Clinical Characteristics of EGPA Patients in Comparison to GPA Subgroup with Increased Blood Eosinophilia from POLVAS Registry.

Objective: To characterize the eosinophilic granulomatosis with polyangiitis (EGPA) population from the POLVAS registry depending on ANCA status and diagnosis onset, including their comparison with the granulomatosis with polyangiitis (GPA) subset with elevated blood eosinophilia (min. 400/µl) (GPA HE) to develop a differentiating strategy. Methods: A retrospective analysis of the POLVAS registry. Results: The EGPA group comprised 111 patients. The ANCA-positive subset (n = 45 [40.54%]) did not differ from the ANCA-negative one in clinics. Nevertheless, cardiovascular manifestations were more common in ANCA-negative patients than in those with anti-myeloperoxidase (MPO) antibodies (46.97% vs. 26.92%, p = 0.045). Patients diagnosed before 2012 (n = 70 [63.06%]) were younger (median 41 vs. 49 years, p < 0.01), had higher blood eosinophilia at diagnosis (median 4,946 vs. 3,200/µl, p < 0.01), and more often ear/nose/throat (ENT) and cardiovascular involvement. GPA HE comprised 42 (13.00%) out of 323 GPA cases with reported blood eosinophil count. Both GPA subsets had a lower prevalence of respiratory, cardiovascular, and neurologic manifestations but more often renal and ocular involvement than EGPA. EGPA also had cutaneous and gastrointestinal signs more often than GPA with normal blood eosinophilia (GPA NE) but not GPA HE. The model differentiating EGPA from GPA HE, using ANCA status and clinical manifestations, had an AUC of 0.92, sensitivity of 96%, and specificity of 95%. Conclusion: Cardiovascular symptoms were more prevalent in the ANCA-negative subset than in the MPO-ANCA-positive one. Since EGPA and GPE HE share similarities in clinics, diagnostic misleading may result in an inappropriate therapeutic approach. Further studies are needed to optimize their differentiation and tailored therapy, including biologics.

Primary angiitis of the CNS and ANCA-associated vasculitis: from pathology to treatment.

Vasculitis of the central nervous system can be a localized process, such as primary angiitis of the central nervous system (PACNS), or systemic vasculitis, such as ANCA-associated vasculitis (AAV). Since both conditions share neurological manifestations, the following review will discuss the neurological aspects of both. This review aims to provide a comprehensive comparison of the pathogenesis, clinical manifestation and assessment, diagnostic workup, and treatment protocol for both PACNS and AAV with central nervous system involvement. To provide a comprehensive comparison and update, a literature review was conducted using PubMed and Ovid databases (Embase and Medline). Then, the references were retrieved, screened, and selected according to the inclusion and exclusion criteria. PACNS and AAV share similarities in clinical presentation and neurological symptoms, especially in terms of headache, focal deficits, and cognitive impairment. Additionally, both conditions may exhibit similarities in laboratory and radiological findings, making brain biopsy the gold standard for differentiation between the two conditions. Moreover, the treatment protocols for PACNS and AAV are nearly identical. Comparing PACNS and AAV with CNS involvement highlights the similarities in clinical presentation, radiological findings, and treatment protocols between the two conditions. Further research should focus on establishing a practical diagnostic protocol.

