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R J Smith

Publications and source records attributed to R J Smith.

At least 181 records · Page 10Linked to original sources
PubMed1997

New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of prelingual inherited hearing impairment. A small consanguineous family with this disorder was ascertained through the Institute of Basic Medical Sciences in Madras, India. Conditions such as rubella, prematurity, drug use during pregnancy, perinatal trauma, and meningitis were eliminated by history. Audiometry was performed to confirm severe-to-profound hearing impairment in affected persons. After excluding linkage to known DFNB genes, two genomic DNA pools, one from the affected persons and the other from their non-affected siblings and the parents, were used to screen 165 polymorphic markers evenly spaced across the autosomal human genome. Two regions showing homozygosity-by-descent in the affected siblings were identified on chromosomes 3q21.3-q25.2 and 19p13.3-p13.1, identifying one (or possibly both) as the site of a novel ARNSHL gene.

Algorithms↗
PubMed1997

Linkage analysis of progressive hearing loss in five extended families maps the DFNA2 gene to a 1.25-Mb region on chromosome 1p.

Thus far, 13 genes for autosomal dominant hearing loss have been localized to specific chromosomal regions, but none of the genes has been cloned. Only a single family has been linked to each of these loci, with the exception of DFNA2. DFNA2 was originally mapped in two extended families originating from Indonesia and the United States. In this study we report linkage to DFNA2 in three additional large families with autosomal dominant hearing loss from Belgium and The Netherlands. These five DFNA2 families show a similar progressive sensorineural hearing loss, starting in the high frequencies and also affecting the middle and low frequencies later in life. Combining the information from all linked families, the candidate region that is most likely to contain the DFNA2 gene was reduced to a 1.25-Mb region between markers D1S432 and MYCL1. Different haplotypes segregating with the hearing loss were found in all five families, suggesting that different mutations are present in the same gene. These results indicate that DFNA2 is most likely an important gene for autosomal dominant hearing loss.

Alleles↗
PubMed1997

Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells.

The stimulation of phosphatidylinositol (PI) 3-kinase by insulin-like growth factor I (IGF-I) in L6 cultured skeletal muscle cells is inhibited by the glucocorticoid dexamethasone. The objective of this study was to investigate the mechanism of dexamethasone action by determining its effects on the expression of the p85alpha and p85beta regulatory subunit isoforms of PI 3-kinase, their coupling with the p110 catalytic subunit, and their association with insulin receptor substrate 1 (IRS-1) in response to IGF-I stimulation. Dexamethasone induced a 300% increase in p85alpha protein content in the L6 cultured myoblast cell line, whereas it increased p110 content by only 38% and had no effect on p85beta. The increase in p85alpha protein was associated with a coordinate increase in p85alpha mRNA. Stimulation with IGF-I induced the association of p85alpha and p85beta with IRS-1, and this was accompanied by increased amounts of the p110 catalytic subunit and markedly increased PI 3-kinase activity in IRS-1 immunoprecipitates. In cells treated with dexamethasone, greater amounts of p85alpha and lower amounts of p85beta, respectively, were found in IRS-1 immunoprecipitates, such that the alpha/beta ratio was markedly higher than in control cells. In spite of the increase in both total and IRS-1-associated p85alpha following dexamethasone treatment, IRS-1-associated p110 catalytic subunit and PI 3-kinase activity were decreased by approximately 50%. Thus, dexamethasone induces a specific increase in expression of the p85alpha regulatory subunit that is not associated with a coordinate increase in the p110 catalytic subunit of PI 3-kinase. As a consequence, in dexamethasone-treated cells, p85alpha that is not coupled with p110 competes with both p85alpha.p110 and p85beta.p110 complexes for association with IRS-1, leading to increased p85alpha but decreased p85beta, p110, and PI 3-kinase activity in IRS-1 immunoprecipitates.

Animals↗
PubMed1997

The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts.

To identify receptor-associated proteins that may contribute to the specificity of insulin and IGF-I signaling responses, a mouse embryo library was screened using the yeast two-hybrid system. Multiple receptor-interactive clones encoding the SH2 domain of the adapter protein Grb10 were isolated. Subsequent cloning of the full-length Grb10 sequence from a mouse fat cDNA library defined a previously unknown Grb10 variant, that appears to be the predominant isoform in mouse tissues. Receptor-deficient R- cells (fibroblasts from mice with homologous disruption of the IGF-I receptor gene) and transfected R- cells expressing either insulin receptors (R-IR cells) or IGF-I receptors (R+ cells) were used to investigate the specificity of Grb10 interaction with the two related receptors. Hormone-activated insulin receptors in R-IR cells coprecipitated with three species, all recognized as Grb10 isoforms by specific Grb10 antibody. Under the same conditions, Grb10 was essentially undetectable in IGF-I receptor immunoprecipitates from stimulated R+ cells. Grb10 association with insulin receptors was maximal at 10 nM insulin stimulation and sustained from 5-10 min after hormone stimulation in R-IR cells. In conclusion, Grb10 interacts preferentially with insulin vs. IGF-I receptors in intact cells and, thus, may have a role in mediating insulin receptor-specific cellular responses.

