A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir).

OBJECTIVE: To investigate the safety, pharmacokinetics, and activity of the orally bio-available protease inhibitor MK-639. DESIGN: An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts < or = 300 x 10(6)/I and > or = 20,000 HIV RNA copies/ml. Pharmacokinetics were performed at days 1 and 15. In order to better understand the relationships between drug exposure, baseline activity markers, and their changes during the study, mathematical modeling was performed using the traditional sigmoid-Emax relationship of pharmacologic effect and first order inhomogeneous differential equations for a two compartment system. RESULTS: The five men enrolled had extensive prior nucleoside therapy (mean, 32.6 +/- 25.6 months), a low mean CD4 lymphocyte cell count (CD4 count, 66.1 +/- 61 x 10(6)/I and CD4 percentage, 4.4 +/- 3.1%), high soluble tumor necrosis factor-alpha type II (sTNFII) receptor concentration (6.23 +/- 2.76 ng/ml) and high viral load (5.13 +/- 0.46 log10 RNA copies/ ml; geometric mean, 133,941 copies/ml). The drug was well tolerated at a dose of 600 mg every 6 h. The steady state concentrations Cmax and Cmin were 4.94 +/- 2.16 microM and 0.28 +/-0.1 microM, respectively, which are approximately equal to 50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143 x 10(6)/ (217% increase ), the mean increase in CD4 percentage was 5.2 percentage points (118%), mean decrease in HIV RNA was 1.55 log10 RNA copies/ml (a geometric mean difference of 130,120 copies/ml or 97% decrease) with a slow upward drift on continued therapy to a mean 0.64 log10 RNA copies/ml decrease by week 24 (a geometric mean difference of 103,084 copies/ml or 77% decrease), and a mean decrease in sTNFII receptors of 2.78 ng/ml (45% decrease). The mean CD4 counts per week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2 = 0.998, P < 0.0001) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. Drug exposure as measured by either the total exposure (area under the concentration/time curve) or as the Cmin gave similar significant relationships to the fractional inhibition of HIV generation (r2 = 0.999, P < 0.0001, and r2 = 0.996, P < 0.0001, respectively). CONCLUSIONS: MK-639 appears to have significant dose-related antiviral activity and is well tolerated.

Persistent coccidioidal seropositivity without clinical evidence of active coccidioidomycosis in patients infected with human immunodeficiency virus.

We retrospectively identified 13 patients infected with human immunodeficiency virus (HIV) who had persistently positive coccidioidal serological tests without evidence of active coccidioidomycosis--to our knowledge, a heretofore undescribed phenomenon. The median duration of follow-up was 19 months. Five patients developed active coccidioidomycosis during this follow-up period; the median interval from the initial positive serological test to the development of active disease was 23 months. There were no significant differences between patients who developed active coccidioidomycosis and those who did not with regard to CD4 lymphocyte count or previous antifungal therapy. Moreover, when all 13 patients were compared with 21 patients who had HIV infection and active coccidioidomycosis, no differences were found with regard to age, race, risk factor for HIV infection, or initial CD4 lymphocyte count. In summary, persistently positive coccidioidal serological tests in HIV-infected patients appear to represent true coccidioidal infection and are associated with a significant risk of the development of active coccidioidomycosis.

Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients.

