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Biomedical subjects

R H Edwards

Publications and source records attributed to R H Edwards.

At least 127 records · Page 7Linked to original sources
PubMed1994

Magnetic resonance relaxation time mapping in multiple sclerosis: normal appearing white matter and the "invisible" lesion load.

Prolonged T1 and/or T2 relaxation times (RT) in the normal appearing white matter (NAWM) of patients with multiple sclerosis (MS) have been attributed either to a diffuse abnormality, or to "small lesions" undetected by visual inspection of conventional MR images. In a comparison of brain slices from five MS patients and five healthy control subjects, we have confirmed that the average T1 and T2 RTs obtained from NAWM in patients with MS are significantly prolonged (p < .04). Quantitative pixel-by-pixel mapping shows that this overall prolongation is due to the averaging of RTs from two subfractions of NAWM. In all patients a proportion (average 54% for T1 and 63% for T2) of the total white matter pixel sample from each MR brain slice had RT values indistinguishable from those found in the white matter of matched healthy control subjects (i.e., "normal normal appearing white matter," NNAWM). Scattered throughout the NAWM were multiple small areas, often of only one or two pixels, with abnormal RT values. These lesions, which were revealed only by pixel-by-pixel mapping of RT, made up a significant proportion (average 47% for T1 or 57% for T2 estimates) of the total (visible plus "invisible") lesion load per slice, and of the NAWM (average 36% for T1, 27% for T2), with wide interpatient variability. Further studies of these minute lesions are required to determine their total volume in the brain, their precise nature, evolution and relevance to the functional deficit in MS.

Brain↗
PubMed1994

The differential response of chronic fatigue, neurotic and muscular dystrophy patients to experimental psychological stress.

A group of patients suffering from chronic fatigue (CF) attending a medical clinic were compared with a group of muscular dystrophy (MD) patients from the same clinic and a psychiatric control (PC) group who were attending a psychiatric unit. A checklist was used to assess the patients' subjective physical and psychological state before and after exposure to a psychological stressor. For both physical and psychological symptoms the CF group had the largest response, the PC group was intermediate, and the MD group had the least response. Explanations may involve physiological arousal and attentional focusing.

Adaptation, Psychological↗
PubMed1994

Preferential localization of a vesicular monoamine transporter to dense core vesicles in PC12 cells.

Neurons and endocrine cells have two types of secretory vesicle that undergo regulated exocytosis. Large dense core vesicles (LDCVs) store neural peptides whereas small clear synaptic vesicles store classical neurotransmitters such as acetylcholine, gamma-aminobutyric acid (GABA), glycine, and glutamate. However, monoamines differ from other classical transmitters and have been reported to appear in both LDCVs and smaller vesicles. To localize the transporter that packages monoamines into secretory vesicles, we have raised antibodies to a COOH-terminal sequence from the vesicular amine transporter expressed in the adrenal gland (VMAT1). Like synaptic vesicle proteins, the transporter occurs in endosomes of transfected CHO cells, accounting for the observed vesicular transport activity. In rat pheochromocytoma PC12 cells, the transporter occurs principally in LDCVs by both immunofluorescence and density gradient centrifugation. Synaptic-like microvesicles in PC12 cells contain relatively little VMAT1. The results appear to account for the storage of monoamines by LDCVs in the adrenal medulla and indicate that VMAT1 provides a novel membrane protein marker unique to LDCVs.

Adrenal Medulla↗
PubMed1994

Sequence variation in the Epstein-Barr virus latent membrane protein 1.

