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To determine whether the series addition of sarcomeres observed during eccentric hypertrophic growth is reversible upon removal of the initiating stimulus, an aortocaval fistula was created and myocyte geometry evaluated at 2 and 12 wk after shunt occlusion. A 76% cardiac enlargement was produced in rats with an aortocaval fistula. This enlargement was reduced to 22 and 18% at 2 and 12 wk of fistula reversal, respectively. Hemodynamic performance was altered as a result of fistula induction as evidenced by a 28% increase in peak rate of pressure rise. This pressure increase remained elevated by 30% 2 wk after fistula reversal but was not different from sham-operated control animals at 12 wk of reversal. Significant increases in overall myocyte length were detected as a result of the creation of the fistula [left ventricle (LV), 20%; right ventricle (RV), 29%; septum, 23% greater than shams]. Although these increases diminished only slightly 2 wk after closure of the fistula (LV, 12%; RV, 17%; septum, 12% greater than shams), linear measurements of myocyte length in two of three regions had reverted to values that were not significantly different from those of age-matched, sham-operated controls at 12 wk after fistula closure (LV, 8%; RV, 10%; septum, 7%). Myocyte cross-sectional area and cell volume followed a similar pattern. Thus myocytes possess the necessary machinery to remove recently added series sarcomeres, returning altered pump function and dilated ventricular chamber geometry toward control values. In addition, it appears that cardiac hypertrophic growth with this experimental model of volume overload is largely, but not completely, reversible.

We evaluated a new liquid perfluorocarbon, perfluorophenanthrene (Vitreon). This material has proven to be non-toxic in vitrectomised rabbit eyes for up to six weeks. Present investigation under FDA guidelines establishes both the safety and efficacy of Vitreon in human eyes. We used Vitreon for intraoperative hydrokinetic retinal manipulation in 15 patients. In cases of proliferative vitreoretinopathy (6), rhegmatogenous retinal detachment (5), giant retinal tear (2), retinal dialysis (1), and tractional retinal detachment (1) the retina was successfully reattached. Postoperatively two patients developed proliferative vitreoretinopathy necessitating further surgery, and one patient developed hypotony. Follow-up showed 100% reattachment rate with a mean duration of 6.3 months. Postoperative visual acuity ranges from light perception to 20/30.

To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 micro g daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA.Original secondary analyses of the NPC to 1993 showed striking inverse associations between SS and prostate cancer incidence. A subsequent report revealed that this effect was accentuated among men with the lowest baseline plasma selenium concentrations. The effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models.SS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29-0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level ofor= 4 ng/mL (0.35, 0.13-0.87), although the interaction of baseline PSA and treatment was not statistically significant. Participants with baseline plasma selenium concentrations only in the lowest two tertiles (123.2 ng/mL) had significant reductions in prostate cancer incidence. A significant interaction between baseline plasma selenium and treatment was detected.To the end of the blinded treatment the NPC trial continued to show a significant protective effect of SS on the overall incidence of prostate cancer, although the effect was restricted to those with lower baseline PSA and plasma selenium concentrations.

The extensive experimental evidence, reviewed by Medina and Morrison (1988), and Combs and Clark (1997), indicates that Se supplementation reduces the incidence of cancer in animals There are over 100 published studies in 20 different experimental animal models of spontaneous, viral, and chemically induced tumours. In two thirds of these studies, a significant reduction in tumour incidence was reported and in one third of these studies, a reduction of over 50% in tumour incidence was observed. This literature indicates that Se supplementation in animals can reduce the incidence of skin, colorectal, breast, stomach, hepatic, oesophageal, oral, tracheal, pancreatic, kidney and lung cancers. Geographic studies have shown a consistent trend for populations with low Se levels to have a higher cancer mortality rate. Epidemiologic cancer studies in groups of individuals have produced more variable results, but the trend in most studies is for individuals with lower Se levels to have a higher incidence of cancer. A number of cohort and nested case-control studies have shown a lower risk of internal malignancies for individuals with higher plasma Se levels. A recent meta-analysis of cohort studies comparing the effect of serum Se, retinol, beta-carotene, and vitamin E suggests that Se has a remarkably consistent protective effect (Comstock, Bush, and Helzlsouer, 1992). Other

This paper considers a latent class model to uncover subpopulation structure for both biomarker trajectories and the probability of disease outcome in highly unbalanced longitudinal data. A specific pattern of trajectories can be viewed as a latent class in a finite mixture where membership in latent classes is modelled with a polychotomous logistic regression. The biomarker trajectories within a latent class are described by a linear mixed model with possibly time-dependent covariates and the probabilities of disease outcome are estimated via a class specific model. Thus the method characterizes biomarker trajectory patterns to unveil the relationship between trajectories and outcomes of disease. The coefficients for the model are estimated via a generalized EM (GEM) algorithm, a natural tool to use when latent classes and random coefficients are present. Standard errors of the coefficients are calculated using a parametric bootstrap. The model fitting procedure is illustrated with data from the Nutritional Prevention of Cancer trials; we use prostate specific antigen (PSA) as the biomarker for prostate cancer and the goal is to examine trajectories of PSA serial readings in individual subjects in connection with incidence of prostate cancer.

Prostate cancer is the second leading cause of cancer deaths in men, therefore it is increasingly important to understand its biology and epidemiology. New approaches for the primary and secondary prevention of prostate cancer are needed, including innovative uses of chemoprevention. This review provides an overview of the epidemiological data suggesting that higher intakes of selenium may reduce the risk of prostate cancer. In addition, a discussion of preclinical data is presented. Special emphasis is placed on the following areas: (1) chemical forms of selenium and antitumorigenic activity, (2) in vitro effects of selenite versus monomethylated selenium, and (3) current clinical intervention trials with selenium in prostate cancer. Chemoprevention, especially with dietary forms of selenium, is a promising new approach that presently is undergoing intensive investigation.

The hypothesis that a dietary supplement of selenium (Se) may reduce cancer risk was tested experimentally in humans. Patients with histories of basal/squamous cell carcinomas of the skin were assigned randomly in double-blind fashion to daily oral supplements of either Se-enriched yeast (200 micrograms Se/day), or a low-Se yeast placebo. A total of 1312 patients recruited in 1983-1990 were followed with regular dermatologic examinations through 1993 for a total of 8269 person-years of observation. Skin cancer diagnoses were confirmed histologically. Plasma Se concentration was determined at 6-12 months intervals. All deaths and patient-reported illnesses were recorded; reported cancers were confirmed and documented by consultation with the patient medical care providers. The results indicate that Se did not significantly affect the primary endpoints: incidences of recurrent basal/squamous cell carcinomas of the skin. However, Se-treatment was associated with reductions in several secondary endpoints: total mortality, mortality from all cancers combined, as well as the incidence of all cancers combined, lung cancer, colorectal cancer and prostate cancer. The consistencies of these associations over time, between study clinics and for the leading cancer sites strongly suggests benefits of Se-supplementation for this cohort of patients, supporting the hypothesis that supplemental Se can reduce cancer risk. Although Se did not shown protective effects against non-melanoma skin cancers, the suggested reductions in risks to other frequent cancers demand further evaluation in well controlled clinical intervention trials.

Statistical methodology is presented for the statistical analysis of non-linear measurement error models. Our approach is to provide adjustments for the usual maximum likelihood estimators, their standard errors and associated significance tests in order to account for the presence of measurement error in some of the covariates. We illustrate the technique with a mixed effects Poisson regression model for recurrent event data applied to a randomized clinical trial for the prevention of skin tumours.

To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.Seven dermatology clinics in the eastern United States.A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.Oral administration of 200 microg of selenium per day or placebo.The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made

It is essential to identify intermediate marker endpoints of carcinogenesis for the evaluation of the effectiveness of cancer-chemopreventive agents. We have observed that levels of proteolytic activities (as detected by 4 different substrates) are increased 2-3-fold (P0.003) in oral buccal mucosa cells of smokers and patients with oral leukoplakia or erythroplakia as compared to a nonsmoking comparison group. In addition, proteolytic activity levels in the buccal cells were increased nearly 3-fold in patients with oral trauma (P0.01) or diabetes (P0.02), as well as pregnant women (P0.04). Excluding these subgroups of patients in epidemiological studies increase the differences in levels of proteolytic activities between both the nonsmoking comparison group and smokers and between the comparison group and patients with oral leukoplakia or erythroplakia. Evaluation of prerandomization levels of proteolytic activities of patients in cancer chemoprevention trials will increase the statistical power by allowing stratified randomization based on levels of proteolytic activities. The observed increases in levels of proteolytic activities in tissues at higher than normal risk of cancer development suggest that levels of proteolytic activities should be used as immediate marker endpoints in human cancer prevention trials using protease inhibitors as potential anticarcinogenic agents.

The number, size, and histologic features of distal colorectal adenomatous polyps have been reported to correlate with the risk of developing proximal colon cancer. To investigate this putative relationship further, we evaluated the frequency of distal colorectal neoplastic polyps in patients with colon cancer located proximal to the splenic flexure.All cases of colorectal adenocarcinomas treated at a tertiary referral center and Veterans Affairs hospital between 1979 and 1992 were identified by International Classification of Diseases coding and review of pathology and colonoscopy reports. The medical records of patients with documented cancers proximal to the splenic flexure were examined for the presence, location, size, and histopathologic features of synchronous neoplastic lesions found at colonoscopy.Among 634 patients with colorectal cancer identifiable by location, 172 had proximally located tumors. Of these, 60 patients were excluded because of lack of complete colonoscopy or because surgical resection was performed elsewhere. Forty percent of the remaining 112 patients for whom data could be evaluated demonstrated neoplastic lesions in addition to the proximal cancer. The colon was devoid of "sentinel" neoplasia distal to the splenic flexure and descending colon-sigmoid colon junction in 69% and 72% of patients, respectively.The majority of proximal colon cancers are not associated with distal sentinel lesions. We surmise that flexible sigmoidoscopy will fail to find evidence of neoplasia in at least 25% of patients with prevalent colon cancers.

The objective of this cross-sectional study was to determine whether plasma selenium concentration predicts the prevalence of adenomatous polyps of the colon and rectum. The source population for the study was 101 patients undergoing sequential colonoscopies at the Veterans Affairs Medical Center, Tucson, AZ. The study population was then limited to the 48 patients (all male) undergoing their initial colonoscopy who did not have a diagnosis of colorectal cancer. For each of these patients, a prediagnostic fasting plasma selenium concentration was determined. The data from this study suggest that fasting plasma selenium concentrations may be an important risk factor for colorectal adenomas. Patients with fasting plasma selenium concentrations below the median (128 mcg/liter) were significantly more likely to have one or more adenomatous polyps (prevalence odds ratio 4.2) and more adenomatous polyps (3.5 times) per patient. There was also a suggestion of a more proximal distribution of adenomatous polyps in the patients with a lower level of selenium. These associations were not confounded by age or smoking. The results of this study are consistent with the experimental animal studies, geographic mortality studies, and prospective cohort studies of selenium and colorectal cancer.

Two preparations of silicone gels were evaluated as long-term vitreous substitutes in the vitrectomized and lensectomized eyes of primates. Both preparations were injected in liquid form and polymerized in the vitreous cavity. There was no toxic effect on the ocular structures up to 13 months after implantation. Fundus examination and fluorescein angiography were possible through the less rigid gel, whereas the preparation with higher rigidity consistently appeared cloudy.

Six African green monkeys (six eyes) underwent vitrectomy and vitreous replacement with Vitreon (perfluorophenanthrene) or Vitreon plus silicone. A seventh animal served as a control. Vitreon alone and in combination remained optically clear and allowed fundus examination up to 162 days. No toxic effects to the retina were detectable. Vitreon exhibited some degree of emulsification and formed some globules at 45 days postoperatively. Interestingly, Vitreon emulsification occurred at a later time (80 days) in one of the silicone plus Vitreon eyes. The combination of silicone plus Vitreon may offer the advantage of tamponading the inferior and superior retina in phakic eyes.

We consider the statistical modeling and analysis of replicated multi-type point process data with covariates. Such data arise when heterogeneous subjects experience repeated events or failures which may be of several distinct types. The underlying processes are modeled as nonhomogeneous mixed Poisson processes with random (subject) and fixed (covariate) effects. The method of maximum likelihood is used to obtain estimates and standard errors of the failure rate parameters and regression coefficients. Score tests and likelihood ratio statistics are used for covariate selection. A graphical test of goodness of fit of the selected model is based on generalized residuals. Measures for determining the influence of an individual observation on the estimated regression coefficients and on the score test statistic are developed. An application is described to a large ongoing randomized controlled clinical trial for the efficacy of nutritional supplements of selenium for the prevention of two types of skin cancer.

Oxygen tension in the peritoneum has been continuously measured with a Silastic tonometer having an integral oxygen electrode and inlet and outlet tubes for gasequilibrated electrolyte solution. Remote kinetic calibration of the system is periodically performed. Tonometers were implanted in six rabbits. Peritoneal oxygen tension was measured in awake and anesthetized rabbits under various oxygen breathing conditions.

