Ancient DNA reveals genetic admixture in China during tiger evolution.

The tiger (Panthera tigris) is a charismatic megafauna species that originated and diversified in Asia and probably experienced population contraction and expansion during the Pleistocene, resulting in low genetic diversity of modern tigers. However, little is known about patterns of genomic diversity in ancient populations. Here we generated whole-genome sequences from ancient or historical (100-10,000 yr old) specimens collected across mainland Asia, including a 10,600-yr-old Russian Far East specimen (RUSA21, 8× coverage) plus six ancient mitogenomes, 14 South China tigers (0.1-12×) and three Caspian tigers (4-8×). Admixture analysis showed that RUSA21 clustered within modern Northeast Asian phylogroups and partially derived from an extinct Late Pleistocene lineage. While some of the 8,000-10,000-yr-old Russian Far East mitogenomes are basal to all tigers, one 2,000-yr-old specimen resembles present Amur tigers. Phylogenomic analyses suggested that the Caspian tiger probably dispersed from an ancestral Northeast Asian population and experienced gene flow from southern Bengal tigers. Lastly, genome-wide monophyly supported the South China tiger as a distinct subspecies, albeit with mitochondrial paraphyly, hence resolving its longstanding taxonomic controversy. The distribution of mitochondrial haplogroups corroborated by biogeographical modelling suggested that Southwest China was a Late Pleistocene refugium for a relic basal lineage. As suitable habitat returned, admixture between divergent lineages of South China tigers took place in Eastern China, promoting the evolution of other northern subspecies. Altogether, our analysis of ancient genomes sheds light on the evolutionary history of tigers and supports the existence of nine modern subspecies.

Magnifying image-enhanced endoscopy-only mode boosted early cancer diagnostic efficiency: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Magnifying image-enhanced endoscopy (MIEE) is an advanced endoscopy with image enhancement and magnification used in preoperative examination. However, its impact on the detection rate is unknown. METHODS: We conducted an open-label, randomized, parallel (1:1:1), controlled trial in 6 hospitals in China. Patients were recruited between February 14, 2022 and July 30, 2022. Eligible patients were aged ≥18 years and undergoing gastroscopy in outpatient departments. Participants were randomly assigned to the MIEE-only mode (o-MIEE) group, white-light endoscopy-only mode (o-WLE) group, and MIEE when necessary mode (n-MIEE) group (initial WLE followed by switching to another endoscope with MIEE if necessary). Biopsy sampling of suspicious lesions of the lesser curvature of the gastric antrum was performed. Primary and secondary aims were to compare detection rates and positive predictive value (PPV) of early cancer and precancerous lesions in these 3 modes, respectively. RESULTS: A total of 5100 recruited patients were randomly assigned to the o-MIEE (n = 1700), o-WLE (n = 1700), and n-MIEE (n = 1700) groups. In the o-MIEE, o-WLE, and n-MIEE groups, 29 (1.51%; 95% confidence interval [CI], 1.05-2.16), 4 (.21%; 95% CI, .08-.54), and 8 (.43%; 95% CI, .22-.85) early cancers were found, respectively (P < .001). The PPV for early cancer was higher in the o-MIEE group compared with the o-WLE and n-MIEE groups (63.04%, 33.33%, and 38.1%, respectively; P = .062). The same trend was seen for precancerous lesions (36.67%, 10.00%, and 21.74%, respectively). CONCLUSIONS: The o-MIEE mode resulted in a significant improvement in diagnosing early upper GI cancer and precancerous lesions; thus, it could be used for opportunistic screening. (Clinical trial registration number: ChiCTR2200064174.).

[Clinical therapeutic strategies of refracture after bone transport for tibial bone defect].

