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Hearing impairment is one of the most common sensory disorders in children, and targeted next-generation sequencing (NGS)-based genetic examinations can assist in its prognostication and management. In 2020, we developed a simplified 30-gene NGS panel from the original 214-gene NGS version based on Taiwanese genetic epidemiology data to increase the accessibility of NGS-based examinations. In this study, we evaluated the diagnostic performance of the 30-gene NGS panel and compared it with that of the original 214-gene NGS panel in patient subgroups with different clinical features. Data on the clinical features, genetic etiologies, audiological profiles, and outcomes were collected from 350 patients who underwent NGS-based genetic examinations for idiopathic bilateral sensorineural hearing impairment between 2020 and 2022. The overall diagnostic yield was 52%, with slight differences in genetic etiology between patients with different degrees of hearing impairment and ages of onset. No significant difference was found in the diagnostic yields between the two panels, regardless of clinical features, except for a lower detection rate of the 30-gene panel in the late-onset group. For patients with negative genetic results, where the causative variant is undetectable on current NGS-based methods, part of the negative results may be due to genes not covered by the panel or yet to be identified. In such cases, the hearing prognosis varies and may decline over time, necessitating appropriate follow-up and consultation. In conclusion, genetic etiologies can serve as references for refining targeted NGS panels with satisfactory diagnostic performance.

Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants.This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes.At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation.The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention.

Background Various systemic immunomodulating therapies have been investigated to treat nail psoriasis, but the efficacy remains unclear. Objective To perform a systematic review and network meta-analysis to evaluate the efficacy of small molecule inhibitors and biologics in treating nail psoriasis. Methods Eligible studies in online databases were identified until March 10, 2020. To assess the efficacy of small molecule inhibitors and biologics, network meta-analyses with surface under the cumulative ranking curve of improvement in nail score at 10 to 16 and at 24 to 26 weeks, as well as 100% improvement of Nail Psoriasis Severity Index (NAPSI), were performed. Results Thirty-nine studies with a total of 13 treatment arms involving 15,673 patients with nail psoriasis were included. An network meta-analysis showed that tofacitinib (weighted mean difference, 56.67; 95% confidence interval [CI], 35.87-77.48) and ixekizumab (weighted mean difference, 59.40; 95% CI, 45.87-72.93) presented the most improvement of nail score at 10 to 16 weeks and 24 to 26 weeks, respectively. For 100% improvement of the Nail Psoriasis Severity Index, ixekizumab showed the best efficacy among all treatments (odds ratio, 2.98; 95% CI, 1.74-5.10). Limitations Insufficiency of eligible data and no long-term follow-up data. Conclusion Tofacitinib and ixekizumab presented the best efficacy for treating nail psoriasis in 10 to 16 weeks and 24 to 26 weeks, respectively.

A single-blind study to investigate the effects of noisy galvanic vestibular stimulation (nGVS) in straight walking and 2 Hz head yaw walking for healthy and bilateral vestibular hypofunction (BVH) participants in light and dark conditions. The optimal stimulation intensity for each participant was determined by calculating standing stability on a force plate while randomly applying six graded nGVS intensities (0–1000 µA). The chest–pelvic (C/P) ratio and lateral deviation of the center of mass (COM) were measured by motion capture during straight and 2 Hz head yaw walking in light and dark conditions. Participants were blinded to nGVS served randomly and imperceivably. Ten BVH patients and 16 healthy participants completed all trials. In the light condition, the COM lateral deviation significantly decreased only in straight walking (p = 0.037) with nGVS for the BVH. In the dark condition, both healthy (p = 0.026) and BVH (p = 0.017) exhibited decreased lateral deviation during nGVS. The C/P ratio decreased significantly in BVH for 2 Hz head yaw walking with nGVS (p = 0.005) in light conditions. This study demonstrated that nGVS effectively reduced walking deviations, especially in visual deprived condition for the BVH. Applying nGVS with different head rotation frequencies and light exposure levels may accelerate the rehabilitation process for patients with BVH.Clinical Trial Registration This clinical trial was prospectively registered at www.clinicaltrials.gov with the Unique identifier: NCT03554941. Date of registration: (13/06/2018).

Patients with systemic lupus erythematosus (SLE) have elevated cardiovascular risk. Hyperhomocysteinemia may be one of the contributing factors to this phenomenon. This study therefore aimed to com...

