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N Howell

Publications and source records attributed to N Howell.

At least 55 records · Page 3Linked to original sources
PubMed1995

Leber hereditary optic neuropathy. Electron microscopy and molecular genetic analysis of a case.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder characterized by bilateral central visual loss typically in early adulthood. Few histopathologic studies, including ultrastructural and molecular genetic analysis, have been reported. METHODS: Ocular tissue was obtained postmortem from an 81-year-old woman with LHON from the Queensland 1 pedigree characterized by mutations at nucleotide positions 4160 and 14484. Routine histopathologic studies, electron microscopy, electron-probe analysis, and molecular genetic analysis were performed. RESULTS: Marked atrophy of the nerve fiber and retinal ganglion cell layers and optic nerves was present. Results of electron microscopic examination demonstrated 1.2 microns electron-dense, double-membrane-bound inclusions, consisting of calcium by electron-probe analysis, in retinal ganglion cells. The optic nerve was homoplasmic for mutations 4160 and 14484. CONCLUSION: Optic nerve and inner retinal atrophy in LHON may be a result of metabolic mitochondrial dysfunction leading to intramitochondrial calcification. Homoplasmy for mitochondrial mutations 4160 and 14484 in the leukocyte/platelet fraction of whole blood may correlate with homoplasmy in the optic nerve.

Aged↗
PubMed1995

Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees.

The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well-supported phylogenetic cluster that apparently arose 60,000 to 100,000 years ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.

Animals↗
PubMed1994

Tobacco amblyopia.

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Alcohol Drinking↗
PubMed1994

Comparison of quality of life in hemodialysis and peritoneal dialysis patients.

This study was designed to compare severity of illness and quality of life variables in chronic peritoneal dialysis (PD) and hemodialysis (HD) patients. The patient sample consisted of 63 PD patients (38 male, 25 female; mean age 54.5 years) and 35 HD patients (23 male, 12 female; mean age 54.9 years). Disease severity was greater in in-center HD patients than in PD patients (p < 0.008), although there were no significant differences in functional status as measured by the Karnofsky Index between HD patients (68.6 +/- 2.3) and PD patients (71.9 +/- 1.7). While both patient groups reported the same number of overall physical symptoms. HD patients reported significantly greater overall discomfort from symptoms than PD patients (p < 0.008). In terms of psychological adjustment, analyses revealed that 22 PD patients (36.7%) and 9 HD patients (25.7%) were classified as clinically depressed. PD patients reported higher anxiety scores than HD patients (p < 0.02) and lower positive mood scores (p < 0.021). HD patients were more severely ill and appeared to suffer from physical symptomatology to a greater degree than PD patients, although they were not more impaired in terms of functional status. Moreover, HD patients showed better psychological adjustment along several dimensions when compared to PD patients. One reason for this finding may be that PD patients experience greater distress, and isolation due to a lack of social support from similar others and medical staff in comparison to in-center HD patients.

Female↗
PubMed1993

Electrochemical and spectral analysis of the long-range interactions between the Qo and Qi sites and the heme prosthetic groups in ubiquinol-cytochrome c oxidoreductase.

The results are presented of an electrochemical and high-resolution spectral analysis of the heme prosthetic groups in the bc1 complex from mouse cells. To study the long-range interactions between the Qo and Qi quinone redox sites and the b heme groups, we analyzed the effects on the proximal and distal b heme groups, and the c1 heme, of inhibitors that tightly and specifically bind to the Qi or Qo redox site. A number of results emerged from these studies. (1) There is inhomogeneous broadening of the b heme alpha band absorption spectra. Furthermore, contrary to the conclusion from low-resolution spectral analysis, the higher energy transition in the split-alpha band spectrum of the bL heme is more intense than the lower energy transition. (2) Inhibitors that bind at the Qi site have significant effects upon the electronic environment of the distal bL heme. Conversely, Qo site inhibitors induced changes in the electronic environment of the distal bH heme. (3) In contrast, inhibitor binding at either site has little effect upon the midpoint potential of the distal heme. (4) Experiments in which both a Qi and a Qo inhibitor are bound at the redox sites indicate that the long-range effects of one inhibitor are not blocked by the second inhibitor; enhanced effects are often observed. (5) In the double-inhibitor titrations involving the Qo inhibitor myxothiazol, there is evidence for two electrochemically and spectrally distinct species of the bL heme group, a phenomenon not observed previously. (6) The high-resolution deconvolutions of alpha band absorption spectra allow an interpretation of these inhibitor-induced changes in terms of homogeneous broadening, inhomogeneous broadening, and changes in x-y degeneracy. The general conclusion from these experiments is that when an inhibitor binds to a quinone redox site of the cytochrome b protein, it produces local conformational changes that, in turn, are transmitted to distal regions of the protein. The ligation of the bH and bL hemes between two parallel transmembrane helices provides a mechanism by which long-distance interactions can be propagated. The lack of long-range effects upon the midpoint potentials of the heme groups suggests, however, that protein conformational changes are unlikely to be a major control mechanism for the transmembrane electron- and proton-transfer steps of the Q cycle.