OBJECTIVE: To explore the clinical therapeutic strategies of refracture after Ilizarov bone transport technique in the treatment of tibial bone defect. METHODS: A retrospective study was performed on 19 patients with infected tibial bone defect treated by Ilizarov bone transport technique and then refracture from August 2010 to January 2020, including 18 males and 1 female with an average age of (37.7±13.0) years old ranging from 15 to 66 years old. Cause of injury invlved falling injury in 4 cases, crashing injury 1 case, crushing injury in 1 case and without obvious injury history in 13 cases. The ipsilateral distal femoral fracture in 2 cases occurred before the external fixator of tibia was removed, and the other 17 cases had a minimum of 1 day and a maximum of 30 months after the external fixator had been removed. The site of refracture was at regenerative zone in 8 cases, at docking site in 9 cases, at ipsilateral femoral shaft in 2 cases. According to the modified Simpson classification proposed by the author, the refracture was classified. The treatment of refracture include plaster splint, traction or external fixation. Bone healing and function were evaluated according to the standards of the Association for the Study and Application of the Method of Ilizarov(ASAMI). RESULTS: All patients were followed up, and the duration ranged from 9 to 17 months with an average of (12.3±3.2) months. According to the modified Simpson classification, there were 3 cases of type Ⅰa, 1 case of type Ⅰb, 3 cases of type Ⅰc, 1 case of type Ⅱ, 9 cases of type Ⅲ and 2 cases of type Ⅴ. All the refractures healed without infection or malunion. The fracture healing time of conservative treatment for 6 cases were 3, 5, 3, 2, 2, 2 months fespectively;and the healing time of fracture treated by surgery for 13 cases was 2 to 6 months, with an average of(4.4±1.4) months. According to ASAMI evaluation criteria, bony results showed all patients obtained excellent results, and functional results showed 6 patients got excellent results, 13 good beacause of ankle or knee stiffness. CONCLUSION: The modified Simpson classification could contain most clinical types of refracture after bone transport, and the external fixation is a simple and effective method for refracture.

COVID-19 is associated with the risk of cardiovascular disease death: A two-sample Mendelian randomization study.

Objective: This study aimed to estimate the causal effects of Coronavirus disease 2019 susceptibility and hospitalization on cardiovascular disease death using two-sample Mendelian randomization analysis. Methods: We used statistics from a genome-wide association study. A total of 2,568,698 participants were assessed in this study, including 1,299,010 in Coronavirus disease 2019 susceptibility databases, 908,494 in Coronavirus disease 2019 hospitalization database, and 361,194 in a cardiovascular disease death database. We performed two-sample Mendelian randomization analysis using the inverse variance weighted method. As sensitivity analysis techniques, Mendelian randomization-Egger regression, heterogeneity analyses, and Leave-one-out analysis were employed. Reverse Mendelian randomization analysis was used to detect reverse causality. Statistical significance was defined as P < 0.05. Results: Coronavirus disease 2019 susceptibility may be a causal factor for cardiovascular disease death (ß = 2.188 × 10-3, P = 0.002), which involves five common single nucleotide polymorphisms. Similarly, Coronavirus disease 2019 hospitalization may also be a causal factor for cardiovascular disease death (ß = 8.626 × 10-4, P = 0.010), which involves nine common single nucleotide polymorphisms. Furthermore, sensitivity and reverse Mendelian randomization analysis suggested that no heterogeneity, horizontal pleiotropy or reverse causality was found between Coronavirus disease 2019 and cardiovascular disease death. Conclusion: Our bidirectional Mendelian randomization analysis showed a causal relationship between Coronavirus disease 2019 susceptibility and hospitalization associated with an increased risk of cardiovascular disease death.

Pharmaceutical administration for severe hypertension during pregnancy: Network meta-analysis.

Aims: To evaluate the efficacy of different pharmacologic treatment for severe hypertension during pregnancy. Methods: Two reviewers searched Ovid MEDLINE, Ovid EMbase, and the Cochrane Library for randomized clinical trials from the establishment of the database to 15 July 2021 that were eligible for inclusion and analyzed the pharmaceuticals used for severe hypertension in pregnancy. Results: 29 relevant trials with 2,521 participants were involved. Compared with diazoxide in rate of achieving target blood pressure, other pharmaceuticals, including epoprostenol (RR:1.58, 95%CI:1.01-2.47), hydralazine\dihydralazine (RR:1.57, 95%CI:1.07-2.31), ketanserin (RR:1.67, 95%CI:1.09-2.55), labetalol (RR:1.54, 95%CI:1.04-2.28), nifedipine (RR:1.54, 95%CI:1.04-2.29), and urapidil (RR:1.57, 95%CI:1.00-2.47), were statistically significant in the rate of achieving target blood pressure. According to the SUCRA, diazoxide showed the best therapeutic effect, followed by nicardipine, nifedipine, labetalol, and nitroglycerine. The three pharmaceuticals with the worst therapeutic effect were ketanserin, hydralazine, and urapidil. It is worth noting that the high ranking of the top two pharmaceuticals, including diazoxide and nicardipine, comes from extremely low sample sizes. Other outcomes were reported in the main text. Conclusion: This comprehensive network meta-analysis demonstrated that the nifedipine should be recommended as a strategy for blood pressure management in pregnant women with severe hypertension. Moreover, the conventional pharmaceuticals, including labetalol and hydralazine, showed limited efficacy. However, it was important to note that the instability of hydralazine reducing blood pressure and the high benefit of labetalol with high dosages intakes should also be of concern to clinicians.

