PubMed Health⌕ Search

Biomedical subjects

R C Griggs

Publications and source records attributed to R C Griggs.

At least 55 records · Page 3Linked to original sources
PubMed1996

Human IgG production in vivo: determination of synthetic rate by nonradioactive tracer incorporation.

Exposure of Ab-secreting cells to selected hormones, cytokines, and drugs alters the rate of Ig production in vitro. Whether these effects are important clinically is unknown because there are no safe, reproducible, and appropriate techniques for measuring Ig synthesis in vivo. We developed a stable isotope tracer method to measure IgG secretion into plasma. L-[1-13C]Leucine was given as a priming dose followed by a constant i.v. infusion over 8 h. Tracer accrual in IgG, determined by mass spectrometry, was linear from 2 to 8 h of the infusion. The normal rate of IgG synthesis into plasma assessed in 21 healthy subjects was 860 +/- 310 mg/day (mean +/- SD). The synthetic rate measurements were remarkably reproducible (coefficient of variation = 10.5 %). Simultaneous analysis of leucine kinetics allows, for the first time, Ig secretion to be studied in the context of whole body protein economy. IgG secretion into plasma accounts for 0.3% of whole body protein synthesis. Experimental support for a key metabolic assumption, that tracer enrichment in plasma and that at the site of IgG synthesis were similar, came from a comparison of synthetic rates derived from low dose and high dose tracer infusions. Measurement of Ig secretion by tracer incorporation is rapid and reproducible. In contrast to older methods that rely on radioisotope disappearance, the tracer incorporation method is safe for serial measurements in an individual and will be useful for quantitative studies of treatment effects and immune regulation in vivo.

Adult↗
PubMed1996

Opportunities and challenges in academic neurology: report of the Long Range Planning Committee of the American Neurological Association.

By most measures, academic neurology is thriving as never before, yet convening forces are changing the face of academic neurology. This report focuses on changes that academic neurology and the American Neurological Association could undertake to seize new opportunities and resist damaging potential changes. These proposals can be categorized in the following four major goals: (1) enhance the quality of a smaller neurology workforce and augment the recruitment of gifted young neuroscientists into neurology; (2) foster new diversity in neurological investigation, including clinical research in neurology; (3) document the benefits and relative costs of neurological care, in general, and of academic neurology, in particular; and (4) foster the role of neurologists as teachers to medical caregivers at all levels, including medical students, nonneurological house staff, and primary practitioners.

Education, Medical, Graduate↗
PubMed1996

Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by marked inter- and intrafamilial heterogeneity in its clinical expression. The contribution of genetic factors to this variability is not well characterized. We examined the relationship of phenotype to genotype in a clinically and genetically well-defined FSHD population. Quantitative isometric myometry (QMT) scores, normalized for age, gender, and height, were used to quantify disease severity. We found a significant (r = 0.92, p < 0.004) correlation between disease severity and the size of the 4q35-associated deletion. In addition, when relative disease severity of parent-offspring pairs was compared, the offspring were found to be significantly more severely affected (p = 0.011). This generational effect suggests the presence of anticipation in FSHD and raises the possibility of an underlying dynamic mutation.

Adolescent↗
PubMed1996

Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients.

Inclusion body myositis, a chronic inflammatory disorder, is the most common cause of myopathy in adults over the age of 50. Diagnosis is based on clinical features and distinctive morphological findings by both light and electron microscopy. The causes of inclusion body myositis are still unknown. Ultrastructural mitochondrial changes and ragged-red fibers are common in patients with sporadic inclusion body myositis, and multiple [correction of mutiple] mitochondrial DNA (mtDNA) deletions have been reported in 3 such patients, suggesting that mtDNA mutations may have a pathogenetic role. We studied 56 patients with sporadic inclusion body myositis, using a combination of clinical, morphological, biochemical, and molecular genetic analyses to determine the frequency and the distribution of mtDNA deletions. Using the polymerase chain reaction, we found multiple mtDNA deletions in 73% of patients, compared to 40% of normal age-matched control subjects and 47% of disease control subjects. The presence of deletions correlated with morphological evidence of ragged-red, cytochrome c oxidase-negative fibers, and with defects of complexes I and IV of the electron transport chain. Although aging may account for a proportion of mtDNA deletions in patients with sporadic inclusion body myositis and control subjects, mtDNA alterations may be accelerated in sporadic inclusion body myositis.

Adult↗
PubMed1996

End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit.

