The treatment of inner ear disease is developing towards local drug delivery to avoid drawbacks of systemic approach.The cochlear implants with drug delivery functions,a newly developed method of drug delivery into inner ear for treatment,has become the focus of research in recent years.In this review,we will describe recent advances in characteristics,product developments and applications of different types of drug loaded cochlear implants for local therapy.

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.
Humans ; Male ; Animals ; Mice ; Semen/metabolism* ; Dyneins/metabolism* ; Cilia/metabolism* ; Mutation ; Ciliary Motility Disorders/genetics*

Objective:To analyze the epidemic characteristics and virus gene sequence of hemorrhagic fever with renal syndrome (HFRS) in an industrial park in Daishan County, Zhejiang Province, and to provide clues and basis for local HFRS prevention and control.Methods:According to the case questionnaire in the "National Surveillance Program for Hemorrhagic Fever with Renal Syndrome", general and epidemiological investigation of HFRS cases was carried out in the epidemic-related industrial park. Serum samples of the cases, people and host animals in the same living environment were collected for hantavirus antibody or nucleic acid detection, the M, S gene amplification and sequence determination. MEGAX 10.1.8 software was used to construct the phylogenetic tree of M and S genes for virus genotyping and evolutionary analysis.Results:A total of 3 confirmed cases of HFRS were reported. They were all workers in the epidemic-related industrial park, male, who lived in the park for more than half a year and had no history of HFRS vaccination. There were no rodent-proof facilities in the industrial park's dormitories and canteens, and the living items were placed in a disorderly manner, the rodents and its excrement could be seen; a total of 38 host animals were captured in the same living environment with cases, all of which were Rattus norvegicus. The 3 reported cases of HFRS were all mild, with atypical clinical manifestations in the early stage of onset, mainly fever and fatigue. The serum specific antibodies of hantavirus IgG and IgM were positive (3/3), and the antibodies of people in the same living environment were negative (100.0%, 100/100). The serum samples of 2 reported cases of HFRS and 4 Rattus norvegicus were positive for nucleic acid, all of which were SEOV type hantavirus. The M gene segment homology of 6 positive serum samples was 100.0%, which was closely related to Rod/2012/QHD/4/Gc isolated from Hebei and RuianRn180 isolated from Ruian Zhejiang Province; the homology of S gene segment was 99.6% to 99.8%, which was closely related to JiangxiXinjianRn-09-2011, a strain isolated from Jiangxi Province. Conclusions:The HFRS epidemic in the industrial park is caused by the transmission of SEOV type hantavirus to humans via Rattus norvegicus; poor living environment, poor hygiene habits of personnel and lack of vaccination are all related to the incidence of HFRS; the main epidemic strains shows high homology and geographical aggregation.

Objective:To systematically review and compare the efficacy of intranasal dexmedetomidine versus oral midazolam for premedication in the pediatric patients.Methods:PubMed, EMbase and Cochrane library were searched for all randomized controlled trials involving the efficacy of intranasal dexmedetomidine versus oral midazolam for premedication in the pediatric patients from inception to August 2019, with an English language restriction.Evaluation indexes included efficacy of preoperative sedation, acceptance of face mask for anesthesia, postoperative requirement for rescue analgesia, incidence of agitation during emergence and postoperative recovery time.The quality of the included trials was assessed according to the relevant criteria recommended in Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1.Meta-analysis was conducted using the Cochrane Collaboration′s Review Manager 5.3 software.Results:Ten randomized controlled trials involving 720 pediatric patients were included.Compared with oral midazolam group, the efficacy of preoperative sedation was better, the requirement for postoperative rescue analgesia was decreased ( P<0.01), and no significant differences were found in acceptance of face mask for anesthesia, incidence of agitation during emergence, and postoperative recovery time in intranasal dexmedetomidine group ( P>0.05). Conclusion:Intranasal dexmedetomidine provides better efficacy than oral midazolam when used for premedication in the pediatric patients.

Blocking the programmed death-ligand 1 (PD-L1) on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy. However, only a minority of patients presented immune responses in clinical trials. To develop an alternative treatment method based on immune checkpoint blockade, we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic copolymer aPBAE to downregulate PD-L1 expression on tumor cells specifically knocking out Cyclin-dependent kinase 5 () gene . The expression of PD-L1 on tumor cells was significantly attenuated by knocking out , leading to effective tumor growth inhibition in murine melanoma and lung metastasis suppression in triple-negative breast cancer. Importantly, we demonstrated that aPBAE/Cas9-Cdk5 treatment elicited strong T cell-mediated immune responses in tumor microenvironment that the population of CD8 T cells was significantly increased while regulatory T cells (Tregs) was decreased. It may be the first case to exhibit direct PD-L1 downregulation CRISPR-Cas9 genome editing technology for cancer therapy. It will provide promising strategy for preclinical antitumor treatment through the combination of nanotechnology and genome engineering.

Objective To investigate the incidence and risk factors of neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture. Methods Live born infants, including those diagnosed with neonatal asphyxia, were recruited from 16 different hospitals in Hubei Enshi Tujia and Miao Autonomous Prefecture from January to December of 2016. The 16 hospitals included four grade A tertiary hospitals (three general hospitals and one traditional Chinese medicine hospital) and 12 grade A secondary hospitals (eight general hospitals, one maternal and child health hospital and three traditional Chinese medicine hospitals). A retrospective investigation was conducted using questionnaire to analyze the basic information, perinatal risk factors and prognosis of those infants. Chi-square test was used for statistical analysis. Results Among 22 294 recruited live born infants, 733 (3.29%) were diagnosed with neonatal asphyxia on discharge, including 627 (85.54%) mild cases and 106 (14.46%) severe cases. And neonatal asphyxia resulted in deaths of 27 cases (3.68%). The risk factors for neonatal asphyxia included multiple pregnancy, pregnancy conceived with assisted reproductive technology, premature infant, low birth weight infant, fetal malposition, congenital malformation, male infant, born during transfer, mother of Tujia nationality, low educational level (primary school or lower), living in rural area, the number of antenatal visits ≤3, history of early threatened abortion, anemia in pregnancy, hypertensive disorders of pregnancy, chorioamnionitis, abnormal pregnancy history and abnormality of umbilical cord, amniotic fluid or placenta. Conclusions The incidence of neonatal asphyxia in Enshi area is obviously higher than the national average. The main risk factors for neonatal asphyxia in this area are related to maternal background and the living condition of the mother during pregnancy, delivery as well as the newborn at birth.

