Construction and validation of chronic pain prediction model after total knee arthroplasty.

Objective: To explore the risk factors of chronic pain after total knee arthroplasty (TKA) and to establish and verify a prediction model. Methods: As a retrospective observational study, medical records of 239 patients who underwent TKA in Affiliated Hospital of Jiangnan University from January 2020 to December 2022 were reviewed. Fifty four patients suffered from chronic pain after TKA surgery. Univariate and multivariate logistic regression were used to analyze factors associated with the occurrence of chronic pain after TKA. A nomogram prediction model was established based on the identified independent risk factors, and its predictive effectiveness was evaluated. Results: Gender, postoperative 24-hourss numerical rating scale (NRS) and postoperative three months Hospital for Special Surgery Knee-Rating (HSS) scores were independent risk factors for chronic pain after TKA (p<0.05). The area of the receiver operating characteristic (ROC) of the nomogram model based on these factors was 0.904 (95% confidence interval [CI): 0.861-0.947), which indicates a good predictive value for the postoperative chronic pain. When the optimal cut off value was selected, the sensitivity and specificity of the model were 92.6% and 74.1%, respectively, indicating that the predictive model is effective. Conclusions: Gender, postoperative 24-hours NRS and postoperative three months HSS score are independent risk factors for chronic pain after TKA. The nomogram prediction model based on these factors is effective and can provide auxiliary reference for patients with chronic pain after TKA.

Postoperative Risk Factors and Outcome of Patients With Liver Transplantation Who Were Admitted to Pediatric Intensive Care Unit: A 10-Year Single-Center Review in China.

INTRODUCTION: The aim of this study was to present our 10-year experience of pediatric intensive care unit (PICU) management with pediatric liver recipients and to understand the importance of close interdisciplinary cooperation in 2 hospitals. METHODS: A retrospective chart review study was performed according to our hospital's medical records and the pediatric liver transplant database of Renji hospital. RESULTS: A total of 767 patients received liver transplantation (LT) performed in Renji hospital between October 2006 and December 2016, of which 97 of them were admitted to PICU in our center for various complications developed after transplantation. 8.8% (16/208) and 14.4% (81/559) of patients were transferred to PICU in stages I and II, respectively, and was comparable in the 2 stages (P = .017). The majority of patients was late postoperative children (median 185 post-LT days) in stage I. More patients were transferred to PICU directly in stage II. PICU admitted more younger (median 8.2 months) and early postoperative patients in stage II. The median length of PICU stay was 11.0 (6.0-20.5) days. The median length of mechanical ventilation was 5.0 (0.0-12.0) days. The most frequent complications were pulmonary complications (52 [53.6%] patients), surgical complications (22 [22.7%] patients), sepsis (7 [7.2%]), and other miscellaneous complications (16 [16.5%] patients). The overall 28-day PICU mortality was 25.8% (n = 25) and 64.0% (n = 16) of the deaths happened in the early postoperative period. There was significant difference concerning mortality in children with surgical complications and medical problems (54.5% [12/22] vs 17.3% [13/75], P = .001). Multivariate analysis by regression showed that the pediatric risk of mortality III score was the only independent prognostic factor (P = .031). CONCLUSIONS: Multiple complications occur in children with LT. Although challenging, interdisciplinary cooperation between different hospitals is an effective mean to enable children to maximize the benefit gained from LT in China.

Respiratory Variations in Aortic Blood Flow to Predict Volume Responsiveness in Ventilated Children With Leukemia and Neutropenic Septic Shock.

