Donald Brambilla

Mortality In Sickle Cell Disease -- Life Expectancy and Risk Factors for Early Death

BACKGROUND Information on life expectancy and risk factors for early death among patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, and the sickle cell-beta-thalassemias) is needed to counsel patients, target therapy, and design clinical trials. METHODS We followed 3764 patients who ranged from birth to 66 years of age at enrollment to determine the life expectancy and calculate the median age at death. In addition, we investigated the circumstances of death for all 209 adult patients who died during the study, and used proportional-hazards regression analysis to identify risk factors for early death among 964 adults with sickle cell anemia who were followed for at least two years. RESULTS Among children and adults with sickle cell anemia (homozygous for sickle hemoglobin), the median age at death was 42 years for males and 48 years for females. Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for males and 68 years for females. Among adults with sickle cell disease, 18 percent of the deaths occurred in patients with overt organ failure, predominantly renal. Thirty-three percent were clinically free of organ failure but died during an acute sickle crisis (78 percent had pain, the chest syndrome, or both; 22 percent had stroke). Modeling revealed that in patients with sickle cell anemia, the acute chest syndrome, renal failure, seizures, a base-line white-cell count above 15,000 cells per cubic millimeter, and a low level of fetal hemoglobin were associated with an increased risk of early death. CONCLUSIONS Fifty percent of patients with sickle cell anemia survived beyond the fifth decade. A large proportion of those who died had no overt chronic organ failure but died during an acute episode of pain, chest syndrome, or stroke. Early mortality was highest among patients whose disease was symptomatic. A high level of fetal hemoglobin predicted improved survival and is probably a reliable childhood forecaster of adult life expectancy.

Prevention of a First Stroke by Transfusions in Children with Sickle Cell Anemia and Abnormal Results on Transcranial Doppler Ultrasonography

BACKGROUND Blood transfusions prevent recurrent stroke in children with sickle cell anemia, but the value of transfusions in preventing a first stroke is unknown. We used transcranial Doppler ultrasonography to identify children with sickle cell anemia who were at high risk for stroke and then randomly assigned them to receive standard care or transfusions to prevent a first stroke. METHODS To enter the study, children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher. The patients were randomly assigned to receive standard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration. The incidence of stroke (cerebral infarction or intracranial hemorrhage) was compared between the two groups. RESULTS A total of 130 children (mean [+/-SD] age, 8.3+/-3.3 years) were enrolled; 63 were randomly assigned to receive transfusions and 67 to receive standard care. At base line, the transfusion group had a slightly lower mean hemoglobin concentration (7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent, P=0.002). Ten patients dropped out of the transfusion group, and two patients crossed over from the standard-care group to the transfusion group. There were 10 cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as compared with 1 infarction in the transfusion group -- a 92 percent difference in the risk of stroke (P<0.001). This result led to the early termination of the trial. CONCLUSIONS Transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography.

A longitudinal analysis of the association between menopause and depression Results from the Massachusetts women's health study

The present article prospectively examines the effect of change in menopause status on depression, while controlling for prior depression. This is a longitudinal follow-up of previous cross-sectional analyses reported by McKinlay, McKinlay, and Brambilla who examined the relative contribution of menopause to depression. The data derive from the Massachusetts Womens Health Study, a 5-year longitudinal study of a cohort of 2565 women aged 45 to 55 years at baseline (1981 to 1982). Results show that prior depression is the variable most predictive of subsequent depression, as measured by the Center for Epidemiologic Studies-Depression (CES-D) scale. Onset of natural menopause was not associated with increased risk of depression. Experiencing a long perimenopausal period (at least 27 months), however, was associated with increased risk of depression. The association between a long perimenopause and depression appeared to be explained by increased menopausal symptoms rather than by the menopause status itself. The observed increase in depression during a lengthy perimenopause appears to be transitory.

Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions

OBJECTIVE To determine the effect of a transfusion program on risk of stroke recurrence in children with sickle cell disease. DESIGN The clinical course and experience with transfusion therapy at eight centers were reviewed for subjects whose initial stroke occurred after January 1988. RESULTS Sixty subjects were observed for 191.7 patient-years. Eight had a single recurrent stroke (two intracranial hemorrhages and six infarctions) for a prevalence of 13.3%, or one recurrence for each 24 patient-years of observation. Thirteen subjects had 15 transient neurologic events; two of these had subsequent strokes, but the overall risk was similar for those who did and those did not have transient events. Hemoglobin S levels were greater than the desired maximum of 30% at the time of 7 of 16 transient events and five of six recurrent infarctions. The stroke recurrence rate was similar to those in previous reports of children receiving long-term transfusion therapy but significantly less than that reported for children who did not receive transfusions (p < 0.001). CONCLUSIONS We conclude that maintenance of hemoglobin S at a level less than 30% appears to be effective in reducing the rate of recurrent infarction but does not prevent transient neurologic events. Transient neurologic events are common but do not appear to be related to recurrent stroke.

The relative contributions of endocrine changes and social circumstances to depression in mid-aged women

Although researched extensively over several decades, the prevalence, costs and reasons for depression among women during the middle years remain a challenge to public health. A vast literature is distilled into two predominant schools of thought, each with profoundly different implications for research and clinical practice. One school (the estrogen-deficiency perspective) holds that depression is associated with or triggered by endocrine changes in women around 50 years of age (menopause). A second school (the social-circumstances perspective) holds that depression is related to social circumstances encountered frequently by women during their fourth and fifth decades. Employing data from a randomly selected cohort of 2,500 premenopausal women sampled in Massachusetts, this paper shows that: * depression is associated with a surgical menopause and may even be a cause rather than a consequence of this surgery for this atypical group of women; * depression is not associated with the natural changes from preto immediately postmenopause; and * the most marked increases in depression are associated with multiple causes of worry and multiple roles among currently married women (including paid work, adolescent children, ailing husbands, and aging parents or parents-in-law). Some implications of these findings are discussed in the context of a rapidly aging population.