Previous reports have shown that pulsed dye laser (PDL) is promising for the treatment of acne; however, results provide conflicting evidence.To determine the efficacy of PDL in treating acne vulgaris.A systematic review and meta-analysis of studies published before March 31, 2020 was conducted. Randomized controlled trials and case series were analyzed. The meta-analysis estimated the standardized mean difference (SMD) in acne severity score changes in patients treated by PDL versus control and also the SMD of the acne severity scores and comedone counts changes before and after PDL treatment.Eleven studies were included in this systematic review. Six studies were included in the meta-analysis. Pulsed dye laser treatment was not found to be superior to the control group in treating acne vulgaris (SMD: -0.285; 95% confidence interval [CI], -0.886 to 0.317). However, single-arm studies revealed a significantly improved acne severity score after PDL therapy (SMD, -1.321; 95% CI, -2.057 to -0.586), especially when a multiple-session treatment and a longer pulse duration were employed. The comedone counts were significantly decreased after PDL therapy (SMD, -0.596; 95% CI, -1.137 to -0.054).When treatment consisted of 4 or more sessions or longer pulse duration, PDL could significantly decrease the acne severity score.

Stroke, which is the second leading cause of mortality in the world, is urgently needed to explore the medical strategies for ischemic stroke treatment. Both icariin (ICA) and icaritin (ICT) are the major active flavonoids extracted from Herba epimedii that have been regarded as the neuroprotective agents in disease models. In this study, we aimed to investigate and compare the neuroprotective effects of ICA and ICT in a middle cerebral artery occlusion (MCAO) mouse model. Male ICR mice were pretreated with both ICA and ICT, which ameliorated body weight loss, neurological injury, infarct volume, and pathological change in acute ischemic stroke mice. Furthermore, administration of both ICA and ICT could also protect against neuronal cell apoptotic death, oxidative and nitrosative stress, lipid peroxidation, and extracellular matrix (ECM) accumulation in the brains. The neuroprotective effects of ICT are slightly better than that of ICA in acute cerebral ischemic stroke mice. These results suggest that pretreatment with both ICA and ICT improves the neuronal cell apoptosis and responses of oxidative/nitrosative stress and counteracts the ECM accumulation in the brains of acute cerebral ischemic stroke mice. Both ICA and ICT treatment may serve as a useful therapeutic strategy for acute ischemic stroke.

Background Nail braces are an alternative treatment for ingrown toenails. Objective This study aimed to prospectively examine the efficacy of nail braces for treatment of acute inflamed (AI)-type and chronic dystrophic-type ingrown toenails. Materials and methods The authors conducted a prospective study of patients with ingrown toenails treated at Wan Fang Hospital between January 1, 2017, and July 31, 2018. Evaluation using physician global assessment scores and patient satisfaction questionnaires was performed at 1, 3, and 6 months after the start of treatment and during the final visit. Patient demographics, treatment courses, and outcomes were compared between the 2 types of ingrown toenails. Results Chronic dystrophic-type and AI-type ingrown toenails were observed in 25 (61 sides) and 28 patients (35 sides), respectively. Of the affected sides, 80.9%, 94.9%, and 100% achieved an excellent or fair result at 1, 3, and 6 months, respectively. Treatment duration and follow-up period were 179.2 ± 96.8 days and 281.6 ± 120.9, respectively. The recurrence rate was 7.4%. The treatment course and response were different between the 2 types of ingrown toenails. Conclusion Ingrown toenails could be effectively treated with nail braces with excellent outcomes, favorable patient satisfaction, and low recurrence rates.

Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A>G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness.

Sm28GST is one of the candidate antigens for Schistosoma mansoni vaccine. Already Sm28GST vaccine formulations have shown to be protective against S. mansoni infection. Currently, efforts have been put into finding an adjuvant to enhance the immunity induced by Sm28GST. In the present work, we investigated whether heat-killed Propionibacterium acnes can be served as a potential adjuvant for recombinant Sm28GST (rSm28GST) antigen. As the results showed, P. acnes successfully modulated the Th1 humoral immune response induced by rSm28GST. Stronger Th1 cytokines responses were also observed in mice immunized with P. acnes-adjuvanted rSm28GST. Immunization of mice with P. acnes-adjuvanted rSm28GST was able to reduce worm burden and hepatic egg burden by 54.20 and 73.61%. Reduced granuloma size and count, as well as improved liver histology, were seen in P. acnes-adjuvanted rSm28GST immunized mice. These data suggest that P. acnes may evoke a stronger rSm28GST-induced immune response, higher resistance to S. mansoni infection, and more profound protection against S. mansoni-induced liver damages.

