Understanding the heterogeneity of alloreactive natural killer cell function in kidney transplantation.

Human Natural Killer (NK) cells are heterogeneous lymphocytes regulated by variegated arrays of germline-encoded activating and inhibitory receptors. They acquire the ability to detect polymorphic self-antigen via NKG2A/HLA-E or KIR/HLA-I ligand interactions through an education process. Correlations among HLA/KIR genes, kidney transplantation pathology and outcomes suggest that NK cells participate in allograft injury, but mechanisms linking NK HLA/KIR education to antibody-independent pathological functions remain unclear. We used CyTOF to characterize pre- and post-transplant peripheral blood NK cell phenotypes/functions before and after stimulation with allogeneic donor cells. Unsupervised clustering identified unique NK cell subpopulations present in varying proportions across patients, each of which responded heterogeneously to donor cells based on donor ligand expression patterns. Analyses of pre-transplant blood showed that educated, NKG2A/KIR-expressing NK cells responded greater than non-educated subsets to donor stimulators, and this heightened alloreactivity persisted > 6 months post-transplant despite immunosuppression. In distinct test and validation sets of patients participating in two clinical trials, pre-transplant donor-induced release of NK cell Ksp37, a cytotoxicity mediator, correlated with 2-year and 5-year eGFR. The findings explain previously reported associations between NK cell genotypes and transplant outcomes and suggest that pre-transplant NK cell analysis could function as a risk-assessment biomarker for transplant outcomes.

Application and prospect of drug discrimination in field of drug abuse / 中国药理学通报

Drug discrimination is a behavioral pharmacological technique to study the discriminative stimulus effects of drug. Currently drug discrimination has been widely used in preclinical drug development of CNS drugs, the most extensive of which is psychodependent research in the field of drug abuse. This review describes in general the basic principles of drug discrimination, preliminarily elaborates on the relevant characteristics and applications of the subjective effects, time-course effect, stereo specificity, individual differences, and receptor mechanisms, and its development prospects for hallucinogens and cannabis drugs are also presented.

Prevalence and risk factors of work-related musculoskeletal disorders in upper back of welders in an automobile factory / 环境与职业医学

Background China's automobile manufacture is a labor-intensive industry, and most of the welding tasks are manual operations. It is often necessary to observe the solder joints during operation, and there are many adverse health outcome-related factors involved in the work process. However, the research on the prevalence and risk factors of work-related musculoskeletal disorders (WMSDs) in the upper back of welders is still insufficient. Objective To explore the prevalence and risk factors of WMSDs in the upper back of welders from an automobile factory. Methods This was a cross-sectional study. A cluster random sampling method was used to select 972 electric welders from an automobile factory as the study subjects. The Musculoskeletal Disorders Questionnaire was used to estimate the prevalence of WMSDs in the upper back in the past year. Results The prevalence rate of WMSDs in the upper back in the welders was 42.2% (410/972). The positive rates of studied occupational risk factors were 72.5% (705/972) for maintaining same posture for a long time, 71.8% (698/972) for bending and twisting for a long time, and 64.7% (629/972) for repetitive trunk movements. The univariate analysis showed that the prevalence rates of WMSDs were significantly different among workers categorized by gender, working age, twisting and/or bending for a long time, working in the same position for a long time, lifting heavy objects in an uncomfortable position, repetitive trunk movements, being unable to exert energy due to discomfort, work involving cold or temperature changes, personnel shortage, no rest between work, working hours per week, and working in an uncomfortable position (P<0.05). The results of multiple logistic regression indicated that female, working in the same position for a long time, working in an uncomfortable position (frequently), lifting heavy objects in an uncomfortable position, and being unable to exert energy due to discomfort were associated with higher risks of reporting WMSDs in the upper back (OR=2.37, 1.46, 1.76, 1.44, and 1.50, respectively, P<0.05); the risk of reporting WMSDs in the upper back increased by 95%, 157%, and 196% for every 10 h increase in weekly working hours (41-50 h, 51-60 h, ≥61 h vs ≤40 h); adequate rest time was associated with a lower risk for WMSDs in the upper back (OR=0.70, 95%CI: 0.49-0.98). Conclusion The prevalence rate of WMSDs in the upper back of welders in the automobile factory is high, and many occupational risk factors are involved. Measures should be taken for intervention and prevention.

NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2A is acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.

MiDAS-Meaningful Immunogenetic Data at Scale.

Human immunogenetic variation in the form of HLA and KIR types has been shown to be strongly associated with a multitude of immune-related phenotypes. However, association studies involving immunogenetic loci most commonly involve simple analyses of classical HLA allelic diversity, resulting in limitations regarding the interpretability and reproducibility of results. We here present MiDAS, a comprehensive R package for immunogenetic data transformation and statistical analysis. MiDAS recodes input data in the form of HLA alleles and KIR types into biologically meaningful variables, allowing HLA amino acid fine mapping, analyses of HLA evolutionary divergence as well as experimentally validated HLA-KIR interactions. Further, MiDAS enables comprehensive statistical association analysis workflows with phenotypes of diverse measurement scales. MiDAS thus closes the gap between the inference of immunogenetic variation and its efficient utilization to make relevant discoveries related to immune and disease biology. It is freely available under a MIT license.

The microRNA miR-33 is a pleiotropic regulator of metabolic and developmental processes in Drosophila melanogaster.

BACKGROUND: miR-33 family members are well characterized regulators of cellular lipid levels in mammals. Previous studies have shown that overexpression of miR-33 in Drosophila melanogaster leads to elevated triacylglycerol (TAG) levels in certain contexts. Although loss of miR-33 in flies causes subtle defects in larval and adult ovaries, the effects of miR-33 deficiency on lipid metabolism and other phenotypes impacted by metabolic state have not yet been characterized. RESULTS: We found that loss of miR-33 predisposes flies to elevated TAG levels, and we identified genes involved in TAG synthesis as direct targets of miR-33, including atpcl, midway, and Akt1. miR-33 mutants survived longer upon starvation but showed greater sensitivity to an oxidative stressor. We also found evidence that miR-33 is a negative regulator of cuticle pigmentation and that miR-33 mutants show a reduction in interfollicular stalk cells during oogenesis. CONCLUSION: Our data suggest that miR-33 is a conserved regulator of lipid homeostasis, and its targets are involved in both degradation and synthesis of fatty acids and TAG. The constellation of phenotypes involving tissues that are highly sensitive to metabolic state suggests that miR-33 serves to prevent extreme fluctuations in metabolically sensitive tissues.

Clinical characteristics of influenza virus infection and risk factors analysis of severe cases in children / 中国小儿急救医学

Objective:To analyze the clinical characteristics and laboratory examinations of hospitalized children with influenza, and improve medical personal awareness of severe influenza.Methods:Data of inpatients with influenza from November 2018 to February 2019 at Shenzhen Children′s Hospital was collected, and the clinical characteristics and laboratory examinations were statistical analyzed.Results:Of the 702 cases, 464(66.1%) cases were mild influenza, and 238 cases(33.9%)were severe influenza; the median age was 3.8 years, and 457(65.1%) cases were 0 to 5 years old.The number of patients with basic diseases and wheezing symptoms in the severe group was more than those in the mild group, with statistically significant differences(all P<0.05). The white blood cell count, percentage of neutrophils, neutrophils to lymphocytes ratio(NLR), C-reactive protein and procalcitonin in the severe group were higher than those in the mild group, while the percentage of lymphocytes was lower than that in the mild group(all P<0.05). Logistic multivariate regression analysis showed that underlying diseases, wheezing and NLR were risk factors for severe influenza.The area under the curve of NLR for severe influenza was 0.574, whose best cutoff value was 1.43. Conclusion:Influenza virus infection among children is mainly influenza A, and mostly affected children are under 5 years old.The blood routine of children with severe influenza mostly showes increased white blood cell, mainly neutrophils increased significantly, and increased C-reactive protein and procalcitonin.Children with underlying diseases, wheezing symptoms during the course of the disease, and elevated NLR are more likely to progress to severe cases, and NLR cannot be used as a independent predictor of severe influenza.