OBJECTIVES: To investigate whether respiratory variations in aortic blood flow by echocardiography can accurately predict volume responsiveness in ventilated children with leukemia and neutropenic septic shock. DESIGN: A prospective study. SETTING: A 25-bed PICU of a tertiary hospital. PATIENTS: Mechanically ventilated children with leukemia who had been exposed to anthracyclines and exhibited neutropenic septic shock were enrolled. INTERVENTIONS: Transthoracic echocardiography was performed to monitor the aortic blood flow before and after fluid administration. MEASUREMENTS AND MAIN RESULTS: After volume expansion, left ventricular stroke volume increased by greater than or equal to 15% in 16 patients (responders) and less than 15% in 14 patients (nonresponders). The performance of respiratory variation in velocity time integral of aortic blood flow and respiratory variation in peak velocity of aortic blood flow for predicting volume responsiveness, as determined by the area under the receiver operating characteristic curve, was 0.74 (95% CI, 0.55-0.94; p = 0.025) and 0.71 (95% CI, 0.53-0.90; p = 0.048), respectively. Positive end-expiratory pressure was higher in nonresponders than in responders (p = 0.035). CONCLUSIONS: Respiratory variation in velocity time integral of aortic blood flow and respiratory variation in peak velocity of aortic blood flow derived from transthoracic echocardiography showed only a fair reliability in predicting volume responsiveness in ventilated children with leukemia and neutropenic septic shock.

Hyperglycemia Predicts Blend Sign in Patients with Intracerebral Hemorrhage.

BACKGROUND Predictive values of admission blood glucose for early hematoma expansion in patients with intracranial hemorrhage (ICH) remain controversial. Blend sign is a novel image predictor for early hematoma growth that suggests presence of active bleeding. We investigated the association between hyperglycemia and blend sign in predicting early hematoma growth in ICH patients. MATERIAL AND METHODS All patients with intracranial hemorrhage were retrospectively reviewed. Clinical characteristics and radiological parameters were collected. Blood glucose was measured within 24 h after onset. CT scan results for hematoma expansion and blend sign were evaluated by 2 readers. Multivariate logistic regression analyses were applied to reveal the associations between hematoma growth and blend sign, as well as other variables. RESULTS Out of 164 patients with ICH, 52 exhibited early hematoma growth and 18 of these were diagnosed with blend sign. Average blood glucose was 7.53 mmol/L among all patients. By using multivariate analyses, the time of CT scan baseline, GCS score, hematoma size, blend sign, and blood glucose were associated with hematoma expansion, whereas only hyperglycemia was associated with blend sign. CONCLUSIONS Admission hyperglycemia is associated with hematoma expansion in the presence of blend sign. These findings suggest that elevated blood glucose is a possible factor predicting continuous bleeding. Strategies to control blood glucose and ameliorate hematoma growth are urgently needed and will be investigated in our future studies.

The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes.

HIV-1 favors integration into active genes and gene-enriched regions of host cell chromosomes, thus maximizing the probability of provirus expression immediately after integration. This requires cleavage and polyadenylation specificity factor 6 (CPSF6), a cellular protein involved in pre-mRNA 3' end processing that binds HIV-1 capsid and connects HIV-1 preintegration complexes to intranuclear trafficking pathways that link integration to transcriptionally active chromatin. CPSF6 together with CPSF5 and CPSF7 are known subunits of the cleavage factor I (CFIm) 3' end processing complex; however, CPSF6 could participate in additional protein complexes. The molecular mechanisms underpinning the role of CPSF6 in HIV-1 infection remain to be defined. Here, we show that a majority of cellular CPSF6 is incorporated into the CFIm complex. HIV-1 capsid recruits CFIm in a CPSF6-dependent manner, which suggests that the CFIm complex mediates the known effects of CPSF6 in HIV-1 infection. To dissect the roles of CPSF6 and other CFIm complex subunits in HIV-1 infection, we analyzed virologic and integration site targeting properties of a CPSF6 variant with mutations that prevent its incorporation into CFIm We show, somewhat surprisingly, that CPSF6 incorporation into CFIm is not required for its ability to direct preferential HIV-1 integration into genes. The CPSF5 and CPSF7 subunits appear to have only a minor, if any, role in this process even though they appear to facilitate CPSF6 binding to capsid. Thus, CPSF6 alone controls the key molecular interactions that specify HIV-1 preintegration complex trafficking to active chromatin.

Prion protein promotes kidney iron uptake via its ferrireductase activity.

