Podocyte-specific Nup160 knockout mice develop nephrotic syndrome and glomerulosclerosis.

More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS. Here, we generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. We investigated NS-associated phenotypes in these Nup160podKO mice. We verified efficient abrogation of Nup160 in Nup160podKO mice at both the DNA and protein levels. We showed that Nup160podKO mice develop typical signs of NS. Nup160podKO mice exhibited progression of proteinuria to average albumin/creatinine ratio (ACR) levels of 15.06 ± 2.71 mg/mg at 26 weeks, and had lower serum albumin levels of 13.13 ± 1.34 g/l at 30 weeks. Littermate control mice had urinary ACR mean values of 0.03 mg/mg and serum albumin values of 22.89 ± 0.34 g/l at the corresponding ages. Further, Nup160podKO mice exhibited glomerulosclerosis compared with littermate control mice. Podocyte-specific Nup160 knockout in mice led to NS and glomerulosclerosis. Thus, our findings strongly support that mutations in NUP160 cause SRNS. The newly generated Nup160podKO mice are a reliable mammalian model for future study of the pathogenesis of NUP160-associated SRNS.

Risk factors for low back pain in the Chinese population: a systematic review and meta-analysis.

BACKGROUND: In China, the world's largest developing country, low back pain (LBP) is a common public health issue affecting workability. This meta-analysis aimed to systematically assess the risk factors of LBP in the Chinese population. METHODS: Four English language and four Chinese databases were searched, and cross-sectional studies on the risk factors for LBP in Chinese populations were identified and collected. The search timeframe covered the period from the establishment of the database to November 2023. Two researchers independently reviewed the literature, extracted the data, and evaluated the risk of bias. Begg's and Egger's tests were used to evaluate publication bias. RESULTS: Fifteen cross-sectional studies involving 86,575 people were included. Seven risk factors for LBP were identified. Six risk factors were statistically significant: Cigarette smoking (odds ratio [OR] = 1.55; 95% confidence interval [CI]: 1.15, 2.08, P = 0.004, I2 = 72%), body mass index (BMI) ≥ 28 kg/m² (OR = 4.51; 95% CI: 3.36, 6.07, P < 0.00001, I2 = 8%), female sex (OR = 1.54; 95% CI: 1.25, 1.90, P < 0.0001, I2 = 63%), vibration exposure at work (OR = 1.65; 95% CI: 1.16, 2.34, P = 0.006, I2 = 84%), working overtime (OR = 2.57; 95% CI: 1.12, 5.91, P = 0.03, I2 = 85%), and lack of exercise (OR = 2.48; 95% CI: 1.62, 3.78, P < 0.0001, I2 = 0%). One risk factor that was not statistically significant was standing for long periods (OR = 1.02; 95% CI: 0.82, 1.26, P = 0.88, I2 = 73%). CONCLUSIONS: This study found that smoking, a BMI ≥ 28 kg/m², female sex, vibration exposure at work, working overtime, and lack of exercise may be risk factors for LBP in the Chinese population. Because the included studies were cross-sectional and the certainty of the evidence was very low, the results need to be interpreted cautiously. Multicentre, high-quality studies should be conducted in the future. To reduce the prevalence of LBP, the Chinese government and hospitals must develop early screening programs and implement effective preventive and interventional measures. TRIAL REGISTRATION: This study is registered in the PROSPERO database (No. CRD42023447857).

Aircraft Engine Fault Diagnosis Model Based on 1DCNN-BiLSTM with CBAM.

