Biomedical subjects

D F Heitjan

Publications and source records attributed to D F Heitjan.

14 recordsLinked to original sources

PubMed1992

Allopurinol preserves cerebral energy metabolism during perinatal hypoxia-ischemia: a 31P NMR study in unanesthetized immature rats.

The effects of high dose allopurinol (ALLOP) pretreatment on the cerebral energy metabolism of unanesthetized 7-day-postnatal rats during exposure to 3 h of cerebral hypoxia-ischemia were serially quantitated using non-invasive 31P NMR spectroscopy. Adenosine triphosphate, integrated over the last 2 h of hypoxia and expressed as a fraction of baseline, was 0.73 +/- 0.16 with ALLOP pretreatment (200 mg/kg s.c.) compared to 0.52 +/- 0.05 for saline pretreatment (P = 0.001). Inorganic phosphate/phosphocreatine (Pi/PCr), integrated over the same time interval, was 2.63 +/- 1.23 relative to baseline with ALLOP versus 5.13 +/- 1.45 for saline-treated pups (P less than 0.0005). We suggest that the neuroprotection achieved with high dose ALLOP pretreatment may be attributed in part to preservation of energy metabolites.

Adenosine Triphosphate↗

PubMed1992

A decision-theoretic evaluation of early stopping rules.

We consider the decision-theoretic evaluation of early stopping rules for clinical trials. We describe a hypothetical phase III, two-arm trial with interim analysis, modelling it as a decision problem. We present methods for constructing a group-sequential test that is optimal for a given utility and prior distribution, and for determining a utility and prior under which a given test is optimal. Using our methods, we construct optimal tests for utilities and priors representing a variety of perspectives: a view that seeks to maximize the long-run response rate, a view that seeks to maximize the chance of a correct decision, and a personal view elicited from a medical oncologist. Characteristics of the optimal rules are sensitive to the input utilities and priors, and their critical values and sampling properties can differ markedly from those of group-sequential tests. We also compute utility functions and priors under which some standard group-sequential stopping rules are optimal. Our results suggest that the group-sequential tests, considered as decision procedures, imply a symmetry in the decision problem that is inconsistent with the response-rate perspective. We conclude that decision theory is a useful device for illuminating the sometimes conflicting goals of clinical research, and that the use of decision theory in designing clinical trials could lead to marked changes in statistical criteria for early termination.

Bias↗

PubMed1992

The multi-site tumour transplantation model for human endometrial carcinoma: a statistical evaluation.

We studied the effect of multi-site tumour transplantation on tumour growth by implanting varying numbers of EnCa 101 human endometrial tumours in athymic mice. One treatment group received a single tumour per mouse, another group received two tumours per mouse and a third group received four tumours per mouse. Tumour growth was sustained in all animals by implantation of oestradiol-17 beta pellets. We observed positive correlation between tumours within the same mouse, which implies that individual tumours are not statistically independent. The correlation is sufficiently large that failure to account for it in statistical design and analysis could result in studies with insufficient power and in spurious assertions of significance. Regression modelling of tumour growth curves showed that mean tumour volume per animal is not affected by the number of tumours growing on the animal; that is, the data are consistent with the null hypothesis that mean tumour volume is the same regardless of the number of tumours present. Our results therefore suggest that the use of multiple tumours per animal can increase the precision of experiments without loss of validity and at relatively little cost. However, correct and efficient analysis of the data so obtained requires more sophisticated techniques than those--such as fixed-effects analysis of variance and the two sample t-test--that assume independence of tumours.

Animals↗

PubMed1992

Effect of insulin-induced and fasting hypoglycemia on perinatal hypoxic-ischemic brain damage.

Experiments in adult animals have indicated that hyperglycemia accentuates whereas hypoglycemia ameliorates hypoxic-ischemic brain damage. To determine whether hypoglycemia is protective or deleterious to the perinatal brain subjected to hypoxia-ischemia, 7-d postnatal rats were rendered hypoglycemic either by receiving an s.c. injection of insulin or fasting for 12 h. All rat pups underwent unilateral common carotid artery ligation followed by exposure to 8% oxygen-balance nitrogen at 37 degrees C for 2 h. Control animals (no insulin or fasting) received s.c. injections of normal saline. Mean blood glucose concentrations were 5.4 +/- 0.1, 4.3 +/- 0.2, and 3.4 +/- 0.1 mmol/L for control, insulin, and fasted animals, respectively. Blood beta-hydroxybutyrate concentrations were identical (0.5 +/- 0.1 mmol/L) for control and insulin-treated animals, but more than doubled in concentration in the fasted animals (p less than 0.001). Mortality rates during hypoxia-ischemia were higher in the insulin-treated animals (30%) than in either the fasted (4%) or control (0%) animals (p less than 0.05). Fasted animals showed a significant reduction in hypoxic-ischemic brain damage as compared with either the insulin-treated or control animals. Insulin-treated animals were not significantly different from controls. The findings indicate that 1) insulin induced hypoglycemia does not provide a protective effect on perinatal hypoxic-ischemic brain damage, as in adults; and 2) fasting adequate to produce hypoglycemia and ketonemia improved neuropathologic outcome.

