Biomedical subjects
Publications and source records attributed to B L Cohen.
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The effectiveness of thrombopoietin (TPO) in alleviating thrombocytopenia was evaluated in a placebo-controlled study involving rhesus monkeys exposed to 5 Gy total-body irradiation (TBI) (300-kV x-rays) to result in 3 weeks of pancytopenia. Supraoptimal treatment with human recombinant TPO (10 microg/kg/d subcutaneously, days 1 to 21 after TBI) was highly effective in preventing thrombocytopenia, with nadirs for thrombocytes, on average, far higher than 100 x 10(9)/L, a greatly accelerated recovery to normal values, and no need for thrombocyte transfusions. TPO appeared to act selectively in that neutrophil regeneration was not influenced but red blood cell lineage recovery was prominently stimulated, with reticulocyte regeneration being initiated 10 days earlier than in placebo-treated animals. The reticulocytosis was followed by a normoblastosis that occurred earlier and was more pronounced than in placebo-treated monkeys. The effect of TPO on the red blood cell lineage was also reflected in a less profound nadir for hemoglobin (Hb) and hematocrit values than in placebo controls. However, this effect was not followed by a rapid recovery to normal values, due to development of a microcytic hypochromic anemia. Iron depletion was demonstrated by measurements of total serum iron and total iron-binding capacity (TIBC) and could be prevented by prophylactic intramuscular (IM) iron before TBI or corrected by IM iron after TPO treatment. Rechallenging with TPO in week 8 after TBI demonstrated a homogenous thrombocyte response similar in magnitude to the initial response, but a greatly diminished reticulocyte response. This demonstrated that the erythropoietic response to TPO administration depends on the hemopoietic state of the animal and may reflect multiple TPO target cells. It is postulated that the extremely rapid erythropoiesis due to TPO treatment in the initial regeneration phase following myelosuppression results in iron depletion by a mechanism similar to that seen following erythropoietin treatment in patients with end-stage renal failure. It is concluded that protracted TPO therapy to counteract thrombocytopenic states may result in iron depletion and that the iron status should be monitored before, during, and after TPO treatment.
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Multiple sources of evidence show that the skuas (Aves:Stercorariidae) are a monophyletic group, closely related to gulls (Laridae. On morphological and behavioural evidence the Stercorariidae are divided into two widely divergent genera, Catharacta and Stercorarius, consistent with observed levels of nuclear and mitochondrial gene divergence. Catharacta skuas are large-bodied and with one exception breed in the Southern Hemisphere. Stercorarius skuas otherwise known as jaegers) are smaller bodied and breed exclusively in the Northern Hemisphere. Evidence from both mitochondrial and nuclear genomes and from ectoparasitic lice (Insecta:Phthiraptera) shows that the Pomarine skua, S. pomarinus, which has been recognized as being somewhat intermediate in certain morphological and behavioural characteristics, is much more closely related to species in the genus Catharacta, especially to the Northern Hemisphere-breeding Great skua, C. skua, than it is to the other two Stercorarius skuas, the Arctic skua, S. parasiticus and the Longtailed skua, S. longicaudus. Three possible explanations that might account for this discordant aspect of skua phylogeny are explored. These involve (i) the segregation of ancestral polymorphism, (ii) convergent evolution of morphology and behaviour or (iii) inter-generic hybridization. The available evidence from both nuclear and mitochondrial genomes does not exclude any of these hypotheses. Thus, resolution of this enigma of skua phylogeny awaits further work.
Plots of lung cancer rates corrected for smoking prevalence vs. average home radon levels are presented for U.S. counties with a wide variety of socioeconomic characteristics. The data are generally well described by the same negative slope linear, plus positive slope quadratic, "standard" curve. Plots are presented for geographic regions and these are also reasonably well fit by the standard curve. The findings are not consistent with predictions based on a linear no-threshold model.
First time measurements of radon levels in homes, self-selected by occupants, were accompanied by questionnaires asking about people who had lived in the house and died of cancer. Responses were received before measurement results were available. The ratio of lung cancer deaths to deaths from other cancers was plotted as a function of radon level in the house. The results seem to indicate essentially no dependence of this ratio on radon exposure, in sharp contrast to the strong increase with increasing radon exposure predicted by the theory which should have been easily observable. Possible explanations of the discrepancy are discussed. Use of two alternative control groups increases the discrepancy with theory. This work has no connection with the recent test of the linear nonthreshold theory in the low dose region by the same author.
It has been shown that lung cancer rates in U.S. Counties, with or without correction for smoking, decrease with increasing radon exposure, in sharp contrast to the increase predicted by the linear no-threshold theory. The discrepancy is by 20 standard deviations, and very extensive efforts to explain it were not successful. It is pointed out that, unless a plausible explanation for this discrepancy (or conflicting evidence) can be found, continued use of the linear no-threshold theory is a violation of "The Scientific Method." Various explanations that have been offered for ignoring these results are examined and shown not to be valid. A simple procedure for clearly settling the issue is proposed.