As the operational status of aircraft engines evolves, their fault modes also undergo changes. In response to the operational degradation trend of aircraft engines, this paper proposes an aircraft engine fault diagnosis model based on 1DCNN-BiLSTM with CBAM. The model can be directly applied to raw monitoring data without the need for additional algorithms to extract fault degradation features. It fully leverages the advantages of 1DCNN in extracting local features along the spatial dimension and incorporates CBAM, a channel and spatial attention mechanism. CBAM could assign higher weights to features relevant to fault categories and make the model pay more attention to them. Subsequently, it utilizes BiLSTM to handle nonlinear time feature sequences and bidirectional contextual feature information. Finally, experimental validation is conducted on the publicly available CMAPSS dataset from NASA, categorizing fault modes into three types: faultless, HPC fault (the single fault), and HPC&Fan fault (the mixed fault). Comparative analysis with other models reveals that the proposed model has a higher classification accuracy, which is of practical significance in improving the reliability of aircraft engine operations and for Remaining Useful Life (RUL) prediction.

Missense variants in CYP4B1 associated with increased risk of lung cancer among Chinese Han population.

INTRODUCTION: Understanding the etiology and risk factors of lung cancer (LC) is the key to developing scientific and effective prevention and control strategies for LC. CYP4B1 genetic polymorphism has been reported to be associated with susceptibility to various diseases. We aimed to explore the association between CYP4B1 genetic variants and LC susceptibility. METHODS: One thousand three hundred thirty-nine participants were recruited to perform an association analysis through SNPStats online software. Statistical analysis of this study was mainly completed by SPSS 22.0 software. False-positive report probability analysis (FPRP) to detect whether the positive findings were noteworthy. Finally, the interaction of SNP-SNP in LC risk was evaluated by multi-factor dimensionality reduction. RESULTS: We found evidence that missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with LC susceptibility. In particular, genotype GA of CYP4B1-rs2297810 was significantly associated with an increased risk of LC in both overall and stratified analyses (genotype GA: OR (95% CI) = 1.35 (1.08-1.69), p = 0.010). CYP4B1-rs4646491 (overdominant: OR (95% CI) = 1.30 (1.04-1.62), p = 0.023) and CYP4B1-rs2297809 (genotype CT: OR (95% CI) = 1.26 (1.01-1.59), p = 0.046) are also associated with an increased risk of LC. FPRP analysis showed that all positive results in this study are noteworthy findings CONCLUSION: Three missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with increasing risk of LC.

Clinical characteristics of bronchopulmonary dysplasia in very preterm infants. / 极早早产儿支气管肺发育不良的临床特征.

OBJECTIVES: With the development of perinatal and neonatal intensive care medicine, the survival rate of very premature infants increases year by year. However, the incidence of bronchopulmonary dysplasia (BPD) increases year by year, which seriously affects the survival prognosis of very premature infants. How to prevent and treat BPD effectively has become the focus of neonatologists. This study aims to provide ideas for the prevention and treatment of BPD in very preterm infants via analyzing the clinical characteristics of BPD. METHODS: A total of 472 cases of very premature infants admitted to the Divison of Neonatology, Department of Pediatrics at the Second Xiangya Hospital of Central South University were retrospectively selected and assigned into a BPD group (n=147) and a non-BPD group (n=325) according to the diagnosis of BPD. Clinical data of each group were collected to find out the clinical characteristics of BPD in very preterm infants. Basic information, maternal pregnancy data, laboratory findings, nutritional support, respiratory support patterns and duration, and systemic complications were included. RESULTS: Compared with the non-BPD group, gestational age, birth weight, head circumference and body length in the BPD group were lower, the Apgar score in 1st min and 5th min and average body weight growth rate were lower (all P<0.05); the ratios of male, very low birth weight (VLBW), and extremely low birth weight (ELBW) in the BPD group were higher than those in the non-BPD group (all P<0.5); the incidence of maternal cervical insufficiency and the rate of using embryo transfer technology in the BPD group were higher than those in the non-BPD group, and the rate of using prenatal hormone in the BPD group was lower than that in the non-BPD group (all P<0.05). The positive rate of sputum culture in the BPD group was higher than that in the non-BPD group (P<0.05), and the white blood cell count, neutrophil ratio, and procalcitonin in the BPD group were higher than those in the non-BPD group (all P<0.05). The period of fasting, minimal feeding, total parenteral nutrition (TPN), and partial parenteral nutrition (PPN) in the BPD group were longer than those in the non-BPD group (all P<0.05). The duration of nasal catheter oxygen inhalation and mechanical ventilation in the BPD group was longer than that in the non-BPD group, and the rates of mechanical ventilation at Day 1, 3, 7, 14, 21 and 28 after birth were higher than those in the non-BPD group (all P<0.05). The incidence of respiratory distress syndrome, apnea of prematurity, respiratory failure, pneumonia, pulmonary hemorrhage, pleural effusion, persistent pulmonary hypertension, hemodynamic patent ductus arteriosus, cytomegalovirus infection, neonatal necrotic enterocolitis, cholestasis, anemia, abnormal blood system, hypothyroidism, retinopathy of prematurity, and internal environment disorders in the BPD group were significantly higher than those in non-BPD group (all P<0.05). CONCLUSIONS: There are significant differences between very premature infants with BPD and those without BPD in general information, maternal history, inflammatory indicators, nutritional support, respiratory support, comorbidities and complication rates. To ensure normal fetal development, reducing the inflammatory reaction of very premature infants, establishing enteral nutrition as early as possible, shortening the time of mechanical ventilation, and reducing the occurrence of complications are beneficial to decrease the incidence of BPD in very premature infants and improve the long-term prognosis of BPD.

