Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder primarily caused by pathogenic variants in the TSC1 or TSC2 genes. It is characterized by multisystem hamartomatous lesions and neuropsychiatric manifestations. Here we report a young male patient with TSC involving multiple organs, caused by a heterozygous frameshift mutation in TSC2 (c.2071delC, p.Arg691Alafs^*7). The patient initially presented with classic facial angiofibromas and hypomelanotic macules, and subsequently developed psychiatric and behavioral disturbances with auditory hallucinations. Neuroimaging revealed an intracranial mass lesion, which was confirmed as a subependymal giant cell astrocytoma on postoperative histopathology following surgery performed at an outside institution. After admission, the patient underwent a comprehensive diagnostic workup, and multidisciplinary treatment evaluation revealed extensive multisystem involve-ment, including the nervous system, skin, kidneys, lungs, heart, eyes, pancreas, liver and bones. Combined with relevant literature, this article discusses the molecular mechanisms, clinical phenotypes, and comprehensive management of TSC, in order to provide a reference for the standardized and individualized management of this disease.

OBJECTIVE: To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. METHODS: Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). RESULTS: In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. CONCLUSION This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families.
Humans ; Female ; Male ; Pedigree ; Exostoses, Multiple Hereditary/diagnosis* ; N-Acetylglucosaminyltransferases/genetics* ; Adult ; Exostosin 1 ; Asian People/genetics* ; Genetic Testing ; Exostosin 2 ; Mutation ; China ; Prenatal Diagnosis ; Pregnancy ; Genetic Counseling ; Preimplantation Diagnosis ; Exome Sequencing ; East Asian People

Objective To analysis the effectiveness and cost of Internet-based anticoagulation clinic versus traditional anticoagulation clinic treatment at Nanjing Drum Tower Hospital during the COVID-19 pandemic.Methods We reviewed and analyzed the clinical data of patients receiving anticoagulation management through Internet-based outpatient care and traditional outpatient care in Nanjing Drum Tower Hospital,from June 1,2020 to June 30,2021.Variability in time in therapeutic range(TTR)and international normalized ratio(INR)were calculated for enrolled patients.Patients meeting TTR≥60%and INR variability<0.65 were considered optimal anticoagulation quality.Cost-effectiveness analysis was conducted from the patients'perspective,with results expressed using the incremental cost-effectiveness ratio(ICER).Results In the"Internet-based anticoagulation outpatient care"and"traditional face-to-face anticoagulation outpatient care"groups,19 individuals(67.86%)and 67 individuals(76.14%)met the criteria for optimal anticoagulation quality,respectively.The mean TTR was(71.83±19.17)%in the Internet-based group and(71.74±23.41)%in the traditional face-to-face group,indicating similar levels of warfarin anticoagulation quality between the two groups.The ICER was calculated as 327.17 yuan,less than the per capita gross domestic product(GDP)of 2021.Conclusion During the COVID-19 pandemic,Nanjing Drum Tower Hospital's Internet-based anticoagulation outpatient care effectively complemented the government's epidemic control policies.It ensured equivalent anticoagulation outcomes and significantly reduced patients'financial burdens.This approach offers new insights and guidance for optimizing healthcare services in the post-pandemic era.

