Comparison of percutaneous nephrolithotomy and flexible ureterorenoscopy in the treatment of single upper ureteral calculi measuring 1 to 2 centimeters: a retrospective study.

PURPOSE: To compare the efficacy and safety of micropercutaneous nephrolithotomy (MPCNL) and flexible ureteroscopy (FURS) in the treatment of single upper ureteral calculi measuring 1 to 2 centimeters. METHODS: This study is a retrospective analysis that combines a review of medical records with an outcomes management database. A total of 163 patients who underwent MPCNL and 137 patients who had FURS were identified between January 2017 and December 2021. Demographic data, operation time, hospitalization time, stone-free rate, and complication rate were collected and analyzed. RESULTS: Preoperative general data of sex, age, BMI, serum creatinine, time of stone existence, stone hardness, stone diameter, preoperative hydronephrosis, and preoperative infection of the MPCNL group have no statistically significant difference with that of the FURS group. All MPCNL or FURS operations in both groups were successfully completed without any instances of reoperation or conversion to another surgical procedure. Patients who underwent MPCNL had a considerably reduced operation time (49.6 vs. 72.4 min; P<0.001), but a higher duration of hospitalization (9.1 vs. 3.9 days; P<0.001) compared to those who underwent FURS. The stone-free rate in the MPCNL group was superior to that of the FURS group, with a percentage of 90.8% compared to 71.5% (P<0.001). There was no statistically significant disparity in the rate of complications between the two groups (13.5% vs. 15.3%; P = 0.741). CONCLUSION: Both MPCNL and FURS are viable and secure surgical choices for individuals with solitary upper ureteral calculi measuring 1 to 2 cm. The FURS procedure resulted in a shorter duration of hospitalization compared to MPCNL. However, it had a comparatively lower rate of successfully removing the stones and required a longer duration for the operation.There were no substantial disparities observed in the complication rate between the two groups.FURS is the preferable option for treating uncomplicated upper ureteral calculi, whereas MPCNL is the preferable option for treating complicated upper ureteral calculi.Prior to making treatment options, it is crucial to take into account the expertise of surgeons, the quality of the equipment, and the preferences of the patient. TRIAL REGISTRATION: No.

Reducing complications of femoral neck fracture management: a retrospective study on the application of multidisciplinary team.

BACKGROUND: Femoral neck fractures are associated with substantial morbidity and mortality for older adults. Multi-system medical diseases and complications can lead to long-term care needs, functional decline and death, so patients sustaining hip fractures usually have comorbid conditions that may benefit from application of multidisciplinary team(MDT). METHODS: This is a retrospective cohort study that incorporates medical record review with an outcomes management database. 199 patients were included who had surgery for a new unilateral femoral neck fracture from January 2018 to December 2021 (96 patients in usual care (UC) model and 103 patients in MDT model. High-energy, pathological, old and periprosthetic femoral neck fracture were excluded. Age, gender, comorbidity status, time to surgery, and postoperative complication, length of stay, in-hospital mortality, 30-day readmission rate, 90-day mortality data were collected and analyzed. RESULTS: Preoperative general data of sex, age, community dwelling and charlson comorbidity score of MDT group (n = 103) have no statistically significant difference with that of usual care (UC) group. Patients treated in the MDT model had significantly shorter times to surgery (38.5 vs. 73.4 h;P = 0.028) and lower lengths of stay (11.5 vs. 15.2 days;P = 0.031). There were no significant differences between two models in In-hospital mortality (1.0% vs. 2.1%; P = 0.273), 30-day readmission rate (7.8% vs. 11.5%; P = 0.352) and 90-day mortality (2.9% vs. 3.1%; P = 0.782). The MDT model had fewer complications overall (16.5% vs. 31.3%; P = 0.039), with significantly lower risks of delirium, postoperative infection, bleeding, cardiac complication, hypoxia, and thromboembolism. CONCLUSION: Application of MDT can provide standardized protocols and a total quality management approach, leading to fewer complications for elderly patients with femoral neck fracture. TRIAL REGISTRATION: No.

