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Biomedical subjects

R J Smith

Publications and source records attributed to R J Smith.

At least 127 records · Page 7Linked to original sources
PubMed1999

Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.

We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss.

Amino Acid Sequence↗
PubMed1999

High prevalence of symptoms of Menière's disease in three families with a mutation in the COCH gene.

We report the genetic analysis of one large Belgian and two small Dutch families with autosomal dominant non-syndromic progressive sensorineural hearing loss associated with vestibular dysfunction. Linkage studies in the Belgian family mapped the disease to the DFNA9 locus on chromosome 14. Mutation analysis of the COCH gene, which is responsible for DFNA9, revealed a missense mutation changing a highly conserved residue. One of the patients, who had an earlier age of onset in comparison with most of the affected family members, was shown to be homozygous for the mutation. After the mutation was found in the Belgian family, we discovered that the same missense mutation was also present in two Dutch families with similar cochleo-vestibular symptoms. In all three families with hearing loss and imbalance problems, >25% of the patients showed additional symptoms, including episodes of vertigo, tinnitus, aural fullness and hearing loss. Clinically, these symptoms are consistent with the criteria for Menière's disease. The importance of genetic factors in Menière's disease has been suggested on many occasions, but this study is the first report of a mutation in a gene leading to the symptoms of Menière's disease in a significant portion of the carriers. The COCH gene may be one of the genetic factors contributing to Menière's disease and the possibility of a COCH mutation should be considered in patients with Menière's disease symptoms.

Chromosomes, Human, Pair 14↗
PubMed1999

Laryngeal motion during exercise.

OBJECTIVE: To compare laryngoscopically observed changes in the larynx during exercise in persons with exercise-induced laryngomalacia (EIL) with changes in asymptomatic control subjects. STUDY DESIGN: Clinical study using a standardized exercise protocol. METHODS: Subjects exercised on an incremental ergometer: videotaped recordings of the larynx were obtained through the entire exercise; pulmonary function tests were completed before and/or immediately after the exercise. RESULTS: Laryngeal lumen size decreases during exercise in subjects with EIL. CONCLUSION: Subjects with EIL had a significant decrease in laryngeal lumen size during exercise compared with asymptomatic control subjects.

Adolescent↗
PubMed1999

Detection of recurrent head and neck squamous cell carcinomas after radiation therapy with 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography.

OBJECTIVES/HYPOTHESIS: Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed as a sensitive method to diagnose and stage various malignancies. We assessed the efficacy of FDG-PET imaging in distinguishing tumor persistence/recurrence from posttreatment changes following radiation therapy for squamous carcinomas of the head and neck STUDY DESIGN: Retrospective analysis of FDG-PET results compared with biopsy results or outcome, or both. METHODS: Twenty-eight patients who had undergone radiation therapy with or without surgery for treatment of squamous cell carcinoma were studied with FDG-PET imaging. There was clinical suspicion for recurrence in each patient, but no obvious mass or lesion to biopsy was found on physical examination or anatomic imaging. The results of FDG-PET imaging were compared with those of biopsy or clinical follow-up of at least 6 months, or both. RESULTS: FDG-PET imaging was positive in 13 patients, and the presence of active disease was confirmed in 12. Two thirds of the 12 received further cancer treatment. There were 15 negative FDG-PET images. Thirteen of these were confirmed true-negative images, but two studies were false-negative images. The sensitivity and specificity of FDG-PET were 86% and 93%, respectively, with positive and negative predictive values of 92% and 87%, respectively. The overall accuracy was 89%. CONCLUSION: FDG-PET imaging is a useful modality to distinguish tumor persistence/recurrence from radiation-induced tissue changes in the neck following treatment for head and neck cancer. FDG-PET can identify patients who may benefit from further treatment, and may lead to improved outcome for individual patients.

Biopsy↗
PubMed1999

Laryngomalacia and its treatment.

