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Biomedical subjects

R Cowan

Publications and source records attributed to R Cowan.

At least 37 records · Page 2Linked to original sources
PubMed1995

Abnormal radiosensitivity of lymphocytes from breast cancer patients with excessive normal tissue damage after radiotherapy: chromosome aberrations after low dose-rate irradiation.

There is a need for a simple, rapid assay for predicting normal tissue reactions in radiotherapy patients to reduce morbidity in sensitive patients and to allow dose escalation in resistant cases. Towards this goal we have investigated the gamma-ray sensitivity of lymphocytes from 16 breast cancer patients who had shown an exaggerated acute or late radiation reaction ('overreaction') of normal tissues after radiotherapy, using chromosome damage (dicentrics) as the endpoint because of its close relationship with cell killing. The use of a low dose-rate (LDR; 0.31 cGy min-1) was found to be better than a high dose-rate (170 cGy min-1) in discriminating between over-reactors and controls, as predicted (and here confirmed) from previous studies on ataxia-telangiectasia (A-T) homozygotes and heterozygotes. Five of seven patients with excessive early skin reactions (e.g. erythema, moist desquamation) showed abnormal radiosensitivity, manifested either as aberration yields above the control range after LDR exposure or as less sparing than controls. The average LDR yield for early over-reactions was significantly higher than for controls (p = 0.009) and average sparing was less (p = 0.0002). Two of 10 patients with late complications (fibrosis, telangiectasia) had LDR yields above the control range, but the average yield for late over-reactors was not significantly above that of controls. Unexpectedly, two patients (one early, one late reaction) had LDR aberration yields below the control range. Quantitatively our results are consistent with the notion that over-reacting breast cancer patients are carriers of the A-T gene. Pilot studies on controls showed that the sparing effect of LDR irradiation was increased by lowering the dose-rate to 0.13 cGy min-1 and by using micronuclei rather than metaphase damage as the endpoint. These modifications to the protocol will be used in a large-scale prospective study.

Adult↗
PubMed1995

A comparison of the radiosensitivity of lymphocytes from normal donors, cancer patients, individuals with ataxia-telangiectasia (A-T) and A-T heterozygotes.

The aim was to determine whether peripheral blood lymphocytes can be used retrospectively to detect hypersensitivity to radiation in breast cancer patients who had exhibited severe reactions to radiotherapy. Blood samples were obtained from patients who developed both acute and late complications. For comparison, samples were also taken from a group of normal individuals, ataxia-telangiectasia (A-T) patients, A-T gene carriers and breast cancer patients previously treated with radiotherapy who failed to develop treatment-related complications. Radiosensitivity was assessed using a limiting dilution clonogenic assay following both high (HDR) and low (LDR) dose-rate irradiation. Following HDR irradiation, only lymphocytes from individuals with A-T were significantly more radiosensitive than those from normal donors. In contrast, at LDR, lymphocytes from A-T heterozygotes and breast cancer over reactors were also, on average, more sensitive than those from normal donors. Lymphocytes from breast cancer patients treated with radiotherapy without developing complications showed no significant differences in radiosensitivity compared with normals. This work has shown that peripheral blood lymphocytes from cancer patients who suffered severe reaction to radiotherapy are, on average, more radiosensitive than those from normal donors, and suggests that lymphocytes may be useful in the future for the development of rapid predictive assays for normal tissue tolerance to radiotherapy.

Ataxia Telangiectasia↗
PubMed1995

An analysis of the growth of the retinal cell population in embryonic chicks yielding proliferative ratios, numbers of proliferative and non-proliferative cells and cell-cycle times for successive generations of cell cycles.

Growth curves of the retinal cell population of embryonic chicks were fitted by a branching-process model of cell population growth, thereby estimating the proliferative ratios and mean cell-cycle times of the generations of cell cycles that underlie retinal growth. The proliferative ratio determines the proportion of cells that divides in the next generation, so the numbers of proliferative and non-proliferative cells in each generation of cell cycles were obtained. The mean cell-cycle times determine the times over which the generations are extant. Assuming growth starts from one cell in generation 0, the proliferative cells reach 3.6 x 10(6) and the non-proliferative cells reach 1.1 x 10(6) by generation 23. The next four generations increase the proliferative cell numbers to 13.9 x 10(6) and produce 20.1 x 10(6) non-proliferative cells. In the next five generations in the end phase of growth, non-proliferative cells are produced in large numbers at an average of 13.9 x 10(6) cells per generation as the retinal lineages are completed. The retinal cell population reaches a maximum estimated here at 98.2 x 10(6) cells. The mean cell-cycle time estimates range between 6.8 and 10.1 h in generations before the end phase of growth and between 10.6 and 17.2 h in generations in the end phase. The retinal cell population growth is limited by the depletion of the proliferative cell population that the production of non-proliferative cells entails. The proliferative ratios and the cell-cycle-time distribution parameters are the likely determinants of retinal growth rates. The results are discussed in relation to other results of spatial and temporal patterns of the cessation of cell cycling in the embryonic chick retina.

