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Factor V Leiden, prothrombin 20210A, methylenetetrahydrofolate reductase 677T, and population genetics.

Thrombosis results from the interaction between predisposing genetic polymorphisms and acquired risk factors. Two of the main prothrombotic alleles, Factor V (FV) Leiden and prothrombin 20210A, are only encountered among European populations. They are estimated to have arisen about 21,000-34,000 years ago as founding mutations after the evolutionary divergence of Caucasians from Asians, and have been subsequently dispersed by the Neolithic migrations. These polymorphisms may have developed by means of genetic drift or natural selection by possibly conferring a reduced risk of bleeding. Of note, FV Leiden is nearly absent in the Basques, a European population of pre-Neolithic individualization. The C677T mutation of the methylenetetrahydrofolate reductase gene may induce hyperhomocysteinemia and could slightly increase the risk of arterial or venous thrombosis and pregnancy loss in individuals with folic acid deficiency. Through a selective phenomenon, the frequency of the mutation may parallel the intake of this vitamin within populations. Hence, this allele is underrepresented in Sub-Saharan Africa, Indonesia, and in the Inuits and a positive North to South gradient has been described in Europe. Thus, these three inherited prothrombotic polymorphisms represent interesting tools for population genetics studies.

Evolution, Molecular↗

[Methanol poisoning].

The neurological signs, the cerebral CAT scan aspects and the ocular problems seen in five cases of acute methanol poisoning are reported; these were, respectively, coma requiring assisted ventilation, convulsions, hypotonicity, hypodensity of the putamen, and amaurosis and papillary oedema. The simplified acute physiologic score varied from 11 to 26; the value of 26 was observed in the only death of the series. Pathogenesis of the metabolic acidosis, as well as the different parts played by formic acid, lactic acid and ketone bodies are discussed. A normal or lowered serum potassium in a case of unexplained metabolic acidosis associated with an osmotic gap should make one think of the diagnosis. Macrocytosis, an indirect sign of folic acid deficiency, was in favour of a poor prognosis. The treatment included early gastric lavage, alkalinization, blocking of the metabolism of methanol by ethanol and haemodialysis with a bicarbonate dialysate enriched in ethanol; this corrected the acidosis and permitted the elimination of the toxic metabolites (clearance of methanol: 159 ml X min-1; half-life of methanol during purification: 3.46 +/- 1.32 h; quantity extracted: 246 g). The possible advantages of 4-methyl-pyrazol and alkyldiol derivatives need further confirmation.

Acidosis↗

Dietary habits and nutritional status of renal transplant patients.

BACKGROUND: Although dialysis nutritional problems are well described, nutritional problems after renal transplantation (RT) have received little attention. METHODS: Body composition as assessed by dual-energy x-ray absorptiometry in 115 stable patients 6.6 +/- 5.9 years after RT and repeated 2.9 years later, when a 3-day dietary history was obtained in 79 patients. RESULTS: Patients diet was generally sufficient, but was characterized by a high fat intake and deficiencies in folic acid, vitamin D, thiamine, iodine, selenium, and iron intake. Patients were often overweight, and at any given weight had a 4% to 5% higher proportion of body fat than normal. Loss of fat weight was related to high initial fat weight, long RT duration, and low plasma bicarbonate, but not steroid dose. CONCLUSION: Dietary advice concerning fat intake is indicated for RT patients, and nutritional supplements with folic acid and vitamin D are generally required. Their main nutritional problem is obesity. This is not adequately measured by body mass index, which should be supplemented by dual-energy x-ray absorptiometry. Attention should be paid to the prevention of acidosis.

Absorptiometry, Photon↗

Anemia in patients with traumatic spinal cord injury.