OBJECTIVE: To determine 1) airway outcome of infants with laryngomalacia who do not undergo routine direct laryngoscopy (DL) and bronchoscopy (B), 2) the age at resolution of laryngomalacia, and, 3) outcome of supraglottoplasty as a function of the type of laryngomalacia and the presence of concomitant disease. STUDY DESIGN: Retrospective chart review. METHODS: The records of all infants diagnosed with laryngomalacia by flexible fiberoptic laryngoscopy (FFL) between 1990 and 1998 in the Department of Otolaryngology--Head and Neck Surgery, University of Iowa (Iowa City, IA) were reviewed. The type of laryngomalacia was designated by a new classification scheme (types 1-3) based on the site of supraglottic obstruction and the type of supraglottoplasty indicated, should the patient later require surgical intervention. The log rank test was used to compare age at resolution and outcome between types of laryngomalacia and between infants with isolated laryngomalacia versus those with additional congenital abnormalities and/or severe neurological compromise. RESULTS: The type of laryngomalacia was evident in 48 of the 58 charts reviewed and included type 1 (57%), type 2 (15%), type 3 (13%), or combined types (15%). Twenty percent had severe neurological compromise and/or multiple congenital anomalies. The median time to resolution of stridor in these patients was not significantly delayed when compared with infants who had isolated airway anomalies (36 and 72 wk, respectively, vs. 36 wk for isolated laryngomalacia; P<.4). Time to resolution did not correlate with the type of laryngomalacia. In 22 infants, clinical symptoms or findings suggested a synchronous airway lesion, and direct laryngoscopy and bronchoscopy were performed. In 11 infants, a second airway lesion was diagnosed (in four cases by FFL and in 7 cases by direct laryngoscopy and bronchoscopy). Complications did not arise in infants who did not undergo direct laryngoscopy and bronchoscopy. Eleven infants with severe laryngomalacia required surgical intervention. The success of supraglottoplasty did not correlate with the type of laryngomalacia or the presence of other congenital anomalies. CONCLUSIONS: Routine direct laryngoscopy and bronchoscopy as part of the evaluation of laryngomalacia are not warranted. Performing these procedures should be based on clinical and physical evidence of a concomitant airway lesion. In general, laryngomalacia will resolve within the first year of life, even in children with multiple congenital anomalies and/or severe neurological compromise. The proposed classification scheme is advantageous in that it is simple and correlates the site of obstruction with the surgical procedure most likely to effect a cure, should the patient require a supraglottoplasty. Surgical management is necessary in approximately 15% to 20% of affected infants.

Female↗
PubMed1999

Surfactant protein A in rabbit sinus and middle ear mucosa.

In the present study, pulmonary surfactant protein A (SP-A) messenger RNA (mRNA) and protein were characterized in adult rabbit middle ear and maxillary sinus. Fifteen adult rabbits were used for the study: 6 with evidence of acute middle ear infections and maxillary sinusitis, 6 with infections that were successfully treated with tetracycline, and 3 that were pathogen-free. We detected SP-A mRNA in maxillary sinus and middle ear tissues by Northern blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). The RT-PCR also revealed the presence of SP-B and SP-C mRNA in middle ear and sinus tissues. We detected SP-A protein, of molecular weight approximately 29 and 70 kd, in middle ear and sinus tissues by immunoblot analysis. Unlike the SP-A protein present in the lung, the molecular weight of the SP-A protein present in the middle ear and paranasal sinus was not altered by digestion with an enzyme that cleaves N-linked carbohydrates. Immunostaining and in situ hybridization showed that SP-A protein and mRNA, respectively, were present in surface epithelial cells of the middle ear and in epithelial cells of submucosal glands in sinus tissues. These data provide the first evidence of the presence of pulmonary surfactant proteins in the paranasal sinuses and confirm previous reports of SP-A in the middle ear epithelium.

Acute Disease↗
PubMed1999

Cervical vertebral anomalies in patients with anomalies of the head and neck.

