Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Interaction Between Genetic Susceptibility and COVID-19 Pathogenesis in Pediatric Multisystem Inflammatory Disorders: The Role of Immune Responses.

Numerous studies have highlighted the emergence of coronavirus disease (COVID-19) symptoms reminiscent of Kawasaki disease in children, including fever, heightened multisystem inflammation, and multiorgan involvement, posing a life-threatening complication. Consequently, extensive research endeavors in pediatric have aimed to elucidate the intricate relationship between COVID-19 infection and the immune system. COVID-19 profoundly impacts immune cells, culminating in a cytokine storm that particularly inflicts damage on the pulmonary system. The gravity and vulnerability to COVID-19 are closely intertwined with the vigor of the immune response. In this context, the human leukocyte antigen (HLA) molecule assumes pivotal significance in shaping immune responses. Genetic scrutiny of HLA has unveiled the presence of at least one deleterious allele in children afflicted with multisystem inflammatory syndrome in children (MIS-C). Furthermore, research has demonstrated that COVID-19 exploits the angiotensin-converting enzyme 2 (ACE-2) receptor, transmembrane serine protease type 2, and various other genes to gain entry into host cells, with individuals harboring ACE-2 polymorphisms being at higher risk. Pediatric studies have employed diverse genetic methodologies, such as genome-wide association studies (GWAS) and whole exome sequencing, to scrutinize target genes. These investigations have pinpointed two specific genomic loci linked to the severity and susceptibility of COVID-19, with the HLA locus emerging as a notable risk factor. In this comprehensive review article, we endeavor to assess the available evidence and consolidate data, offering insights into current clinical practices and delineating avenues for future research. Our objective is to advance early diagnosis, stabilization, and appropriate management strategies to mitigate genetic susceptibility's impact on the incidence of COVID-19 in pediatric patients with multisystem inflammation.

The disease burden of degenerative mitral valve disease in the Chinese population from 1990 to 2019 / 中华心血管病杂志

Objective: To explore the trend of disease burden of degenerative mitral valve disease (DMVD) in the Chinese population from 1990 to 2019. Methods: Based on the 2019 Global Burden of Disease database (GBD 2019), the number of patients, the number of new cases, the number of deaths, the disability-adjusted life years (DALY) as well as the prevalence, incidence and death rate, DALY rate and their age-standardized rates were used to analyze the trend of the burden of DMVD in the Chinese population from 1990 to 2019. Results: In 2019, the number of patients, the number of new cases, and the number of deaths with DMVD in China were 461.2, 27.0 and 0.129 ten thousand, respectively, which increased by 209.0%, 199.1% and 13.2% when compared with 1990. In 2019, the age-standardized prevalence, incidence and death rate were 228.1/100 000, 12.7/100 000 and 0.075/100 000, respectively. Compared with 1990, the change of the age-standardized prevalence, incidence and death rate were 32.6%, 42.8% and -54.1%, respectively. In addition, the 2019 data also showed that the age-standardized prevalence and incidence were higher in females than in males (the age-standardized prevalence was 190.1 (181.5-198.9)/100 000 for males and 262.0 (250.3-273.9)/100 000 for females); the age-standardized incidence was 10.5 (10.0-11.0)/100 000 for males and 14.9 (14.3-15.6)/100 000 for females. The age group with the largest number of DMVD patients was 65 to 69 years old, and the highest incidence was 60 to 64 years old. From 1990 to 2019, DALY caused by DMVD showed an upward trend in China, from 46 439 person-years in 1990 to 69 402 person-years in 2019, with an increase of 49.4%. While the age-standardized DALY rate continued to decline, from 5.5/100 000 in 1990 to 3.8/100 000 in 2019, with a drop of 30.8%. The DALY and the age-standardized DALY rate of females were always higher than that of males in different years. Conclusion: From 1990 to 2019, DALY and the age-standardized prevalence and incidence of DMVD in China shows an increasing trend, and the disease burden caused by DMVD is severe in China.

Limb Remote Ischemic Preconditioning Applied During Sevoflurane Anesthesia Does Not Protect the Lungs in Patients Undergoing Adult Heart Valve Surgery.

