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Anand N Mhatre

Publications and source records attributed to Anand N Mhatre.

10 recordsLinked to original sources
PubMed2003

Effect of SOD1 overexpression on age- and noise-related hearing loss.

Reactive oxygen species (ROS) have been implicated in hearing loss associated with aging and noise exposure. Superoxide dismutases (SODs) form a first line of defense against damage mediated by the superoxide anion, the most common ROS. Absence of Cu/Zn SOD (SOD1) has been shown to potentiate hearing loss related to noise exposure and age. Conversely, overexpression of SOD1 may be hypothesized to afford a protection from age- and noise-related hearing loss. This hypothesis may be tested using a transgenic mouse model carrying the human SOD1 gene. Contrary to expectations, here, we report that no protection against age-related hearing loss was observed in mice up to 7 months of age or from noise-induced hearing loss when 8 week old mice were exposed to broadband noise (4-45 kHz, 110 dB for 1 h). Mitochondrial DNA deletion, an index of aging, was elevated in the acoustic nerve of transgenic mice compared to nontransgenic littermates. The results indicate the complexity of oxidative metabolism in the cochlea is greater than previously hypothesized.

Age Factors↗
PubMed2003

Macrothrombocytopenia and progressive deafness is due to a mutation in MYH9.

BACKGROUND: In 1992, a family with hereditary macrothrombocytopenia and progressive sensorineural hearing impairment without renal dysfunction was described. Recently, mutations in MYH9, a nonmuscle myosin heavy chain, have been found in several forms of hereditary macrothrombocytopenia. HYPOTHESIS: The hereditary macrothrombocytopenia and hearing loss in the previously reported family is due to a mutation in MYH9 gene. METHODS: Genomic DNA was extracted from the affected proband. Mutation screening of all MYH9 coding exons was carried out using denaturing high-performance liquid chromatography. Abnormal results were followed by direct sequencing of the exon and comparison of the sequence with the normal MYH9 sequence. RESULTS: The results of denaturing high-performance liquid chromatography suggested a potential sequence alteration in exon 30 of MYH9. Direct sequence analysis of this exon in the affected individual identified a G to A single base pair transition at nucleotide 4270 altering codon 1424. This mutations leads to an amino acid change from aspartate (D) to asparagine (N) in the highly conserved coiled-coil domain. CONCLUSIONS: A single base pair transition in MYH9, resulting in an amino acid substitution D1424N, is responsible for macrothrombocytopenia and hearing loss in the kindred under study. The presence of hearing impairment and the absence of renal symptoms, as reported in other families with the same mutation MYH9, further highlights the role of genetic background in expression and modification of the affected phenotype.

Amino Acid Substitution↗
PubMed2002

Aquaporin 4 expression in the mammalian inner ear and its role in hearing.

Aquaporin 4 (Aqp4), a member of a family of water transport proteins, is a candidate for playing a critical role in inner ear fluid homeostasis. In this study, we assess cross-species Aqp4 expression in the inner ear, sequence conservation in the 5'-UTR, and hearing in Aqp4 knockout mice. A single Aqp4 isoform was expressed in a highly conserved pattern within the supporting epithelia surrounding the sensory cells of the auditory and vestibular sensory organs and the glial cells surrounding the auditory nerve of the mouse and rat. In the 5'-UTR of mouse and rat Aqp4 gene, sequence conservation was highest in the region spanning the transcription start site. Aqp4 knockout mice demonstrated impaired hearing, but normal neural conduction time. Similar Aqp4 expression pattern and regulatory sequence conservation across species suggest a highly conserved role for Aqp4 in the inner ear. In the Aqp4 deficient mouse, cochlear dysfunction is suggested as the primary cause of hearing impairment in the absence of neural conduction abnormality.

5' Untranslated Regions↗
PubMed2002

Role of Epstein-Barr virus and cytomegalovirus in the etiology of benign parotid tumors.

BACKGROUND: Pleomorphic adenomas and Warthin's tumors are the two most common benign parotid tumors. Previous studies investigating the role of viruses in tumorigenesis of these neoplasms have been conflicting. The aim of this study was to determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) might play a role in the pathogenesis of pleomorphic adenomas and Warthin's tumors. METHODS: Paraffin-embedded surgical specimens of 24 pleomorphic adenomas, 10 Warthin's tumors, and 13 normal parotid tissues were obtained from the University of California-San Francisco Pathology Department. Genomic DNA was extracted from the specimens, and primers for connexin 26, a gap junction protein, were used to confirm the integrity of this DNA. The presence or absence of EBV and CMV DNA within the samples was determined with PCR-based assays, in which radiolabeled primers were used for maximal sensitivity of detection. RESULTS: PCR analysis of serially diluted control DNA revealed that using radiolabeled primers, five copies of viral DNA could be detected. By use of this method, we showed that none of the 24 pleomorphic adenomas, 10 Warthin's tumors, or 13 normal parotid samples contained EBV DNA or CMV DNA. CONCLUSIONS: These results do not support CMV or EBV as etiologic factors in pleomorphic adenomas or Warthin's tumors. In addition, normal parotid seems not to harbor either of these viruses. Future studies with larger numbers of specimens are needed to confirm these findings.