Safety of protease inhibitors and Arbidol for SARS-CoV-2 pneumonia in Zhejiang Province, China / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The aim of this study was to evaluate the safety of an antiviral regimen of protease inhibitors combined with Arbidol (umifenovir) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients. The genomic sequence of SARS-CoV-2 is highly homologous to that of SARS-CoV (Zhou et al., 2020). Previously published basic and clinical research on anti-SARS-CoV treatment found that lopinavir/ritonavir (LPV/r) could improve the prognosis of SARS patients (Chan et al., 2003; Chu et al., 2004). Darunavir (DRV) is another protease inhibitor that blocks the binding of SARS-CoV-2 to human angiotensin-converting enzyme 2 (Omotuyi et al., 2020). The broad-spectrum antiviral drug Arbidol (umifenovir) also shows in vitro anti-SARS-CoV activity (Khamitov et al., 2008).

CD56 as a marker of an ILC1-like population with NK cell properties that is functionally impaired in AML.

An understanding of natural killer (NK) cell physiology in acute myeloid leukemia (AML) has led to the use of NK cell transfer in patients, demonstrating promising clinical results. However, AML is still characterized by a high relapse rate and poor overall survival. In addition to conventional NKs that can be considered the innate counterparts of CD8 T cells, another family of innate lymphocytes has been recently described with phenotypes and functions mirroring those of helper CD4 T cells. Here, in blood and tissues, we identified a CD56+ innate cell population harboring mixed transcriptional and phenotypic attributes of conventional helper innate lymphoid cells (ILCs) and lytic NK cells. These CD56+ ILC1-like cells possess strong cytotoxic capacities that are impaired in AML patients at diagnosis but are restored upon remission. Their cytotoxicity is KIR independent and relies on the expression of TRAIL, NKp30, NKp80, and NKG2A. However, the presence of leukemic blasts, HLA-E-positive cells, and/or transforming growth factor-ß1 (TGF-ß1) strongly affect their cytotoxic potential, at least partially by reducing the expression of cytotoxic-related molecules. Notably, CD56+ ILC1-like cells are also present in the NK cell preparations used in NK transfer-based clinical trials. Overall, we identified an NK cell-related CD56+ ILC population involved in tumor immunosurveillance in humans, and we propose that restoring their functions with anti-NKG2A antibodies and/or small molecules inhibiting TGF-ß1 might represent a novel strategy for improving current immunotherapies.

Monalizumab: inhibiting the novel immune checkpoint NKG2A.

The implementation of immune checkpoint inhibitors to the oncology clinic signified a new era in cancer treatment. After the first indication of melanoma, an increasing list of additional cancer types are now treated with immune system targeting antibodies to PD-1, PD-L1 and CTLA-4, alleviating inhibition signals on T cells. Recently, we published proof-of-concept results on a novel checkpoint inhibitor, NKG2A. This receptor is expressed on cytotoxic lymphocytes, including NK cells and subsets of activated CD8+ T cells. Blocking antibodies to NKG2A unleashed the reactivity of these effector cells resulting in tumor control in multiple mouse models and an early clinical trial. Monalizumab is inhibiting this checkpoint in human beings and future clinical trials will have to reveal its potency in combination with other cancer treatment options.

Clinical analysis of typhoid fever complicated with hemophagocytic syndrome in one case / 临床儿科杂志

Objectives To analyze the clinical features and outcome of typhoid fever complicated with hemophagocytic syndrome (Ty-AHS) in children.Methods The clinical data from one case of Ty-AHS was retrospectively analyzed, and related articles were reviewed.Results A 4-year-old boy suffered from persistent diarrhea, alternating high and low temperature, apathia, hepatosplenomegaly, manifestation of acute peritonitis, and pyoperitoneum. Routine blood examination showed that eosinophil was 0, and hemoglobin and platelet were obviously decreased; CRP and procalcitonin were obviously increased;plasma ifbrinogen was dropped to 0.8 g/L; lactate dehydrogenase was elevated to 3835 U/L; Serum ferritin was 1884 ng/mL;triglyceride was 2.42 mmol/L; EBV-DNA titer was 2.81×104 copies/mL; Blood culture showed salmonella enterica serotype IIIb. Abdominal ultrasonography showed enlargement of mesenteric lymph node and middle volume of pyoperitoneum. Chest X-ray showed pneumonia. Lymphocyte analysis showed that the ratio of CD4+/CD8+ was decreased; CD3-CD16+56+ cell and CD19+ cell were all decreased. Bone marrow cytomorphologic examination revealed that bone marrow hyperplasia was active, there were no obvious abnormalities in granulocyte, macrophage and macrophage and there were a lot of tissue cells and white blood cells. After two weeks of strengthened anti-infection and dexamethasone treatment, the symptoms in patients were disappeared, and signs and laboratory tests gradually returned to normal.Conclusions Ty-AHS is a rare complication in children with acute onset and rapid progression, and combination of antibiotics and hormone therapy is effective.