OBJECTIVE: Bo investigate the regulatory relationship between NKD1 and YWHAE and the mechanism of NKD1 for promoting tumor cell proliferation. METHODS: HCT116 cells transfected with pcDNA3.0-NKD1 plasmid, SW620 cells transfected with NKD1 siRNA, HCT116 cells with stable NKD1 overexpression (HCT116-NKD1 cells), SW620 cells with nkd1knockout (SW620-nkd1^-/- cells), and SW620-nkd1^-/- cells transfected with pcDNA3.0-YWHAE plasmid were examined for changes in mRNA and protein expression levels of YWHAE using qRT-PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assay was used to detect the binding of NKD1 to the promoter region of YWHAE gene. The regulatory effect of NKD1 on YWHAE gene promoter activity was analyzed by dual-luciferase reporter gene assay, and the interaction between NKD1 and YWHAE was analyzed with immunofluorescence assay. The regulatory effect of NKD1 on glucose uptake was examined in the tumor cells. RESULTS: In HCT116 cells, overexpression of NKD1 significantly enhanced the expression of YWHAE at both the mRNA and protein levels, while NKD1 knockout decreased its expression in SW620 cells (P < 0.001). ChIP assay showed that NKD1 protein was capable of binding to the YWHAE promoter sequence; dual luciferase reporter gene assay showed that NKD1 overexpression (or knockdown) in the colon cancer cells significantly enhanced (or reduced) the transcriptional activity of YWHAE promoter (P < 0.05). Immunofluorescence assay demonstrated the binding of NKD1 and YWHAE proteins in colon cancer cells. NKD1 knockout significantly reduced glucose uptake in colon cancer cells (P < 0.01), while YWHAE overexpression restored the glucose uptake in NKD1-knockout cells (P < 0.05). CONCLUSION NKD1 protein activates the transcriptional activity of YWHAE gene to promote glucose uptake in colon cancer cells.
Humans ; Colonic Neoplasms ; HCT116 Cells ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; RNA, Messenger ; Glucose ; Calcium-Binding Proteins/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; 14-3-3 Proteins/metabolism*

Objective:To explore the feasibility of functional reconstruction of muscle power in treatment of traumatic muscle defects by transferring part of superficial vastus of lateral thigh.Methods:From March 2020 to March 2023, reconstruction of muscle power with transfer of superficial lateral thigh muscle was performed on 9 patients in the Department of Hand and Foot Microsurgery of Xi'an Fengcheng Hospital. Nine patients were assigned in a study group. A total of 48 patients who previously had the surgery of chimerically grafted superficial vastus of lateral thigh were recruited as the "previous surgery group" and another group of 71 staff volunteers from our hospital were recruited as the "healthy control group". Of the study group, 5 patients had Gustilo type ⅢB injury in forearm (two with defects of flexor muscle group and 3 with extensor muscle group, 2 with the defects in the left and 3 in the right), one had defect of both flexor and extensor muscle groups in dorsal hand, one had defect of right 1st metacarpal with defects of soft tissue and thenar muscle, one had a completely severed right upper arm with a withdrawn musculocutaneous nerve from the biceps brachii and one had Gustilo ⅢC injury in right calf with defects of tibialis anterior, extensor longus and extensor phalangeal muscle. In the emergency surgery, part of the superficial muscles of lateral thigh were taken to reconstruct the muscular power for the defected traumatic muscles. During the surgery, the excessed nerve with a length of 3.0 cm proximally was removed at 3.0 cm from the point where the nerve entered the muscle. In the transfer of superficial chimeric muscle of lateral thigh, a 3.0 cm of sample nerve tissue was taken for HE staining to find out the number of nerve fibers. Musculoskeletal ultrasonography, electromyography and muscle strength test were performed in the postoperative follow-up for observations and evaluations of the effects of surgery. Average length and thickness of muscle were taken from the 48 patients in the "previous surgery group". The measurement was compared with the length of muscle fibers and the number of nerve fibers in the gracilis muscle of the 9 patients in study group. The cross-sectional areas (SCA) at contraction state (C) and resting state (R) of the superficial vastus of lateral thigh were taken from the 71 volunteers in the healthy control group, and the C/R ratio was calculated (CR value). All the 9 patients were included in the postoperative follow up by outpatient visits and via telephone or internet reviews to observe the recovery of muscle strength of the reconstruction of muscle dynamics.Results:In the study group, the number of nerve fibers shown by immunohistochemical HE staining was 1 088±213, with the CR value of graft muscle measured by musculoskeletal ultrasonography at 1.44±0.17. The wound healed smoothly without complication. The average time of postoperative follow-up for the 9 patients was 22.6 (10-38) months. Recovery of muscle strength was found at M5 in 6 patients and M4 in 3 patients. The appearance of the joints was normal. In the previous surgery group, the average muscle thickness of the superficial vastus lateralis muscle was 1.74 cm±0.35 cm and the length of muscle fiber was 8.86 cm±1.59 cm. In the healthy control group, the CR value of the superficial muscle vastus of lateral thigh was found at 1.17±0.12.Conclusion:Reconstruction of muscular power with partial muscle transfer of the superficial vastus of lateral thigh is proposed in this study.

