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Biomedical subjects

G E Green

Publications and source records attributed to G E Green.

At least 19 recordsLinked to original sources
PubMed2002

Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3.

Clinical otosclerosis (OMIM 166800/605727) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this group. It is caused by abnormal bone homeostasis of the otic capsule with the consequent development of sclerotic foci that invade the stapedio-vestibular joint (oval window) interfering with free motion of the stapes. Impaired ossicular chain mobility results in a conductive hearing loss. We identified the first locus for otosclerosis (OTSC1) on chromosome 15 in 1998 and reported a second locus (OTSC2) on chromosome 7 last year. Here we present results of a genome wide linkage study on a large Cypriot family segregating otosclerosis. Results of this study exclude linkage to OTSC1 and OTSC2 and identify a third locus, OTSC3, on chromosome 6p. The defined OTSC3 interval covers the HLA region, consistent with reported associations between HLA-A/HLA-B antigens and otosclerosis.

Chromosome Mapping↗
PubMed2001

Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations.

Mutations in PDS (SLC26A4) cause both Pendred syndrome and DFNB4, two autosomal recessive disorders that share hearing loss as a common feature. The hearing loss is associated with temporal bone abnormalities, ranging from isolated enlargement of the vestibular aqueduct (dilated vestibular aqueduct, DVA) to Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2(1/2) turns is replaced by a hypoplastic coil of 1(1/2) turns. In Pendred syndrome, thyromegaly also develops, although affected persons usually remain euthyroid. We identified PDS mutations in the proband of 14 of 47 simplex families (30%) and nine of 11 multiplex families (82%) (P=0.0023). In all cases, mutations segregated with the disease state in multiplex families. Included in the 15 different PDS allele variants we found were eight novel mutations. The two most common mutations, T416P and IVS8+1G>A, were present in 22% and 30% of families, respectively. The finding of PDS mutations in five of six multiplex families with DVA (83%) and four of five multiplex families with Mondini dysplasia (80%) implies that mutations in this gene are the major genetic cause of these temporal anomalies. Comparative analysis of phenotypic and genotypic data supports the hypothesis that the type of temporal bone anomaly may depend on the specific PDS allele variant present.

Abnormalities, Multiple↗
PubMed2000

Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA).

Mutations in GJB2 are the most common cause of hereditary congenital hearing loss in many countries and are found in about half of persons with severe-to-profound congenital autosomal recessive non-syndromic hearing loss (ARNSHL). We report the results of GJB2 mutation screening in 209 consecutive persons with congenital deafness of indeterminate etiology using an allele-specific polymerase chain reaction assay, single-strand conformational polymorphism analysis, and direct sequencing. GJB2 allele variants were detected in 74 of 209 deaf individuals (35%). Over one-fourth of screened individuals were either homozygous (n=31) or heterozygous (n=24) for the 35delG mutation. Of those with the 35delG mutation, 51 (92.7%) were diagnosed with GJB2-related deafness. Nineteen persons were identified with other GJB2 allele variants - two novel deafness-causing mutations (R32C, 645-648delTAGA), one mutation of unknown significance (E47K), and one benign polymorphism (I128I). While these data enable health care professionals to provide parents and patients with improved genetic counseling data, difficulty still exists is determining whether some missense mutations compromise auditory function and are deafness-causing.

Alleles↗
PubMed2000

Pathogenesis and treatment of juvenile onset recurrent respiratory papillomatosis.

Juvenile onset recurrent respiratory papillomatosis is the most common cause of laryngeal tumors in children. This disease is caused by infection of the human papillomavirus, a virus whose complete genetic structure is now known. New, more directed agents show promise for improved control of papillomatosis in preliminary studies. Concurrently, there is an increasing awareness of methods to reduce surgical morbidity. At present, the role of preventive efforts including elective caesarian section remains uncertain.

Adult↗
PubMed2000

The M34T allele variant of connexin 26.

GJB2 encodes the protein Connexin 26, one of the building blocks of gap junctions. Each Connexin 26 molecule can oligomerize with five other connexins to form a connexon; two connexons, in turn, can form a gap junction. Because mutations in GJB2 are the most common cause of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss, the effect of the Connexin 26 allele variants on this dynamic 'construction' process and the function of any gap junctions that do form is particularly germane. One of the more controversial allele variants, M34T, has been hypothesized to cause autosomal dominant nonsyndromic hearing loss. In this paper, we present clinical and genotypic data that refutes this hypothesis and suggests that the effect of the M34T allele variant may be dependent on the mutations segregating in the opposing allele.

Alleles↗
PubMed2000

Temporal bone histopathology in connexin 26-related hearing loss.

