Objective:To evaluate the feasibility and safety of PT Scope (short for intelligent pressure and temperature controlled flexible ureteroscopy)combined with Thulium laser in the intracavitary treatment of upper urinary tract stones.Methods:A retrospective analysis was conducted on the clinical data of 13 patients with upper urinary tract stones who were treated with PT Scope combined with Thulium laser lithotripsy in Sun Yat-Sen Memorial Hospital from February to April 2024. There were 7 males and 6 females. The patients had a mean age of (46±10) years old, with an accumulated stone diameter of (25.8±13.3) mm. There were 7 cases of lower calyx stones (53.8%), and 3 cases of concomitant ureteral stones (23.1%).Four patients (30.8%) had positive preoperative urine cultures, and six patients (46.2%) had leukocyte counts greater than 100 cells/μl in their urine tests. The Thulium laser power was set at 45 W (1.5 J at 30 Hz, 0.3 J at 150 Hz). The renal pelvic pressure threshold was set at 30 mmHg (1 mmHg=0.133 kPa), and the temperature threshold at 43 ℃. Postoperatively, double J stents were placed for 2 to 4 weeks.Results:All 13 patients successfully completed the surgery. The median operative time was 30 (25, 90) minutes. The intraoperative average renal pelvic pressure in these 13 patients ranged from 8 mmHg to 24 mmHg, and the average renal pelvic temperature ranged from 25 ℃ to 34 ℃. Postoperatively, 1 patient experienced a fever (38.0 ℃) and 2 patients required analgesic treatment due to postoperative pain. There were no other intraoperative or postoperative complications. The median postoperative hospital stay was (1.5±0.8) days. The stone-free rate of 1 month was 84.6%(11/13).Conclusions:PT Scope combined with Thulium laser could effectively control renal pelvic pressure and temperature, achieve a high stone-free rate, and have a low complication rate. It is a safe and effective treatment for upper urinary tract stones.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.

The rostral agranular insular cortex (RAIC) has been associated with pain modulation. Although the endogenous cannabinoid system (eCB) has been shown to regulate chronic pain, the roles of eCBs in the RAIC remain elusive under the neuropathic pain state. Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve (CPN) ligation. The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice, glutamatergic, or GABAergic neuron cannabinoid receptor 1 (CB1R) knockdown mice with the whole-cell patch-clamp and pain behavioral methods. The E/I ratio (amplitude ratio between mEPSCs and mIPSCs) was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice. Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice. The analgesic effect of ACEA (a CB1R agonist) was alleviated along with bilateral dorsolateral funiculus lesions, with the administration of AM251 (a CB1R antagonist), and in CB1R knockdown mice in GABAergic neurons, but not glutamatergic neurons of the RAIC. Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
Mice ; Animals ; Insular Cortex ; Peroneal Nerve ; Mice, Inbred C57BL ; Neuralgia ; GABAergic Neurons ; Analgesia ; Analgesics ; Receptors, Cannabinoid

As a branched chain amino acid, L-valine is widely used in the medicine and feed sectors. In this study, a microbial cell factory for efficient production of L-valine was constructed by combining various metabolic engineering strategies. First, precursor supply for L-valine biosynthesis was enhanced by strengthening the glycolysis pathway and weakening the metabolic pathway of by-products. Subsequently, the key enzyme in the L-valine synthesis pathway, acetylhydroxylate synthase, was engineered by site-directed mutation to relieve the feedback inhibition of the engineered strain. Moreover, promoter engineering was used to optimize the gene expression level of key enzymes in L-valine biosynthetic pathway. Furthermore, cofactor engineering was adopted to change the cofactor preference of acetohydroxyacid isomeroreductase and branched-chain amino acid aminotransferase from NADPH to NADH. The engineered strain C. glutamicum K020 showed a significant increase in L-valine titer, yield and productivity in 5 L fed-batch bioreactor, up to 110 g/L, 0.51 g/g and 2.29 g/(L‧h), respectively.
Valine ; Corynebacterium glutamicum/genetics* ; Metabolic Engineering ; Amino Acids, Branched-Chain ; Bioreactors