Continuous hydrodynamic mixing weakens the dominance of Microcystis: evidences from microcosm and lab experiments.

Hydrodynamic mixing is one of the important environment factors in determining phytoplankton community compositions. Here the influences of continuous hydrodynamic mixing on abundance, morphology, and dominance of Microcystis were investigated in microcosm and lab experiments. Our research results showed that Cyanophyta contributed 57.16% to the total biomass in control, but Chlorophyta was the dominant group in continuous hydrodynamic mixing (CHM) group, contributing 76.54% to the total biomass in the microcosm experiment. The average number of Microcystis in control was 1.95 folds in CHM group. However, the mean abundance of Scenedesmus quadricauda and Pseudanabaena limnetica in CHM was 2.47 and 2.97 folds in control. In the lab experiment, the average number of Microcystis flos-aquae in control was 2.97 folds in CHM group. The mean size of M. flos-aquae colony in control (34.65 µm) group were significantly bigger than that in the CHM (26.78 µm) group. This research results demonstrated that continuous hydrodynamic mixing weakened the dominance of Microcystis, but was beneficial for the others algae (S. quadricauda and P. limnetica) and is helpful in understanding the effect of hydrodynamic mixing on Microcystis blooms in freshwater ecosystem.

Exploring the Role of Epicardial Adipose Tissue in Coronary Artery Disease From the Difference of Gene Expression.

OBJECTIVES: Epicardial adipose tissue (EAT) is closely adjacent to the coronary arteries and myocardium, its role as an endocrine organ to affect the pathophysiological processes of the coronary arteries and myocardium has been increasingly recognized. However, the specific gene expression profiles of EAT in coronary artery disease (CAD) has not been well characterized. Our aim was to investigate the role of EAT in CAD at the gene level. METHODS: Here, we compared the histological and gene expression difference of EAT between CAD and non-CAD. We investigated the gene expression profiles in the EAT of patients with CAD through the high-throughput RNA sequencing. We performed bioinformatics analysis such as functional enrichment analysis and protein-protein interaction network construction to obtain and verify the hub differentially expressed genes (DEGs) in the EAT of CAD. RESULTS: Our results showed that the size of epicardial adipocytes in the CAD group was larger than in the control group. Our findings on the EAT gene expression profiles of CAD showed a total of 747 DEGs (fold change >2, p value <0.05). The enrichment analysis of DEGs showed that more pro-inflammatory and immunological genes and pathways were involved in CAD. Ten hub DEGs (GNG3, MCHR1, BDKRB1, MCHR2, CXCL8, CXCR5, CCR8, CCL4L1, TAS2R10, and TAS2R41) were identified. CONCLUSION: Epicardial adipose tissue in CAD shows unique gene expression profiles and may act as key regulators in the CAD pathological process.

lncRNA expression profiles and associated ceRNA network analyses in epicardial adipose tissue of patients with coronary artery disease.