A prospective study of factors affecting age at menopause.

Abstract This paper describes a multivariate analysis of a 3-year prospective study of the covariates of age at menopause among women who were randomly sampled from a general population. This approach avoids three problems that may account for the inconsistent results of prior studies: recall bias in retrospectively collected data, failure to control confounding in data analyses, and self-selection in the target populations. At baseline, the 2014 subjects in this study were 46.5–56.5 years old and still menstruating. Median age at last menstruation, estimated from a model of the marginal distribution of age at menopause, was 50.7 years. When covariates were considered singly, age at menopause varied with smoking, education and income but not with marital status, parity, location, height, weight or use of either oral contraceptives or menopausal estrogens. Multivariate analyses showed that education and income were confounded with smoking status. The results indicate that many previously identified sources of variation in age at menopause reflect confounding with smoking and self-selection in target populations, rather than real effects.

The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men.

CONTEXT Although diurnal variation of testosterone and other hormones in men has been well documented, the effect of this variation on sampling during typical clinic hours has not been examined. OBJECTIVE Our objective was to examine temporal variation in serum testosterone and five other hormones in men over normal clinic hours. DESIGN Blood samples were collected at six separate visits, three morning visits 1-3 d apart and three afternoon visits 1-3 d apart. SETTING AND PARTICIPANTS In Boston, MA, 66 men participated, 30-80 yr of age, randomly selected from the Boston Area Community Health Survey who completed at least five visits. MAIN OUTCOME MEASURES The age-specific ratio of hormone level at times ranging from 0801-1600 h to hormone level at 0800 h was calculated. Ratios were calculated from parameter estimates obtained from cosinor models. RESULTS In men 30-40 yr old, testosterone levels were 20-25% lower at 1600 h than at 0800 h. The difference declined with age, with a 10% difference at 70 yr. 17 men with at least one of three measurements less than 300 ng/dl (10.4 nmol/liter) after 1200 h had normal testosterone levels at all three visits before 1200 h (five of eight men 30-47 yr old, four of nine men 66-80 yr old). Much lower levels of diurnal variation were found for dihydrotestosterone, SHBG, LH, FSH, and estradiol at all ages. CONCLUSIONS Our results support the recommendation of restricting testosterone measurements to morning hours in both young and older men. Limited diurnal variation in other hormones indicates that sampling through the day is appropriate.

Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men.

Background  Estimates of intraindividual variation in hormone levels provide the basis for interpreting hormone measurements clinically and for developing eligibility criteria for trials of hormone replacement therapy. However, reliable systematic estimates of such variation are lacking.

Underestimation of HIV Type 1 Drug Resistance Mutations: Results from the ENVA-2 Genotyping Proficiency Program

Current recommendations indicate the use of HIV-1 drug resistance genotyping in the treatment of HIV-1 infection, primarily on treatment failure, and in specific instances also before the initiation of therapy. As such, HIV-1 genotyping is becoming a standard of care parameter in HIV-1 treatment monitoring and a rapidly increasing number of laboratories now use this technology routinely. A study of proficiency, using the ENVA-2 panel, was performed to evaluate the current HIV-1 resistance genotyping quality in 34 laboratories from different parts of the world. The results demonstrated extensive interlaboratory variation in the quality of genotyping and a significant underestimation of resistance mutations, even in samples expressing pure mutant genotype. The level of variation could not be attributed to the sequencing technology used and was therefore considered to be laboratory associated. The direct clinical consequences of this may be inadequate treatment of HIV-1-infected individuals and a more rapid exhaustion of therapeutic options for the patients. Drug resistance mutations are frequently missed. Therefore, quality control programs are urgently needed. Until these are widely implemented, clinicians must consider this issue and interpret the reported genotyping results with caution.

The normal menopause transition

This paper presents analyses from a comprehensive prospective cohort study of mid‐aged women [the Massachusetts Womens Health Study (MWHS)], with numbers sufficient to provide stable estimates of parameters in the normal menopause transition. Three questions are addressed: what are the natural menopause transitions and when do they occur; what factors affect the transitions; and what signs and/or symptoms accompany the transitions? The data were obtained primarily from 5 years of follow‐up of 2,570 women in Massachusetts who were aged 44–55 years as of January 1, 1982. Prospective study of the cohort consisted of six telephone contacts (T1–T6) at 9 month intervals with excellent retention. A subset of the full cohort was defined that consisted of women who were premenopausal (rather than perimenopausal) at baseline (To) (n = 1,178). Confirming prior reports, the age at natural menopause occurred at 51.3 years with a highly significant median difference (1.8 years) between current smokers and non‐smokers. The new analyses reported here on median age at inception of perimenopause (47.5 years) and factors affecting it are consistent with findings for age at last menstrual period. Smokers tend to have not only an earlier but also shorter perimenopause. The length of the perimenopausal transition, estimated at about 3.5 years, has not been previously reported. The relationship between menopause transitions and symptom reporting appears to be transitory, with reporting rates showing an increase in the perimenopause and a compensatory decrease in postmenopause. The implications of combined hormone replacement therapy for future research on menopause in industrial societies is discussed in relation to these findings.