We describe a congenital myasthenic syndrome associated with severe end-plate (EP) acetylcholine receptor (AChR) deficiency not associated with an EP myopathy, and with evidence of immature AChR, containing the gamma instead of the epsilon subunit (gamma-AChR) at the EPs. Molecular genetic analysis of AChR-subunit genes revealed two mutations in the epsilon-subunit gene: insertion of a thymine after epsilon nucleotide 1101 (epsilon 11O1insT) that generates a nonsense codon directly, and insertion of a guanine after epsilon nucleotide 1293 (epsilon 1293insG) that generates three missense codons followed by a nonsense codon. Each mutation predicts truncation of the epsilon subunit at the level of the long cytoplasmic loop, between the third (M3) and fourth (M4) membrane spanning domains. The propositus' asymptomatic son carries epsilon 1293G, indicating that the two mutations are heteroallelic. Expression of AChR harboring either mutation in human embryonic kidney (HEK) fibroblasts was markedly reduced. Single-channel activity recorded from HEK cells expressing epsilon 11O1insT-AChR was infrequent but resembled activity of wild-type AChR channels in amplitude and open duration. No channel activity could be recorded from HEK cells expressing epsilon 1293insG-AChR. Expression of gamma-AChR at the EPs may serve as the means of phenotypic rescue from potentially fatal nonsense mutations in the epsilon-subunit gene.

Amino Acid Sequence↗
PubMed1996

Sustained myoglobinuria: the presenting manifestation of dermatomyositis.

We describe two patients with sustained myoglobinuria that did not resolve with supportive treatment. After we established a diagnosis of dermatomyositis and started treatment with corticosteroids, there was rapid resolution of the myoglobinuria. Well-documented cases of inflammatory myopathy causing myoglobinuria are rare, but their prompt recognition has important therapeutic implications.

Adult↗
PubMed1996

Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita.

Myotonia, defined as delayed relaxation of muscle after contraction, is seen in a group of genetic disorders that includes autosomal dominant myotonia congenita (Thomsen's disease) and autosomal recessive myotonia congenita (Becker's disease). Both disorders are characterized electrophysiologically by increased excitability of muscle fibers, reflected in clinical myotonia. These diseases are similar except that transient weakness is seen in patients with Becker's, but not Thomsen's disease. Becker's and Thomsen's diseases are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). Genetic screening of a panel of 18 consecutive myotonia congenita (MC) probands for mutation in CLCN1 revealed that a novel Gln-68-Stop nonsense mutation predicts premature truncation of the chloride channel protein. Four previously reported mutations, Arg-894-stop, Arg-338-Gln, Gly-230-Glu, and del 1437-1450, were also noted in our sample set. The Arg-338-Gln and Gly-230-Glu mutations were found in patients with different phenotypes from those of previous reports. Further study of the Arg-338-Gln and Gln-230-Glu alleles may shed light on variable modes of transmission (dominant versus recessive) in different families. Physiologic study of these mutations may lead to better understanding of the pathophysiology of myotonia in these patients and of voltage-gated chloride channel structure/function relationships in skeletal muscles.

Chloride Channels↗
PubMed1995

Scapuloperoneal syndromes. Absence of linkage to the 4q35 FSHD locus.

OBJECTIVE: To investigate whether two forms of the scapuloperoneal syndrome result from genetic defects allelic to facioscapulohumeral dystrophy (FSHD). DESIGN: Two kindreds with scapuloperoneal syndromes underwent clinical, histologic, and electrophysiologic evaluation followed by genetic evaluation with probes closely linked to FSHD. RESULTS: Although the proband in each kindred had facial, scapular stabilizer, and humeral weakness, raising the possibility of FSHD, evaluation of multiple other affected family members showed patterns of involvement that were clinically distinct from typical FSHD. In addition, DNA studies showed no linkage to the 4q35 FSHD locus in either kindred. CONCLUSION: We conclude that these two forms of the scapuloperoneal syndrome are genetically distinct from FSHD.

Adolescent↗
PubMed1995

Effect of prednisone on protein metabolism in Duchenne dystrophy.

Prednisone improves strength in Duchenne dystrophy and changes the natural history of the disease. We studied the in vivo effects of prednisone (0.75 mg.kg-1.day-1) on muscle and whole body protein metabolism in six patients with Duchenne dystrophy and three patients with Becker dystrophy. Patients were admitted to the Clinical Research Center for study and consumed a constant flesh-free diet. Strength was measured by manual and quantitative muscle testing. Fractional muscle protein breakdown was estimated by the ratio of 3-methylhistidine to creatinine excretion determined in three consecutive 24-h urine collections. Whole body protein kinetics were studied in the postabsorptive state using a primed continuous infusion of L-[1-13C]leucine. Fractional muscle protein synthesis was determined from tracer incorporation into noncollagen muscle protein obtained by needle biopsy. After 6-8 wk of prednisone treatment, average muscle strength increased by 15% (P < 0.04), and 24-h creatinine excretion (an index of muscle mass) increased by 21% (P = 0.002). 3-Methylhistidine excretion decreased by 10%, but the change was not statistically significant. The ratio of 3-methylhistidine to creatinine excretion decreased by 26% (P < 0.04). Fractional muscle protein synthesis and whole body protein synthesis and breakdown did not change significantly. We conclude that the beneficial effect of prednisone on strength in Duchenne dystrophy appears to be associated with an increase in muscle mass, which may be mediated by inhibition of muscle proteolysis rather than stimulation of muscle protein synthesis.