The function of gamma delta T cells, particularly the minor population of circulating gamma delta T cells, remains unclear. To study these lymphoid gamma delta T cells, a transgenic SCID mouse containing the KN6 gamma delta TCR whose ligand is the TL gene product, T22b, was created. KN6-SCID mice contain a monoclonal population of naive KN6+ gamma delta T cells. Using these mice, we have studied the APC required for activation of KN6+ gamma delta T cells in vitro and in vivo. Analysis of an in vitro mixed lymphocyte response identified a hierarchy of potency for stimulation: dendritic cells = T cell blasts > B cell blasts > B cells > resting T cells. In contrast, in vivo, only alpha beta T cells fully activated KN6+ gamma delta T cells as measured by an increase in the number of splenic KN6+ cells, the development of blast morphology, and the development of proliferative anergy in the responding KN6+ cells. The strong stimulatory properties of C57BL/6J T cells appeared to depend on their having been activated by KN6-SCID alloantigens. T cells from (C57BL/6J x BALB/c)F1 mice, which are tolerant of KN6-SCID alloantigens, could not fully activate KN6+ cells. However, the F1 T cells could activate KN6+ cells if they were activated in vivo by the mitogen, staphylococcal enterotoxin B. A mixture of third party activated T cells plus T22b+ non-T cells only partially activated KN6+ cells, implying that activated T22b+ T cells are acting directly as stimulatory cells. Although the Ags recognized by gamma delta T cells are generally unknown, Ag presentation by activated alpha beta T cells may be an important method of activation.
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PURPOSE: The purpose of this study was to evaluate the utility of basal serum follicle stimulating hormone and estradiol levels in predicting pregnancy in women undergoing artificial insemination with donor sperm for severe male factor infertility. METHOD: A retrospective chart review of 48 women who had at least 2 cycles of artificial insemination with donor sperm and who had undergone testing for basal serum follicle stimulating hormone and estradiol levels prior to or during therapy. RESULTS: There was no difference in age or mean basal serum follicle stimulating hormone between women who conceived (clinical pregnancy) and those who did not. Women who conceived had significantly lower mean serum basal estradiol levels (P = 0.02) and significantly fewer numbers of treatment cycles (P = 0.041). The highest pregnancy rate was among those women with normal basal serum follicle stimulating hormone and estradiol levels. Receiver operating characteristic curve analysis revealed basal serum estradiol to be a more reliable predictor of pregnancy than follicle stimulating hormone. CONCLUSIONS: Basal serum follicle stimulating hormone and estradiol levels may be useful in predicting success with artificial insemination with donor sperm. It may be useful to obtain basal serum follicle stimulating hormone and estradiol prior to initiating artificial insemination with donor sperm.
Data on lung cancer mortality rates vs. average radon concentration in homes for 1,601 U.S. counties are used to test the linear-no threshold theory. The widely recognized problems with ecological studies, as applied to this work, are addressed extensively. With or without corrections for variations in smoking prevalence, there is a strong tendency for lung cancer rates to decrease with increasing radon exposure, in sharp contrast to the increase expected from the theory. The discrepancy in slope is about 20 standard deviations. It is shown that uncertainties in lung cancer rates, radon exposures, and smoking prevalence are not important and that confounding by 54 socioeconomic factors, by geography, and by altitude and climate can explain only a small fraction of the discrepancy. Effects of known radon-smoking prevalence correlations--rural people have higher radon levels and smoke less than urban people, and smokers are exposed to less radon than non-smokers--are calculated and found to be trivial. In spite of extensive efforts, no potential explanation for the discrepancy other than failure of the linear-no threshold theory for carcinogenesis from inhaled radon decay products could be found.
Problems in the theoretical basis for the linear-no threshold theory of radiation carcinogenesis are reviewed, and it is shown that they very strongly suggest that the theory greatly overestimates the risk of low level radiation. A direct test of the theory, based on the radon-lung cancer relationship is described; it strongly reinforces that conclusion. However, it is shown that even if the linear-no threshold theory is valid, the public's fear of low level radiation, at least in some contexts, is grossly exaggerated.
It was recently shown that the E2F-pRB complex is a negative transcriptional regulator. However, it was not determined whether the whole complex or pRB alone is required for repression. Here we show that pRB and the related protein p107 are capable of direct transcriptional repression independent of E2F. When fused to the DNA binding domain of GAL4, pRB or p107 represses transcription of promoters with GAL4 binding sites. Thus, E2F acts as a tether for pRB or p107 but is not actively involved in repression of other enhancers. This function of pRB maps to the pocket and is abrogated by mutation of this domain. This result suggests an intriguing model in which the pocket has a dual function, first to bind E2F and second to repress transcription directly, possibly through interaction with other proteins. We also show that direct transcriptional repression by pRB is regulated by phosphorylation. Mutations which render pRB constitutively hypophosphorylated potentiate repression, while phosphorylation induced by cyclin A or E reduces repression ninefold.
The concentrations of beta-carotene, retinol and alpha-tocopherol were measured by high-pressure liquid chromatography in ovarian follicular fluid and plasma samples collected at the time of oocyte recovery from patients enrolled in our in vitro fertilization program. The mean beta-carotene levels in follicular fluid [0.182 +/- (SEM) 0.04 nmol/ml] and plasma (0.37 +/- 0.34 mmol/ml) of smokers (n = 5) were significantly (p < 0.025 and p < 0.001, respectively) lower compared with the mean levels in follicular fluid (0.58 +/- 0.10 nmol/ml) and plasma (1.11 +/- 0.09 mmol/ml) in nonsmokers (n = 11). The follicular fluid and plasma retinol and alpha-tocopherol levels were comparable among the nonsmokers and smokers. These findings direct attention to a possible role of the antioxidant beta-carotene, per se, as a biological marker in ovarian oocyte follicular maturation and function.
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