Animals↗
PubMed1997

The gene for Pendred syndrome is located between D7S501 and D7S692 in a 1.7-cM region on chromosome 7q.

Pendred syndrome is an autosomal recessive disorder characterized by goiter and congenital deafness. The primary defect is not yet known, although the gene causing Pendred syndrome has been localized very recently on chromosome 7q, a region that also contains a gene responsible for nonsyndromal hearing loss (DFNB4). We confirmed linkage to this chromosome 7 region in five Pendred families originating from different ethnic groups, with a highest cumulative lod score of 8.26 for marker D7S501. In combination with previous reports, our results define a candidate region for the Pendred gene of 1.7 cM flanked by markers D7S501 and D7S692.

Chromosome Mapping↗
PubMed1997

Body mass in comparative primatology.

Data are presented on adult body mass for 230 of 249 primate species, based on a review of the literature and previously unpublished data. The issues involved in collecting data on adult body mass are discussed, including the definition of adults, the effects of habitat and pregnancy, the strategy for pooling data on single species from multiple studies, and use of an appropriate number of significant figures. An analysis of variability in body mass indicates that the coefficient of variation for body mass increases with increasing species mean mass. Evaluation of several previous body mass reviews reveals a number of shortcomings with data that have been used often in comparative studies.

Adult↗
PubMed1997

Tissue-specific effects of chronic dietary protein restriction and gastrostomy on the insulin-like growth factor-I pathway in the liver and colon of adult rats.

Dietary protein restriction decreases plasma concentrations of insulin-like growth factor-I (IGF-I) and reduces IGF-I mRNA levels in the liver. In addition to the actions of systemic IGF-I, locally produced IGF-I is thought to mediate autocrine and paracrine growth effects in the colon. The objectives of the present study were to investigate the IGF-I pathway in the colon and liver of adult rats under conditions of dietary protein restriction, surgical stress, and dietary protein repletion. Two groups of rats were placed on either a 20% or 2% casein diet for 19 days. Two additional groups of rats underwent gastrostomy after a 2% casein diet for 2 weeks, and then were either kept on the 2% casein diet or changed to a 20% casein diet until day 19. Dietary protein restriction reduced plasma concentrations of IGF-I and IGF-binding proteins (IGFBPs) and hepatic IGF-I mRNA content, while increasing colonic IGF-I receptor mRNA. Gastrostomy in protein-depleted animals had no effect on hepatic IGF-I mRNA, but led to a marked increase in colonic IGF-I mRNA levels. Dietary protein repletion resulted in a decrease in colonic IGF-I receptor mRNA. The distinct effects of dietary protein depletion and operative stress on the IGF pathway in the colon as compared with the liver may serve to maintain the level of IGF-I signaling in the colon by autocrine or paracrine mechanisms under these conditions.

Animals↗
PubMed1997

Treatment of massive or life-threatening hemangiomas with recombinant alpha(2a)-interferon.

OBJECTIVE: To assess the response of massive, life-threatening, or function-impairing hemangiomas in pediatric patients receiving daily alpha(2a)-interferon subcutaneously. METHODS: The effect of 3 or more months of subcutaneous alpha(2a)-interferon (3 mU/m2) was prospectively evaluated in 10 patients with hemangiomas necessitating medical intervention. Hemangioma characteristics and extent were initially assessed by radiographic imaging in all but one patient. alpha(2a)-Interferon tolerance was monitored, and reduction in hemangioma size was recorded as marked (>50%), moderate (25% to 50%), or minimal (<25%). RESULTS: Hemangiomas were apparent at birth in 8 of 10 patients, and alpha(2a)-interferon was initiated at a median age of 4.5 months. Symptoms necessitating therapeutic intervention included congestive heart failure, airway obstruction, dysphagia, infection, failure to thrive, external auditory canal occlusion, visual axis impairment, and severe facial deformity. Four patients received treatment before referral that included systemic steroids (n = 2), intralesional steroids (n = 1), or surgical/laser excision (n = 2). alpha(2a)-Interferon therapy was well tolerated. Most patients had a temporary elevation in body temperature during the first month of therapy. One patient with anorexia required nasogastric feedings and a temporary reduction in her alpha(2a)-interferon dose. An additional patient with irritability was withdrawn from the study at his parents' request even though this symptom persisted after drug cessation. Hemangioma response to alpha(2a)-interferon was marked in six patients, moderate in two, and minimal in one whose lesion had features suggestive of a vascular malformation. Early signs of involution were usually evident within 6 weeks and often heralded by cutaneous blanching. alpha(2a)-interferon therapy was concluded in four patients after a mean duration of 20 months. CONCLUSIONS: Daily subcutaneous alpha(2a)-interferon is well tolerated in pediatric patients and appears effective in hastening involution of symptomatic hemangiomas. A significant response is unlikely in lesions with features suggestive of a vascular malformation.

