Carcinogenicity of diethylstilbestrol in the Wistar rat: effect of postnatal oral contraceptive steroids.

Diethylstilbestrol (DES) has been associated with vaginal neoplasia and malformations in humans. We have studied a test population of 504 female Wistar rats given diethylstilbestrol at from 0.0 to 0.5 mg/kg maternal body weight on days 18, 19, and 20 of gestation. Animals were euthanized in extremis, or at 2 years of age. The incidence of vaginal epithelial tumors was dose related. The types of epithelial tumors of the vagina were adenocarcinoma, squamous cell carcinoma, and mixed carcinoma, containing discrete adenomatous and squamous components. The incidence of vaginal epithelial tumors was determined to be dose related: rats exposed to 0 mg DES/kg maternal weight had an incidence of 0.6% (1 of 167 rats); 0.1 mg/kg, 4.1%; and 0.5 mg/kg, 4.3% (6 of 140); 25 mg/kg, 1.6% (1 of 63); and 50 mg/kg, 11.5% (3 of 26). Tumors of other reproductive tissues (mammary gland, ovary, oviduct, cervix, or uterus) demonstrated no discernible DES dose-response relationship. There was no oncogenic effect of postnatal administration of oral contraceptives (0 oral contraceptives, 31.25 micrograms/kg diet ethynylestradiol, and 31.25 micrograms/kg diet norethindrone or 104 micrograms/kg diet ethynylestradiol and 31.25 micrograms/kg diet norethindrone). Thus, vaginal tumors can be induced in a dose-related manner in the rat following in utero DES exposure. Oral contraceptive treatment did not increase the risk of neoplasia.

Biplots in biomedical research.

The biplot is a graphical display of multivariate data. A number of examples from biomedical research illustrate its use. Biplots allow for inspection of data preliminary to formal analysis, and can follow an analysis by the graphical inspection of residuals. The simplicity and intuitive appeal of these displays is stressed. An appendix indicates their method of construction and the software for producing them.

A controlled clinical trial of baclofen as protective therapy in early Huntington's disease.

We carried out a controlled clinical trial to examine the potential of baclofen to slow the functional decline of patients with early Huntington's disease (HD). The basis of the trial was: (1) the hypothesis that excitatory amino acid neurotransmission mediates the neuronal degeneration of HD, (2) preclinical evidence that baclofen retards corticostriatal release of glutamate and aspartate, and (3) reports that baclofen produces short-term clinical benefits in some HD patients. Sixty patients with early HD were randomized to chronic baclofen, 60 mg/day, or placebo treatments and followed systematically for up to 42 months. Total functional capacity was not favorably influenced by baclofen treatment. Factors that contributed, although nonsignificantly, to a more rapid rate of total functional capacity decline included younger age (less than 35 years), earlier stage (stage I) of illness, paternal inheritance of the HD gene, and baclofen treatment. Our patients declined at a pace slower than that observed in other prospective studies, a finding likely due to selection criteria, avoidance of neuroleptic therapy, and strong psychosocial support.

The accuracy of blood glucose testing by children.

While studies have evaluated the accuracy of adult patients and health personnel in reading various glucose oxidase impregnated strips to estimate blood glucose, there are no studies exclusively evaluating the accuracy of children with diabetes reading their own strips as compared to a staff member, and meter to meter variability in reading these strips. We evaluated the accuracy of reading chemstrip bG by children at a summer camp. The children's visual readings of their own strips were compared to the visual reading of a single staff member. A total of 356 Chemstrip bG's were visually read by diabetic children and a single trained staff member at a summer camp for diabetics. The strips were then analyzed by two Accu-Chek bG meters. Intermachine variability was found to be negligible over the entire bG range. For the purposes of this study, we define accurate visual readings as those within +/- 15 percent of the meter reading of a given strip. At low bG values (40-79 mg/dl), accuracy by children and staff is low, with underestimating occurring in 39 percent of staff readings and 57 percent of children's readings. At intermediate bG values (120-239 mg/dl) readings are more accurate, especially when read by the staff, with misreadings occurring in only 16-19 percent of the strips. At high bG values (240-399 mg/dl), accuracy by children is decreased, with underestimation 500 percent more often than staff. We conclude that children are less accurate at reading Chemstrip bG than a trained staff member (51% versus 33% misreading), especially at the upper and lower ranges of bG values when visual readings are least accurate, and the need for therapeutic intervention is the greatest.

The mortality risk associated with digitalis treatment after myocardial infarction.

