexual contact (50%). Persons primarily sought HIV testing because of illness (58%); other reasons included being in a known risk group (13%) and having had a known HIV-infected sex partner (8%). Testing because of being in a known risk group was least common among persons infected through heterosexual contact (1%). Among persons in these exposure categories, testing differed by race/ethnicity. CONCLUSION: Most persons with AIDS were tested relatively late in their course of HIV infection, in acute health-care settings, and because of illness. Not knowing one's serostatus precludes early medical intervention and may increase transmission.

Toxoplasmic encephalitis in HIV-infected persons: risk factors and trends. The Adult/Adolescent Spectrum of Disease Group.

OBJECTIVE: To evaluate the incidence of and risk factors for toxoplasmic encephalitis among HIV-infected persons. DESIGN: Medical facility-based prospective medical record reviews of consecutive patients. METHODS: We analysed data collected from January 1990 through August 1995 in more than 90 inpatient and outpatient medical facilities in nine US cities. Incidence was calculated as cases per 100 person-years and risk ratios (RR) for annual incidence were calculated using proportional hazards regression while controlling for city, sex, race, age, county of birth, HIV exposure mode, and prior prescription of trimethoprim-sulfamethoxazole (TMP-SMX). RESULTS: The incidence of TE was 4.0 cases per 100 person-years among persons with a CD4+ T-lymphocyte count of < 100 x 10(6)/l. In multivariate analysis, among the nine cities the annual incidence of toxoplasmosis was significantly lower only in Denver [RR, 0.3; 95% confidence interval (CI), 0.1-0.7; referent city, Seattle]. Persons prescribed TMP-SMX were half as likely to develop toxoplasmic encephalitis as those who were not (RR, 0.5; 95% CI, 0.4-0.7). Of the 4173 persons with AIDS (1987 Centers for Disease Control and Prevention definition) who died during the study period, 267 (6.4%) had toxoplasmic encephalitis in the course of HIV disease. CONCLUSIONS: Toxoplasmic encephalitis in HIV-infected persons varies by geographic area in the United States. TMP-SMX reduces the risk for toxoplasmic encephalitis.

Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin.

We studied the pharmacokinetics and beta-blocking effects of a single, oral 20 mg dose of timolol in six poor metabolizers (PMs) and six extensive metabolizers (EMs) of debrisoquin. The plasma timolol concentration was significantly higher in PMs than in EMs. There was a fourfold difference in mean AUC (1590 +/- 1133 vs. 394 +/- 239 ng X hr/ml; P less than 0.01) and a twofold difference in mean t1/2 (7.5 +/- 3 vs. 3.7 +/- 1.7 hours; P less than 0.01), reflecting differences in oral clearance (13.1 +/- 7.8 vs. 48.5 +/- 23.2 L/hr; P less than 0.01). The degree of beta-blockade was greater in PMs than in EMs at 12 hours (30.9% vs. 18.2%; P less than 0.05) and at 24 hours (28.3% vs. 13.1%; P less than 0.05). In the group as a whole the metabolic ratio correlated positively with both kinetic data and beta-blockade, but some overlap was observed. Hence timolol metabolism appears to be subject to debrisoquin-type polymorphism, which results in interphenotypic variation in plasma concentration and beta-blocking effect.

Heterosexual transmission of human immunodeficiency virus type 1 from transfusion recipients to their sex partners.

Using lookback procedures and other methods, we identified and then prospectively followed human immunodeficiency virus type 1 (HIV-1)-infected transfusion recipients and their sex partners to determine AIDS incidence and risks of heterosexual transmission of HIV-1. At enrollment, 7 of 32 (21.9%) female partners of male recipients were themselves infected with HIV-1, as compared with none of 14 male partners of female recipients (p = 0.08). No additional episodes of transmission were observed. The prevalence of advanced immunodeficiency at enrollment was similar in male and female recipients. Male recipients with advanced immunodeficiency (CD4+ lymphocyte count < or = 0.20 x 10(9)/L or a history of clinical AIDS) at enrollment were more likely to have infected their female partners (odds ratio = 7.9; p = 0.03) than men with neither condition. Similarly, AIDS-free survival, as estimated by the product-limit method, was lower among male transmitters than among male nontransmitters (p = 0.01). Transmission was not associated with frequency of unprotected vaginal intercourse. Our data suggest that HIV-1-infected men who develop immunodeficiency rapidly are more likely to infect their sex partners and that the greater efficiency of male-to-female HIV-1 transmission is not explained by a greater number of sexual contacts or more advanced immunodeficiency in index subjects.