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Biomedical subjects

R J Smith

Publications and source records attributed to R J Smith.

At least 19 recordsLinked to original sources
PubMed2000

Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23.

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

Alleles↗
PubMed1992

Separation of the enantiomers of some potassium channel activators using an alpha 1-acid glycoprotein column.

The separations of the enantiomers of some 3,4-dihydro-2,2'-dimethyl-2H-1-benzopyrans and a related tetrahydronaphthalene on alpha 1-acid glycoprotein (Chiral-AGP) are presented, together with the results from an investigation of the effects of organic modifier and pH on the separations achieved. The general utility of Chiral-AGP in separating the enantiomers of compounds from this class of antihypertensive agents is demonstrated in this paper.

Antihypertensive Agents↗
PubMed1992

Clinical variability and genetic heterogeneity within the Acadian Usher population.

A number of Usher syndrome (USH) families are found among the French-Acadians living in southwestern Louisiana. These families are descended from a few common ancestors, suggesting that USH may be homogeneous within this ethnic group. However, we report distinct phenotypic variability. Based on differences in psychomotor development and tests of auditory and vestibular function, Acadian individuals with both USH Type 1 and Type 2 can be identified. One additional family, with unusual findings, represents a third clinical phenotype. Linkage data strongly support these clinical observations.

Blindness↗
PubMed1992

Insulin-like growth factor I receptor gene structure.

The insulin-like growth factor I (IGF I) receptor is a tyrosine kinase-containing transmembrane protein that plays an important role in cell growth control. We have isolated and characterized human genomic DNA clones containing the entire coding sequence of the IGF I receptor. Results of restriction analysis and sequencing of multiple overlapping clones were consistent with the existence of a single IGF I receptor gene. The complete receptor coding sequence is contained in 21 exons. There is striking homology with the insulin receptor gene in overall size (approximately 100 kilobases) and in the number and size of individual exons. An exon analogous to the alternatively spliced exon 11 of the insulin receptor gene could not be detected. An alternative internal splice site corresponding to a known alternatively spliced mRNA transcript was shown to be located at the 5' end of exon 14. Knowledge of the structure of the IGF I receptor gene should facilitate further studies on the structural determinants of receptor function, the relationships between insulin and IGF I receptors, and the molecular basis for multiple IGF I receptor species.

Amino Acid Sequence↗
PubMed1992

The glutamate dehydrogenase gene of Clostridium symbiosum. Cloning by polymerase chain reaction, sequence analysis and over-expression in Escherichia coli.

The gene encoding the NAD(+)-dependent glutamate dehydrogenase (GDH) of Clostridium symbiosum was cloned using the polymerase chain reaction (PCR) because it could not be recovered by standard techniques. The nucleotide sequence of the gdh gene was determined and it was overexpressed from the controllable tac promoter in Escherichia coli so that active clostridial GDH represented 20% of total cell protein. The recombinant plasmid complemented the nutritional lesion of an E. coli glutamate auxotroph. There was a marked difference between the nucleotide compositions of the coding region (G + C = 52%) and the flanking sequences (G + C = 30% and 37%). The structural gene encoded a polypeptide of 450 amino acid residues and relative molecular mass (M(r) 49,295 which corresponds to a single subunit of the hexameric enzyme. The DNA-derived amino acid sequence was consistent with a partial sequence from tryptic and cyanogen bromide peptides of the clostridial enzyme. The N-terminal amino acid sequence matched that of the purified protein, indicating that the initiating methionine is removed post-translationally, as in the natural host. The amino acid sequence is similar to those of other bacterial GDHs although it has a Gly-Xaa-Gly-Xaa-Xaa-Ala motif in the NAD(+)-binding domain, which is more typical of the NADP(+)-dependent enzymes. The sequence data now permit a detailed interpretation of the X-ray crystallographic structure of the enzyme and the cloning and expression of the clostridial gene will facilitate site-directed mutagenesis.

Amino Acid Sequence↗
PubMed1992

Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study.

