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Biomedical subjects

P E Hart

Publications and source records attributed to P E Hart.

16 recordsLinked to original sources
PubMed2001

Silver syndrome is not linked to any of the previously established autosomal dominant hereditary spastic paraplegia loci.

The hereditary spastic paraplegias are a clinically variable and genetically heterogeneous group of disorders characterized by progressive and lower limb spasticity and weakness. Silver syndrome (SS) is a particularly disabling autosomal dominant form of the disease in which there is associated wasting of the hand muscles. In view of the fact that genes for hereditary spastic paraplegia can produce highly variable phenotypes, the eight known autosomal dominant loci were investigated for linkage to Silver syndrome. Genotyping of these loci in two large multigenerational families was incompatible with linkage to any of these regions, suggesting that an additional locus is responsible for this syndrome.

Adult↗
PubMed2001

The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype.

The hereditary spastic paraplegias (HSPs) are a complex group of neurodegenerative disorders characterized by lower-limb spasticity and weakness. Silver syndrome (SS) is a particularly disabling dominantly inherited form of HSP, complicated by amyotrophy of the hand muscles. Having excluded the multiple known HSP loci, we undertook a genomewide screen for linkage of SS in one large multigenerational family, which revealed evidence for linkage of the SS locus, which we have designated "SPG17," to chromosome 11q12-q14. Haplotype construction and analysis of recombination events permitted the minimal interval defining SPG17 to be refined to approximately 13 cM, flanked by markers D11S1765 and D11S4136. SS in a second family was not linked to SPG17, demonstrating further genetic heterogeneity in HSP, even within this clinically distinct subtype.

Adolescent↗
PubMed2001

Characterization of the X-linked murine centrin Cetn2 gene.

A multi-gene family (Cetn1, Cetn2, and Cetn3) encodes the calcium-binding protein, centrin, in the mouse. This work characterizes the Cetn2 gene. Structurally, Cetn2 consists of five exons and four introns, and contains a classical TATA-less promoter. Cetn2 has two alternate transcription start sites, and a single length 3' untranslated region. Fluorescence in situ hybridization demonstrates that Cetn2 is an X-linked gene whose alleles replicate asynchronously during S-phase. Cetn2 encodes a 172 amino acid protein, with a predicted molecular mass of 19,795 Da (pI=4.71), that contains all of the defining characteristics of centrin. Northern blot analysis indicates that Cetn2 is ubiquitously expressed in the tissues of adult mice. RT-PCR shows that Cetn2 and Cetn3, but not Cetn1, are expressed in NIH 3T3 cells. Immunofluorescence microscopy demonstrates that mouse centrin 2 protein localizes to the region immediately surrounding the centrioles in the centrosome of NIH 3T3 cells.

3T3 Cells↗
PubMed2001

Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia.

Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease-modifying strategy in this neurodegenerative disorder.

Adolescent↗
PubMed2000

Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse.

Huntington's disease is a progressive neurodegenerative disease caused by an abnormally expanded (>36) CAG repeat within the ITI5 gene encoding a widely expressed 349-kd protein, huntingtin. The medium spiny neurons of the caudate preferentially degenerate in Huntington's disease, with the presence of neuronal intranuclear inclusions. Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease; the recently described mitochondrial respiratory chain and aconitase defects in Huntington's disease brain are consistent with this hypothesis. A transgenic mouse model (R6/2) of Huntington's disease develops a movement disorder, muscle wasting, and premature death at about 14 to 16 weeks. Selective neuronal death in these mice is not seen until 14 weeks. Biochemical analysis of R6/2 mouse brain at 12 weeks demonstrated a significant reduction in aconitase and mitochondrial complex IV activities in the striatum and a decrease in complex IV activity in the cerebral cortex. Increased immunostaining for inducible nitric oxide synthase and nitrotyrosine was seen in the transgenic mouse model but not control mouse brains. These results extend the parallels between Huntington's disease and the transgenic mouse model to biochemical events and suggest complex IV deficiency and elevated nitric oxide and superoxide radical generation precede neuronal death in the R6/2 mouse and contribute to pathogenesis.

Animals↗
PubMed2000

Control of development and motility in the spermatozoids of lower plants.

The spermatozoids of lower plants have long been recognized as remarkably complex motile gametes. Spermatozoids differ markedly from the other gametophyte cells that surround or give rise to them. Their differentiation process involves the synthesis and assembly of a complex cytoskeleton and a motile apparatus that can be simple or complex, having as few as two to as many as thousands of ciliary axonemes. An important aspect of spermiogenesis involves the de novo synthesis of basal bodies in a cytoplasmic particle known as the blepharoplast: that is, the cells that produce spermatocytes do not contain centrioles. Thus, these cells provide an ideal system in which to study the formation of basal bodies. The cytoskeletons of spermatozoids from different organisms display a common architecture, with a multilayered structure (MLS) at the anterior end of the cell and a dorsally situated planar ribbon of crosslinked microtubules extending the length of the elongated gamete. The function of the MLS is not known, but it could be involved in cell-body elongation during development and in the control of ciliary motility in the mature gamete, particularly during chemotaxis. The application of modern techniques on these cells can shed light on long-standing problems relating to spermiogenesis and motility.