Anemia is often a complication following spinal cord injury which interferes with the patient's rehabilitation. Hematological profiles of 65 male patients with traumatic spinal cord injury revealed a 52.3% incidence of mild anemia. The age, duration or level of injury had no correlation with the incidence and type of anemia. The anemia was normocytic-normochromic in 32%, normocytic mild hypochromic in 56%, and microcytic hypochromic in 12% of the patients. Factors in pathogenesis included decubitus ulcers, urinary tract infections, acute and chronic blood loss, and folic acid deficiency due to psychosocial maladjustment, alcohol and/or drug abuse. Often, multiple factors were operative in changing proportions. The success of management depends on a careful assessment of causes and removal of inciting factors. The most common type of anemia was that due to chronic disorder, associated with either decubitus ulcers and/or urinary tract infections. Since this type of anemia mimics iron deficiency in presentation it should be differentiated from the latter by evaluation of iron status. Normal hemoglobin levels can be attained only after the chronic disorder is eliminated. Unpredictable fluctuations of hemoglobin level secondary to changes in plasma volume due to autonomic hyperreflexia are common in SCI patients, and should be taken into account for diagnosis and follow-up in therapy.

Adult↗

Free radicals and birth defects.

Maternal diabetes significantly increases the risk for birth defects. Studies using animal models indicate that oxidative stress may play a causative role. Oxidative stress can result from exposure to certain drugs, ionizing radiation and folic acid deficiency. Therefore, study of the mechanisms by which maternal diabetes affects embryogenesis may provide insight into general processes by which birth defects occur. Study of embryonic gene expression has demonstrated that maternal diabetes causes birth defects by disturbing expression of genes that control essential developmental processes, and that oxidative stress is involved. A model in which oxidative stress-induced deficient gene expression leads to congenital defects involving p53-dependent apoptosis is discussed.

Animals↗

Nutritional status of a population sample in Macon County, Alabama.

A nutrition survey was conducted in Macon County, Alabama, with a population sample of 102 individuals, 76% of whom were black. Three 24-hr dietary recalls were obtained for each participant and 24 nutrients and energy were calculated for each combined 3-day intake. Serological and hematological analyses of blood were performed. Dietary calculations indicated that intakes of calcium, vitamin B12, calories, and iron were lowest within the population sample. Blood analyses did not confirm the calculated inadequacies of dietary calcium, vitamin B12, or iron. Body weight data did not support the calculated inadequate energy intakes. Serum analysis indicated a folic acid deficiency. Mean intakes of energy and macronutrients were higher in nonblacks than in blacks; for most vitamins and minerals, the same was true. The lower calcium intakes among blacks than among nonblacks in the growing years exceeded the differential in energy intakes. Higher serum vitamin B12 levels in blacks than in nonblacks were observed but not explained.

Adolescent↗

Comparison of methyltransferase activities of pair-fed rats given adequate or methyl-deficient diets.

The short-term effects of a lipotrope-deficient (methyl-deficient) diet on tRNA and protein methyltransferase activities have been studied using pair-fed male Fischer rats. The activity of liver N2-guanine tRNA methyltransferase II (NMG2) of animals receiving the methyl-deficient diet (MDD) for 2 weeks was found to be elevated more than 2-fold. This is in agreement with the results of earlier experiments in which the animals were fed ad libitum. These data indicate that the effects of lipotrope-deficient diets on NMG2 activity observed in the earlier studies can be attributed to the nature of the diet, and not to differences in caloric intake. In the same pair-fed animals, very little effect of MDD on the activity of NMG2 of either brain or spleen was observed. In liver, the activity of one of the enzymes that catalyze protein methylation--protein methylase I (S-adenosyl-methionine: protein-arginine N-methyltransferase)--was significantly elevated in response to the lipotrope-deficient diet. In contrast, the activities of protein methylase II (S-adenosylmethionine: protein-carboxy-O-methyltransferase), from control and experimental animals did not differ significantly. Lipotrope-deficient diets are thus seen to induce, within a short period of time, selective changes in the activities of some, but not all, of the liver enzymes that catalyze the methylation of tRNA and protein.