OBJECTIVE: To determine whether glutamine-supplemented parenteral nutrition improves nitrogen retention and reduces hospital morbidity compared with standard parenteral nutrition after bone marrow transplantation. DESIGN: Double-blind, randomized, controlled clinical trial. SETTING: University teaching hospital. PATIENTS: Forty-five adults receiving allogeneic bone marrow transplants for hematologic malignancies. INTERVENTION: Parenteral nutrition was initiated the day after bone marrow transplantation (day 1). The experimental solution was supplemented with L-glutamine (0.57 g/kg body weight per day) and provided estimated requirements for energy and protein. The control solution was a standard, glutamine-free, isonitrogenous, isocaloric formula. MEASUREMENTS: Nitrogen balance was determined between days 4 and 11 in the initial 23 patients. The incidence of clinical infection and microbial colonization, time until bone marrow engraftment, indices of clinical care, and other data related to hospital morbidity were recorded for all patients. RESULTS: The glutamine-supplemented patients (n = 24) were clinically similar to the controls (n = 21) at entry. Nutrient intake was similar in both groups; however, nitrogen balance was improved in the glutamine-supplemented patients relative to the controls (-1.4 +/- 0.5 g/d compared with -4.2 +/- 1.2; P = 0.002). Fewer experimental patients developed clinical infection (three compared with nine in the control group; P = 0.041), and the incidence of microbial colonization was also significantly reduced. Hospital stay was shortened in patients receiving glutamine supplementation (29 +/- 1 d compared with 36 +/- 2 d; P = 0.017). CONCLUSION: Patients receiving glutamine-supplemented parenteral nutrition after bone marrow transplantation had improved nitrogen balance, a diminished incidence of clinical infection, lower rates of microbial colonization, and shortened hospital stay compared with patients receiving standard parenteral nutrition. These effects occurred despite no differences between groups in the incidence of fever, antibiotic requirements, or time to neutrophil engraftment.

Adult↗
PubMed1992

A histologic study of nonmorphogenetic forms of hereditary hearing impairment.

It appears that many forms of syndromic and nonsyndromic hereditary hearing impairment are secondary to either neuroepithelial or cochleosaccular dysfunction. Making this distinction can be difficult in human temporal bone specimens; however, this added knowledge may ultimately provide prognostic and therapeutic information in hearing habilitation. Fundamental studies using animal models of different types of hereditary deafness may also prove useful in this respect.

Adult↗
PubMed1992

Screening audiometry using the high-risk register in a level III nursery.

Several factors, including those in the high-risk register, were studied in 1240 graduates of an intensive care nursery who underwent auditory brain-stem response testing. Univariate analysis, with chi 2 and Fisher's Exact Test, and stepwise logistic regression were used to identify variables associated with auditory brain-stem response outcomes. Results suggest that factors in the high-risk register do not carry equal weight and that universal screening in the intensive care nursery may be preferable.

Apgar Score↗
PubMed1992

Postreceptor events associated with human neutrophil activation by interleukin-8.

Recombinant human monocyte-derived interleukin-8 (IL-8M), recombinant human endothelium-derived IL-8 (IL-8E), and a recombinant human truncated form of IL-8 (IL-8T) stimulated a time-dependent (t 1/2 approximately 2-3 s) and concentration-dependent (0.1-100 nM) release of azurophil (myeloperoxidase) and specific (vitamin B12 binding protein, gelatinase) granule constituents from cytochalasin B-treated human neutrophils (HNs) wherein IL-8T = IL-8M greater than IL-8E. An increase in the cytosolic free calcium concentration ([Ca2+]i) was greater in IL-8T- than in IL-8M- or IL-8E-activated HNs, and IL-8T was more potent than either IL-8M or IL-8E in sequentially desensitizing the HNs to the effects of the other IL-8 forms. IL-8 induced a time- and concentration-dependent (0.1-100 nM) increase in the production of inositol 1,4,5-trisphosphate (IP3) in HNs. U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17- yl]amino]hexyl]-1H-pyrrole-2,5-dione), a potent inhibitor of phospholipase C-catalyzed events in HNs, suppressed IL-8-triggered IP3 production, increased [Ca2+]i and granule exocytosis in HNs. The membrane-associated activity of the alpha and beta subtypes of protein kinase C was significantly enhanced in IL-8-activated cells.

Antibodies↗
PubMed1992

Regulation of glucose kinetics in trauma patients by insulin and glucagon.