Patients with systemic lupus erythematosus (SLE) have elevated cardiovascular risk. Hyperhomocysteinemia may be one of the contributing factors to this phenomenon. This study therefore aimed to compare the serum homocysteine levels and the levels of folate and vitamin B12, cofactors for homocysteine metabolism, between individuals with and without SLE.A literature search was performed in PubMed, Embase, and the Cochrane library (from inception to March 31, 2019). Studies comparing serum homocysteine, folate or vitamin BA total of 50 studies involving 4396 patients with SLE were included. Patients with SLE had a significantly higher serum level of homocysteine (standardized mean difference [SMD], 1.134; 95% CI, 0.795-1.474) and lower level of vitamin BSerum homocysteine levels were higher and vitamin B

Chondrosarcoma is a malignant primary bone tumor. Sirtuin-1 (SIRT1), which is a member of sirtuin family, plays a dual role either in cancer promotion or suppression. There is no report about the role of SIRT1 in the human chondrosarcoma cells. Resveratrol is a potent activator of SIRT1. However, its effects on chondrosarcoma have not been extensively studied. Here, we investigated the role of SIRT1 induction by resveratrol in human chondrosarcoma cell growth and tumor progression. Resveratrol significantly decreased cell viability and induced cell apoptosis in human chondrosarcoma cells in a dose-dependent manner. The protein expression and activity of SIRT1 were activated after treatment with resveratrol. Resveratrol significantly inhibited NF-κB signaling by deacetylating the p65 subunit of NF-κB complex, which could be reversed by siRNA-SIRT1 transfection or deacetylation inhibitor MS-275. Resveratrol induced-apoptosis involved a caspase-3-mediated mechanism. Both siRNA-SIRT1 transfection and MS-275 significantly inhibited the resveratrol-induced caspase-3 cleavage and activity in human chondrosarcoma cells. Moreover, in vivo chondrosarcoma xenograft study revealed a dramatic reduction in tumor volume and the increased SIRT1 and cleaved caspase-3 expressions in tumors by resveratrol treatment. These results suggest that resveratrol induces chondrosarcoma cell apoptosis via a SIRT1-activated NF-κB deacetylation and exhibits anti-chondrosarcoma activity in vivo.

This study investigated the influence of pathological eye movements on the recordings of ocular vestibulo-evoked myogenic potential (oVEMP).Ten patients with pathological eye movements of non-vestibular origin (nine congenital nystagmus and one opsoclonus) who had negative MRI result were assigned to Group A. Another 20 vestibular neuritis (VN) patients with spontaneous nystagmus were assigned to Group B. Both groups underwent audiometry, and caloric, oVEMP and cervical VEMP (cVEMP) tests.In Group A, the caloric, oVEMP and cVEMP tests showed 40%, 55% and 50% abnormalities, respectively. In Group B (VN), caloric, oVEMP and cVEMP tests revealed 100%, 80% and 45% abnormalities on the lesion ears, and 0%, 40% and 0% abnormalities on the healthy (opposite) ears, respectively. The 40% oVEMP abnormality on the healthy ears may be due to recording failure from the presence of spontaneous nystagmus, since five of five VN patients showed normal oVEMPs on the healthy ears, one year after presentation.Presence of pathological eye movements may affect the recordings of oVEMP. Thus, the oVEMP test is recommended to perform after acute vertiginous episode to exclude the influence of pathological eye movements on the oVEMP recordings.

The therapeutic effects of low intensity pulsed ultrasound (LIPUS) on renal ischemia/reperfusion injury (IRI) with acute kidney injury (AKI) are still unclear. A renal tubule cell model under H2O2 or hypoxia/reoxygenation (H/R) conditions with or without LIPUS pre-treatment (1 MHz, 30 and 100 mW/cm2, 15 min) was used to test the in vitro effects of LIPUS. An AKI mouse model of unilateral IRI with nephrectomy of the contralateral kidney for 48 h with or without LIPUS treatment (3 MHz, 100 mW/cm2, 20 min/day) 5 day before IRI were used to investigate the in vivo effects of LIPUS. LIPUS significantly protected the renal tubule cell viability and prevented inflammatory signals against H2O2 challenge. LIPUS could inhibit the apoptosis-related molecular signals and increase the protein levels of endogenous antioxidant enzymes, α-Klotho, and Sirt1 in renal tubule cells after H/R challenge. LIPUS alleviated the increases in the serum levels of blood urea nitrogen, creatinine, and cystatin C, renal pathological changes and apoptosis-related molecular signals, and impaired antioxidant enzymes in AKI mice. The IRI-induced inflammatory responses in the kidneys and spleens could be reversed by LIPUS. These findings suggest that LIPUS treatment displays the benefits for renal protection in IRI-induced AKI mice.

