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Severe congenital neutropenia with unique features of dysgranulopoiesis.

Congenital dysgranulopietic neutropenia (CDN) is a recently proposed entity that describes a small subgroup of children with clinically severe neutropenia. We followed and studied a 3-year-old girl with neutropenia (less than 500/mm3) and recurrent severe infections in whom repeated marrow evaluations revealed large (30-50 microns) multinucleated promyelocytes to polymorphonuclear cells with as many as 4 to 16 nuclei or nuclear lobes, respectively. In addition to the nuclear endoreduplication, ultrastructural and cytochemical evaluation of these cells demonstrated abnormalities in granule genesis and centriole structure. Concomitantly, immunoperoxidase staining indicated that many of the granules were devoid of lactoferrin but not lysozyme. In vitro proliferation studies revealed normal to increased thymidine labeling, normal numbers of colony-forming cells, and normal colony-stimulating activity from blood and marrow mononuclear cells, findings consistent with ineffective myelopoiesis. However, serum folate, B12, and lysozyme levels were normal. The nuclear and cytoplasmic abnormalities in this patient result in an extreme example of CDN, distinct from previously described cases.

Agranulocytosis↗

Ramsay Hunt syndrome and coeliac disease: a new association?

Two patients with the syndrome of Ramsay Hunt (dyssynergia cerebellaris myoclonica, DCM), associated with malabsorption due to adult coeliac disease, are reported. Both presented with progressive cerebellar ataxia, action myoclonus, and epilepsy. One had gastrointestinal symptoms (recurrent diarrhea and weight loss which responded satisfactorily to a gluten-free diet), but the other did not. In both patients, jejunal biopsy revealed subtotal villous atrophy; serum folate and vitamin E level were also reduced. Neither a gluten-free diet nor vitamin supplements improved the neurological picture. However, some symptomatic relief was afforded by treatment with clonazepam, sodium valproate, carbamazepine, and piracetam. It could be argued that the association between these two disorders is coincidental. However, since we have found this combination in 2 of 14 consecutive cases with DCM, a causal relationship seems likely, although the underlying mechanism remains unknown. Patients with the Ramsay Hunt syndrome should be investigated for malabsorption, and also undergo small intestinal biopsy.

Adult↗

Functional inference of the methylenetetrahydrofolate reductase 677C > T and 1298A > C polymorphisms from a large-scale epidemiological study.

Two functional single nucleotide polymorphisms, 677C > T and 1298A > C have been described for the methylenetetrahydrofolate (MTHFR) gene. Both are associated with reduced enzyme activity in vitro. For the 677T, but not the 1298C allele, significantly lower serum folate and higher plasma total homocysteine (tHcy) have been reported. We genotyped 10,034 middle-aged (50-64 years old) subjects and measured serum folate and tHcy. Within strata of 677 genotypes, 1,298 genotypes had significantly different serum folate and tHcy (P < or = 0.03 for all comparisons). Each additional 1298C allele reduced mean serum folate and increased mean tHcy, by (on average) 4.5 and 3.0%, respectively. In comparison, within strata of 1,298 genotypes, the increase from no, to one 677T-allele reduced serum folate and increased tHcy by, 7.1 and 6.3%, respectively. Lowest serum folate and highest tHcy level was found for the 677TT/1298AA genotype. The difference in tHcy was significantly larger at low folate than at high folate when genotypes 677TT/1298AA and 677CT/1298AA, 677CT/1298AC and 677CC/1298AC, and genotypes 677CT/1298AC and 677CT/1298AA were compared. We interpreted these data in the context of a model of the MTHFR enzyme that describes the enzyme as a dimer that mainly exist in six different configurations. The model reconciled the observed phenotypic effects of the 677/1,298 combination genotypes with previous in vitro measurements, and identified enzyme configurations that are sensitive to low folate levels. In conclusion, this report demonstrates functional inference of the MTHFR 677 C > T and 1,298 A > C polymorphisms from a large-scale epidemiological study.

