Enrollment of women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute

BACKGROUND: With the recognition that certain aspects of cardiovascular disease are specific to sex, the government has sought to ensure that federally funded clinical research yields adequate high-quality information about heart disease in women. METHODS: We tabulated the numbers of men and women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute (NHLBI) between 1965 and 1998, recording both total numbers and the numbers for each type of cardiovascular disease. We analyzed the data according to the sex-specific prevalence of disease and assessed changes in enrollment over time. We performed a similar analysis after excluding all single-sex trials. RESULTS: A total of 398,801 subjects (215,796 women and 183,005 men) were enrolled in NHLBI-funded studies of cardiovascular disease. The overall enrollment rate for women (54 percent) exceeded the prevalence of cardiovascular disease in women in the general population (49 percent) and increased over time (P=0.002). With single-sex trials excluded, the enrollment rate for women was 38 percent, which did not change significantly over time. In studies of coronary artery disease and hypertension the rates of enrollment of women were similar to or exceeded the prevalence of these disorders in women. The enrollment rate increased significantly over time in studies of coronary artery disease (P<0.001) but not in studies of hypertension or arrhythmia. Women were under-enrolled in studies of heart failure, and the rate of enrollment did not change significantly over time. When single-sex trials were excluded from the analysis of enrollment rates according to the prevalence of disease, the results were similar. There was no change in enrollment rates overtime for any category of disease. CONCLUSIONS: Federal efforts to increase the representation of women in clinical trials have been moderately successful primarily because of the institution of a small number of large, single-sex trials involving coronary artery disease. There has been no change in the sex composition of cohorts in the majority of studies of cardiovascular disease.     

Confirmation of trisomy 22 by trypsin-giemsa staining.

A small-for-dates male infant with mental retardation, microcephaly, malformed ears, preauricular sinuses, epicanthal folds, micrognathia, congenital heart diseases, micropenis, and micropolygyria of the parietal and occipital lobes of the cerebral cortex was shown to have a 47,XY,+22 karyotype by trypsin-giemsa banding. Review of reported cases confirms that there may be distinctive trisomy 22 syndrome.     

Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy

A deficiency of the protein dystrophin has recently been shown to be the probable cause of Duchenne's muscular dystrophy. We sought to determine the relation between the clinical phenotype and the status of dystrophin in muscle-biopsy specimens from 103 patients with various neuromuscular disorders. We found very low levels (less than 3 percent of normal levels) or no dystrophin in the severe Duchenne phenotype (35 of 38 patients), low concentrations of dystrophin in the intermediate (outlier) phenotype (4 of 7), and dystrophin of abnormal molecular weight in the mild Becker phenotype (12 of 18). Normal levels of dystrophin of normal molecular weight were found in nearly all the patients (38 of 40) with 20 other neuromuscular disorders we studied. These data show the clinical consequences of both quantitative alterations (in Duchenne's and intermediate dystrophy) in a single protein. The biochemical assay for dystrophin should prove helpful in delineating myopathies that overlap clinically with Duchenne's and Becker's dystrophies, and it shows promise as an accurate diagnostic tool.     

The plasma catecholamine stress response is characteristic for a given animal over a one-year period

The same male and female rats with indwelling jugular catheters were stressed (immobilization) on two occasions at the ages of 3 to 4 and 15 to 16 months. Plasma levels of the catecholamines (CA) norepinephrine (NE) and epinephrine (E) were determined before and during stress at each session. During stress, plasma NE and E levels increased markedly. At the younger age, female animals showed markedly higher CA levels than male animals. After one year, stress CA levels were higher for both sexes, but had increased markedly in male and little in female animals. A positive correlation was found between the plasma CA stress response of individual animals at both sessions; this correlation was stronger for males and NE. This indicates that "high" responders usually remain high responders, "low" responders remain low and intermediate responders intermediate. In conclusion, the plasma CA stress response increases markedly in male, but little in female rats over the period of 1 year and the relative magnitude of the individual stress response remains a characteristic of each given animal.     