BACKGROUND: Two consistent overall cell protective preconditioning treatments should provide more protection. We hypothesized that limb remote ischemic preconditioning (RIPC, second preconditioning stimulus) applied during sevoflurane inhalation (first preconditioning stimulus) would provide more protection to the lungs of patients undergoing adult heart valve surgery. METHODS: In this randomized, placebo-controlled, double-blind trial, 50 patients were assigned to the RIPC group or the placebo group (1:1). Patients in the RIPC group received three 5-min cycles of 300 mmHg cuff inflation/deflation of the left-side lower limb before aortic cross-clamping. Anesthesia consisted of opioids and propofol for induction and sevoflurane for maintenance. The primary end point was comparison of the postoperative arterial-alveolar oxygen tension ratio (a/A ratio) between groups. Secondary end points included comparisons of pulmonary variables, postoperative morbidity and mortality and regional and systemic inflammatory cytokines between groups. RESULTS: In the RIPC group, the a/A ratio and other pulmonary variables exhibited no significant differences throughout the study period compared with the placebo group. No significant differences in either plasma or bronchoalveolar lavage levels of TNF- α were noted between the groups at 10 min after anesthetic induction and 1 h after cross-clamp release. The percentage of neutrophils at 12 h postoperation was significantly increased in the RIPC group compared with the placebo group (91.34±0.00 vs. 89.42±0.10, P = 0.023). CONCLUSIONS: Limb RIPC applied during sevoflurane anesthesia did not provide additional significant pulmonary protection following adult valvular cardiac surgery.

Surface-engineered smart nanocarrier-based inhalation formulations for targeted lung cancer chemotherapy: a review of current practices.

Lung cancer is the second most common and lethal cancer in the world. Chemotherapy is the preferred treatment modality for lung cancer and prolongs patient survival by effective controlling of tumor growth. However, owing to the nonspecific delivery of anticancer drugs, systemic chemotherapy has limited clinical efficacy and significant systemic adverse effects. Inhalation routes, on the other hand, allow for direct delivery of drugs to the lungs in high local concentrations, enhancing their anti-tumor activity with minimum side effects. Preliminary research studies have shown that inhaled chemotherapy may be tolerated with manageable adverse effects such as bronchospasm and cough. Enhancing the anticancer drugs deposition in tumor cells and limiting their distribution to other healthy cells will therefore increase their clinical efficacy and decrease their local and systemic toxicities. Because of the controlled release and localization of tumors, nanoparticle formulations are a viable option for the delivery of chemotherapeutics to lung cancers via inhalation. The respiratory tract physiology and lung clearance mechanisms are the key barriers to the effective deposition and preservation of inhaled nanoparticle formulations in the lungs. Designing and creating smart nanoformulations to optimize lung deposition, minimize pulmonary clearance, and improve cancerous tissue targeting have been the subject of recent research studies. This review focuses on recent examples of work in this area, along with the opportunities and challenges for the pulmonary delivery of smart nanoformulations to treat lung cancers.

Serratus Anterior Plane Block Combined with General Analgesia and Patient-Controlled Serratus Anterior Plane Block in Patients with Breast Cancer: A Randomized Control Trial.

INTRODUCTION: Anterior serratus muscle plane block is a novel regional block technique for blockade of the sensory plane of the lateral cutaneous branch of the intercostal nerve (T2-T9), which effectively relieves the pain of patients and improves the quality of recovery. This study aimed to observe the early effectiveness and safety of serratus anterior plane block combined with general anesthesia and patient-controlled serratus anterior plane block in early postoperative recovery in breast cancer. METHODS: The study involved a total of 84 patients undergoing radical mastectomy in our hospital. The patients were randomly divided into three groups: the serratus anterior block + general anesthesia + patient-controlled serratus anterior plane block group (PCSAPB group), the serratus anterior block + general anesthesia + patient-controlled intravenous analgesia group (PCIA group), and the general anesthesia + PCIA group (control group), with n = 28 cases in each group. RESULTS: The visual analogue scale (VAS) scores of the three groups were compared before and after the operation (P < 0.001), and the anxiety visual analogue scale (AVAS) scores after operation were compared among the three groups (P < 0.001). The total number of postoperative analgesic pumps in the PCSAPB group was significantly lower than that in the control group (P < 0.05). The incidence of adverse reactions in the three groups was statistically significant (P < 0.05). CONCLUSION: The combination of anterior serratus plane block and general anesthesia and patient-controlled anterior serratus plane block reduced pain and adverse events, alleviating anxiety, improving the quality of early postoperative recovery among patients with breast cancer after modified radical mastectomy.