SIRT1 and HSP90α feed-forward circuit safeguards chromosome segregation integrity in diffuse large B cell lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma in adults, exhibiting highly heterogenous clinical behavior and complex molecular background. In addition to the genetic complexity, different DLBCL subsets exhibit phenotypic features independent of the genetic background. For example, a subset of DLBCLs is distinguished by increased oxidative phosphorylation and unique transcriptional features, including overexpression of certain mitochondrial genes and a molecular chaperone, heat shock protein HSP90α (termed "OxPhos" DLBCLs). In this study, we identified a feed-forward pathogenetic circuit linking HSP90α and SIRT1 in OxPhos DLBCLs. The expression of the inducible HSP90α isoform remains under SIRT1-mediated regulation. SIRT1 knockdown or chemical inhibition reduced HSP90α expression in a mechanism involving HSF1 transcription factor, whereas HSP90 inhibition reduced SIRT1 protein stability, indicating that HSP90 chaperones SIRT1. SIRT1-HSP90α interaction in DLBCL cells was confirmed by co-immunoprecipitation and proximity ligation assay (PLA). The number of SIRT1-HSP90α complexes in PLA was significantly higher in OxPhos- dependent than -independent cells. Importantly, SIRT1-HSP90α interactions in OxPhos DLBCLs markedly increased in mitosis, suggesting a specific role of the complex during this cell cycle phase. RNAi-mediated and chemical inhibition of SIRT1 and/or HSP90 significantly increased the number of cells with chromosome segregation errors (multipolar spindle formation, anaphase bridges and lagging chromosomes). Finally, chemical SIRT1 inhibitors induced dose-dependent cytotoxicity in OxPhos-dependent DLBCL cell lines and synergized with the HSP90 inhibitor. Taken together, our findings define a new OxPhos-DLBCL-specific pathogenetic loop involving SIRT1 and HSP90α that regulates chromosome dynamics during mitosis and may be exploited therapeutically.

Effect of Physical Activity on Static and Dynamic Postural Balance in Women Treated for Breast Cancer: A Systematic Review.

BACKGROUND: Therapies against breast cancer (BC) frequently involve complications that impair patients' daily function and quality of life, the most common of which are motor coordination and balance disorders, increasing the risk of falls and injuries. In such cases, physical activity is recommended. Designed following the PRISMA guidelines, this study presents a systematic review of randomised and pilot clinical trials investigating the effect of physical exercises on postural balance in women treated for BC. METHODS: Scientific databases (PubMed, EBSCO) and the online resources of grey publications were searched for trial reports published between January 2002 and February 2022. The inclusion criteria necessitated full-text, English-language reports from randomised clinical trials (RCTs) or pilot clinical trials (pilot CTs), whose authors used physical exercises to treat women with BC and the experimental and control groups consisted of at least 10 women. The methodological quality of the RCTs and pilot CTs were measured using the Physiotherapy Evidence Database (PEDro) scale and the Methodological Index for Non-Randomized Studies (MINORS), respectively. Data were extracted on the effect of exercise on the women's static and dynamic balance. RESULTS: Seven reports, five RCTs and two pilot CTs involving a total of 575 women (aged 18-83 years) were included in the systematic review. Their training protocols utilised a variety of aerobic, strength, endurance, sensorimotor, Pilates exercises, and fitness exercises with elements of soccer. The experimental groups usually worked out in fitness or rehabilitation centres under the supervision of physiotherapists or trainers. Training sessions of 30-150 min were held 2 or 3 times a week for 1.5-24 months. Most trials reported that static and dynamic balance in the experimental groups improved significantly more compared with the control groups. CONCLUSIONS: Physical exercises are able to improve static and dynamic postural balance in women treated for BC. However, as all evidence in support of this conclusion comes from only two pilot CT and five RCTs whose methodologies varied widely, more high quality research is needed to validate their findings and determine which exercise protocols are the most effective in improving postural control in women with BC.

Effect of Whole-Body Vibration Training on Selected Intrinsic Risk Factors in Women Aged 60+ at Fall Risk: A Randomized Controlled Trial.

The aim of the study was to determine whether Whole Body Vibration Training (WBVT) affects intrinsic risk factors for falls in women aged 60+ at fall risk. DESIGN: Randomized controlled clinical trial. Blinding was applied to the persons in charge of evaluating the intervention's clinical results and statistical analysis. METHODS: Forty-two women over 60 years old were randomly assigned to an experimental group (EG-12-week WBVT; n = 22) and a control group (CG-no additional physical activities; n = 20). Fear of falling was measured by the FES-I questionnaire, gait and dynamic balance using the Time-Up and Go test (TUG), aerobic endurance with the 6-Minute Walk Test (6MWT), and the functional strength of the lower body muscles with the 30-s Chair Stand Test (30SCST) at baseline and post-intervention. Additionally assayed were participants' blood concentrations of interleukin-6 (IL-6). RESULTS: The 12-week WBVT improves gait and balance (TUG, p = 0.009), exercise tolerance (6MWT, p = 0.001), and functional strength (30SCST; p = 0.027) but does not reduce the intensity of fear of falling (FES-I, p = 0.655) and the IL-6 serum concentration (p = 0.377). CONCLUSIONS: WBVT affects selected fall risk factors in women aged 60+ at fall risk.

Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies.

The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism.

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.

Osteoporosis in Polish Older Women: Risk Factors and Osteoporotic Fractures: A Cross-Sectional Study.

Background: Osteoporosis is a skeletal disease. It is still not known which of the risk factors have the greatest impact on osteoporosis development. The study aimed to determine how the selected osteoporosis risk factors contribute to the development of the disease and to assess the risk of osteoporotic fractures in older women. Methods: A cohort of 99 older females was divided into two groups (with and without osteoporosis). The risk of osteoporosis was determined using assessment forms and bone densitometry data subjected to logistic regression. The risk of osteoporotic fractures was assessed by the FRAX tool (FRAX, Center for Metabolic Bone Diseases, University of Sheffield, UK). Results: The logistic regression analysis showed that the highest risk of developing osteoporosis associated with lifestyle, mainly cigarette smoking (odds ratio: OR = 2.12), past gynecological operations (OR = 1.46), corticosteroid therapies (OR = 1.38). More than half of participants were at a medium risk of femoral neck fractures (over 90% in the osteoporotic group). Conclusion: Most of the Polish women living in care facilities are at medium risk of low-energy fractures. Smoking appeared to have the strongest effect on osteoporosis among analyzed risk factors. The results may contribute to the creation of more appropriate prevention strategies.

BRAF inhibition curtails IFN-gamma-inducible PD-L1 expression and upregulates the immunoregulatory protein galectin-1 in melanoma cells.

Although melanoma is considered one of the most immunogenic malignancies, spontaneous T-cell responses to melanoma antigens are ineffective due to tumor cell-intrinsic or microenvironment-driven immune evasion mechanisms. For example, oncogenic BRAF V600E mutation in melanoma cells fosters tumor immune escape by modulating cell immunogenicity and microenvironment composition. BRAF inhibition has been shown to increase melanoma cell immunogenicity, but these effects are transient and long-term responses are uncommon. For these reasons, we aimed to further characterize the role of BRAF-V600E mutation in the modulation of PD-L1, a known immunoregulatory molecule, and galectin-1 (Gal-1), a potent immunoregulatory lectin involved in melanoma immune privilege. We report herein that vemurafenib downregulates IFN-γ-induced PD-L1 expression by interfering with STAT1 activity and by decreasing PD-L1 protein translation. Surprisingly, melanoma cells exposed to vemurafenib expressed higher levels of Gal-1. In coculture experiments, A375 melanoma cells pretreated with vemurafenib induced apoptosis of interacting Jurkat T cells, whereas genetic inhibition of Gal-1 in these cells restored the viability of cocultured T lymphocytes, indicating that Gal-1 contributes to tumor immune escape. Importantly, Gal-1 plasma concentration increased in patients progressing on BRAF/MEK inhibitor treatment, but remained stable in responding patients. Taken together, these results suggest a two-faceted nature of BRAF inhibition-associated immunomodulatory effects: an early immunostimulatory activity, mediated at least in part by decreased PD-L1 expression, and a delayed immunosuppressive effect associated with Gal-1 induction. Importantly, our observations suggest that Gal-1 might be utilized as a potential biomarker and a putative therapeutic target in melanoma patients.

Serine Biosynthesis Pathway Supports MYC-miR-494-EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells.

Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.

Interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) axis in idiopathic inflammatory myopathies and its association with laboratory and clinical parameters: a pilot study.