Auditory neuropathy is an important entity in childhood sensorineural hearing loss. Due to diverse etiologies and clinical features, the management is often challenging. This study used an integrative patient-history, audiologic, genetic, and imaging-based approach to investigate the etiologies and audiologic features of 101 children with auditory neuropathy. Etiologically, 48 (47.5%), 16 (15.8%), 11 (10.9%), and 26 (25.7%) children were categorized as having acquired, genetic, cochlear nerve deficiency-related, and indefinite auditory neuropathy, respectively. The most common causes of acquired and genetic auditory neuropathy were prematurity and OTOF mutations, respectively. Patients with acquired auditory neuropathy presented hearing loss earlier (odds ratio, 10.2; 95% confidence interval, 2.2–47.4), whereas patients with genetic auditory neuropathy had higher presence rate of distortion product otoacoustic emissions (odds ratio, 10.7; 95% confidence interval, 1.3–85.4). In patients with different etiologies or pathological sites, moderate to strong correlations (Pearson’s r = 0.51–0.83) were observed between behavioral thresholds and auditory steady-state response thresholds. In conclusion, comprehensive assessments can provide etiological clues in ~75% of the children with auditory neuropathy. Different etiologies are associated with different audiologic features, and auditory steady-state responses might serve as an objective measure for estimating behavioral thresholds.

The incidence of stroke recurrence is still higher despite the advanced progression of therapeutic treatment and medical technology. Low intensity pulsed ultrasound (LIPUS) has been demonstrated to possess therapeutic effects on neuronal diseases and stroke via brain-derived neurotrophic factor (BDNF) induction. In this study, we hypothesized that LIPUS treatment possessed therapeutic benefits for the improvement of stroke recurrence. Adult male C57BL/6J mice were subjected to a middle cerebral artery occlusion (MCAO) surgery and then followed to secondary MCAO surgery as a stroke recurrence occurred after nine days from the first MCAO. LIPUS was administered continuously for nine days before secondary MCAO. LIPUS treatment not only decreased the mortality but also significantly moderated neuronal function injury including neurological score, motor activity, and brain pathological score in the recurrent stroke mice. Furthermore, the administration of LIPUS attenuated the apoptotic neuronal cells and increased Bax/Bcl-2 protein expression ratio and accelerated the expression of BDNF in the brain of the recurrent stroke mice. Taken together, these results demonstrate for the first time that LIPUS treatment arouses the expression of BDNF and possesses a therapeutic benefit for the improvement of stroke recurrence in a mouse model. The neuroprotective potential of LIPUS may provide a useful strategy for the prevention of a recurrent stroke.

Angiostrongylus cantonensis is a metastrongyloid nematode that causes eosinophilic meningoencephalitis in humans. A high infestation of A. cantonensis can cause permanent brain damage or even death. The inflammasome is an oligomeric molecular platform that can detect microbial pathogens and activate inflammatory cytokines. The recognition of larval surface antigens by pattern recognition receptors (PRRs) can cause oligomerization of the NOD-like receptor (NLR) or absent in melanoma 2 (AIM2) with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to form a caspase-1-activating scaffold. Activated caspase-1 converts pro-inflammatory cytokines into their mature, active forms. Helminths infection has been shown to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes. In this study, we aimed to investigate the mechanism of inflammasome activation upon A. cantonensis infection in a mouse model. This study provides evidence that A. cantonensis infection can activate NLRP1B and NLRC4 inflammasomes and promote pyroptosis to cause meningoencephalitis.

