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Biomedical subjects

J A Kark

Publications and source records attributed to J A Kark.

At least 19 recordsLinked to original sources
PubMed1995

Antisickling effects of 2,3-diphosphoglycerate depletion.

Elevation of 2,3-bisphosphoglycerate (2,3-DPG) in sickle erthrocytes (SS RBCs) and concomitant acidification of the cell interior promote polymerization by decreasing the solubility (csat) of deoxyhemoglobin S. The antisickling effect of 2,3-DPG depletion was evaluated after activation of the 2,3-DPG phosphatase activity of bisphosphoglycerate mutase by glycolate-2-phosphate, leading to rapid loss of intracellular 2,3-DPG. To ensure its maximal reduction in a physiologic medium, isosmotic CO2/bicarbonate-buffered saline, pH 7.0, was used. Substitution of K+ for Na+ as the major extracellular cation suppressed K:Cl cotransport, prevented cell shrinkage, and allowed demonstration of the full antisickling effect of 2,3-DPG depletion. The modest effect on solubility per se of removing intraerythrocytic 2,3-DPG (delta Csat = 1.6 g/dL) was amplified into a much larger antisickling effect by interaction with three other cellular variables affecting solubility and polymer content (intracellular pH, O2 saturation, and mean cell hemoglobin concentration). Acting in concert, these four antisickling effects (three solubilizing, one osmotic) reduced polymer fraction of glycolate-treated SS RBCs by 32% to 63%, with a concomitant decrease in sickling of 46% to 95% at the nominal pO2 of the microcirculation (20 mm Hg). A decrement in sickling of this magnitude should significantly ameliorate the vasoocclusive severity of sickle cell disease.

2,3-Diphosphoglycerate↗
PubMed1994

Fatal rhabdomyolysis presenting as mild heat illness in military training.

A 30-year-old black male soldier with sickle cell trait presented with fatal exertional rhabdomyolysis (which was unrecognized during 14 hours at a field clinic). After prompt treatment for heat exhaustion, his symptoms seemed mild and he was afebrile. His clinical course illustrates the potential for severe illness in the absence of fever, the importance of assessing mental dysfunction, indications for laboratory evaluation, the need for comprehensive management of severe dehydration and acidosis, common laboratory features of acute renal failure and exertional rhabdomyolysis, and the increased risk of exercise-related death in those with sickle cell trait.

Adult↗
PubMed1987

Sickle-cell trait as a risk factor for sudden death in physical training.

Case reports of sudden death during exertion have not established an association between the sickle-cell trait (hemoglobin AS) and exercise-related death. To test this association, all deaths occurring among 2 million enlisted recruits during basic training in the U.S. Armed Forces in 1977 to 1981 were classified from autopsy and clinical records as non-sudden deaths or as sudden deaths explained or unexplained by preexisting disease. On the basis of known numbers of entering recruits (according to race, age, and sex) and published prevalence rates for hemoglobin AS (8 percent for black and 0.08 percent for nonblack recruits), death rates (per 100,000) were 32.2 for sudden unexplained deaths, 2.7 for sudden explained deaths, and 0 for non-sudden deaths among black recruits with hemoglobin AS, as compared with 1.2, 1.2, and 0.7 among black recruits without hemoglobin S and 0.7, 0.5, and 1.1 among nonblack recruits without hemoglobin S. Among black recruits the relative risk of sudden unexplained death (hemoglobin AS vs. non-hemoglobin S) was 27.6 (95 percent confidence interval, 9 to 100; P less than 0.001), whereas among all recruits this risk was 39.8 (95 percent confidence interval, 17 to 90; P less than 0.001). The relative risk of sudden unexplained death among all recruits increased with age (P less than 0.04), from 13 (ages 17 to 18) to 95 (ages 26 to 30). We conclude that recruits in basic training with the sickle-cell trait have a substantially increased, age-dependent risk of exercise-related sudden death unexplained by any known preexisting cause.

Adolescent↗
PubMed1987

Pulmonary function in sickle cell trait.