Brain iron-dyshomeostasis is an important cause of neurotoxicity in prion disorders, a group of neurodegenerative conditions associated with the conversion of prion protein (PrP(C)) from its normal conformation to an aggregated, PrP-scrapie (PrP(Sc)) isoform. Alteration of iron homeostasis is believed to result from impaired function of PrP(C) in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrP(C) is lacking. Kidney provides a relevant model for this evaluation because PrP(C) is expressed in the kidney, and ∼370 µg of iron are reabsorbed daily from the glomerular filtrate by kidney proximal tubule cells (PT), requiring ferrireductase activity. Here, we report that PrP(C) promotes the uptake of transferrin (Tf) and non-Tf-bound iron (NTBI) by the kidney in vivo and mainly NTBI by PT cells in vitro. Thus, uptake of (59)Fe administered by gastric gavage, intravenously, or intraperitoneally was significantly lower in PrP-knock-out (PrP(-/-)) mouse kidney relative to PrP(+/+) controls. Selective in vivo radiolabeling of plasma NTBI with (59)Fe revealed similar results. Expression of exogenous PrP(C) in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles and increased transepithelial transport of (59)Fe-NTBI and to a smaller extent (59)Fe-Tf from the apical to the basolateral domain. Notably, the ferrireductase-deficient mutant of PrP (PrP(Δ51-89)) lacked this activity. Furthermore, excess NTBI and hemin caused aggregation of PrP(C) to a detergent-insoluble form, limiting iron uptake. Together, these observations suggest that PrP(C) promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity and modulates kidney iron metabolism.

A Survey of the First-Hour Basic Care Tasks of Severe Sepsis and Septic Shock in Pediatric Patients and an Evaluation of Medical Simulation on Improving the Compliance of the Tasks.

BACKGROUND: Application of the sepsis resuscitation bundle is limited by clinician knowledge, skills, and experience. We used the adjusted first-hour basic care tasks in pediatric patients in three tertiary hospitals in Shanghai, China. OBJECTIVE: The aim of this study is to survey the compliance of the adjusted tasks and to evaluate in situ simulation team training on improving the compliance. METHODS: A prospective observational study was performed with the survey checklists from May 2011 to January 2012 in three pediatric intensive care units. A simulated case scenario was administered to the practitioners in one hospital. RESULTS: Seventy-three patients were enrolled, including 47 patients in one simulation hospital (SH) and 26 patients in two nonsimulation hospitals (NSH). The total compliance of the tasks was 47.9% (35/73). The compliance in the SH was significantly higher compared to that in the NSHs (61.7% [29/47] vs. 23.1% [6/26], p < 0.01). Compared to the SH, the main problems in the NSH were giving intravenous or intraosseous fluid resuscitation in a longer time (35.3 min vs. 19.9 min, p = 0.000), a smaller percentage of measurement of accurate urine output (38.5% vs. 68.1%, p = 0.027), delivering high-flow oxygen (73.1% vs. 93.6%, p = 0.028), and measurement of lactate (69.2% vs. 100%, p = 0.000). CONCLUSIONS: In situ simulation team training is an effective method of teaching the tasks of septic shock care to clinicians and nurses on the front line and of improving the compliance of the tasks.

A MDM2-dependent positive-feedback loop is involved in inhibition of miR-375 and miR-106b induced by Helicobacter pylori lipopolysaccharide.

Dysregulation of microRNAs (miRNAs) has been linked to virulence factors of Helicobacter pylori and shown to contribute to the progression of gastric cancer. However, the mechanisms of these processes remain poorly understood. The aim of this study was to investigate the mechanisms by which lipopolysaccharide (LPS), a virulence factor of H. pylori, regulates miR-375 and miR-106b expression in gastric epithelial cells. The results show that LPS from H. pylori 26695 downregulated the expression of miR-375 and miR-106b in gastric epithelial cells, and low levels of Dicer were also observed. Downregulation of miR-375 was found to increase expression of MDM2 with SP1 activation. Overexpression of MDM2 inhibited Dicer by repressing p63 to create a positive-feedback loop involving SP1/MDM2/p63/Dicer that leads to inhibition of miR-375 and miR-106b expression. In addition, we demonstrated that JAK1 and STAT3 were downstream target genes of miR-106b. H. pylori LPS also enhanced the tyrosine phosphorylation of JAK1, JAK2 and STAT3. Together, these results provide insight into the regulatory mechanisms of MDM2 on H. pylori LPS-induced specific miRNAs, and furthermore, suggest that gastric epithelial cells treated with H. pylori LPS may be susceptible to JAK/STAT3 signal pathway activation via inhibition of miR-375 and miR-106b.

