Search PubMed⌕ Search

Biomedical subjects

R J Smith

Publications and source records attributed to R J Smith.

At least 55 records · Page 3Linked to original sources
PubMed2001

Haplotype analysis of the USH1D locus and genotype-phenotype correlations.

Usher syndrome (USH) is characterised by hearing impairment and progressive pigmentary retinopathy. USH can be divided into three subtypes based on the severity and progression of the major clinical findings. These subtypes are genetically heterogeneous, with at least six loci for USH1, three for USH2 and one for USH3. In the present study, five unrelated consanguineous families with USH1 were analysed for linkage to markers flanking the six USH1 loci. Two of these families, one Pakistani and one Turkish, demonstrated linkage to the USH1D locus. In another family, haplotype segregation was consistent with linkage to USH1C. The remaining families were not linked to any of the six USH1 loci, providing support for the existence of at least one additional USH1 locus. Analysis of these two new USH1D families allowed us to narrow the USH1D candidate region to a 7.3-cM interval with a telomeric flanking marker at D10S1752. Comparison of the affected haplotypes in our Pakistani family with the original Pakistani USH1D family yielded no evidence for a founder effect. The identification of two additional affected families suggests that the USH1D may be a more common form of USH1 than originally suspected. The USH1D (CDH23) gene has recently been cloned. Mutation analysis has shown two different CDH23 mutations in the two Pakistani USH1D families studied, which confirmed our finding that there was no evidence for a founder effect by haplotype analysis. The interesting correlations between genotype and phenotype in CDH23 are also summarised.

Cadherin Related Proteins↗
PubMed2001

Genetics of hearing impairment.

Our understanding of the genetics of hearing impairment (HI) has advanced rapidly during the last decade. In this review, we focus on HI due to single gene abnormalities, highlighting some of the more common causes of syndromic HI. We also outline the current state of knowledge of the genetics of non-syndromic HI. The most significant clinical advance has been the finding that mutations in GJB2 cause half of moderate-to-profound congenital hereditary deafness in many world populations. The implications of this finding for screening and genetic counseling are discussed.

Branchio-Oto-Renal Syndrome↗
PubMed2001

Towards improvement of the accuracy and completeness of medication registration with the use of an electronic medical record (EMR).

BACKGROUND: Approximately 80% of GPs use a GP information system (GIS) and an electronic medical record (EMR) in their daily practice. To reap the full benefits of an EMR for patient care, post-graduate education and research, the data input must be well structured and accurately coded. OBJECTIVES: The quality and user-friendliness of the software positively influence the completeness and reliability of the data recorded in the GIS. To assess this in actual practice, this study examined whether or not an increase occurred in the accuracy and completeness of indication-related medication registration after the GIS's software package was upgraded. METHOD: GPs recorded data for the Registration Network Groningen (RNG) concerning four medication groups: insulin, trimethoprim, the contraceptive pill and beta-blocking agents. The completeness and accuracy of the registered data were assessed both before and after the change to the new software package. The completeness is evaluated on the basis of the indications missing for the prescribed medications. To assess accuracy, a check was made to determine whether the indications corresponded to those deemed relevant for that particular medication according to National Pharmaceutical Guidelines. RESULTS: The percentage of missing indications decreased notably, especially in the chronically prescribed medication groups. For insulin, the percentage decreased from 40.5 to 3% and for the contraceptive pill from 34.5 to 1%. For trimethoprim, the percentage decreased from 10 to 1%, and for beta-blocking agents from 22 to 1.5%. Of the indications present, the percentage of relevant indications showed a slight increase, with the largest increase observed for the contraceptive pill where the percentage rose from 86 to 96%. CONCLUSIONS: The completeness of recorded indications improved considerably after the change of software. This is due mostly to the efforts of the GPs, their practice assistants and the support of the RNG organization involved in the conversion procedure. Accuracy improved slightly, especially due to the software modifications which ensured that non-existent codes could not be entered. To summarize, with increased user-friendliness of the software, combined with the training of motivated GPs, the quality of recorded data improved.

Adrenergic Antagonists↗
PubMed2001

Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade.

