[Mild hypothermia combined with hydrogen sulfide alleviates hippocampal endoplasmic reticulum stress after global cerebral ischemia-reperfusion].

Objective: To investigate the effect of mild hypothermia combined with hydrogen sulfide on hippocampal endoplasmic reticulum stress (ERS) after global cerebral ischemia-reperfusion (I/R) injury. Methods: Sixty healthy male Sprague-Dawley rats, 8-10 week old, weighing 280-320 g, were randomly divided into 5 groups (n=12) using a random number table: sham operation group (group Sham), global cerebral I/R group (group I/R), hydrogen sulfide group (group H(2)S), mild hypothermia group (group MH) and hydrogen sulfide + mild hypothermia group (group H(2)S+ MH). Cardiac arrest was induced with transoesophageal cardiac pacing followed by cardiopulmonary resuscitation to establish the global cerebral I/R model. The administration regimen for sodium hydrosulfide (NaHS) was as follows: Sodium hydrosulfide was intraperitoneal injection as a bolus of 2.5 mg/kg immediately restoration of spontaneous circulation. The implementation of mild hypothermia: wipe the body surface of rats with ethanol immediately after restoration of spontaneous circulation, and reduce the rectal temperature to 32-34 ℃ within 15 min, and maintain 6 h with the ice bag. At 72 h of reperfusion, neurological deficit was scored, and the rats were sacrificed (Neurological Deficit Scores, NDS), the expression of glucose-regulated protein 78 (GRP78), CHOP and Caspase-12 were detected by Western blot. After reperfusion 72 h, the hippocampal tissue were removed and stained with haematoxylin and eosin to examine the pathological findings in hippocampal CA1 area (under microscope). The apoptosis rate of hippocampal CA1 area cells was detected by TUNEL staining and the apoptosis index was calculated. Results: The expression levels of endoplasmic reticulum stress marker, GRP78, CHOP and Caspase-12, were upregulates during the global cerebral ischemia reperfusion injury, indicating activation of severe endoplasmic reticulum stress. The GRP78 contents of Sham group, I/R group, H(2)S group, MH group and H(2)S+ MH group were as follows: GRP78: 0.11±0.03, 1.11±0.10, 0.67±0.09, 0.66±0.08, 0.48±0.04, CHOP contents: 0.16±0.03, 1.60±0.11, 1.39±0.09, 1.34±0.08, 1.13±0.09, Caspase-12 contents: 0.09±0.02, 0.87±0.08, 0.65±0.08, 0.59±0.06, 0.45±0.06, the differences were statistically significant (F=147.569, 264.983, 119.356, all P<0.01). The apoptosis index of Sham group, I/R group, H(2)S group, MH group and H(2)S+ MH group were as follows: (1.83±0.75)%, (53.17±4.62)%, (35.17±2.14)%, (32.67±2.25)%, (17.83±2.79)%, the differences were statistically significant (F=284.962, P<0.01). The neurological deficit scores of Sham group, I/R group, H(2)S group, MH group and H(2)S+ MH group were as follows: 0%, (76±9)%, (54±5)%, (47±6)%, (35±6)%, the differences were statistically significant(F=135.218, P<0.01). Conclusion: Mild hypothermia combined with hydrogen sulfide alleviates hippocampal endoplasmic reticulum stress after global cerebral ischemia-reperfusion, and the combined effect is better than that of a single application.