OBJECTIVE: Mutations in GJB2, a gene that encodes a gap junction protein, Connexin 26 (Cx26), are responsible for approximately one third of sporadic severe-to-profound or profound congenital deafness and half of severe-to-profound or profound autosomal recessive nonsyndromic hearing loss (ARNSHL). Mouse mutants homozygous for knockouts of this gene are nonviable, precluding histopathologic studies of the associated inner ear pathology in this animal model. Therefore, we studied archival temporal bone sections to identify temporal bone donors with Cx26-related deafness. STUDY DESIGN: Temporal bone donors with a history of congenital severe-to-profound or profound deafness were identified in the registry of the Temporal Bone Library at the University of Iowa. Histological findings were interpreted in a blinded fashion. DNA extracted from two celloidin-embedded mid-modiolar sections from each temporal bone was screened for the 35delG Cx26 mutation. The entire coding region of Cx26 was screened for other deafness-causing mutations if the 35delG mutation was detected. RESULTS: Of five temporal bone donors with congenital severe-to-profound deafness, one donor was found to have Cx26-related deafness. This individual was a Cx26 compound heterozygote, carrying the 35delG mutation and a noncomplementary Cx26 missense mutation on the opposing allele. Microscopic evaluation of this temporal bone showed no neural degeneration, a good population of spiral ganglion cells, near-total degeneration of hair cells in the organ of Corti, a detached and rolled-up tectorial membrane, agenesis of the stria vascularis, and a large cyst in the scala media in the region of the stria vascularis. CONCLUSION: This study is the first to report the temporal bone histopathology associated with Cx26-related deafness. Preservation of neurons in the spiral ganglion suggests that long-term successful habilitation with cochlear implants may be possible in persons with severe-to-profound or profound Cx26-related deafness.

Adult↗
PubMed1999

Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness.

CONTEXT: Mutations in the GJB2 gene are the most common known cause of inherited congenital severe-to-profound deafness. The carrier frequency of these mutations is not known. OBJECTIVES: To determine the carrier rate of deafness-causing mutations in GJB2 in the midwestern United States and the prevalence of these mutations in persons with congenital sensorineural hearing loss ranging in severity from moderate to profound, and to derive revised data for counseling purposes. DESIGN: Laboratory analysis, performed in 1998, of samples from probands with hearing loss for mutations in GJB2 using an allele-specific polymerase chain reaction assay, single-strand conformation polymorphism analysis, and direct sequencing. SETTING AND SUBJECTS: Fifty-two subjects younger than 19 years sequentially referred to a midwestern tertiary referral center for hearing loss or cochlear implantation, with moderate-to-profound congenital hearing loss of unknown cause, parental nonconsanguinity, and nonsyndromic deafness with hearing loss limited to a single generation; 560 control neonates were screened for the 35delG mutation. MAIN OUTCOME MEASURE: Prevalence of mutations in the GJB2 gene by congenital deafness status. RESULTS: Of 52 sequential probands referred for congenital sensorineural hearing loss, 22 (42%) were found to have GJB2 mutations. The 35delG mutation was identified in 29 of the 41 mutant alleles. Of probands' sibs, all homozygotes and compound heterozygotes had deafness. Fourteen of 560 controls were 35delG heterozygotes, for a carrier rate expressed as a mean (SE) of 2.5% (0.66%). The carrier rate for all recessive deafness-causing GJB2 mutations was determined to be 3.01% (probable range, 2.54%-3.56%). Calculated sensitivity and specificity for a screening test based on 35delG mutation alone were 96.9% and 97.4%, respectively, and observed values were 94% and 97%, respectively. CONCLUSIONS: Our data suggest that mutations in GJB2 are the leading cause of moderate-to-profound congenital inherited deafness in the midwestern United States. Screening of the GJB2 mutation can be offered to individuals with congenital deafness with high sensitivity and specificity by screening only for the 35delG mutation. A positive finding should establish an etiologic diagnosis and affect genetic counseling.

Adolescent↗
PubMed1999

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13).

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

Amino Acid Sequence↗
PubMed1998

Androgen receptors mediate hypertrophy in cardiac myocytes.