OBJECTIVES Recessive mutations in GJB2 are the most common genetic cause of sensorineural hearing impairment (SNHI) in humans. SNHI related to GJB2 mutations demonstrates a wide variation in audiological features, and there has been no reliable prediction model for hearing outcomes until now. The objectives of this study were to clarify the predominant factors determining hearing outcome and to establish a predictive model for SNHI in patients with GJB2 mutations. DESIGN A total of 434 patients confirmed to have biallelic GJB2 mutations were enrolled and divided into three groups according to their GJB2 genotypes. Audiological data, including hearing levels and audiogram configurations, were compared between patients with different genotypes. Univariate and multivariate generalized estimating equation (GEE) analyses were performed to analyze longitudinal data of patients with multiple audiological records. RESULTS Of the 434 patients, 346 (79.7%) were homozygous for the GJB2 p.V37I mutation, 55 (12.7%) were compound heterozygous for p.V37I and another GJB2 mutation, and 33 (7.6%) had biallelic GJB2 mutations other than p.V37I. There was a significant difference in hearing level and the distribution of audiogram configurations between the three groups. Multivariate GEE analyses on 707 audiological records of 227 patients revealed that the baseline hearing level and the duration of follow-up were the predominant predictors of hearing outcome, and that hearing levels in patients with GJB2 mutations could be estimated based on these two parameters: (Predicted Hearing Level [dBHL]) = 3.78 + 0.96 × (Baseline Hearing Level [dBHL]) + 0.55 × (Duration of Follow-Up [y]). CONCLUSION The baseline hearing level and the duration of follow-up are the main prognostic factors for outcome of GJB2-related SNHI. These findings may have important clinical implications in guiding follow-up protocols and designing treatment plans in patients with GJB2 mutations.

Background: Otomycosis still remains intractable in clinical practice, likely because topical antifungal agents lack efficacy or are potentially toxic to the inner ear end organs. Objectives: The aim of this study was to investigate whether terbinafine solution is a potential candidate for treating intractable otomycosis in humans. In addition, the toxic effect on the inner ear was also assessed by animal models treated with terbinafine. Methods: Guinea pigs were instilled with 0.1 mL terbinafine (10 and 25 mg/mL) in the left round window membrane. At 2 weeks after treatment, all animals underwent an inner ear test battery and were then sacrificed for morphological study. Clinically, 20 patients with otomycosis were treated with terbinafine solution at a dosage of 0.4 mg. Results: All terbinafine-treated animals showed intact inner ear function when total dosage of terbinafine was Conclusion: The paucity of inner ear toxicity of terbinafine even at a dosage of 2.5 mg was identified in guinea pig models morphologically and physiologically. Topical application of terbinafine solution at a dosage of 0.4 mg may be a potential treatment for otomycosis in humans.

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon found in tobacco smoke and air pollution products. BaP exposure has been recently suggested to be a risk factor for hypertension in coke oven workers. The mechanisms of BaP on vascular smooth muscle function remain unclear. Here, we examined the influence and possible mechanism of BaP on vasoconstriction in rat thoracic aortas ex vivo and in vivo. In vivo exposure of rats to BaP (20 mg/kg) for 8 weeks caused a significant enhancement in the systolic blood pressure and enhanced aortic hyperreactivity to α1-adrenoceptor selective agonist phenylephrine in aortas. BaP (1 and 10 μM) treatment for 18 h induced an enhancement of phenylephrine-induced vasoconstriction in the organ cultures of aortas. Aryl hydrocarbon receptor antagonist α-naphthoflavone, protein kinase C (PKC) inhibitor chelerythrine, mitogen-activated protein kinases (MAPK) inhibitor PD98059, myosin light chain kinase (MLCK) inhibitor ML-9, and Rho-kinase inhibitor Y-27632 significantly suppressed BaP-enhanced vasoconstriction. BaP time-dependently triggered reactive oxygen species (ROS) production in primary vascular smooth muscle cells. Both antioxidant N-acetylcysteine and NAD(P)H oxidase inhibitor diphenyleneiodonium significantly inhibited BaP-triggered ROS production and vasoconstriction. These results suggest that BaP enhances aortic vasoconstriction via the activation of ROS and muscular signaling molecules PKC, MAPK, MLCK, and Rho-kinase.

Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A&gt, G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness.