Animals↗
PubMed1993

Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. A potential disease mechanism.

A patient with a mitochondrial myopathy and biochemically proven profound complex I deficiency has a new mutation in mtDNA. This A-to-G transition at position 3302, involving the aminoacyl stem of tRNA(Leu(UUR)), is associated with abnormal mitochondrial RNA processing. Northern analysis demonstrates marked accumulation of a polycistronic RNA precursor containing sequence for 16 S rRNA, tRNA(Leu(UUR)), and ND1. Comparison of skeletal muscle and skin fibroblasts suggests that the processing error may be quantitatively less severe in this tissue, and biochemical analysis shows that fibroblasts do not express a biochemical defect despite containing the mutation. Important qualitative differences in the processing of this RNA precursor were found when comparing muscle and skin fibroblasts. In muscle, processing appears to occur first at the 5'-end of the tRNA, generating 16 S rRNA plus a tRNA + ND1 intermediate. In fibroblasts, processing occurs at the 3'-end of the tRNA, generating a 16 S rRNA + tRNA intermediate. We suggest that the mutation at position 3302 induces abnormal mitochondrial RNA processing that is linked to the biochemical defect (profound loss of complex I activity), either by qualitative or quantitative abnormalities in the ND1 message. The restriction to skeletal muscle of both the processing error and the biochemical defect suggests that the observed tissue differences in RNA processing play a protective role in skin fibroblasts.

Adult↗
PubMed1993

Sequence analysis of mitochondrial chloramphenicol resistance mutations in Chinese hamster cells.

A series of mitochondrially inherited chloramphenicol-resistant (CAP-R) mutants were isolated in Chinese hamster cells. To determine whether the Chinese hamster CAP-R mutations were homologous to those isolated in mouse and human cell culture systems, we determined the nucleotide sequence of the region of the mitochondrial 16S rRNA gene spanning the peptidyl transferase-encoding region for eight CAP-R mutant lines in addition to the parental wild-type line. Three main conclusions are drawn from these studies. (1) Although the region of the gene encoding the peptidyl transferase domain is highly conserved relative to that of mice and rats, the contiguous sequences show less conservation. This sequence divergence not only includes the accumulation of single base pair replacements, but also the presence of small insertions or deletions. (2) For six of the CAP-R mutants, heteroplasmic single base pair changes were detected. These mapped to the same sites within the peptidyl transferase domain as the mutations found previously in mouse and human CAP-R mutants. (3) Two Chinese hamster CAP-R mutants, both with an unusual drug resistance phenotype, did not carry any mutations within the CAP-R peptidyl transferase domain. However, both carried a heteroplasmic mutation at the position corresponding to nucleotide 2505 of the mouse 16S rRNA gene, a site predicted to map within a stem/loop structure attached to this key domain of the ribosome. This is the first evidence for mitochondrial CAP-R mutations that map outside the peptidyl transferase region.

Animals↗
PubMed1993

Pulse intravenous calcitriol therapy of secondary hyperparathyroidism in peritoneal dialysis patients.

This study was undertaken to evaluate high-dose intravenous (IV) calcitriol therapy in chronic peritoneal dialysis (PD) patients. Nine stable chronic PD patients (7 male, 2 female, mean age 54 years) with secondary hyperparathyroidism and a mean duration of PD of 33 months, were studied for 6 months. Pulse calcitriol was administered IV in dosages of 4-8 micrograms every 2 weeks. Eight patients received oral calcitriol prior to IV pulse. Five patients were on continuous ambulatory peritoneal dialysis, and 4 patients were on continuous cycling peritoneal dialysis. Seven patients were on low-calcium dialysate (2.5 mEq/L) and 2 on high-calcium dialysate (3.5 mEq/L). All patients received calcium acetate or calcium carbonate to control hyperphosphatemia during the study. Mean serum parathyroid hormone N-terminal (PTHN) levels (35.4 +/- 9.5 pg/mL) decreased significantly from premean serum PTHN levels (79.7 +/- 10.4 pg/mL). No significant changes were observed in premean serum total calcium, ionized calcium, and phosphorus levels and posttherapy levels. No correlation was observed between serum PTHN and serum calcium, 1,25(OH)2D3, serum aluminum, and duration of dialysis. No significant difference in total body calcium and total body bone mineral density (BMD) was observed between pre and post study periods. In conclusion, biweekly IV calcitriol therapy is effective in suppressing secondary hyperparathyroidism in PD patients.

