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1.
Am J Med Genet A ; 152A(3): 646-52, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20186779

RESUMO

Mutations in miRNA genes have been implicated in hearing loss in human families and mice. It is also possible that mutations in miRNA binding sites of inner ear targets alter gene expression levels and lead to hearing loss. To investigate these possibilities we screened predicted target genes of the miR-183 miRNA cluster known to be expressed in the inner ear sensory epithelium. In one Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL), we identified a homozygous variant in a predicted miR-96/182 binding site in the 3'UTR of the RDX (DFNB24) gene. However, in vitro functional studies showed that this site is not a functional target for miR-96/182. We extended our study to include the miR-183 genes themselves and 24 additional predicted target genes of the miRNA-183 cluster. Screening these miRNAs and target sequences in numerous families segregating either autosomal dominant non-syndromic deafness (ADNSHL) or ARNSHL did not identify any potential deafness-causing mutations. These results suggest that mutations disrupting gene regulation by the miR-183 cluster are not a common cause of human hearing loss.


Assuntos
Surdez/genética , MicroRNAs/genética , Mutação , Regiões 3' não Traduzidas , Animais , Sequência de Bases , Sítios de Ligação/genética , Proteínas do Citoesqueleto/genética , Primers do DNA/genética , Feminino , Genes Dominantes , Genes Recessivos , Homozigoto , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Família Multigênica , Linhagem , Homologia de Sequência do Ácido Nucleico
2.
Mol Ther ; 16(2): 224-236, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28178538

RESUMO

Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration.

3.
Mol Ther ; 16(2): 224-36, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18223547

RESUMO

Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration.


Assuntos
Modelos Animais de Doenças , Perda Auditiva/terapia , Animais , Terapia Genética/métodos , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Modelos Teóricos , Interferência de RNA , Transplante de Células-Tronco/métodos
4.
Int Arch Otorhinolaryngol ; 22(3): 317-329, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29983775

RESUMO

Introduction A majority of otolaryngologists have not had direct experience with many vaccine-preventable diseases since the creation of national vaccination programs. Despite the elimination of endemic transmission of some of these diseases in the United States, outbreaks can occur anywhere and still pose a threat to public health around the world. Recent outbreaks and changing trends in exemption rates indicate that it is important for physicians to maintain a working knowledge of how these diseases present and of the recommended treatment guidelines. Objectives This review will evaluate the current state of vaccination rates, vaccine exemption rates and disease incidence in the United States and in the world. It will also examine the clinical presentation and treatment recommendations of these diseases. Data Synthesis United States estimated vaccination rates, vaccine exemption rates and vaccine-preventable disease incidences were obtained from data compiled by the Centers for Disease Control and Prevention. World vaccination rates and disease incidences were obtained from the World Health Organization databases, which compile official figures reported by member states. A PubMed literature review provided information on the current state of vaccination exemptions and outbreaks in the United States. Conclusion Vaccination and vaccine exemption rates continue to put the United States and many areas of the world at risk for outbreaks of vaccine-preventable diseases. Clinical guidelines should be reviewed in the event of a local outbreak.

5.
J Appl Physiol (1985) ; 96(6): 2265-72, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14978002

RESUMO

The locations, projections, and functions of the intracardiac ganglia are incompletely understood. Immunocytochemical labeling with the general neuronal marker protein gene product 9.5 (PGP 9.5) was used to determine the distribution of intracardiac neurons throughout the cat atria and ventricles. Fluorescence microscopy was used to determine the number of neurons within these ganglia. There are eight regions of the cat heart that contain intracardiac ganglia. The numbers of neurons found within these intracardiac ganglia vary dramatically. The total number of neurons found in the heart (6,274 +/- 1,061) is almost evenly divided between the atria and the ventricles. The largest ganglion is found in the interventricular septum (IVS). Retrogradely labeled fluorescent tracer studies indicated that the vagal intracardiac innervation of the anterior surface of the right ventricle originates predominantly in the IVS ganglion. A cranioventricular (CV) ganglion was retrogradely labeled from the anterior surface of the left ventricle but not from the anterior surface of the right ventricle. These new neuroanatomic data support the prior physiological hypothesis that the CV ganglion in the cat exerts a negative inotropic effect on the left ventricle. A total of three separate intracardiac ganglia innervate the left ventricle, i.e., the CV, IVS, and a second left ventricular (LV2) ganglion. However, the IVS ganglion provides the major source of innervation to both the left and right ventricles. This dual innervation pattern may help to coordinate or segregate vagal effects on left and right ventricular performance.


Assuntos
Gânglios Parassimpáticos/fisiologia , Sistema de Condução Cardíaco/fisiologia , Coração/inervação , Nervo Vago/fisiologia , Animais , Transporte Axonal , Gatos , Coração/anatomia & histologia , Átrios do Coração/anatomia & histologia , Átrios do Coração/inervação , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/inervação , Modelos Animais
6.
J Appl Physiol (1985) ; 96(6): 2279-87, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14978003

RESUMO

The vagal postganglionic control of cardiac rate is mediated by two intracardiac ganglia, i.e., the sinoatrial (SA) and posterior atrial (PA) ganglia. Nothing is known about the vagal preganglionic neurons (VPNs) that innervate the PA ganglion or about the neurochemical anatomy of central afferents that innervate these VPNs. These issues were examined using light microscopic retrograde labeling methods and dual-labeling electron microscopic histochemical and immunocytochemical methods. VPNs projecting to the PA ganglion are found in a narrow column exclusively in the ventrolateral nucleus ambiguus (NA-VL). These neurons are relatively large (37.6 +/- 2.7 microm by 21.3 +/- 3.4 microm) with abundant cytoplasm and intracellular organelles, rare somatic and dendritic spines, round uninvaginated nuclei, and myelinated axons. Previous physiological data indicated that microinjections of neuropeptide Y (NPY) into the NA-VL cause negative chronotropic effects. The present morphological data demonstrate that NPY-immunoreactive nerve terminals formed 18 +/- 4% of the axodendritic or axosomatic synapses and close appositions on VPNs projecting to the PA ganglion. Three approximately equal populations of VPNs in the NA-VL were retrogradely labeled from the SA and PA ganglia. One population each projects to the SA ganglion, the PA ganglion, or to both the SA and PA ganglia. Therefore, there are both shared and independent pathways involved in the vagal preganglionic controls of cardiac rate. These data are consistent with the hypothesis that the central and peripheral parasympathetic controls of cardiac rate are coordinated by multiple potentially redundant and/or interacting pathways and mechanisms.