Total hip arthroplasty versus hemiarthroplasty in the treatment of active elderly patients over 75 years with displaced femoral neck fractures: a retrospective study.

BACKGROUND: Femoral neck fractures are associated with substantial morbidity and mortality for older adults. Total hip arthroplasty (THA) and hemiarthroplasty (HA) are widely used in elderly patients with displaced femoral neck fractures (DFNF), but there is still controversy refering to the optimal chose for the management of DFNF in active elderly patients. METHODS: This is a retrospective cohort study that incorporates medical record review with an outcomes management database. 73 patients who underwent HA and 66 patients who underwent THA were identified from January 2015 to December 2017. Data of age, gender, BMI, comorbidity status, operation time, blood loss, hospitalization time, in-hospital complication were collected and analyzed. Clinical follow-up and radiographic examinations were performed at approximately five years, and hip complications, Harris Hip Score (HHS) and EuroQol-5 Dimensions (EQ-5D) were assessed. RESULTS: Preoperative general data of sex, age, BMI and charlson comorbidity score of THA group(n=55) has no statistically significant difference with that of HA group. Patients treated by THA had significantly longer operation time (105.5 vs 76.7 minutes; P < 0.001), more blood loss (524.1 vs 350.1 ml; P < 0.001) and longer hospitalization time (15.8 vs 13.8 days; P < 0.001). There was no significant differences between two groups in complications (32.7% vs 25.8%, P=0.432). No patients died during the hospitalization. After five years, only 33 patients in the THA group and 34 patents in the HA group were still alive, and the fraction surviving were not statistically significant between two groups (60.0% vs 54.8%, P> 0.05). The differences in hip function in favor of THA appeared to increase after the five-year follow-up, and the difference was significant in terms of the total Harris hip score (81.3 vs 73.1, P < 0.001) as well as in the dimensions of pain (38.9 vs 35.9, P=0.033), function (33.7 vs 29.2, P=0.001), absence of deformity (4.0 vs 3.9, P=0.023) and range of motion (4.6 vs 4.2, P=0.008). There was no significant differences between groups in hip dislocation rate (6.1% vs 0.0%, P=0.239). The erosion rate of hip joint in the THA group was significantly lower than that of the HA group (0.0% vs 26.5%, P=0.002). The health-related quality of life, according to EQ-5D index score, was found to be higher (0.69 vs 0.63, P= 0.001) in the THA group than the HA group after five years. CONCLUSION: THA may be a preferred management option for active elderly patients over 75 years. The more extensive surgery of THA is not associated with higher in-hospital complication rate or mortality rate. These patients can benefit from THA in terms of hip function and quality of life. TRIAL REGISTRATION: No.

TLR2 agonist Pam3CSK4 enhances the antibacterial functions of GM-CSF induced neutrophils to methicillin-resistant Staphylococcus aureus.

A proliferation of studies have demonstrated that the toll-like receptor 2 (TLR2) pathway affects the chemotaxis, phagocytosis, and cytokine release of neutrophils when pathogens invade. Our previous studies have demonstrated that pretreatment with high doses of Pam3CSK4 (>25 µg/ml) improves the antimicrobial activity of neutrophils, however, short-lived neutrophils limit their therapeutic functions. Here, we used granulocyte macrophage-colony stimulating factor (GM-CSF) to generate neutrophils from murine bone marrow, and assessed their effect on the immune response against methicillin-resistant Staphylococcus aureus. As comparing with classical method of generating neutrophils directly from murine bone marrow, our findings show that pretreatment with Pam3CSK4 enhanced the phagocytic and killing activities against MRSA by the GM-CSF induced neutrophils (GM-CSF neutrophils). Chemotaxis of GM-CSF induced neutrophils was significantly increased after the pretreatment with Pam3CSK4. Furthermore, Pam3CSK4 pretreatment enhanced iNOS, CRAMP, TNF-α, IL-1ß, IL-10, and IL-6 expression. Finally, we observed that p38MAPK and Akt phosphorylation kinases were increased significantly in GM-CSF neutrophils pretreatment with Pam3CSK4 in a dose- and time-dependent manner, whereas p38MAPK inhibitor (SB2021190) and PI3K inhibitor (LY294002) attenuated the antimicrobial activities including phagocytosis, killing activity, respiratory burst, and the release of lactoferrin(LTF) by the GM-CSF induced neutrophils. Together, these findings suggest that pretreatment with Pam3CSK4 enhances the antibacterial function of GM-CSF neutrophils against MRSA, and this could be related to the p38MAPK and PI3K signaling pathways.