Animals↗

Dementia is not inevitable: a population-based study of Danish centenarians.

The authors evaluated the prevalence of dementia in centenarians. In this population-based survey, persons living in Denmark who turned 100 during the period April 1, 1995--May 31, 1996 (N = 276) were interviewed and examined at their residences. Additional health information was retrieved from medical files, including the National Discharge Registry. A participation rate was 75%, and no differences were found between participants and nonparticipants regarding sex and type of housing. The prevalence of mild to severe dementia in centenarians was 51%; 37% had no signs of dementia. Among the 105 demented centenarians, 13 (12%) had diseases (vitamin B12 and folic acid deficiencies, hypothyroidism, Parkinson's disease) that could contribute to a dementia diagnosis. Of the remaining 92 demented participants, 46 (50%) had 1 one or more cerebro- or cardiovascular diseases known to be risk factors in the development of dementia. The prevalence of these risk factors was the same in demented and nondemented participants, whereas hypertension was significantly more frequent in nondemented than demented participants. Dementia is common but not inevitable in centenarians. Cerebro- and cardiovascular diseases are equally common in demented and nondemented persons.

Age Distribution↗

Alterations in immune function in rats caused by dietary lipotrope deficiency: effect of age.

Weanling male Sprague-Dawley rats were maintained on a control (C), folacin-deficient (F) or marginal methionine-choline diet (M/C) for 3 weeks, 3 months or 12 months. The immunocompetence of the animals was determined by in vivo (response to infection with salmonella typhimurium) and in vitro (lymphocyte transformation assay) methods. It was found that young animals were most sensitive to dietary lipotrope deficiency, and the in vivo response to bacterial infection did not always correlate with in vitro assessment of immune function. Histopathologic examination of spleens from S. typhimurium-infected rats maintained for 3 weeks on the experimental diets showed an overall decreased cellularity especially in the follicular areas, compared to controls. No differences were seen in the spleens of infected animals at later time points. A short-term (3-week) lipotrope deficiency resulted in a depressed lymphocyte transformation response to concanavalin A (Con A) in the spleen, thymus and lymph nodes; to phytohemagglutinin A (PHA) in the spleen and lymph nodes only. After 3 months on the F or M/C diets, a depressed Con A-induced transformation response was still seen in the spleen, but the normal aging-induced immunosuppression resulted in a low response in all animals, with few significant differences existing among groups.

Aging↗

Ferritin as an index of bone marrow iron stores.

We examined the relationship of serum ferritin to bone marrow iron stores in 73 anemic male medical inpatients with liver disease, alcoholism, chronic inflammatory disease, and malignancies. A correlation of r = 0.75 (P less than .00005) was found between serum ferritin and bone marrow iron stores (BMIS) for the entire group. Liver disease as manifested clinically or by increased levels of serum glutamic-oxaloacetic transaminase did not appear to significantly affect this relationship. Patients with folic acid deficiency did tend to have a disproportionate increase in ferritin in relation to BMIS, but this did not seem to destroy the usefulness of ferritin levels. A useful clinical rule seems to be that serum ferritin of greater than 100 ng/ml tends to exclude iron deficiency, and a level of less than 30 ng/ml tends to confirm decreased iron stores.

Alcoholism↗

The clinical significance of macrocytosis.

The cause of macrocytosis (mean corpuscular volume (MCV) greater than or equal to 105 fl) was investigated over a period of 16 months in the 70 known cases of +/- 4000 patients seen by the Department of Internal Medicine. By means of simple laboratory investigations the cause of elevated MCV was found in more than 90% of the cases. We found vitamin B12 or folic acid deficiency in 27 patients, alcohol abuse in 18, chronic persistent hepatitis in 2, hematological (pre-) malignancy in 9, hemolysis in 4, hypothyroidism in 2, and a drug effect in one patient. In 6 cases the elevated MCV could not be explained. Macrocytosis, a frequent finding that is not related to the hemoglobin concentration, is an indicator of serious pathology. The MCV level can be used to differentiate between the diagnostic categories. Only 21 patients (30%) had megaloblastic erythropoiesis that was difficult to recognize in the peripheral blood. Among the findings at routine laboratory investigations an elevated MCV may be the only indicator of vitamin deficiency, preleukemia or alcoholism.