The Influence of NDRG1 Single Nucleotide Polymorphisms on Glioma Risk and Prognosis in Chinese Han Population.

Glioma is a highly fatal malignant tumor with a high recurrence rate, poor clinical treatment effect, and prognosis. We aimed to determine the association between single nucleotide polymorphisms (SNPs) of NDRG1 and glioma risk and prognosis in the Chinese Han population. 5 candidate SNPs were genotyped by Agena MassARRAY in 558 cases and 503 controls; logistic regression was used to analyze the relationship between SNPs and glioma risk. We used multi-factor dimensionality reduction to analyze the interaction of 'SNP-SNP'; the prognosis analysis was performed by log-rank test, Kaplan-Meier analysis, and Cox regression model. Our results showed that the polymorphisms of rs3808599 was associated with the reduction of glioma risk in all participants (OR 0.41, p = 0.024) and the participants ≤ 40 years old (OR 0.30, p = 0.020). rs3802251 may reduce glioma risk in all participants (OR 0.79, p = 0.008), the male participants (OR 0.68, p = 0.033), and astrocytoma patients (OR 0.81, p = 0.023). rs3779941 was associated with poor glioma prognosis in all participants (HR = 2.59, p = 0.039) or astrocytoma patients (HR = 2.63, p = 0.038). We also found that the key factors for glioma prognosis may include surgical operation, radiotherapy, and chemotherapy. This study is the first to find that NDRG1 gene polymorphisms may have a certain association with glioma risk or prognosis in the Chinese Han population.

Irisin Protects Cerebral Neurons from Hypoxia/Reoxygenation via Suppression of Apoptosis and Expression of Pro-Inflammatory Cytokines.

BACKGROUND: Ischemic stroke is a major health issue that causes high incidents of morbidity and mortality worldwide. Irisin is an excise-induced protein that has exhibited pleiotropic properties. Accumulating evidence reveals its critical roles in the regulation of various cellular functions, including nervous system functions. This study aims to disclose the effect of irisin on rat cerebral neurons suffering from hypoxia/reoxygenation (H/R) treatment and to explore the potential underlying molecular mechanisms. METHODS: The percentage of rat cerebral neuron cell death was determined by flow cytometry analysis and MTT assay. The expression levels of target genes were measured by western blotting and real-time quantitative reverse transcription PCR assay. RESULTS: Our results demonstrated that irisin treatment substantially reduced H/R-induced apoptosis of rat cerebral neurons. Further investigation revealed that irisin treatment markedly decreased mitogen-activated protein kinase (MAPK) signaling pathway activation and suppressed pro-informatory cytokine expression in cerebral neurons with H/R challenge. Finally, we showed that the neuroprotective effect and anti-inflammatory effect of irisin were comparable with three MAPK signaling inhibitors. CONCLUSION: Irisin exerts profound neuroprotective and anti-inflammatory effects on H/R-stimulated cerebral neurons by inhibiting the MAPK signaling activation. Therefore, irisin may serve as a potential drug for the treatment of patients with ischemic stroke.

