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Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.T260A, p.R422W, and p.R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%‒49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‒17.9%, which was significantly higher than that (6.9%‒7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.
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Humanos , Fator de Indução de Apoptose/metabolismo , NAD/metabolismo , Dimerização , ApoptoseRESUMO
Objective To study the auditory brainstem response (ABR) of normal adult CBA,C57BL,Kunming and 129 mice and analyze the ABR thresholds and latencies in order to obtain normal values and standardized testing process,thereby providing important reference for future auditory hearing research in mouse.Methods Six -week-old normal mice of CBA,C57BL,Kunming and 129(each strain containing 20 ears of 20 mice) were used in this study.ABR test with both the click and tone burst were carried on.The incidence of each wave and the thresholds and latencies of various strains of mice were recorded.Results For these four strains of mice,wave Ⅱ had the highest occurrence rate and was used to determine the thresholds.Four strains of mice all were sensitive to the sound at 8,12,16 kHz,most to 12 kHz.Under anesthesia condition,the latency of each ABR wave prolonged as testing time increase,especially the waves Ⅲ ～ V which reflected the functions of the part near the cerebral center.Conclusion Under anesthesia state,for these four strains of mice,wave Ⅱ has the highest occurrence rate and is used to determine the threshold.We determine the intensity level at which Wave Ⅱ just appeared as the ABR threshold.The stain of CBA mice is the best one to establish an animal model related to hearing function research because ABR of the other three strains are not stable as the CBA mice.Wave SP can reflect the hair cell functions indirectly.
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Objective To investigate the relationship between serum uric acid (SUA) levels and insulin secretion and insulin re-sistance in subjects with different glucose loads .Methods Totally 389 patients met the requirements ,and the subjects underwent o-ral glucose tolerance test (OGTT) to measure fasting SUA ,OGTT 0 ,30 ,60 ,120 min glucose (GLU) and insulin (INS) .According to the results of OGTT ,the subjects were divided into normal glucose tolerance group (NGT group ,n= 88) ,pre diabetes group (preDM group ,n=109) and diabetes mellitus (DM group ,n= 182) ,the insulin secretion index (IGI) ,120 min insulin secretion (AUC INS120/AUC GLU120 ) ,insulin resistance index (HOMA-IR) and Matsuda index were calculated .Calculated the quartile of SUA to divide the subjects to four groups ,the levels of insulin secretion and insulin resistance were compared between different glu-cose loading groups at different levels of SUA .The linear regression equation between SUA and insulin secretion and HOMA-IR was calculated .Results The SUA in DM group was lower than that of PreDM group [(346 .66 ± 90 .60)mmol/L vs .(367 .36 ± 92 .34)mmol/L] ,but slightly higher than that of NGT group[(339 .34 ± 89 .51)mmol/L] ,the difference was statistically significant (P<0 .01) .The IGI index and AUC INS120/AUC GLU120 index of DM group decreased with the increase of SUA (P<0 .01) ,and the Matsuda index decreased with the increase of SUA level (P<0 .05) .The linear equation of SUA and the IGI ,AUC INS120/AUC GLU120 ,HOMA-IR ,Matsuda index was Y=4 .050+0 .144X ,Y=2 .343+0 .206X ,Y =1 .288+0 .176X ,Y=129 .373-0 .202X re-spectively .Conclusion SUA was significantly associated with insulin secretion and insulin sensitivity .Insulin secretion in group DM increased with increasing SUA levels ,and insulin sensitivity decreased with increasing SUA levels .The linear equation of SUA and insulin secretion ,insulin sensitivity may be used to assess insulin function .