The application of response surface methodology in studying the effect of heat and high hydrostatic pressure on anthocyanins, polyphenol oxidase, and peroxidase of mulberry (Morus nigra) juice.

BACKGROUND: Mulberry juice is an excellent source of phytochemicals with medicinal properties. The effects of four independent variables (temperature, heating time, pressure, and pressurising time) on three response variables [% anthocyanin retained, and % residual activities of the enzymes polyphenol oxidase (PPO), and peroxidase (POD)] of mulberry juice were studied using response surface methodology. Mathematical models and optimum levels of the response variables were generated. RESULTS: Temperature had the greatest effect on all the response variables. The synergistic effect of temperature and pressure had significant effect (P < 0.05) on anthocyanin retained and residual PPO activity. The prediction of the desirability model, based on 95% confidence in the range of the independent variables, gave optimal treatment conditions of 83.39°C, 2.38 min, 480.00 MPa, and 21.67 min, respectively for temperature, heating time, pressure, and pressurising time. At these levels, the corresponding response variables were 91.68%, 44.69% and 20.17% for the amounts of anthocyanin retained, and residual activities of PPO and POD, respectively. The desirability index obtained was 0.741. CONCLUSION: The results were desirable and the mathematical models developed could be used to predict the outcome of the response variables to a high degree of accuracy.

Heuristic data-driven anchor generation for UAV-based maritime rescue image object detection.

The specificity of scenarios and tasks in Unmanned Aerial Vehicles (UAV)-based maritime rescue poses challenges for detecting targets within images captured by drones in such environments. This study focuses on leveraging heuristic methods to extract data features from specific UAV maritime rescue images to optimize the generation of anchor boxes in detection models. Experiments conducted on the large-scale SeaDronesSee maritime rescue dataset, using the MMDetection object detection framework, demonstrated that the optimized anchor boxes, improved model performance by 48.9% to 62.8% compared to the framework's default configuration, with the most proficient model surpassing the official highest SeaDronesSee baseline by over 49.3%. Further analysis of the results revealed the variation in detection difficulty for different objects within the dataset and identified the reasons behind these differences. The methodology and analysis presented in this study hold promise for optimizing UAV-based maritime rescue object detection models as well as refining data analysis and enhancement.

Modular YOLOv8 optimization for real-time UAV maritime rescue object detection.

The task of UAV-based maritime rescue object detection faces two significant challenges: accuracy and real-time performance. The YOLO series models, known for their streamlined and fast performance, offer promising solutions for this task. However, existing YOLO-based UAV maritime rescue object detection methods tend to prioritize high accuracy, often at the expense of real-time performance and ease of implementation and expansion. This study proposes a modular plug-and-play optimization approach based on the YOLOv8 framework, aiming to enhance real-time performance while maintaining high accuracy for UAV maritime rescue object detection. The proposed optimization modules are flexible, easy to implement, and extendable. In experiments on the large-scale publicly available SeaDronesSee dataset, our method achieved a 13.53% improvement in accuracy over YOLOv8x while reducing computational cost by 85.63%. Additionally, it surpassed the detection speed of the SeaDronesSee official code's two-stage detector by over 20 times, while maintaining comparable accuracy. Furthermore, our analysis of the experimental results highlights differences in detection difficulty among various objects and potential biases within the dataset.