Through a retrospective review, we identified 77 previously unreported cases of coccidioidomycosis during HIV infection. Patients were classified into 1 of 6 categories based on their primary clinical presentation: 20 had focal pulmonary disease (Group 1), 31 had diffuse pulmonary disease (Group 2), 4 had cutaneous coccidioidomycosis (Group 3), 9 had meningitis (Group 4), 7 had extrathoracic lymph node or liver involvement (Group 5), and 6 has positive coccidioidal serology without a clinical focus of infection (Group 6). Coccidioidal serologies were positive on initial testing in 83% of the patients in whom such serologic testing was performed. Sera from 39% of patients were positive for TP antibodies while 74% had CF antibodies. Eleven of 12 seronegative patients had pulmonary disease (Group 1 or 2). Serologic results of other patients sent to a single reference laboratory were similar, with 26% positive for immunodiffusion TP antibodies and 79% positive for immunodiffusion CF antibodies. For the 77 patients in this study, the CD4-lymphocyte count was below 0.250 X 10(9) cells/L in 46 of the 55 patients who had this test performed, and a low CD4 count was significantly associated with mortality (p less than 0.01). At the time of follow-up, 32 of the 77 patients (42%) had died. There were significantly more deaths in those with diffuse pulmonary disease (Group 2) than in other groups (p less than 0.001). Amphotericin B, ketoconazole, fluconazole, and itraconazole were all used as antifungal therapies. Outcome could not be related to the therapy used. Of note, 3 patients developed coccidioidomycosis while receiving ketoconazole for other conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the careers of graduates of the University of Manitoba's BSc (Medicine) program.

The careers of graduates who had taken the BSc (Medicine) (BScMed) program at the University of Manitoba, Winnipeg, between 1950 and 1975 were compared with those of matched classmate controls to determine whether the program had any influence on the research careers of the graduates. More BScMed graduates than control subjects chose an academic career (49% v. 21%), achieved specialty certification (83% v. 65%), and obtained grants (51% v. 18%) and personal awards (37% v. 18%). The BScMed graduates also had significantly more publications than the control subjects. Although part of the difference between the two groups may be explained by the tendency of students who were more inclined toward an academic career to enter the BScMed program, it was evident that the program has a substantial effect on promoting the development of clinical investigators.

Tuberculosis status and social adaptation of Indochinese refugees.

The relationship between tuberculosis and social adaptation of Indochinese refugees in Manitoba, Canada, is examined in 43 randomly selected refugees treated for active and inactive tuberculosis (cases) and their matched controls. Tuberculosis status did not significantly affect adaptation as measured by selected scales and indicators. Significant predictors of better personal well-being included a low number of family members outside the household in Manitoba, non-use of traditional medicine, female gender, and high individual income. Tuberculosis status was not a significant predictor.

Where Manitoba children obtain their cigarettes.

People who start to smoke as children put themselves at greater risk of dying prematurely or being disabled by tobacco-induced disease. One solution is to restrict children's access to cigarettes, thereby reducing consumption of the product and, ultimately, damage to health. This study found that in 1985 the majority of Manitoba public school children 8 to 15 years of age who smoked "regularly" (defined as usually every day) obtained their cigarettes from stores. This source could be reduced, if not eliminated, were a federal regulation passed in 1908 enforced. Under Canada's Tobacco Restraint Act it is illegal for merchants to sell tobacco to anyone under the age of 16 years. By implementing this existing law, authorities would not only be keeping the profit from almost a million dollars in cigarette sales in Manitoba alone out of tobacco company coffers but also be having an impact on the leading cause of preventable premature death and disability in Canada.

The educational, vocational, and marital status of growth hormone-deficient adults treated with growth hormone during childhood.

The goal of growth hormone therapy in childhood is to increase stature, thereby facilitating normal psychosocial development. To determine the social outcome of patients with growth hormone deficiency (GHD), we interviewed 116 adults with GHD across Canada, including 86 men and 30 women 18 to 38 years of age who were treated with growth hormone during childhood. The education of the 96 patients who had completed their formal education was similar to their siblings and to the general population. Of the patients in the labor force, 35.4% were unemployed; the unemployment rates for those patients less than 25 years of age and those 25 years of age or older were 45% and 23%, respectively, compared with national rates of 21.2% and 9.4% for the same age groups, respectively. Of the 90 patients with GHD who were not attending school, 70 lived with their parents or relatives. Only 15 patients were married; one was divorced. The percentage of patients with GHD who were married was less than 30% of the expected age-adjusted rate. No difference in the rate of employment or marriage was found between the patients with idiopathic isolated GHD and organic hypopituitarism. In summary, the achievements of patients with GHD seem to be normal in the education system, but the rate of employment and marriage are much lower than expected. This poor outcome was unrelated to the response to growth hormone therapy and emphasizes the need to develop strategies that lead to more satisfactory psychosocial integration of patients with GHD in adult life.