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Objective To investigate the relationship between serum uric acid (SUA) levels and insulin secretion and insulin re-sistance in subjects with different glucose loads .Methods Totally 389 patients met the requirements ,and the subjects underwent o-ral glucose tolerance test (OGTT) to measure fasting SUA ,OGTT 0 ,30 ,60 ,120 min glucose (GLU) and insulin (INS) .According to the results of OGTT ,the subjects were divided into normal glucose tolerance group (NGT group ,n= 88) ,pre diabetes group (preDM group ,n=109) and diabetes mellitus (DM group ,n= 182) ,the insulin secretion index (IGI) ,120 min insulin secretion (AUC INS120/AUC GLU120 ) ,insulin resistance index (HOMA-IR) and Matsuda index were calculated .Calculated the quartile of SUA to divide the subjects to four groups ,the levels of insulin secretion and insulin resistance were compared between different glu-cose loading groups at different levels of SUA .The linear regression equation between SUA and insulin secretion and HOMA-IR was calculated .Results The SUA in DM group was lower than that of PreDM group [(346 .66 ± 90 .60)mmol/L vs .(367 .36 ± 92 .34)mmol/L] ,but slightly higher than that of NGT group[(339 .34 ± 89 .51)mmol/L] ,the difference was statistically significant (P<0 .01) .The IGI index and AUC INS120/AUC GLU120 index of DM group decreased with the increase of SUA (P<0 .01) ,and the Matsuda index decreased with the increase of SUA level (P<0 .05) .The linear equation of SUA and the IGI ,AUC INS120/AUC GLU120 ,HOMA-IR ,Matsuda index was Y=4 .050+0 .144X ,Y=2 .343+0 .206X ,Y =1 .288+0 .176X ,Y=129 .373-0 .202X re-spectively .Conclusion SUA was significantly associated with insulin secretion and insulin sensitivity .Insulin secretion in group DM increased with increasing SUA levels ,and insulin sensitivity decreased with increasing SUA levels .The linear equation of SUA and insulin secretion ,insulin sensitivity may be used to assess insulin function .
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Objective To study the effect of chloral hydrate on click sound evoked auditory brainstem re-sponse (ABR) in healthy adult guinea pig .Methods A total of 20 healthy wild type albino male guinea pigs were se-lected for ABR assessment with click sound stimulation conscious and cholral hydrate anesthesia conditions .The ABR threshold was determined according to the wave that presents highest occurrence rate under different stimulus intensity .The latency ,interpeak latency of each wave at 90 dB peSPL stimulation as well as the amplitude of waveⅡ ,Ⅲ ,Ⅳ under different stimulus intensity were recorded .Results The ABR threshold in chloral hydrate anes-thesia was 25 .50 ± 2 .76 dB peSPL and at the waking state was 28 .5 ± 3 .66 dB peSPL from control group (P>0 .05) .The latencies of each wave recorded under chloral hydrate anesthesia state were prolonged compared to those of under waking state ,wave Ⅲ ,Ⅳ and Ⅴ had significance differences (P0 .05) .The interpeak latency between wave Ⅰ - Ⅴ ,Ⅲ - Ⅳ ,Ⅳ - Ⅴ in chloral hydrate anesthesia were longer compared to those of under waking state with significant differences (P 0 .05) .The amplitude and occurrence rate of wave Ⅱwere the highest among all the waves in both experimental group and control group .The amplitude of wave Ⅱ and Ⅲ in chloral hydrate anesthesia was higher than that of the waking state under acoustic stimulation conditions ofhigh intensity(P<0 .05) while the amplitude of wave Ⅳ was lower than the waking state (P<0 .05) .Conclusion The chloral hydrate anesthesia may be able to apparently lengthen the ABR latencies of wave Ⅲ ,Ⅳ ,Ⅴ and affect the amplitude .This effect should be considered during the assessment of ABR under anesthesia state in guinea pig ;The ABR threshold of guinea pig could be determined according to the wave Ⅱ because it 's highest occurrence rate .
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Hearing loss is the most frequent sensorineural disorder worldwild, among which about 50% are caused by genetic factors. TMC1 is one of the common genes causing hereditary hearing loss. TMC1 mutations can cause pre-lingual profound/severe autosomal recessive (DFNB7/11) and post-lingual progressive autosomal dominant (DFNA36) non-syndromic hearing loss. Murine models studies show that TMC1, 2 are expressed in cochlea inner and outer hair cells and maintain normal mechanoelectrical transduction (MET) functions of the hair cells. A growing number of evidence indicate that TMC1, 2 are components of the MET complex. It is necessary to definite the precise distribution and exact function of TMC1, 2, because it is important to understand the regulating mechanism of auditory function.
