AAV-Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness.

Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness.

Preclinical Efficacy And Safety Evaluation of AAV-OTOF in DFNB9 Mouse Model And Nonhuman Primate.

OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof-related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell-specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual-AAV-OTOF-hybrid strategy to transfer full-length OTOF is generated, which can stably restore hearing in adult OTOFp.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild-type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application.

The external jugular vein is a feasible and safe alternative access for retrieval of inferior vena cava filter.

PURPOSE: The purpose is to analyze whether the external jugular vein (EJV) is a feasible and safe alternative access for the retrieval IVCFs designed for the jugular approach. METHODS: This study was designed as a nonrandomized, controlled study. The patients were divided into two groups: the IJV or EJV access groups. All operations were performed by the vascular surgery team. The main outcome was the technical success rate. The secondary outcomes included (1) the IVCF retrieval rate; (2) the time required to puncture the access vein (min); (3) the number of punctures required for access, and other aspects. RESULTS: A total of 119 patients were recruited for IVCF retrieval. Seventeen patients refused to join this trial, leaving 58 patients in the IJV group and 44 patients in the EJV group. In the IJV group, technical success was not achieved in one patient who started in the EJV group and was transferred to the IJV group. There was no significant difference in age, comorbidities, or technical success rate between the two groups. Significant differences were observed in puncture time (min), number of punctures, and inadvertent puncture of the carotid artery. All of the patients were discharged 1 or 2 days after the operation. CONCLUSION: EJV is safe and feasible alternative access for the retrieval of IVCFs that are designed for jugular approaches.

Comparative Transcriptome Analysis of the Skin and the Peritoneal Wall Layer of Triplophysa stenura Distributed in High Elevations.

A total of 81,868 All-Unigenes were sequenced and assembled by the transcriptome in the dorsal skin, the lateral skin, and the peritoneal wall layer of Triplophysa stenura with a total assembly length of 123,827,585 bp, and 68,750 unigenes were annotated to seven functional databases. A total of 588 DEGs were screened between the dorsal and lateral skin, 17,097 DEGs were screened between the dorsal skin and the peritoneal wall layer, and 16,598 DEGs were screened between the lateral skin and the peritoneal wall layer. Most of DEGs in three tissues were annotated to GO terms related to cellular structures, binding, cellular processes, and catalytic activity. They were also annotated to KEGG pathways such as the MAPK signaling pathway, PI3K-Akt signaling pathway, Wnt signaling pathway, melanogenesis, tyrosine metabolism, and cell cycle. A total of twenty-three DEGs were found to be enriched in the melanin synthesis pathway by a local Blast comparison, of which nine DEGs were significantly upregulated in the peritoneal wall layer and six DEGs were significantly upregulated in the dorsal and lateral skin. The results suggest that these genes may be associated with the molecular mechanism of melanin synthesis in T. stenura, and the differential regulation of genes may be related to the differences in UVR intensity and tissue sites of melanin synthesis. Further investigation is needed on how these genes specifically regulate melanin synthesis.

The complete mitochondrial genome of Micropercops swinhonis (Perciformes: Gobioidei: Odontobutidae).

For understanding the phylogenetic position of Micropercops swinhonis within the family Odontobutidae, the complete nucleotide sequence of M. swinhonis mitochondrial genome was firstly determined. The genome is 16,493 bp in length, and consists of 37 genes (13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes) and 2 main noncoding regions (the control region and the origin of the light strand replication). The gene composition and order of which were similar to most other vertebrates. Within the control region, typical conserved domains, such as the termination-associated sequence, central and conserved sequence blocks domains were identified.

Efficacy and safety of dutasteride in Chinese adults with symptomatic benign prostatic hyperplasia: a randomized, double-blind, parallel-group, placebo-controlled study with an open-label extension.