Congenital head and neck anomalies can occur in association with vertebral anomalies, particularly of the cervical vertebrae. While the former are easily recognized, especially when part of a syndrome, the latter are often occult, thereby delaying their diagnosis. The presence of vertebral anomalies must be considered in pediatric patients with head and neck abnormalities to expedite management of select cases and to prevent neurologic injury. We present our experience with 5 pediatric patients who were referred to the Department of Otolaryngology-Head and Neck Surgery at the University of Iowa with a variety of syndromic anomalies of the head and neck. Each patient was subsequently also found to have a vertebral anomaly. The relevant embryogenesis of the anomalous structures is discussed, with highlighting of potential causes such as teratogenic agents and events and germ-line mutations. A review of syndromes having both head and neck and vertebral anomalies is presented to heighten awareness of otolaryngologists evaluating children with syndromic disorders. Finally, the findings on radiographic imaging studies, particularly computed tomography, are discussed to facilitate the prompt diagnosis of vertebral anomalies.

Abnormalities, Multiple↗
PubMed1999

Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in vivo.

The bacterial lipopolysaccharide endotoxin induces a catabolic response characterized by resistance to multiple anabolic hormones. The objective of this study was to determine the effects of endotoxin on the GH signaling pathway in rat liver in vivo. After the iv injection of Escherichia coli endotoxin (1 mg/kg), there was a progressive decrease in liver STAT5 (signal transducer and activator of transcription-5) tyrosine phosphorylation in response to GH (40% decrease 6 h after endotoxin), which occurred in the absence of a change in abundance of the STAT5 protein. Endotoxin resulted in a rapid 40-fold increase in liver Janus family kinase-2 (JAK2) messenger RNA, followed by a 2-fold increase in JAK2 protein abundance. This was associated with a 50% decrease in phosphorylated/total JAK2 after GH stimulation. GH receptor abundance was unchanged, suggesting a postreceptor site of endotoxin-induced GH resistance. Rat complementary DNAs for three members of the suppressor of cytokine signaling gene family were cloned [cytokine-inducible sequence (CIS), suppressor of cytokine signaling-2 (SOCS-2), and SOCS-3] and, using these probes, messenger RNAs for SOCS-3 and CIS were shown to be increased 10- and 4-fold above control values, respectively, 2 h after endotoxin infusion. The finding of endotoxin inhibition of in vivo STAT5 tyrosine phosphorylation in response to a supramaximal dose of GH in the absence of a change in GH receptor abundance or total GH-stimulated JAK2 tyrosine phosphorylation provides the first demonstration of acquired postreceptor GH resistance. We hypothesize that this may occur through a specificity-spillover mechanism involving the induction of SOCS genes by cytokines released in response to endotoxin and subsequent SOCS inhibition of GH signaling.

Animals↗
PubMed1999

In vivo insulin signaling in the myocardium of streptozotocin-diabetic rats: opposite effects of diabetes on insulin stimulation of glycogen synthase and c-Fos.

Diabetes induced by streptozotocin (STZ) in laboratory rats leads to impaired glucose metabolism in the heart and changes in myocardial contractile protein isoform expression and cardiac function. The purpose of this study was to investigate in vivo insulin signaling responses in the myocardium of STZ-diabetic rats. Insulin rapidly stimulated tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1) and, to a lesser extent, IRS-2 in normal and diabetic myocardium. In diabetic rats, there was 2-fold higher insulin receptor content and insulin-stimulated receptor tyrosine phosphorylation in comparison with control rats. IRS-1 tyrosine phosphorylation also increased in STZ diabetes in spite of a decrease in IRS-1 content, resulting in a 4-fold higher ratio of phosphorylated to total IRS-1. This was associated with 2-fold higher IRS-1 precipitable phosphatidylinositide 3-kinase activity in diabetic animals. Insulin stimulation of glycogen synthase activity was significantly diminished in STZ diabetes, consistent with resistance to insulin in a step downstream from phosphatidylinositide 3-kinase activation. Under the same experimental conditions, there was a marked increase in insulin stimulation of myocardial c-fos messenger RNA content in diabetic animals in comparison with controls. These data demonstrate altered early steps in insulin signaling in STZ-diabetic rat myocardium. Consequent oppositely directed disturbances in growth regulatory and glucose regulatory responses to insulin may contribute to the development of myocardial functional abnormalities in this model of diabetes.

