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Biomedical subjects

R Mandell

Publications and source records attributed to R Mandell.

At least 19 recordsLinked to original sources
PubMed2005

Ornithine aminotransferase deficiency: diagnostic difficulties in neonatal presentation.

We describe two unrelated cases of ornithine aminotransferase (OAT) deficiency with rare neonatal presentation of hyperammonaemia. The diagnosis in the neonatal presentation of OAT deficiency is hampered as hyperornithinaemia is absent. Enzyme and mutation studies confirmed the diagnosis. OAT deficiency should be included in differential diagnosis of neonatal hyperammonaemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Inflammation, homocysteine, and vitamin B6 status after ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies have described an association between low vitamin B6 (measured as pyridoxal 5'-phosphate [PLP]) and ischemic stroke, independent of homocysteine (tHcy). We investigated B6 status, tHcy, and inflammation (measured by C-reactive protein [CRP]) in patients with stroke and controls. METHODS: Consecutive cases with new ischemic stroke were compared with matched controls. Fasting tHcy, PLP, and CRP were measured. RESULTS: The adjusted odds ratio of low PLP in the highest compared with the lowest CRP quartile was 16.6 (2, 139.9, P=0.01). Age, CRP, supplemental vitamin use, and albumin were independent predictors of PLP (P<0.05 for all). No relationship was observed between CRP and tHcy. CONCLUSIONS: The relationship between inflammation and low B6 status may partially explain the findings of previous epidemiological studies.

Aged↗
PubMed2003

Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency.

BACKGROUND: Although hyperhomocyst(e)inemia (Hyper-Hcy) may predispose to atherosclerosis and venous thrombosis, the mechanisms of stroke associated with Hyper-Hcy are not defined. METHODS: Clinical and biochemical phenotypes and genetic features of three unrelated patients with premature stroke and severe Hyper-Hcy due to cystathionine beta-synthase (CBS) deficiency are described. Plasma Hcy and amino acids were measured by fluorescence polarization immune assay and ion exchange chromatography. Analysis of the CBS and methylenetetrahydrofolate reductase genes was performed by restriction enzyme digestion and sequence analysis. RESULTS: Two of the three index cases had no known diagnosis of homocystinuria and initially presented with embolic cerebral and retinal infarction in mid-adulthood. Mechanisms of cerebrovascular disease were carotid intraluminal thrombosis, arterial dissection, and possible cardiac embolism. Family screening revealed additional members with clinically silent homocystinuria and severe Hyper-Hcy. Excluding tall stature in two individuals, all had mild phenotypes, without classic findings of CBS deficiency. Plasma total and free Hcy, methionine, and urine Hcy were elevated. Genotyping revealed heterozygous CBS mutations (I278T, D444N, G307S) in affected individuals. CONCLUSION: Artery-to-artery embolism and dissection may cause stroke in young adults with homocystinuria. The results also support a rationale for screening for Hyper-Hcy in young adults with stroke without a phenotype suggestive of classic homocystinuria.

Adolescent↗
PubMed1999

Cystathionine beta-synthase mutations in homocystinuria.

The major cause of homocystinuria is mutation of the gene encoding the enzyme cystathionine beta-synthase (CBS). Deficiency of CBS activity results in elevated levels of homocysteine as well as methionine in plasma and urine and decreased levels of cystathionine and cysteine. Ninety-two different disease-associated mutations have been identified in the CBS gene in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations are missense, and the vast majority of these are private mutations. The two most frequently encountered of these mutations are the pyridoxine-responsive I278T and the pyridoxine-nonresponsive G307S. Mutations due to deaminations of methylcytosines represent 53% of all point substitutions in the coding region of the CBS gene.

CpG Islands↗
PubMed1998

Molecular analysis and prenatal diagnosis of human fumarase deficiency.

Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle causing severe neurological impairment. The cDNA for both the rat and human enzymes has been cloned previously and shown to encode a coding region of 1.46 kb. To scan for mutations in fumarase-deficient patients we amplified the coding region of fumarase from fibroblast/lymphoblast cDNA employing the oligonucleotide primers designed from the published human and rat cDNA sequence. We then directly sequenced the polymerase chain reaction product. In seven unrelated patients, we detected four missense mutations (A265T, D383V, F269C, K187R), a nonsense mutation (W458X), a 3-bp AAA insertion that introduces an additional lysine residue at codon 435, and a spontaneous new mutation resulting in a 74-bp deletion (66del74). Seven at-risk pregnancies were monitored with one prenatal diagnosis of fumarase deficiency by molecular analysis and favorable outcome of the other pregnancies as predicted by enzyme assay of cultured fetal cells or molecular analysis.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Use of amniotic fluid amino acids in prenatal testing for argininosuccinic aciduria and citrullinaemia.

Prenatal testing of 12 pregnancies at risk for argininosuccinic aciduria due to argininosuccinate lyase (ASAL) deficiency and three pregnancies at risk for citrullinaemia due to argininosuccinate synthatase (ASAS) deficiency was performed by metabolite detection in amniotic fluid and measurement of enzyme activity in uncultured and cultured chorionic tissue and in cultured amniocytes. From our data and those of previous studies, amniotic fluid argininosuccinate measurement alone is clearly a reliable and rapid diagnostic test for both severe and mild ASAL deficiency if maternal ASAL deficiency can be excluded. For prenatal diagnosis of ASAS deficiency, however, both measurement of the amniotic fluid citrulline level and enzyme assay should be employed.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype.

Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder characterized by homocystinuria and multisystem clinical disease. Patients responsive to pyridoxine usually have a milder clinical phenotype than do nonresponsive patients, and we studied the molecular pathology of this disorder in an attempt to understand the molecular basis of the clinical variation. We previously reported a T833C transition in exon 8 causing a substitution of threonine for isoleucine at codon 278 (I278T). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-nonresponsive patients. Two pyridoxine-responsive patients are homozygous and five are heterozygous for I278T. We have now observed the I278T mutation in 41% (9 of 22) of the independent alleles in pyridoxine-responsive patients of varied ethnic backgrounds. In two of the compound heterozygotes we identified a novel mutation (G139R and E144K) in the other allele. The finding that the two patients who are homozygous for I278T have only ectopia lentis and mild bone demineralization suggests that this mutation is associated with both in vivo pyridoxine responsiveness and mild clinical disease. Compound heterozygous patients who have one copy of this missense mutation are likely to retain some degree of pyridoxine responsiveness.

Adult↗
PubMed1993

Evidence for cigarette smoking as a major risk factor for periodontitis.

The role of smoking as a risk factor for periodontitis was assessed separately in diabetic and nondiabetic study groups. Subject listings stratified for age (19 to 40 years) and sex were obtained for subjects with insulin-dependent diabetes mellitus (IDDM) and nondiabetic subjects. For both the IDDM group (n = 132) and the nondiabetic group (n = 95), age and sex stratified samples were constructed by random selection of subjects from each subject listing. Patients were recruited by phone, examined, and their medical and dental histories obtained. Among nondiabetic subjects, the prevalence of periodontitis was markedly higher among current smokers compared with never smokers (P < or = 0.005) in both the 19 to 30 year-old (46% vs. 12%) and 31 to 40 year-old groups (88% vs. 33%). The subject mean percent of sites with gingival pocket depth > or = 4 mm was higher among current smokers than never smokers (P = 0.001) in the 19 to 30 (8.2% vs. 3.4%) and 31 to 40 (14.3% vs. 4.3%) age groups. The effects of smoking among IDDM subjects were similar to that observed in the nondiabetic population. There were no differences between current and never smokers in the proportion of sites positive for plaque. Attributable risk percents from prevalence data suggest that among nondiabetic subjects, a large proportion, perhaps as much as 51% of the periodontitis in the 19 to 30 year old group and 32% of the periodontitis in the 31 to 40 year old group, is associated with smoking.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Molybdenum cofactor biosynthesis in humans. Identification of two complementation groups of cofactor-deficient patients and preliminary characterization of a diffusible molybdopterin precursor.