Adenine Nucleotides↗

The Wechsler subtests in mild organic brain damage associated with folate deficiency.

Forty-nine patients with low serum and cerebrospinal fluid folate levels completed the Ottawa-Wechsler Scale after 7-11 months of folate supplementation (10 mg daily). Twelve patients exhibited major neurological symptoms, while 37 patients displayed depression and minor neurological signs. After folate therapy, Verbal, Performance and Full Wechsler scores were significantly improved (P less than 0.001). The order of improvement in scores on the Wechsler subtests (from the statistically most significant to the least as measured by the t-statistics) was: Block Design, Digit Symbol, Similarities, Picture Completion, Picture Arrangement, Arithmetic, Object Assembly, Digit Span, Information, and Comprehension.

Adult↗

The utility of laboratory screening in medically III patients with psychiatric symptoms.

The presence of psychiatric illness in general hospital medical inpatients can complicate a patient's clinical course. Currently, there is no standard laboratory work-up recommended for this patient population. To begin to assess the utility of a routine panel of tests, the results of serum vitamin B12 (cobalamin) levels, folate levels, thyroid stimulating hormone levels, and syphilis serology of 349 patients were reviewed. These patients had been admitted to the hospital for nonpsychiatric conditions but either had preexisting psychiatric disturbances or developed a mood spectrum disorder or cognitive spectrum disorder during their hospitalization. The incidence of vitamin B12 and folate deficiencies in these patients was found to be higher than has been reported for the general population. Thus, routine screening for these vitamin deficiencies may be indicated because of their prevalence in this patient population.

Adolescent↗

Evaluation of DNA analysis for evidence of apoptosis in megaloblastic anaemia.

This study involved DNA analysis of bone marrow cells of 15 patients with megaloblastic anaemia. The diagnosis was based on the morphological changes seen in the bone marrow, associated with either a low red cell folate or serum vitamin B12 level and an adequate response to appropriate therapy as confirmation of the diagnosis. Flow cytometric DNA analysis showed an increase in the S and G2 phases of the cell cycle, but conventional agarose gel electrophoretic DNA analysis did not confirm the characteristic 'ladder pattern' which might have been expected in classic apoptosis. In addition, cells showing morphological changes suggestive of apoptosis, such as nuclear condensation and fragmentation, did not show evidence of DNA fragmentation using the ApopTag in situ digoxigenin nucleotide labelled, peroxidase detection system. Further studies using annexin V flow cytometric analysis and pulsed field gel electrophoresis were also unable to detect evidence of apoptosis as a significant cause of cell death in megaloblastic anaemia.

Anemia, Megaloblastic↗

Diagnosis of anemia. Clues to greater precision.

Typical features on the blood smear suggest the diagnosis in some types of anemia, such as the common microcytic anemias, megaloblastic anemias, and certain hemolytic anemias. Some laboratory tests used in anemia, particularly measurement of serum vitamin B12 and folate levels, may present problems in interpretation, which must be recognized if diagnostic errors are to be avoided. Normocytic anemias that are nonhemolytic, have no obvious cause, and are characterized by marked red cell changes on the blood smear should prompt careful investigation for malignancy or marrow fibrosis. Anemias are often multifactorial, and the diagnosis must be reevaluated after the apparent contributing causes have been treated. A number of "danger signs" in a patient with anemia point to the need for hematologic consultation.

Anemia↗

Investigation of statistical decision rules for sequential hematologic laboratory tests.

A statistical data processing program for identifying patients who are likely to have abnormalities on various hematologic laboratory tests is described. The prediction of abnormal levels of serum vitamin B12, serum folate, transferrin saturation, and reticulocyte counts is based on a statistical analysis of the patient's age, sex, and routine blood cell measurements. The program was developed using data from normal-value studies and data from patients who had these laboratory abnormalities. The sensitivity and specificity of the program were evaluated in a controlled prospective study of about 5,000 ambulatory adult patients. The program's predictions also were compared with the laboratory tests requested by the patients' attending physicians. The program was most sensitive for predicting low serum vitamin B12 (74%) and low transferrin saturation (78%). In the prospective evaluation, the predictive values varied from 11% for predicting low serum folate to 65% for predicting low transferrin saturation.