Animals↗

PubMed1991

Beneficial effects of androgen-primed chemotherapy in the Dunning R3327 G model of prostatic cancer.

The objective of this study was to test the hypothesis that androgen administration prior to chemotherapy (androgen priming) may potentiate tumor cytotoxicity in hormone-responsive prostate cancer. Accordingly, six groups of Copenhagen rats bearing small (i.e., 40-mm3 median volume) Dunning R3327 G tumors were left untreated or received castration, chemotherapy, or a combination of the two, with or without androgen priming. Groups without priming included: intact untreated, castrate alone, intact plus chemotherapy, and castrate plus chemotherapy (cyclophosphamide, 30 mg/kg/day, for 2 days, with repeat cycle in 24 days) (Cx). To specifically evaluate the effect of androgen priming on Cx cytotoxicity, two additional castrate groups were studied. One received testosterone propionate (4 mg/kg/day) for 2 days prior to Cx and the other after Cx. Treatment effect was evaluated by quantitating tumor volume as well as animal survival to an ethically allowable, maximal tumor burden. As expected, castration and Cx produced a retardation of tumor growth and prolongation of survival when compared to untreated animals. The addition of androgen priming prior to but not after Cx enhanced the degree of tumor suppression. Specifically, 26 days after the second Cx cycle, all androgen-primed tumors had regressed; 70% of tumors had disappeared and those remaining were barely palpable. At this same time point, tumors in all the other groups were actively growing and had volumes greater than initial values (P less than 0.01). Although tumor regrowth occurred, median survival for the androgen-primed group was significantly prolonged, to 186 days versus 39 days (P less than 0.01) for untreated animals and 153 days for the non-primed castrate plus Cx animals (P less than 0.01). These data suggested that androgen priming potentiates the effects of Cx in castrate animals bearing R3327 G tumors.

Animals↗

PubMed1991

Generalized Norton-Simon models of tumour growth.

This paper considers the analysis of serial data on the growth of tumours in laboratory rodents. I propose a model-a generalization of the tumour growth model of Norton and Simon-that leads to a rich family of growth and decay curves. The model assumes that unperturbed growth follows the generalized logistic form; it accommodates time-varying treatment effects through an effective dose function. I fit two such models to data on a human prostate tumour growing in nude mice and compare the fitted curves and dose functions with a non-parametric curve and dose function estimated from a cubic spline model. All three models account for both random animal effects and autocorrelation. Monte Carlo results suggest that (a) maximum likelihood estimates of growth parameters are biased, although not severely, and (b) standard errors are conservative in small samples but become increasingly accurate in larger samples.

Animals↗

PubMed1991

Using a state cancer registry to increase screening behaviors of sisters and daughters of breast cancer patients.

The Pennsylvania Cancer Registry was used to contact breast cancer patients and, through them, their adult sisters and daughters. The sisters and daughters were counseled concerning their higher than average risks for breast cancer and their need for mammography and breast self-examination. Results showed a 9 percent increase in mammography and a 10 percent increase in breast self-examination rates for the counseled over control group. Costs were $49 per counseled sister or daughter indicating a need to increase cost effectiveness before implementation is practical.

Breast Neoplasms↗

PubMed1991

Regression with bivariate grouped data.

The problem of accounting for the grouping of continuous, bivariate data in regression analyses is considered. Reasons why grouping must be taken seriously are advanced, and a strategy for accounting for grouping is demonstrated. The specific model asserts that, in the absence of grouping, the data would be bivariate normal. This model is used to adjust estimates of parameters in a regression relating disease severity to a grouped exposure variable, using data on pneumoconiosis in English coal miners (Ashford, 1959, Biometrics 15, 573-581). The choice of computing methods is discussed and likelihood formulas are presented.