We examined the effects of digitalis therapy on postinfarction mortality throughout a 24-month to 48-month follow-up in 867 patients who survived an acute myocardial infarction. During follow-up, 145 patients died (16.7% mortality). At the time of hospital discharge, 31% of the patients were taking digitalis. The digitalis-treated patients were older, had more medical-cardiac risk factors, and had a higher mortality rate throughout the follow-up than the nondigitalis-treated patients. Statistical techniques were used to adjust for clinical imbalances between the digitalis-treated patients and nondigitalis-treated patients. The survival analysis (n = 728 patients) utilized the Cox regression model, and the digitalis-associated mortality risk was identified only after all significant covariates were allowed, so that mortality could be predicted as accurately as possible. Digitalis therapy was associated with a significantly increased postinfarction mortality risk after adjustment for the predictor covariates (relative risk 2.3, 95% confidence interval 1.4-3.7, p less than 0.001). The findings from this large multicenter study suggest that it would be prudent to exercise caution in the use of digitalis in postinfarction patients.

Infant mortality and economic instability in Yugoslavia.

Efforts to manage Yugoslavia's debt crisis beginning in 1979 led to economic policies which resulted in declining real income in subsequent years. This has been associated with a slowing of the rate at which infant mortality has declined. There is no evidence, however, that populations in poor parts of the country experienced a more dramatic impact on infant mortality than did populations in more favored regions. The lack of difference is attributed to redistributive social policies among and within republics.

Predicting risk of pneumothorax in needle biopsy of the lung.

We prospectively studied results of 103 consecutive transthoracic needle biopsies of lung lesions suspicious for malignancy to determine if lesion size, depth within the lung, hyperinflation, second needle passes, or 100 percent oxygen breathing influenced the incidence of pneumothorax. Thirty-eight patients (37 percent) developed pneumothorax. Ten (10 percent) required tube thoracostomy for re-expansion. Five of the ten requiring the chest tube had clinically severe obstructive lung disease. In all patients, greater depth (D) in centimeters of needle penetration significantly increased the probability (p) of pneumothorax (p much less than .001) and can be estimated by the equation: (formula see text) The estimated probability of pneumothorax is 13 percent at 1 cm, 49 percent at 4 cm, and 86 percent at 7 cm. An increase in total lung capacity above predicted added additional risk of pneumothorax (p less than .02). Oxygen breathing did not significantly reduce the incidence of pneumothorax, but may reduce size by increasing the rate of reabsorption. The other factors had little influence. We conclude that the more central location of the lesion and pre-existing lung hyperinflation determine the risk of pneumothorax.

Active and passive capillary control in red muscle at rest and in exercise.

Capillary control was quantified in dog gracilis muscles from in situ. About 550 capillaries/mm2, one-third the total number present, were perfused with erythrocytes simultaneously at rest; two-thirds the total could be perfused during maximal vasodilation. The functional capillary reserve was about 600/mm2. Capillary distribution at rest reflects a passive, random process at individual capillaries and an active process that coordinates perfusion of small groups of capillaries. The latter creates long diffusion distances. These are unaltered by denervation, or flow per se, but are abolished by adenosine. Twitch contraction at 4/min recruited about 400 capillaries/mm2 without any change in flow. Capillaries opened selectively where diffusion distances were longest. The same changes occurred within 5 s during work at 4/s, even if flow was held constant. If flow could increase, about 200 additional capillaries/mm2 were slowly recruited, without change in capillary distribution. Conclusions are that 1) hemodynamics and active vasomotion contribute equally to capillary density at rest; 2) active papillary control in exercise is ungraded and solely responsible for eliminating metabolically significant diffusion paths; 3) flow and capillary density can be controlled independently by proximal and terminal arterioles, respectively.

Digitalis-associated cardiac mortality after myocardial infarction.

The effect of digitalis therapy on 4-month posthospital cardiac mortality was investigated in 812 patients who survived the hospital phase of acute myocardial infraction. A stepwise multiple logistic regression analysis was used to identify variables associated with increased mortality and to adjust for differences in confounding variables between digitalis and nondigitalis patients. The major 4-month mortality (10 of 26 patients [38.5%]) occurred in digitalis-treated patients with congestive heart failure in the coronary care unit and complex ventricular premature depolarizations (VPDs) on the predischarge Holter recording. Logistic analyses that controlled for confounding variables indicated that digitalis use contributed to the increased mortality rate in this high-risk subset. The predicted mortality difference due to digitalis in patients with congestive heart failure and complex VPDs, adjusted for relevant nondigitalis risk factor variables, was 30% (90% confidence interval 18-42%). This retrospective study suggests that digitalis use increases the early posthospital mortality of myocardial infarction patients with combined electrical and mechanical dysfunction.

Calculated dispersion of capillary transit times: significance for oxygen exchange.

