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Biomedical subjects

N Cooper

Publications and source records attributed to N Cooper.

At least 55 records · Page 3Linked to original sources
PubMed1989

Studies of HIV infection and the development of Epstein-Barr virus-related B cell lymphomas following transfer of human lymphocytes to mice with severe combined immunodeficiency.

Mice with severe combined immunodeficiency (C.B-17 scid, hereafter SCID) accept xenografts of adult human peripheral blood leukocytes (PBL). The transplanted human PBL expand in number and survive for at least thirteen months and have been shown to reconstitute human immune function at both the T and B cell levels. Human immunoglobulin production is restored, and secondary antibody responses to antigens such as tetanus toxoid can be induced. All SCID mice reconstituted with 50 x 10(6) or more PBL from donors with evidence of exposure to Epstein-Barr virus (EBV) have developed human B cell lymphomas at 8-16 weeks after PBL engraftment, whereas mice reconstituted with PBL from EBV-seronegative donors fail to develop tumors. These tumors involve both lymphatic and non-lymphatic organs, and histologically they resemble large cell or immunoblastic lymphomas. The tumors are associated with high levels of human immunoglobulin secretion and serum electrophoresis reveals oligoclonal immunoglobulin banding patterns. Analysis of tumor DNA shows the presence of EBV genomes and oligoclonal patterns of immunoglobulin JH gene rearrangement. Taken together, these observations suggest an EBV-related proliferation of B lymphocytes leading to the rapid appearance of oligoclonal B cell malignancies following transfer of B lymphocytes from "normal" donors to SCID mice. SCID mice reconstituted with PBL from EBV-seronegative donors have been infected with the LAV-1 strain of human immunodeficiency virus (HIV-1). Virus has been recovered from most infected animals by co-culture of mouse tissue with human T lymphoblasts. Some mice with high virus titers have developed an acute wasting syndrome and depletion of human T cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1982

Genetic evidence for vaccinia virus-encoded DNA polymerase: isolation of phosphonoacetate-resistant enzyme from the cytoplasm of cells infected with mutant virus.

Phosphonoacetate (PAA), at concentrations of 200 micrograms/ml or more, prevented growth of vaccinia virus in HeLa and BSC-1 cells. Spontaneous vaccinia virus mutants, selected at high PAA levels, were resistant to the antiviral effects of the drug. The action of PAA was directed toward an early viral function, since the drug was inhibitory only during the first 4 h of the approximately 15-h growth cycle. Conversely, significant reversal of the antiviral effects was obtained only when the drug was removed at or before the fourth hour of infection. Incorporation of [3H]thymidine into cytoplasmic viral DNA was severely inhibited in cells infected with wild-type virus but not in cells infected with mutant virus. Virus-induced DNA polymerase isolated from the cytoplasm of cells infected with wild-type or mutant virus had indistinguishable chromatographic properties on DEAE-cellulose and phosphocellulose columns. However, the wild-type enzyme was inhibited by relatively low concentrations of PAA, whereas 10-fold higher concentrations were needed for equivalent inhibition of the mutant enzyme. Kinetic analysis indicated that PAA inhibition was noncompetitive with deoxyribonucleoside triphosphates; Ki values for wild-type and mutant DNA polymerases were approximately 25 and 300 microM, respectively. Inhibition of wild-type DNA polymerase was immediate and complete even when PAA was added after initiation of DNA synthesis in vitro, suggesting that chain elongation was affected. These results established that the DNA polymerase is a target of the antiviral action of PAA and provided genetic evidence that this enzyme is virus encoded.

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PubMed1981

Instability and reiteration of DNA sequences within the vaccinia virus genome.

The sequence arrangement within the nontranscribed portion of the inverted terminal repetition of the vaccinia virus genome exists in quasi-stable and unstable forms that are not distinguishable on the basis of viral infectivity. The unstable forms, which composed about 20% of a serially passaged stock of virus, were recognized by terminal heterogeneity on restriction endonuclease analysis. Instead of a single terminal fragment from each end of the genome, an array of eight or more fragments differing in size by 1650-base-pair increments was detected. This feature was not eliminated by repeated plaque purification, indicating that the population of DNA molecules with various numbers of reiterations can rapidly evolve from the DNA of a single virus particle. However, at each successive round of plaque purification, about 20% of the unstable isolates revert back to the more stable form. Stable forms are characterized by the presence of a set of 13-17 tandem 70-base-pair repeats on each side of a 435-base-pair intervening sequence near both ends of the genome. In contrast, the unstable forms possess sets of tandem repeats and intervening sequences that alternate many times in series. The transition between the two genomic forms and the evolution of the unstable form appear to be mediated by recombinational events.

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PubMed1977

Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. III. Effects of temperature, time, and perfusion pressure in fibrillating hearts.