Epicardial adipose tissue (EAT) contributes to the pathophysiological process of coronary artery disease (CAD). The expression profiles of long non-coding RNAs (lncRNA) in EAT of patients with CAD have not been well characterized. We conducted high-throughput RNA sequencing to analyze the expression profiles of lncRNA in EAT of patients with CAD compared to patients without CAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were executed to investigate the principal functions of the significantly dysregulated mRNAs. We confirmed a dysregulated intergenic lncRNA (lincRNA) (LINC00968) by real-time quantitative PCR (RT-qPCR). Subsequently, we constructed a ceRNA network associated with LINC00968, which included 49 mRNAs. Compared with the control group, lncRNAs and genes of EAT in CAD were characterized as metabolic active and pro-inflammatory profiles. The sequencing analysis detected 2539 known and 1719 novel lncRNAs. Then, we depicted both lncRNA and gene signatures of EAT in CAD, featuring dysregulation of genes involved in metabolism, nuclear receptor transcriptional activity, antigen presentation, chemokine signaling, and inflammation. Finally, we identified a ceRNA network as candidate modulator in EAT and its potential role in CAD. We showed the expression profiles of specific EAT lncRNA and mRNA in CAD, and a selected non-coding associated ceRNA regulatory network, which taken together, may contribute to a better understanding of CAD mechanism and provide potential therapeutic targets.Trial registration Chinese Clinical Trial Registry, No. ChiCTR1900024782.

Intermittent disturbance benefits colony size, biomass and dominance of Microcystis in Lake Taihu under field simulation condition.

Wind-driven wave disturbance is one of the environmental factors that shapes the formation of Microcystis blooms. Here we present data on the effect of different disturbance modes (continuous vs intermittent disturbances) on colony size, biomass and dominance of Microcystis in Lake Taihu under field conditions. Small submersible pumps were used to simulate different disturbance modes at turbulent dissipation rate (ε) of 2.98 × 10-6 m2 s-3. Our results show that the mean colony sizes of Microcystis in intermittent and continuous disturbance group were 1.94 and 1.23 times that of the control group, respectively. The mean densities of Microcystis in intermittent and continuous disturbance group were 4.23 and 2.91 times that of the control group, respectively. The mean proportion of Microcystis to total algae abundance in control group and continuous disturbance group changed from 78.3% at beginning of the experiment to 4.5% and 9.1% at the end of the experiment. However, the proportion of Microcystis to total algae cells in intermittent disturbance group was 65.7-94.3% during the whole experiment. The results demonstrated intermittent disturbances favored colony morphology, biomass and dominance of Microcystis. Our results suggested that intermittent disturbance benefited the formation of Microcystis bloom and was important in the development of predictive models for toxic cyanobacterial blooms under changing climates in shallow lakes.

Exploring the Risk Factors for the Misdiagnosis of Osteonecrosis of Femoral Head: A Case-Control Study.

OBJECTIVE: The purpose of the present study was to evaluate the present situation and risk factors for the misdiagnosis of osteonecrosis of femoral head (ONFH), providing the basis for accurate diagnosis of ONFH. METHODS: For this retrospective study, 1471 patients with ONFH were selected from the China Osteonecrosis of Femoral Head Database (CONFHD). These patients had been recruited between July 2016 and December 2018. According to whether or not they were misdiagnosed, the patients were divided into two groups, with 1168 cases (22-84 years old) included in the diagnosis group and 303 cases (21-80 years old) in the misdiagnosis group. Misdiagnosis was measured using the following criteria: (i) the patient had the same symptoms and signs, and the second diagnosis was not consistent with the initial diagnosis within 6 months; and (ii) the patient was admitted to a hospital participating in CONFHD and the previous diagnosis was inconsistent with the diagnosis given by the expert group. Comparisons of age, visual analogue scale for pain, and body mass index between the two groups were performed using a t-test. Gender, causes of ONFH, primary diseases requiring corticosteroids, methods of corticosteroid use, corticosteroid species, type of trauma, onset side of the disease, pain side, whether symptoms are hidden, and type of imaging examination at the initial visit were compared using the χ2 -test. Years of alcohol consumption, weekly alcohol consumption, and physician title at the initial visit were compared using a Mann-Whitney U-test. Furthermore, the statistically significant factors were evaluated using multiple regression analysis to investigate the risk factors of misdiagnosis. RESULTS: A total of 303 patients (20.6%) were misdiagnosed: 118 cases were misdiagnosed as lumbar disc herniation, 86 cases as hip synovitis, 48 cases as hip osteoarthritis, 32 cases as rheumatoid arthritis, 11 cases as piriformis syndrome, 5 cases as sciatica, and 3 cases as soft-tissue injury. Whether symptoms are hidden (P = 0.038, odds ratio [OR] = 1.546, 95% confidence interval [CI] = 1.025-2.332), physician title at the initial visit (P < 0.001, OR = 3.324, 95% CI = 1.850-5.972), X-ray examination (P < 0.001, OR = 4.742, 95% CI = 3.159-7.118), corticosteroids (P < 0.001, OR = 0.295, 95% CI = 0.163-0.534), alcohol (P < 0.001, OR = 0.305, 95% CI = 0.171-0.546), and magnetic resonance imaging (MRI) examination (P = 0.042, OR = 0.649, 95% CI = 0.427-0.985) were each found to be associated with misdiagnosis. CONCLUSION: Osteonecrosis of the femoral head is easily misdiagnosed as lumbar disc herniation, hip synovitis, hip osteoarthritis, and rheumatoid arthritis. Patient history of corticosteroid use or alcohol abuse and MRI examination at the initial diagnosis may be protective factors for misdiagnosis. Hidden symptoms, physician title at the initial visit (as attending doctor or resident doctor), and only X-ray examination at the initial diagnosis may be risk factors for misdiagnosis.