Alcoholism↗

Chromosome abnormalities in infantile autism and other childhood psychoses: a population study of 66 cases.

Sixty-six psychotic children aged between two and 20 years, examined by the same child psychiatrist and diagnosed according to strict criteria as suffering from infantile autism, other psychoses and Asperger's syndrome, were examined with chromosomal cultures in folic-acid deficient medium. 47 per cent of the children showed major or minor chromosomal aberrations. The infantile autistic group comprised a total population of autistic children. The fra(X)(q27) marker was seen in 25 per cent of autistic boys. A subgroup of children with the fra(X)(q27) abnormality, infantile autism, psychomotor epilepsy and brainstem dysfunction was identified. Other chromosome markers and abnormalities occurring in several cases included long Y chromosomes, fra(X)(p22), fra(16)(q23) and fra(6)(q26). The results are discussed and correlated with certain clinical characteristics.

Adolescent↗

Long-term erythropoietin therapy improves response in myelodysplastic syndrome.

We report on a 53-year-old Japanese female on hemodialysis with myelodysplastic syndrome whose condition improved with recombinant human erythropoietin (epoetin) therapy. In 1992, based on a diagnosis of folic acid deficiency anemia, folate derivatives were administered. However, the anemia did not improve, and red blood cells had to be transfused subsequently. The transfusion volume was gradually increased afterward, as renal failure progressed, probably due to nephropathy by phenacetin. In 1998, when hemodialysis started, epoetin therapy was started with a dose of 3000 units three times per week. In July 2001, myelodysplastic syndrome (MDS) of a refractory anemia type was diagnosed through bone marrow aspiration. Myelodysplastic syndrome might cause an epoetin-resistant renal anemia. Afterwards the transfusion volume was gradually reduced, and transfusions were not performed after March 2002. Improvements of histological findings of MDS as well as anemia were confirmed by bone marrow aspiration in July 2003. This is an unusual case of a patient with a previously existing MDS, who subsequently develops end stage renal disease, and has an amelioration of her underlying MDS with the administration of epoetin over a long-term period, while being treated with chronic hemodialysis, even when not effective for a short-term.

Erythropoietin↗

Minimal criteria for the diagnosis of megaloblastic anaemia of pregnancy.

The routine examination of buffy coat films is a valuable diagnostic aid to screening large numbers of specimens of blood and is applicable to hospital and general practice, provided that a bottle of sequestrinated venous blood can be examined in the laboratory within 24 hours.The diagnosis of folic-acid deficiency anaemia of pregnancy can be made, in many cases, before the appearance of megaloblasts in the peripheral blood by finding macrocytes, polylobing of polymorphonuclear leucocytes, and ;out of step' haemoglobinization of normoblasts in the buffy coat film. Accurate haemoglobin estimations at intervals throughout pregnancy, and particularly in the last three months, are an important and in some cases essential part of ante-natal care. Any haemoglobin found to be below 75% (11.1 g.%) should be followed by the examination of a series of buffy coat films while the anaemia is being treated.

Anemia↗

Acidosis and severe megaloblastic anaemia.

Ten patients with severe megaloblastic anaemia were studied to investigate whether the causative metabolic defects might predispose them to lactic or other acidosis. One patient had compensated acidosis with hyperlactataemia before treatment but there were obvious causes other than anaemia. No other patient developed an acidosis. Neither anaemia per se nor the metabolic defects of vitamin B(12) or folic acid deficiency are likely to cause clinically significant lactic acidosis or hyperlactataemia.

Acidosis↗