Comparative complications of prepectoral versus subpectoral breast reconstruction in patients with breast cancer: a meta-analysis.

Introduction: This meta-analysis aims to evaluate the complications associated with prepectoral breast reconstruction (PBR) compared to subpectoral breast reconstruction (SBR) in patients diagnosed with breast cancer. Materials and methods: A comprehensive search was performed in four databases, including Medline, Embase, Web of Science and CENTRAL, to collect literature published up until December 31, 2024. In addition, we conducted a thorough manual examination of the bibliographies of the identified papers, as well as pertinent reviews and meta-analyses. We conducted a search on three clinical trial registries, namely ClinicalTrials.gov, Controlled-trials.com, and Umin.ac.jp/ctr/index.htm. Meta-analyses were conducted on total complications, hematoma, infection, wound healing issues, necrosis, capsular contracture, rippling, animation deformity, and reoperation. Results: A total of 40 studies were included in the meta-analysis. Compared with SBR, PBR significantly reduced the incidence of animated malformations (OR=0.37, 95% CI: 0.19 to 0.70, P=0.003, I ²=12%), but increased the incidence of ripples (OR=2.39, 95% CI: 1.53 to 3.72, P=0.0001, I ²=10%) and seroma (OR=1.55, 95% CI: 1.02 to 2.35, P=0.04, increasing I ²=70%). Conclusions: Our findings indicate that PBR and SBR have comparable safety profiles, with similar total complication rates. Specifically, PBR is more likely to cause rippling and seroma, whereas SBR is more prone to causing animation deformity. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024565837, identifier CRD42024565837.

Age-related changes of node degree in the multiple-demand network predict fluid intelligence.

Fluid intelligence is an individual's innate ability to cope with complex situations and is gradually reduced across adults aging. The realization of fluid intelligence requires the simultaneous activity of multiple brain regions and depends on the structural connection of distributed brain regions. Uncovering the structural features of brain connections associated with fluid intelligence decline will provide reference for the development of intervention and treatment programs for cognitive decline. Using structural magnetic resonance imaging data of 454 healthy participants (18-87 years) from the Cam-CAN dataset, we constructed structural similarity network for each participant and calculated the node degree. Spearman correlation analysis showed that age was positively correlated with degree centrality in the cingulate cortex, left insula and subcortical regions, while negatively correlated with that in the orbito-frontal cortex, right middle temporal and precentral regions. Partial least squares (PLS) regression showed that the first PLS components explained 32 % (second PLS component: 20 %, p perm < 0.001) of the variance in fluid intelligence. Additionally, the degree centralities of anterior insula, supplementary motor area, prefrontal, orbito-frontal and anterior cingulate cortices, which are critical nodes of the multiple-demand network (MDN), were linked to fluid intelligence. Increased degree centrality in anterior cingulate cortex and left insula partially mediated age-related decline in fluid intelligence. Collectively, these findings suggest that the structural stability of MDN might contribute to the maintenance of fluid intelligence.

Effects of IL-6R Expression on IL-6/STAT3/HIF-1α Signaling Pathway in a Mouse Model of Parkinson's Disease with Type 2 Diabetes Co-Morbidity.

