RESUMEN
OBJECTIVE: To examine the results of meta-analyses in otolaryngology and compare these results with the individual component studies that constitute each meta-analysis. DESIGN: A retrospective review of the literature. MAIN OUTCOME MEASURES: Studies that conducted pooled statistical systematic analyses indexed on MEDLINE for the 10-year period from January 1989 to January 1999 were selected for keyword or subject headings of meta-analysis and otolaryngology (N = 22). Analysis consisted of a modified funnel graph depiction of the individual studies that made up each meta-analysis. Each meta-analysis was evaluated for consistency among these individual studies and comparison of the median result with the weighted mean meta-analysis result. In addition, the methodologic quality of each meta-analysis was assessed in terms of the rigor with which component studies were evaluated. RESULTS: Ten (46%) of the 22 meta-analyses did not provide the individual study results that made up their meta-analyses. The results of 10 studies (46%) were similar to the median result of their individual component studies. The results of 2 studies (9%) differed from this median result, with widely heterogeneous component study results. CONCLUSIONS: A large proportion of meta-analyses in otolaryngology (46%) fail to provide the individual study results necessary to analyze the meta-analysis result critically. Most remaining studies do provide results that accurately compare with the median of their component study results. Only a small proportion of meta-analyses were found to have disparate results, and each appropriately discusses the heterogeneity of the individual studies that comprise their meta-analysis.
Asunto(s)
Metaanálisis como Asunto , Otolaringología , Estudios de Evaluación como Asunto , Humanos , Estudios RetrospectivosRESUMEN
Neurons of the avian cochlear nucleus, nucleus magnocellularis (NM), are activated by glutamate released from auditory nerve terminals. If this stimulation is removed, the intracellular calcium ion concentration ([Ca2+]i) of NM neurons rises and rapid atrophic changes ensue. We have been investigating mechanisms that regulate [Ca2+]i in these neurons based on the hypothesis that loss of Ca2+ homeostasis causes the cascade of cellular changes that results in neuronal atrophy and death. In the present study, video-enhanced fluorometry was used to monitor changes in [Ca2+]i stimulated by agents that mobilize Ca2+ from intracellular stores and to study the modulation of these responses by glutamate. Homobromoibotenic acid (HBI) was used to stimulate inositol trisphosphate (IP3)-sensitive stores, and caffeine was used to mobilize Ca2+ from Ca2+-induced Ca2+ release (CICR) stores. We provide data indicating that Ca2+ responses attributable to IP3- and CICR-sensitive stores are inhibited by glutamate, acting via a metabotropic glutamate receptor (mGluR). We also show that activation of C-kinase by a phorbol ester will reduce HBI-stimulated calcium responses. Although the protein kinase A accumulator, Sp-cAMPs, did not have an effect on HBI-induced responses. CICR-stimulated responses were not consistently attenuated by either the phorbol ester or the Sp-cAMPs. We have previously shown that glutamate attenuates voltage-dependent changes in [Ca2+]i. Coupled with the present findings, this suggests that in these neurons mGluRs serve to limit fluctuations in intracellular Ca2+ rather than increase [Ca2+]i. This system may play a role in protecting highly active neurons from calcium toxicity resulting in apoptosis.
Asunto(s)
Canales de Calcio/fisiología , Señalización del Calcio/fisiología , Núcleo Coclear/química , Núcleo Coclear/fisiología , Ácido Glutámico/farmacología , Receptores Citoplasmáticos y Nucleares/fisiología , Inhibidores de Adenilato Ciclasa , Adenilil Ciclasas/metabolismo , Alanina/análogos & derivados , Alanina/farmacología , Animales , Benzoatos/farmacología , Cafeína/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Quelantes/farmacología , Embrión de Pollo , Núcleo Coclear/citología , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacología , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Cisteína/análogos & derivados , Cisteína/farmacología , Ácido Egtácico/farmacología , Inhibidores Enzimáticos/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Colorantes Fluorescentes , Fura-2 , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Ácido Iboténico/análogos & derivados , Ácido Iboténico/farmacología , Receptores de Inositol 1,4,5-Trifosfato , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Neuronas/química , Neuronas/enzimología , Fármacos Neuroprotectores/farmacología , Neurotransmisores/farmacología , Técnicas de Placa-Clamp , Inhibidores de Fosfodiesterasa/farmacología , Rianodina/farmacología , Sistemas de Mensajero Secundario/efectos de los fármacos , Sistemas de Mensajero Secundario/fisiología , Tionucleótidos/farmacologíaRESUMEN
