Megaloblastic anaemia is due to a derangement of DNA synthesis caused by insufficient supply of one or other of the four deoxyribonucleoside triphosphate (dNTP) precursors of DNA synthesis or by direct inhibition of one or other DNA polymerase. Reduced supply of the pyrimidine deoxythymidine triphosphate (dTTP) may be caused by folate or vitamin B12 deficiencies or by the action of dihydrofolate reductase inhibitors (e.g. methotrexate, pyrimethamine or trimethoprim), all of which cause reduced supply of the coenzyme 5, 10 methylene tetrahydrofolate (pentaglutamate) needed for thymidylate synthetase. Reduced dTTP supply may also be caused by direct inhibition of thymidylate synthetase by 5-fluorouracil. Reduced supply of both purines, deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP), may be caused by hydroxyurea, 6-mercaptopurine (and probably by another purine antagonist azaserine), whilst reduced supply of both pyrimidine DNA precursors, dTTP and dCTP (deoxycytidine triphosphate) may be due to inherited orotic aciduria or to treatment with azauridine. Cytosine arabinoside directly inhibits DNA polymerase. DNA replication is a discontinuous process and a number of enzymes are concerned with different aspects of the process. The parental strands partly unwind and a large number of initiation points or origins are activated on both strands. A primer RNA is first synthesised using the parental strand of DNA as template. Fragments of new DNA are then synthesised on the parental DNA template, starting at the RNA primer, under the action of one or other DNA polymerase (probably gamma). The RNA primer is then removed and the gap left is filled by further DNA synthesis under the action of a different DNA polymerase (probably alpha). The fragments of new DNA are joined to give newly synthesised stretches of DNA (replicons) which are then liigated together to form bulk DNA of enormous molecular weight. It is suggested here that reduced supply of one or other of the four deoxyribonucleoside triphosphate (dNTP) during the 'S' phase of the cell cycle (due to vitamin B12 or folate deficiency, drug treatment or other congenital or acquired abnormality in synthesis of the dNTP) impairs the cell's ability to elongate newly initiated DNA fragments by preventing gap-filling, the polymerase needed for gap-filling requiring substantially greater concentrations of the deoxyribonucleoside triphosphates than the polymerase involved in chain initiation. Cytosine arabinoside, which also may cause megaloblastosis, may affect principally the synthesis of new DNA fragments. Since active protein synthesis is needed for the cell to enter the S phase and RNA synthesis is needed to prime new DNA synthesis, megaloblastic anaemia may be expected to occur only when DNA synthesis is inhibited but protein and RNA synthesis are relatively unimpaired...

Anemia, Megaloblastic↗

PubMed1976

National Leprosy Control Programme.

Explore the source record for details and available documents.

Health Expenditures↗

PubMed1976

Respiratory syncytial virus-specific RNA synthesis in primary monkey kidney cell cultures.

Primary rhesus monkey kidney (MK) cell cultures were inoculated with respiratory syncytial virus and treated or untreated with actinomycin D before pulse labeling with uridine-5-3H. The virus-specific RNA synthesis was noted at its peak in the nucleoplasm and possibly less so in the cytoplasm of infected cells. At 48 and 72 hours post-inoculation (p.i.), small fractions of available cells were synthesising virus-specific RNA with labeling index of 15% and 18% respectively. By 48 hours p.i. syncytia started appearing and a higher grain count in the cytoplasm of actinomycin D-treated infected cells was noted.

Animals↗

PubMed1975

Erythropoiesis and erythropoietin in hypo- and hyperthyroidism.

Qualitative and quantitative studies of erythropoiesis in 23 patients with hypothyroidism and 21 patients with hyperthryoidism included routine hematologic evaluation, bone marrow morphology, status of serum iron, B12 and folate red blood cell mass and plasma volume by radioisotope methods, erythrokinetics and radiobioassay of plasma erythropoietin. A majority of patients with the hypothyroid state had significant reduction in red blood cell mas per kg of body weight. The presence of anemia in many of these patients was not evident from hemoglobin and hematocrit values due to concomitant reduction of plasma volume. The erythrokinetic data in hypothyroid patients provided evidence of significant decline of the erythropoietic activity of the bone marrow. Erythroid cells in the marrow were depleted and also showed reduced proliferative activity as indicated by lower 3H-thymidine labeling index. Plasma erythropoietin levels were reduced, often being immeasurable by the polycythemic mouse bioassay technique. These changes in erythropoiesis in the hypothyroid state appear to be a part of physiological adjustment to the reduced oxygen requirement of the tissues due to diminished basal metabolic rate. Similar investigations revealed mild erythrocytosis in a significant proportion of patients with hyperthyroidism. Failure of erythrocytosis to occur in other patients of this group was associated with impaired erythropoiesis due to a deficiency of hemopoietic nutrients such as iron, vitamin B12 and folate. The mean plasma erythropoietin level of these patients was significantly elevated; in 4 patients the levels were in the upper normal range whereas in the rest, the values were above the normal range. The bone marrow showed erythyroid hyperplasia in all patients with hyperthyroidism. The mean 3H-thymidine labeling index of the erythroblasts was also significantly higher than normal in hyperthyroidism; in 8 patients the index was within the normal range whereas in the remaining 13 it was above the normal range. Erythrokinetic studies also provided evidences of increased erythropoietic activity in the bone marrow. It is postulated that thyroid hormones stimulate erythropoiesis, sometimes leading to erythrocytosis provided there is no deficiency of hemopoietic nutrients. Stimulation of erythropoiesis by thryoid hormones appears to be mediated through erythropoietin.

Biological Assay↗

PubMed1975

Acute renal failure following snakebite.

Eight patients with acute renal failure following snakebite were studied. Intravascular hemolysis and disseminated intravascular coagulation contributed to the development of acute renal failure in 6 patients. Direct nephrotoxicity causing acute renal failure is postulated in 2 patients, 1 of whom also revealed evidence of mild, disseminated intravascular coagulation. Three patients had histopathological lesions of acute symmetrical cortical necrosis and 3 had acute tubular necrosis. In 1 patient with acute tubular necrosis, in whom direct nephrotoxicity seemed to be responsible for renal failure, the striking histological feature was a uniform debasement and disappearance of tubular epithelium. In 2 patients with a clinical course of acute tubular necrosis, histological lesions could not be documented. All the 5 patients with acute tubular necrosis regained full recovery of renal function, 3 of them with the help of dialysis and 2 with conservative management. None of the 3 patients with acute cortical necrosis survived in spite of intermittent dialysis therapy.

Acute Kidney Injury↗

PubMed1975