BACKGROUND: More and more evidence has shown the process of Parkinson's disease (PD). Probably, inflammation exerts a crucial role between them. Therefore, the aim of this study was to analyze the impact of interleukin-6 receptor (IL-6R) expression on the IL-6/signal transducer and activator of transcription 3 (STAT3)/hypoxia-inducible factor-1α (HIF-1α) inflammatory signaling pathway within a mouse model of PD with type 2 diabetes mellitus (T2DM) as co-morbidity. METHODS: We chose healthy wild-type C57BL/6J male mice at the age of 10 weeks to prepare a mouse model of PD with T2DM co-morbidity. Adeno-associated virus (AAV) overexpressing IL-6R or AAV IL-6R-shRNA genes were injected into the substantia nigra (SN) of the mice. The behavioral indices of the pole test were used for examining the motor function of the mice. Using immunofluorescence analysis, the impacts of IL-6R on the level of tyrosine hydroxylase (TH) and anti-ionized calcium-binding adaptor molecule 1 (IBA-1) on dopaminergic neurons and microglia were examined. Additionally, enzyme-linked immunosorbent assay (ELISA) was adopted for determining the expressions of HIF-1α and inflammatory cytokines like tumor necrosis factor-α (TNF-α), IL-1ß, IL-6, and IL-4 in the serum. In this study, the protein expression levels of TH, α-Synuclein (α-Syn), IBA-1, IL-6, IL-6R, phosphorylated and total signal transducer and activator of transcription 3 (p-STAT3 (Tyr705) and STAT3) and HIF-1α in the SN were tested via western blotting. To ascertain the mRNA expressions of TNF-α, IL-1ß, IL-6, IL-4, and HIF-1α, we used quantitative Real-Time Polymerase Chain Reaction (RT-qPCR). RESULTS: IL-6R-shRNA treatment could markedly shorten the total time of PD in the T2DM co-morbidity mouse model based on the pole test results, reverse the decrease in TH-positive neurons stimulated by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), and lower the activation of microglia (all p < 0.05). Further, IL-6R-shRNA treatment hindered the expression of IL-6, p-STAT3 (Tyr705), and HIF-1α in the SN, lowered the levels of TNF-α, IL-1ß, IL-6, IL-4, and HIF-1α in the serum, and mRNA expressions of TNF-α, IL-1ß, IL-6, and HIF-1α in the SN (all p < 0.05). In contrast, IL-6R overexpression reduced TH levels, upregulated the level of IBA-1, IL-6, p-STAT3 (Tyr705), and HIF-1α, increased the level of IL-1ß, TNF-α, IL-6, IL-4, and HIF-1α (all p < 0.05) in the serum and SN in the PD mouse model with T2DM as a co-morbidity. CONCLUSIONS: PD progression with T2DM as a co-morbidity can be boosted by AAV IL-6R-overexpression through upregulation of the IL-6/STAT3/HIF-1α axis. Conversely, AAV IL-6R-shRNA treatment suppressed the IL-6/STAT3/HIF-1α pathway and alleviated neuroinflammation, thus weakening the development of PD with T2DM as a co-morbidity.

Efficacy and safety of anti-interleukin-1 therapeutics in the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to evaluate the efficacy and safety of anti-interleukin-1 therapeutics, including IL-1 antibodies, interleukin-1 receptor antagonists (IL-1 Ras) and IL-1 inhibitors, for knee osteoarthritis (KOA) treatment. METHODS: Databases (Medline, Embase, Web of Science and CENTRAL) and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) of anti-interleukin-1 therapeutics from inception to August 31, 2022. The outcomes were the mean change in pain and function scores and the risk of adverse effects (AEs). RESULTS: In the 12 studies included, anti-interleukin-1 therapeutics were superior to placebo in terms of pain relief (standardized mean difference [SMD] = - 0.38, 95% confidence interval [CI] = - 1.82 to - 0.40, p < 0.001, I2 = 77%) and functional improvement (SMD = - 1.11, 95% CI = - 1.82 to - 0.40, p = 0.002, I2 = 96%). The incidence of any AE (risk ratio [RR] = 1.02, 95% CI = 0.88-1.18, p < 0.001, I2 = 76%) was higher following treatment with anti-interleukin-1 therapeutics than placebo, while no significant difference was found in the incidence of serious AEs (SAEs) or discontinuations due to AEs. Subgroup analyses showed that IL-1 antibodies and the IL-1 inhibitor provided pain relief (IL-1 antibodies: SMD = - 0.61, 95% CI = - 0.92 to - 0.31, p < 0.001; IL-1 inhibitor: SMD = - 0.39, 95% CI = - 0.72 to - 0.06, p = 0.02, I2 = 74.0%) and functional improvement (IL-1 antibodies: SMD = - 1.75, 95% CI = - 2.10 to - 1.40, p < 0.001; IL-1 inhibitor: SMD = - 0.28, 95% CI = - 0.83 to 0.27, p = 0.31, I2 = 88%) superior to those of placebo, whereas IL-1 Ras did not. However, the IL-1 inhibitor increased the incidence of any AE (RR = 1.35, 95% CI = 0.92-1.98, p < 0.001, I2 = 85%) but not the risk of SAEs or discontinuations due to AEs. IL-1 antibodies and IL-1 Ras showed no difference in safety compared with placebo. CONCLUSIONS: Anti-interleukin-1 therapeutics could relieve OA-related pain and improve function, but is probably associated with an increased risk of adverse events. Specially, IL-1 antibodies and an IL-1 inhibitor could relieve OA-related pain and improve function, whereas IL-1 Ras could not. IL-1 antibodies and IL-1 Ras were relatively safe options, but IL-1 inhibitors were associated with safety concerns.