[Mechanical Design and Research of Wearable Exoskeleton Assisted Robot for Upper Limb Rehabilitation].

Based on the biomechanical mechanism of human upper limb, the disadvantages of traditional rehabilitation training and the current status of upper limb rehabilitation robot, a six degree of freedom, flexible adjustment, wearable upper limb rehabilitation exoskeleton design scheme is proposed. Firstly, the mechanics of each joint of the upper limb is analyzed, and the virtual prototype design of the whole mechanical structure of the upper limb rehabilitation wearable exoskeleton is carried out by using CATIA three-dimensional software. The tooth transmission of the forearm and the upper arm single row four point contact ball bearing with internal/external rotation and the shoulder flexible passive adjustment mechanism (viscoelastic damper) are innovatively designed. Then, the joints of the upper limb rehabilitation exoskeleton are analyzed, theoretical analysis and calculation of the driving torque, the selection of the motor and gearbox of each driving joint are carried out. Finally, the whole finite element analysis of the upper limb exoskeleton is carried out. The research and experimental results showed that the design scheme of the upper limb exoskeleton assist structure is highly feasible, which can help the patients with upper limb paralysis and motor dysfunction self-rehabilitation.

[A 10-year retrospective study of pathogens and antimicrobial resistance in neonatal sepsis]. / æ–°ç”Ÿå„¿è´¥è¡€ç—‡ç— åŽŸèŒåŠè€è¯æ€§10年回顾性分析.

OBJECTIVES: To investigate the changes in the pathogen spectrum and antimicrobial resistance over time in neonatal sepsis. METHODS: The medical data were collected from the neonates who were diagnosed with sepsis in the Second Xiangya Hospital of Central South University from January 2010 to December 2019. The incidence rate of sepsis, the pathogen spectrum, and the characteristics of antimicrobial resistance were analyzed. RESULTS: The incidence rate of neonatal sepsis was 4.02% (447/11 111). The top four pathogens detected were coagulase-negative staphylococci (CoNS), Klebsiella pneumoniae, Escherichia coli, and Candida. The incidence rate of sepsis and the pathogen spectrum showed no significant changes over time. Klebsiella pneumoniae was the most frequent pathogen in preterm infants, very low birth weight infants, and small-for-gestational-age infants, accounting for 33.9%, 29.5%, and 42.5%, respectively. CoNS, Klebsiella pneumoniae, and Escherichia coli had a high resistance rate to penicillins and third-generation cephalosporins. CONCLUSIONS: The incidence of neonatal sepsis is high, and the main pathogen is CoNS. The pathogens of neonatal sepsis have a high resistance rate to penicillins and third-generation cephalosporins. It is recommended to enhance the prevention and control of neonatal infection, strengthen the surveillance of pathogens, and further standardize the rational use of antibiotics.

Plasma levels of amino acids and derivatives in retinopathy of prematurity.

Background: Retinopathy of prematurity (ROP) is a retinal disease that causes blindness in premature infants. This study aimed to reveal the changes in amino acids and derivatives in the plasma of ROP patients compared with premature infants without ROP. Methods: Metabolomics targeting amino acids and their derivatives was conducted to assess their plasma levels in ROP patients (n=58) and premature infants without ROP (n=25), and KEGG pathway analysis was used to identify the involved pathways. Results: Among the 31 assessed metabolites, the levels of 4 amino acids were significantly altered in the ROP group. Creatinine was downregulated in the plasma of the ROP patients, while the levels of citrulline, arginine, and aminoadipic acid were upregulated in the ROP group. Significant correlations were identified between the ROP stage and plasma levels of citrulline, creatinine, and aminoadipic acid. The involved pathways included biosynthesis of amino acids, arginine and proline metabolism, and arginine biosynthesis. Conclusion: The plasma levels of citrulline, creatinine, arginine, and aminoadipic acid were significantly changed in ROP patients. These metabolites could be considered potential biomarkers of ROP, and their related metabolic pathways might be involved in ROP pathogenesis.