Probability densities for red cell velocity (V) and capillary length (L) in dog gracilis muscles were computed from mean length and mean velocity assuming two-parameter gamma distributions [Honig, Feldstein, and Frierson, Am. J. Physiol. 233 (Heart Circ. Physiol. 2): H122-H129, 1977]. The distribution of capillary transit times (L/V) was obtained from the ratio of the two gamma distributions. The lower tails of transit time distributions were compared with times thought required for O2 release from capillaries. Results indicate the following. 1) Transit time exceeds O2 release time at rest in all capillaries, regardless of assumptions in the calculation. 2) Transit time appears long enough even in moderate exercise provided mean L is about 1,000 microns and release time is about 100 ms. 3) Capillary recruitment prevents a functional O2 shunt during work at one- to two-thirds maximum O2 uptake (VO2max). 4) Recruitment is insufficient to prevent O2 shunting during exercise to VO2max. 5) Quantitative analysis of O2 transport is severely limited by lack of information about a) microvascular geometry, b) the probability distributions of parameters, and c) the kinetics of O2 release from capillaries.

Capillary recruitment in exercise: rate, extent, uniformity, and relation to blood flow.

Erythrocyte-containing capillaries were counted in dog gracilis muscles freeze-clamped at rest and after twitch contraction at 4/s. In each of 21 muscles, 6--8 blocks were examined at -70 degrees C without fixation or staining; 15 fields were counted per block. Frequency analysis of capillaries per field based on the negative binomial distribution indicated that capillary density at rest was controlled by arterioles. Active vasomotion of these arterioles was "switched off" within 5 s after onset of exercise. Capillary density was then determined passively by stochastic rheologic factors acting at the individual capillaries. Thus exercise changes the site and the mechanism of capillary control. Recruitment occurred first where capillary density was lowest, and was complete in 15 s; this greatly decreased the heterogeneity of capillary spacing. Mean capillary density increased 1.5- to 3-fold, whereas flow increased almost 7-fold. Calculated mean velocity and mean transit time of erythrocytes in capillaries were 1.1 mm/s and 920 ms at rest and 4.2 mm/s and 215 ms after 3 min of exercise.

Intercapillary distance and capillary reserve in hypertrophied rat hearts beating in situ.

Functional intercapillary distance (ICD) was measured in stop-motion photomicrographs of hypertrophied, normally compensated, well oxygenated rat hearts beating in situ. Left ventricular hypertrophy was produced by salt loading and unilateral nephrectomy. Minimum ICD (when all capillaries are open) also was measured. Ventricular weight increased by 30-40% within 8-9 weeks after nephrectomy. To compare the effect of normal and pathological growth, ICD was also measured in normal rats. In normal animals, minimum ICD and functional ICD increased linearly and proportionately with left ventricular weight. Consequently, the extent to which capillary recruitment could decrease ICD was the same in large and small normal hearts (about 2 micrometer). In the hypertrophied hearts, capillary recruitment could have maintained ICD within normal limits at rest for several weeks. After 8-9 weeks, however, the capillary reserve in hypertrophy was fully utilized at rest, and mean functional ICD was 1.5-2.0 micrometer greater than normal for the age of the animal. An analysis of O2 transport indicates that anoxic foci would exist throughout the hypertrophied heart and particularly in subendocardium when the capillary reserve is exhausted. The calculated amount of anoxic tissue appears sufficient to account for the focal necrosis and fibrosis observed in hypertrophy and for the development of circulatory failure.

Coronary intercapillary distance during growth: relation to PtO2 and aerobic capacity.

Intercapillary distance (ICD) was measured in left ventricles of rats beating in situ. Between 40 and 400 days of age, left ventricular weight increased threefold and ICD increased from 12.5-19.5 mum. ICD could be decreased by at least 2 mum at all ages studied. The number of capillaries which must be recruited to reduce ICD by 2 mum fell from 1,200/mm2 at 40 days to 280/mm2 at 400 days. Ventricular growth did not affect the O2 sensitivity of precapillary sphincters or the uniformity of capillary spacing. Calculations indicate that under basal conditions tissue PO2 (Pto2) in subepicardium is about the same at 40 and 400 days, even though VO2 per gram, capillary density, and ICD change twofold, twofold, and 7 mum, respectively. Nevertheless, as the ventricle grows, capillary recruitment becomes progressively less effective in defending Pto2 under conditions of stress. Diminished coronary capillary compensation for stress may, in part, account for the effect of age on the maximum aerobic capacity of the whole animal.

The use-effectiveness of two contraceptive methods in a Navajo population: the problem of program dropouts.

Navajo Indian intrauterine contraceptive device (IUD) and oral contraceptive users between 1966 and 1971 were followed up to estimate life table rates of complications and continuation. Because of high rates of dropping out, 41.6 per cent of 291 oral contraceptive users and 18.2 per cent of 534 IUD users, a 26 per cent sample survey of the dropout population was used to collate the dropout population data into the life table analysis. Estimates of the IUD continuation rates for one, two, and three years are similar to rates published elsewhere; however, continuation rates for the oral contraceptive are clearly lower than those for other populations, which only 33 per cent continuing after one year, 23 per cent after two years, and 12 per cent after three years. The IUD user is two to three times more successful than the oral contraceptive user in this population.