Direct comparison of circulating tumor DNA sequencing assays with targeted large gene panels.

Next generation sequencing (NGS) assays with large targeted gene panels can comprehensively profile cancer somatic mutations in a tumor sample. Given the rapid adoption of such assays for circulating tumor DNA (ctDNA) analysis in clinical oncology, it is essential for the community to understand their analytical performance in liquid biopsy settings. Here, we directly compared five ctDNA NGS assays, most of which having a panel of 400 or more genes, with simulated samples harboring mutations relevant to solid tumors or myeloid malignancy. Our results indicate that the detection sensitivity and reproducibility of all five assays was 90% or higher when the mutations were at 0.5% or 1.0% allele frequency, and with optimal DNA input of 30 ng or 50 ng per vendor's protocol. The performances decreased and varied dramatically, when mutations were at a 0.1% allele frequency and/or when a lower genomic input of 10 ng DNA was used. Interestingly, one of the assays repeatedly showed higher rate of false positivity than the others across two different sample sets. Multiple intrinsic technical factors pertaining to the NGS assays were further investigated. Notable differences among the assays were seen for depth of coverage and background noise, which profoundly impacted assay performance. The results derived from this study are highly informative and provide a framework to assess and select suitable assays for specific application in cancer monitoring and potential clinical use.

Quantum correlation of qubit-reservoir system in dissipative environments.

In this work, the dynamics of quantum correlation (QC) in terms of geometric discord and its transfer coupled with dissipative reservoirs are investigated. Taken two canonical cases where the qubits of interest are initially prepared in extended Werner-like state and W-like states into account, we specifically reveal the dynamical behaviors of the geometric discord as each qubit locally interacts with its surrounding infinite degree-of-freedom reservoir. In the scenarios, the short-term and long-term dynamics of the geometric discord for the qubit- and reservoir-subsystem as well as its transfers between them are observed detailedly. It turns out that the geometric discord of qubit-subsystem decays asymptotically to zero while the counterpart of reservoir-subsystem can revive from time t = 0 to steady value, which sheds light on a transfer of the discord from the qubit-subsystem to the corresponding reservoir-subsystem.

[Protective effect of pretreatment with TLR2 agonist Pam3Csk4 on mice challenged by methicillin-resistant Staphylococcus aureus].