Algorithms↗

PubMed1990

Wound complications of autogenous subcutaneous infrainguinal arterial bypass surgery: predisposing factors and management.

To identify factors predisposing to wound infection and necrosis complicating in situ or other subcutaneous autogenous lower extremity vein bypass procedures, we retrospectively analyzed all such cases performed in our hospital between July 1983 and July 1988. Among 163 subcutaneous autogenous bypass grafts, wound complications developed in 28 (17%). According to progressive depth of involvement as defined in the text, 10 patients had grade I complications, six had grade II, and 12 had grade III complications with threatened or actual graft exposure. Factors significantly associated with wound morbidity were female gender, chronic steroid therapy, in situ bypass grafting, use of continuous incision (all p less than or equal to 0.05, chi square); diabetes mellitus, ipsilateral limb ulcer, limb salvage indication (all p less than 0.01); and bypass grafting to the dorsalis pedis artery (p less than 0.02). A logistic regression analysis identified four factors (in situ bypass grafting, steroid therapy, ipsilateral ulcer, and dorsalis pedis bypass grafting) that predicted a cumulatively increasing risk of wound complications, and in whose absence wound complications were rare. Grade I and II complications responded to standard regimens of wound care and intravenous antibiotics without loss of any graft or limb. In spite of aggressive efforts to provide secondary soft tissue coverage, grade III complications led directly to four major amputations and one death. Measures to prevent these morbid sequelae must include preoperative control of infection in the ischemic foot and meticulous attention to operative technique.

Aged↗

PubMed1990

Systolic thickening increases from subepicardium to subendocardium.

STUDY OBJECTIVE: The aim was to determine the relation between systolic function and depth below the epicardial surface, using pulsed Doppler crystals. DESIGN: Systolic excursion in mm was measured at multiple depths below the epicardial surface. Measurements were made during control conditions. SUBJECTS: Thirty four anaesthetised mongrel dogs were studied. MEASUREMENTS AND MAIN RESULTS: A total of 333 measurements of systolic excursion were made during control conditions at 1 to 3 crystal sites per dog. Two models were constructed; the model which assumed a quadratic relation between depth (d) and systolic excursion (EX) (EX = 0.498 + 0.176d + 0.006d2) fit the data better than did a model which assumed a linear relation (EX = -0.0716 + 0.254d). CONCLUSIONS: These data support the prediction from geometric models that systolic excursion increases in a non-linear fashion from subepicardium to subendocardium.

Animals↗

PubMed1989

Gamma-interferon-induced monocyte major histocompatibility complex class II antigen expression individuals with acquired immune deficiency syndrome.

Twelve patients with the acquired immune deficiency syndrome (AIDS) and Kaposi's sarcoma were treated with recombinant human gamma-interferon (rIFN-gamma). A rapid, substantial increase in the fraction of HLA-DQ-positive monocytes was noted after treatment with rIFN-gamma. The rIFN-gamma-induced increase in monocyte HLA-DQ was seen throughout the course of treatment, with the percentage of HLA-DQ-positive monocytes dropping slightly following each week's treatment with rIFN-gamma and then rapidly increasing following the next course of treatment. Although the percentage of HLA-DR-positive monocytes was unchanged (HLA-DR was expressed on greater than 80% of monocytes prior to treatment), the density of HLA-DR on monocytes also increased following rIFN-gamma treatment. Following rIFN-gamma treatment, no changes were seen in CD3, CD4, CD8 T cell numbers, in T cell subset ratio (CD4/CD8), in Leu 7 or CD16 (Leu 11) cell number, in spontaneous Ig secretion, in PHA-induced in vitro proliferation, or in NK activity. These results indicate that exposure to rIFN-gamma in vivo led to the increased expression of class II antigens on monocytes in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Serum and effector-cell antibody-dependent cellular cytotoxicity (ADCC) activity remains high during human immunodeficiency virus (HIV) disease progression.