Assuntos
Gânglios Parassimpáticos/fisiologia , Frequência Cardíaca/fisiologia , Coração/inervação , Terminações Nervosas/fisiologia , Neuropeptídeo Y/análise , Sinapses/fisiologia , Nervo Vago/fisiologia , Animais , Transporte Axonal/fisiologia , Gatos , Gânglios Parassimpáticos/citologia , Microscopia de Fluorescência , Modelos Animais , Terminações Nervosas/ultraestrutura , Sinapses/ultraestrutura
7.
Int. arch. otorhinolaryngol. (Impr.) ; 22(3): 317-329, July-Sept. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-975585

RESUMO

Abstract Introduction A majority of otolaryngologists have not had direct experience with many vaccine-preventable diseases since the creation of national vaccination programs. Despite the elimination of endemic transmission of some of these diseases in the United States, outbreaks can occur anywhere and still pose a threat to public health around the world. Recent outbreaks and changing trends in exemption rates indicate that it is important for physicians to maintain a working knowledge of how these diseases present and of the recommended treatment guidelines. Objectives This review will evaluate the current state of vaccination rates, vaccine exemption rates and disease incidence in the United States and in the world. It will also examine the clinical presentation and treatment recommendations of these diseases. Data Synthesis United States estimated vaccination rates, vaccine exemption rates and vaccine-preventable disease incidences were obtained from data compiled by the Centers for Disease Control and Prevention. World vaccination rates and disease incidences were obtained from the World Health Organization databases, which compile official figures reported by member states. A PubMed literature review provided information on the current state of vaccination exemptions and outbreaks in the United States. Conclusion Vaccination and vaccine exemption rates continue to put the United States and many areas of the world at risk for outbreaks of vaccine-preventable diseases. Clinical guidelines should be reviewed in the event of a local outbreak.


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Surtos de Doenças/estatística & dados numéricos , Vacinação/estatística & dados numéricos , Otorrinolaringologistas/educação , Ásia , Rubéola (Sarampo Alemão)/prevenção & controle , Rubéola (Sarampo Alemão)/epidemiologia , Estados Unidos , América , Vacinas , Saúde Global/estatística & dados numéricos , Incidência , África , Difteria/prevenção & controle , Difteria/epidemiologia , Europa (Continente) , Erradicação de Doenças/estatística & dados numéricos , Infecções por Haemophilus/prevenção & controle , Sarampo/prevenção & controle , Sarampo/epidemiologia , Caxumba/prevenção & controle , Caxumba/epidemiologia
8.
Hear Res ; 277(1-2): 28-36, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21530627

RESUMO

Gene-based therapeutics are being developed as novel treatments for genetic hearing loss. One roadblock to effective gene therapy is the identification of vectors which will safely deliver therapeutics to targeted cells. The cellular heterogeneity that exists within the cochlea makes viral tropism a vital consideration for effective inner ear gene therapy. There are compelling reasons to identify a viral vector with tropism for organ of Corti supporting cells. Supporting cells are the primary expression site of connexin 26 gap junction proteins that are mutated in the most common form of congenital genetic deafness (DFNB1). Supporting cells are also primary targets for inducing hair cell regeneration. Since many genetic forms of deafness are congenital it is necessary to administer gene transfer-based therapeutics prior to the onset of significant hearing loss. We have used transuterine microinjection of the fetal murine otocyst to investigate viral tropism in the developing inner ear. For the first time we have characterized viral tropism for supporting cells following in utero delivery to their progenitors. We report the inner ear tropism and potential ototoxicity of three previously untested vectors: early-generation adenovirus (Ad5.CMV.GFP), advanced-generation adenovirus (Adf.11D) and bovine adeno-associated virus (BAAV.CMV.GFP). Adenovirus showed robust tropism for organ of Corti supporting cells throughout the cochlea but induced increased ABR thresholds indicating ototoxicity. BAAV also showed tropism for organ of Corti supporting cells, with preferential transduction toward the cochlear apex. Additionally, BAAV readily transduced spiral ganglion neurons. Importantly, the BAAV-injected ears exhibited normal hearing at 5 weeks of age when compared to non-injected ears. Our results support the use of BAAV for safe and efficient targeting of supporting cell progenitors in the developing murine inner ear.


Assuntos
Adenoviridae/genética , Surdez/terapia , Dependovirus/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos , Células Labirínticas de Suporte/virologia , Órgão Espiral/virologia , Tropismo Viral , Estimulação Acústica , Animais , Audiometria de Tons Puros , Limiar Auditivo , Surdez/genética , Surdez/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico , Técnicas de Transferência de Genes/efeitos adversos , Terapia Genética/efeitos adversos , Vetores Genéticos/efeitos adversos , Idade Gestacional , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Células Labirínticas de Suporte/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microinjeções , Microscopia de Fluorescência , Órgão Espiral/embriologia , Órgão Espiral/metabolismo , Órgão Espiral/fisiopatologia , Células-Tronco/virologia , Transdução Genética
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