Genetic variant rs4982958 at 14q11.2 is associated with allergic rhinitis in a Chinese Han population running title: 14q11.2 is a susceptibility locus for allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is one of the most common diseases caused by the combined effects of intrinsic factors (susceptibility genes and immunological status) and the external environment. Analyses of ascendant family history of atopic disease suggest that AR and atopic dermatitis might share a similar genetic background. OBJECTIVE: To conduct a case-control study in a Chinese Han population to evaluate the potential influence of single nucleotide polymorphisms (SNPs) at FLG, 5q22.1, 11q13.5, 14q11.2 and 20q13.33 on AR. METHODS: Ten SNPs--rs11204971 and rs3126085 at FLG, rs10067777, rs7701890, rs13360927, and rs13361382 at 5q22.1, rs6010620 at 20q13.33, rs7936562 and rs7124842 at 11q13.5, and rs4982958 at 14q11.2 were genotyped in 363 cases and 668 controls using the Sequenom MassArray system. Data were analyzed with PLINK 1.07 software. RESULTS: The T allele of rs4982958 at 14q11.2 was observed to be significantly associated with AR (P = .002, OR = 0.73, P(Bonferront) = .02). Genotype-based association testing revealed that the recessive model might provide the best fit for rs4982958 (P(Bonferroni) = .01). In subphenotype analyses, the rs4982958 T allele was also significantly associated with persistent AR (P = .01) and more than 2 positive skin prick tests (P = .038). CONCLUSION: We identified a novel susceptibility locus 14q11.2 for AR that might bear candidate genes conferring susceptibility to AR and affecting disease phenotypes.

Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3.

Hearing is conveyed from the auditory receptors, the hair cells in the organ of Corti, to the brain via the spiral ganglion neurons. Damage or loss of either spiral ganglion neurons or hair cells causes hearing impairment. Such hearing disorders are often permanent and can be caused by therapeutic agents, such as aminoglycoside antibiotics and cisplatin, or by aging, loud sounds, infections and mechanical injury (1). Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), members of the neurotrohin family of neurotrophic factors that also include nerve growth factor (NGF) and neurotrophin-4/5 (NT-4), are important in development of the neuronal components of the inner ear. We report here that the loss of target innervation and the degeneration of approximately 90% of the adult spiral ganglion neurons caused by aminoglycoside toxicity can be prevented by infusion of the neurotrophic factor, neurotrophin-3 (NT-3) in the membranous labyrinth in guinea pigs. The potency of NT-3 in protecting spiral ganglion neurons from degenerating suggests that neurotrophins may be useful for the treatment of hearing disorders.

Timing of continuous renal replacement therapy in severe acute kidney injury patients with fluid overload: A retrospective cohort study.

PURPOSE: We aimed to evaluate the association of early versus late initiation of Continuous renal replacement therapy (CRRT) with mortality in patients with fluid overload. METHODS: This was a retrospective cohort study of patients with fluid overload (FO) treated with CRRT due to severe acute kidney injury (AKI) between January 2015 and December 2017 in a mixed medical intensive care unit of a teaching hospital in Beijing, China. Patients were divided into early (≤15 h) and late (>15 h) groups based on the median time from ICU admission to CRRT initiation. The primary outcome was all-cause mortality at day 60. Multivariable Cox model analysis was used for analysis. RESULTS: The study patients were male predominant (84/150) with a mean age of 64.8 ± 16.7 years. The median FO value before CRRT initiation was 10.1% [6.2-16.1%]. The 60-day mortality rates in the early vs the late CRRT groups were 53.9% and 73%, respectively. On multivariable Cox modelling, the late initiation of CRRT was independently associated with an increased risk of death at 60 days (HR 1.75, 95% CI 1.11-2.74, p = 0.015). CONCLUSIONS: Early initiation of CRRT was independently associated with survival benefits in severe AKI patients with fluid overload.

[In vivo dynamic changes of inner ear guinea pigs with 9.4 T esla MRI].