OBJECTIVE: To evaluate the protective effect of pretreatment with Pam3Csk4, a Toll-like receptor 2 (TLR2) agonist, on mice against methicillin-resistant Staphylococcus aureus (MRSA) infection. METHODS: Kunming mice were injected with Pam3Csk4 (25, 50, 100 µg/mice) via tail vein. 12 and 24 hours later, the mice were inoculated with live MRSA (7×10(10) CFU/kg, ATCC43300) via tail vein. All mice were observed at 2-hour intervals for the first 24 hours and 6-hour intervals for the rest time, and survival was monitored for at least 7 days. Bacterial burden in liver, spleen and kidney of the mice were estimated by colony counting on nutrient agar 6 hours after infection (3×10(8) CFU/mice, ATCC43300). In addition, 6, 12 and 24 hours after MRSA challenge, the concentrations of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interferon γ (IFN-γ) and IL-10 were measured by ELISA, and the mRNA levels of these cytokines were detected by fluorescence quantitative PCR (qPCR). Finally, 24 hours after being pretreated with Pam3Csk4, mRNA levels of CXC chemokine ligand 1 (CXCL1) and Fcγ receptor III (FcγRIII) in spleen of the mice were evaluated by qPCR. RESULTS: Compared with normal saline-pretreated mice, we found that mice pretreated with the Pam3Csk4 (100 µg/mice) had higher survival in sepsis models caused by MRSA in dose- and time-dependent manners, and Pam3Csk4 (over 50 µg/mice)-pretreated mice had a survival rate more than 70%. In addition, the protein and mRNA levels of TNFα were markedly reduced in Pam3Csk4-pretreated mice at 6 and 12 hours, but not different from the controls at 24 hours post-infection. While IL-6 at protein and mRNA levels decreased in Pam3Csk4-pretreated mice only at 6 hours post-infection. Both protein and mRNA levels of IFN-γ greatly decreased in Pam3Csk4-pretreated mice compared with those of the control group. However, IL-10 level was unchanged between the two groups at all time points. Further studies showed that the mRNA levels of CXCL1 and FcγRIII were notably raised in spleen of the mice 24 hours after administered with Pam3Csk4 compared with normal saline-pretreated mice. CONCLUSION: Our results suggest that Pam3Csk4 pretreatment can protect mice from challenged by MRSA.

Na+/HCO3- cotransporter is expressed on ß and α cells during rat pancreatic development.

AIM: To determine the expression and localization of the electrogenic Na+/HCO3- cotransporter (NBC1) in rat pancreas during development. METHODS: The rat pancreas from postnatal and embryos removed from the uterus of pregnant rats that had been sacrificed by CO2 asphyxiation were used. Rat pancreas from embryonic day (E) 15.5 and E18.5 rat embryos was isolated under a stereomicroscope. Rat pancreas from postnatal (P) days 0, 7, 14, 21 and adult was directly isolated by the unaided eye. The RT-PCR analysis of the NBC1 specific region on rat pancreas tissues from different developmental stages. The two antibodies which target the NBC1 common COOH-terminal region and NH2-terminal region detected a clear band of about 145 kDa in the Western blot analysis. The localization of NBC1 was examined by immuno-fluorescence detection. RESULTS: The results revealed the first peak of NBC1 expression at E18.5 and the second peak at P14. Meanwhile, the low NBC1 expression occurred at P7 and adult stages. Our results demonstrated, for the first time, the presence of NBC1 in the plasma membrane of ß and α cells, as well as in the basolateral membrane of acinar cells of the rat pancreas at different stages of development. CONCLUSION: The data strongly suggests that NBC1 is diversely expressed in the pancreas at different developmental stages, where it may exert its functions in pancreatic development especially islet cell growth through HCO3- transport and pH regulation.

Control of Methicillin-Resistant Staphylococcus aureus Pneumonia Utilizing TLR2 Agonist Pam3CSK4.