Common household traditional Chinese medicines / 中国中药杂志

With the enhancement in the awareness of self-diagnosis among residents, it's very common for each family to prepare common medicines for unexpected needs. Meanwhile, with the popularization of the traditional Chinese medicine knowledge, the proportion of common traditional Chinese medicines prepared at residents' families is increasingly higher than western medicines year by year. To make it clear, both pre-research and closed questionnaire research were adopted for residents in Chaoyang District, Beijing, excluding residents with a medical background. Based on the results of data, a analysis was made to define the role and influence on the quality of life of residents and give suggestions for relevant departments to improve the traditional Chinese medicine popularization and promote the traditional Chinese medicine market.

Efficacyof hydromorphone hydrochloride injection for treatment of chronic pain : a meta-analysis / 中华麻醉学杂志

Objective To systematically review the efficacy of hydromorphone hydrochloride injection for treatment of chronic pain.Methods Web of Science Proceedings and PubMed were searched for clinical trials involving the efficacy of hydromorphone for treatment of chronic pain, with no language or time limit.Evaluation indexes included visual analogue scale (VAS) score and the rate of pain control or relief.The studies were screened independently, and the data were extracted by two researchers.Meta-analysis was conducted using the Stata 10 software.Results Eleven studies involving 452 patients were included in our meta-analysis.VAS score was significantly decreased after treatment compared with that before treatment.For the patients with cancer pain, VAS score was significantly decreased after treatment with hydromorphone hydrochoride injection, and the rate of pain control or relief was increased when compared with the other opioid analgesics.Conclusion Hydromorphone hydrochloride injection can treat chronic pain, and it may provide better therapeutic effect than the other opioid analgesics for the patients with cancer pain.

Effect of sitz bath with 1.6%brine solution and metronidazole on perianal infections in acute leukemia patients / 现代临床护理

Objective To study the effect of sitz bath with 1.6%concentrated brine solution and metronidazole on perianal infection in acute leukemia patients. Methods Seventy-six acute leukemia patients admitted from June 2010 to December 2014 with perianal infections were randomly divided into the control group and the observation group in equal number. The two groups were given routine nursing care and symptomatic supportive treatment . Apart from the basic nursing , the control group was treated with sitz bath with 10 min 1 ∶ 5000 potassium permanganate. The observation group was treated with sitz bath with 1.6% brine solution and 0.1%metronidazole two times every day and another one if defecation was done. The perianal infections of two groups were compared in 7 days. Result The total effectiveness in the observation group was significantly better than that of the control group (P < 0.05). Conclusions Sits bath with 1.6% brine solution and metronidazole two times a day is more effective than with 1 ∶ 5000 potassium permanganate. It is economic and convenient, safe and effective for the treatment of perianal infections and therefore worth popularizing in clinical application.

Clinical analysis of 4 children with negative pressure pulmonary edema / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze the clinical characteristics of negative pressure pulmonary edema (NPPE).</p><p><b>METHOD</b>A retrospective investigation of the clinical manifestation, imageology, clinical course and outcome of 4 children with NPPE seen between June 2012 and July 2013 in a children's hospital. The causation of the airway obstruction was also explored.</p><p><b>RESULT</b>All the 4 cases were boys, the range of age was 40 days to 9 years. They had no history of respiratory and circulatory system disease. In 3 cases the disease had a sudden onset after the obstruction of airway, and in one the onset occurred 1.5 hours after removing the airway foreign body. All these cases presented with tachypnea, dyspnea, and cyanosis, none had fever. Three cases had coarse rales. Chest radiography was performed in 3 cases and CT scan was performed in 1 case, in all of them both lungs displayed diffuse ground-glass-like change and patchy consolidative infiltrates. Three cases were admitted to the ICU, duration of mechanical ventilation was less than 24 hours in 2 cases and 39 hours in one. Oxygen was given by mask to the remaining one in emergency department, whose symptoms were obviously improved in 10 hours. None was treated with diuretics, glucocorticoids or inotropic agents. Chest radiographs were taken within 24 hours of treatment in 2 cases and 24-48 hours in the other 2; almost all the pulmonary infiltrates were resolved. All the 4 cases were cured. The causes of airway obstruction were airway foreign bodies in two cases, laryngospasm in one and laryngomalacia in the other.</p><p><b>CONCLUSION</b>NPPE is a life-threatening emergency, which is manifested by rapid onset of respiratory distress rapidly (usually in several minutes, but might be hours later) after relief of the airway obstruction, with findings of pulmonary edema in chest radiograph. The symptoms resolve rapidly by oxygen therapy timely with or without mechanical ventilation. In children with airway obstruction, NPPE should be considered.</p>