Imaging findings of Bowen's disease: A comparison between ultrasound biomicroscopy and conventional high-frequency ultrasound.

OBJECTIVES: To compare the imaging findings of Bowen's disease (BD) between ultrasound biomicroscopy (UBM) and conventional high-frequency ultrasound (HFUS). METHODS: A total of 29 pathologically proven BD lesions in 28 patients were retrospectively enrolled in the study, and all were after surgery. All the lesions were imaged with both UBM and HFUS. The imaging features on HFUS and UBM were analyzed and compared. The diagnostic results of ultrasound for BD were referenced with pathology results. RESULTS: All the 29 (100%) BD lesions appeared hypoechogenicity, solid component, and superficial hyperechoic layer (ie, keratinization) on both UBM and HFUS. The typical imaging feature of BD lesions, that was, infiltration depth confined to the epidermis, was visualized in 25 (86.2%, 25/29) lesions on UBM whereas 15 (51.7%, 15/29) on HFUS (P = .002). A "wave sign," which corresponds to the surface keratinization of BD lesion, was visualized in 17 (58.6%, 17/29) of BD lesions on UBM whereas 6 (20.7%, 6/29) on HFUS (P = .001). UBM and HFUS correctly diagnosed 25 (86.2%, 25/29) and 15 (51.7%, 15/29) BD lesions, respectively (P = .002). CONCLUSIONS: Bowen's disease has some typical imaging features on US. The "wave sign" of the superficial hyperechoic layer and the clear borderline between the tumor in epidermis and the slightly hyperechoic dermis layer are better depicted by UBM in comparison with HFUS, which leads to a more accurate diagnosis of BD. UBM has potential to be used as a diagnostic tool for characterization of BD on account of its high resolution.

Relationships between Morphological Changes of Lower Limbs and Gender During Medial Compartment Knee Osteoarthritis.

OBJECTIVES: To evaluate the dynamic changes of key morphology indicators of the lower extremities in the coronal plane with progressing medial compartment knee osteoarthritis (KOA) with an emphasis on gender-dependent regional differences. METHODS: The radiographs of patients with non-traumatic knee pain and varying degrees of genu varus were reviewed. Radiographs were studied in 1538 lower limbs of 883 consecutive patients who visited our hospital from January to July 2017; all patients had long-standing anteroposterior image-splicing radiographs taken of their lower limbs. Morphological indicators of bones and joints that can change the alignment of lower limbs or reflect cartilage wear and soft-tissue relaxation were selected and measured with the help of picture archiving and communication systems. After comparing the data of different genders, the data of males and females was separated into three age groups, <40 years, 40-60 years, >60 years respectively, and then compared among age groups using the Kruskal-Wallis and Mann-Whitney U tests. Scatterplots of age and all the measurements were drawn to determine the strength of the relations. The Pearson correlation test was performed to reveal correlations of measurements and age. RESULTS: Femoral bowing angle (FBA) and joint line convergence angle (JLCA) have obvious differences between different genders (P = 0.001, 0.000, respectively). This suggests that females have greater femoral curvature and joint space angle than males. Significant differences were found in hip-knee-ankle angle (HKA), FBA, distal femoral valgus resection angle (DFVRA), medial proximal tibial angle (MPTA), JLCA, and minimum joint space width (min-JSW) by age groups in females (P = 0.000, 0.000, 0.000, 0.000, 0.003, 0.002, respectively). The difference of mechanical medial distal femoral angle (mMDFA) was significant with P values less than 0.05 deemed significant (P = 0.030). Significant correlations were found between age and all measurements (r = -0.166, 0.253, 0.270, -0.147, 0.089, -0.105, -0.076, respectively, P < 0.01). Whereas, the difference in min-JSW by age group was the only significant one in males (P = 0.001), and no significant correlation was found between age and measurements (r = -0.107, 0.041, 0.134, -0.067, 0.079, -0.134, -0.098, respectively, P > 0.01). CONCLUSIONS: As KOA progressed, both dynamic deformation of lower extremities and degeneration of articular cartilage could be found in females, while no obvious dynamic deformations were found in males. Dynamic deformation of lower extremities was the important feature and the major causative factor of KOA in females.