This study compares the effects of normothermic and hypothermic spontaneous fibrillation at perfusion pressures of 100 and 50 mm. Hg on the adequacy and distribution of coronary blood flow. During normothermia (37 degrees C.), subendocardial oxygen delivery decreased 45 per cent ( p less than 0.01) and left ventricular flow became redistributed away from the subendocardium (endo-epi flow ratio fell from 1.2 to 0.8) when perfusion pressure was lowered to 50 mm. Hg; abnormal glycolysis (lactate washout) became evident when perfusion pressure was raised to 100 mm. Hg and ischemia was demonstrated by histochemical stains. Hypothermia (28 degrees C) reduced myocardial oxygen uptake 52 per cent (p less than 0.01) at 100 mm. Hg perfusion pressure; left ventricular flow, distribution, and metabolism did not change from control values. Lowering perfusion 50 mm Hg caused a pronounced reduction in subendocardial oxygen delivery (63 per cent, p less than 0.01); abnormal glycolysis developed and histochemical ischemia was seen. These studies show that lowering perfusion pressure in normothermic fibrillating hearts impairs oxygen delivery to the left ventricular subendocardium. While hypothermia significantly reduces left ventricular oxygen requirements, the ventricle is not protected against subendocardial ischemia if perfusion pressure falls to levels frequently used during clinical open-heart surgery.

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PubMed1977

Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart.

The effects of hypothermia (32 degrees, 28 degrees, and 22 degrees C.) on left ventricular flow distribution (microspheres) and oxygen uptake in adequately perfused, beating, empty, fibrillating, and arrested hearts were studied. Minute left ventricular oxygen uptake fell progressively as myocardial temperature was reduced under all conditions. In beating hearts, however, left ventricular oxygen uptake per beat increased significantly due to the inotropic effect of hypothermia and diastolic compliance fell. Cold fibrillating hearts consumed slightly less oxygen per minute than beating hearts at comparable temperatures as fibrillation became less forceful with hypothermia. Myocardial wall tension, however, was always higher in fibrillating than beating hearts at each level of hypothermia. The lowest myocardial oxygen requirements were always found in arrested hearts (70 to 80 per cent less than either beating empty or fibrillating hearts) at any myocardial temperature. Left ventricular coronary flow remained distributed evenly across the beating heart at all myocardial temperatures and in fibrillating hearts at 28 degrees, and 22 degrees C. Left ventricular flow became redistributed toward the subendocardium in fibrillating hearts at 37 degreegs and 32 degrees C. and in arrested hearts at all myocardial temperatures.

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PubMed1977

Studies of the effects of hypothermia on regional myocardial blood flow and metabolsim during cardiopulmonary bypass. II. Ischemia during moderate hypothermia in continually perfused beating hearts.

The effect of varying perfusion pressure on the adequacy and distribution of coronary flow was studied in normothermic and hypothermic beating hearts. At 37 degrees C., lowering perfusion pressure from 100 to 50 mm. Hg did not change oxygen uptake or total or regional coronary flow or cause biochemical or histochemical ischemia. Vasodilator reserve capacity, however, was expended in order to maintain adequate subendocardial perfusion. At 28 degrees C., myocardial oxygen uptake per minute fell but oxygen consumption per beat rose significantly. Reduction of perfusion pressure to 50 mm. Hg caused a 44 percent (p less than 0.01) reduction in subendocardial flow and resulted in redistribution of flow away from the subendocardium (endocardial/epicardial flow ratio fell from 1.25 to 1.0). Ischemia was evident from intracavitary electrocardiogram, abnormal glycolysis, and histochemical staining. These studies show that during normothermia the coronary arteries dilate to provide adequate coronary flow when perfusion pressure is reduced. In contrast, compensatory vasodilatation is inadequate in hypothermic hearts and ischemia occurs at low perfusion pressures.

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PubMed1977

Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. IV. Topical atrial hypothermia in normothermic beating hearts.

This study compares (1) the effects of slowing heart rate by topical hypothermia in hearts perfused at 37 degrees C. with bradycardia produced by perfusion hypothermia (28 degrees C.) and (2) the consequences of counteracting the bardycardic effects of perfusion hypothermia by atrial pacing. Topical atrial hypothermia (myocardial temperature 37 degrees C.) produced a level of bradycardia comparable to perfusion hypothermia (82 vs. 71 beats per minute), but reduced myocardial oxygen requirements 25 per cent more than perfusion with 28 degrees C. blood. Myocardial oxygen uptake per beat did not change with topical atrial hypothermia but increased 40 per cent with perfusion hypothermia. Counteracting the bradycardic effects of perfusion hypothermia with atrial pacing (to 130 beats per minute) reduced subendocardial flow 25 per cent, caused a redistribution of flow away from the subendocardium, and produced evidence of ischemia on the intracavitary electrocardiogram. This study shows that (1) topical atrial hypothermia with systemic normothermia reduced myocardial oxygen demands as effectively as perfusion hypothermia and (2) subendocardial ischemia develops in beating empty hearts when the expected bradycardia of hypothermia does not occur.

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