BACKGROUND: Dutasteride is a dual inhibitor of type I and type II 5α-reductases and provides nearly complete suppression of dihydrotestosterone, which plays a key role in the aetiology and development of benign prostatic hyperplasia (BPH). Most knowledge about the efficacy and safety of dutasteride in BPH derives from three pivotal phase III studies conducted primarily in Caucasian populations. OBJECTIVE: This study aimed to evaluate the efficacy and safety of dutasteride in Chinese adults with symptomatic BPH. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled study conducted over 6 months, followed by an open-label extension of 12 months. A total of 253 BPH subjects with a total prostate volume (TPV) of ≥30 cm3, a maximal urinary flow rate (Q(max)) between 5 and 15 mL/s, and an American Urology Association Symptom Index (AUA-SI) score of ≥12 units were randomized to dutasteride 0.5 mg/day orally or matching placebo treatment in a 1:1 ratio. After 6 months, eligible subjects who volunteered to enter the open-label extension received dutasteride 0.5 mg/day orally. Changes in TPV, Q(max) and AUA-SI as well as drug safety were evaluated. RESULTS: Dutasteride significantly reduced mean TPV compared with placebo at 3 and 6 months (both p < 0.05). At 6 months, mean TPV decreased by 17.14% versus 3.71% in the dutasteride and placebo groups, respectively. Numerically higher improvements in Q(max) and AUA-SI were observed in the dutasteride group at 3 and 6 months, but there was no statistically significant difference between treatment groups. However, ad hoc analysis indicated that, at 6 months, significantly higher proportions of subjects in the dutasteride group experienced a Q(max) improvement of ≥3 mL/s, or an AUA-SI improvement of ≥1 unit, compared with the placebo group (both p < 0.05). According to these criteria, the Q(max) responder rates were 33.63% and 19.83% in the dutasteride- and placebo-treated groups, respectively, and the AUA-SI responder rates were 87.61% and 76.92%, respectively. During the open-label extension, continuous improvements in TPV, Q(max) and AUA-SI were noted in both groups. Dutasteride was well tolerated with a low incidence of treatment-related adverse events over 18 months. CONCLUSION: Dutasteride was effective compared with placebo in the treatment of symptomatic BPH among Chinese patients. The efficacy data from trials involving subjects of different ethnic origins showed some similarities. Dutasteride was generally well tolerated during the study period.

Efficacy and Safety of Dutasteride in Chinese Adults with Symptomatic Benign Prostatic Hyperplasia : A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Extension.

BACKGROUND: Dutasteride is a dual inhibitor of type I and type II 5α-reductases and provides nearly complete suppression of dihydrotestosterone, which plays a key role in the aetiology and development of benign prostatic hyperplasia (BPH). Most knowledge about the efficacy and safety of dutasteride in BPH derives from three pivotal phase III studies conducted primarily in Caucasian populations. OBJECTIVE: This study aimed to evaluate the efficacy and safety of dutasteride in Chinese adults with symptomatic BPH. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled study conducted over 6 months, followed by an open-label extension of 12 months. A total of 253 BPH subjects with a total prostate volume (TPV) of ≥30 cm3, a maximal urinary flow rate (Qmax) between 5 and 15 mL/s, and an American Urology Association Symptom Index (AUA-SI) score of ≥12 units were randomized to dutasteride 0.5 mg/day orally or matching placebo treatment in a 1 : 1 ratio. After 6 months, eligible subjects who volunteered to enter the open-label extension received dutasteride 0.5 mg/day orally. Changes in TPV, Qmax and AUA-SI as well as drug safety were evaluated. RESULTS: Dutasteride significantly reduced mean TPV compared with placebo at 3 and 6 months (both p<0.05). At 6 months, mean TPV decreased by 17.14% versus 3.71% in the dutasteride and placebo groups, respectively. Numerically higher improvements in Qmax and AUA-SI were observed in the dutasteride group at 3 and 6 months, but there was no statistically significant difference between treatment groups. However, ad hoc analysis indicated that, at 6 months, significantly higher proportions of subjects in the dutasteride group experienced a Qmax improvement of ≥3 mL/s, or an AUA-SI improvement of ≥1 unit, compared with the placebo group (both p<0.05). According to these criteria, the Qmax responder rates were 33.63% and 19.83% in the dutasteride- and placebo-treated groups, respectively, and the AUA-SI responder rates were 87.61% and 76.92%, respectively. During the open-label extension, continuous improvements in TPV, Qmax and AUA-SI were noted in both groups. Dutasteride was well tolerated with a low incidence of treatment-related adverse events over 18 months. CONCLUSION: Dutasteride was effective compared with placebo in the treatment of symptomatic BPH among Chinese patients. The efficacy data from trials involving subjects of different ethnic origins showed some similarities. Dutasteride was generally well tolerated during the study period.