Objective:To explore the feasibility and clinical effect of emergency lateral thigh muscle transfer in functional reconstruction of major traumatic muscle defects.Methods:Emergency surgeries for 8 patients(7 males and 1 female) with muscle defects were carried out subject to emergently reconstruct the power of lateral femoral muscle superficial region, between March 2020 and December 2021, in the Department of Hand and Foot Microsurgery Hospital, Xi'an Fengcheng Hospital. The 8 patients were 23 to 52 years old with an average of 37.6 years old. Five patients injured by machine crush, 2 by heavy object crush and 1 by traffic accident. Five patients were in Gustilo III B injury in forearm, including 2 with flexor muscle group defects, 2 with extensor muscle group defects and 1 with defect of dorsal metacarpal flexor muscle and extensor muscle. Among the 5 patients, 2 patients had the defects in left forearm and 3 in right forearm. One patient had defect of right 1st metacarpal bone and skin and thenar muscle. One patient suffered a complete right upper arm detachment with musculocutaneous nerve being drawn out from the bicipital muscle. One patient had Gustilo III C injury in the right calf with defects of extensor hallucis longus and extensor digitorum. The areas of soft tissue defect were 10.0 cm×8.0 cm-36.0 cm×11.0 cm and the size of flaps was 12.0 cm×6.0 cm-38.0 cm×12.0 cm with the volumes of excised muscle at 18.0 cm×9.0 cm×1.5 cm-10.0 cm×2.0 cm×1.0 cm. The anatomical cross-section and length of the corresponding muscle on the healthy side were measured by musculoskeletal ultrasound. The chimeric tissue flap was designed on the anterolateral side of the thigh. The flap was designed according to the size of the wound and the corresponding flap. Then 1 or 2 muscle tissue blocks were designed and cut from the superficial region of the lateral femoral muscle according to the condition of the muscle defect, to cover the wound and reconstruct the muscle power. Postoperative follow-ups were conducted by scheduled hospital visit. The contents of follow-up included dynamic observation, evaluation and record through musculoskeletal ultrasound, electromyography and strength of muscle.Results:For the 8 patients who were subject to a muscle reconstruction, the transferred muscles and flaps survived in stage-one without vascular event. Postoperative follow-ups lasted for 10 to 32 months with an average of 19.6 months. The strength of muscle was evaluated according to the M 4 strength of muscle. Strength of muscle restored to M 4 or above in 7 patients who could lift, hook or push a heavy object in 5-30 kg of weight, with free joint movement. One patient restored the strength of muscle to M 3+. Muscle contraction was detected 2-4 months after surgery by musculoskeletal B ultrasound. The average ratio of contraction to resting cross sectional area in 5 cases was 1.45±0.42. The shape of limb was bilaterally symmetrical. There was no discomfort in the donor site and knee joint. The flaps were soft and glossy, with protective sensation restored. Conclusion:Muscle transfer from the lateral femoral muscle superficial region in emergency surgery for functional reconstruction of traumatic muscle defects is feasible and effective with a good clinical effect.