Objective: To observe the imaging characteristics of guinea pig cochlear structure using 9.4 Tesla magnetic resonance imaging system at different time intervals of contrast agent distribution in the inner ear. Methods: Form May 2015 to October 2015, five albino guinea pigs were injected with Gd-DTPA via the right internal jugular vein (3 ml/kg). Inner ears were scanned with 9.4T MRI. At the 10 th, 30 th, 60 th, 90 th and 120 th minutes post-Gd-DTPA, we took inner ear images to detect changes of endolymph and perilymph. Using Image J software, we acquired MRI gray value through the first, second, third and apical turn of cochlear at different time points. Analysis by one-way ANOVA was taken to analyze the resultsusing GraphPad Prism 5 software. Results: Only outlines of the cochlea and vestibule were visible before Gd-DTPA injection and there was no clear distinction between endolymph and perilymph. Cochlea vestibule on T1 weighted images was enhanced at the 10 th (the first turn of cochlear 8 203±819) after injection, and then imaging of each part of cochlea, including cochlea, vestibule, semicircular canal and even endolymph and perilymph, can be distinguished clearly, because they enhanced gradually at the 30 th(10 489±819), 60 th(13 965±591), and at 90 th(18 050±1 250) after injection. While at the 120 th(18 952±1 185) minute, imaging was not significantly enhanced than at the 90 th minute. The speed and volume of contrast agent spreaded into the various parts of the inner ear were different, and changes with distribution of contrast agent in each part of the inner ear showed a rising process in a certain period of time. The distribution of contrast agent in the inner ear had concentration gradient via basal turn higher and apical turn lower. Conclusions: Endolymph of inner ear can be distinguished from the perilymph using a 9.4T MRI system with Gd-DTPA, and the best observation timer was 90 minutes after intravenous injection of contrast agent. In summary, our study provides the clearly visualized imaging evidence of the changes of the lymphatic fluid, which may be useful for diagnosis of inner ear diseases such as Meniere's Disease.

Hydroxytyrosol suppresses LPS-induced intrahepatic inflammatory responses via inhibition of ERK signaling pathway activation in acute liver injury.

OBJECTIVE: Acute liver injury (ALI) leads to inflammatory response and tissue damage. Inflammatory activation of infiltrative macrophages plays a critical role in liver histology destruction and dysfunction. Hydroxytyrosol (3,4-dihydroxyphenil-ethanol, HT), one of the polyphenols extracted from extra virgin olive oil, currently acts as a treatment for neuroinflammatory responses, but its effect on ALI is elusive. The present study aims to examine the mechanism of HT in macrophages inflammation and evaluate treatment effect of HT on ALI. MATERIALS AND METHODS: In vitro, the expressions of type M1/M2 macrophages biomarkers (CD11c/CD206) and cytokines (TNF-α, IL-1ß, IL-6, IL-10, IL-4) following lipopolysaccharide (LPS) stimulation and HT administration were detected using immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). Mechanically, HT was used to treat cells and phosphorylation level of extracellular-signal-regulated kinase 1/2 (ERK1/2) protein in cells was analyzed using Western blotting. In murine acute liver injury, inflammatory cytokines and liver injury degree were exhibited by qRT-PCR, IHC and HE staining. Furthermore, hepatic function was exhibited via hepatic metabolic enzymes (ALT/AST) and total bilirubin (TBil) in serum. RESULTS: It was demonstrated that HT treatment attenuated M1 macrophages and increased M2 macrophages after LPS stimulation. Furthermore, the pro-inflammatory cytokine level was descended, while an-inflammatory cytokine was increased via HT suppressing ERK pathway in macrophages. In vivo, HT reduced inflammatory level and mitigated hepatic histological injury, thus ameliorating liver function after acute liver injury. CONCLUSIONS: HT exerts a hepatoprotective and anti-inflammation effect on acute liver injury, which restrains inflammation by inhibiting ERK pathway and regulating macrophages polarization. Moreover, HT prevents liver tissues from inflammatory injury. Therefore, HT serves as a potential implication to treat ALI through modulating inflammation of macrophages.

Tramadol regulates proliferation, migration and invasion via PTEN/PI3K/AKT signaling in lung adenocarcinoma cells.