Vitiligo is associated with (autoimmune) thyroid disease. However, confounding factors, including type and onset of vitiligo, require elucidation. We conducted a meta-analysis to identify vitiligo patients with increased risk of (autoimmune) thyroid disease. Studies were identified based on searches in PubMed, MEDLINE, Embase, and the Cochrane Library from inception of these databases to August 31st, 2017. Odds ratios (ORs) for the prevalence of (autoimmune) thyroid disease and thyroid antibodies in vitiligo patients were pooled, and subgroup analysis was performed. Thirty-seven studies with 78,714 vitiligo patients met the inclusion criteria. The prevalence of thyroid disease (TD) (OR: 3.932; 95% CI: 2.230-6.933), autoimmune TD (OR: 5.879; 95% CI: 2.682-12.885), anti-thyroperoxidase (TPO) antibody (OR: 3.838; 95% CI: 2.968-4.963), and anti-thyroglobulin antibody (OR: 3.513; 95% CI: 2.346-5.260) was significantly higher in vitiligo patients than in controls. Notably, the prevalence of TD and anti-TPO antibody was significantly higher in patients with non-segmental vitiligo, compared to those with segmental vitiligo. In contrast, the prevalence of TD was significantly lower in early-, compared to the late-onset vitiligo group (OR: 0.333; 95% CI: 0.244-0.453). Physicians should be aware of the increased risk of (autoimmune) thyroid disease in vitiligo patients. We recommend routine screening for anti-thyroid antibodies in vitiligo patients.

Stroke is known as the top 10 causes of death worldwide. Development of effectively neuroprotective or preventive strategies for ischemia stroke is imperative. For the purpose of stroke prevention, we tested the neuroprotective effects of low-intensity pulsed ultrasound (LIPUS) on ischemic stroke. Adult C57BL/6 mice were used to daily treatment with LIPUS for 5 days on left hemisphere before middle cerebral artery occlusion (MCAO)-induced cerebral ischemia/reperfusion injury. Western blotting and immunohistochemistry were performed to assess the protein expressions of signaling molecules. Pretreatment with LIPUS significantly ameliorated the brain ischemic damage, including the reduction of neurological deficit score, infarct area, histopathological score, and showed a better performance in neurological and behavior functions. LIPUS pretreatment could also significantly decrease the neuronal cell apoptosis and upregulation of apoptosis-related signaling molecules and downregulation of brain-derived neurotrophic factor (BDNF) in brain tissues of MCAO-treated mice. Furthermore, LIPUS significantly prevented the decreased cell viability, the increased caspase-3 cleavage, and the decreased BDNF expression in ischemia/reperfusion-treated microglial cells. These results demonstrate that LIPUS effectively prevented the cerebral ischemia/reperfusion injury through apoptosis reduction and BDNF induction in a MCAO mouse model. The neuroprotective potential of LIPUS may provide a novel preventive strategy for ischemic stroke in high-risk patients.

Diabetic myopathy, a less studied complication of diabetes, exhibits the clinical observations characterized by a less muscle mass, muscle weakness and a reduced physical functional capacity. Accumulation of advanced glycation end-products (AGEs), known to play a role in diabetic complications, has been identified in ageing human skeletal muscles. However, the role of AGEs in diabetic myopathy remains unclear. Here, we investigated the effects of AGEs on myogenic differentiation and muscle atrophy in vivo and in vitro. We also evaluated the therapeutic potential of alagebrium chloride (Ala-Cl), an inhibitor of AGEs. Muscle fibre atrophy and immunoreactivity for AGEs, Atrogin-1 (a muscle atrophy marker) and phosphorylated AMP-activated protein kinase (AMPK) expressions were markedly increased in human skeletal muscles from patients with diabetes as compared with control subjects. Moreover, in diabetic mice we found increased blood AGEs, less muscle mass, lower muscular endurance, atrophic muscle size and poor regenerative capacity, and increased levels of muscle AGE and receptor for AGE (RAGE), Atrogin-1 and phosphorylated AMPK, which could be significantly ameliorated by Ala-Cl. Furthermore, in vitro, AGEs (in a dose-dependent manner) reduced myotube diameters (myotube atrophy) and induced Atrogin-1 protein expression in myotubes differentiated from both mouse myoblasts and primary human skeletal muscle-derived progenitor cells. AGEs exerted a negative regulation of myogenesis of mouse and human myoblasts. Ala-Cl significantly inhibited the effects of AGEs on myotube atrophy and myogenesis. We further demonstrated that AGEs induced muscle atrophy/myogenesis impairment via a RAGE-mediated AMPK-down-regulation of the Akt signalling pathway. Our findings support that AGEs play an important role in diabetic myopathy, and that an inhibitor of AGEs may offer a therapeutic strategy for managing the dysfunction of muscle due to diabetes or ageing.