Self-efficacy on rehabilitative exercise and the influential factors in patients having undergone total hip or knee arthroplasty / 现代临床护理

Objective To explore the exercise self-efficacy and its influential factors in patients having undergone total hip or knee arthroplasty.Method The Self-Efficacy Rehabilitation Outcome Scale(SER)and demographic questionnaire were used in the investigation among sixty-five patients recruited by convenient sampling.Results The average score on exercise self-efficacy was(67.94±17.22)and the influential factors included age,family income,types of surgery,whether there were monitors for their exercise and whether there were other patients communicating on exercise methods(all P<0.05).Conclusions The self-efficacy in patients after total hip or knee arthroplasty is at lower level.It is necessary to enhance rehabilitative education to improve their self-efficacy in rehabilitative exercise.

Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article.

OBJECT: The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors. METHODS: The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide. RESULTS: The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities. CONCLUSIONS: This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide's novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.

Chemical constituents from Scolopendra multidens (I) / 中草药

Objective: To study the chemical constituents from Scolopendra multidens. Methods: Compounds were isolated and purified by a combination of chromatographic techniques including silica gel, ODS, Sephadex LH-20 column chromatography, middle and low pressure preparative chromatograms, and pre-HPLC. The structures were elucidated on the basis of physicochemical properties and spectroscopic analyses. Results: Ten compounds were separated and identified as uracil (1), 7, 8-dimethyl-isoalloxazine (2), indole-3-acetamide (3), N-(2-phenylethyl) acetamide (4), (3S)-1, 2, 3, 4-tetrahydro-β-carboline-3-carboxylic acid (5), cyclo-(L-Ile-L-Pro) (6), cyclo-(L-Leu-L-Pro) (7), cyclo-(L-Phe-L-Pro) (8), cyclo-(L-Phe-L-Tyr) (9), and cyclo-(L-Val-L-Pro) (10). Conclusion: All the compounds are isolated from S. multidens for the first time.

The substitution effect of nicotine in heroin discriminative rats / 中华行为医学与脑科学杂志

ObjectiveTo evaluate the discriminative stimulus effects of nicotine on the basis of a rat model of heroin discrimination.MethodsMale Sprague-Dawley rats were trained to discriminate 0.3 mg/kg heroin from saline under a fixed-ratio (FR10) schedule of food reinforcement.After training,different doses of heroin and nicotine were used to substitute for training dose of heroin,the dose-response curve for heroin and the discriminative stimulus effects of nicotine were identified in rats.ResultsAll rats reliably discriminated 0.3 mg/kg heroin from saline.Different doses of heroin ( 0.03,0.1,0.3,0.56 mg/kg ) produced ( 33.9 ± 15.0 ) ％,( 43.3 ± 13.3 ) ％,(98.7 ± 0.5 ) ％,(99.4 ± 0.2 ) ％ total responding on heroin associated lever,heroin at the doses of lower than 0.3 mg/kg produced the dose-dependent relationship in heroin-appropriate responding.In heroin-trained rats,nicotine at the dose of 0.03,0.1 mg/kg produced(1.9 ±1.1)％,(13.7 ±5.6)％ total responding on heroin associated lever,there were extremely significant differences with 0.3 mg/kg heroin control (P＜0.01).However,nicotine at the dose of 0.3,0.5 mg/kg produced ( 60.4 ± 16.1 ) ％,(65.9 ± 16.4) ％ total responding on heroin associated lever,there were no significant differences with 0.3 mg/kg heroin control (P＞ 0.05 ).ConclusionNicotine at the dose of 0.3,0.5 mg/kg can partially produce heroin-like discriminative stimulus effects.