Enhanced L-lysine production from pretreated beet molasses by engineered Escherichia coli in fed-batch fermentation.

Faster sugar consumption rate and low-cost nitrogen source are required for the chemical biosynthesis using molasses. Five pretreatment methods were applied to beet molasses prior to fermentation through engineered Escherichia coli, respectively, and corn steep liquid was used as an organic nitrogen source to replace expensive yeast extract. Furthermore, the effects of different feeding strategy in fed-batch fermentation on L-lysine production were investigated. The experimental results showed that combined tricalcium phosphate, sulfuric acid, and activated carbon pretreatment method (TPSA) pretreatment could improve the sugar consumption rate most greatly, and the initial total sugar concentration of 35 g/L from TPSA-pretreated beet molasses gave the best results with respect to L-lysine production, dry cell weight concentration, and L-lysine yield in batch fermentation. Moreover, a mixture of low-cost corn steep liquid and yeast extract containing equal amount of nitrogen could be used as the organic nitrogen source for effective L-lysine fermentation, and constant speed feeding strategy of TPSA-pretreated beet molasses promoted L-lysine production by engineered E. coli. The TPSA-pretreated beet molasses had a sugar consumption rate of 1.75 g/(L h), and a L-lysine yield of 27.81% was achieved, compared with the theoretical yield of 62% by glucose. It was clarified that the pretreatment significantly enhanced the conversion of sugars in beet molasses to L-lysine.

Composite diffuse large B-cell lymphoma and peripheral T-cell lymphoma: a case report with two-year follow-up and literature review.

Composite lymphoma is an uncommon type of lymphoid malignancy, and those consisting of concurrent diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in the same organ are rare. Here, we report a case of a 75-year-old male patient admitted to our emergency department with intestinal obstruction presenting with abdominal pain and vomiting. He underwent partial resection of the small intestine under general anesthesia, and subsequent histopathology confirmed the mass to be composite DLBCL and PTCL-NOS. The patient received chemotherapy with a rituximab-based regimen and achieved complete remission (CR). However, the recurrent disease presented with obstruction again ten months after treatment. He refused a second surgery, but salvage treatment was not effective. The patient survived for 20 months after diagnosis. In addition, we did a literature review to understand the clinical features, pathology, treatment, and prognosis of this type of composite lymphoma.

Histiocytic sarcoma following CAR T-cell therapy: a case report.

BACKGROUND: Development of secondary tumor after CART treatment is not well investigated. We report a pediatric B-cell acute lymphoblastic leukemia (B-ALL) patient who developed histiocytic sarcoma shortly after CART therapy. CASE REPORT: A 9-year-old boy diagnosed with relapsed B-ALL presenting the KRAS A146T mutation received autologous mouse-derived CD19 and CD22 chimeric antigen receptor T-cell therapy at our center (Chinese Clinical Trial Registry: ChiCTR2000032211). Thirty days post-CART therapy, the bone marrow showed complete remission. At 85 days post-CART therapy, the boy presented with fever and chills. An abdominal CT scan showed massive hepatomegaly with multiple low-density lesions in the liver. At 130 days post-CART therapy, a bone marrow smear showed abnormal proliferation of macrophages, some of which exhibited phagocytosis. On day 136 post-CART therapy, laparoscopic liver biopsy was performed, revealing multiple yellow-white lesions on the surface of the liver. Microscopically, multifocal lesions were observed, predominantly composed of cells with abundant cytoplasm. Immunohistochemical staining indicated histiocytic origin. Based on the immunohistochemical results, histiocytic sarcoma was diagnosed. The same cytogenetic markers were identified in histiocytic sarcoma. CONCLUSION: Our case illustrates a rare complication after CART therapy. The diagnosis and treatment of histiocytic sarcoma pose many challenges.

Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1.

An ability to sense pathogens by a number of specialized cell types including the dendritic cells plays a central role in host's defenses. Activation of these cells through the stimulation of the pathogen-recognition receptors induces the production of a number of cytokines including Type I interferons (IFNs) that mediate the diverse mechanisms of innate immunity. Type I IFNs interact with the Type I IFN receptor, composed of IFNAR1 and IFNAR2 chains, to mount the host defense responses. However, at the same time, Type I IFNs elicit potent anti-proliferative and pro-apoptotic effects that could be detrimental for IFN-producing cells. Here, we report that the activation of p38 kinase in response to pathogen-recognition receptors stimulation results in a series of phosphorylation events within the IFNAR1 chain of the Type I IFN receptor. This phosphorylation promotes IFNAR1 ubiquitination and accelerates the proteolytic turnover of this receptor leading to an attenuation of Type I IFN signaling and the protection of activated dendritic cells from the cytotoxic effects of autocrine or paracrine Type I IFN. In this paper we discuss a potential role of this mechanism in regulating the processes of innate immunity.

Vascular endothelial growth factor-induced elimination of the type 1 interferon receptor is required for efficient angiogenesis.

Angiogenesis is stimulated by vascular endothelial growth factor (VEGF) and antagonized by type 1 interferons, including IFN-α/ß. On engaging their respective receptors (VEGFR2 and IFNAR), both stimuli activate protein kinase D2 (PKD2) and type 1 IFNs require PKD2 activation and recruitment to IFNAR1 to promote the phosphorylation-dependent ubiquitination, down-regulation, and degradation of the cognate receptor chain, IFNAR1. Data reveal that PKD2 activity is dispensable for VEGF-stimulated down-regulation of VEGFR2. Remarkably, VEGF treatment promotes the recruitment of PKD2 to IFNAR1 as well as ensuing phosphorylation, ubiquitination, and degradation of IFNAR1. In cells exposed to VEGF, phosphorylation-dependent degradation of IFNAR1 leads to an inhibition of type 1 IFN signaling and is required for efficient VEGF-stimulated angiogenesis. Importance of this mechanism for proangiogenic or antiangiogenic responses in cells exposed to counteracting stimuli and the potential medical significance of this regulation are discussed.

Case Report: Unedited allogeneic chimeric antigen receptor T cell bridging to conditioning-free hematopoietic stem cell transplantation for a child with refractory Burkitt lymphoma.

Purpose: Burkitt lymphoma (BL) is the most common tumor of non-Hodgkin's lymphoma (NHL) in children, accounting for about 40% of cases. Although different combined short-course chemotherapies have achieved a good effect, refractory/relapsed BL has a poor prognosis with cure rates less than 30%. Chimeric antigen receptor T cell (CAR-T) therapy has developed rapidly in recent years and achieved excellent results in acute lymphoblastic leukemia (ALL). However, in some cases, there is a failure to produce autologous CAR-T cells because of T-cell dysfunction. In such cases, allogeneic CAR-T therapy has to be considered. Methods: A 17-year-old boy with stage II BL did not respond to extensive chemotherapy and sequential autologous CAR-T therapy. Lentiviral vectors containing anti-CD20-BB-ζ (20CAR) and anti-CD22-BB-ζ (22CAR) transgenes were used to modify the T cells from an HLA-identical matched unrelated donor. Flow cytometry was used to assess the cytokine analyses and CAR-T cell persistence in peripheral blood, enumerated by qPCR as copies per ug DNA. Informed consent for autologous/allogeneic CAR-T therapy was obtained from the patient and his legal guardian. Results: Unedited HLA-matched allogeneic CD20 and CD22 CAR-T cells were infused after lymphodepletion chemotherapy with cyclophosphamide and fludarabine. The patient experienced Grade IV cytokine release syndrome (CRS) and went into complete remission (CR) after anti-inflammatory treatment including tocilizumab. Because of persistent pancytopenia and full donor chimerism, the same donor's conditioning-free peripheral blood stem cells were successfully transplanted 55 days post CAR-T. Neutrophils were engrafted at day +11 and platelets were rebuilt at day +47 without obvious acute graft-versus-host disease (GVHD), but there was mild chronic GVHD in the skin and eyes. Currently, active anti-rejection therapy is still underway. Conclusion: Unedited HLA-matched allogeneic CAR-T cell therapy could be an innovative, effective, and safe treatment for children with refractory/relapse BL without obvious acute GVHD. Conditioning-free allogeneic hematopoietic stem cell transplantation (HSCT) from the same donor is feasible for a patient with full donor T-cell chimerism after allogeneic CAR-T. It cannot be ignored that close GVHD monitoring is needed post HSCT.

Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapy in Childhood B-Cell Acute Lymphoblastic Leukemia: A Single-Arm, Multicenter, Phase II Trial.

PURPOSE: We determined the safety and efficacy of coadministration of CD19- and CD22-chimeric antigen receptor (CAR) T cells in patients with refractory disease or high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia. PATIENTS AND METHODS: This phase II trial enrolled 225 evaluable patients age ≤ 20 years between September 17, 2019, and December 31, 2021. We first conducted a safety run-in stage to determine the recommended dose. After interim analysis of the first 30 patients treated (27 at the recommended dose) showing that the treatment was safe and effective, the study enrolled additional patients according to the study design. RESULTS: Complete remission was achieved in 99.0% of the 194 patients with refractory leukemia or hematologic relapse, all negative for minimal residual disease. Their overall 12-month event-free survival (EFS) was 73.5% (95% CI, 67.3 to 80.3). Relapse occurred in 43 patients (24 with CD19+/CD22+ relapse, 16 CD19-/CD22+, one CD19-/CD22-, and two unknown). Consolidative transplantation and persistent B-cell aplasia at 6 months were associated with favorable outcomes. The 12-month EFS was 85.0% (95% CI, 77.2 to 93.6) for the 78 patients treated with transplantation and 69.2% (95% CI, 60.8 to 78.8) for the 116 nontransplanted patients (P = .03, time-dependent covariate Cox model). All 25 patients with persistent B-cell aplasia at 6 months remained in remission at 12 months. The 12-month EFS for the 20 patients with isolated testicular relapse was 95.0% (95% CI, 85.9 to 100), and for the 10 patients with isolated CNS relapse, it was 68.6% (95% CI, 44.5 to 100). Cytokine release syndrome developed in 198 (88.0%) patients, and CAR T-cell neurotoxicity in 47 (20.9%), resulting in three deaths. CONCLUSION: CD19-/CD22-CAR T-cell therapy achieved relatively durable remission in children with relapsed or refractory B-acute lymphoblastic leukemia, including those with isolated or combined extramedullary relapse.[Media: see text].

Tyrosine phosphorylation of protein kinase D2 mediates ligand-inducible elimination of the Type 1 interferon receptor.

Type 1 interferons (including IFNα/ß) activate their cell surface receptor to induce the intracellular signal transduction pathways that play an important role in host defenses against infectious agents and tumors. The extent of cellular responses to IFNα is limited by several important mechanisms including the ligand-stimulated and specific serine phosphorylation-dependent degradation of the IFNAR1 chain of Type 1 IFN receptor. Previous studies revealed that acceleration of IFNAR1 degradation upon IFN stimulation requires activities of tyrosine kinase TYK2 and serine/threonine protein kinase D2 (PKD2), whose recruitment to IFNAR1 is also induced by the ligand. Here we report that activation of PKD2 by IFNα (but not its recruitment to the receptor) depends on TYK2 catalytic activity. PKD2 undergoes IFNα-inducible tyrosine phosphorylation on specific phospho-acceptor site (Tyr-438) within the plekstrin homology domain. Activated TYK2 is capable of facilitating this phosphorylation in vitro. Tyrosine phosphorylation of PKD2 is required for IFNα-stimulated activation of this kinase as well as for efficient serine phosphorylation and degradation of IFNAR1 and ensuing restriction of the extent of cellular responses to IFNα.