BACKGROUND: The role of androgens in producing cardiac hypertrophy by direct action on cardiac myocytes is uncertain. Accordingly, we tested the hypothesis that cardiac myocytes in adult men and women express an androgen receptor gene and that myocytes respond to androgens by a hypertrophic response. METHODS AND RESULTS: We used reverse transcription-polymerase chain reaction methods to demonstrate androgen receptor transcripts in multiple tissues and [3H]phenylalanine incorporation and atrial natriuretic peptide secretion as markers of hypertrophy in cultured rat myocytes. Messenger RNA encoding androgen receptors was detected in myocytes of male and female adult rats, neonatal rat myocytes, rat heart, dog heart, and infant and adult human heart. Both testosterone and dihydrotestosterone produced a robust receptor-specific hypertrophic response in myocytes, determined by indices of protein synthesis and atrial natriuretic peptide secretion. CONCLUSIONS: Androgen receptors are present in cardiac myocytes from multiple species, including normal men and women, in a context that permits androgens to modulate the cardiac phenotype and produce hypertrophy by direct, receptor-specific mechanisms. There are clinical implications for therapeutic or illicit use of androgens in humans.

Adult↗
PubMed1996

Calcium channel subunits in the mouse cochlea.

Messages for subunits of voltage-gated calcium channels were examined in the cochlea of the CBAJ mouse by PCR analysis. Total RNA was extracted from the auditory organs of 16-18-day-old animals. After reverse transcription, resulting cDNA was amplified by PCR with primers targeted to nucleotide sequences corresponding to 12 different calcium channel subunits. PCR products representing subunit gene expression were strongly and consistently amplified for alpha1C, alpha1D, alpha1E, alpha2delta, beta1, beta3, and beta4 but not for alph1A, alpha1B, alpha1S, beta2, or gamma. The chosen primers amplified cochlear cDNA to yield an overall pattern of bands different from that of any tissue studied thus far, in particular with respect to the alpha2delta and beta1 subunits; the alpha2delata product was found to be significantly shorter than the corresponding brain and skeletal muscle isoforms. Nucleotide sequencing confirmed the identity of mouse cochlear subunit cDNAs. The results suggest that L-type and presumptive R-type calcium channels are expressed in the mammalian cochlea and that the alpha2delta subunits may be coded by a characteristic splice-variant mRNA.

Animals↗
PubMed1995

Internal thoracic artery grafts: 20-year clinical follow-up.

OBJECTIVES: This study compared the long-term clinical results of coronary artery bypass surgery in patients with internal thoracic artery grafts with those in patients with vein grafts only. BACKGROUND: Aortocoronary artery bypass surgery has been performed for > 25 years, primarily utilizing the saphenous vein and internal thoracic artery as conduits. Although the internal thoracic artery has been shown to confer a clinical advantage, it is not known for how many years this benefit will continue. METHODS: All consecutive patients undergoing initial coronary artery bypass surgery between 1970 and 1973 were followed for up to 20 years. Clinical evaluation included survival, late myocardial infarction, need for reoperation and recurrence of angina. Patients were analyzed in three groups: vein grafts only (214 patients); a single internal thoracic artery graft with or without associated vein grafts (490 patients); and bilateral internal thoracic artery grafts (39 patients). Use of the operating microscope was also analyzed with regard to effect on survival. RESULTS: The internal thoracic artery graft and use of the operating microscope were independent predictors of mortality and reduced the risk of dying by a factor of 0.68 and 0.76, respectively. An internal thoracic artery graft resulted in a mean survival of 4.4 years longer than that with vein grafts alone. The internal thoracic artery graft compared with vein grafts was associated with fewer reoperations (p < 0.001), fewer late myocardial infarctions, lower associated mortality rates (p < 0.04) and less early recurrence of angina (p = 0.03). CONCLUSIONS: The internal thoracic artery graft and use of the operating microscope confer a superior clinical advantage over the saphenous vein graft throughout a 20-year follow-up period. The advantage of an internal thoracic artery graft does not decrease with time, suggesting that the choice of conduit at the initial operation is more important clinically than progression of coronary artery disease.

Angina Pectoris↗
PubMed1995

Analysis of nicotinic acetylcholine receptor subunits in the cochlea of the mouse.

The present study was designed to catalogue and compare nicotinic receptor subunit messages in the mammalian cochlea. Fourteen nicotinic acetylcholine receptor subunit messages were examined by polymerase chain reaction (PCR) analysis and nucleotide sequencing. Total RNA was extracted from the auditory organs of 14- to 18-day-old CBAJ mice, and mRNA was purified using oligo-dT cellulose. After reverse transcription, resulting cDNA was amplified by PCR with the use of primers specific for the nucleotide sequences representing the following nicotinic receptor subunits: muscle types alpha 1, beta 1, gamma, delta and epsilon and neuronal types alpha 2,3,4,5,6,7 and beta 2,3,4. cDNA from cochlear tissue corresponding to the muscle-type receptor subunit beta 1 and to neuronal-type receptor subunits alpha 2,4,5,6 and beta 2,3 was amplified, whereas cDNA for muscle types alpha 1, gamma, delta and epsilon and neuronal types alpha 3,7 and beta 4 was not. All PCR products were homologous in nucleotide sequence to the corresponding reference cDNAs from which the primers were designed. The current results indicate that nicotinic acetylcholine receptor (nAChR) subunits that are similar or identical to the stated muscle and neuronal types are expressed in the murine cochlea. The presence of messages corresponding to the muscle-type beta 1 and neuronal-type nAChR subunits may be correlated with the atypical cholinergic response of cochlear hair cells to agonists and antagonists.