The current study was undertaken to evaluate the contribution of insulin and glucagon to regulation of glucose metabolism in man following severe, traumatic injury by manipulating concentrations of insulin and glucagon with infusions of somatostatin. Glucose kinetics were assessed with [U-14C, 6-(3)H]glucose in severely injured patients and compared with data obtained from patients recovering from minor, elective operative procedures. Glucose production was significantly increased in subjects with traumatic injury compared with control subjects (13.0 +/- 0.63 mumol/kg/min v 8.6 +/- 0.27 mumol/kg/min). There was no impairment in glucose oxidation by the injured patients. Modulation of insulin and glucagon with somatostatin indicated that non-insulin-mediated glucose uptake (NIMGU) was significantly elevated in injured patients (12.2 +/- 0.94 mumol/kg/min v 7.4 +/- 0.61 mumol/kg/min). Hepatic glucose output (HGO) in the absence of glucagon was also significantly elevated in injured patients (12.2 +/- 1.20 mumol/kg/min v 5.8 +/- 1.08 mumol/kg/min). Indirect calorimetry showed a 27% increase in resting energy expenditure (REE). Increased protein oxidation accounted for 56% of the increase in REE. Changes in carbohydrate and lipid oxidation accounted for 28% and 15% of the increase in REE. There was no correlation between the injury severity score of the injured patient and the degree of metabolic abnormality. It is concluded from these studies that (1) injured patients have a high rate of glucose turnover in the absence of glucagon and insulin; (2) the reliance on glucose as a source of energy is not diminished in injured subjects; and (3) increases in protein oxidation account for the majority of the increased REE found in injured patients.

Adolescent↗
PubMed1992

Induction of neutral proteinase and prostanoid production in bovine nasal chondrocytes by interleukin-1 and tumor necrosis factor alpha: modulation of these cellular responses by interleukin-6 and platelet-derived growth factor.

We have previously reported that recombinant human interleukin-1 (IL-1) stimulates matrix erosion in bovine nasal cartilage explants (R. J. Smith et al., Inflammation 13, 367-382, 1989). This action of IL-1 is believed to be caused by matrix-degrading neutral proteinases produced by activated chrondrocytes. Accordingly, we investigated the effects of recombinant human interleukin-1 alpha (IL-1 alpha), recombinant human interleukin-1 beta (IL-1 beta), and recombinant human tumor necrosis factor alpha (TNF alpha) on bovine nasal chondrocyte (BNC) responsiveness. IL-1 alpha and IL-1 beta stimulated a time (0-72 hr) and concentration-dependent (0.01-10 ng/ml) production of collagenase, gelatinase, caseinase, and prostaglandin E2 (PGE2) in BNC monolayer cultures. Neutral proteinase and PGE2 production by BNC was also induced by TNF alpha (0.2-200 ng/ml) in a time-dependent (0-72 hr) manner. Recombinant human interleukin-6 (IL-6) caused a concentration-dependent (6-200 ng/ml) potentiation of IL-1-stimulated neutral proteinase and PGE2 production by BNC. However, recombinant human platelet-derived growth factor homodimer BB suppressed BNC responsiveness to IL-1. A recombinant human IL-1 receptor antagonist protein inhibited BNC activation by IL-1 but not TNF alpha.

Animals↗
PubMed1992

Preparation and stability of a radioiodinated pentamidine isethionate analog.

Iodopentamidine isethionate was heated for 70 min with [I-123]- or [I-125]-sodium iodide and ammonium sulphate in the absence of solvent at 140 degrees C. The product, [I-123]- or [I-125]-iodopentamidine isethionate, was purified by ion exchange chromatography. It was stable at room temperature in aqueous solution over several days, in human blood in vitro for at least 24 h (showing no binding to either cells or proteins), in urine over at least 15 h, and during nebulization in both ultrasonic and jet nebulizers.

Aerosols↗
PubMed1992

The duration of orthodontic treatment.