Animals↗
PubMed1999

Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats.

Insulin-dependent diabetes in rats is characterized by abnormalities of post-binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the kidney capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes.

Animals↗
PubMed1999

Cloning genes for non-syndromal hearing impairment.

Over 45 genes that cause autosomal non-syndromic hearing impairment (NSHI) have been localized and many more are predicted to exist. To clone these genes, a number of different strategies can be used. This paper focuses on four general approaches: functional cloning, positional cloning, position-dependent candidate gene cloning, and position-independent candidate gene cloning.

Cloning, Organism↗
PubMed1999

A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus.

Non-syndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 reported gene localisations. We have identified a large Dutch family with autosomal dominant non-syndromic sensorineural hearing impairment. In most patients, the onset of hearing impairment is in the first or second decade of life, with a slow decline in the following decades, which stops short of profound deafness. The hearing loss is bilateral, symmetrical, and only affects low and mid frequencies up to 2000 Hz. In view of the phenotypic similarities of this family with an American family that has been linked to chromosome 4p16.3 (DFNA6), we investigated linkage to the DFNA6 region. Lod score calculations confirmed linkage to this region with two point lod scores above 6. However, as haplotype analysis indicated that the genetic defect in this family is located in a 5.6 cM candidate region that does not overlap the DFNA6 region, the new locus has been named DFNA14.

Adolescent↗
PubMed1999

Prognostic value of FDG PET imaging in malignant pleural mesothelioma.

UNLABELLED: Despite several attempts at treating malignant pleural mesothelioma with various modalities, mortality remains high, with median survival between 12 and 18 mo. This disease may have a highly variable clinical course, with occasional long-term survivors. The purpose of this study was to assess whether tumor metabolic activity, as assessed by fluorodeoxyglucose (FDG) PET imaging, correlates inversely with survival. METHODS: Twenty-eight patients with suspected mesothelioma underwent FDG PET scanning between September 1995 and May 1997. A diagnosis of mesothelioma was confirmed in 22. Fully corrected scans with attenuation correction of the entire chest were available in 17 patients with sufficient follow-up for survival analysis. Standardized uptake values (SUVs) were determined from the most active tumor site in each patient. RESULTS: Seven patients died during follow-up, at a median period of 5.3 mo after FDG PET scanning. Follow-up information was available on the remaining 10 patients for a median period of 15.6 mo after the PET study. The mean SUV of the deceased patients was 6.6+/-2.9, compared with 3.2+/-1.6 among the combined survivors. The deceased patients had tumor SUVs that were highly correlated with duration of survival after the PET study (r = 0.87, P < 0.05). The cumulative survival estimate by the Kaplan-Meier product limit method was 0.17 at 12 mo for the patients with tumor SUVs greater than the median value and 0.86 for those with lower SUVs. The survival distribution of the high SUV group showed significantly shorter survivals compared with the low SUV group (P < 0.01). CONCLUSION: Patients with highly active mesotheliomas on FDG PET imaging have a poor prognosis. High FDG uptake in these tumors indicates shorter patient survival.

Aged↗
PubMed1999

Clinical evaluation of processing techniques for attenuation correction with 137Cs in whole-body PET imaging.

