Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To understand the current situation of care needs for disabled elderly people, analyze the impact of the family environment and community services on the care needs and care pathways of older people with disabilities and to formulate effective interventions.Methods:A cross-sectional survey was conducted from August 2022 to March 2023 in five tertiary-level hospitals in Tangshan city. The survey included 332 elderly people who were disabled before hospitalization and their primary caregivers, who were selected using a convenience sampling method. The survey investigated their general information, degree of disability, family members′ support, children′s filial piety and old age ethical level, family relationships, and the care needs of the elderly people who were disabled. SPSS 22.0 was used for one-way and correlation analyses as well as multiple linear regression analyses, and AMOS 22.0 was used for the development of structural equations for path analysis.Results:Among 332 disabled elderly individuals, there were 166 males and 166 females each. The care needs score for elderly people with disabilities was 101.54 ± 16.38. The care needs of this population can be influenced by several factors, including the level of disability, number of chronic conditions, presence of chronic pain, filial piety and old age ethical level of caregivers, family relationships, and the availability of care services in the community or village. These factors had direct effects of 0.468, 0.155, -0.083, -0.350, -0.094, and 0.104, respectively.Chronic diseases and chronic pain indirectly affected the demand for care through the degree of incapacity (with respective indirect effect values of 0.065 and 0.049). Additionally, the demand for care was indirectly influenced by the level of filial piety and ethics of the caregiver through the degree of incapacity and the family relationships (an indirect effect value of -0.162).Conclusions:The care needs of the disabled elderly are high, and the personal physiology, family environment and community support of the disabled elderly will directly or indirectly affect their care needs. Therefore, many factors should be considered comprehensively considered to improve the quality of care of the disabled elderly.

The effects of host factors ADP-ribosylation factor 4 (ARF4) and ADP-ribosylation factor 5 (ARF5) upon Zika virus (ZIKV) infection in vivo were characterized by construction of gene knockout mice via CRISPR-Cas9. Firstly, ARF5 and ARF4 genes were modified by the CRISPR-Cas9 system and then microinjected into the fertilized eggs of C57BL/6JGpt mice. Fertilized eggs were transplanted to obtain ARF4 or ARF5 knockout (ARF4KO or ARF5KO) mice, and ARF4/5 double knockout mice were achieved by the mating between ARF4KO and ARF5KO mice (ARF4KO/ARF5KO). Then, the mouse genotypes were identified by PCR to identify the positive knockout mice, and RT-qPCR was employed to examine the knockout efficiency. The mice were then infected with ZIKV and the blood and tissue samples were collected after 2, 4, and 6 days. RT-qPCR was then employed to determine the virus load, and hematoxylin-eosin staining was employed to observe the pathological changes in the tissue. The results showed that expected PCR bands were detected from ARF4KO^-/+, ARF5KO^-/-, and ARF4KO^-/+/ARF5KO^-/- mice, respectively. The results of mRNA transcription measurement indicated the significant knockdown of ARF4 by 37.8%-50.0% but not ARF5 in ARF4KO^-/+ compared with the wild-type mice. Meanwhile, complete knockout of ARF5 and no changes in ARF4 were observed in ARF5KO^-/- mice. Additionally, completed knockout of ARF5 and down-regulated mRNA level of ARF4 in the lung, kidney, and testis were detected in ARF4KO^-/+/ARF5KO^-/-mice in comparison with the wild-type mice. The virus load in the serum decreased in ARF4KO^-/+ mice, while it showed no significant change in ARF5KO^-/- or ARF4KO^-/+/ARF5KO^-/- mice compared with that in the wild type. Meanwhile, ARF4KO^-/+ mice showcased no significant difference in virus load in various tissues but attenuated pathological changes in the brain and testis compared with the wild-type mice. We successfully constructed ARF4KO and ARF5KO mice by CRISPR-Cas9 in this study. ARF4 rather than ARF5 is essential for ZIKV infection in vivo. This study provided animal models for studying the roles of ARF4 and ARF5 in ZIKV infection and developing antivirals.
Animals ; ADP-Ribosylation Factors/metabolism* ; Zika Virus Infection/genetics* ; Mice ; Mice, Knockout ; Zika Virus/genetics* ; Mice, Inbred C57BL ; CRISPR-Cas Systems ; Viral Load ; Male ; Female

The child was a 9-year-old girl, and sought medical advice due to "proteinuria for over a month". Renal biopsy result showed focal segmental glomerulosclerosis with diffuse vacuolization of glomerular podocytes and tubular epithelial cells. The child was diagnosed as type Ⅱ sialidosis with a compound heterozygote mutation in neuraminidase 1 gene for c.239C>T(p.Pro80Leu), c.220G>C(p.Val74Leu) and c.205A>G(p.Arg69Gly). Her father was proved to carry the first mutation, and her mother carried the other two, respectively. The report aims to improve the clinician's understanding of the rare disease. Early diagnosis can help avoid overuse of immunosuppressants, guide treatment reasonably and improve prognosis.