Animals↗
PubMed1992

The extent of clonal structure in different lymphoid organs.

To gain insight into the clonal organization of lymphoid organs, we studied the distribution in situ of donor-derived cells in near-physiological chimeras. We introduced RT7b fetal liver cells into nonirradiated congenic RT7a neonatal rats. The chimerism 6-20 wk after injection ranged from 0.3 to 20%. The numbers of cell clones simultaneously contributing to cell generation in a particular histological feature were deduced from the variance in donor cell distribution. In bone marrow and thymus, donor-derived lymphoid cells were found scattered among host cells, indicating a high mobility of cells. In bone marrow, donor cells were evenly distributed over the entire marrow, even at low chimerism. This indicates that leukopoiesis is maintained by the proliferation of many clones. In the thymus, the various lobules showed different quantities of donor-derived lymphoid cells. Mathematical analysis of these differences indicated that 17-18 cell division cycles occur in the cortex. In spleen, the distribution of donor-derived cells over the germinal centers indicated that 5 d after antigenic stimulation, germinal centers develop oligoclonally. The main conclusions of this work are that (a) bone marrow and thymus are highly polyclonal; (b) 17-18 divisions occur between prothymocyte and mature T cell; and (c) lymphoid cells disperse rapidly while proliferating and differentiating.

Animals↗
PubMed1992

Neonatal morbidity according to gestational age and birth weight from five tertiary care centers in the United States, 1983 through 1986.

OBJECTIVES: This study details the incidence, by gestational age and birth weight, of specific neonatal morbidities in singleton neonates without major congenital anomalies. STUDY DESIGN: Data were prospectively collected on all deliveries at five tertiary centers in the United States during the years 1983 through 1986. Pregnancies were meticulously dated and the gestational ages of the neonates at delivery were confirmed by Dubowitz score. RESULTS: The incidence of respiratory distress syndrome gradually decreases with increasing gestational age until 36 weeks. A marked decrease in the incidence of necrotizing enterocolitis, patent ductus arteriosus, intraventricular hemorrhage, and sepsis occurs after 32 completed weeks. The number of days of mechanical ventilation for respiratory distress syndrome and newborn stay in the tertiary care facility also were significantly reduced after 32 weeks. CONCLUSIONS: The incidence of both respiratory distress syndrome and patent ductus arteriosus is markedly decreased by both increasing gestational age and birth weight. The incidence of grade III and IV intraventricular hemorrhage, necrotizing enterocolitis, and sepsis virtually vanishes after 34 weeks. These data relating neonatal morbidities to gestational age are important to the obstetrician in the critical decision regarding the timing of delivery and to the parents, who can benefit from a realistic prediction of the neonatal course.

Academic Medical Centers↗
PubMed1992

Recombinant human erythropoietin in patients with ovarian carcinoma and anaemia secondary to cisplatin and carboplatin chemotherapy: preliminary results.

Preliminary results from the first 21 patients of a group of 30 with International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV epithelial ovarian carcinoma and anaemia are reported. Patients entered this open-label, comparative-group, out-patient study and were randomized to receive conventional support alone (control patients) or recombinant human erythropoietin (r-HuEPO) in addition to conventional support for 6 months. The aim of the study was to determine the effects of r-HuEPO on the anaemia induced by platinum-based chemotherapy. Patients randomized to r-HuEPO therapy received 300 U/kg subcutaneously 3 times weekly in addition to conventional chemotherapy. All patients underwent regular haematological monitoring. One patient developed a deep venous thrombosis after 17 doses of r-HuEPO; it was thought that this event may have been related to therapy and the patient was withdrawn from the study. Three other withdrawals occurred after 11, 15 and 40 doses of r-HuEPO because of progressive anaemia, metoclopramide-induced skin rash and change of chemotherapy, respectively. In the 21 patients analysed to date, there was a notable reduction in blood transfusion requirements during the 6 months of chemotherapy and an improvement in mean serial haemoglobin concentrations in patients on r-HuEPO compared with the control group. In conclusion, r-HuEPO has the potential for reducing haematological toxicity in patients with ovarian carcinoma receiving platinum-based chemotherapy. Also, r-HuEPO may allow modest dosage increments in chemotherapy or the addition of abdominopelvic radiotherapy.