The Demand Supply Steady-State Process-Based Multi-Level Spare Parts Optimization.

Spare parts are one of the important components of the equipment comprehensive support system. Spare parts management plays a decisive role in achieving the desired availability with the minimum cost. With the equipment complexity increasing, the price of spare parts has risen sharply. The traditional spare parts management makes the contradiction between fund shortage and spare parts shortage increasingly prominent. Based on the analysis of the multi-echelon and multi-indenture spare parts support model VARI-METRIC (vary multi-echelon technology for recoverable item control, VARI-METRIC), which is widely used by troops and enterprises in various countries, the model is mainly used in high system availability scenarios. However, in the case of low equipment system availability, the accuracy and cost of model inventory prediction are not ideal. This paper proposed the multi-level spare parts optimization model, which is based on the demand-supply steady-state process. It is an analytical model, which is used to solve the low accuracy problem of the VARI-METRIC model in the low equipment system availability. The analytical model is based on the multi-level spare parts support process. The article deduces methods for solving demand rate, demand-supply rate, equipment system availability, and support system availability. The marginal analysis method is used in the model to analyze the spare parts inventory allocation strategy's current based cost and availability optimal value. Finally, a simulation model is established to evaluate and verify the model. Then, the simulation results show that, when the low availability of equipment systems are 0.4, 0.6, the relative errors of the analytical model are 3.54%, 3.86%, and its costs are 0.52, 1.795 million ¥ RMB. The experiment proves that the inventory prediction accuracy of the analytical model is significantly higher than that of the VARI-METRIC model in low equipment system availability. Finally, the conclusion and future research directions are discussed.

Bone Turnover Markers and Bone Histomorphometry in Pubertal Rats with Intrauterine Growth Restriction.

OBJECTIVE: To investigate the effect of malnutrition during pregnancy on bone development in rat pups with intrauterine growth restriction (IUGR). Methods: IUGR offspring were induced with a 10% low protein diet, while the control group was given a 21% protein diet during pregnancy. Serum biomarkers including bone glutamyl protein (BGP), amino-terminal propeptide of type 1 procollagen (P1NP), cross linked N-telopeptide of type I collagen (NTX), and insulin like growth factor 1 (IGF-1) levels were measured at 7, 21 and 56 d. Left femurs taken at 56 d were used for bone histomorphometry analysis by micro-computed tomography (micro-CT). Results: Compared with the control group, the IUGR group had lower IGF-1 and BGP levels at 7 and 21 d, and higher P1NP and NTX levels at 7 d. The IUGR group had thinner trabecular thickness (Tb.Th), lower trabecular number (Tb.N), and increased trabecular separation (Tb.Sp) at 56 d. Conclusion: The effect of IUGR on bone development may persist after birth.

[Risk factors for metabolic bone disease of prematurity in very/extremely low birth weight infants: a multicenter investigation in China].