Molybdenum cofactor deficiency is a devastating disease with affected patients displaying the symptoms of a combined deficiency of sulfite oxidase and xanthine dehydrogenase. Because of the extreme lability of the isolated, functional molybdenum cofactor, direct cofactor replacement therapy is not feasible, and a search for stable biosynthetic intermediates was undertaken. From studies of cocultured fibroblasts from affected individuals, two complementation groups were identified. Coculture of group A and group B cells, without heterokaryon formation, led to the appearance of active sulfite oxidase. Use of conditioned media indicated that a relatively stable, diffusible precursor produced by group B cells could be used to repair sulfite oxidase in group A recipient cells. Although the extremely low levels of precursor produced by group B cells preclude its direct characterization, studies with a heterologous, in vitro reconstitution system suggest that the precursor that accumulates in group B cells is the same as a molybdopterin precursor identified in the Neurospora crassa molybdopterin mutant nit-1, and that a converting enzyme is present in group A cells which catalyzes an activation reaction analogous to that of a converting enzyme identified in the Escherichia coli molybdopterin mutant ChlA1.

Cells, Cultured↗
PubMed1989

Age differences in corneal hydration control.

Dynamic changes in corneal thickness were measured in eight young and eight older normal subjects (mean ages 24.4 +/- 4.3 years and 71.9 +/- 7.3 years, respectively) to provide data for quantitative assessment of corneal hydration control and thereby provide information for studying age differences in this important aspect of corneal function. For each subject, pachometry data were obtained by (A) monitoring corneal recovery following hypoxic stress, and by either (B1) measuring recovery after sleep or (B2) by measuring corneal thickness in the late afternoon. The combined data from A and B1 or A and B2 were analyzed through an exponential model to provide information on the: (1) percent recovery per hour (PRPH) following induced corneal hydration; (2) open-eye steady-state (OESS) corneal thickness; (3) residual corneal swelling just before the hypoxic stress test; (4) amount of corneal edema induced by hypoxic stress; and (5) time to reach 95% recovery back to the OESS thickness level (T95%). The results show that between the two age groups, there are substantial differences in some characteristics of corneal hydration while other aspects are similar. For example, the mean PRPH values (58.9 +/- 7.8% and 34.2 +/- 6.4%/hr) were significantly higher in the younger subjects (P = 0.0002) and the mean time for 95% recovery to OESS thickness (207 +/- 42 min and 452 +/- 117 min) was significantly lower in the younger vs. the older group (P = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Molybdenum cofactor deficiency in a patient previously characterized as deficient in sulfite oxidase.

The metabolic status of a patient previously characterized as deficient in sulfite oxidase was reexamined applying new methodology which has been developed to distinguish between a defect specific to the sulfite oxidase protein and sulfite oxidase deficiency which arises as a result of molybdenum cofactor deficiency. Urothione, the metabolic degradation product of the molybdenum cofactor, was undetectable in urine samples from the patient. Analysis of molybdenum cofactor levels in fibroblasts by monitoring reconstitution of apo nitrate reductase in extracts of the Neurospora crassa mutant nit-1 revealed that cells from the patient were severely depleted. Quantitation of urinary oxypurines showed that hypoxanthine and xanthine were highly elevated while uric acid remained in the normal range. These results were interpreted to indicate a severe but incomplete deficiency of the molybdenum cofactor. The presence of very low levels of active cofactor, supporting the synthesis of low levels of active sulfite oxidase and xanthine dehydrogenase, could explain the metabolic patterns of sulfur and purine products and the relatively mild clinical symptoms in this individual.

Cells, Cultured↗
PubMed1988

Clinical results of pericardial xenograft valves: the Ionescu-Shiley and Hancock valves.