Pulmonary function abnormalities, which have been reported to occur in persons with sickle cell trait (hemoglobin AS), could intensify the hypoxic stimulus for the systemic formation of sickle cells at high altitude. We sought to determine whether pulmonary function abnormalities occur as a result of exposure to high altitudes in persons with hemoglobin AS. In a prospective study, 13 men with hemoglobin AS ("cases") and 13 controls (hemoglobin AA) matched by age, sex, and race were exposed to five to seven altitude simulations (ranging from 1524 to 7620 m [5000 to 25,000 ft]) in a hypobaric chamber. Measurements of diffusing capacity for carbon monoxide (DLco), forced vital capacity, forced expiratory volume in one second, and forced midexpiratory flow were obtained before and after each exposure. Data before exposures did not differ statistically between cases and controls. Altitude had no systematic effect on DLco or spirometric values in cases compared with values in controls (p greater than 0.05). Individual declines in forced vital capacity or DLco of more than 10% occurred with similar frequency in both groups. Measurements made after the series of exposures showed no change from those made before. We conclude that short serial exposures to hypoxia at high altitudes does not acutely or cumulatively alter DLco or spirometric values in healthy, nonexercising persons with sickle cell trait.

Adult↗
PubMed1983

Pyridoxal phosphate as an antisickling agent in vitro.

Although pyridoxal phosphate is known to inhibit gelation of purified hemoglobin S, antisickling activity has never been demonstrated for intact erythrocytes. We incubated washed erythrocytes at 37 degrees C either in buffer alone, or with added pyridoxal phosphate or pyridoxal, washed these cells, suspended them in untreated buffer, and compared the percent modified hemoglobin, the oxygen affinity, and the extent of sickling under hypoxia. Pyridoxal phosphate modified intracellular hemoglobin more slowly than pyridoxal. Pyridoxal phosphate lowered the oxygen affinity of normal cells, but had no effect on oxygen binding by sickle cells. Pyridoxal increased the oxygen affinity of normal and sickle erythrocytes equally. Pyridoxal phosphate significantly inhibited sickling of sickle or sickle trait erythrocytes (P less than 0.001). Inhibition of sickling by pyridoxal phosphate was largely independent of oxygen binding; whereas inhibition of sickling by pyridoxal was almost entirely dependent on increased oxygen binding. Although pyridoxal phosphate and pyridoxal both inhibit sickling by modification of hemoglobin S, they differ in the kinetics of whole cell modification, the effect on oxygen affinity of intact cells, and the mechanism of action of the antisickling activity.

Anemia, Sickle Cell↗
PubMed1983

The effect of bloodletting on exercise performance in a subject with a high-affinity hemoglobin variant.

We studied two young army recruits with erythrocytosis. One had a variant hemoglobin with high affinity for oxygen (hemoglobin Osler, also known as Fort Gordon and Nancy, beta 145 Tyr leads to Asp). The other had normal oxygen affinity and erythrocytosis of undetermined etiology. Both were asymptomatic. We studied exercise capacity on a cycle ergometer before and after hemodilution. In the subject with high oxygen affinity, hemodilution resulted in reduced maximal work and increased heart rate at every work level. In addition, minute ventilation and arterial lactic acid increased, while anaerobic threshold decreased, indicating diminished oxygen supply to tissues. In contrast, the subject with normal oxygen affinity had no significant changes in exercise performance after hemodilution. These results suggest that when blood oxygen affinity is high, loss of efficiency in tissue oxygenation can be expected after phlebotomy or hemodilution. Therefore, it may be useful to measure blood oxygen affinity and exercise performance in polycythemic subjects in whom such procedures are intended to ameliorate symptoms of hyperviscosity.

Adult↗
PubMed1982

Hemoglobin Osler: report of a new family with exercise studies before and after phlebotomy.