The most important biomarker associated with coagulation and inflammation among COVID-19 patients.

Coronavirus disease 2019 (COVID-19) induced by SARS-Cov-2 can be related to coagulopathy. Also, the infection-induced inflammatory changes are found in patients with disseminated intravascular coagulopathy (DIC). The lack of previous immunity to COVID-19 has caused infection of a large number of patients worldwide and unpredictability regarding the management of the complications that appear in the course of this viral illness. Lungs are the most important target organ of the SARS-COV-2. In COVID-19 patients, acute lung injury leads to respiratory failure. However, multiorgan failure can also occur in these patients. The primary coagulopathy of COVID-19 is marked by a considerable elevation of D-dimer, ferritin, and fibrinogen degradation products. In comparison, abnormalities in platelet count, prothrombin time, and partial thromboplastin time are partly uncommon in initial presentations. Inflammatory biomarkers including CRP, LDH, and IL-6 are significantly elevated in the early stages of the disease. In this regard, inflammation-associated biomarkers and coagulation test screening, including the assessment of IL-6, CRP, LDH, D-dimer, platelet count, PT&PTT time, ferritin, and fibrinogen levels are suggested for detecting infection by this virus. Overall, COVID-19-associated coagulopathy should be managed like other patients with critical conditions, and supportive care and thromboembolic prophylaxis should be used for severe patients.

Risk factors for peripheral arterial disease in elderly patients with Type-2 diabetes mellitus: A clinical study.

OBJECTIVES: To determine risk factors for peripheral arterial disease (PAD) in elderly patients with Type-2 diabetes mellitus. METHODS: The elderly patients with Type-2 diabetes treated in the Central Hospital of Cangzhou were enrolled and divided into PAD group and non-PAD group between October 2016 and November 2019, The data of the patients including age, gender, body mass index, blood pressure, hemoglobin A1c, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, total cholesterol, triglyceride, white cell count, lymphocyte count, high-sensitivity C-reactive protein, uric acid as well as living habits and complications of Type-2 diabetes mellitus were recorded to determine the risk factors for PAD. RESULTS: One thousand four hundred seventy six (1476) patients were enrolled, in which 465 patients were included in group of PAD, and 1011 in non-PAD group. The univariate analysis revealed that the two groups significantly differed in age (p=0.003), course of T2DM (p=0.001), hypertension (p=0.006), smoking habits (p<0.001), hyperuricemia (p<0.01), high-sensitivity C-reactive protein (p<0.01), white cell count (p<0.001), lymphocyte count (p<0.001) and diabetic neuropathy (p<0.001). In the multivariate analysis, age (OR: 1.56, 95% CI: 1.21-1.89), smoking habit (OR: 1.37, 95% CI: 1.19-1.68), hypertension (OR: 1.44, 95% CI: 1.15-1.98), diabetic neuropathy (OR: 3.55, 95% CI: 2.14-4.29), high-sensitivity C-reactive protein (OR: 1.74, 95% CI: 1.39-2.61) and hyperuricemia (OR: 2.71, 95% CI: 1.66-3.87) were significant risk factors for PAD. CONCLUSIONS: Age, smoking habit, hypertension, diabetic neuropathy, high-sensitivity C-reactive protein and hyperuricemia were independent risk factors for peripheral arterial disease in elderly patients with Type-2 diabetes mellitus.

[Responses of productivity of typical natural secondary forests and plantations to climate change in Shaanxi Province, China]. / é™•è¥¿çœå ¸åž‹å¤©ç„¶æ¬¡ç”Ÿæž—å’Œäººå·¥æž—ç”Ÿäº§åŠ›å¯¹æ°”å€™å˜åŒ–çš„å“åº”.