OBJECTIVE: To investigate the incidence rate and risk factors for metabolic bone disease of prematurity (MBDP) in very low birth weight/extremely low birth weight (VLBW/ELBW) infants. METHODS: The medical data of 61 786 neonates from multiple centers of China between September 1, 2013 and August 31, 2016 were retrospectively investigated, including 504 VLBW/ELBW preterm infants who met the inclusion criteria. Among the 504 infants, 108 infants diagnosed with MBDP were enrolled as the MBDP group and the remaining 396 infants were enrolled as the non-MBDP group. The two groups were compared in terms of general information of mothers and preterm infants, major diseases during hospitalization, nutritional support strategies, and other treatment conditions. The multivariate logistic regression analysis was used to investigate the risk factors for MBDP. RESULTS: The incidence rate of MBDP was 19.4% (88/452) in VLBW preterm infants and 38.5% (20/52) in ELBW preterm infants. The incidence rate of MBDP was 21.7% in preterm infants with a gestational age of < 32 weeks and 45.5% in those with a gestational age of < 28 weeks. The univariate analysis showed that compared with the non-MBDP group, the MBDP group had significantly lower gestational age and birth weight, a significantly longer length of hospital stay, and a significantly higher incidence rate of extrauterine growth retardation (P < 0.05). Compared with the non-MBDP group, the MBDP group had significantly higher incidence rates of neonatal sepsis, anemia, hypocalcemia, and retinopathy of prematurity (P < 0.05). The MBDP group had a significantly lower mean feeding speed, a significantly higher age when reaching total enteral feeding, and a significantly longer duration of parenteral nutrition (P < 0.05). The use rate of caffeine citrate in the MBDP group was significantly higher, but the use rate of erythropoietin was significantly lower than that in the non-MBDP group (P < 0.05). The multivariate logistic regression analysis showed that gestational age < 32 weeks, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis were risk factors for MBDP (P < 0.05). CONCLUSIONS: A lower gestational age, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis may be associated an increased risk of MBDP in VLBW/ELBW preterm infants. It is necessary to strengthen perinatal healthcare, avoid premature delivery, improve the awareness of the prevention and treatment of MBDP among neonatal pediatricians, and adopt positive and reasonable nutrition strategies and comprehensive management measures for preterm infants.

Evaluation of genetic variants in IL-1B and its interaction with the predisposition of osteoporosis in the northwestern Chinese Han population.

BACKGROUND: Interleukin (IL)-1ß stimulates the proliferation and differentiation of osteoclast precursors into mature osteoclasts. IL-1B polymorphisms may influence the gene and protein expression of IL-1ß. The present study aimed to investigate the association of IL-1B variants (rs2853550, rs1143643, rs3136558, rs1143630, rs1143627, rs16944 and rs1143623) and their interaction with osteoporosis risk among the northwestern Chinese Han population. METHODS: AN Agena MassARRAY system (Agena, San Diego, CA, USA) was employed for genotyping in 594 osteoporosis patients and 599 healthy controls. The possible association between IL-1B polymorphisms and risks of osteoporosis development was identified with odds ratios (OR) and 95% confidence intervals (CI) using logistic regression models. Haplotype analysis and multifactor dimension reduction analysis were used to explore the potential association between combined single nucleotide polymorphisms (SNPs) and osteoporosis risk. RESULTS: The AA genotype of rs2853550 was a protective factor for osteoporosis occurrence (OR = 0.11, p = 0.038), whereas rs16944 (OR = 1.19, p = 0.037) and rs1143623 (OR = 1.21, p = 0.025) conferred an increased risk of osteoporosis. Moreover, rs1143627, rs16944 and rs1143623 were associated with an elevated susceptibility to osteoporosis, especially in females and individuals aged > 60 years or with a body mass index > 24 kg/m2 . Haplotype Grs1143630 Ars1143627 Grs16944 was a risk factor of osteoporosis occurrence (OR = 1.20, p = 0.032). The best model of SNP-SNP analysis was a four-locus combination of rs1143643, rs3136558, rs1143630 and rs1143623 (testing accuracy = 0.5623). CONCLUSIONS: IL-1B polymorphisms and haplotype Grs1143630 Ars1143627 Grs16944 might contribute to susceptibility to osteoporosis. The SNP-SNP interaction of polymorphisms in IL-1B revealed the accumulated effect on osteoporosis risk.

Irisin Protects Brain against Ischemia/Reperfusion Injury through Suppressing TLR4/MyD88 Pathway.