Characteristics of the patient, the treatment plan, and the practitioner's office were examined to evaluate causes for variation in the duration of orthodontic treatment. From six offices 118 patients were evaluated. All patients were treated in a single phase with fixed appliances. Appliances were worn for an average of 23.1 months. The mean duration for offices ranged from 19.4 to 27.9 months. Thirty-eight percent of the patients had extractions, and 32% wore headgear. Fifty percent of the variation in treatment duration among patients was explained by a five-step multiple regression equation. The variables entering this equation were (1) number of extracted premolars, (2) number of broken appointments, (3) pretreatment mandibular plane angle, (4) pretreatment ANB angle, and (5) pretreatment Salzmann Index. Observations within each office suggested that the time spent by individual clinicians in detailed finishing, which would not be detected by measures such as the Salzmann Index, was an important source of unexplained variation in treatment duration.

Adolescent↗
PubMed1992

Cephalometrics of anterior open bite: a receiver operating characteristic (ROC) analysis.

A new approach is presented for the evaluation of cephalometric measurements in which a measurement is considered to be a diagnostic test for the presence or the absence of some component of malocclusion. This approach allows cephalometric measurements to be judged by the criteria that are generally used for clinical diagnostic tests, including determination of sensitivities, specificities, positive and negative predictive values, and, most important, receiver operating characteristic (ROC) curves. In this study, ROC curves are generated for the relationship between several skeletal cephalometric measurements and anterior dental open bite in a sample of 1541 orthodontic patients. The overbite depth indicator is found to be a better diagnostic criterion for the presence of dental open bite than any other commonly used skeletal cephalometric measurement or ratio. ROC curves are of substantial value for evaluating the diagnostic information of cephalometric measurements.

Adolescent↗
PubMed1992

Localization of the gene for branchiootorenal syndrome to chromosome 8q.

Branchiootorenal syndrome is an autosomal dominant disorder that affects an estimated 2% of profoundly deaf children. In addition to hearing impairment, it is characterized by a lop-ear deformity, preauricular pits, branchial cleft sinus tracts, and renal anomalies. The pathogenesis of the disease remains unknown; however, the defective gene has been localized to chromosome 8q by family linkage studies.

Abnormalities, Multiple↗
PubMed1992

Localization of two genes for Usher syndrome type I to chromosome 11.

The Usher syndromes (USH) are autosomal recessive diseases characterized by congenital sensorineural hearing loss and progressive pigmentary retinopathy. While relatively rare in the general population, collectively they account for approximately 6% of the congenitally deaf population. Usher syndrome type II (USH2) has been mapped to chromosome 1q (W. J. Kimberling, M. D. Weston, C. Möller, et al., 1990, Genomics 7: 245-249; R. A. Lewis, B. Otterud, D. Stauffer, et al., 1990, Genomics 7: 250-256), and one form of Usher syndrome type I (USH1) has been mapped to chromosome 14q (J. Kaplan, S. Gerber, D. Bonneau, J. Rozet, M. Briord, J. Dufier, A. Munnich, and J. Frezal, 1990. Cytogenet. Cell Genet. 58: 1988). These loci have been excluded as regions of USH genes in our data set, which is composed of 8 French-Acadian USH1 families and 11 British USH1 families. Both of these sets of families show linkage to loci on chromosome 11. Linkage analysis demonstrates locus heterogeneity between these sets of families, with the French-Acadian families showing linkage to D11S419 (Z = 4.20, theta = 0) and the British families showing linkage to D11S527 (Z = 6.03, theta = 0). Genetic heterogeneity of the data set was confirmed using HOMOG and the M test (log likelihood ratio > 10(5)). These results confirm the presence of two distinct USH1 loci on chromosome 11.

Chromosome Mapping↗
PubMed1992

Linkage studies of Usher syndrome type 1: exclusion results from the Usher syndrome consortium.

Usher Syndrome Type 1 is an autosomal recessive disease characterized by profound congenital hearing impairement and vestibular dysfunction followed by the onset of retinitis pigmentosa in childhood or early adolescence. Members of the Usher Syndrome Consortium, whose objective is to locate and isolate the genes for Usher syndrome, have pooled linkage data from 36 families with 111 affected individuals. We report the analysis of 206 blood group, protein, and DNA marker polymorphisms. No evidence of linkage heterogeneity among families was found for any of the markers studied; the negative lod scores exclude the locus for this disease from about 39% of the genome. Our results indicate the regions of the genome to which our continuing efforts should be directed.

Chromosome Mapping↗