Antineoplastic Agents↗
PubMed1997

Intraoperative diagnosis of primary ciliary dyskinesia.

Primary ciliary dyskinesia refers to clinical disease attributable to congenitally abnormal or absent ciliary motility. Diagnosis typically requires electron microscopy to document aberrant axoneme ultrastructure. Electron microscopy, however, remains inaccurate and Inconvenient as a screening test for symptomatic individuals. To avoid delays in diagnosis and to ensure adequacy of the tissue sample, we recommend a tracheal biopsy with an intraoperative histologic examination of ciliary motion. This study included patients evaluated at our institution for recurrent or chronic upper respiratory conditions characterized by chronic sinusitis, chronic mucoid otitis, and chronic bronchitis. A tracheal mucosa biopsy sample was obtained from each patient and was immediately examined in the operating room using light microscopy. If the magnified image demonstrated normal ciliary motility, primary ciliary dyskinesia was excluded and electron microscopy was not ordered. In the absence of normal ciliary motility, the specimen was placed in glutaraldehyde and ultrastructural axoneme morphology was evaluated. In the last 5 years, we have evaluated ciliary motility in 20 patients. Three patients had abnormal ciliary motility identified by light microscopy, and primary ciliary dyskinesia was confirmed histologically in each patient. In the remaining 17 patients, normal ciliary motility was observed, obviating the need for electron microscopy. We advocate intraoperative microscopic study of ciliary motility as a rapid, simple, accurate, and inexpensive technique to screen patients for primary ciliary dyskinesia.

Adolescent↗
PubMed1997

Growth hormone attenuates early left ventricular remodeling and improves cardiac function in rats with large myocardial infarction.

OBJECTIVES: We sought to investigate the cardiac effects of growth hormone (GH) administration during the early phase of pathologic remodeling in a rat model of large myocardial infarction (MI). BACKGROUND: Recent evidence suggests that exogenous administration of GH evokes a hypertrophic response and increases left ventricular (LV) function in vivo in rats with normal or chronically failing hearts. We hypothesized that these effects would attenuate ventricular remodeling early after MI. METHODS: Fifty-eight male rats underwent sham operation (n = 19) or had induced MI (n = 39). The day after the operation, the infarcted rats were randomized to receive 3 weeks of treatment with GH, 3 mg/kg body weight per day (n = 19) or placebo (n = 20). Echocardiography, catheterization and isolated whole heart preparations were used to define cardiac structure and function. RESULTS: Growth hormone caused hypertrophy of the noninfarcted myocardium in a concentric pattern, as noted by higher echocardiographic relative wall thickness at 3 weeks and by morphometric histologic examination. Left ventricular dilation was reduced in the GH-treated versus placebo group (echocardiographic LV diastolic diameter to body weight ratio 2.9 +/- 0.1 vs. 3.5 +/- 0.2 cm/kg; p < 0.05). In vivo and in vitro cardiac function was improved after GH treatment. Despite elevated insulin-like growth factor-1 (IGF-1) serum levels in GH-treated rats, myocardial IGF-I messenger ribonucleic acid was not different among the three groups, suggesting that an increase in its local expression does not appear necessary to yield the observed effects. CONCLUSIONS: These data demonstrate that early treatment of large MI with GH attenuates the early pathologic LV remodeling and improves LV function.

Animals↗
PubMed1997

PET regional cerebral blood flow change during working and declarative memory: relationship with task performance.

Functional and anatomical relationships between working and declarative memory were investigated by contrasting regional cerebral blood flow (rCBF) change during standard working (Wisconsin Card Sorting Test, WCST) and declarative memory (Paired Associate Recognition Test, PART) tasks using identical stimulus-response modalities. The tasks and a resting baseline were administered to 30 participants (16 men, 14 women) during successive 10-min positron emission tomography 15O-water measures of rCBF. For both tasks, rCBF increased over baseline in inferior frontal and occipitotemporal regions, with more consistent dorsolateral prefrontal activation for WCST than PART. Additional orbitofrontal increases and dorsomedial decreases were seen for the PART. Activation patterns diverged when performance was considered. For the WCST, high performers activated dorsolateral and inferior frontal regions, whereas top PART performers activated only the occipitotemporal region. These results suggest operation of a frontotemporal network subserving both types of memory function that becomes more focal as performance increases.