Role of p38 protein kinase in the ligand-independent ubiquitination and down-regulation of the IFNAR1 chain of type I interferon receptor.

Phosphorylation-dependent ubiquitination and degradation of the IFNAR1 chain of type I interferon (IFN) receptor is a robust and specific mechanism that limits the magnitude and duration of IFNα/ß signaling. Besides the ligand-inducible IFNAR1 degradation, the existence of an "inside-out" signaling that accelerates IFNAR1 turnover in the cells undergoing the endoplasmic reticulum (ER) stress and activated unfolded protein responses has been recently described. The latter pathway does not require either presence of ligands (IFNα/ß) or catalytic activity of Janus kinases (JAK). Instead, this pathway relies on activation of the PKR-like ER kinase (PERK) and ensuing specific priming phosphorylation of IFNAR1. Here, we describe studies that identify the stress activated p38 protein kinase as an important regulator of IFNAR1 that acts downstream of PERK. Results of the experiments using pharmacologic p38 kinase inhibitors, RNA interference approach, and cells from p38α knock-out mice suggest that p38 kinase activity is required for priming phosphorylation of IFNAR1 in cells undergoing unfolded protein response. We further demonstrate an important role of p38 kinase in the ligand-independent stimulation of IFNAR1 ubiquitination and degradation and ensuing attenuation of IFNα/ß signaling and anti-viral defenses. We discuss the distinct importance of p38 kinase in regulating the overall responses to type I IFN in cells that have been already exposed to IFNα/ß versus those cells that are yet to encounter these cytokines.

Eradication of Helicobacter pylori infection reduces the incidence of peptic ulcer disease in patients using nonsteroidal anti-inflammatory drugs: a meta-analysis.

AIM: To investigate the association between use of nonsteroidal anti-inflammatory drugs (NSAID) and Helicobacter pylori infection, interactive effect of H. pylori infection and NSAID use on the development of peptic ulcer disease (PUD), and the effect of H. pylori eradication therapy on PUD development. MATERIAL AND METHODS: We performed a systematic literature search in EMBASE and PubMed for relevant articles published in English between January 1989 and August 2010, with the following MeSH and/or key words: non-steroidal anti-inflammatory drugs, or NSAIDs, Helicobacter pylori, or H. pylori, peptic ulcer disease or PUD, and randomized-control study or clinical trial. The meta-analysis was conducted using the Review Manager 4.2.2. RESULTS: In the analysis of five studies, the pooled prevalence of H. pylori infection was 74.5% and 71.1% in NSAID users and non-NSAID users, respectively, (OR = 0.65; 95% CI: 0.35-1.20, p = .170). In the analysis of nine studies, the pooled prevalence of PUD in NSAID users was 31.2% and 17.9% in the presence and absence of H. pylori infection, respectively, (OR = 3.08; 95% CI: 1.26-7.55, p = .010). Moreover, in the analysis of seven studies, PUD developed in 6.4% and 11.8% of NSAID users with and without eradication therapy, respectively (OR = 0.50; 95% CI: 0.36-0.74, p < .001). The preventive effect of the eradication therapy was further revealed in NSAID-naive users (OR = 0.26; 95% CI: 0.14-0.49, p < .0001) and in the Asian population (OR = 0.30; 95% CI: 0.16-0.56, p < .001). CONCLUSION: NSAID use is not associated with H. pylori infection in patients with PUD. PUD is more common in H. pylori positive than in negative NSAID users. Moreover, H. pylori eradication therapy reduces PUD incidence in NSAID users, especially in naive users and in the Asian population.