Objective:To discuss outcomes of emergency repairing for Gustilo III B and III C fractures of forearm with complicated tissue defects and the related influence factors.Methods:From January 2014 to Feburary 2022, data of 98 cases of Gustilo III B and III C fractures with large compound defects of soft tissue, blood vessel, bone, tendon or muscle from elbow to wrist were collected. Primary debridement, bone fixation, wound coverage by free flap, bone transfer(or bone cement filling) or dynamic reconstruction of muscle were completed with emergency surgery in Department of Hand and Foot Microsurgery, Xi'an Fengcheng Hospital. Postoperative follow-ups were conducted through outpatient clinic visits, telephone and WeChat reviews. Video clips, questionnaires and the latest information of patients were also analysed. Rank sum test and Chi-square test were used to examine the relationship between independent variables such as general condition, disease condition and surgical procedures of chimeric tissue transfer group and simple flap transfer group, together with dependent variables such as limb salvage, number of surgery, wound healing, function scores, and complications. P<0.05 were further included in the regression equation to discover the relationship between multiple independent variables and dependent variables. Results:Follow-up lasted for 6-96 months, with an average of 71.1 months. In the chimeric group, the limb salvage rate was at 95.1%, with an infection rate of 8.50% and an average number of surgery was 2.13±0.89. In the simple flap transfer group, the limb salvage rate was at 87.5%, with an infection rate of 15.38% and an average number of surgery was 2.62±0.64. The good rate of Anderson score was 65.3% and the average score of Disability of the Arm, Shoulder and Hand(DASH) was 32.9(0-60) points for all the patients. There were significant differences in dependent variables of limb salvage and infection rate between the 2 groups ( P<0.05). Ischemia time and method of bone fixation led to significant differences in number of surgery ( P<0.05). Methods of bone fixation and the types of flap made significant differences in wound healing ( P<0.05). Underlying disease, bonedefect, Gustilo classification and method of bone fixation all contributed to the significant differences in function score ( P<0.05 or P<0.01) . Conclusion:Emergency surgery for repair of serious injury of forearm has a relatively high limb salvage rate and good functional effects. The limb salvage rate is not correlated with independent variables such as severity of injury, Mangledextremity Severity Score (MESS) and ischemia time, while transfer of a simple flap or a chimeric flap is significantly correlated with the limb salvage rate, infection and wound healing. The severity of injury, ischemia time and bone defect are correlated with functional assessment, number of surgery and bone healing.

This study aimed to define the most consistent white matter microarchitecture pattern in Parkinson's disease (PD) reflected by fractional anisotropy (FA), addressing clinical profiles and methodology-related heterogeneity. Web-based publication databases were searched to conduct a meta-analysis of whole-brain diffusion tensor imaging studies comparing PD with healthy controls (HC) using the anisotropic effect size-signed differential mapping. A total of 808 patients with PD and 760 HC coming from 27 databases were finally included. Subgroup analyses were conducted considering heterogeneity with respect to medication status, disease stage, analysis methods, and the number of diffusion directions in acquisition. Compared with HC, patients with PD had decreased FA in the left middle cerebellar peduncle, corpus callosum (CC), left inferior fronto-occipital fasciculus, and right inferior longitudinal fasciculus. Most of the main results remained unchanged in subgroup meta-analyses of medicated patients, early stage patients, voxel-based analysis, and acquisition with 30 diffusion directions. The subgroup meta-analysis of medication-free patients showed FA decrease in the right olfactory cortex. The cerebellum and CC, associated with typical motor impairment, showed the most consistent FA decreases in PD. Medication status, analysis approaches, and the number of diffusion directions have an important impact on the findings, needing careful evaluation in future meta-analyses.
Anisotropy ; Brain/diagnostic imaging* ; Corpus Callosum ; Diffusion Tensor Imaging ; Humans ; Parkinson Disease/diagnostic imaging* ; White Matter/diagnostic imaging*

Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation, and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues. The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells. Initially, we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells. Moreover, Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line. In addition, micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo. Unexpectedly, Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2, Dlx5, Msx2, and Osterix, but led to upregulation of Alp and Osteocalcin (OCN), both of which play critical roles in promoting osteoblast maturation. Importantly, luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity. Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis, we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes. Based on these findings, we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene, suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation.
Animals ; Cell Differentiation ; physiology ; Core Binding Factor Alpha 1 Subunit ; Homeodomain Proteins ; metabolism ; Mesenchymal Stem Cells ; metabolism ; Mice ; Mice, Nude ; Osteoblasts ; metabolism ; Osteocalcin ; drug effects ; Osteogenesis ; physiology ; Transcription Factors ; metabolism ; Up-Regulation

Irreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9 basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9 BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9 BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient's lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9 BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3-12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.
Bronchiectasis ; genetics ; metabolism ; Humans ; Pulmonary Alveoli ; cytology ; metabolism ; SOX9 Transcription Factor ; genetics ; metabolism ; Stem Cell Transplantation ; methods ; Stem Cells ; cytology ; metabolism