We analyzed the changes of net primary productivity (NPP) and net ecosystem productivity (NEP) of Quercus spp. forest and Robinia pseudoacacia plantation under different future climate scenarios in Shaanxi Province during 2015-2100, using the process-based dynamic vegetation model-LPJ-GUESS. The results showed that compared with the benchmark period (1961-1990), NPP of Quercus spp. forest and R. pseudoacacia plantation in northern Shaanxi would decrease by 4.9%-29.5% and 22.5%-56.2% respectively, while that in Guanzhong and southern Shaanxi would increase by 13.0%-49.0% and 21.3%-62.9% respectively in the future. The NPP of Quercus spp. forest and R. pseudoacacia plantation under the RCP8.5 scenario was the highest, followed by that under the RCP4.5 and RCP2.6 scenarios. Those two types of forest would be carbon sink in three subregions in the future. Quercus spp. forest would have stronger carbon sink function in nor-thern Shaanxi and Guanzhong, while R. pseudoacacia plantation would have stronger carbon sink function in Southern Shaanxi. Under different RCP scenarios, the NEP variation range of R. pseu-doacacia plantation was greater than that of Quercus spp. forest in three subregions.

Bacteria-Instructed Click Chemistry between Functionalized Gold Nanoparticles for Point-of-Care Microbial Detection.

Bacterial infections pose mounting public health concerns and cause an enormous medical and financial burden today. Rapid and sensitive detection of pathogenic bacteria at the point of care (POC) remains a paramount challenge. Here, we report a novel concept of bacteria-instructed click chemistry and employ it for POC microbial sensing. In this concept of bacteria-instructed click chemistry, we demonstrate for the first time that pathogenic bacteria can capture and reduce exogenous Cu2+ to Cu+ by leveraging their unique metabolic processes. The produced Cu+ subsequently acts as a catalyst to trigger the click reaction between gold nanoparticles (AuNPs) modified with azide and alkyne functional molecules, resulting in the aggregation of nanoparticles with a color change of the solution from red to blue. In this process, signal amplification from click chemistry is complied with the aggregation of functionalized AuNPs, thus presenting a robust colorimetric strategy for sensitive POC sensing of pathogenic bacteria. Notably, this colorimetric strategy is easily integrated in a smartphone app as a portable platform to achieve one-click detection in a mobile way. Moreover, with the help of the magnetic preseparation process, this smartphone app-assisted platform enables rapid (within 1 h) detection of Escherichia coli with high sensitivity (40 colony-forming units/mL) in the complex artificial sepsis blood samples, showing great potential for clinical early diagnosis of bacterial infections.

[Dynamic change of Pinus tabuliformis forest productivity and its response to future climate change in Shaanxi Province, China.] / 陕西省油松林生产力动态及对未来气候变化的响应.

This study analyzed the dynamics of net primary productivity (NPP) of Pinus tabuliformis forest under future climate scenarios in Shaanxi Province during 2015-2100, using a dynamic vegetation model (LPJ-GUESS). The results showed that in the 2015-2100 period, annual mean temperature of this region would significantly increase by 0.12, 0.23 and 0.54 ℃·10 a-1 under RCP2.6, RCP4.5 and RCP8.5 scenarios, respectively, while the annual precipitation would have no significant change under climate scenarios except RCP4.5, under which it would significantly increase by 14.36 mm·10 a-1. Compared with the NPP of P. tabuliformis forest in the historical period (1961-1990), it would increase by 1.6%-29.6% in the future period, and the enhancement could reach 45.4% at the end of this century (2071-2100) under RCP8.5 scenario. The NPP under the RCP8.5 scenario was the highest, followed by the RCP4.5 and RCP2.6 scenarios. During 2015-2100, the NPP in the northern Shaanxi region would significantly decrease with the rate of 41.00 and 21.00 g C·m-2·10 a-1 under the RCP2.6 and RCP4.5 scenarios, respectively, implying that this area has the potentiality to be carbon source.

Research progress on pharmacological action of notoginsenoside R1 / 中国药理学通报

Sanqi in Chinese herbal medicine is the root and rhi-zoma of Panax notoginseng (Burk.)F.H.Chen. As the effects of strengthening with tonics, promoting blood circulation to re-move blood stasis,relieving swelling and pain and hemostasia,it is widely used as a tonic medicine in the traditional Chinese medicine. The main active constituents of Sanqi are panax noto-ginseng saponins,including ginsenoside Rg1,Rb1 and notogin-senoside R1. Notoginsenoside R1 is one of the unique monomer compositions of panax notoginseng,which is often used as an in-gredient indicator in new drug research and development.In cur-rent years, the scientists have been conducted tremendous fun-damental studies to research the pharmacological activities of no-toginsenoside R1, to reveal its protective effects on the cardio-vascular system,central nervous system as well as to many other aspects. It is hoped that the relevant study about the pharmaco-logical action of notoginsenoside R1 would help its further clini-cal application. This paper mainly reviews the research on the pharmacological mechanism of notoginsenoside R1 in recent years.