Aging and diabetes are known to be the major cause to affect the progression of osteoarthritis (OA). Advanced glycation end products (AGEs) have been observed to accumulate in various organs especially in joint tissue and do damage to the joint tissue during aging and diabetes. Synovial angiogenesis and inflammation are observed across the full range of OA severity. The signaling pathway of AGEs on vascular endothelial growth factor (VEGF) production and inflammatory responses in synoviocytes are still unclear. Here, we investigated the role of receptor for AGEs (RAGE) and the signaling pathway involved in AGEs-induced VEGF production and inflammatory responses in human synoviocytes. Human synoviocytes were cultured and treated with AGEs (25-100 µg/ml). AGEs significantly induced the protein expressions of cyclooxygenase-2 (COX-2) and VEGF and the productions of prostaglandin-E2 (PGE2), VEGF, interleukin-6 (IL-6), and metalloproteinase-13 (MMP-13) in human synoviocytes in a dose-dependent manner. Moreover, AGEs markedly activated the phosphorylations of IκB kinase (IKK)α/β, IκBα, and nuclear factor (NF)-κB-p65 proteins in human synoviocytes in a time-dependent manner. Treatment with neutralizing antibody for RAGE statistically significantly decreased the AGEs-induced increase in COX-2, VEGF, PGE2, IL-6, and MMP13 and AGEs-activated NF-κB pathway activation. Taken together, these findings indicate that AGEs are capable of inducing VEGF production and inflammatory responses via RAGE-NF-κB pathway activation in human synoviocytes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:791-800, 2016.

Background: Age-related hearing impairment (ARHI), the most common sensory deficit in the elderly, is associated with enormous social and public health burdens. Emerging evidence has suggested that obesity and comorbidities might increase the risk of ARHI. However, no reviews have been published that address the role of nutritional interventions for obesity and comorbidities in the prevention of ARHI. Methods: A PubMed database search was conducted to identify the relationship between obesity and ARHI. “Obesity”, “metabolic syndrome”, “adipose-derived hormone”, “fatty acid”, and “age-related hearing impairment” were included as keywords. Results: A total of 89 articles was analyzed with 39 articles of relevance to ARHI. A high-fat diet may induce oxidative stress, mitochondrial damage, and apoptosis in the inner ear. Statins have been shown to delay the progression of ARHI by improving the lipid profile, reducing oxidative stress, and inhibiting endothelial inflammation. Aldosterone could exert protective effects against ARHI by upregulating the Na-K-2Cl co-transporter 1 in the cochlea. Omega-3 polyunsaturated fatty acids could preserve the cochlear microcirculation by reducing dyslipidemia and inhibiting inflammation. Alpha-lipoic acid and lecithin might delay the progression of ARHI by protecting cochlear mitochondrial DNA from damage due to oxidative stress. Tea and ginseng might protect against ARHI through their anti-obesity and anti-diabetic effects. Conclusions: Nutritional interventions for obesity and comorbidities, including a low-fat diet, supplementation with statins, aldosterone, omega-3 polyunsaturated fatty acids, alpha-lipoic acids, lecithin, tea, and ginseng, may protect against the development of ARHI.

Osteoarthritis (OA) is a degenerative joint disease involving a combination of cartilage degradation and inflammation. EGb761, a standardized extract of Ginkgo biloba leaves, holds an anti-inflammatory potency. Here, we determined whether EGb761 could inhibit lipopolysaccharide (LPS)- and IL-1β-induced inflammatory responses in human articular chondrocytes and apply the chondroprotection in OA rats. We found that LPS markedly induced the productions of PGE2 and NO and the protein expressions of COX-2 and iNOS in human chondrocytes. LPS was also seen to up-regulate the expressions of toll-like receptor-4 (TLR4), its downstream signal TNF receptor-associated factor 6 (TRAF6), and nuclear factor (NF)-κB signaling. These LPS-induced inflammatory responses were efficaciously reversed by EGb761 and its active components quercetin and kampferol. The similar results could be observed by using IL-1β as an in vitro model to mimic an inflammatory response. In an OA rat model, PGE2 and NO levels in blood, the histological alterations, and COX-2 and nitrotyrosine expressions in cartilages were markedly increased, which were effectively reversed by EGb761. Our results suggested that EGb761 exerts the anti-inflammatory effects on human articular chondrocytes and OA rats.