Adult↗
PubMed1991

Measures of maternal alcohol use as predictors of development in early childhood.

The effect of prenatal alcohol exposure on growth, dysmorphology, and cognitive development at 6 years was examined in children whose mothers had completed a self-administered questionnaire during pregnancy. Drinking patterns prior to pregnancy recognition and indications of problem drinking (IPD) were assessed. Heavier alcohol intake was associated with slower growth in height and head circumference and increased dysmorphology, as evidenced by facial features associated with fetal alcohol syndrome (FAS) and the prevalence of probable/possible fetal alcohol effects (FAE). Indications of problem drinking predicted facial features associated with FAS and cognitive deficits (i.e., lower WPPSI Verbal IQ scores and lower scores on a test of receptive language function, the Token Test). Effects of alcohol consumption on head circumference and of indications of problem drinking on Verbal IQ and Token Test scores remained significant, even after excluding children born to mothers having drinkers (over seven drinks a day) and children with probable/possible FAE. Verbal IQ was an average of 7.1 points (95% confidence interval = 0.01, 14.25) lower among children born to mothers having more than one indication of problem drinking than it was among those born to women having fewer indications; Token Test scores were 4.3 points lower (95% confidence interval = 1.38, 7.24). Although the confidence intervals for these estimates are broad in this small, heterogeneous sample, their magnitude, if confirmed, is significant given that the population standard deviation for Verbal IQ is 15, and that for the Token Test is 5.

Alcohol Drinking↗
PubMed1991

The prognostic value of ambulatory blood pressure monitoring in treated hypertensive patients.

The clinical course of 459 treated hypertensive patients who wore the Remler M-2000 patient-activated, semi-automatic, portable blood pressure recorder was reviewed in order to determine whether the average awake ambulatory blood pressure was better able than office blood pressure and standard risk prognosticators to predict the development of cardiovascular morbid events. The patients who developed events were older, had higher office blood pressures and more evidence of target-organ damage, and were more likely to have suffered a clinical cardiovascular event before entry into the study. Ambulatory pressures were lower than office blood pressure in 78% of patients; the correlation coefficients were 0.67 for systolic pressure and 0.60 for diastolic pressure. Each patient was classified according to whether his observed ambulatory blood pressure was greater than or equal to 10/6 mmHg above, within 9/5 mmHg or greater than or equal to 10/6 mmHg below the level derived from his or her office blood pressure and the regression line derived from the scatter plot of ambulatory blood pressure on office blood pressure for the entire sample. Using life-table analyses to record the rate of development of a first cardiovascular event, and log rank tests to compare curves, significant differences in outcome were found between patients whose observed ambulatory blood pressure was above the regression line compared with those whose ambulatory blood pressure was below the regression line. We conclude that ambulatory blood pressure measurements can provide additional prognostic information to that available from office blood pressure and from the standard prognostic indicators, age and severity of disease.

Antihypertensive Agents↗
PubMed1989

Children's use of counting and guidelines in judging relative number.

Nine 5-year-old infant school children, nine children with moderate learning difficulties, and nine children attending a school for the aphasic were selected on the basis of a counting test to judge relative number under three conditions: counting, guidelines, and control. The displays used consisted of two rows of dots and varied in numerosity and configuration. Length consistent displays were judged right by all children in all conditions on all numerosities. Many errors were made in judging length conflict displays. All groups judged better when they were told to count and when guidelines were added to the displays than in the control condition. Counting did not help more than guidelines. Small number displays were judged best in all conditions.

Aphasia↗
PubMed1988

Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study.