Levofloxacin-containing triple and sequential therapy or standard sequential therapy as the first line treatment for Helicobacter pylori eradication in China.

AIMS: To compare the efficacy and the adverse effects of levofloxacin-containing triple therapy, standard sequential therapy, and levofloxacin-containing sequential therapy as first-line treatment for Helicobacter pylori eradication. METHODS: Three hundred and forty-five naive H. pylori-positive patients were randomized to receive levofloxacin-containing 7-day triple therapy (Levo triple, i.e., esomeprazole, 20 mg, twice daily, amoxicillin, 1 g, twice daily, and levofloxacin, 500 mg, once daily for 7 days, n = 114), standard sequential therapy (SST-10, 5-day esomeprazole, 20 mg, twice daily and amoxicillin, 1 g, twice daily followed by 5-day esomeprazole, 20 mg, twice daily, clarithromycin, 500 mg, twice daily and tinidazole, 500 mg, twice daily for 5 days, n = 115) or levofloxacin-containing sequential therapy (Levo-ST-10, 5-day esomeprazole, 20 mg, twice daily and amoxicillin, 1 g, twice daily for 5 days followed by 5-day esomeprazole, 20 mg, twice daily, levofloxacin, 500 mg, once daily and tinidazole, 500 mg, twice daily, n = 116). Eradication was confirmed by a (13) C-urea breath test 4 weeks after completion of treatment. RESULTS: Intention to treat (ITT) eradication rates were 78.1% (95% CI: 69.4, 85.3%), 78.3% (95% CI: 69.6, 85.4%), and 82.8% (95% CI: 74.6, 89.1%) for Levo triple, SST-10, Levo-ST-10, respectively (p = .599). Per protocol (PP) eradication rates were 80.9% (95% CI: 72.3, 87.8%), 82.6% (95% CI: 74.1, 89.2%), and 86.5% (95% CI: 78.7, 92.2%), respectively, for the three therapies (p = .513). Overall, 3.8% experienced mild to moderate adverse events; the rates were 1.75, 4.35, and 5.17%, respectively, in the three groups (p = .325). CONCLUSIONS: Standard sequential therapy and 7-day levofloxacin triple therapy produced unacceptably therapeutic efficacy in China. Only levofloxacin-containing sequential therapy achieved borderline acceptable result. None of the regimens tested reliably achieved 90% or greater therapeutic efficacy in China.

Immunohistochemical detection of uPA, PAI-1, and alpha-SMA in aneurysms of patients with perimembranous ventricular septal defect.

BACKGROUND AND AIM OF THE STUDY: A perimembranous ventricular septal defect (PMVSD) may be partially or completely occluded by aneurysms that originate from the tricuspid valve leaflets, though the exact mechanisms of closure remain unknown. It is hypothesized that valvar interstitial cells (VICs) mediate extracellular matrix (ECM) remodeling in aneurysms via the secretion of a serine proteinase and its inhibitor. METHODS: The functional characteristics of VICs in 15 aneurysms and in four normal tricuspid valve leaflets obtained at autopsy were evaluated by detecting the expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and alpha-smooth muscle actin (alpha-SMA) in the specimens, using immunohistochemical methods. RESULTS: uPA and alpha-SMA were recognized predominantly in VICs located mainly in regions adjacent to the endothelium and smooth muscle cells of blood vessels. PAI-1 was identified in VICs found mainly in granulation tissues, and in endothelial cells. Two types of granulation tissue (myxoid and fibrous tissue) were associated with aneurysms. Nine aneurysms expressed a high uPA activity and a low PAI-1 activity (uPA/PAI-1 ratio 1.78), while six aneurysms expressed a low uPA activity and a high PAI-1 activity (uPA/PAI-1 ratio 0.14). CONCLUSION: The expression of uPA, PAI-1 and alpha-SMA in VICs suggests that interactions among these molecules contribute to ECM remodeling during aneurysm formation and development. This provides a potential mechanism for defect closure in patients with PMVSD.