Immune activation markers and AIDS prognosis.

Four assays for serum levels of cellular products of immune activation were examined as prognostic markers for AIDS in a prospective study of asymptomatic HIV-seropositive homosexual men. Baseline serum values of beta 2-microglobulin (beta 2M), neopterin, soluble CD8 (sCD8), and soluble interleukin-2 receptor (sIL-2R) for 185 men were examined univariately and multivariately as predictors of AIDS during 36 months of follow-up. Thirty-three cases of AIDS (18%) were diagnosed during the follow-up period. All four assays correlated highly with each other (r = 0.48-0.63), and all four were good univariate predictors of AIDS and comparable to CD4 lymphocyte count. beta 2M, neopterin, and sCD8 predicted AIDS independently of both CD4 count and HIV p24 antigen or p24 antibody in multivariate analysis. Within the range of CD4 count 200-499 x 10(6) cells/l, an immune activation marker used in combination with an assay for p24 antigen identifies those at 3-6% risk of AIDS over 36 months (low risk on both assays) and those at 63-86% risk (high risk on both assays). These results can be used to guide physicians and patients making decisions about treating asymptomatic HIV infection with zidovudine in individuals with CD4 lymphocyte count of 200-499 x 10(6) cells/l.     

Space time clustering of births in SIDS: do perinatal infections play a role?

The aetiology of sudden infant death syndrome (SIDS) remains uncertain; many causal pathways have been proposed. In this paper we have examined firstly the variation in the risk of SIDS with age, month of death and month of birth; and secondly the space time clustering of SIDS deaths, and, separately, space time clustering of their births. Data were obtained from the Office of Populations, Censuses and Surveys on all certified SIDS deaths in the period; children were assigned grid references for the address of birth and of death. Data on number of births were abstracted from published material. A log-linear modelling technique was used to investigate the separate effects of age, month of death and month of birth on the risk of SIDS. The Knox method was used to investigate space time clustering of deaths and of births of children who died of SIDS. Separate, statistically significant effects were found for age, month of death and month of birth. There was minor space time clustering of SIDS births and deaths at large time and space intervals, and a marked space time clustering of births in short space time intervals in the first quarter of the year. The finding of an effect of month of birth on the risk of SIDS, and of space time clustering of births suggest that a perinatal hazard--possibly of infectious origin--may play a role in the aetiology of SIDS.     

Seasonality in the sudden infant death syndrome

Distinctive epidemiological features of the sudden infant death syndrome (SIDS) are its age at death distribution and pronounced winter excess. Whether or not these effects are independent of the month of birth of the infant is uncertain. We used a loglinear model to separate the effects of age at death, month of death and month of birth amongst 6229 infants who died from SIDS in England and Wales during the period 1979-1983. The results suggest that month of birth and month of death independently influence the risk of the infant dying from SIDS, the risk related to month of death being much greater.     

What Are the Etiology and Epidemiology of Out‐of‐hospital Pediatric Cardiopulmonary Arrest in Ontario,Canada?

Background: Pediatric cardiopulmonary arrest (CPA) outside of the hospital has a very high mortality rate. Objectives: To evaluate the etiology and initial compromise of pediatric CPA cases in hopes of developing strategies to improve out‐of‐hospital resuscitation. Methods: The Ontario Prehospital Advanced Life Support (OPALS) study was a large multicenter initiative to evaluate the impact of emergency medical services (EMS) programs on 17 communities with 40,000 critically ill and injured patients who were older than 11 years. As part of this study, the authors conducted a retrospective observational cohort study that included all children younger than 18 years of age with out‐of‐hospital CPA, during an 11‐year period from 1991–2002. CPA was defined as patient being pulseless, apneic, and requiring chest compressions. Data were collected from ambulance call reports and centralized dispatch data and were reviewed by two independent investigators. Results: There were 503 children with CPA in the sample. Mean age was 5.6 years (range, 0–17 yr); 58.4% of patients were male, and 37.8% were younger than 1 year of age. Cardiopulmonary resuscitation (CPR) first was started by a bystander in 32.4% of cases, whereas 66.0% were unwitnessed arrests. Initial rhythms were asystole 77.2% of the time, pulseless electrical activity 16.4% of the time, and ventricular fibrillation or ventricular tachycardia 4% of the time. Annual incidence was 9.1/100,000 children. CPA was witnessed in 34.0% of cases; 80.7% of these were bystander‐witnessed, and 18.1% were EMS‐witnessed. Primary pathogenic cause of arrest was medical in 61.2% of cases, trauma in 37.2% of cases, and indeterminate in 1.6% of cases. Initial underlying physiologic compromise of witnessed arrests was judged to be respiratory in 39.8% of cases, sudden collapse (presumed electrical) in 16.4% of cases, progressive shock in 1.2% of cases, and indeterminate in 42.6% of cases. Presumed etiology was trauma, 37.6%; sudden infant death syndrome (SIDS), 20.3%; and respiratory disease, 11.6%, most commonly. Survival to hospital discharge was 2.0%. Conclusions: This is one of the largest population‐based, prospective cohorts of pediatric CPA reported to date, and it reveals that most pediatric arrests are unwitnessed and receive no bystander CPR. Those that are witnessed most often are caused by respiratory arrests or trauma. Trauma, SIDS, and respiratory disease are the most common etiologies overall. These data are vital to planning large resuscitation trials looking at specific interventions (i.e., increasing bystander CPR) and highlight the need for better strategies for prevention and early recognition.     

Atopy, lung function, and obstructive airways disease after prenatal exposure to famine

BACKGROUND: Associations have been found between a large head size at birth and atopy, and between low birth weight and obstructive airways disease. A study was undertaken of people born around the time of the Dutch famine in 1944-5 to determine the effects of maternal malnutrition during specific periods of gestation on the prevalence of obstructive airways disease and atopy. METHODS: Nine hundred and twelve people aged about 50, born at term between November 1943 and February 1947 in Amsterdam, were asked about their medical history. Lung function was measured in 733 and serum concentrations of total IgE and specific IgE against mite, pollen and cat were measured in 726. Those exposed in late, mid, and early gestation (exposed participants) were compared with those born before or conceived after the famine (non-exposed participants). RESULTS: Exposure to famine during gestation affected neither the concentrations of total or specific IgE nor lung function values. The prevalence of obstructive airways disease was increased in people exposed to famine in mid gestation (odds ratio adjusted for sex 1.7, 95% confidence interval (CI) 1.1 to 2.6) and tended to be higher in those exposed in early gestation (odds ratio 1.5, 95% CI 0. 9 to 2.6). CONCLUSIONS: The observed increase in the prevalence of obstructive airways disease in people exposed to famine in mid and early gestation was not parallelled by effects on IgE concentrations or lung function. The link between exposure to famine in mid and early gestation and obstructive airways disease in adulthood suggests that fetal lungs can be permanently affected by nutritional challenges during periods of rapid growth.     

Differences in mean and variability of heart rate and ambulatory rate-pressure product when valsartan or carvedilol is added to lisinopril

Guidelines recommend combining β-blockers and angiotensin-converting enzyme (ACE) inhibitors in high-risk heart disease but not in the initial treatment of hypertension. The mechanism of this benefit has not been determined. After 3 weeks of lisinopril (L, 40 mg/day) run-in, 30 subjects entered a single-blinded, forced-titration, crossover study in which carvedilol (C, 20 then 40 mg/day) or a control renin-angiotensin blocker, valsartan (V, 160 then 320 mg/day) were added to L. Ambulatory blood pressure (ABP) and heart rate monitoring was performed at the end of each period. Rate-pressure product (RPP, systolic BP × heart rate, an indicator of cardiac oxygen consumption) was measured over 24 hours, daytime (6 am to midnight), and nighttime (midnight to 6 am) periods. Variability (standard deviation and range) of RPP, BP, and heart rate was also investigated. After 4 weeks, mean 24-hour systolic BP was about 8 mm Hg lower when either V or C was added to L (P < .01 each). Heart rate was consistently lower with C (8 beats/min over 24 hours, P < .000) but was slightly increased with V (about 2 beats/min, P = NS). Consequently, C lowered RPP to a greater degree than V over 24 hours (about 8% vs. 2%, P < .000) and during daytime and nighttime periods (P < .000 each). In addition, RPP variability (SD but not range) was consistently lower on C than V. When added to L, C reduces the mean and variability (SD) of 24-hour heart rate and cardiac workload to a greater degree than valsartan. These effects may contribute to the outcome benefits observed with β-blocker–ACE inhibitor combinations.     

Impact of Kaposi sarcoma-associated herpesvirus (KSHV) burden and HIV coinfection on the detection of T cell responses to KSHV ORF73 and ORF65 proteins

Cellular immune responses to Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS and several other malignancies, are incompletely characterized. We assessed KSHV-specific interferon- gamma enzyme-linked immunospot responses in a cohort of 154 individuals, using overlapping peptide sets spanning the KSHV-encoded latency-associated nuclear antigen (ORF73) and the minor capsid glycoprotein (ORF65). Among KSHV-seropositive subjects, ORF73-specific responses dominated over responses to ORF65 and were preferentially detected in human immunodeficiency virus-coinfected individuals who had elevated levels of cell-associated KSHV DNA, indicating that the viral antigen burden may have been driving these responses. Responses to both ORF73 and ORF65 were also detected in several KSHV-seronegative subjects who were at increased risk for KSHV infection, which demonstrates that cellular immunity can be found in the absence of detectable humoral responses. These data have implications for the reliable identification of KSHV infection and may help guide the design of immune-based therapeutic and prophylactic interventions.     

Interactions between peroxisome proliferator-activated receptor-gamma 2 gene polymorphisms and size at birth on blood pressure and the use of antihypertensive medication

OBJECTIVE: The combination of small birth size and the Pro12Pro variant of the peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) gene has been shown to be associated with insulin resistance, which is linked to hypertension. We examined whether the association between small body size at birth and adult blood pressure is modulated by PPAR-gamma 2 gene polymorphism, and whether the use of any class of antihypertensive medication is related to birth size. DESIGN AND METHODS: A total of 500 subjects from an original epidemiological cohort of 7086 men and women aged 65-75 years attended a clinical study. Two hundred and eight of them (73 men and 135 women) were taking antihypertensive medication and are included in this study. The Pro12Ala polymorphism of the PPAR-gamma 2 gene was determined using the polymerase chain reaction single-strand conformation polymorphism method. RESULTS AND CONCLUSIONS: Hypertensive subjects with low birth weight or short length at birth and the Pro12Pro variant had raised systolic blood pressure. We suggest that insulin resistance enhances the regulatory responses of the renin-angiotensin system, leading to raised blood pressure levels. Those hypertensive subjects who had small birth size and the Pro12Pro variant tended to use angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARB). This could be because insulin resistance interacts with the renin-angiotensin system in ways that make ACEI/ARB an effective therapy. Alternative explanations include more severe and treatment resistant hypertension, leading to application of ACEI/ARB, or co-morbid conditions, such as myocardial infarction and type 2 diabetes, known to be linked to low birth weight.     

Placental glucose transport and utilisation is altered at term in insulin-treated, gestational-diabetic patients

Aims/hypothesis: We have previously shown that placentae from patients with gestational diabetes mellitus who did not receive insulin had lower glucose transport and utilisation than non-diabetic control subjects. To assess the placental glucose handling characteristics of women with gestational diabetes mellitus receiving insulin, we examined glucose transport and utilisation in placentae from three groups of women after term delivery: those with gestational diabetes mellitus and receiving insulin (n = 9, insulin group); those with gestational diabetes mellitus and not receiving insulin (n = 10, no insulin group); and those with normal, non-diabetic pregnancies (n = 9, control group). Methods: Dual perfusion of an isolated placental lobule was done using maternal glucose concentrations of 4, 8, 16 and 24 mmol/l. Glucose and l-lactate concentrations in the maternal and fetal effluents were measured. Direct glucose transfer from the maternal to the fetal effluent was measured using ¹⁴C-d-glucose. Mean rates in μmol ming^–1 (wet tissue) at maternal glucose concentration of 8 mmol/l are shown. Results: Glucose uptake from the maternal perfusate (insulin group 0.57, no insulin group 0.30) and net glucose transfer to the fetal effluent (insulin group 0.41, no insulin group 0.20) both increased in the placentae of women receiving insulin compared with the diabetic group not receiving insulin. Both groups of patients had lower placental glucose utilisation than the control group (insulin group 0.16, no insulin group 0.10, control group 0.25). Conclusion/interpretation: These results suggest that materno-fetal glucose transport increases in the placentae of women with gestational diabetes mellitus who receive insulin compared with those women who do not receive insulin. [Diabetologia (2001) 44: 1133–1139] Received: 19 February 2001 and in revised form: 17 April 2001