Objective:To summarize and analyze the application effect of combined polyfoliate and free flaps of superficial temporal artery and its branches in the wounds on the head and face.Methods:From February 2019 to January 2020, patients diagnosed with head and face skin tumors in the Department of Plastic Surgery of Xiangya Changde Hospital were selected. The lesions were excised, and the superficial temporal artery and its different branches (the parietal branch, the frontal branch, and the perforating branch of the frontal branch) were used to design polyfoliate and free flaps for wound repair. Patients were treated with polyfoliate flaps designed using the parietal or frontal branch with the proximal end of the trunk as the vascular pedicle, polyfoliate flap designed using the perforating branch of the frontal branch with the proximal end of the frontal branch as the vascular pedicle, polyfoliate flap designed using the trunk and parietal branch with the frontal branch as the vascular pedicle, and a free flap designed using the trunk with the proximal end of the parietal branch as the vascular pedicle. All donor sites of the flaps were closed primarily. The survival of the flaps were observed after surgery, and the appearance of the flaps and the recurrence of facial tumors were followed up.Results:In this study, all the patients were aged 18 to 69 years with an average age of 57 years and were diagnosed with head and face skin tumors. Among the six patients, there were five men and one woman. All the flaps survived, and no tumor recurrence was noted during the postoperative follow-up period of 1 month to 10 months. The texture of these flaps was similar to the surrounding skin, with no color difference. In addition, no noticeable scar was noted on both the flaps and the donor sites. The outcome of the repair was satisfactory.Conclusions:The design of polyfoliate and free flaps using different combinations of the superficial temporal artery and its branches can facilitate flexible repair of the wounds on the head and face. This method exhibits certain advantages, such as skin characteristics of the flaps similar to that of the surrounding skin, direct closure of the donor sites, and a satisfactory repair.

Objective:To summarize and analyze the application effect of combined polyfoliate and free flaps of superficial temporal artery and its branches in the wounds on the head and face.Methods:From February 2019 to January 2020, patients diagnosed with head and face skin tumors in the Department of Plastic Surgery of Xiangya Changde Hospital were selected. The lesions were excised, and the superficial temporal artery and its different branches (the parietal branch, the frontal branch, and the perforating branch of the frontal branch) were used to design polyfoliate and free flaps for wound repair. Patients were treated with polyfoliate flaps designed using the parietal or frontal branch with the proximal end of the trunk as the vascular pedicle, polyfoliate flap designed using the perforating branch of the frontal branch with the proximal end of the frontal branch as the vascular pedicle, polyfoliate flap designed using the trunk and parietal branch with the frontal branch as the vascular pedicle, and a free flap designed using the trunk with the proximal end of the parietal branch as the vascular pedicle. All donor sites of the flaps were closed primarily. The survival of the flaps were observed after surgery, and the appearance of the flaps and the recurrence of facial tumors were followed up.Results:In this study, all the patients were aged 18 to 69 years with an average age of 57 years and were diagnosed with head and face skin tumors. Among the six patients, there were five men and one woman. All the flaps survived, and no tumor recurrence was noted during the postoperative follow-up period of 1 month to 10 months. The texture of these flaps was similar to the surrounding skin, with no color difference. In addition, no noticeable scar was noted on both the flaps and the donor sites. The outcome of the repair was satisfactory.Conclusions:The design of polyfoliate and free flaps using different combinations of the superficial temporal artery and its branches can facilitate flexible repair of the wounds on the head and face. This method exhibits certain advantages, such as skin characteristics of the flaps similar to that of the surrounding skin, direct closure of the donor sites, and a satisfactory repair.