STUDY OBJECTIVE: To ascertain the efficacy and toxicity of trimethoprim-sulfamethoxazole or pentamidine when either is given alone during the entire treatment period for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Prospective, randomized, noncrossover comparison of trimethoprim-sulfamethoxazole with pentamidine. Trimethoprim-sulfamethoxazole dosage was adjusted to maintain serum trimethoprim at 5 to 8 micrograms/mL. Pentamidine dosage was reduced by 30% to 50% for an absolute rise in serum creatinine of more than 88 mumol/L (1 mg/dL). SETTING: Tertiary care hospital and AIDS clinic. PATIENTS: Thirty-six patients were treated with trimethoprim-sulfamethoxazole and 34 with pentamidine. Pretreatment clinical features and laboratory test results were similar in the two groups. MEASUREMENTS AND MAIN RESULTS: Thirty-six recipients of trimethoprim-sulfamethoxazole and 33 recipients of pentamidine completed therapy without crossover. Trimethoprim-sulfamethoxazole caused a rash (44%) and anemia (39%) more frequently (P less than or equal to 0.03, whereas pentamidine caused nephrotoxicity (64%), hypotension (27%), or hypoglycemia (21%) more frequently (P less than or equal to 0.01). The (A - a)DO2 improved by greater than 1.3 kPa (10 mmHg) 8 days earlier for trimethoprim-sulfamethoxazole recipients (95% CI for the difference in response, -1 to 17; P = 0.04). Thirty-one (86%) patients treated with trimethoprim-sulfamethoxazole and 20 (61%) with pentamidine survived and were without respiratory support at completion of treatment (95% CI for the difference in response, 5% to 45%; P = 0.03). CONCLUSIONS: For most patients with AIDS and P. carinii pneumonia, successful treatment with a single agent is possible. Toxicity associated with the two standard treatments is rarely life-threatening and may be diminished if the trimethoprim-sulfamethoxazole dosage is modified by pharmacokinetic monitoring and the pentamidine dosage is reduced for nephrotoxicity. Oxygenation improved more quickly and survival was better with trimethoprim-sulfamethoxazole.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Steric effects in antibody reactions with polyvalent antigen.

Antigen valency has been defined (Singer, 1965) as the maximum number of epitopes per antigen which can be simultaneously occupied by antibody. If the epitopes are closely spaced, steric hindrance prevents the simultaneous occupancy of all epitopes. Current methods of estimating both the antigen valency and the association constant (Ka) from equilibrium binding data do not allow for the effects of steric hindrance. We have developed a theory which accounts rigorously for steric hindrance when monovalent ligands of quite general shape (antibodies) react reversibly with multivalent acceptor molecules (antigens). The surfaces of the acceptors are modelled by completely general two-dimensional lattices. Using this theory we demonstrate that curvature of Scatchard plots can arise from steric effects alone in the absence of other known causes such as cross-linking, cooperativity and heterogeneous epitope affinities. Our results generalize the conclusions of McGhee & von Hippel (1974) who dealt with one-dimension acceptor molecules such as DNA. We discuss inaccuracies in the estimation of both Ka and antigen valency using the traditional approach of fitting straight lines to Scatchard plots.

Animals↗
PubMed1988

Division rules for polygonal cells.

A number of fascinating mathematical problems concerning the division of two-dimensional space are formulated from questions about the planes of cell division in embryonic epithelia. Their solution aids in the quantitative description of cellular arrangement in epithelia. Cells, considered as polygons, site their division line according to stochastic rules, eventually forming a tessellation of the plane. The equilibrium distributions for the resulting mix of polygonal types are explored for a range of stochastic rules. We find surprising links with some classical distributions from the theory of probability.

Cell Division↗
PubMed1988

Improved peptide function from random mutagenesis over short 'windows'.

We have applied random mutagenesis over short contiguous residue tracts ('windows') within an active peptide (the alpha-peptide of beta-galactosidase) such that all window residues are replaced simultaneously. A novel technique using mixed synthetic oligonucleotides and selection against an EcoK restriction site has allowed the construction of libraries of mutants for two separate windows, sites A and B. Mutant phenotypes can be easily assessed in vivo by a complementation test, and panels of mutants have been quantitatively tested in vitro. This allowed the rapid probing of structural requirements for each site. The two windows yielded markedly disparate results. Site B was much less stringent in its sequence requirements for significant function than Site A, and mutants with improved function were isolated at Site B alone. In addition, one Site B mutant with wild-type levels of activity showed enhanced stability to heat or a protein denaturant. We propose that short tracts with the characteristics of Site B constitute 'secondary' interaction sites which are more tolerant of sequence diversity. Random manipulation of such secondary sites is thus more likely to yield upmutations for standard or altered environments. Window mutagenesis can in principle be applied to any protein--protein or protein--ligand interaction.

Amino Acid Sequence↗