The sequence of the latent membrane protein 1 (LMP-1) gene was analysed in Epstein-Barr virus (EBV) isolates from specific regions representing both type 1 and type 2 EBV. A predominant strain marked by an XhoI restriction enzyme polymorphism (REP) within the LMP-1 gene has been identified in type 1 EBV in nasopharyngeal carcinoma (NPC) from Southern China. This polymorphism was also present in type 2 EBV in NPC from Alaska. In this study, the sequence of the LMP-1 gene was determined in these samples representing type 1 and type 2 EBV and was compared with the prototype lymphoid strains. Consistent nucleotide variation in the amino terminus of LMP-1 was identified in strains marked by the XhoI REP. These changes were present in both EBV type 1 and type 2 strains. Three types of sequence variation were detected in the carboxy terminus of LMP-1. The LMP-1 sequences differed in the number of an 11 amino acid repeat element. In the prototype EBV type 1 (B95-8) sequence and in the type 1 Raji and type 2 HR-1 strains, the third repeat element contained an insertion of 5 amino acids that were also the first five unique amino acids after the last partial repeat element. The third variation was a deletion of amino acids 343 to 352 of the B95-8 LMP-1. This deletion was detected in the type 1 Chinese EBV strains, but was not detected in the type 2 Alaskan strains although the Chinese and Alaskan strains have nearly identical amino acid changes at the amino terminus. Numerous other amino acid changes were detected in the carboxy terminus which did not cosegregate with either EBV type, amino acid changes in the amino terminus, or specific geographic regions. These data indicate that EBV strains can be distinguished by sequence differences within LMP-1 and that unlike the divergence between type 1 and type 2 EBV in Epstein-Barr nuclear antigen sequences, different EBV types are nearly identical in LMP-1 sequence.

Amino Acid Sequence↗
PubMed1994

Alterations of the p53 gene in Epstein-Barr virus-associated immunodeficiency-related lymphomas.

Mutations of the p53 tumor suppressor gene are among the most common genetic alterations found in many different human malignancies, including those of the colon, lung, and breast. Alterations in wild-type p53 lead to loss of the suppressor function and thus contribute to tumorigenesis. The potential role of p53 mutations in a sampling of B-cell lymphomas, the majority of which were associated with Epstein-Barr virus (EBV), was investigated. Twenty-six biopsy specimens from immunocompromised patients, including allograft recipients and patients with AIDS, Wiscott-Aldrich syndrome, and human T-cell leukemia virus type 1 infection, in comparison with three Burkitt lymphomas and four Burkitt lymphoma cell lines were analyzed. Mutation in p53 was detected in all four Burkitt lymphoma cell lines as well as the three Burkitt lymphoma biopsy specimens. In patients with AIDS, 5 of 10 lymphomas were EBV positive, and 1 had a mutation in p53. Mutation in p53 was not detected in 14 EBV-positive lymphomas which arose in transplant recipients. These data indicate that with the exception of Burkitt lymphomas, p53 mutations are not involved in the majority EBV-positive B-cell lymphomas which develop in immunocompromised patients.

Alleles↗
PubMed1994

Respiratory effort perception at rest and during carbon dioxide rebreathing in patients with dystrophia myotonica.

BACKGROUND: Breathlessness appears to be closely related to the perception of the outgoing motor command to breathe and should be increased in the presence of muscle weakness. However, breathlessness is not a common symptom in patients with chronic muscle disease who have weak respiratory muscles. The factors that determine the perception of respiratory effort in such patients have not been examined. METHODS: The inspiratory effort sensation during resting breathing and progressive hypercapnia was investigated in 12 patients with dystrophia myotonica with weak respiratory muscles (nine men and three women of mean (SD) age 41.1 (10.5) years; maximum inspiratory pressure 43.1 (17.2) cm H2O) and an age and sex matched control group of normal subjects of mean age 39.6 (10.6) years and a maximum inspiratory pressure of 123 (15.2) cm H2O. RESULTS: During resting breathing with a mouthpiece no differences were seen in inspiratory effort sensation, mouth occlusion pressure, or tidal volume, but inspiratory time and cycle duration were significantly shorter in the patients with dystrophia. Minute ventilation (VE) was significantly higher in the patients (15.8 (4.0) l/min v 12.5 (2.6) l/min), while resting breathing was no more variable in the patients than in controls. The ventilatory response to carbon dioxide (VE/PCO2) was not significantly lower in the patients (14.9 (6.9) l/min/kPa) than in the controls (17.4 (4.3) l/min/kPa). Effort sensation responses to carbon dioxide driven breathing were similar in the control subjects and the patients. With regression analysis of pooled data neither maximum inspiratory pressure nor disease state contributed to perceived inspiratory effort during hypercapnia. CONCLUSIONS: Moderately severe global respiratory muscle weakness does not appear to influence the ventilatory response to rising carbon dioxide tension or the perception of inspiratory effort in patients with dystrophia myotonica.