Expression of CD95 antigen and Bcl-2 protein in non-Hodgkin's lymphomas and Hodgkin's disease.

CD95 (APO-1/Fas) is a member of the superfamily that includes the nerve growth factor and tumor necrosis factor receptors, OX40, CD27, CD30, and CD40. Present on a minority of resting blood lymphocytes, CD95 expression is upregulated on activated T and B lymphocytes and natural killer cells, where binding of the antigen by anti-Fas and anti-APO-1 antibodies has been shown to induce apoptosis. This CD95-mediated apoptosis is at least partially inhibited by expression of the Bcl-2 protooncogene. To evaluate possible roles of CD95 and Bcl-2 in growth regulation of lymphoid neoplasms, we studied by immunohistochemistry the expression of CD95 and Bcl-2 in 67 B- and 5 T-cell lymphomas, and 10 cases of Hodgkin's disease. In all, 29 B and 2 T cell lymphomas, and 9 cases of Hodgkin's disease expressed CD95. Compared with diffuse large B-cell and Burkitt-like lymphomas, lowgrade B-cell lymphomas more frequently expressed CD95 (52% versus 26%; P < .005). None of the B-cell small lymphocytic lymphomas or mantle cell lymphomas expressed CD95, whereas the majority of follicle center lymphomas, extranodal marginal zone B-cell lymphomas, and immunocytomas were CD95+. Of the 29 CD95+ B-cell lymphomas, only 33% of the high-grade group coexpressed Bcl-2, compared with 87% of the low-grade group (P < .04). Two of three peripheral T-cell lymphomas--including one anaplastic large cell lymphoma--expressed CD95. Staining for CD95 was seen in 9 of 10 cases of Hodgkin's disease. The infrequent expression of CD95 in high-grade B-cell lymphomas suggests an association between loss of CD95 expression/function and a more aggressive tumor grade. Whereas frequent coexpression of Bcl-2 with CD95 may protect low-grade B-cell lymphomas against CD95-mediated apoptosis, in the high-grade group such coexpression is infrequent, and other regulators besides Bcl-2 may be involved in modulating the apoptosis signal delivered by CD95.     

Synthesis of DNA by the spleens of germ-free mice during the primary response to sheep red cells

The mitotic activity of the spleens of non-immunized germ-free (GF) mice was less than in similar specific pathogen-free (SPF) animals. No evidence of germinal center activity was noted in these GF mouse spleens before challenge with sheep erythrocytes (SRC). These centers only began to develop 4 days after immunization and were not fully developed before 8 days. In control SPF mice, the spleens showed very few germinal centers which were small in size, but they showed the same pattern of evolution as in similarly immunized GF mice. The changes in the red pulp, characterized by the development of clusters of nuclei labeled with [³H]thymidine, followed closely the development of plaqueforming cells (PFC). The numbers of direct PFC reached the same peak level in GF and SPF mice on day 4 of the response to SRC, but were not so well sustained in the former animals after this time. Indirect PFC were much lower in the spleens of GF mice than in SPF animals. The pattern and degree of increase of DNA synthesis in the spleen of GF and SPF mice following immunization with SRC differed from and was less than that of mice reared in less clean conditions. Increased DNA synthesis occurred very soon after injection of SRC (6 to 24 h) and the increase was sustained for 4 days without further significant rise and then declined. Autoradiographs of the spleen of immunized GF mice given [³H]thymidine showed that the first increase of labeled nuclei in the white pulp occurred around the central arterioles as early as 6 h after SRC. This was followed by increased labeling in the mantle layer of the white pulp and the characteristic pattern of germinal center labeling developed after 4 days. Increased labeling of nuclei developed in the red pulp as early as in the white pulp, while the subcapsular and trabecular areas showed high labeling indices even in the spleens of non-immunized controls. The ratio of labeling index/mitotic index which is governed by the respective durations of DNA synthesis and mitosis in those cells in division cycle, varied between 10 and 280 in different areas of the spleen. This indicated a vast excess of cells synthesising DNA in relation to the numbers of dividing cells actually present in the spleens of these mice.