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Animais , Humanos , Camundongos , Cóclea , Metabolismo , Modelos Animais de Doenças , Células Ciliadas Auditivas Externas , Metabolismo , Perda Auditiva Neurossensorial , Genética , Proteínas de Membrana , Genética , MutaçãoRESUMO
OBJECTIVE@#The aim of this retrospective study was to analyze the recovery rate of sudden sensorineural hearing loss in children, and explore the prognostic factors in order to guide the clinical diagnosis and treatment.@*METHOD@#A retrospective review was conducted for the prognosis of children with sudden sensorineural hearing loss during the past 5 years (from November 2010 to May 2015) in Chinese PLA General Hospital. This paper have a complete clinical data of 101 patients (113 ears)with sudden hearing loss, ranging from 0 to 18 years old Patients were divided into four groups according to hearing recovery and eight putative prognostic factors were analyzed.@*RESULT@#Among 101 patients (113 ears), the ratio of male and female was 60:53. Treatment was initiated from 1 to 183 days after disease onset, with an average of (18.5 ± 22.1) d. Bilateral and unilateral hearing loss were 24 ears and 89 ears, respectively. The proportion of mild hearing loss, moderate hearing loss, severe hearing loss and profound hearing loss were 7.1%, 6.2%, 23.9% and 62.8%, respectively. Vertigo and tinnitus occurred in 54.9% and 77.9% of the patients, respectively. After the treatment, the complete recovery rate was 9.7% and the overall recovery rate was 36.3%. The degree of hearing loss, earlier treatment onset, sex and bilateral involvement were significantly associated with hearing recovery (P < 0.05).@*CONCLUSION@#Sudden sensorineural hearing loss in children was generally identified as severe and profound hearing loss, but after positive and timely treatment, it can be improved or even cured. The mild hearing loss, earlier treatment onset, unilateral hearing loss and female were positive prognostic factors. The concurrence of tinnitus or vertigo, the results of ABR and DPOAE had no significant influence on prognosis.
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Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Perda Auditiva Neurossensorial , Diagnóstico , Perda Auditiva Súbita , Diagnóstico , Perda Auditiva Unilateral , Diagnóstico , Testes Auditivos , Prognóstico , Estudos Retrospectivos , Zumbido , VertigemRESUMO
Objective To explore the relationship between fasting serum concentration of uric acid (SUA)and the secretion of insulin under oral glucose tolerance test(OGTT)in 877 eligible subjects.Methods A 75g OGTT was administrated to all 877 eligible subjects,fasting uric acid,concentration of glucose and insulin of 0,30,60,120 and 180 min utes after OGTT were measured.Subjects were divided into high SUA group (HUA)and normal SUA group (NUA)according the concen-tration of SUA.SPSS 13.0 were used to analyze these data.Results Subjects in HUA had higher concentration of insulin in 0,30,60,120 and 180 min utes than NUA.There were positive correlation between SUA and INS in 0,30,60,120 and 180 min utes,Pearson r-value was 0.107,0.154,0.195,0.157 and 0.112(all P <0.01)respectively.By stepwise linear regression analyze,there were four parameters correlated with SUA:gender(female),INS60,cholesterol (TC),high density lipoprotein (HDL),β-vaule was -0.214,0.194,0.253,-0.119 (all P <0.01)respectively.Conclusion SUA positive correlated with secretion of INS after glycemia burden,SUA may be used as a potential biomark of secretin of INS (especially the concentra-tion of INS 60).
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Objective To sum up the specificity in clinical care of repetitive transcranial magnetic stimulation (rTMS),and provide reference for putting forward scientific and effective clinical care project.Methods 200 male schizophrenia patients with rTMS treatment were divided into the research group and the control group with 100 cases in each group randomly.Then,the research group adopted the specific nursing which was obtained from the pre-experiment while the control group adopted the routine care.Moreover,NORS scale was used to evaluate the treatment effect.Changhai Pain Measuring Scale was employed to assess headaches in pre-treatment and post-treatment.Results The data of the research group in NORS scale was obviously lower than the control group,and the difference between two groups had statistical significance.No case occurred adverse reaction in the research group,in contract with many cases with adverse reaction in the control group.Conclusions Specific nursing can reduce complications effectively for schizophrenia patients receiving rTMS treatment,and it is a scientific,effective and mature clinical care method.