Ultrasound Biomicroscopy and High-Frequency Ultrasound for Evaluating Extramammary Paget Disease With Pathologic Correlation.

OBJECTIVES: The purpose of this study was to investigate the performance of ultrasound biomicroscopy (UBM) and high-frequency ultrasound (HFUS) in the assessment of extramammary Paget disease (EMPD) and to correlate the imaging features with pathologic findings. METHODS: In this retrospective study, we described the imaging features from UBM and HFUS based on 17 pathologically proven EMPD cases. The performance for visualizing layer involvement by UBM and HFUS was compared. Additionally, we checked the consistency between layer involvement of the lesions on UBM images and the pathologic results. Additionally, blood flow and the status of lymph nodes were investigated with HFUS. RESULTS: Ultrasound biomicroscopy revealed that all 17 lesions (100%) were hypoechoic and grew in a creeping form. The feature of layer involvement was shown in 10 lesions (58.8%) limited to the epidermis and 6 lesions (35.3%) involving the dermis, and the remaining lesion (5.9%) involved the full skin layers. Layer involvement was clearly displayed by UBM for all lesions (100%) but for only 5 lesions (29.4%) by HFUS (P < .001). Additionally, the layer involvement of 15 lesions (88.2%) on UBM was consistent with the pathologic results (κ = 0.746). High-frequency ultrasound revealed profuse blood flow in most lesions (64.7% [11 of 17]), and 1 case showed inguinal lymph node metastasis. CONCLUSIONS: Combined use of UBM and HFUS can provide key information on EMPD based on ultrasound features. Comparatively, UBM provides clearer morphologic information, whereas HFUS provides information on lymph node metastasis and blood flow.

Treatment of fingertip avulsion injuries using two periposition pedicled flaps.

We described a treatment of fingertip avulsion injury by two periposition pedicled flaps, the reversed pedicle island flap of dorsal branch of proper digital artery and the cross-finger flap. From February 2009 to January 2017, 22 patients (22 fingers) with fingertip avulsion injury were treated with two periposition pedicled flaps, 14 male and 8 female, aged from 17 to 47 years (mean 32 ± 9 years). All of the patients were followed up more than 6 months after operations (mean 9.6 ± 2.6 months). All flaps survived completely. Compared with the traditional abdominal flaps, two periposition pedicled flaps had less pedicle division time. At last follow-up, the 2PD of the palmar part of the flaps, the TAM of the injured finger and the MHQ summary score of the two periposition pedicled flaps were much better than the traditional abdominal flaps. The reconstruction using two periposition pedicled flaps is a versatile treatment with better functions, less morbidity and better aesthetics. Level of evidence: Therapeutic, level III.

In vitro neuroprotective effects of ciliary neurotrophic factor on dorsal root ganglion neurons with glutamate-induced neurotoxicity.