OBJECTIVE To optimize the extraction process of polysaccharides from Dendrobium officinale， and preliminarily study its effect on acute lung injury （ALI） in mice. METHODS Using D. officinale as raw material， the polysaccharides were extracted from D. officinale by ultrasonic-assisted hot water immersion. Using the extraction rate of D. officinale polysaccharides as response value， the single-factor experiments and Box-Behnken response surface method were used to optimize the ratio of material to liquid， extraction time and extraction temperature. ALI mice were induced by lipopolysaccharide. Using prednisone acetate （5 mg/kg） as the positive control， the effects on the mass ratio of wet and dry lung and pathological changes of lung tissue （HE staining and Masson staining） of low-dose， medium-dose and high-dose D. officinale polysaccharides （50，100，200 mg/kg） were investigated. RESULTS The optimal extraction technology of D. officinale polysaccharides was as follows： the ratio of material to liquid was 1∶25 （g/mL）， the extracting time was 1 h， and the extracting temperature was 58 ℃ . Under these conditions， the average extraction rate of D. officinale polysaccharides was 37.75% （RSD＝1.12%，n＝3）， the relative error of which with predicted value （38.63%） was 2.28%. Compared with the model group， the ratios of wet and dry lung in the positive control group and D. officinale polysaccharides groups were all decreased significantly （P＜0.05 or P＜0.01）， and the pathological changes in lung tissue （severe destruction of alveolar structure， significant widening of alveolar septa， extensive infiltration of inflammatory cells and proliferation of fibroblasts） were alleviated to varying degrees. CONCLUSIONS The optimal extraction process of D. officinale polysaccharides is feasible； the obtained polysaccharide extract has a certain improvement effect on ALI in mice.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective: To trace and characterize the whole genome of SARS-CoV-2 of confirmed cases in the outbreak of COVID-19 on July 31, 2021 in Henan Province. Method: Genome-wide sequencing and comparative analysis were performed on positive nucleic acid samples of SARS-CoV-2 from 167 local cases related to the epidemic on July 31, 2021, to analyze the consistency and evolution of the whole genome sequence of virus. Results: Through high-throughput sequencing, a total of 106 cases of SARS-CoV-2 whole genome sequences were obtained. The results of genome analysis showed that the whole genome sequences of 106 cases belonged to the VOC/Delta variant strain (B.1.617.2 clade), and the whole genome sequences of 106 cases were shared with the genomes of 3 imported cases from Myanmar admitted to a hospital in Zhengzhou. On the basis of 45 nucleotide sites, 1-5 nucleotide variation sites were added, and the genome sequence was highly homologous. Conclusion: Combined with the comprehensive analysis of viral genomics, transmission path simulation experiments and epidemiology, it is determined that the local new epidemic in Henan Province is caused by imported cases in the nosocomial area, and the spillover has caused localized infection in the community. At the same time, it spills over to some provincial cities and results in localized clustered epidemics.
Humans ; COVID-19 ; SARS-CoV-2/genetics* ; Genome, Viral ; Epidemics ; Phylogeny

Objective:To analyze the risk factors of bronchopulmonary dysplasia(BPD)in very preterm infants(VPI), and to provide scientific basis for the prevention and treatment of BPD in VPI.Methods:A prospective multicenter study was designed to collect the clinical data of VPI in department of neonatology of 28 hospitals in 7 regions from September 2019 to December 2020.According to the continuous oxygen dependence at 28 days after birth, VPI were divided into non BPD group and BPD group, and the risk factors of BPD in VPI were analyzed.Results:A total of 2 514 cases of VPI including 1 364 cases without BPD and 1 150 cases with BPD were enrolled.The incidence of BPD was 45.7%.The smaller the gestational age and weight, the higher the incidence of BPD( P<0.001). Compared with non BPD group, the average birth age, weight and cesarean section rate in BPD group were lower, and the incidence of male infants, small for gestational age and 5-minute apgar score≤7 were higher( P<0.01). In BPD group, the incidences of neonatal respiratory distress syndrome(NRDS), hemodynamically significant patent ductus arteriosus, retinopathy of prematurity, feeding intolerance, extrauterine growth restriction, grade Ⅲ~Ⅳ intracranial hemorrhage, anemia, early-onset and late-onset sepsis, nosocomial infection, parenteral nutrition-associated cholestasis were higher( P<0.05), the use of pulmonary surfactant(PS), postnatal hormone exposure, anemia and blood transfusion were also higher, and the time of invasive and non-invasive mechanical ventilation, oxygen use and total hospital stay were longer( P<0.001). The time of starting enteral nutrition, cumulative fasting days, days of reaching total enteral nutrition, days of continuous parenteral nutrition, days of reaching 110 kcal/(kg·d) total calorie, days of reaching 110 kcal/(kg·d) oral calorie were longer and the breastfeeding rate was lower in BPD group than those in non BPD group( P<0.001). The cumulative doses of amino acid and fat emulsion during the first week of hospitalization were higher in BPD group( P<0.001). Multivariate Logistic regression analysis showed that NRDS, invasive mechanical ventilation, age of reaching total enteral nutrition, anemia and blood transfusion were the independent risk factors for BPD in VPI, and older gestational age was the protective factor for BPD. Conclusion:Strengthening perinatal management, avoiding premature delivery and severe NRDS, shortening the time of invasive mechanical ventilation, paying attention to enteral nutrition management, reaching whole intestinal feeding as soon as possible, and strictly mastering the indications of blood transfusion are very important to reduce the incidence of BPD in VPI.