Adult↗
PubMed1994

Release of creatine kinase and prostaglandin E2 from regenerating skeletal muscle fibers.

To study the effect of regeneration on the release of creatine kinase (CK) and prostaglandin E2 from muscle, extensor digitorum longus muscles of mice were injected with 50 microliters of BaCl2 solution in saline (1.2% wt/vol). Injected muscles showed almost complete degeneration at 3 days postinjection but had regenerated to approximately the same fiber cross-sectional area as contralateral control muscles by 12 days postinjection. These muscles released reduced amounts of intracellular CK compared with contralateral control muscles in response to excessive isometric contractile activity or treatment with the calcium ionophore A-23187 (20 microM) in vitro. However, regenerating muscles contained a lower total CK activity than contralateral control muscles, which accounted for the reduced CK efflux after experimental damage. Regenerating muscles released an increased amount of prostaglandin E2 compared with control muscles after both damaging stimuli. We conclude that regenerated muscles show no reduced susceptibility to contraction-induced damage (as assessed by CK release) but show an elevated release of prostaglandin E2 in response to contractile activity or an increase in intracellular calcium.

Animals↗
PubMed1994

Estimation of fetal volume by magnetic resonance imaging and stereology.

The current methods to monitor fetal growth in utero are based on ultrasound image measurements which, lacking a proper sampling methodology, may be biased to unknown degrees. The Cavalieri method of stereology guarantees the accurate estimation of the volume of an arbitrary object from a few systematic sections. Non-invasive scanning methods, and magnetic resonance imaging (MRI) in particular, are valuable tools to provide the necessary sections, and therefore offer interesting possibilities for unbiased quantification. This paper describes how to estimate fetal volume in utero with a coefficient of error of less than 5% in less than 5 min, from three or four properly sampled MRI scans. MRI was chosen because it does not use ionizing radiations on the one hand, and it offers a good image quality on the other. The impact of potential sources of bias such as fetal motion, chemical shift and partial voluming artefacts is discussed. The methods are illustrated on four subjects monitored between weeks 28 and 40 of gestation.

Adult↗
PubMed1994

Immunohistochemical and biochemical indicators of muscle damage in vitro: the stability of control muscle and the effects of dinitrophenol and calcium ionophore.

The biochemical, histological and ultrastructural effects of 2,4-dinitrophenol and the calcium ionophore, A23187, on rat soleus muscle incubated in vitro have been examined to test the hypothesis that immunohistochemical techniques can be used to recognize early structural features of fibre damage. In control muscles, despite mild glycogen depletion and a mild reduction in protein synthetic rate in the central portion of the muscle, fibres throughout the muscle appear to be viable with normal cytoskeletal and contractile protein architecture, normal concentrations of high energy phosphates and no creatine kinase efflux. Dinitrophenol causes rapid creatine kinase efflux, extensive loss of immunolabelling for desmin and dystrophin, and abnormal myosin immunolabelling. Creatine kinase efflux and the changes in desmin and dystrophin are reduced by the exclusion of calcium. A23187 causes more gradual creatine kinase efflux associated with changes in myosin immunolabelling, but loss of desmin and dystrophin immunolabelling is restricted to a few of the most peripheral fibres. The results suggest that immunohistochemical methods can be used to reveal differences in the intracellular mechanisms of muscle damage. Although both dinitrophenol and A23187 may act, in part, through calcium-mediated processes, their effects on cytoskeletal proteins differ. Creatine kinase efflux after A23187 may not be due to gross sarcolemmal damage.