Ciliary neurotrophic factor has neuroprotective effects mediated through signal transducer and Janus kinase (JAK) 2/activator of transcription 3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. Whether ciliary neurotrophic factor is neuroprotective for glutamate-induced excitotoxicity of dorsal root ganglion neurons is poorly understood. In the present study, the in vitro neuroprotective effects of ciliary neurotrophic factor against glutamate-induced excitotoxicity were determined in a primary culture of dorsal root ganglion neurons from Wistar rat embryos at embryonic day 15. Whether the JAK2/STAT3 and PI3K/Akt signaling pathways were related to the protective effects of ciliary neurotrophic factor was also determined. Glutamate exposure inhibited neurite outgrowth, cell viability, and growth-associated protein 43 expression and promoted apoptotic neuronal cell death, all of which were reversed by the administration of exogenous ciliary neurotrophic factor. Additionally, preincubation with either JAK2 inhibitor AG490 or PI3K inhibitor LY294002 blocked the neuroprotective effect of ciliary neurotrophic factor. These data indicate that the two pathways JAK2/STAT3 and PI3K/Akt play major roles in mediating the in vitro neuroprotective effects of ciliary neurotrophic factor on dorsal root ganglion neurons with glutamate-induced neurotoxicity.

Protection against cerebral infarction by Withaferin A involves inhibition of neuronal apoptosis, activation of PI3K/Akt signaling pathway, and reduced intimal hyperplasia via inhibition of VSMC migration and matrix metalloproteinases.

PURPOSE: Stroke is a major public health concern with high rates of morbidity and mortality worldwide. Cerebral ischemia and infarction are commonly associated with stroke. Currently used medications, though effective, are also associated with adverse effects. Development of effective neuroprotective agents with fewer side effects would be of clinical value. We evaluated the effects of Withaferin A (WA), a steroidal lactone derived from the plant Withania somnifera, on experimentally induced cerebral infarction. MATERIALS AND METHODS: The ability of WA to inhibit neuroapoptosis and modulate vascular smooth muscle cell (VSMC) migration and PI3K/Akt signaling was assessed. Separate groups of Sprague Dawley rats were subjected to cerebral occlusion and reperfused for 24h. RESULTS: WA treatment (25, 50 or 100mg/kg bodyweight) significantly reduced the infarct area in a carotid ligation model; WA reduced intimal hyperplasia and proliferating cell nuclear antigen (PCNA)-positive cell counts. Western blotting analysis revealed significantly suppressed PI3K/Akt signaling following cerebral ischemia/reperfusion injury. WA supplementation was found to downregulate apoptotic pathway proteins. WA suppressed PTEN and enhanced p-Akt and GSK-3ß levels and elevated mTORc1, cyclinD1 and NF-κB p65 expression, suggesting activation of the PI3K/Akt pathway. In vitro studies with PDGF-stimulated A7r5 cells revealed that WA exposure severely downregulated matrix metalloproteinases (MMP)-2 and -9 and inhibited migration of A7r5 cells. Additionally, WA reduced the proliferation of A7r5 cells significantly. CONCLUSIONS: WA exerted neuroprotective effects by activating the PI3K/Akt pathway, modulating the expression of MMPs, and inhibiting the migration of VSMCs.

Acid Sphingomyelinase Mediates Oxidized-LDL Induced Apoptosis in Macrophage via Endoplasmic Reticulum Stress.

AIM: Macrophage apoptosis is a vital event in advanced atherosclerosis, and oxidized low-density lipoprotein (ox-LDL) is a major contributor to this process. Acid sphingomyelinase (ASM) and ceramide are also involved in the induction of apoptosis, particularly in macrophages. Our current study focuses on ASM and investigates its role in ox-LDL-induced macrophage apoptosis. METHODS: Human THP-1 and mouse peritoneal macrophages were cultured in vitro and treated with ox-LDL. ASM activity and ceramide levels were quantified using ultra performance liquid chromatography. Protein and mRNA levels were analyzed using Western blot analysis and quantitative real-time PCR, respectively. Cell apoptosis was determined using Hoechst staining and flow cytometry. RESULTS: Ox-LDL-induced macrophage apoptosis was triggered by profound endoplasmic reticulum (ER) stress, leading to an upregulation of ASM activity and ceramide levels at an early stage. ASM was inhibited by siRNA or desipramine (DES), and/or ceramide was degraded by recombinant acid ceramidase (AC). These events attenuated the effect of ox-LDL on ER stress. In contrast, recombinant ASM upregulated ceramide and ER stress. ASM siRNA, DES, recombinant AC, and ER stress inhibitor 4-phenylbutyric acid were blocked by elevated levels of C/EBP homologous protein (CHOP); ox-LDL induced elevated levels of CHOP. These events attenuated macrophage apoptosis. CONCLUSION: These results indicate that ASM/ceramide signaling pathway is involved in ox-LDL-induced macrophage apoptosis via ER stress pathway.