OBJECTIVES: To determine the effects of sustained, 3-day endotoxin infusion on early steps of the insulin-signaling pathway in rat liver and skeletal muscle in vivo; to examine insulin signaling in well-established acute endotoxin models of insulin resistance. DESIGN: Prospective, controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats: 24 in the 3-day endotoxin study, 22 in each acute endotoxin study. INTERVENTIONS: In prolonged endotoxemia studies, endotoxin (1 mg.kg-1.24 hrs-1) was administered via jugular venous catheter for 74 hrs. Insulin was then injected, and liver and skeletal muscle were removed after 5 mins. In acute endotoxemia studies, an endotoxin bolus (1 mg/kg) was administered, and insulin-signaling responses were studied after 4 hrs. MEASUREMENTS AND MAIN RESULTS: In liver of rats with sustained endotoxemia, there were significant decreases in insulin-stimulated tyrosine phosphorylation of insulin receptors (74%), insulin receptor substrate (IRS)-1 (74%), and IRS2 (53%); binding of the p85 subunit of phosphatidylinositide 3-kinase to IRS1 (80%); and IRS1-precipitable phosphatidylinositide 3-kinase activity (>90%). These findings were associated with significant reductions in abundance of insulin receptors (37%), IRS1 (60%), and IRS2 (23%). Signaling in skeletal muscle was similarly affected, with reduced IRS1 phosphorylation (49%), IRS1 abundance (50%), and binding of p85 to IRS1 (57%). Insulin signaling 4 hrs after endotoxin administration was not different from controls. CONCLUSIONS: Prolonged endotoxemia is associated with marked deficits in early steps of the insulin-signaling pathway, which are at least partly explained by reduced abundance of the insulin receptor and IRS proteins. Signaling defects were not evident 4 hrs after endotoxin administration under conditions of adequate nutrition, indicating that insulin resistance develops gradually, may require concomitant malnutrition, and is not reversed by the development of endotoxin tolerance.

Analysis of Variance↗
PubMed2001

A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment.

Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein connexin 26. One mutation of this gene, the 35delG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder effect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for different single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJB2, while two were positioned up to 76 kb from it. Significant differences between the genotypes of patients and controls for the five SNPs closest to GJB2 were found, with nearly complete association of one SNP allele with the 35delG mutation. For the most remote SNP, we could not detect any association. We conclude that the 35delG mutation is derived from a common, albeit ancient founder.

Alleles↗
PubMed2001

Mapping of genes and transcribed sequences in a gene rich 400-kb region on human chromosome 11p15.1-->p14.

We have identified a number of transcribed sequences within a 400-kb interval on chromosome 11p15.1--> p14. Six genes and 13 novel transcripts including ESTs, cDNAs and exons have been identified and assigned to this region. Comparison of mRNA sequence with genomic sequence has enabled us to determine the exon/intron structure of four of the genes (NUCB2, PIK3C2A, RPS13 and OR7E14P).

Base Sequence↗
PubMed2001

Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study.

OBJECTIVE: Neuropsychological studies have shown that deficits in verbal episodic memory in schizophrenia occur primarily during encoding and retrieval stages of information processing. The current study used positron emission tomography to examine the effect of schizophrenia on change in cerebral blood flow (CBF) during these memory stages. METHOD: CBF was measured in 23 healthy comparison subjects and 23 patients with schizophrenia during four conditions: resting baseline, motor baseline, word encoding, and word recognition. The motor baseline was used as a reference that was subtracted from encoding and recognition conditions by using statistical parametric mapping. RESULTS: Patients' performance was similar to that of healthy comparison subjects. During word encoding, patients showed reduced activation of left prefrontal and superior temporal regions. Reduced left prefrontal activation in patients was also seen during word recognition, and additional differences were found in the left anterior cingulate, left mesial temporal lobe, and right thalamus. Although patients' performance was similar to that of healthy comparison subjects, left inferior prefrontal activation was associated with better performance only in the comparison subjects. CONCLUSIONS: Left frontotemporal activation during episodic encoding and retrieval, which is associated with better recognition in healthy people, is disrupted in schizophrenia despite relatively intact recognition performance and right prefrontal function. This may reflect impaired strategic use of semantic information to organize encoding and facilitate retrieval.