Adult↗

Erythrocyte survival in patients with porcine xenograft aortic and mitral valves.

Ten patients with porcine xenograft aortic and mitral valve prostheses were studied three to 36 months (mean 15 months) postoperatively for evidence of hemolysis. Studies included complete blood count, reticulocyte count, red cell indices, percentage of schistocytes on blood smears, bilirubin concentration, lactic dehydrogenase, serum iron, total iron binding capacity, haptoglobin, serum folate and vitamin B12 levels, Coombs' test, methemoglobin reduction test, autologous 51Cr erythrocyte survival, and urinary examination for iron and hemosiderin. All patients were hemodynamically stable. Nine patients had normal valve function and no evidence of hemolysis. One patient with paravalvular aortic regurgitation had mechanical hemolytic anemia with a negative Coombs' test. Porcine valve xenografts do not seem to be associated with hemolysis unless complicated by a paravalvular leak.

Anemia, Hemolytic↗

Excess alcohol consumption is common in patients with cytopenia: studies in blood and bone marrow cells.

BACKGROUND: Although alcohol abuse is known to create a variety of adverse effects on hematopoiesis, the associations between ethanol consumption and hematological abnormalities have not been fully established. METHODS: We studied 144 consecutive adult patients who underwent clinical and bone marrow examinations due to abnormal findings in peripheral blood cell counts or red blood cell indices without previously established diagnoses of specific hematological diseases, malignancies, or infections. Assessment included the amount of alcohol consumption, complete blood cell counts, morphological review of peripheral blood and bone marrow, markers of liver status, and erythrocyte folate and serum vitamin B12 levels. RESULTS: There were 57 (40%) patients who showed a history of hazardous drinking and 87 patients who were either nondrinkers or social drinkers. The incidence of anemia was 51% in the alcohol abusers, as compared with 69% of the nonalcoholics (p < 0.05). A diverse pattern of hematological effects was observed in the alcohol abusers. Abnormal platelet and leukocyte levels were common, especially in the anemic alcoholics. Both increased mean cell volume of erythrocytes (macrocytosis; 67 vs. 18%; p < 0.0001) and mean cell hemoglobin (63 vs. 22%; p < 0.0001) were more frequent in the alcoholics than in the nonalcoholics. Reticulocytosis (37%), thrombocytopenia (41%), and combined cytopenias (34-38%) were also common findings in the alcoholic patients. The blood smears from such patients typically showed round macrocytes, stomatocytes, and knizocytes. Bone marrow aspirates revealed vacuolization of pronormoblasts in 24% of the alcoholic patients. Interestingly, megakaryocytes in the cell periphery were also vacuolized in 20% of the alcohol abusers, especially in those with recent intoxication. CONCLUSIONS: Our findings suggest that alcohol abuse results in diverse patterns of hematological effects and affects several cell lines. Therefore, in patients undergoing bone marrow examinations due to cytopenias, the probabilities for likely findings seem to be different between alcoholics and nonalcoholics. Information on ethanol consumption should be systematically included in the clinical assessment of such patients.

Adult↗

Intestinal folate absorption in methotrexate treated psoriatic patients.

Thirty-one psoriatic patients 14 of whom were being treated with methotrexate (MTX), participated in a controlled study to evaluate the influence of MTX therapy on the intestinal absorption of folate. Low serum and red cell folate levels in the MTX treated group confirmed previously reported findings. However, analysis of the intestinal absorption profile yielded no significant difference between the two groups. It was concluded that MTX therapy for psoriasis does not adversely affect the intestinal absorption of folate and the observed low body folate status is probably mainly the result of enhanced renal excretion.