Adolescent↗
PubMed1997

Hierarchy of SPEA presentation to T cells by mouse MHC haplotypes.

The ability of splenic antigen-presenting cells (APC) from nine independent mouse major histocompatibility complex (MHC) haplotypes to present recombinant streptococcal exotoxin A (rSPEA) to heterogeneous T cells and mouse T cell clones were compared using proliferation assays. We report that there is marked variation between MHC haplotypes, which can be ranked as follows: H2z > H2s = H2f = H2p = H2r = H2k > H2d > H2b = H2q. In some haplotypes both A and E molecules bind rSPEA with low affinity. In addition, we show that presentation is preferentially by E molecules in haplotypes where A and E are coexpressed, but that A alleles also bind and present rSPEA, based on inhibition of responses by anti-E and anti-A mAbs. Furthermore, using strains of mice which fail to express E, we demonstrate that A(s) and Af present rSPEA with high efficiency, whereas Aq and Ab are the least efficient of all haplotypes. The results suggest that there is significant variation in the ability of different alleles of both E and A molecules to bind and present rSPEA.

Animals↗
PubMed1997

A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13, maps to chromosome 6p.

Nonsyndromic hearing loss (NSHL) is the most common type of hearing impairment in the elderly. Environmental and hereditary factors play an etiologic role, although the relative contribution of each is unknown. To date, 39 NSHL genes have been localized. Twelve produce autosomal dominant hearing loss, most frequently postlingual in onset and progressive in nature. We have ascertained a large, multigenerational family in which a gene for autosomal dominant NSHL is segregating. Affected individuals experience progressive hearing loss beginning in the 2d-4th decades, eventually making the use of amplification mandatory. A novel locus, DFNA13, was identified on chromosome 6p; the disease gene maps to a 4-cM interval flanked by D6S1663 and D6S1691, with a maximum two-point LOD score of 6.409 at D6S299.

Adolescent↗
PubMed1997

Imported yellow fever in a United States citizen.

The last imported case of yellow fever seen in this country was in 1924. We report a case of yellow fever acquired by an American tourist who visited the jungles of Brazil along the Rio Negro and Amazon Rivers. The patient died 6 days after hospital admission and 10 days after his first symptoms appeared. Yellow fever virus was recovered from clinical specimens, and the isolate was genetically similar to the E genotype IIB of South American yellow fever viruses. This patient's illness represents a case of vaccine-preventable death since he failed to be immunized with a recommended preexposure yellow fever vaccine.

Animals↗
PubMed1997

Aging, physical activity, insulin-like growth factor I, and body composition in Guatemalan women.

Aging is associated with diminished secretion of growth hormone and the major endogenous mediator of growth hormone action, insulin-like growth factor I (IGF-I). Aging is also associated with decreased physical activity. Alterations in body composition characteristic of the aging process (increased fat mass and decreased lean body mass) may be related to the decline in anabolic effects of IGF-I with aging, decreased physical activity, or both. Guatemalan women often maintain a high level of physical activity during aging. The purpose of this study was to determine whether IGF-I concentrations correlated with physical activity level (determined by standardized scoring of a self-report questionnaire) and body composition (determined by bioelectrical impedance analysis) in elderly Guatemalan women. In 112 women aged 20-87 y, we found a progressively lower serum IGF-I with age (r = -0.732). In subjects > 60 y of age, the self-reported activity level was associated with a lower percentage body fat (P < 0.001) but there was no significant relation between physical activity level and either lean body mass or IGF-I. We conclude that there is a significant age-related decline in serum IGF-I concentrations in Guatemalan women, similar to that observed in both men and women in the United States. An increased level of physical activity in the elderly Guatemalan population was associated with reduced body fat but did not modify the expected reduction in circulating IGF-I concentrations that occurs with aging.

Adult↗
PubMed1997

Value-based pathology: a cost-benefit analysis of the examination of routine and nonroutine tonsil and adenoid specimens.

To study the cost-effectiveness of the histologic examination of tonsil and adenoid specimens, the histologic diagnoses for all routine (2,700) and nonroutine (71) tonsil and adenoid specimens during a 10-year period were reviewed. There were 27 routine cases (1%) and 56 nonroutine cases (79%) with a diagnosis other than normal, tonsillitis, or hyperplasia. Twelve of the 27 routine cases did not have a significant clinical history, and a potentially significant pathologic diagnosis was made in only 6 cases; in none of these cases did the pathologic diagnosis affect patient care. In all nonroutine cases, the pathologic diagnosis affected patient care. The average charge per case to detect potentially significant disease in routine and nonroutine cases was $64,718 and $525, respectively. We conclude that histologic examination of nonroutine cases is cost-effective, whereas in most routine cases with adequate clinical history, histologic examination is not cost-effective.

Adenoidectomy↗