BACKGROUND: Inflammatory response exerts an important role in ischemia/reperfusion (I/R) injury. TLR4 and myeloid differentiation factor 88 (MyD88) are key components in inflammation and are involved in the cerebral I/R injury. Irisin is a skeletal muscle-derived myokine produced after exercise, which was found to suppress inflammation. In this study, we investigated whether irisin could protect the brain from I/R injury through the TLR4/MyD88 pathway. METHODS: Male Sprague Dawley rats (20 months, 190 ∼ 240 g) were pretreated with irisin at 10, 50, or 100 mg/kg for consecutive 3 days and then subjected to surgery of middle cerebral artery occlusion or sham operation. Infarct size and neuron loss were measured to evaluate brain damage. The mRNA and protein levels of TLR4 and MyD88 were measured by in situ hybridization and immunohistochemistry, respectively. NF-κB activation was assessed by electrophoretic mobility shift assay. Neurological function was evaluated by neurobehavior score test and passive avoidance test. RESULTS: Irisin could reduce neuronal damage and neurofunctional impairment after I/R injury. This effect was mediated by downregulating the TLR4/MyD88 and inhibiting NF-κB activation. CONCLUSION: Irisin plays a beneficial effect in I/R injury through regulating the TLR4/MyD88 pathway.

Application of a modified electrocardiogram-guided technique for umbilical venous catheterisation in neonates: A retrospective trial.

AIM: To investigate the effectiveness and safety of modified electrocardiogram (ECG)-guided technique in umbilical venous catheterisation in neonates. METHODS: Sixty-six critically ill neonates underwent umbilical venous catheterisation with (ECG group) or without (control group) ECG guidance from January 2017 to March 2019. We retrospectively analysed and compared the rate of correct tip placement on first try, unplanned extubation rate and incidence of catheter-related complications between the two groups. RESULTS: There were 33 patients in each group. The ECG group showed significantly higher rate of correct tip placement on first try (P < 0.001), lower unplanned extubation rate (P < 0.001), but identical incidence of catheter-related complications (P = 0.492) comparing with the control group. CONCLUSION: The ECG-guided technique is an effective and safe method for umbilical venous catheterisation. The connecting method we modified made this technique more practical and can be promoted to areas without access to specific ECG adaptors.

Mutations in NUP160 Are Implicated in Steroid-Resistant Nephrotic Syndrome.

BACKGROUND: Studies have identified mutations in >50 genes that can lead to monogenic steroid-resistant nephrotic syndrome (SRNS). The NUP160 gene, which encodes one of the protein components of the nuclear pore complex nucleoporin 160 kD (Nup160), is expressed in both human and mouse kidney cells. Knockdown of NUP160 impairs mouse podocytes in cell culture. Recently, siblings with SRNS and proteinuria in a nonconsanguineous family were found to carry compound-heterozygous mutations in NUP160. METHODS: We identified NUP160 mutations by whole-exome and Sanger sequencing of genomic DNA from a young girl with familial SRNS and FSGS who did not carry mutations in other genes known to be associated with SRNS. We performed in vivo functional validation studies on the NUP160 mutations using a Drosophila model. RESULTS: We identified two compound-heterozygous NUP160 mutations, NUP160R1173× and NUP160E803K . We showed that silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by expression of the wild-type human NUP160 gene in nephrocytes. By contrast, expression of the NUP160 mutant allele NUP160R1173× completely failed to rescue nephrocyte phenotypes, and mutant allele NUP160E803K rescued only nuclear pore complex and nuclear lamin localization defects. CONCLUSIONS: Mutations in NUP160 are implicated in SRNS. Our findings indicate that NUP160 should be included in the SRNS diagnostic gene panel to identify additional patients with SRNS and homozygous or compound-heterozygous NUP160 mutations and further strengthen the evidence that NUP160 mutations can cause SRNS.