Tracking intrahepatically transplanted islets labeled with Feridex-polyethyleneimine complex using a clinical 3.0-T magnetic resonance imaging scanner.

OBJECTIVES: To evaluate the images acquired with a clinical 3.0-T magnetic resonance imaging machine as the quantification of transplanted and surviving islets in vivo. METHODS: Polyethyleneimine (PEI) was introduced to increase the labeling efficiency of Feridex, a dextran-coated superparamagnetic iron oxide. Allogeneic (Lewis-to-Wistar) and syngeneic (Wistar-to-Wistar) intraheptatic islet transplantations were performed to study the relationship among magnetic resonance imaging, metabolic monitoring, and pathological examination. RESULTS: After receiving Feridex-PEI-labeled islets, dark voids could be observed in the livers of both groups, accompanied with a significant decrease in liver/muscle intensity ratio from 1.25 +/- 0.03 to 1.09 +/- 0.05 (P < 0.01). One week after transplantation, islet grafts were rejected in the allogeneic group. Rapid disappearance of dark voids and a significant increase of liver/muscle ratio were observed. No islet grafts could be found in the paraffin sections of livers by that time. Meanwhile, in the syngeneic group, islet grafts survived indefinitely. Dark voids persisted and low liver/muscle ratios retained. The fact that the dark voids represented the labeled islets was confirmed by combined staining of insulin activity and Prussian blue. CONCLUSIONS: Either spot counting or signal intensity measurement provides a perfect quantification of transplanted and surviving islets in vivo. Feridex-PEI provides an effective and safe way to label islets.

Constitutive expression of three novel catfish CXC chemokines: homeostatic chemokines in teleost fish.

Chemokines are best known for their vital role in leukocyte chemotaxis, as part of the larger inflammatory response. Expression analysis and functional characterization of chemokines in mammalian species have often overlooked the role of these proteins under homeostatic conditions. Recent investigations of chemokine diversity in teleost fish have also centered on the immune-related functions of chemotactic cytokines, such as CXCL8 and CXCL10. While a disease-based approach to chemokines is essential to the development of remediative therapies for both human and animal infections, it may be a poor measure of the overall complexity of chemokine functions. As part of a larger effort to assess the conservation of chemokine diversity in teleost fish, we report here the identification of three novel, constitutively expressed CXC chemokines from channel catfish (Ictalurus punctatus). Phylogenetic analyses indicated that two of the three CXC chemokines were orthologues for mammalian CXCL12 and CXCL14, respectively. Whereas a clear orthology could not yet be established for the third CXC chemokine, it shared highest amino acid identity with mammalian CXCL2. All three CXC chemokines show expression in a wide range of tissues, and early expression during development was observed for CXCL12. The expression of this new set of catfish CXC chemokines was not induced during challenge by infection of Edwardsiella ictaluri, the causative agent of the fish pathogen enteric septicemia of catfish. In contrast to the gene duplication of CXCL12 in carp and zebrafish, Southern blot analysis indicated that all three catfish CXC chemokines exist as single copy genes in the catfish genome suggesting that gene duplication of CXC chemokines in specific teleost fish was a recent evolutionary event.

Thirty years of kidney transplantation in two Chinese centers.

Since the first kidney transplantation was performed in 1976, 4,306 renal transplantations have been performed at Shanghai No. 1 People's Hospital and Fujian Oriental Hospital. Nearly all (99%) of the grafts were from deceased donors. Graft survival rates in the era of modern immunosuppression and HLA-based organ allocation have improved substantially. The one-, 5- and 10-year graft survival rates for 2,575 transplants performed during 1995-2004 were 93.9%, 71.8% and 53.9%, respectively. Chronic rejection accounted for 54.3% of graft failures and 54.2% of patient deaths resulted from graft failure. We performed 48 combined liver-kidney transplants since 2001 and the first simultaneous human islet-kidney transplantation last year.