Repair of articular cartilage defects by autologous bone mesenchymal stem cells and allogeneic costal chondrocytes in the knee of Wuzhishan miniature pigs / 中南大学学报(医学版)

Objective:To investigate the feasibility of construction of tissue engineered cartilage by co-culture of bone marrow mesenchymal stem cells (BMSCs) and costal chondrocytes (CCs),and to provide theoretical basis and experimental basis for clinical repair of articular cartilage defects by Wuzhishan miniature pig knee cartilage defects with co-cultured cells.Methods:Density gradient centrifugation method was used to isolate BMSCs from Wuzhishan miniature pig.The double enzyme digestion method was used to isolate CCs.The passage 3 generation of BMSCs and passage 2 generation of CCs were randomly divided into 3 groups:a co-culture group of BMSCs∶CCs for 1∶2 (Group A),a simple CCs (Group B),and a simple BMSCs (Group C).The cell growth curve was drawn,and the content of glycosaminoglycan (GAG) of external separation in chondrocytes was determined.The 12 Wuzhishan miniature pigs were randomly divided into a co-culture cells/collagen membrane experimental group,a collagen membrane control group and the blank group.In the co-culture cells/collagen membrane experimental group,the co-cultured cells/collagen membrane were implanted into the cartilage defects of the mandibular condyle;in the collagen membrane control group,only collagen membrane was implanted;while in the blank group,nothing was implanted.Six animals were sacrificed at 8 and 16 weeks after surgery respectively (2 animals in each group).General observation,cartilage histological score and histopathological examination were carried out.Results:The BMSCs and co-culture cells grew well.The biological activity of CCs was good.After 16 weeks of operation,the repair tissues in the co-cultured cells/collagen membrane experimental group showed hyaline cartilage features:smooth,flat,and integrated well with the surrounding cartilage and subchondral bone.The collagen membrane in the collagen membrane control group was fibrously repaired.Repair tissue gross score in the co-culture cells/collagen membrane experimental group was significantly better than that in the collagen membrane control group and the blank group (both P0.05).Conclusion:BMSCs,CCs and co-cultured cells can function as the seed cells for cartilage tissue engineering,and the co-culture cells (BMSCs∶CCs=1∶2) possess more advantages;the short-term effect of co-culture cells with collagen membrane on repairing cartilage defects is satisfied.

Peritoneal dialysis for autosomal dominant polycystic kidney disease: a retrospective study.

To describe the long-term clinical outcomes of patients with autosomal dominant polycystic kidney disease (ADPKD) who are on peritoneal dialysis (PD) therapy. We performed a retrospective matched-cohort analysis comparing the clinical outcomes of 30 ADPKD patients with those of 30 non-diabetic patients who had bilateral small kidneys between July 1 2007 and July 31 2014. The patient groups were matched by age, gender, and time of PD initiation. There were no significant differences in the demographic or biochemical parameters, comorbid conditions, residual glomerular filtration rate, or Charlson comorbidity score at the beginning of PD. The median renal volume was 1315 ml for the ADPKD group and 213 ml for the control group. Patients with ADPKD had similar 3-year patient survival (90.6% versus 86.3%, P=0.807) and technique survival (89.2% versus 74.3%, P=0.506) compared with non-ADPKD patients. Also, there was no significant difference in the peritonitis-free survival between the ADPKD and control groups (P=0.22), and rates of peritonitis were similar (0.19 versus 0.21 episodes per patient-year, P=0.26). No differences were observed in the incidence of PD-related complications, such as hernia and dialysate leak. ADPKD is not a contraindication for PD, and a subgroup of ADPKD patients with relatively small kidney volume can be treated using PD.