A nationwide survey on neonatal medical resources in mainland China: current status and future challenges.

BACKGROUND: With the rapid development of economy in recent two decades, neonatology has been progressing quickly in China. However, there is little knowledge about the exact developmental status of neonatal departments in China. The aim of this study was to assess resources available for care of sick newborns in mainland China. METHODS: Questionnaires were sent to the membership of the Chinese Neonatologist Association (CNA) and used to survey the scale, facilities, staff, technologies, transport systems and preterm infants' outcomes of neonatal departments (NDs) in different areas of China from June 2012 to December 2012. RESULTS: The result of this survey including a total of 117 questionnaires showed that investigated ND had a mean of 65 (median 47; range 5-450) beds, including 19.59 (median 15, range 0-100) NICU beds. The overall doctor/bed and nurse/bed ratio was 1:3.84 and 1:1.43, respectively. Lack of medical equipment was one of the main problems in most NDs surveyed, and only 26 NDs (22.2%) had more than one neonatal incubator per bed. Only 70.1, 30.6, 30.8 and 4.3% NDs carried out high-frequency ventilation, hypothermia, nitric oxide inhalation, and ECMO respectively. The capacity to provide advanced therapies increased with the size of the NDs (P < .01). A total of 81 NDs (69.2%) carried out neonatal transport, but only 70 NDs (86.4%) were equipped with transport incubators, 36 NDs (44.4%) had the ability of performing intrauterine transport of the preterm infants, and 3 NDs (3.7%) had the ability of performing air transport. The survival rate of extremely preterm infants (Gestational age less than 28w) to discharge home was 47.8% in 2011. CONCLUSION: NDs in mainland China are not well distributed and still face many problems, such as staff shortage, inadequate facilities, and imperfect transport. It is urgent to set up a classification of neonatal care to enhance the utilization rate of medical resources and improve the prognosis of critically ill infants.

Mannan-Binding Lectin Suppresses Peptidoglycan-Induced TLR2 Activation and Inflammatory Responses.

Peptidoglycan (PGN), as the major components of the bacterial cell wall, is known to cause excessive proinflammatory cytokine production. Toll-like receptor 2 (TLR2) is abundantly expressed on immune cells and has been shown to be involved in PGN-induced signaling. Although more and more evidences have indicated that PGN is recognized by TLR2, the role of TLR2 PGN recognition is controversial. Mannan-binding lectin (MBL), a plasma C-type lectin, plays a key role in innate immunity. More and more evidences show that MBL could suppress the amplification of inflammatory signals. Whether MBL can alter PGN-elicited cellular responses through TLR2 in macrophages is still unknown, and possible mechanism underlying it should be investigated. In this study, we found that MBL significantly attenuated PGN-induced inflammatory cytokine production, including TNF-α and IL-6, in PMA-stimulated THP-1 cells at both mRNA and protein levels. The expression of TLR2 was strongly induced by PGN stimulation. Furthermore, the administration of TLR2-neutralized antibody effectively suppressed PGN-induced TNF-α and IL-6 expression. These results supplied the evidence that PGN from Saccharomyces cerevisiae could be recognized by TLR2. In addition, we also found that MBL decreased PGN-induced TLR2 expression and suppressed TLR2-mediated downstream signaling, including the phosphorylation of IκBα, nuclear translocation of NF-κBp65, and phosphorylation of MAPK p38 and ERK1/2. Administration of MBL alone did not have an effect on the expression of TLR2. Finally, our data showed that PGN-mediated immune responses were more severely suppressed by preincubation with MBL and indicated that MBL can combine with both TLR2 and PGN to block the inflammation cytokine expression induced by PGN. All these data suggest that MBL could downregulate inflammation by modulating PGN/TLR2 signaling pathways. This study supports an important role for MBL in immune regulation and signaling pathways involved in inflammatory responses.

Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction.

DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure-activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads - namely compounds 3g, 3k, 4d, 4e and 4g - all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest.