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Biomedical subjects

L C Clark

Publications and source records attributed to L C Clark.

At least 37 records · Page 2Linked to original sources
PubMed1997

Langerhans cell histiocytosis with orbital involvement.

PURPOSE: To review three cases of Langerhans cell histiocytosis with orbital involvement that represent a significantly excessive incidence of this rare disease in one community. Current diagnostic criteria and therapeutic modalities related to Langerhans cell histiocytosis are reviewed. METHODS: Case reports. We present clinical, radiologic, histopathologic, and epidemiologic information on three patients with Langerhans cell histiocytosis. RESULTS: All three children, born within 18 months of one another, manifested rapidly progressive unilateral proptosis at age 2 years. By computed tomography, all had moderately enhancing lesions with involvement of the sphenoid bone and lateral orbit as well as the temporal lobe of the brain. All patients were treated with a combination of vincristine and prednisone, with variable resolution of their lesions. The occurrence of three cases in children born in Nogales, Arizona/ Mexico, suggests an incidence rate of 40 per million, which is approximately 26 times the expected rate (P = .0001). CONCLUSIONS: The extraordinarily high incidence and the concentration of cases in both time and space of this cluster implies that Langerhans cell histiocytosis may be a sentinel disease for unusual environmental exposures.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Involvement of polyamines in selenomethionine induced apoptosis and mitotic alterations in human tumor cells.

The efficacy of dietary selenium supplementation is currently being evaluated in intervention trials. However, the biological mechanisms underlying the cancer chemopreventive effects of selenium supplementation have yet to be elucidated. Selenium metabolism and polyamine biosynthesis are linked in their common requirement for S-adenosylmethionine. Selenomethionine was the predominant form of selenium in the dietary supplement, therefore we evaluated the anti-tumorigenic effects of selenomethionine. We found that selenomethionine inhibited tumor growth (both in A549 lung and HT29 colon cancer cells) in a dose-dependent manner. At 24 and 72 h, polyamine content of A549 and HT29 cancer cell lines was decreased at doses that inhibited 50% of normal growth. Selenomethionine treatment induced apoptosis in both cancer cell lines. Exogenous spermine administration, which replenishes intracellular polyamine levels, prevented selenomethionine induced apoptosis. Selenomethionine administration to the cancer cell lines increased the number of cells in metaphase. This cell cycle effect appeared to be reversed with the co-administration of selenomethionine and spermine. These data suggested that at least part of the anti-carcinogenic effects of selenium supplementation might be due to a depletion in polyamine levels. This depletion of polyamines leads to an induction in apoptosis and perturbations in the cell cycle.

Antineoplastic Agents↗
PubMed1997

Reduction of cancer risk with an oral supplement of selenium.

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.

Basal Cell Carcinoma↗
PubMed1996

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.

OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: 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. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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

Adult↗
PubMed1996

A computer program for sample size and power calculations in the design of multi-arm and factorial clinical trials with survival time endpoints.

This paper presents a computer program for use in the design of long-term clinical trials with multiple treatment arms in which the primary outcome variables are censored survival times. The treatment arms may be structured as a one-way or multi-way factorial design. It is assumed that patients are entered and randomized to a treatment arm during an accrual period. The patients are then followed for a fixed period during which there may be dropouts. Various distributional assumptions can be used to model the survival times. These include an option in which there is an effect of treatment duly after a lag or delay time. The program then computes the power of various statistical tests of hypotheses concerning treatment differences, interactions and trends. The power computations are "exact" in that they use the Monte Carlo method to obtain Type I and II error probabilities. However the program also outputs the normal approximations for comparison, although they are typically not accurate in these situations. Fisher's LSD method is used to adjust for the multiple comparisons. By comparing the power for various sets of design parameters, such as sample size, numbers of factor levels, patient accrual rate, and length of follow-up, an appropriate design can be constructed. Two examples are provided. The first is a simple one-way layout with multiple treatment arms; the second a two-way factorial design for a proposed large scale cancer chemoprevention trial.

Clinical Trials as Topic↗
PubMed1996

Liquid ventilation in premature lambs: uptake, biodistribution and elimination of perfluorodecalin liquid.

Perfluorochemical (PFC) liquids are biologically inert and nonbiotransformable substances that, when used as breathing medium, may be transported across the lung epithelium in small quantities, distributed throughout the body, and ultimately vapourized through the lungs and transpired through the skin. To further evaluate the uptake, biodistribution and elimination of a PFC liquid (perfluorodecalin) in the neonatal population, arterial blood, tissue and expired gas samples were obtained from preterm lambs (105-114 days gestation). Two groups of premature lambs were studied: Group I (n = 4) lambs were liquid ventilated from birth for 1 h and killed without exposure to gas ventilation (GV) and Group II (n = 5) lambs were liquid ventilated for 1 h followed by up to 2 h of GV. Samples were analysed by electron-capture gas chromatography and data were expressed in nl of PFC/ml of blood or gas and nl of PFC/gm tissue. During liquid ventilation and subsequent GV, PFC blood levels significantly increased (P < 0.001) from baseline control levels (0.007 +/- 0.001 SE nl PFC/ml blood) to a high of 2.95 +/- 1.03 SE nl PFC/ml blood. Perfluorochemical levels measured in expired gas (Group II) demonstrated a rapid decrease as a function of time of GV. Tissue levels of PFC indicated that uptake of PFC in Group I was significantly different (P < 0.001) than baseline levels and organ dependent; the highest levels were in the lungs (221 +/- 26.2 SE nl PFC/g tissue) and the lowest in the liver (2.24 +/- 1.6 SE nl PFC/g tissue). Comparison of tissue levels of PFC between groups indicated a 34.8% mean decrease across organs in Group II compared with Group I. These data indicate that PFC uptake and elimination is organ dependent and that PFC liquids can be eliminated through the lungs upon return to GV. Sustained PFC blood levels may be related to residual PFC in the organs and lung as well as regional variation in ventilation-perfusion matching upon return to GV.

Analysis of Variance↗
PubMed1995

Regression of cardiac hypertrophy after closing an aortocaval fistula in rats.

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.

Animals↗
PubMed1994

Prevalence of distal colonic neoplasia associated with proximal colon cancers.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed1994

A computer program for the statistical analysis of repeated event data using a mixed effects regression model.

This paper presents a computer program for fitting mixed effects regression models to repeated events data. The method has been described by Abu-Libdeh, Turnbull and Clark (Biometrics 46 (1990) 1017-1034). Such data can occur in longitudinal studies where subjects experience repeated events over time. The program allows the stepwise construction of a series of regression models which can be used to examine and test the influence of the various measured covariates upon the event rates. Two examples are provided. The first is a simple example involving the incidence of mammary tumors in rats. The second involves a very large complex data set from a clinical trial for the prevention of recurrent skin tumors.

Animals↗
PubMed1993

Perfluorooctylbromide (PFOB) as a vitreous substitute in non-human primates.

We evaluated the toxicity of perfluorooctylbromide in the primate eye as a short-term postoperative vitreous substitute. Four eyes of 4 African green monkeys underwent complete vitrectomy and vitreous replacement with 1.5-2.0 ml of PFOB. One additional animal received BSS as a control vitreous substitute in one eye. Animals were examined twice weekly for clarity and consistency of the vitreous replacement substance. Anterior segment and lenses remained clear in all eyes, although in the immediate postoperative period one eye became inflamed and had a culture-negative vitritis. The other eyes showed a minimal anticipated postoperative vitreous inflammation. Emulsification of the PFOB began within 3 days of injection and progressed up to 3 weeks, precluding fundus examination and fluorescein angiography after 2 weeks. Eyes were enucleated and light microscopy performed at 2 days, 10 days, 33 days, and 45 days. No toxic effects to the retinal cells were detectable by histological examination, but perivasculitis of retinal vessels was noted at 45 days. Indirect examination was normal up to 10 days; thereafter, the fundus view was obscured by the emulsified PFOB. Because of cellular migration into the vitreous cavity and retinal perivasculitis, observed histologically, PFOB seems most suitable for intraoperative rather than postoperative use.

Animals↗
PubMed1992

Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy.

BACKGROUND: Chronic ischemic heart disease may lead to ventricular dilation and congestive heart failure (ischemic cardiomyopathy [ICM]). The changes in cardiac myocyte shape associated with this dilation, however, are not known. METHODS AND RESULTS: Left ventricular myocyte dimensions were assessed in cells isolated from explanted human hearts obtained from patients with ICM (n = 6) who were undergoing heart transplantation. Cells were also examined from three nonfailing donor hearts with normal coronary arteries (NCA). Compared with cells from patients with NCA, myocyte length was 40% longer in hearts from patients with ICM (197 +/- 8 versus 141 +/- 9 microns, p less than 0.01), cell width was not significantly different, and cell length/width ratio was 49% greater (11.2 +/- 0.9 versus 7.5 +/- 0.6, p less than 0.01). Sarcomere length was the same in myocytes from both groups. The extent of myocyte lengthening is comparable to the increase in end-diastolic diameter commonly reported in patients with ICM. CONCLUSIONS: These data suggest that increased myocyte length (an intracellular event), instead of myocyte slippage (an extracellular event), is largely responsible for the chamber dilation in ICM. Furthermore, maladaptive remodeling of myocyte shape (e.g., increased myocyte length/width ratio) may contribute to the elevated wall stress (e.g., increased chamber radius/wall thickness) in ICM.

Animals↗
PubMed1992

Arterial blood gases and brain oxygen availability following infusion of intratracheal fluorocarbon neat liquids.

Eight adult New Zealand Swiss rabbits (3-5 kg) having previously implanted chronic bilateral platinum electrodes in the visual cerebral cortex and subcutaneous silver reference electrodes were tranquilized and monitored in multiple 2-3 hour sessions using voltammetric techniques. Six of these were given intratracheal neat liquid fluorocarbons ranging in boiling point from 132 degrees C to 215 degrees C at doses of 2 or 4cc/kg. Each animal received only one fluorocarbon liquid. Two additional rabbits were match-studied as controls. Half of the rabbits have survived more than five months. Both controls and two experimental rabbits were sacrificed after more than seven months due to gastric hairballs. The period of daytime monitoring sessions, when cathodic brain oxygen currents (aO2), arterial blood gases and pH were obtained, was between 34 and 263 days. In some animals the arterial pCO2 was increased during the first week but the pO2 and pH remained nearly normal in all eight animals throughout. The two best fluorocarbons for liquid breathing on the basis of this limited but intensive work are F-methyldecalin and F-5,6H-dec-5-ene (F44E).

Animals↗
PubMed1992

Response of the rabbit lung as a criterion of safety for fluorocarbon breathing and blood substitutes.

From the first liquid breathing experiments until now, the lung, not surprisingly, has played a central role in the evolution of fluorocarbon blood substitutes. The first breathable fluorocarbon, a mixture of F-alkylfurans(FC75), bp 102 degrees C, while a poor solvent for the lung's lining and a good solvent for oxygen and carbon dioxide, proved to cause a characteristic gas/vapor microbubble embolism following intravenous administration as an emulsion. Higher boiling fluorocarbons, e.g. F-tributylamine (FC47), bp 174 degrees C, do not produce such gas-vapor emboli. However, intermediate boiling compounds such as F-decalin (PP5), bp 141 degrees C, produce lungs which, although they certainly appear not to contain microbubble emboli, do not collapse when the thorax is opened. Such hyperinflated non-collapsible lungs (HNCL) occur in the rabbit after the intravenous infusion of F-decalin emulsions as well as after the intratracheal infusion of F-decalin neat liquid. F-decalin induced HNCL retain their appearance and low specific gravity for many weeks, gradually returning toward normal after many months. F-methyl decalin, bp 165 degrees C, does not cause HNCL after intravascular or intratracheal administration. Fluorocarbons having boiling points between 140 degrees C and 165 degrees C are being tested in order to find a perfluorinate with the highest transpiration rate, and hence vapor pressure, compatible with an acceptable body dwell time. We have given fluorocarbons intratracheally to 75, intravenously to 221 and both intratracheally and intravenously to 8 rabbits. Free radical trapping agents, antineutrophil, antiinflammatory and other drugs have been administered without appreciable decrease of HNCL. Fluorocarbon critical solution temperature, lipid solubility, emulsifiability, and other physicochemical properties may mediate the pulmonary effect. One method of preventing and treating low dose F-decalin-induced HNCL in rabbits is described.

Animals↗