Between 1979 and 1985, 552 Ionescu-Shiley valves were implanted in 511 patients. The Hancock valve was implanted in 122 patients (129 valves) between 1982 and 1983. Sixty percent of procedures were isolated aortic valve replacements. In the Ionescu series, 59% of these were 19 or 21 mm valves while only 15% of the Hancock valves were of this size. For isolated mitral valve replacement, 76% of Ionescu-Shiley valves were 25 to 27 mm, compared to 36% of the Hancock valves. Patient age, sex, prior operations, concomitant surgery (usually coronary bypass), operative mortality and late deaths were similar for both valves. A mean follow-up of 38 months was obtained for each valve population (99% complete) representing a cumulative 1497 patient-years for the Ionescu-Shiley valve and 375.4 patient-years for the Hancock valve. Actuarial survival for the former was 73 +/- 4% at 72 months, and 65 +/- 14% for Hancock valves at 60 months. The frequency of major events during follow-up (thromboembolism, anticoagulant related hemorrhage, bland perivalvular leak and prosthetic valve endocarditis) were similar, but the frequency of primary tissue valve failure was markedly different for the two valves (1.1% per patient-year for Ionescu-Shiley valves and 5.9% for the Hancock valve). The mean interval to replacement of an Ionescu mitral prosthesis was significantly shorter (23.4 months) than for replacement of an aortic prosthesis (42 months) while the mean interval to replacement of an Ionescu aortic and/or a Hancock aortic or mitral were all similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1988

Pyridoxine effects on ornithine ketoacid transaminase activity in fibroblasts from carriers of two forms of gyrate atrophy of the choroid and retina.

Gyrate atrophy of the choroid and retina that is due to ornithine ketoacid transaminase (OKT) deficiency is an autosomal recessive disorder. Fibroblasts from heterozygotes for the pyridoxine-responsive variant as well as those for the pyridoxine-nonresponsive variant contain intermediate levels of OKT activity. These two variants can be distinguished by the in vitro responsiveness of OKT activity to pyridoxal phosphate (PLP) stimulation. The ratios of OKT activity at 0.04 mM PLP compared with activity at 0 mM PLP were, respectively, lowest for controls (1.18 +/- 0.18; N = 12), intermediate for pyridoxine-nonresponsive heterozygotes (1.43 +/- 0.26; N = 5), and highest for pyridoxine-responsive heterozygotes (2.20 +/- 0.14; N = 3).

Atrophy↗
PubMed1982

Defective ornithine metabolism in cultured skin fibroblasts from patients with the syndrome of hyperornithinemia, hyperammonemia and homocitrullinuria.

The syndrome of hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) is a metabolic disorder resulting in protein intolerance and mental retardation. The primary metabolic defect has yet to be determined. We studied some aspects of ornithine metabolism in cultured skin fibroblasts from two patients from two patients with the HHH syndrome. The fibroblasts failed to incorporate 14C-label from ornithine into protein, a defect also observed in fibroblasts from patients with gyrate atrophy of the choroid and retina and a deficiency of ornithine aminotransferase activity. The defect can be corrected in heterokaryons formed between these two types of fibroblasts. These findings indicate that fibroblasts are suitable for further studying the underlying metabolic defect in HHH syndrome. The combination of the ornithine incorporation assay and genetic complementation analysis provide a confirmatory test for the diagnosis of this syndrome.

Amino Acid Metabolism, Inborn Errors↗
PubMed1982

Bacteremia caused by Streptococcus pneumoniae of nonvaccine serotypes.

Comparison of serotypes of Streptococcus pneumoniae blood isolates showed a 2.5-fold increase in nonvaccine strains from the Cleveland Veterans Administration Hospital compared with those from other Cleveland area hospitals. Death was more frequently associated with nonvaccine than vaccine serotypes. No patient at any of the hospitals involved in the study received pneumococcal vaccine. This suggests that Cleveland Veterans Administration Hospital represents a unique population of patients within the Cleveland area and emphasizes the need for continued serotyping of blood and body fluid isolates.

Adult↗