Adult↗
PubMed2001

Endobronchial tumors in children: an uncommon clinical entity.

We performed a retrospective chart review of 10 children in whom endobronchial tumors were diagnosed in a tertiary-care children's medical center from 1988 to 1998. Of the 10 patients, 6 were male and 4 were female (8 white, 1 Hispanic, 1 African American). The mean age at presentation was 5.2 years. Eight tumors were benign, and 2 were malignant; 4 were on the right side, 3 were on the left side, and 3 were bilateral. Histologic findings included 3 bronchial papillomas, 3 inflammatory masses, 1 endobronchial hemangioma, 1 leiomyoma, 1 mucoepidermoid carcinoma, and 1 bronchial carcinoid. Endobronchial tumors in children are a rare disorder. The diagnosis requires a high index of suspicion in children with atypical or chronic respiratory complaints. Newer adjuvant medical therapies and surgical innovations offer improved disease control in these patients, and a multidisciplinary approach is often warranted.

Adolescent↗
PubMed2001

The DFNA10 phenotype.

We present a detailed analysis of the DFNA10 phenotype based on data from 25 hearing-impaired persons coming from a large American pedigree segregating for deafness at the DFNA10 locus (chromosome 6q22.3-23.2). Cross-sectional analysis of air conduction threshold-on-age data from all available last-visit audiograms (linear regression analysis, age over 15 years) showed progression of hearing loss at a rate of 0.6 dB/y over all frequencies, with a flat to gently sloping age-corrected threshold of about 50 dB. The results were significant at 0.25, 4, and 8 kHz, but only if corrections for presbycusis were not included. Longitudinal threshold analysis performed in 1 case, covering ages 6 to 32 years, showed progression of hearing loss at a rate of 2 to 3 dB/y over 0.25 to 8 kHz. Nonlinear regression analysis was performed on phoneme discrimination scores with use of sigmoidal dose-response curves with variable slope. On the basis of these data, the hearing loss phenotype in this American DFNA10 family can be described as postlingual, initially progressive, and resulting, without the influence of presbycusis, in largely stable, flat sensorineural deafness.

Adolescent↗
PubMed2001

Nontraumatic atlantoaxial rotary subluxation in the pediatric otolaryngology patient. A report of four cases.

Nontraumatic atlantoaxial rotary subluxation (NAARS) is a relatively uncommon entity, with inconsistent presentations. It most commonly follows infectious processes or operative procedures. We present our experience with 4 pediatric otolaryngology patients with NAARS who were treated at the University of Iowa Hospitals and Clinics during a 2-year period beginning in 1997. A review of the symptoms, physical findings, and radiographic abnormalities is presented. Treatment options, varying from muscle relaxants to surgical fusion, are discussed. A high index of suspicion in evaluating children with a stiff neck or pain on attempted motion is essential in order to facilitate prompt diagnosis and appropriate intervention.

Atlanto-Axial Joint↗
PubMed2001

Identification of imprinted loci by methylation: use of methylation-sensitive representational difference analysis (Me-RDA).

The technique of representational difference analysis (RDA) was originally described by Lisitsyn et al. (1993) as a means of identifying differences between complex genomes by the use of subtractive hybridisation (1). This protocol for methylation-sensitive RDA (Me-RDA) describes adaptations to the original technique that, by the use of oligonucleotides for HpaII or Hin6I sites, allow the identification of sequences whose methylation differs between two sources of DNA. Differences in the methylation of the maternal and paternal alleles of imprinted genes have been described for most imprinted genes studied to date (2). The importance of methylation in the control of imprinted gene expression has been clearly demonstrated by the perturbation of allelic expression in mice deficient in Dnmt1, the major mammalian DNA methyltransferase (3), and methylation has been suggested to fulfill the necessary requirements of an "imprint" (4).

Animals↗
PubMed2001

Disgust sensitivity and attitudes toward organ donation among African-American college students.