UNLABELLED: Transmission scanning can be successfully performed with a 137Cs single-photon emitting point source for three-dimensional PET imaging. However, the attenuation coefficients provided by this method are underestimated because of the energy difference between 662- and 511-keV photons, as well as scatter and emission contamination when the transmission data are acquired after injection. The purpose of this study was to evaluate, from a clinical perspective, the relative benefits of various processing schemes to resolve these issues. METHODS: Thirty-eight whole-body PET studies acquired with postinjection singles transmission scans were analyzed. The transmission images were processed and applied to the emission data for attenuation correction. Three processing techniques were compared: simple segmentation (SEG) of the transmission scan, emission contamination subtraction with scaling (ECS) of the resulting data to 511-keV attenuation coefficient values and a hybrid technique performing partial segmentation of some tissue densities on the ECS scan (THR). The corrected emission scans were blindly assessed for image noise, the presence of edge artifacts at the lung-soft-tissue interface and for overall diagnostic confidence using a semiquantitative scoring system. The count densities and the SDs in uniform structures were compared among the various techniques. The observations for each method were compared using a paired t test. RESULTS: The SEG technique produced images that were visually less noisy than the ECS method (P < 0.0001) and the THR technique, but at the expense of increased edge artifacts at the boundaries between the lungs and surrounding tissues. The THR technique failed to eliminate these artifacts compared with the ECS technique (P < 0.0001) but preserved the activity gradients in the hilar areas. The count densities (and thus, the standardized uptake values) were similar among the three techniques, but the SEG method tended to underestimate the activity in the lung fields and in chest tumors (slope = 0.79 and 0.94, respectively). CONCLUSION: For many clinical applications, SEG data remain an efficient method for processing 137Cs transmission scans. The ECS method produced noisier images than the other two techniques but did not introduce artifacts at the lung boundaries. The THR technique, more versatile in complex anatomic areas, allowed good preservation of density gradients in the lungs.

Cesium Radioisotopes↗
PubMed1999

Identification of two different mutations in the PDS gene in an inbred family with Pendred syndrome.

Recently the gene responsible for Pendred syndrome (PDS) was isolated and several mutations in the PDS gene have been identified in Pendred patients. Here we report the occurrence of two different PDS mutations in an extended inbred Turkish family. The majority of patients in this family are homozygous for a splice site mutation (1143-2A-->G) affecting the 3' splice site consensus sequence of intron 7. However, two affected sibs with non-consanguineous parents are compound heterozygotes for the splice site mutation and a missense mutation (1558T-->G), substituting an evolutionarily conserved amino acid. The latter mutation has been found previously in two Pendred families originating from The Netherlands, indicating that the 1558T-->G mutation may be a common mutation.

Base Sequence↗
PubMed1998

Identification and mutation analysis of a cochlear-expressed, zinc finger protein gene at the DFNB7/11 and dn hearing-loss loci on human chromosome 9q and mouse chromosome 19.

The DFNB7/11 locus for autosomal recessive non-syndromic hearing loss (ARNSHL) has been mapped to an approx. 1.5 Mb interval on human chromosome 9q13-q21. We have determined the cDNA sequence and genomic structure of a novel cochlear-expressed gene, ZNF216, that maps to the DFNB7/11 interval. The mouse orthologue of this gene maps to the murine dn (deafness) locus on mouse chromosome 19. The ZNF216 gene is highly conserved between human and mouse, and contains two regions that show homology to the putative zinc linger domains of other proteins. To determine it mutations in ZNF216 might be the cause of hearing loss at the DFNB7/11 locus, we screened the coding region of this gene in DFNB7/11 families by direct sequencing. No potential disease-causing mutations were found. In addition, Northern blot analysis showed no difference in ZNF216 transcript size or abundance between dn and control mice. These data Suggest that the ZNF216 gene is unlikely to be responsible for hearing loss at the DFNB7/11 and dn loci.

Algorithms↗
PubMed1998

Localization of a novel gene for nonsyndromic hearing loss (DFNB17) to chromosome region 7q31.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary hearing impairment (HHI). To date, 16 different loci have been reported, making ARNSHL an extremely heterogeneous disorder. One of these loci, DFNB4, was mapped to a 5-cM interval of 7q31 in a large Middle-Eastern Druze family. This interval also includes the gene for Pendred syndrome. We report on three new families with HHI from the Madras region of southern India that demonstrate linkage to 7q. Their pedigrees are compatible with autosomal recessive inheritance. Furthermore, the largest family identifies a novel locus (DFNB17) telomeric to the DFNB4 and Pendred intervals. A 3-cM region of homozygosity by descent between markers D7S486 and D7S2529 is present in all affected individuals in this family and generates a multipoint LOD score of 4.24. The two other families map to the previously reported DFNB4 region but have insufficient power to attain significant LOD scores. However, mutations in the Pendred syndrome gene are present in one of these families.

Adult↗