OBJECTIVETo explore the genetic basis for a patient with oculodentodigital dysplasia.

METHODSGenomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole-exome sequencing was carried out for the trio family. Suspected mutation was verified by Sanger sequencing.

RESULTSA de novo c.412G>A mutation of the GJA1 gene was identified in the patient, which was validated by Sanger sequencing.

CONCLUSIONThe c.412G>A mutation of the GJA1 gene probably underlies the disease in the patient.

Adult ; Connexin 43 ; genetics ; Craniofacial Abnormalities ; genetics ; Exome ; Eye Abnormalities ; genetics ; Foot Deformities, Congenital ; genetics ; Humans ; Male ; Mutation ; Sequence Analysis, DNA ; Syndactyly ; genetics ; Tooth Abnormalities ; genetics

Objective To compare the suture bridge (SB) and conventional double-row (DR) suture in the repair of full-thickness rotator cuff tear.Methods From May 2013 through July 2016,48 patients with full-thickness rotator cuff tear were randomly divided into 2 even groups (n =24).SB group was repaired using the SB technique while DR group using conventional DR technique.The 2 groups were compared in terms of operation time,postoperative shoulder function scoring and incidence of re-tear.Results All the patients were followed up for 8 to 24 months (average,15.3 months).In DR group,the visual analogue scale (VAS) scores decreased from preoperative 6.3 ± 2.3 to 1.0 ± 0.4 at the last follow-up,the America Shoulder and Elbow Surgeons (ASES) scores increased from preoperative 49.3 ± 8.5 to 90.0 ± 2.5 at the last follow-up,and the Constant scores increased from preoperative 58.7 ± 12.5 to 88.1 ± 4.0 at the last follow-up.In SB group,the VAS scores decreased from preoperative 6.0 ± 1.9 to 0.9 ± 0.8 at the last follow-up,the ASES scores increased from preoperative 50.2 ± 6.2 to 89.5 ± 3.4 at the last follow-up,and the Constant scores increased from preoperative 57.3 ± 7.5 to 90.0 ± 3.2 at the last follow-up.All the comparisons showed a significant difference between preoperation and the last follow-up (P ＜ 0.05),but an insignificant difference between the 2 groups (P ＞ 0.05).SB group used significantly less operation time (74.5 ± 19.0 min) than DR group (86.5 ± 21.0 min),and reported significantly lower incidence of re-tear (4.2％) than DR group (25.0％) (P ＜ 0.05).Conclusions In arthroscopic repair of full-thickness rotator cuff tear,SB technique shows few therapeutic advantages over conventional DR technique,but the former needs less operation time and leads to lower incidence of re-tear.

Objective: To analyze whether heat-shock protein 90 (HSP90) be involved in a permanently abnormal activated JAK/STAT signaling in ATL cells in vitro. Methods: The effect of 17-AAG on proliferation of ATL cell lines HUT-102 was assessed using CCK8 at different time points. Cell apoptosis was measured by flow cytometry. The specific proteins HSP90, STAT5, p-STAT5 and JAK3 were detected by Western blotting. Results: Overexpression of HSP90 in HUT-102 cell lines was disclosed (P<0.05) , and constitutive activation of JAK3/STAT5 signaling was observed in HTLV-1-infected T-cell lines but not in normal PBMCs; Treatment of ATL cell lines with 17-AAG led to reduced cell proliferation, but there was no significant change in terms of cell proliferation when the concentration of 17-AAG between 2 000-8 000 nmol/L (P>0.05) . 17-AAG induced cell apoptosis in different time-points and concentrations. 17-AAG don’t affect the expression of JAK3 gene. Conclusion This study indicated that JAK3 as HSP90 client protein was aberrantly activated in HTLV-1-infected T-cell lines, leading to constitutive activation of p-STAT5 in JAK/STAT signal pathway, which demonstrated that HSP90-inhibitors 17-AAG inhibited the growth of HTLV-1-infected T-cell lines by reducing cell proliferation and inducing cell apoptosis.

Objective To investigate the correlation between EBV-LMP2-specific cell responses,EBV DNA copies and titers of IgA antibody to viral capsid antigen (IgA/VCA).Methods IgA/VCA antibody were tested with immune-enzyme method.Both of plasma and lymphocytes were respectively separated from IgA/VCA-positive individuals and patients with nasopharyngeal carcinoma (NPC) without treatment.EBV DNA copies and LMP2-specific cell responses were detected by interferon-gamma Elispots assay and fluorescent quantitative PCR method.Results IgA/VCA antibody in 80 of 1 233 individuals was positive in Cangwu county,and the positive rate is 6％.EBV-LMP2-specific cell responses and EBV DNA copies were detected in 72 of 80 IgA/VCA positive individuals and patients with NPC.EBV DNA copies in plasma were increased with rise of titers of IgA/VCA antibody,while EBV-LMP2-specific cell responses were declined.Conclusion EBV-LMP2-specific cell responses and EBV DNA copies are probably associated with titers of IgA/VCA antibody.