Adult↗
PubMed1995

Monozygotic twins with facioscapulohumeral dystrophy (FSHD): implications for genotype/phenotype correlation. FSH-DY Group.

Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant disorder with a characteristic and distinctive distribution of weakness but a high degree of variation in the age of onset and rate of progression. Monozygotic twins provide the opportunity to assess the relative importance of genetic as opposed to nongenetic influences on the course of disease. We have studied three sets of monozygotic twins with FSHD and compared the similarity of their degree of involvement using quantitative studies of individual muscle function. Similar quantitative studies of 59 other subjects with FSHD served as a reference population for contrast with the twin studies. One set of twins was discordant for FSHD, presumably as a reflection of a postzygotic mutation in the affected twin. The other two sets were concordant and both had evidence of autosomal dominantly inherited gene rearrangements. Both sets were similarly affected in terms of age of onset, overall degree of disability, and quantitative tests of muscle, but there were major differences in the symmetry of involvement of specific muscles. Cerebral dominance was not related to asymmetries of involvement. These data suggest age of onset and severity are determined by the gene lesion in FSHD. Other factors may influence the frequently encountered asymmetries in FSHD.

Adult↗
PubMed1994

Dihydropyridine receptor mutations cause hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant skeletal muscle disorder manifested by episodic weakness associated with low serum potassium. Genetic linkage analysis has localized the hypoKPP gene to chromosome 1q31-q32 near a dihydropyridine (DHP) receptor gene. This receptor functions as a voltage-gated calcium channel and is also critical for excitation-contraction coupling in a voltage-sensitive and calcium-independent manner. We have characterized patient-specific DHP receptor mutations in 11 probands of 33 independent hypoKPP kindreds that occur at one of two adjacent nucleotides within the same codon and predict substitution of a highly conserved arginine in the S4 segment of domain 4 with either histidine or glycine. In one kindred, the mutation arose de novo. Taken together, these data establish this DHP receptor as the hypoKPP gene. We are unaware of any other human diseases presently known to result from DHP receptor mutations.

Alleles↗
PubMed1994

Dementia of adult polyglucosan body disease. Evidence of cortical and subcortical dysfunction.

OBJECTIVES: To characterize the dementia associated with adult polyglucosan body disease (APBD) and to correlate the cognitive deficits with abnormalities found on magnetic resonance imaging (MRI). METHODS: Quantitative neuropsychological testing and MRI in one man with APBD and a review of the literature. RESULTS: The dementia of APBD affects cortical and subcortical functions. The cognitive deficits correlate with MRI findings of cortical atrophy and white-matter abnormalities. CONCLUSION: Neuropsychological testing and MRI are helpful in the evaluation of patients with APBD.

Brain Diseases↗
PubMed1994

Plasma exchange and intravenous immunoglobulin treatment of neuromuscular disease.

Removal of immunoglobulin by plasma exchange and administration of immunoglobulin by intravenous infusion each improve selected neuromuscular diseases. Both treatments are expensive and relatively brief in their duration of action, but they benefit both self-limited neuromuscular diseases such as the Guillain-Barré syndrome and acute exacerbations of more chronic neuromuscular diseases including myasthenia gravis and chronic inflammatory demyelinating polyneuropathy. It is likely that plasma exchange acts by removing pathogenic antibodies. The mechanism by which intravenous immunoglobulin acts is less clear. Possibilities include (1) antiidiotypic antibody effect, (2) complement absorption, (3) downregulation of immunoglobulin production, (4) receptor blockade, (5) virus neutralization, (6) enhancement of suppressor cells, and (7) inhibition of lymphocyte proliferation. Although plasma exchange and intravenous immunoglobulin have major side effects, severe reactions are uncommon with plasma exchange and rare with intravenous immunoglobulin. Because of their low incidence of life-threatening complications, both treatments have major appeal to clinicians. Because of their brief action and high cost as well as the uncertainty as to whether either or both should be employed, their role in the therapeutic armamentarium of the neurologist requires further study.

Blood Proteins↗