241 African-American college students (94 men and 147 women, mean age = 20.3 +/- 3.4 yr.) completed the 1994 Disgust Scale of Haidt, McCauley, and Rozin and a modified form of Parisi-Rizzo's 1987 Attitudes Toward Organ Donation Scale (negative subscale only) as well as a behavioral measure of intention to donate organs after death. Analyses indicated that the higher the disgust sensitivity, the more negative the attitude toward organ donation and the less likely the student was to indicate intent to donate organs. It was further shown that negative attitudes toward organ donation mediated the relationship between disgust sensitivity and the behavioral intention measure. Results highlight the complexity of the issues surrounding organ donation within an African-American population and provide additional empirical evidence for the development of a theoretical model to explain the organ donation phenomenon.

Adolescent↗
PubMed2001

Performance of a whole-body PET scanner using curve-plate NaI(Tl) detectors.

UNLABELLED: A whole-body PET scanner, without interplane septa, has been designed to achieve high performance in clinical applications. The C-PET scanner, an advancement of the PENN PET scanners, is unique in the use of 6 curved NaI(Tl) detectors (2.54 cm thick). The scanner has a ring diameter of 90 cm, a patient port diameter of 56 cm, and an axial field of view of 25.6 cm. A (137)Cs point source is used for transmission scans. METHODS: Following the protocols of the International Electrotechnical Commission ([IEC] 61675-1) and the National Electrical Manufacturers Association ([NEMA] NU-2-1994 and an updated version, NU2-2001), point and line sources, as well as uniform cylinders, were used to determine the performance characteristics of the C-PET scanner. An image-quality phantom and patient data were used to evaluate image quality under clinical scanning conditions. Data were rebinned with Fourier rebinning into 2-dimensional (slice-oriented) datasets and reconstructed with an iterative reconstruction algorithm. RESULTS: The spatial resolution for a point source in the transaxial direction was 4.6 mm (full width at half maximum) at the center, and the axial resolution was 5.7 mm. For the NU2-1994 analysis, the sensitivity was 12.7 cps/Bq/mL (444 kcps/microCi/mL), the scatter fraction was 25%, and the peak noise equivalent count rate (NEC) for a uniform cylinder (diameter = 20 cm, length = 19 cm) was 49 kcps at an activity concentration of 11.2 kBq/mL. For the IEC protocol, the peak NEC was 41 kcps at 12.3 kBq/mL, and for the NU2-2001 protocol, the peak NEC was 14 kcps at 3.8 kBq/mL. The NU2-2001 NEC value differed significantly because of differences in the data analysis and the use of a 70-cm-long phantom. CONCLUSION: Compared with previous PENN PET scanners, the C-PET, with its curved detectors and improvements in pulse shaping, integration dead time, and triggering, has an improved count-rate capability and spatial resolution. With the refinements in the singles transmission technique and iterative reconstruction, image quality is improved and scan time is shortened. With single-event transmission scans interleaved between sequential emission scans, a whole-body study can be completed in <1 h. Overall, C-PET is a cost-effective PET scanner that performs well in a broad variety of clinical applications.

Adult↗
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↗
PubMed2000

Parental attitudes toward genetic testing for pediatric deafness.

Recent molecular genetic advances have resulted in genetic testing becoming an option for deaf individuals and their families. However, there is little information about the interest in such testing. To investigate this issue, parents with normal hearing who have one or more deaf children were surveyed about their attitudes toward diagnostic, carrier, and prenatal genetic testing for deafness. This population was chosen because it represents the majority of individuals who are encountered in clinical practice, given that 90%-95% of deaf individuals are born to persons with normal hearing. Of 328 surveys distributed, 96 were completed and returned. Of the respondents, 96% recorded a positive attitude toward genetic testing for deafness, including prenatal testing, although none would use this information to terminate an affected pregnancy. All respondents had a poor understanding of genetics, with 98% both incorrectly estimating the recurrence risk of deafness and misunderstanding the concept of inheritance. Notably, these findings were similar in the group who had had genetic testing for their children and in the group who had not, suggesting either that the parents who received genetic testing did not receive genetic counseling or that the counseling was not effective. On the basis of these results, it was concluded that this population is interested in the use of genetic testing and that testing should not be done without first providing formal genetic counseling. Appropriate counseling can help parents to understand the risks, benefits, and limitations of genetic testing.

Adult↗
PubMed2000

Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I.

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

Abnormalities, Multiple↗