The activity of both serum and effector cell antibody-dependent cellular cytotoxicity (ADCC) against human immunodeficiency virus (HIV-1, HIV) was assessed in HIV-infected individuals. The goal was to relate ADCC levels with the stage or progression of HIV disease. Serial serum samples, usually collected at 6-month intervals, from individuals at defined stages of HIV disease (seroconversion, the HIV-seropositive period before AIDS, and around the time of clinical AIDS diagnosis) were tested. HIV-coated CEM tumor cells were used as targets. Effector-cell ADCC activity was evaluated using fresh peripheral blood mononuclear cells (PBMC) from HIV-infected individuals at different stages of HIV disease. Samples were obtained from male homosexual participants in the Multicenter AIDS Cohort Study (MACS). In seroconverters, ADCC-inducing HIV-specific antibodies were detected at the time that the ELISA antibody test was first positive. Within several months, serum ADCC activity stabilized in each individual. In 29 HIV-seroprevalent individuals (HIV seropositive on their first visit), serum ADCC activity remained constant regardless of whether the individual's HIV disease was stable (high stable CD4; n = 9) or rapidly deteriorating (sharply declining CD4, n = 10; AIDS progressors, n = 10). With respect to effector-cell activity, PBMC from HIV-infected individuals with or without AIDS were capable of mediating ADCC with heterologous and usually with autologous sera. Although the level of NK cytotoxic activity and the level of antibody-armed effector cell activity have been reported to decline as disease progresses, our results support previous observations that ADCC effector-cell activity against antibody-coated targets does not decline in HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1987

Antibodies to human immunodeficiency virus in human sera induce cell-mediated lysis of human immunodeficiency virus-infected cells.

The capacity of human immunodeficiency virus (HIV) antibody-positive sera from homosexually active men without acquired immune deficiency syndrome to lyse the HIV-infected T cell lines MOLT-4f and CCRF-CEM (CEM) in cooperation with lymphocytes from normal donors was investigated. Twenty-seven HIV antibody-positive sera, most of which enhanced the killing of HIV-infected MOLT-4f and CEM target cells by normal mononuclear cells were studied in detail. HIV antibody-positive sera resulted in lysis at dilutions as high as 1/10,000. HIV antibody-negative sera did not augment lysis of infected target cells. In addition, lysis of uninfected targets was not enhanced in the presence of HIV antibody-positive sera. Because fractionation of the HIV antibody-positive sera on a protein A affinity column resulted in recovery of the activity from the IgG fraction, the extra cytotoxic activity mediated by nonimmune cells in the presence of immune sera appears to be antibody-dependent. Furthermore, the cytotoxic effector cells were in the nonrosetting fraction of lymphocytes and expressed Leu-11 (cluster designation (CD)15) antigens, which is characteristic of cells participating in antibody-dependent cellular cytotoxicity reactions. The antibody specificity of the sera, determined by radioimmunoprecipitation, provides evidence that antibody-dependent cellular cytotoxicity can occur even when there are no detectable antibodies directed against gag proteins. Sera which lacked detectable antibodies to the envelope protein gp120 by radioimmunoprecipitation did not mediate antibody-dependent cellular cytotoxicity.

Adult↗

PubMedDate not supplied

31P NMR spectroscopy of perinatal hypoxic-ischemic brain damage: a model to evaluate neuroprotective drugs in immature rats.

Cerebral energy metabolism can be measured non-invasively in unanesthetized neonatal rats with 31P NMR spectroscopy. Using this technique, serial changes in high energy phosphates were determined from the right cerebral hemispheres of 7 day postnatal rat pups during a hypoxic-ischemic insult known to produce focal brain injury. During 3 h of hypoxia-ischemia the concentration of ATP dropped to 33 +/- 8% of prehypoxic (baseline) levels, phosphocreatine (PCr)/Pi decreased from 1.5 +/- 0.51 to 0.16 +/- 0.06, while pH decreased nominally by 0.2 units. After 2.5 h of recovery in air, ATP returned to 75 +/- 10% of baseline levels, PCr/Pi rose to 1.1 +/- 0.28, and pH returned to its normal value of 7.16 +/- 0.06. This model was used to test the efficacy of the adenosine deaminase inhibitor, 2-deoxycoformycin (DCF) as a potential neuroprotective drug. The data for the drug- and saline-treated populations were analyzed by integrating ATP and Pi/PCr levels over specific time intervals, expressing it relative to baseline levels, and modeling it with cubic splines. Pretreatment with 500 micrograms/kg DCF shows a small, but statistically significant, preservation of both ATP and phosphorylation potential during hypoxia and initial recovery. Brain water content (edema) at 42 h recovery was apparently associated with both mean ATP and mean Pi/PCr in the last 2 h of hypoxia-ischemia. When ATP fell below 70% of baseline, brain edema was evident at 42 h of recovery. This methodology is suitable for extension to human infants.

Adenosine Triphosphate↗