In this rapid and specific micro-scale electrochemical enzymic assay for cholesterol and cholesterol esters, 10 microL of standard or sample is injected directly into a heated (50 degrees C) thermostated, oxystated cuvet containing pH 7.25 buffer, cholesterol oxidase (EC 1.1.3.6), and cholesterol esterase (EC 3.1.1.13). The cholesterol esters are hydrolyzed by the esterase, and the cholesterol is simultaneously oxidized by the oxidase. The hydrogen peroxide produced from oxidation of the unesterified cholesterol is measured by a polarographic anode covered with an acetate/polycarbonate membrane. The membrane allows hydrogen peroxide to diffuse to the platinum anode, where it is oxidized, but prevents the diffusion of ascorbic acid, uric acid, and bilirubin to the electroactive surface. Turbidity does not interfere. The correlation (r) between results by our method and the Abell-Kendall method for 105 samples of serum was 0.9994 and for 105 samples of plasma was 0.9997. Our method is convenient for the analysis of high-density lipoprotein cholesterol in plasma and serum supernates and in many kinds of tissue homogenates. Its limitations are also described.

Two behavioural indices for psychotomimetic activity have been used to elucidate the probable role of methoxy group configuration in the mescaline molecule. The first method using a shuttle box CAR has been reported previously in this series. The second is based on the Sidman Avoidance schedule and utilizes the Bovet-Gatti profiles. Our results indicate that only two analogues of mescaline are active-the 2,3,4,5 and 2,3,4,5,6 compounds. This indicates that the 3,4,5 configuration is necessary and that adding extra methoxy groups increases activity. The great activity of the penta methoxy compound may be due to the fact that this compound substituted in the 2 and 6 positions cannot be metabolized by mescaline oxidase. The significance of these results is discussed.

(1987). Relationships between the Type a Behavior Pattern and Intelligence in Children. The Journal of Genetic Psychology: Vol. 148, No. 4, pp. 529-531.

In this rapid and specific micro-scale electrochemical enzymic assay for cholesterol and cholesterol esters, 10 microL of standard or sample is injected directly into a heated (50 degrees C) thermostated, oxystated cuvet containing pH 7.25 buffer, cholesterol oxidase (EC 1.1.3.6), and cholesterol esterase (EC 3.1.1.13). The cholesterol esters are hydrolyzed by the esterase, and the cholesterol is simultaneously oxidized by the oxidase. The hydrogen peroxide produced from oxidation of the unesterified cholesterol is measured by a polarographic anode covered with an acetate/polycarbonate membrane. The membrane allows hydrogen peroxide to diffuse to the platinum anode, where it is oxidized, but prevents the diffusion of ascorbic acid, uric acid, and bilirubin to the electroactive surface. Turbidity does not interfere. The correlation (r) between results by our method and the Abell-Kendall method for 105 samples of serum was 0.9994 and for 105 samples of plasma was 0.9997. Our method is convenient for the analysis of high-density lipoprotein cholesterol in plasma and serum supernates and in many kinds of tissue homogenates. Its limitations are also described.

Emulsions of fluorocarbons are finding considerable use in physiology for intravascular oxygen transport. Their wide clinical application as blood substitutes, anti-shock, and anti-ischemic agents seems imminent. Whole body NMR imaging is rapidly gaining clinical application and may one day almost completely supplant X-ray imaging. All of the 19F compounds used in biocompatible fluorocarbon emulsions give 19F signals identical to those in the corresponding neat liquid. In concentrations of 10% w/v they are readily imaged. The paramagnetic oxygen molecule reduces T1 in such a way as to make possible whole body imaging of oxygen. T1 typically decreases from 1-4 to 0.3-0.5 seconds and is an inverse linear function of oxygen tension. Spin-lattice relaxation times versus oxygen tensions from 0 to 600 torr have been obtained for F-decalin, F-tributylamine, and F-44E. The usefulness of these 19F effects in clinical NMR imaging depends upon the sensitivity of the method and the tolerable dose. The 19F signal may find use in monitoring 19F compounds as vapors or gases dissolved in plasma or in perfluorocarbons in neat liquid or particle form.

The rapid specific quantitative measurement of a number of substances which are important to clinical, food and fermentation chemists is made possible by immobilizing enzymes on membranes • which are used with Polarographie electrodes. We wish to illustrate the usefulness of such enzyme analytical probes in the intermittent and continuous measurement of glucose, sucrose, galactose, lactose, glycerol, and dihydroxyacetone.