OBJECTIVE: Tramadol is used mainly for the treatment of moderate to severe chronic cancer pain. However, the effect of tramadol on lung cancer remains unclear. Therefore, it is important to explore the mechanism accounting for the function of tramadol on lung cancer. MATERIALS AND METHODS: We investigated the effects of tramadol on the proliferation, migration and invasion in human lung adenocarcinoma cells in vitro by CCK-8 assay, wound healing assay and Transwell assay, respectively. We also explored the potential mechanism of tramadol on lung cancer cells by Western blotting. RESULTS: A549 and PC-9 cells were incubated with 2 µM tramadol for different time (0, 7, 14 and 28 d). The in vitro experiments showed that tramadol treatment significantly inhibited cell proliferation, migration and invasion in a time-dependent manner. Moreover, administration of tramadol suppressed tumor growth in vivo. The data also revealed that tramadol could up-regulate the protein expression level of PTEN and consistently inhibit the phosphorylation level of PI3K and Akt, whereas the total level of PI3K and Akt remain unchanged. CONCLUSIONS: These findings indicated that tramadol inhibited proliferation, migration and invasion of human lung adenocarcinoma cells through elevation of PTEN and inactivation of PI3K/Akt signaling.

Tramadol inhibits proliferation, migration and invasion via α2-adrenoceptor signaling in breast cancer cells.

OBJECTIVE: The aim of this study was to examine the function of tramadol on cell proliferation, migration and invasion in breast cancer cells in vitro, and to evaluate the effect of tramadol in vivo. Further, we explore the mechanism accounting for the role of tramadol on breast cancer cells. MATERIALS AND METHODS: Cell proliferation was detected by the methyl thiazolyl tetrazolium (MTT) assay. Wound healing assay and transwell assay was applied to quantify the migration and invasion ability of MDA-MB-231 cells. The expression of endogenous α2-adrenoceptor and ERK was measured by Western blotting. RESULTS: Tramadol at a clinical dose of up to 2 µM significantly inhibited the proliferation, migration and invasion in a time-dependent manner from day 0 to 28 in vitro. Moreover, tramadol suppressed the growth of xenotransplant tumor in vivo markedly. Furthermore, the protein levels of α2-adrenoceptor and phosphorylated ERK were decreased by tramadol, whereas the expression of total ERK remained unchanged. In addition, downregulation of α2-adrenoceptor by yohimbine could mimic the effect of tramadol treatment. CONCLUSIONS: Collectively, we demonstrated that tramadol could inhibit proliferation, migration and invasion of breast cancers via inactivating α2-adrenoceptor signaling pathway. Our data provide the experimental fundamental for further investigation of the anti-cancer effect of tramadol in breast cancer cells.

Dexmedetomidine regulate the malignancy of breast cancer cells by activating α2-adrenoceptor/ERK signaling pathway.

OBJECTIVE: Breast cancer is one of the most aggressive and pervasive cancers identified in females. Dexmedetomidine (Dex) is an efficient anesthetic used in surgery. Our study aimed to explore the role of Dex in the malignancy of breast cancer cells in vitro and in vivo. Further, we investigate the molecular mechanism involved in the function of Dex on breast cancer cells. MATERIALS AND METHODS: The methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell proliferation. The migration and invasion capacity of MDA-MB-231 cells was tested by wound healing assay and transwell assay. Western blot analysis was performed to quantify the protein expression levels of α2-adrenoceptor and ERK. RESULTS: The proliferation, migration and invasion ability of MDA-MB-231 cells was gradually increased after treatment of Dex in a dose-dependent manner in vitro. In addition, Dex could significantly elevate the volume and weight of xenotransplant tumor in vivo. Furthermore, Dex up-regulated the protein level of a2-adrenoceptor and consistently enhanced the phosphorylation of ERK without changing the total level of it. Similarity, over-expression of a2-adrenoceptor via its agonist Clonidine could mimic the function of Dex on breast cancer. CONCLUSIONS: These data suggest that Dex could promote the proliferation, migration and invasion of breast cancer cells through the activation of α2B-adrenoceptor /ERK signaling.

MiR-26b suppresses tumor cell proliferation, migration and invasion by directly targeting COX-2 in lung cancer.