Benzo[a]pyrene, a ubiquitous environmental pollutant, has been suggested to be capable of initiating and/or accelerating atherosclerosis. Accumulation of vascular smooth muscle cells (VSMCs) in vessel intima is a hallmark of atherosclerosis. Nitric oxide (NO) can suppress VSMCs proliferation and induce VSMCs apoptosis. NO plays a compensatory role in the vascular lesions to reduce proliferation and/or accelerate apoptosis of VSMCs. The aim of this study was to investigate whether benzo[a]pyrene can affect VSMCs growth and apoptosis induced by NO. Benzo[a]pyrene (1-30 μmol/L) did not affect the cell number and cell cycle distribution in VSMCs under serum deprivation condition. Sodium nitroprusside (SNP), a NO donor, decreased cell viability and induced apoptosis in VSMCs. Benzo[a]pyrene significantly suppressed SNP-induced cell viability reduction and apoptosis. VSMCs cultured in conditioned medium from cells treated with benzo[a]pyrene could also prevent SNP-induced apoptosis. Benzo[a]pyrene was capable of inducing the activation of nuclear factor (NF)-κB and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in VSMCs. Both NF-κB inhibitor and p38 MAPK inhibitor significantly reversed the anti-apoptotic effect of benzo[a]pyrene on SNP-treated VSMCs. Incubation of VSMCs with benzo[a]pyrene significantly and dose-dependently increased interleukin (IL)-6 production. A neutralizing antibody to IL-6 effectively reversed the anti-apoptotic effect of benzo[a]pyrene on SNP-treated VSMCs. Taken together, these results demonstrate for the first time that benzo[a]pyrene activates IL-6 induction and protects VSMCs from NO-induced apoptosis. These findings propose a new mechanism for the atherogenic effect of benzo[a]pyrene.

// Siao-Syun Guan 1,2,* , Meei-Ling Sheu 3,* , Rong-Sen Yang 4,* , Ding-Cheng Chan 5,* , Cheng-Tien Wu 1 , Ting-Hua Yang 6 , Chih-Kang Chiang 1,7 and Shing-Hwa Liu 1,8,9 1 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Institute of Nuclear Energy Research, Atomic Energy Council, Executive Yuan, Taoyuan, Taiwan 3 Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan 4 Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan 5 Department of Geriatrics and Gerontology, College of Medicine, National Taiwan University, Taipei, Taiwan 6 Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan 7 Department of Integrated Diagnostics and Therapeutics and Internal Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan 8 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 9 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Shing-Hwa Liu, email: // Chih-Kang Chiang, email: // Keywords : diabetes, advanced glycation end products, β-cell hypertrophy, heat shock protein 60, Pathology Section Received : March 16, 2016 Accepted : March 29, 2016 Published : April 05, 2016 Abstract Heat shock protein 60 (HSP60) is a mitochondrial chaperone. Advanced glycation end products (AGEs) have been shown to interfere with the β-cell function. We hypothesized that AGEs induced β-cell hypertrophy and dysfunction through a HSP60 dysregulation pathway during the stage of islet/β-cell hypertrophy of type-2-diabetes. We investigated the role of HSP60 in AGEs-induced β-cell hypertrophy and dysfunction using the models of diabetic mice and cultured β-cells. Hypertrophy, increased levels of p27 Kip1 , AGEs, and receptor for AGEs (RAGE), and decreased levels of HSP60, insulin, and ATP content were obviously observed in pancreatic islets of 12-week-old db/db diabetic mice. Low-concentration AGEs significantly induced the cell hypertrophy, increased the p27 Kip1 expression, and decreased the HSP60 expression, insulin secretion, and ATP content in cultured β-cells, which could be reversed by RAGE neutralizing antibody. HSP60 overexpression significantly reversed AGEs-induced hypertrophy, dysfunction, and ATP reduction in β-cells. Oxidative stress was also involved in the AGEs-decreased HSP60 expression in β-cells. Pancreatic sections from diabetic patient showed islet hypertrophy, increased AGEs level, and decreased HSP60 level as compared with normal subject. These findings highlight a novel mechanism by which a HSP60-correlated signaling pathway contributes to the AGEs-RAGE axis-induced β-cell hypertrophy and dysfunction under diabetic hyperglycemia.