Adult↗

Chronic bullous dermatosis of childhood--clinical and immunological features seen in African patients.

During the period 1985-88, 30 children with a chronic blistering dermatosis were studied. Of these 25 were found to have chronic bullous dermatosis of childhood (CBDC) and five had bullous pemphigoid (BP). No case of dermatitis herpetiformis (DH) was seen in the same period. Except for the difference in immunofluorescence (IMF) there were no definite clinical, histological or therapeutic differences between the two groups. All the children were Africans with the exception of one Indian girl. Their ages ranged from 1 year to 12 years with a mean of 5 years. The females outnumbered the males in a ratio of 3:2. All children had a generalized eruption consisting of large tense blisters arising on normal skin. The blisters were more profuse on the lower trunk, pelvic region and limbs. Face and scalp were also affected. Histological features of BP and DH were seen. Direct IMF in the CBDC patients showed linear deposits of IgA at the basement membrane zone (BMZ) while linear deposits of IgG were seen in the BP group. Complement and IgM were also seen in some cases in both groups. Sixty per cent of the CBDC patients showed IgA BMZ antibodies by indirect IMF. There were no symptoms or signs of malabsorption. Serum vitamin B12 and folate levels were normal. HLA studies showed the B-8 antigen in five of the 20 patients studied. Therapy was difficult in most cases. All patients haemolysed on therapeutic doses of dapsone, sulphapyridine and/or prednisone had to be added. Follow-up was generally poor as six patients failed to return after discharge from hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗

A method for performing deoxyuridine suppression tests on microtitre plates.

A method of performing deoxyuridine suppression tests on bone marrow cells using microtitre plates is described. The geometric mean and 95% reference interval derived from 19 patients with normoblastic erythropoiesis and normal levels of serum B12 and folate were, respectively, 5.1 and 2.0-12.8%. In 70 deoxyuridine suppression tests on 60 patients, the correlation between the results from the conventional tube test and the plate method was good, r = 0.9, P less than 0.001, and replicate tests with both techniques showed equal degrees of precision. The microtitre plate method uses fewer cells and is easier to perform than the tube method: thus each test may be performed in triplicate, and additional investigations carried out on cells obtained from a single marrow aspiration. We conclude that the microtitre plate method of performing a deoxyuridine suppression test is useful for both diagnostic and research purposes.

Bone Marrow Cells↗

Folic acid absorption in patients infected with the human immunodeficiency virus.

To determine the folic acid absorption characteristics of patients with human immunodeficiency virus (HIV) infection, a prospective, controlled, result-blind single-dose oral absorption study was conducted. A total of 25 subjects were fasted and given 5 mg oral folic acid; blood samples were taken at time zero and after 30, 60, 90 and 180 min. Absorption of folic acid appears to be significantly impaired in HIV disease, irrespective of the stage of the disease and notwithstanding gastro-intestinal complaints, pathogen-negative diarrhoea or drug treatment. We here present functional data, complementary to previously reported structural and biochemical findings, to support the hypothesis that the virus can cause an enteropathy in the absence of opportunist infection. Folinic acid is absorbed by the same gut mechanism as folic acid, so caution may be needed when employing oral folinic acid rescue procedures in these patients, even when resting serum and red cell folate levels appear to be normal.

Absorption↗

Pregnancy and the risk of teratogenicity.