Five members of a new family with hemoglobin Osler are described. Exercise studies were performed before and after phlebotomy in one patient. These studies demonstrated that anaerobic threshold was directly related to hematocrit. Our data suggest that the elevation of red cell mass seen with this high oxygen affinity hemoglobin is an appropriate physiologic response which improves tissue oxygen delivery. Despite the increase in whole blood viscosity associated with erythrocytosis, our data do not support the use of therapeutic phlebotomy to improve exercise performance in patients with hemoglobin Osler.

Adult↗
PubMed1982

The effects of pyridoxine on pituitary hormone secretion in amenorrhea-galactorrhea syndromes.

Six patients with amenorrhea, five of whom had galactorrhea and elevated PRL levels, were evaluated on a metabolic ward. All had normal sella tomograms, normal thyroid functions, and routine laboratory evaluations. None of the patients had taken any medication in the previous 6 months. On alternate days, five patients received 500 microgram of TRH iv with the measurement of PRL, TSH, FSh, LH, and hGH; 500 mg L-dopa orally with the measurement of PRL, FSH, and LH; a bolus infusion of 300 mg pyridoxine (B6) with measurement of PRL, hGH, TSH, FSH, and LH; and 25 mg chlorpromazine (CPZ) im with the measurement of PRL, LH, and FSH. The patients were then discharged on 600 mg oral pyridoxine/day and were readmitted for a repeat of the complete protocol 21 days later. The patients were continued on 600 mg oral pyridoxine for 3-4 months with monthly evaluations of serum PRL, LH, and FSH levels. These evaluations continued for 3 months after discontinuing pyridoxine. There was no demonstrable change in serum PRL after acute or chronic B6 therapy, mor was there a significant change in the response of PRL to CPZ, L-dopa, or TRH. The mean basal PRL was 97.5 +/- 9.7 ng/ml and after 3-4 months of oral pyridoxine was 97.1 +/- 14.8. In addition, there was no significant change in LH or FSH levels in response to acute or chronic B6, TRH, L-dopa, or CPZ. Neither acute B6 infusion nor chronic B6 therapy had any effect on TSH or the TSH response to TRH. Finally, acute B6 infusion had no effect on hGH levels and there were no paradoxical hGH responses to TRH. Two patients began having regular menses while on chronic pyridoxine. Their hormonal responses did not differ from those of the group, however.

Adult↗
PubMed1982

Erythrocytosis in patients on long-term hemodialysis.

Erythrocytosis was seen in two men during maintenance hemodialysis therapy for end-stage renal disease secondary to apparent chronic glomerulonephritis. Nonrenal causes of erythrocytosis such as polycythemia vera, chronic hypoxemia, high-oxygen affinity hemoglobin, and hepatoma were excluded by appropriate clinical studies. A computed tomographic scan of the abdomen showed numerous renal cysts in each patient consistent with acquired cystic disease of end-stage kidneys. Peripheral serum erythropoietin levels were elevated as measured by sensitive radioimmunoassay. The findings suggest that the erythrocytosis is caused by an erythropoietic mechanism related to the diseased kidneys. A review of the literature failed to show previous reports of this clinical association.

Erythropoietin↗
PubMed1982

Modification of intracellular hemoglobin with pyridoxal and pyridoxal 5'-phosphate.

The aldehyde forms of vitamin B6, pyridoxal and pyridoxal 5'-phosphate (PLP) have aroused interest as antisickling agents because of their ability to modify hemoglobin (Hb) and their low toxicity. To study their rate of formation and stability inside red cells, pyridoxal-Hb and PLP-Hb were measured in lysates from treated normal and sickle erythrocytes using isocratic high pressure liquid chromatography on Bio-Rex 70. The validity of this assay was confirmed by isoelectric focussing, fluorescence scans of reduced globin, and treatment of cells with pyridoxal 14C. Optimal conditions were described for treatment of whole blood with pyridoxal and washed erythrocytes with PLP. Although there was competition between 2,3-DPG and PLP, but not pyridoxal, for binding to Hb, depletion of 2,3-DPG prior to treatment was unnecessary. No special requirements were noted for the anticoagulants or buffers used. Sickle erythrocytes formed PLP-Hb more rapidly than normal erythrocytes, but pyridoxal-Hb appeared at the same rate in both types of erythrocytes. During incubation of treated erythrocytes in untreated plasma, the stability of pyridoxal-Hb varied inversely with the hematocrit, but PLP-Hb was stable at all hematocrits tested. The absence of hemolysis during a 4 day incubation of treated normal red cells implies that treatment with pyridoxal or PLP did not severely impair red cell metabolism.