Adult↗
PubMed1992

Low calcium (2.5 mEq/l) and high calcium (3.5 mEq/l) dialysate in peritoneal dialysis patients.

STUDY OBJECTIVE: To compare the effects of low-calcium and high-calcium dialysate in stable ESRD patients on peritoneal dialysis (PD). DESIGN: Dialysate containing 2.5 mEq/l and 3.5 mEq/l calcium in combination with oral calcium salts as phosphate binders were evaluated. SETTING: Tertiary-referral university hospital. PATIENTS AND METHODS: Fifteen patients (6 male, 9 female) on low-calcium (2.5 mEq/l) and 15 patients (6 male, 9 female) on high-calcium (3.5 mEq/l) dialysate were studied for 6 months. All patients received calcium acetate or calcium carbonate to control hyperphosphatemia before the study. RESULTS: Serum calcium, phosphorus and albumin did not differ before and after between the two groups. Three patients in low-calcium and five in high-calcium group developed hypercalcemia. Three in low-calcium group and four in high-calcium group required sucralfate to control hyperphosphatemia and hypercalcemia. Mean dose of elemental calcium was 1152 mg/day in low-calcium group and 790 mg/day in high-calcium group. A negative correlation (r = -0.82, p < 0.005) was observed between serum calcium and PTH at the end of study period in the low-calcium group. No such relationship was observed in the high-calcium group. CONCLUSIONS: Degree and frequency of hypercalcemia appeared similar with low-calcium and high-calcium dialysate in peritoneal dialysis patients.

Calcium↗
PubMed1992

A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology.

The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON). The risk of developing the optic neuropathy shows strict maternal inheritance, and the ophthalmological changes in affected family members are characteristic of LHON. However, in contrast to the common form of the disease, members of these two families show a high frequency of vision recovery. To ascertain the mitochondrial genetic etiology of the LHON in these families, both (a) the the nucleotide sequences of the seven mitochondrial genes encoding subunits of respiratory-chain complex I and (b) the mitochondrial cytochrome b gene were determined for representatives of both families. Neither family carries any of the previously identified primary mitochondrial LHON mutations: ND4/11778, ND1/3460, or ND1/4160. Instead, both LHON families carry multiple nucleotide changes in the mitochondrial complex I genes, which produce conservative amino acid changes. From the available sequence data, it is inferred that the Vic2 and Tas2 LHON families are phylogenetically related to each other and to a cluster of LHON families in which mutations in the mitochondrial cytochrome b gene have been hypothesized to play a primary etiological role. However, sequencing analysis establishes that the Vic2 and Tas2 LHON families do not carry these cytochrome b mutations. There are two hypotheses to account for the unusual mitochondrial genetic etiology of the LHON in the Tas2 and Vic2 LHON families. One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses. Alternatively, the disease in these families may result from the cumulative effects of multiple secondary LHON mutations that have less severe phenotypic consequences.

Adolescent↗
PubMed1991

Multiple defects of the mitochondrial respiratory chain in a mitochondrial encephalopathy (MERRF): a clinical, biochemical and molecular study.

We describe a young man with a progressive neurological disorder including myoclonus, mental retardation, muscle weakness and a mitochondrial myopathy (myoclonus epilepsy and ragged red fibres--MERRF). Multiple abnormalities of the mitochondrial respiratory chain in skeletal muscle are shown by direct measurement of the flux through the individual complexes, low-temperature redox spectroscopy and decreased immunodetectable subunits of complexes I and IV by immunoblotting. No abnormality of mitochondrial DNA was found. This is the first report of combined defects of complexes I, III and IV as a cause of this clinical syndrome. However, we propose that the occurrence of multiple respiratory chain defects may be more common than previously recognised and that this particular combination of defects, involving complexes I, III and IV, may be the predominant biochemical abnormality in MERRF.

Adult↗