Neurons of the avian cochlear nucleus, nucleus magnocellularis (NM), are stimulated by glutamate, released from the auditory nerve, and GABA, released from both interneurons surrounding NM and from cells located in the superior olivary nucleus. In this study, the Ca2+ indicator dye Fura-2 was used to measure Ca2+ responses in NM stimulated by glutamate- and GABA-receptor agonists using a chicken brainstem slice preparation. Glutamatergically stimulated Ca2+ responses were evoked by kainic acid (KA), alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA), and N-methyl-D-aspartate (NMDA). KA- and AMPA-stimulated changes in [Ca2+]i were also produced in NM neurons stimulated in the presence of nifedipine, an L-type Ca2+ channel blocker, suggesting that KA- and AMPA-stimulated changes in [Ca2+]i were carried by Ca2(+)-permeable receptor channels. Significantly smaller changes in [Ca2+]i were produced by NMDA. When neurons were stimulated in an alkaline (pH 7.8) superfusate, NMDA responses were potentiated. KA- and AMPA-stimulated responses were not affected by pH. Several agents known to stimulate metabotropic receptors in other systems were tested on NM neurons bathed in a Ca2+ free-EGTA--buffered media, including L-cysteine sulfinic acid (L-CSA), trans-azetidine dicarboxylic acid (t-ADA), trans-aminocyclo-pentanedicarboxylic acid (t-ACPD), and homobromoibotenic acid (HBI). The only agent to reliably and dose-dependently increase [Ca2+]i was HBI, an analog of ibotenate. GABA also stimulated increases in [Ca2+]i in NM neurons. GABA-stimulated responses were reduced by agents that block voltage-operated channels and by agents that inhibit Ca2+ release from intracellular stores. Whereas GABA-A receptor agonist produced increases in [Ca2+]i GABA-B and GABA-C receptor agonists had no effect. There appear to be several ways for [Ca2+]i to increase in NM neurons. Presumably, each route represents a means by which Ca2+ can alter cellular processes.
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Calcio/metabolismo , Núcleo Coclear/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas del GABA/farmacología , Neuronas/efectos de los fármacos , Animales , Embrión de Pollo , Núcleo Coclear/citología , Núcleo Coclear/metabolismo , Colorantes Fluorescentes , Fura-2 , Técnicas In Vitro , Ácido Kaínico/farmacología , N-Metilaspartato/farmacología , Neuronas/metabolismo , Estimulación Química , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacologíaRESUMEN
1. Fura-2 imaging was used to measure the effects of glutamate on caffeine-sensitive Ca2+ stores in neurons of the avian cochlear nucleus, n. magnocellularis (NM). 2. On average, 100-mM caffeine stimulated a 250-nM increase in intracellular calcium ion concentration {[Ca2+]i} in Ca(2+)-free media; 1-mM glutamate significantly attenuated caffeine-stimulated Ca2+ responses. 3. The metabotropic glutamate receptor agonist, ACPD, also inhibited the caffeine-stimulated rise in [Ca2+]i. 4. Glutamate has an important role in regulating Ca2+ stores in NM neurons. Glutamate-deprivation (viz. cochlear removal) results in a rise in [Ca2+]i that may, in part, be the result of release from Ca2+ stores. We hypothesize that Ca(2+)-induced Ca2+ release stores (CICRs) may be involved in deprivation-induced cell death.
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Tronco Encefálico/efectos de los fármacos , Calcio/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Ácido Glutámico/farmacología , Neuronas/efectos de los fármacos , Animales , Tronco Encefálico/citología , Tronco Encefálico/metabolismo , Embrión de Pollo , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Neuronas/metabolismoRESUMEN
In an earlier study, epidermal growth factor (EGF) was shown to be effective in healing chronic tympanic membrane (TM) perforations in the chinchilla. The original protocol required rimming of the perforation's epithelial edge, application of a paper patch, placement of a Gelfoam pledget, and then administration of EGF solution. To develop a simple outpatient method of healing chronic TM perforations, an attempt was made to simplify the treatment protocol while preserving efficacy. In the modified experimental protocol, a large Gelfoam pledget was placed over the chronic perforation in contact with the residual TM, without mechanical disruption of the perforation edge or use of a paper patch. Then EGF in phosphate buffered saline (PBS) was applied to the Gelfoam pledget (50 microL of 0.5 mg EGF/mL PBS). A series of control ears received Gelfoam pledgets and PBS. Complete closure of the TM perforation was achieved in 80 percent (12/15) of treated ears but in only 20 percent (3/15) of controls (p < 0.01), results similar to those obtained with the original protocol. At long-term follow-up, 4 to 9 months after treatment, EGF-healed TMs were histologically similar to normal TMs, both in their overall thickness and in the relative proportions of the three component layers. In contrast, the few spontaneously healed TMs from the control group were less than half the thickness of normal TMs. To ascertain the optimal EGF concentration for therapeutic effect, a dose ranging study was undertaken.(ABSTRACT TRUNCATED AT 250 WORDS)