OBJECTIVE: Lung cancer, including non-small cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Despite recent advances in clinical and experimental oncology, the prognosis of patients with NSCLC still remains poor and the average survival time of patients suffer from lung cancer is low. Therefore, the potential mechanism accounting for the tumorigenesis of NSCLC is still needed to be explored. MATERIALS AND METHODS: A lentiviral vector over-expressing miR-26b in A549 lung cancer cells was constructed. Cell proliferation, migration and invasion analysis were measured by cell counting kit (MTT), would healing assay and Transwell assay. Direct target of miR-26b in A549 cells was examined using bioinformatics and Luciferase assay. RESULTS: Herein, we found that over-expression of miR-26b significantly inhibited the proliferation, migration and invasion of A549 lung cancer cell in vitro and suppressed the growth of established tumors in vivo. By using bioinformatics, we found that COX-2 (Cyclooxygenase-2) is one of the potential targets of miR-26b. Moreover, miR-26b was found to negatively regulate COX-2 protein level by directly targeting its 3'UTR. In addition, depletion of endogenous COX-2 by the specific siRNA could mimic the function of miR-26b overexpression. CONCLUSIONS: Taken together, our results demonstrate that miR-26b could suppress lung cancer cells proliferation, migration and invasion by directly negative regulation of COX-2. MiR-26b could serve as a novel potential marker for NSCLC therapy.

Magnetic resonance imaging of the membranous labyrinth during in vivo gadolinium (Gd-DTPA-BMA) uptake in the normal and lesioned cochlea.

MRI with a T1 contrast agent was used to investigate the normal and noise-damaged cochlea. The time course and distribution of the in vivo uptake of the gadodiamide chelate bound paramagnetic Gd ion (GdDTPA-BMA) throughout the membranous labyrinth of normal and impulse noise-damaged guinea pig cochleae were measured by MRI at 4.7T. Simultaneous signal enhancement of the basal, medial and apical scala tympani (ST) and scala vestibuli (SV) was observed within 10 min following i.v. injection, reaching maximum levels at around 100 min. ANOVA and post hoc paired t-tests showed statistically significant differences in the levels and rates of Gd uptake-enhancement between the scalae. The ST revealed the most rapid and extensive enhancement throughout the period of active Gd uptake, while the SV showed comparatively slower and less enhancement, and the intact scala media (SM) indicated insignificant enhancement. The in vivo Gd penetration and enhancement of the membranous SM increased significantly in the noise-damaged cochlea, suggesting lesioning of the cochlear membranes.

Short-term adaptation in the peripheral auditory system is related to the AMPA receptor.

The role of glutamate receptors was investigated by infusing N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-isoxazol-propionate (AMPA) into the guinea pig cochlea. Auditory brainstem response thresholds and forward masking were used to determine auditory sensitivity. In the presence of 330 microM NMDA, the auditory brainstem response (ABR) thresholds were elevated by 20-30 dB at 2 kHz and 8 kHz, and the slopes of the forward masking curves were not significantly different from controls. When a high concentration of NMDA (15 mM) was used, ABR thresholds were elevated by 40-50 dB at 2 kHz and 8 kHz and the slopes of the forward masking curves were significantly decreased. In contrast, when AMPA (150 microM) was infused, ABR thresholds were elevated by 20-35 dB at 2 and 8 kHz and the slopes of the forward masking curves were significantly decreased from the control group. When the concentration of AMPA was decreased (100 microM). ABR thresholds were not significantly altered but the slopes of the forward masking curves were significantly decreased from control values. The present study suggests that AMPA receptors play a significantly more important role in short-term adaptation than NMDA receptors.

[Future cure of hearing disorders? Gene therapy and stem cell implantation are possible new therapeutic alternatives]. / Framtida bot för hörselskador? Genterapi och implantation av stamceller möjliga nya behandlingsvägar.

Hearing loss is a very common disorder; nearly 10 per cent of the population is affected. Recently, a few findings such as the roles of neurotrophins, nitric oxide, reactive oxygen species and glutamate receptors in the peripheral hearing system have been highlighted. In this review, focus is set on possible mechanisms of peripheral hearing disorders, and on recent advances to prevent and treat hearing loss. Clinically useful treatment strategies, especially gene therapy and the use of embryonic stem cells, are particularly stressed.

[Relationship between endotoxemia and APACHE-III scoring and integrated therapy of Chinese and Western medicine].