Carbapenemase-Producing Enterobacteriaceae in Yunnan Province, China.

Among 144 carbapenem-resistant Enterobacteriaceae strains isolated from 4 hospitals in Yunnan province, 113 were identified as carbapenemase-producing Enterobacteriaceae (CPE). BlaKPC-2 (99/113, 87.6%) was the most common carbapenemase gene and Klebsiella pneumoniae (100/113, 88.5%) was the most common species. BlaNDM-1 (11/113, 9.7%), blaIMP-4 (10/113, 8.8%), and blaIMP-1 (1/113, 0.9%) genes were also detected. Extended-spectrum ß-lactamase genes were common in CPE, and the SHV- and CTX-M-types were predominant.

CGRP 8-37 enhances lipopolysaccharide-induced acute lung injury and regulating aquaporin 1 and 5 expressions in rats.

Calcitonin gene-related peptide (CGRP) has been shown to play important roles in biological functions. However, there is very little evidence on the value of CGRP in lipopolysaccharide (LPS)-induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate the role of CGRP in LPS-induced ALI in rats. In the experiment, Sprague-Dawley (SD) rats were randomized into control, an antagonist of α-calcitonin gene-related peptide receptor (CGRP8-37), LPS groups, and CGRP8-37 + LPS groups. ALI model was prepared through retrograde injection of LPS (10 mg/kg). At 6 and 12 h, bronchoalveolar lavage was performed and used to assess total cell count and levels of tumor necrosis factor-α, interleukin-1ß, -6, and -10 by enzyme-linked immunosorbent assay (ELISA). Lung tissue was collected for assessing wet-to-dry (W/D) ratio, hematoxylin and eosin staining. Aquaporin (AQP)-1 and -5 expressions in lung tissues were detected by quantitative PCR and Western blot. The results showed that histological injury, total cell count, and W/D ratio significantly reduced in LPS group after 6 h. The levels of inflammatory cytokines in CGRP8-37 + LPS-treated rats were higher than that in LPS-treated rats (all, P < 0.001). Real-time RT-PCR analysis showed that levels of AQP-1 in rats from CGRP8-37 + LPS group was lower than that in LPS-treated rats (P = 0.005 and P < 0.001). Western blotting analysis showed that AQP-1 protein levels at 6 h significantly decreased in CGRP8-37 + LPS rats. Together, our data suggest that CGRP antagonists, CGRP8-37 could enhance ALI induced by LPS in the rat model, and regulate the expression levels of AQP-1 and AQP-5 by affecting inflammatory cytokines. Thereby, regulating endogenous CGRP may be a potential treatment for ALI/ARDS.

Antimicrobial resistance surveillance of Salmonella isolates from the First People's Hospital of Yunnan Province, China.

INTRODUCTION: Typhoid fever is a common disease in Yunnan province; however, the resistant phenotype and epidemic characteristics of Salmonella in this area are still unclear. In this study, a 15-year surveillance of antimicrobial susceptibility of Salmonella is reported. METHODOLOGY: From January 1999 to December 2013, Salmonella isolates were recovered from patients in the First People's Hospital of Yunnan Province. Antimicrobial susceptibility was detected and data were analyzed using WHONET5.6. RESULTS: A total of 845 Salmonella isolates were recovered between 1999 and 2013. The most frequently isolated Salmonella serovar was S. Paratyphi A (93%), and 75.1% (635/845) of the isolates were from the young and middle-aged population. The resistance rates of Salmonella spp. to ciprofloxacin, ampicillin, and ceftriaxone increased dramatically during the 15 years. Carbapenems retained the highest and most stable activity against isolates. The resistance rates of all Salmonella isolates to chloramphenicol and sulfamethoxazole were 0.4% (3/845) and 1.8% (15/845), respectively. CONCLUSIONS: As Salmonella isolates have been observed to be resistant to first-line antibiotics, antimicrobial agents should be used rationally and prescriptions should be based on case-by-case susceptibility testing.