2,4-Dinitrophenol↗
PubMed1993

bcl-2 inhibits death of central neural cells induced by multiple agents.

The protooncogene bcl-2, which has been implicated in B-cell lymphoma development, inhibits apoptosis due to growth factor withdrawal in some, but not all, hematopoietic cells. Recently we found that bcl-2 also inhibits apoptosis in PC12 pheochromocytoma cells. We now report that bcl-2 inhibits the death of a central neural cell line due to serum and growth factor withdrawal, the calcium ionophore A23187, glucose withdrawal, membrane peroxidation, and, in some cases, free radical-induced damage. This broad range of protective effects of BCL-2 protein suggests that BCL-2 may interact with a central step in neural cell death. Measurements of intracellular free calcium suggest that BCL-2 alters the transduction of neural death signals at a point distal to the rise in intracellular free calcium.

Animals↗
PubMed1993

Reserpine binding to a vesicular amine transporter expressed in Chinese hamster ovary fibroblasts.

The potent antihypertensive drug reserpine inhibits the transport of biogenic amines into adrenal chromaffin granules and synaptic vesicles. Reserpine acts by binding almost irreversibly to the vesicular amine transporter, and this interaction has been used both to study the mechanism of transport and to purify the protein responsible. Recent isolation of a cDNA for the rat chromaffin granule amine transporter (CGAT) by selection in the neurotoxin 1-methyl-4-phenylpyridinium now permits an analysis of the interaction with reserpine at a molecular level. Using membranes from stable transformants expressing the transporter, we show that reserpine binds specifically and quantitatively to CGAT. As with the native protein in bovine chromaffin granules, a pH gradient accelerates reserpine binding, and amine substrates compete for binding with reserpine. However, 1-methyl-4-phenylpyridinium and tetrabenazine, the other principal inhibitor of vesicular amine transport, compete very poorly with reserpine for binding, suggesting that they interact with CGAT at distinct sites.

1-Methyl-4-phenylpyridinium↗
PubMed1993

Muscle histopathology and physiology in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is characterized by fatigue at rest which is made worse by exercise. Previous biopsy studies on small numbers of CFS patients have shown a range of morphological changes to which have been attributed fatigue and myalgia. We have now studied 108 patients with CFS or muscle pain and 22 normal volunteers by light and electron microscopy. There was no consistent correlation between symptoms and changes in fibre type prevalence, fibre size, degenerative or regenerative features, glycogen depletion, or mitochondrial abnormalities. Physiological contractile properties of quadriceps (maximal isometric force generation, frequency: force characteristics and relaxation rate) were also examined before and for up to 48 hours after a symptom-limited incremental cycle ergometer exercise test in 12 CFS patients and 12 normal volunteers. Voluntary and stimulated force characteristics were normal at rest and during recovery. Exercise duration was similar in the two groups although CFS patients had higher perceived exertion scores in relation to heart rate during exercise, indicating a reduced effort sensation threshold. On physiological and pathological grounds it is clear that CFS is not a myopathy. Psychological/psychiatric factors appear to be of greater importance in this condition.

Adolescent↗
PubMed1993

Neural degeneration and the transport of neurotransmitters.

A number of neurodegenerative diseases selectively affect distinct neuronal populations, but the mechanisms responsible for selective cell vulnerability have generally remained unclear. The toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces the selective degeneration of dopaminergic neurons in the substantia nigra characteristic of Parkinson's disease. The plasma membrane dopamine transporter mediates this selective toxicity through accumulation of the active metabolite N-methyl-4-phenylpyridinium (MPP+). In contrast, the vesicular amine transporter protects against this form of injury by sequestering the toxin from its primary site of action in mitochondria. Together with the identification of defects in glutamate transport from patients with amyotrophic lateral sclerosis, these observations suggest that neurotransmitter transport may have a major role in neurodegenerative disease. The recent cloning of cDNAs encoding these transport proteins will help to explore this hypothesis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Chromosomal localization of the human vesicular amine transporter genes.