OBJECTIVE: To explore the relationship between endotoxemia and the severity of disease condition and therapeutic effect. METHODS: According to randomized controlled principle, the 153 acute infectious patients were divided into simple antibiotics treated group and antibiotics plus Chinese drugs combined treated group, and patients in each group were subdivided into 3 types according to acute physiology and chronic health evaluation (APACHE-III) scoring: type A (APACHE-III scoring < or = 20 points), type B (APACHE-III scoring 21-40 points) and type C (APACHE-III scoring > 40 points). The 77 cases in the simple treated group were 40 males and 37 females, aging 18-76 years, mean 46.5 +/- 27.5 years, 41 cases of type A, 28 of type B and 8 of type C, treatment course 10-14 days, mean 11.5 +/- 2.5 days. The 76 cases in the combined treated group were 39 males and 37 females, aging 18-70 years, mean 44.5 +/- 25.5 years, 37 of type A, 30 of type B and 9 of type C, treatment course 10-14 days, mean 10.5 +/- 2.5 days. Limulus test was used to determine the endotoxin content in peripheral blood of patients, and further analysis on the relationship between endotoxemia and APACHE-III scoring was conducted. RESULTS: Acute severe infectious patients whose APACHE-III scoring > 20 points occurred endotoxemia (P < 0.05), and the condition of disease was positively related to the APACHE-III scoring (r = 0.718, P < 0.05). Chinese drugs plus antibiotics can obviously alleviate endotoxemia (P < 0.05) and improve the prognosis of patients. CONCLUSION: Endotoxemia can serve as a referential parameter for predicting the severity of disease. Integrated therapy of Chinese and western medicine in treating bacterial infection revealed better results than that of antibiotics solely.

[Study of mechanism of selective head cooling-dehydration combined therapy for brain resuscitation: effect on function of brain cellular membrane].

We induced cerebral complete ischemia (CCI) by "four-vessel" model. The changes of Na+,K(+)-ATPase, Ca2+, Mg(2+)-ATPase, phospholipase A2 (PLA2), total phospholipids on brain cellular membrane (BCM) at 30, 180, 360 min of reperfusion following 30 min CCI were observed. The effects of selective head cooling (SHC, 28C, surface cooling method), mannitol dehydration (MD), and selective head cooling-dehydration combined therapy (SHCDCT) on these changes were also investigated. Compared with non-ischemic, during reperfusion activities of Na+, K(+)-ATPase, Ca2+, Mg(2+)-ATPase decreased while PLA2 increased (P < 0.001), phospholipids decreased at 180 and 360 min of reperfusion (P < 0.01). SHC and SHCDCT blocked all above changes, MD had no effect. These results suggest that SHCDCT after starting reperfusion do promote recruitment of BCM function by blockade of the successive reperfusion damage on BCM.

Brain damage following severe acute normovolemic hemodilution in combination with controlled hypotension in rats.

BACKGROUND AND AIM: The reduced oxygen content and perfusion pressure during acute normovolemic hemodilution (ANH) and controlled hypotension (CH) raise concerns about hypoperfusion and ischemic injury to the brain. In this study on rats, we examined the brain damage following four different degrees of ANH combined with CH. METHODS: Forty rats were randomly assigned to receive a sham operation or CH and ANH [with a hematocrit (Hct) of 30, 25, 20 or 15%]. ANH was performed after baseline physiological parameters had been monitored for 20 min; 30 min later, CH was induced using sodium nitroprusside, and the mean arterial blood pressure was maintained at 50-60 mmHg for 1 h. Rats were killed 3.5 h after hemodilution. Ultrastructural alterations in the CA1 region of the rat hippocampus were observed, and serum concentrations of S100B and neuron-specific enolase (NSE) were measured before and after ANH. RESULTS: The serum S100B concentration increased significantly in the Hct 20% + CH and Hct 15% + CH groups. However, there were no significant differences in the serum levels of NSE between the groups. In the CA1 region of the rat hippocampus, marked ultrastructural alterations, such as mitochondrial denaturalization and nucleus distortion, were observed in the Hct 20% + CH and Hct 15% + CH groups. CONCLUSION: Severe ANH (Hct < or = 20%) combined with CH may induce cerebral damage, as confirmed by marked ultrastructural alterations in the CA1 region of the rat hippocampus and significantly increased serum levels of S100B, and should be avoided.