Animals↗
PubMed1994

Five-year follow-up of microsurgical multiple internal thoracic artery grafts.

In a consecutive series of 143 patients requiring multiple coronary artery bypass grafts, 317 of 441 anastomoses (72%) were constructed from internal thoracic arteries. Of these 143 patients, 103 had bilateral, 51 sequential, and 49 free internal thoracic artery grafts. When compared with an earlier series of 494 patients who underwent only one internal thoracic artery anastomosis, the surgical morbidity and mortality were not increased, but, during 5 years of follow-up, the incidences of postoperative angina and myocardial infarction were found to decrease significantly--32.5% versus 10.5% (p < 0.001) and 5.7% versus 1.4% (p < 0.03), respectively. We conclude that, for patients with multivessel disease, multiple internal thoracic artery grafts confer better protection from the clinical manifestations of ischemic heart disease than does one internal thoracic artery graft. The use of high magnification (8 to 12x, surgical microscope) was essential to the success of this method.

Coronary Disease↗
PubMed1993

Sternal blood flow during mobilization of the internal thoracic arteries.

A laser Doppler tissue perfusion monitor was used to measure sternal blood flow before, during, and after mobilization of the internal thoracic arteries in 24 patients undergoing coronary artery bypass grafting. To minimize chest wall injury, a narrow pedicle was mobilized. Bilateral flow data were available from 15 of the 24 patients. Analysis of these 39 studies showed no significant reduction of sternal blood flow as a consequence of mobilization of the internal thoracic arteries except in 2 patients who were both diabetic and obese.

Aged↗
PubMed1993

Analysis of gamma-aminobutyric acidA receptor subunits in the mouse cochlea by means of the polymerase chain reaction.

Thirteen GABAA receptor subunits were examined in the cochlea of the CBAJ mouse by PCR analysis. Total RNA was extracted from the auditory organs of 14-18-day-old animals, and mRNA was isolated using oligo-dT cellulose. After reverse transcription, resulting cDNA was amplified by PCR with primers specific for nucleotide sequences representing GABAA subunits. PCR products corresponding to subunits alpha 1-alpha 6, beta 1-beta 3, and gamma 2 were amplified, whereas those representing gamma 1, gamma 3, and delta were not amplified above background. These results provide the most direct evidence to date that GABAA receptors composed of the detected subunits are expressed in the mammalian cochlea, lending new support to previous studies implicating GABA as a cochlear transmitter. The pronounced expression of alpha 2 and alpha 6 subunits suggests type II and "cerebellar-type" benzodiazepine pharmacology in the cochlea.

Animals↗
PubMed1989

Bilateral internal thoracic artery surgery: 17-year experience.

Angiographic comparisons of late morphology of internal thoracic artery (ITA) and saphenous vein grafts (SVG) in the same patients established morphologic superiority of the ITA grafts (1983). 15-year clinical follow-up of 748 consecutive patients having ITA and SVGs (532) or SVGs alone (216) established the clinical advantages given to patients by ITA grafts (1986): (1) higher cumulative survival rate (P less than 0.01); (2) less early recurrence of angina (P less than 0.01); (3) fewer late myocardial infarctions (P less than 0.02); (4) lower reoperation rate (P less than 0.001). Benefits to patients having bilateral ITA grafts (38) exceeded even those of single ITA grafts: (1) operative mortality = 0%; (2) cumulative survival (10 years) = 89.0%; (3) annual recurrence of angina = 1.5%; (4) annual late myocardial infarction = 1.1%; (5) mortality rate = 0%; (6) annual reoperation rate = 0%. These data prompted routine use of bilateral ITA grafts for all patients requiring multiple bypasses, and use of each ITA for as many bypasses as seemed feasible. Since 1986, ITA anastomoses have accounted for two thirds of anastomoses in all patients requiring multiple bypasses (average 3.2 anastomoses/patient). Results have been gratifying. Potential technical pitfalls are emphasized, and means of avoiding them described.

Adult↗