During the past several years we have progressed from the use of perfluorinated substances, which were good gas solvents but often produced unexpected physiological reactions, to a point where emulsions of pure perfluorinated substances can be made in a reproducible way. A standardized method of making emulsions has now been developed. The physical properties of the perfluorinated substances needed to make useful emulsions have been defined. Specifically, perfluorinated substances having vapor pressures above about 40 torr must be avoided as they produce pulmonary gas embolism; also lower boiling components having vapor pressures above about 40 torr must be excluded. The relationship between chemical structure and several physiological and pharmacological effects has been delineated. Perfluorinated substances containing only carbon and fluorine, or those containing carbon, fluorine, and either bromine or iodine have reasonably short dwell times in the liver. Perfluorinated iodo- and bromo-compounds dissolve oxygen and are radiopaque. Present iodo-perfluorinates are unstable in the presence of light. Perfluorodecalin can enter and leave the liver without changing the liver's ultrastructure. Both egg phospholipid and Pluronic F68 are useful in making perfluorodecalin emulsions. Perfluorodimethyladamantane makes a fine-particle stable emulsion. There is a bright future for perfluorinated substances in a number of areas of research in biology and medicine.

Protection of the enzyme layer of glutaraldehyde vapor-stabilized glucose oxidase-based glucose sensors from attack by proteolytic enzymes and peritoneal macrophages can be accomplished by covering with a regenerated cellulose (viscose) membrane, as commonly used for laboratory dialysis. These implanted sensors are not externally polarized, but continuously consume oxygen and glucose and generate gluconic acid and hydrogen peroxide. On the average (sensors in 45 mice) the activity declines with time, almost vanishing by 600 days. However, the fact that some sensors retain nearly all of their activity for over 500 days indicates that glucose sensors can be made with a life span compatible with the requirements for an artificial pancreas (glucose sensor/insulin pump). Limited observation with similar implanted lactate sensors indicates their life span to be shorter.

Nuclear magnetic resonance (NMR) imaging of perfluorocarbon (PFC) emulsions and neat liquids has shown potential for in vivo oxygen imaging in blood and organ tissue. PFC compounds exhibit complicated NMR spectra caused by chemical shifts and spin-spin couplings which can lead to artifacts and degraded spatial resolution of resulting NMR images. To correct for the chemical shift artifacts, the technique of spectral deconvolution has been applied to NMR imaging of PFC compounds. The temporal filter for this process can be directly applied to raw free induction decay data in projection reconstruction or to spin-echo data in two-dimensional Fourier transform imaging techniques. The effect of chemical shift artifacts was demonstrated through the NMR imaging of two PFC compounds (F-tributylamine and F-decalin) in phantoms. Methods are presented and demonstrated which allow the chemical shift artifacts to be removed and true images of the spatial distribution of the PFC's to be recovered.

PIP: There is striking evidence that there is an increased risk of early cancer mortality in women treated with diethylstilbestrol during pregnancy. Exposure to the drug is associated with more than a twofold increase in risk of all cancer, which increases to 2.89 for breast cancer, and to 2.73 for endocrine related tumors. Most published studies on the subject lack the statistical power to reject the hypothesis that there are no significant differences between treated and untreated women, especially in the presence of a 50% increase in risk. There is a difference in the magnitude of the relative risk between premenopausal and postmenopausal breast cancer, the mortality cases being primarily in premenopausal women. Additional studies on diethylstilbestrol are needed.

Although experimental studies in animals show that selenium may prevent cancer, case-control studies of internal human cancers have been difficult to interpret because neoplastic tissue sequesters selenium. We therefore conducted a case-control study to examine the association between plasma selenium level and skin cancer, a neoplasm with minimal tumor mass at the time of diagnosis. The mean selenium level among patients with either basal cell epithelioma (N = 142), squamous cell carcinoma (N = 48), or both (N = 50), was 0.141 micrograms/g. This was significantly lower than the mean plasma selenium level of the 103 control subjects, which was 0.155 micrograms/g. The noncancer control groups were drawn from current clinic patients and past clinic patients. The logistic estimate of the odds ratio for the lowest versus the highest decile of selenium for all cases combined versus the group of current patient controls was 4.39; for all cases combined versus the past patient controls, the logistic estimate of the odds ratio was 5.81.