Inhibition of nicotine on apoptosis of chondrocytes induced by monosodium iodoacetate / 中国比较医学杂志

Objective To explore inhibition of nicotine on apoptosis of chondrocytes induced by monosodium iodoacetate ( MIA) .Methods Rat primary chondrocytes were isolated by enzyme digestion, and the cells were treated with 10 -8 , 10 -7 , 10 -6 , 10 -5 mol/L nicotine for 48 h.The cases were randomly divided into five groups, except for normal group, the other four groups were treated with 4μmol/L MIA 24 h, and three groups were treated 10 -8 , 10 -7 , 10 -6 mol/L nicotine.The viability of chondrocytes was detected by MTT assay.The apoptosis of chondrocytes was examed by Annexin V-FITC/PI flow dual-staining method.The activity of cysteinyl aspartate specific proteinase 3 ( Caspase 3 ) was measured by spectrophotography method.The activation of phosphatidylinositol 3 kinase ( PI3K)/protein kinase B ( AKT) and the expression of down-stream molecule Bax, Bcl-2 was assayed by western blot.Results 10 -7 , 10 -6 mol/L nicotine increased chondrocytes' viability (P0.05).10 -8, 10 -7, 10 -6 mol/L nicotine could increase MIA-induced chondrocytes' viability (P<0.05), suppress MIA-induced chondrocytes' apoptosis and the activity of MIA-induced Caspase 3 (P <0.05).Moreover, 10 -7, 10 -6 mol/L nicotine could increase the expression of PI3K and phosphorylation of AKT ( P<0.05) , down-regulate the expression of Bax and up-regulate the expression of Bcl-2 in MIA-induced rat chondrocytes ( P<0.05 ) .Conclusion These results suggested nicotine could exert anti-apoptosis in MIA-induced rat chondrocytes, which might be related to PI3K/AKT signal pathway.

Deletion of Smad3 improves cardiac allograft rejection in mice.

T cells play a critical role in acute allograft rejection. TGF-ß/Smad3 signaling is a key pathway in regulating T cell development. We report here that Smad3 is a key transcriptional factor of TGF-ß signaling that differentially regulates T cell immune responses in a mouse model of cardiac allograft rejection in which donor hearts from BALB/c mice were transplanted into Smad3 knockout (KO) and wild type (WT) mice. Results showed that the cardiac allograft survival was prolonged in Smad3 KO recipients. This allograft protection was associated with a significant inhibition of proinflammatory cytokines (IL-1ß, TNF-α, and MCP-1) and infiltration of neutrophils, CD3+ T cells, and F4/80+ macrophages. Importantly, deletion of Smad3 markedly suppressed T-bet and IFN-γ while enhancing GATA3 and IL-4 expression, resulting in a shift from the Th1 to Th2 immune responses. Furthermore, mice lacking Smad3 were also protected from the Th17-mediated cardiac injury, although the regulatory T cell (Treg) response was also suppressed. In conclusion, Smad3 is an immune regulator in T cell-mediated cardiac allograft rejection. Loss of Smad3 results in a shift from Th1 to Th2 but suppressing Th17 immune responses. Thus, modulation of TGF-ß/Smad3 signaling may be a novel therapy for acute allograft rejection.

Influence of peritoneal transport characteristics on nutritional status and clinical outcome in Chinese diabetic nephropathy patients on peritoneal dialysis.

BACKGROUND: High peritoneal transport status was previously thought to be a poor prognostic factor in peritoneal dialysis (PD) patients. However, its effect on diabetic nephropathy PD patients is unclear in consideration of the adverse impact of diabetes itself. The purpose of this study was to investigate the influence of peritoneal transport characteristics on nutritional status and clinical outcome in diabetic nephropathy patients on PD. METHODS: One hundred and two diabetic nephropathy patients on PD were enrolled in this observational cohort study. According to the initial peritoneal equilibration test result, patients were divided into two groups: Higher transport group (HT, including high and high average transport) and lower transport group (LT, including low and low-average transport). Demographic characteristics, biochemical data, dialysis adequacy, and nutritional status were evaluated. Clinical outcomes were compared. Risk factors for death-censored technique failure and mortality were analyzed. RESULTS: Compared with LT group (n = 37), serum albumin was significantly lower and the incidence of malnutrition by subjective global assessment was significantly higher in HT group (n = 65) (P < 0.05). Kaplan-Meier analyses showed that death-censored technique failure and mortality were significantly increased in HT group compared with that in LT group. On multivariate Cox analyses, higher peritoneal transport status and lower residual renal function (RRF) were independent predictors of death-censored technique failure when adjusted for serum albumin and total weekly urea clearance (Kt/V). Independent predictors of mortality were advanced age, anemia, hypoalbuminemia, and lower RRF, but not higher peritoneal transport status. CONCLUSIONS: Higher peritoneal transport status has an adverse influence on nutrition for diabetic nephropathy patients on PD. Higher peritoneal transport status is a significant independent risk factor for death-censored technique failure, but not for mortality in diabetic nephropathy patients on PD.