Objective: To examine the clinical effect of minimally invasive duodenum preserving pancreatic head resection(DPPHR) for benign and pre-malignant lesions of pancreatic head. Methods: The clinical data of patients with diagnosis of benign or pre-malignant pancreatic head tumor were retrospectively collected and analyzed,all of them underwent laparoscopic or robotic DPPHR between October 2015 and September 2021 at Division of Gastrointestinal and Pancreatic surgery,Zhejiang Provincial People's Hospital. Thirty-three patients were enrolled with 10 males and 23 females. The age(M(IQR)) was 54(32) years old(range: 11 to 77 years old) and the body mass index was 21.9(2.9)kg/m²(range: 18.1 to 30.1 kg/m²). The presenting symptoms included abdominal pain(n=12), Whipple triad(n=2), and asymptomatic(n=19). There were 7 patients with hypertension and 1 patient with diabetes mellitus. There were 19 patients who were diagnosed as American Society of Anesthesiologists class Ⅰ and 14 patients who were diagnosed as class Ⅱ. The student t test,U test, χ² test or Fisher exact test was used to compare continuous data or categorized data,respectively. All the perioperative data and metabolic morbidity were analyzed and experiences on minimally invasive DPPHR were concluded. Results: Fourteen patients underwent laparoscopic DPPHR,while the rest of 19 patients received robotic DPPHR. Indocyanine green fluorescence imaging was used in 19 patients to guide operation. Five patients were performed pancreatico-gastrostomy and the rest 28 patients underwent pancreaticojejunostomy. Pathological outcomes confirmed 9 solid pseudo-papillary neoplasms, 9 intraductal papillary mucinous neoplasms, 7 serous cystic neoplasms, 6 pancreatic neuroendocrine tumors, 1 mucous cystic neoplasm, 1 chronic pancreatitis. The operative time was (309.4±50.3) minutes(range:180 to 420 minutes),and the blood loss was (97.9±48.3)ml(range:20 to 200 ml). Eighteen patients suffered from postoperative complications,including 3 patients experienced severe complications(Clavien-Dindo Grade ≥Ⅲ). Pancreatic fistula occurred in 16 patients,including 8 patients with biochemical leak,7 patients with grade B pancreatic fistula and 1 patient with grade C pancreatic fistula. No one suffered from the duodenal necrosis and none perioperative death was occurred. The length of hospital stay was 14(7) days (range:6 to 87 days). The follow-up was 22.6(24.5)months(range:2 to 74 months). None suffered from recurrence or metastasis. During the follow-up,all the patients were free of refractory cholangitis. Moreover,in the term of endocrine dysfunction,no postoperative new onset of diabetes mellitus were observed in the long-term follow-up. However,in the view of exocrine insufficiency,pancreatic exocrine insufficiency and non-alcoholic fatty liver disease (NAFLD) was complicated in 2 and 1 patient,respectively,with the supplement of pancreatic enzyme,steatorrhea and weight loss relieved,but NAFLD was awaited to be seen. Conclusions: Minimally invasive DPPHR is feasible and safe for benign or pre-malignant lesions of pancreatic head. Moreover,it is oncological equivalent to pancreaticoduodenectomy with preservation of metabolic function without refractory cholangitis.
Adolescent ; Adult ; Aged ; Child ; Duodenum/surgery* ; Female ; Humans ; Male ; Middle Aged ; Pancreas/surgery* ; Pancreatectomy ; Pancreatic Neoplasms/surgery* ; Pancreaticoduodenectomy ; Postoperative Complications ; Retrospective Studies ; Young Adult

OBJECTIVES: To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China. METHODS: A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined. RESULTS: The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05). CONCLUSIONS It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.
Female ; Fetal Growth Retardation ; Gestational Age ; Hospitalization ; Humans ; Incidence ; Infant ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight ; Prospective Studies ; Risk Factors