Outer hair cell activity is not required for the generation of the forward masking curve.

Forward masking of the auditory brainstem response (ABR) was achieved by increasing the time interval from 0 to 12 ms between the masker offset and the probe onset. The forward masking response demonstrated a near linear function with an approximate 3.0-dB increase in masking threshold for every millisecond interval increase in the control guinea pig. The slope of the masking curve at selected frequencies together with the quantification of hair cell loss through the analysis of cochlear surface morphology was studied before and after chemical insult. The intracochlear infusion of sodium salicylate caused an approximately 45-dB threshold shift of the ABR whereas the slope of the forward masking curve was not significantly different from the control values at the tested frequencies (1, 4, and 8 kHz). Systemic kanamycin administration (400 mg/kg body weight for 9 consecutive days) caused a permanent ABR threshold shift of 43-63 dB at 1, 4, and 8 kHz. The slope of the forward masking curve was not significantly different at 1 kHz despite significant outer hair cell loss. The slope of the forward masking curve at 4 and 8 kHz showed significant reductions at the time intervals between 0 and 4 ms. Analysis of the kanamycin-treated cochleae revealed not only significant outer hair cell loss throughout the cochlea but significant inner hair cell and inner pillar cell loss in the basal end of the cochlea. The results suggest that the outer hair cells are not needed for maintaining a normal forward masking curve, whereas the slope of the forward masking curve is sensitive to alterations induced to either the inner hair cells or the inner pillar cells.

Forward masking is dependent on inner hair cell activity.

The goal of this study was to test the hypothesis that the inner hair cell complex (inner hair cell and dendritic contacts) is solely responsible for generating the slope of the forward masking curve. To test this hypothesis two experiments were performed. The first was to measure forward masking from the Bronx waltzing mouse, a mutant possessing an inner hair cell defect. The Bronx waltzing mouse demonstrated an approximately 60-dB auditory brainstem response (ABR) threshold shift compared to CBA/CBA mice at 8 and 12 kHz. The slope of the forward masking curve was significantly reduced compared to the control group, particularly at the early delay times between 0 and 4 ms. The second model employed kainic acid to affect the dendrites beneath the inner hair cell. After the intracochlear infusion of kainic acid, there was an approximately 47-dB ABR threshold shift at 4 and 8 kHz compared to pre-infusion thresholds. The slope of the forward masking curve from the kainic-acid group was significantly reduced compared to the artificial-perilymph group. Primarily the early delay times were affected by kainic acid (0-4 ms). Morphological analysis showed that there was extensive swelling of the afferent nerve radial dendrites under the inner hair cells. The results from the present study, as well as the preceding article, suggest that the analysis of the slope of the forward masking curve may be used for the detection of inner hair cell or radial dendrite damage, independent of outer hair cell damage. The present finding could provide a useful means of employing a clinical test for determining the function of the inner hair cell complex using a non-invasive measure of auditory function.

Differences in forward masking after a temporary and a permanent noise-induced hearing loss.

The forward masking curve of the auditory brainstem response (ABR) at selected frequencies together with the quantification of hair cell loss through the analysis of cochlear surface morphology was studied in guinea pigs before and after acoustic trauma resulting in either a temporary or a permanent threshold shift. In the presence of a noise-induced temporary threshold shift, the slope of the forward masking curve was not significantly different from the pre-exposure curve. In contrast, during the acute phase of the permanent threshold shift, the slope of the forward masking curve was significantly reduced compared to the pre-exposure value. After a recovery period of 2 weeks, the slope of the forward masking curve from the permanently damaged group returned to nearly normal values despite a persisting ABR threshold shift and significant loss of outer hair cells. The potential for analyzing the slope of the forward masking curve in order to distinguish between the acute phase of a permanent threshold shift and a temporary threshold shift is discussed.