Over-expression of P2X7 receptors in spinal glial cells contributes to the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR) in rats.

Many patients suffer from chronic postsurgical pain (CPSP) following surgery, and the underlying mechanisms are poorly understood. In the present work, with use of the skin/muscle incision and retraction (SMIR) model, the role of P2X7 receptors (P2X7Rs) in spinal glial cells in the development of CPSP was evaluated. Consistent with previous reports, we found that SMIR decreased the ipsilateral 50% paw withdrawal threshold (PWT), lasting for at least 2weeks. No injury was done to L3 dorsal root ganglia (DRG) neurons and no axonal or Schwann cell damage at the retraction site in the saphenous nerve was observed 7days after SMIR. The results of immunofluorescence showed that both microglia and astrocytes were activated in the spinal dorsal horn following SMIR. In addition, both P2X7Rs and tumor necrosis factor-alpha (TNF-α) were up-regulated following SMIR. Double immunofluorescence staining revealed that the up-regulated P2X7R immunoreactivity was mainly located in microglia, and to a lesser extent in astrocytes, but not in neurons. Intrathecal delivery of specific P2X7R antagonist BBG (10µM in 10µl volume) or A438079 (10µM in 10µl volume), started 30min before the surgery and once daily thereafter for 7days, prevented the mechanical allodynia. Intrathecal injection of BBG inhibited the activation of microglia and astrocytes, and the up-regulation of TNF-α induced by SMIR. These data suggest that P2X7Rs in the spinal dorsal horn might mediate the development of CPSP via activation of glial cells and up-regulation of TNF-α.

Proteins induced by telomere dysfunction are associated with human IgA nephropathy.

Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers (cathelin-related antimicrobial peptide (CRAMP), stathmin, elongation factor-1α (EF-1α), and chitinase) were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these biomarkers and IgA nephropathy (IgAN) progression in the Chinese population. For 260 individuals, the four markers are determined in blind datasets using direct enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. The expression levels of CRAMP and chitinase increased in blood plasma, urine, and kidney tissues during human IgAN progression. And for the other nephropathy, such as systemic lupus erythematosus (SLE), diabetic nephropathy (DN), and focal segmental glomerulosclerosis (FSGS), there is no protein upregulation with telomere shortening. Moreover, a combination of CRAMP and chitinase can distinguish patients with IgAN from healthy individuals with 88.2%/92.5% (plasma) and 74.3%/84.2% (urine) sensitivity/specificity. These data provide the experimental evidence that telomere shortening and related inflammatory proteins are associated with human IgAN, and it could be a new direction for the disease progression study.

[Spatial distribution of aboveground biomass of shrubs in Tianlaochi catchment of the Qilian Mountains].

This study estimated the spatial distribution of the aboveground biomass of shrubs in the Tianlaochi catchment of Qilian Mountains based on the field survey and remote sensing data. A relationship model of the aboveground biomass and its feasibly measured factors (i. e. , canopy perimeter and plant height) was built. The land use was classified by object-oriented technique with the high resolution image (GeoEye-1) of the study area, and the distribution of shrub coverage was extracted. Then the total aboveground biomass of shrubs in the study area was estimated by the relationship model with the distribution of shrub coverage. The results showed that the aboveground biomass of shrubs in the study area was 1.8 x 10(3) t and the aboveground biomass per unit area was 1598.45 kg x m(-2). The distribution of shrubs mainly was at altitudes of 3000-3700 m, and the aboveground biomass of shrubs on the sunny slope (1.15 x 10(3) t) was higher than that on the shady slope (0.65 x 10(3) t).