Anemia, Sickle Cell↗
PubMed1980

Optic atrophy in experimental vitamin B12 deficiency in monkeys.

The clinical findings and pathological changes of the visual pathway of vitamin B12 deficient monkeys have been described. The cellular morphology and counts of the peripheral blood and bone marrow remained normal during the study (nine deficient, three controls: one still alive in each group). Visual impairment was noted in all seven of the deficient animals that were evaluated by clinical observations. Ophthalmoscopic examination disclosed optic atrophy in six of the seven deficient monkeys. Degeneration of the visual pathway was demonstrated by pathological examination in eight of the deficient group of nine (one is still alive). Loss of ganglion cells was noted in the maculae of two of three deficient animals with completed studies. In the three control animals there were neither visual disturbances nor ophthalmoscopic changes and in two animals autopsies disclosed no lesions in the visual pathways. The third animal is still alive and well.

Animals↗
PubMed1978

Low erythrocyte pyridoxal-kinase activity in Blacks: Its possible relation to falciparum malaria.

The red-cell glucose-6-phosphate dehydrogenase (G.-6-P.D.) activity and red-cell pyridoxal-kinase (P.L.K.) activity of 27 Nigerian children with severe Plasmodium falciparum parasitaemia were compared with those of 26 healthy Nigerian children and 6 White adults. The mean P.L.K. activity of the malaria patients was similar to that of the Whites but significantly higher than that of the Nigerian controls. Correction for reduced mean red-cell age in patients was made by comparing the P.L.K.: G.-6-P.D. ratio for those subjects with stable G.-6-P.D. phenotypes. The mean P.L.K.:G.-6-P.D. ratio was the same for malaria patients and adult White but significantly higher than that for the Nigerian controls. These results suggest that the relatively high frequency of low red-cell P.L.K. activity among Blacks may have been selected for by falciparum malaria.

Adult↗
PubMed1978

An ultrastructural study of subacute combined degeneration of the spinal cord in vitamin B12-deficient rhesus monkeys.

Prolonged deprivation of vitamin B12 in rhesus monkeys produced changes in the central nervous system that were indistinguishable topographically and histologically from those of human subacute combined degeneration. Ultrastructural studies of early lesions of the spinal cord disclosed a degeneration of myelin characterized by separation of myelin lamellae and formation of intramyelinic vacuoles, leading eventually to complete destruction of myelin sheaths. At a later stage, there was degeneration and loss of axons, and marked gliosis. The theories of pathogenesis of subacute combined degeneration are reviewed in the light of these observations.

Animals↗
PubMed1978

Inhibition of erythrocyte sickling in vitro by pyridoxal.

To test the antisickling activity of pyridoxal, we compared the oxygen affinity and the percent sickling at low PO2 of untreated erythrocytes with values for cells from the same blood sample incubated with pyridoxal, glyceraldehyde, or pyridoxine. Pyridoxal increased oxygen affinity much more than glyceraldehyde. 20 mM pyridoxal and glyceraldehyde had equivalent antisickling activity. At PO2 levels above 20 mm Hg, both agents reduced sickling to less than 2%. In samples examined by electron microscopy, pyridoxal reduced the percent sickled cells and the percent cells that contain hemoglobin S fibers by the same amount (from 74 to 3%). Pyridoxine had no effect on oxygen affinity or sockling. Pyridoxal reacts with intracellular hemoglobin to increase oxygen affinity, which inhibits hemoglobin S polymerization and sickling.

Anemia, Sickle Cell↗