The spread of methicillin-resistant Staphylococcus aureus (MRSA) is a critical health issue that has drawn greater attention to the potential use of immunotherapy. Toll-like receptor 2 (TLR2), a pattern recognition receptor, is an essential component in host innate defense system against S. aureus infection. However, little is known about the innate immune response, specifically TLR2 activation, against MRSA infection. Here, we evaluate the protective effect and the mechanism of MRSA murine pneumonia after pretreatment with Pam3CSK4, a TLR2 agonist. We found that the MRSA-pneumonia mouse model, pretreated with Pam3CSK4, had reduced bacteria and mortality in comparison to control mice. As well, lower protein and mRNA levels of TNF-α, IL-1ß and IL-6 were observed in lungs and bronchus of the Pam3CSK4 pretreatment group. Conversely, expression of anti-inflammatory cytokine IL-10, but not TGF-ß, increased in Pam3CSK4-pretreated mice. Our additional studies showed that CXCL-2 and CXCL1, which are necessary for neutrophil recruitment, were less evident in the Pam3CSK4-pretreated group compared to control group, whereas the expression of Fcγ receptors (FcγⅠ/Ⅲ) and complement receptors (CR1/3) increased in murine lungs. Furthermore, we found that increased survival and improved bacterial clearance were not a result of higher levels of neutrophil infiltration, but rather a result of enhanced phagocytosis and bactericidal activity of neutrophils in vitro and in vivo as well as increased robust oxidative activity and release of lactoferrin. Our cumulative findings suggest that Pam3CSK4 could be a novel immunotherapeutic candidate against MRSA pneumonia.

Developmentally restricted genetic determinants of human arsenic metabolism: association between urinary methylated arsenic and CYT19 polymorphisms in children.

We report the results of a screen for genetic association with urinary arsenic metabolite levels in three arsenic metabolism candidate genes, PNP, GSTO, and CYT19, in 135 arsenic-exposed subjects from the Yaqui Valley in Sonora, Mexico, who were exposed to drinking water concentrations ranging from 5.5 to 43.3 ppb. We chose 23 polymorphic sites to test in the arsenic-exposed population. Initial phenotypes evaluated included the ratio of urinary inorganic arsenic(III) to inorganic arsenic(V) and the ratio of urinary dimethylarsenic(V) to monomethylarsenic(V) (D:M). In the initial association screening, three polymorphic sites in the CYT19 gene were significantly associated with D:M ratios in the total population. Subsequent analysis of this association revealed that the association signal for the entire population was actually caused by an extremely strong association in only the children (7-11 years of age) between CYT19 genotype and D:M levels. With children removed from the analysis, no significant genetic association was observed in adults (18-79 years). The existence of a strong, developmentally regulated genetic association between CYT19 and arsenic metabolism carries import for both arsenic pharmacogenetics and arsenic toxicology, as well as for public health and governmental regulatory officials.

Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans.

Individual variability in human arsenic metabolism has been reported frequently in the literature. This variability could be an underlying determinant of individual susceptibility to arsenic-induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic profiles suggests that genetic factors could underlie interindividual variation in arsenic metabolism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phosphorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylarsonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive catalog of commonly occurring genetic polymorphisms in these genes. This catalog was generated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of indigenous American (IA) ancestry. In (Italic)hNP(/Italic), 48 polymorphic sites were observed, including 6 that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. Populations representing genetic admixture between the EA and IA groups, such as Mexican Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of admixture. These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism.

Th2 cell-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation.

IL-13 is a central mediator of allergic inflammation. The single nucleotide polymorphism IL13-1112C>T (rs1800925) is associated with allergic phenotypes in ethnically distinct populations, but the underlying mechanism(s) remain unknown. Using in vivo, in vitro, and in silico analysis, we show that the IL13-1112T allele enhanced IL13 promoter activity in primary human and murine CD4(+) Th2 lymphocytes. Increased expression of IL13-1112T in Th2 cells was associated with the creation of a Yin-Yang 1 binding site that overlapped a STAT motif involved in negative regulation of IL13 expression and attenuated STAT6-mediated transcriptional repression. Because IL-13 secretion was increased in IL13-1112TT homozygotes, we propose that increased expression of IL13-1112T in vivo may underlie its association with susceptibility to allergic inflammation. Interestingly, IL13-1112T had opposite transcriptional effects in nonpolarized CD4(+) T cells, paralleled by distinct patterns of DNA-protein interactions at the IL13 promoter. Our findings suggest the nuclear milieu dictates the functional outcome of genetic variation.