Objective:To summarize the clinical features, genetic testing and treatment efficacy of 6 children with Dent disease.Methods:Six children diagnosed with Dent disease in Guangzhou Women and Children′s Medical Center from January 2014 to March 2019 were enrolled.Their medical history, clinical manifestations, laboratory results, genetic test results, and proteinuria level, calciuria level and renal function after medication were measured.Results:All patients were male, with the onset age ranged from 1 to 9 years old.They were followed up for 6 months to 4 years.All the children had low molecular weight proteinuria.Urine protein electrophoresis showed that the ratio of low molecular weight proteinuria in only 2 cases was more than 50%.Renal biopsy suggested that all cases were combined with glomerular lesions.Five cases had hypercalciuria.Under the microscope, there were 5 cases of hematuria.Two case had rickets, and there was no renal calcium deposition and hypophosphatemia.Five cases were detected with CLCN5 mutations, of which p. C160Yfs*49 and p. G523D were first reported.One case had an OCRL1 mutation.Patients were treated with Hydrochlorothiazide and angiotensin converting enzyme inhibitor (ACEI). The 24 h urinary calcium level after treatment was lower than that before treatment [0.40 (0.24, 0.43) mmol/kg vs.0.12 (0.11, 0.14) mmol/kg, U=2.00, P<0.01]. However, there was no significant decrease in the 24 h-urinary protein level before and after treatment [77.09 (62.41, 88.01) mg/kg vs.80.33 (66.03, 92.52) mg/kg, U=12.00, P>0.05]. Conclusions:Dent disease is mainly characterized by low molecular weight proteinuria, and some patients may not be associated with hypercalciuria.Gene tests help to identify the disease type.ACEI and Hydrochlorothiazide can reduce the urinary calcium level, but cannot improve the level of urinary protein.

Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.

OBJECTIVETo compare the prognostic value of different models in patients with early-stage diffuse large B-cell lymphoma (DLBCL).

METHODSEarly-stage DLBCL patients diagnosed from January 2000 to December 2012 were analyzed retrospectively. All patients received with at least 2 cycles of immunochemotherapy R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with or without radiotherapy. The prognostic value of international prognostic index (IPI) , revised IPI (R-IPI) and enhanced IPI (NCCN-IPI) was compared.

RESULTSNinety-seven cases of early-stage DLBCL were included in the study. The median age was 58 years (15-88 years) with a median follow-up of 34.7 months (range 7.3-77.4 months). The expected 5-year overall survival (OS) for entire group was 82%. There was no patient in the high risk group according to IPI or NCCN-IPI. According to IPI, the 5-year OS in the low, low intermediate, high intermediate risk groups were 95%, 38% and 60%, respectively. According to R-IPI, the 5-year OS in the very good, good, and poor risk groups were 93%, 75% and 60%, respectively. According to NCCN-IPI, the 5-year OS in the low, low intermediate, high intermediate risk groups were 92%, 85% and 29%, respectively.

CONCLUSIONNCCN-IPI would be of an ideal prognostic model for early-stage DLBCL patients.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Murine-Derived ; Antineoplastic Combined Chemotherapy Protocols ; Cyclophosphamide ; Doxorubicin ; Humans ; Immunotherapy ; Lymphoma, Large B-Cell, Diffuse ; diagnosis ; Middle Aged ; Prednisone ; Prognosis ; Retrospective Studies ; Rituximab ; Vincristine ; Young Adult

Objective To assess efficacy, infection rate and recurrence rate of tacrolimus prescribed in infants with steroid-resistant nephrotic syndrome (SRNS). Method From August 2011 to August 2014, 22 cases of SRNS infants (treatment group) received oral tacrolinms treatment, 0.1 to 0.15 mg/ kg per day and once every 12 hours were enrolled in this retrospective longitudinal study and were compared with 23 cases infant SRNS (control group) treated with high-dose methylprednisolone pulse therapy. Followed up for 1 year we analysed the data of proteinuria, lymphocyte count, proteinuria relapse and complication (infection, hyperglycemia) of the two groups’ patients at every point time. Results The pathology of the patients maintains of MCD, MsPGN, FSGS and IgM nephropathy so on. Follow-up to 6 months, the total remission rate 95.45% of treatment group was significantly higher than that in control group (60.87%). Follow-up to 6 months , 24 h urinary protein of the treatment group were respectively 67.88 mg/(kg·d) which were remarkably lower than base line [657.5 mg/(kg·d)], meanwhile which were obviously lower than the 6th month point of control group [305.55 mg/(kg·d)]. Lymphocyte counts had been done during the initial and the destination in the treatment group. Follow-up to 12 months, the CD4+ 795.16/uL, CD8+ 496.85/uL, CD19+ 358.23/uL had decreased observably than when at origin what was 2697.45/uL, 2265.63/uL, 1579.34/uL. Followed-up 1 year, the person-time of infection of treatment group existed superior to the control groups; The recurrence rate was 71.43% in treatment group, which compared with control groups (60.87%) without no significant difference. The treatment group with BG and CCr maintained stably. Conclusion Tacrolimus show its own advantages of reliable effect and less side-effect on the infant with steroid-resistant nephrotic symdrome associated with genes , but it could not lessen the relapse of the disease, and it′s long-term prognosis is still not very clear.