One in every 250 newborns is exposed to antiepileptic drugs (AEDs) in utero. Various studies have attributed a teratogenic effect to these AEDs, mainly consisting of major malformations, minor anomalies, intrauterine or postnatal growth failure, and psychomotor retardation. Prospective studies confirm the increased risk of major malformations. The absolute risk of 7-10% is about 3-5% higher than that in the general population. Barbiturates and phenytoin (PHT) are particularly associated with congenital heart malformations, facial clefts, and some other malformations. Valproate (VPA) and carbamazepine (CBZ) are associated predominantly with spina bifida aperta (1-2 and 0.5-1.0% risk, respectively) and hypospadias. Bilateral radial aplasia is a rare but specific effect of VPA. Several studies identified additional risk factors, i.e., high daily AED dosage, high maternal serum AED concentrations, low folate levels, or polytherapy [phenobarbital (PB) plus primidone (PRM) plus PHT or CBZ plus VPA plus PB with or without PHT]. The few prospective studies controlled for socioeconomic factors or that considered parental findings indicate that risk of specific cognitive defects rather than risk of overall mental retardation may be increased, that early growth retardation is followed by a catch-up growth to normal, and that ocular hypertelorism and nail hypoplasia are the only minor anomalies causally related to PHT exposure. However, no final conclusions can be made. Genetic predisposition to the teratogenic side effects of AEDs plays a role, codetermining the recurrence risk if the woman has previously given birth to a child with a major malformation. The molecular genetic basis of this predisposition is unclear.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗

Effects of topical and systemic folic acid supplementation on gingivitis in pregnancy.

A double-blind study evaluated the effects of systemic and topical folate on gingival inflammation during the fourth and eighth months of pregnancy. Thirty women were randomly divided into three groups. Group A received placebo mouthwash and tablets; Group B; placebo mouthwash and 5 mg folate tablets; Group C: folate mouthwash and placebo tablets. Supplementation lasted for 14 days during months 4 and 8. Subjects took one tablet daily and rinsed twice daily for 1 min with the mouthwash. At the start and finish of each 14-day period, fasting serum and red cell folate levels were estimated and oral status assessed by a plaque index (P1I), a gingival index (GI), and gingival exudate flow meter (GEF). Subjects completed 1-week diet sheets which were analysed for dietary folate. All groups were similar in each parameter at the start. Correlation was demonstrated between GI and P1I, and between GI and GEF. GI tended to increase throughout pregnancy in all groups except Group C, when in the eighth month there was a highly significant improvement (0.001 less than P 0.01) despite no significant change in P1I. Although dietary intake of folate was significantly higher during the eighth month in Group C as compared with Groups A and B, (0.001 less than P less than 0.01), the folate mouthwash produced highly significantly improvement in gingival health in pregnancy.

Administration, Oral↗

Megaloblastic anemia and immune abnormalities in a patient with methionine synthase deficiency.

We report a case of methionine synthase deficiency associated with cellular immune deficiency discovered in a 14-year-old boy. Principal findings were: developmental delay, recurrent upper and lower respiratory tract infections, megaloblastic anemia, discovered at 3 months of age, unresponsive to cyanocobalamin and poorly responsive to folinic acid. Biochemical studies showed: an abnormal deoxyuridine suppression test despite normal serum folate, cobalamin and transcobalamin levels; a normal intracellular uptake of these two coenzymes; and an absolute requirement of methionine for fibroblast growth, suggestive of defective methionine synthesis. An absence of methionine synthase activity in the patient's bone marrow and a profound depression of this activity in lymphocytes and liver were found. Hypergammaglobulinemia with variable lymphopenia, depressed lymphocyte transformation after lectin or recall-antigen stimulation, defective delayed-type hypersensitivity and decreased natural killer activity were noted as well. The patient died at the age of 14.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

Folate deficiency after anticonvulsant drugs: an effect of hepatic enzyme induction?

Serum and red cell folate levels were reduced in 59% and 58% respectively of 75 children with epilepsy attending a residential school. The degree of folate deficiency was significantly related to increased hepatic microsomal enzyme activity, assessed from increased urinary excretion of D-glucaric acid and also correlated with the daily dose of anticonvulsant taken. Anticonvulsant drugs are known to have inducing properties, and since folate is required as a cofactor in drug hydroxylations it is suggested that folate depletion results from increased demand for the cofactor after induction of drug-metabolizing enzymes. As folate deficiency may ultimately limit drug metabolism this hypothesis would explain why blood phenytoin levels decrease and fit control may worsen after correction of folate deficiency in epileptic patients.

Adipates↗