Cell Movement↗
PubMed1999

Testis-specific murine centrin, Cetn1: genomic characterization and evidence for retroposition of a gene encoding a centrosome protein.

Centrin is a centrosome component in species from yeast to humans. Here, the mouse centrin 1 gene (Cetn1) is analyzed with respect to its genomic structure, chromosome localization, tissue-specific expression, and phylogenetic relationship to the other mouse centrin genes and their human orthologs. Cetn1 is an intronless gene located on chromosome 18A2 that encodes a 172-amino-acid protein with a predicted molecular mass of 19,696 Da (pI 4.61) and all of the structural features common to centrin. Cetn1 possesses the sequence features of an expressed retroposon: the gene lacks introns, the open reading frame is not interrupted by stop codons, and the coding region is flanked by a pair of direct repeats. Reverse transcriptase-polymerase chain reaction and Northern blot analysis demonstrate that Cetn1 expression is limited exclusively to the testis in adult male mice. Cetn1 expression is first seen in the neonatal testis at 14 days postpartum, reaching adult levels by day 17. These observations provide new insight into the regulation, function, and evolutionary history of centrin in higher eukaryotes.

Amino Acid Sequence↗
PubMed1999

Molecular cloning of a centrin homolog from Marsilea vestita and evidence for its translational control during spermiogenesis.

Spermiogenesis in the water fern Marsilea vestita is a process that reaches completion 11 h after dry microspores are immersed in an aqueous medium at 20 degrees C. Each microspore produces 32 spermatozoids and each spermatozoid has a coiled cell body and approximately 140 cilia. The spermatids make basal bodies de novo, from a structure known as a blepharoplast. From the onset of development, the spores contain a large quantity of protein and stored mRNA. We have found previously that centrin, a protein involved in the function of microtubule organizing centers and present in association with basal bodies in motile cells, is made in large quantity approximately 4 h after the microspores are placed into liquid medium. In this paper, we show that a centrin cDNA (MvCen1) we isolated from M. vestita closely resembles centrin cDNAs from other eukaryotic organisms. MvCen1, synthesized in Escherichia coli as a GST-fusion protein, reacted with anti-centrin monoclonal antibodies on immunoblots. Northern blot analysis demonstrates that centrin mRNA is present in the dry microspore at the time of imbibition, at levels that remain constant over 10 h of development and are unaffected by treatment of spores with alpha-amanitin. The centrin transcripts, stored in dry microspores, cannot be translated in vitro for at least 30 min after imbibition.

Amino Acid Sequence↗
PubMed1998

Spermiogenesis in Marsilea vestita: a temporal correlation between centrin expression and blepharoplast differentiation.

The motile male gamete of the water fern Marsilea vestita is a spirally shaped cell that possesses a complex cytoskeletal array of microtubules and approximately 140 cilia. Spermiogenesis in this organism is a rapid process that requires only approximately 11 h at 20 degrees C and involves the de novo synthesis of basal bodies from an organelle known as a blepharoplast. The developmental program that gives rise to the spermatozoids begins with nine mitotic divisions that occur in rapid succession during the first 5.5 h after imbibition of the dry microspore. During the next 5.5 h, the spermatids undergo a complicated differentiation process. We have asked what new proteins must be made for differentiation to proceed. Inhibitor treatments reveal that some translation is a necessary prerequisite for the differentiation and release of spermatozoids, but methionine-labeling studies demonstrate that relatively few types of proteins must be translated for this developmental program to reach completion. We have found that the dry microspores contain alpha-, beta-, and gamma-tubulin, at levels that may be sufficient for the entire developmental process. The abundance of the tubulins remains essentially constant until very late stages of spermiogenesis. In contrast to the tubulins, we show that centrin begins to increase in abundance at approximately 4 h after imbibition and that it reaches a peak at 6 h after imbibition. We also show that centrin mRNA is stored in the dry microspore, and that centrin protein abundance is regulated at the translational level. We believe that the translation of stored centrin transcripts serves as a rate-limiting step in the rapid differentiation process of spermiogenesis M. vestita. We suggest that centrin functions in the microtubule organizing centers that are required for the construction of the cytoskeleton and the motile apparatus in these structurally complicated cells.

Amanitins↗
PubMed1996

Cutaneous and pharyngeal diphtheria imported from the Indian subcontinent.

We report the case of a 32-year-old woman who presented upon returning from India with cutaneous ulcers on the feet and pharyngitis. Microbiological testing showed the causative organism to be a toxigenic strain of Corynebacterium diphtheriae. She was treated successfully with penicillin and diphtheria antitoxin. This case emphasises the importance of maintaining a high index of suspicion for such rare but significant infectious diseases.

Adult↗
PubMed1978

Computerized systems cut dietary department's costs.

The department of dietetics at a large teaching hospital has substantially reduced its food and labor costs through use of computerized systems that ensure efficient inventory management, recipe standardization, ingredient control, quantity and quality control, and identification of productive man-hours and appropriate staffing levels.

Computers↗