Physicians and nurse practitioners: do they provide equivalent health care?

Data from 40 patients attending a hypertension clinic staffed by physicians were compared to data from 40 patients attending a hypertension clinic staffed by nurses over a period of 15 months. Nurses appeared to have more success in handling obesity and to achieve somewhat better control of hypertension. Attrition rate was 50 per cent, but particularly high in patients not receiving medication in the physician clinic. There were no differences in appointment keeping.

Factors influencing morbidity in termination of pregnancy.

This study analyzes the morbidity of therapeutic abortion and identifies predisposing factors. A retrospective case evaluation of 2,105 pregnancy terminations was performed. Major complications occurred in 5% of those undergoing curettage procedures, 41% of women undergoing prostaglandin amnioinfusion, and 17% of those who had hysterotomy as a method of abortion. Age, parity, and history of previous pregnancy termination, had little effect on morbidity. Surgical/technical factors and reliance on amnioinfusion and hysterotomy as procedures of choice for pregnancy termination contributed significantly to the high morbidity rates. This contribution, however, was overshadowed by the influence of patient delay, physician delay, and limited abortion facilities, resulting in 35.4% of pregnancy terminations being performed in the midtrimester. Improvements in abortion technique may lower the incidence of complications, but the need for more appropriate facilities is emphasized.

PIP: The morbidity of pregnancy termination in a large university hospital in Winnipeg, Manitoba, Canada is described, and predisposing factors are analyzed. A retrospective case evaluation of 2105 pregnancy terminations was performed. Major complications occurred in 5% of those undergoing curettage procedures, 41% of women undergoing postaglandin amnioinfusion, and 17% of those who had hysterotomy as a method of abortion. Age, parity, and history of previous abortion had little effect on morbidity. Surgical/technical factors and reliance on amnioinfusion and hysterotomy as procedures of choice for abortion contributed significantly to the high morbidity rates. The influence of patient delay, physician delay, and limited abortion facilities was greater, resulting in 35.4% of abortions being performed during the midtrimester. The variable most significantly associated with abortion-related morbidity was choice of procedure. Patients undergoing midtrimester abortions had 7 times the risk of major complications compared to those having 1st trimester abortions.

Teaching community medicine to undergraduates: the role of student projects.

The community medicine primary care clerkship at the University of Manitoba integrates didactic elements, clinical placements and student projects in teaching community medicine. The clinical clerkship is undertaken in a variety of community settings and emphasizes ambulatory care. The rotation for each student is eight weeks, six of which are spent in the clinical clerkship, bracketed by two weeks of community medicine. Student research projects allow medical students to become familiar with the principles of population-based and community-oriented medicine as applied in clinical practice. Evaluation of 156 projects completed during the first two years of the program indicates that a wide range of community-based health problems were identified and a variety of methodological approaches applied.

The professional objectives of canadian dental students.

Data from a 1971 national study of Canadian dental education are used as a basis for examining the relative importance which dental students and faculty place on the professional objectives of economic gain and service. Students (N = 1,247) were asked to rank a set of career attributes in terms of their importance both for themselves and for other students. Dental school faculty (N = 510) were asked to assess whether students under emphasized or overemphasized a group of 16 parallel objectives. The results indicate substantial variations between the professional objectives of individual students, those ascribed to others by students, and the faculty's perception of student objectives.

Career and training patterns of students entering Canadian medical schools in 1965.

This paper follows the careers of the 1128 students who entered Canadian medical schools in 1965, most of whom graduated in 1969. The type of career pursued (whether general or specialty practice or some combination thereof), the type of specialty undertaken, the place of internship and residency training and the 1973 practice location of the graduates are examined. The wide variation in careers followed by the 12 schools' graduates provides the major focus of the paper.