Adenolymphoma↗
PubMed2002

Aquaporin-2 expression in the mammalian cochlea and investigation of its role in Meniere's disease.

The expression pattern of aquaporin-2 (AQP2), a vasopressin regulated member of the aquaporin gene family, in the cochlea and its potential role in Meniere's disease was investigated. RT-PCR screen of multiple rat tissues identified AQP2 transcripts in the cochlea, testis and kidney and an absence of tissue-specific splice variants. The level of AQP2 transcript in the cochlea was 10-fold lower relative to its expression in the testis and kidney. Western blot analysis demonstrated a single, 29 kDa band in the membrane fractions from cochlea, testis and the kidney. In the rat and mouse cochlea, AQP2 was expressed in the structures bordering the endolymph, including Reissner's membrane, the organ of Corti, inner and outer sulcus cells and the spiral limbus. A mutation screen of AQP2 in 12 individuals with Meniere's disease did not identify any sequence alterations or mutations within the four coding exons of AQP2 and their intron-exon junctions. The physiological role of AQP2 in water transport and its expression pattern in the cochlea suggests an important role for AQP2 in fluid homeostasis of the inner ear; however, its role in the pathogenesis in Meniere's disease remains to be established.

Animals↗
PubMed2002

In vitro and in vivo assessment of the ability of adeno-associated virus-brain-derived neurotrophic factor to enhance spiral ganglion cell survival following ototoxic insult.

OBJECTIVES/HYPOTHESIS: Auditory dysfunction following ototoxic insult results from loss of cochlear hair cells. Secondary degeneration of auditory neurons ensues from withdrawal of neurotrophic support from hair cells and can be prevented with administration of neurotrophins. Administration of adeno-associated virus containing the gene for brain-derived neurotrophic factor will promote spiral ganglion neuron survival after the destruction of hair cells. METHODS: Prevention of aminoglycoside-induced spiral ganglion neuron loss through the expression of brain-derived neurotrophic factor mediated by means of the adeno-associated virus was tested in vitro in cochlear explants and in vivo in mammalian cochlea. RESULTS: Neuronal survival was significantly enhanced in adeno-associated virus-brain-derived neurotrophic factor transfected rat cochlear explants compared with control samples (30% vs. 19%, P <.05) following exposure to aminoglycoside. Following deafening with aminoglycoside and loop diuretic and introduction of adeno-associated virus-brain-derived neurotrophic factor through osmotic minipump, the experimental group of animals infused with adeno-associated virus-brain-derived neurotrophic factor displayed enhanced spiral ganglion neuron survival in the basal turn of the cochlea when compared with the control group infused with adeno-associated virus containing green fluorescent protein reporter gene. CONCLUSIONS: Administration of adeno-associated virus-brain-derived neurotrophic factor enhances spiral ganglion neuron survival following ototoxic exposure in vitro and in vivo. These studies lay the groundwork for further exploration of its application as an adjunct therapy for patients undergoing cochlear implantation because the success of implantation depends directly on the population of neurons available for electrical stimulation.

Adenoviridae↗
PubMedDate not supplied

Current issues in cochlear gene transfer.

Cochlear gene therapy represents a potential experimental and therapeutic tool to understand and treat deafness. In designing cochlear gene transfer studies, the chosen route of delivery of vector and the choice of gene therapy vector have to be given careful consideration. Several different routes of delivery have been tested in our laboratory including infusion with osmotic minipump, direct microinjection into the cochlea and application of vector-transgene complex-soaked Gelfoam((R)) into the direct contact with the round window membrane. In our experience, the latter is an easy, safe and atraumatic technique to deliver gene into the cochlea. A number of different gene transfer vectors have been investigated in vivo for their efficacy, utility and safety in intracochlear gene transfer. Vectors successfully studied include cationic liposomes, adeno-associated virus, adenovirus, lentivirus, herpes simplex virus and vaccinia virus. While the viral vectors offer clear experimental advantages, human gene therapy in the future will likely utilize nonviral vectors to maximize safety. Finally, safety issues regarding dissemination of gene transfer vectors beyond the target cochlea will need to be adequately addressed.

Animals↗