The physiologic and behavioral effects of pharmacologic agents that interfere with the transport of monoamine neurotransmitters into vesicles suggest that vesicular amine transport may contribute to human neuropsychiatric disease. To determine whether an alteration in the genes that encode vesicular amine transport contributes to the inherited component of these disorders, we have isolated a human cDNA for the brain transporter and localized the human vesicular amine transporter genes. The human brain synaptic vesicle amine transporter (SVAT) shows unexpected conservation with rat SVAT in the regions that diverge extensively between rat SVAT and the rat adrenal chromaffin granule amine transporter (CGAT). Using the cloned sequences with a panel of mouse-human hybrids and in situ hybridization for regional localization, the adrenal CGAT gene (or VAT1) maps to human chromosome 8p21.3 and the brain SVAT gene (or VAT2) maps to chromosome 10q25. Both of these sites occur very close to if not within previously described deletions that produce severe but viable phenotypes.

Adrenal Glands↗
PubMed1993

McArdle's disease: a nonsense mutation in exon 1 of the muscle glycogen phosphorylase gene explains some but not all cases.

McArdle's disease is an inherited disease that results from a lack of functional muscle glycogen phosphorylase. We report here the identification of a C to T transition in exon 1 of the muscle phosphorylase gene found in all patients studied. This base pair mutation results in the substitution of a stop codon (TGA) for the codon (CGA) for Arg49 in the mature protein, and generates a novel restriction site for NlaIII. Of sixteen McArdle's patients, ten are homozygous for this mutation; the remainder are heterozygous. Additional unidentified mutations must lead to the McArdle's phenotype in the latter group of patients.

Base Sequence↗
PubMed1993

Unbiased estimation of human body composition by the Cavalieri method using magnetic resonance imaging.

The classical methods for estimating the volume of human body compartments in vivo (e.g. skin-fold thickness for fat, radioisotope counting for different compartments, etc.) are generally indirect and rely on essentially empirical relationships--hence they are biased to unknown degrees. The advent of modern non-invasive scanning techniques, such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) is now widening the scope of volume quantification, especially in combination with stereological methods. Apart from its superior soft tissue contrast, MRI enjoys the distinct advantage of not using ionizing radiations. By a proper landmarking and control of the scanner couch, an adult male volunteer was scanned exhaustively into parallel systematic MR 'sections'. Four compartments were defined, namely bone, muscle, organs and fat (which included the skin), and their corresponding volumes were easily and efficiently estimated by the Cavalieri method: the total section area of a compartment times the section interval estimates the volume of the compartment without bias. Formulae and nomograms are given to predict the errors and to optimize the design. To estimate an individual's muscle volume with a 5% coefficient of error, 10 sections and less than 10 min point counting (to estimate the relevant section areas) are required. Bone and fat require about twice as much work. To estimate the mean muscle volume of a population with the same error contribution, from a random sample of six subjects, the workload per subject can be divided by square root of 6, namely 4 min per subject. For a given number of sections planimetry would be as accurate but far more time consuming than point counting.

Body Composition↗
PubMed1993

The protooncogene bcl-2 inhibits apoptosis in PC12 cells.

During development, many neuronal populations undergo a process of normal, programmed cell death, or apoptosis. Trophic factors regulate this process, but the mechanism by which they suppress apoptosis remains unclear. In the immune system, recent studies have implicated the protooncogene bcl-2 in the lymphocyte survival response to growth factors. To determine whether a similar survival pathway exists in a neuroendocrine cell type, we have expressed bcl-2 in the rat pheochromocytoma PC12 cell line and found that it abrogates the requirement for stimulation by growth factors to survive. bcl-2 expression also substantially delays the onset of injury by the calcium ionophore A23187.

Animals↗