Idiopathic inflammatory myopathies (IIM) are rare connective tissue diseases, which can lead to internal organ involvement. IL-33/ST2 pathway is involved in the pathogenesis of numerous diseases including autoimmune disorders. IL-33 fulfils cardioprotective function, while soluble ST2 (sST2) is a decoy receptor that reduces protective impact of IL-33. The aim of the study was to evaluate the concentrations of sST2 and IL-33 in sera of patients with IIM and evaluate its associations with the clinical course of the disease. Patients with IIM as well as age- and sex-matched healthy controls were recruited. Concentrations of sST2 and IL-33 were assessed with ELISA in sera of both patients and controls. Patients were asked to fill in the questionnaires concerning clinical symptoms and physical functioning. Concentrations of sST2 and IL-33 were correlated with the results of laboratory tests and clinical symptoms. Concentrations of sST2 were significantly higher in IIM group than in healthy subjects (median sST2 in IIM 26.51 vs in healthy controls 21.39; p = 0.03). In the majority of patients, IL-33 concentrations did not exceed the detection limit. Anti-SRP-positive patients presented significantly higher concentrations of sST2 as compared to anti-SRP-negative patients (p = 0.04). In patients with anti-Ro52 antibodies, sST2 concentrations were significantly lower than in anti-Ro52-negative patients (p = 0.02). Concentrations of sST2 correlated with the degree of disability evaluated with Health Assessment Questionnaire. sST2 is increased in patients with IIM and its concentration correlates with the degree of disability. In patients with anti-SRP antibodies, levels of sST2 are exceptionally high.

The clinical utility of remote ischemic preconditioning in protecting against cardiac surgery-associated acute kidney injury: A pilot randomized clinical trial.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a well-known, serious complication and a well-recognized independent risk factor for higher morbidity and mortality among patients undergoing cardiac surgery. OBJECTIVES: The aim of the study was to assess the efficacy of remote ischemic preconditioning (RIPC) in reducing the incidence of CSA-AKI, measured with the standard creatinine technique and using neutrophil gelatinase-associated lipocalin (NGAL) serum concentrations as a potential new biomarker of kidney damage. The ethics committee of the Medical University of Lodz prospectively approved the protocol (approval No. RNN/286/13/KE). The study was retrospectively registered with the U.S. National Institutes of Health - NIH (29 June 2017; ClinicalTrials.gov identifier: NCT03205410). MATERIAL AND METHODS: We conducted a prospective single-center double-blind randomized and controlled tudy. Data was collected from patients admitted to the Cardiosurgery Clinic at the Medical University of Lodz (Poland) between January and December 2014, scheduled for elective cardiac surgery (an off-pump coronary artery bypass). A total of 28 patients were randomized to receive either RIPC (n = 14) or sham RIPC (n = 14). After the induction of anesthesia, the patients assigned to the RIPC group underwent 3 cycles of five-minute inflation to 200 mm Hg and five-minute deflation of the upper-arm cuff. The control group had a deflated cuff placed on the upper arm for 30 min. The authors measured the patients' serum creatinine concentration to check for the occurrence of a CSA-AKI within 48 h after cardiac surgery, and NGAL serum concentration to check its level within 3 h after the operation. RESULTS: Fewer patients in RIPC group developed CSA-AKI within 48 h after cardiac surgery than in the control group (29% vs 93%; p = 0.003). Fewer patients in the RIPC group presented an increase in NGAL 3 h after surgery (medians: 124 vs 176.7; p = 0.0003). CONCLUSIONS: In patients undergoing an off-pump coronary artery bypass, RIPC significantly reduces the occurrence of CSA-AKI and protects against increased postoperative NGAL levels.

Pressure Injuries Treated With Anodal and Cathodal High-voltage Electrical Stimulation: the Effect on Blood Serum Concentration of Cytokines and Growth Factors in Patients With Neurological Injuries. A Randomized Clinical Study.

It remains unclear whether electrical currents can affect biological factors that determine chronic wound healing in humans. PURPOSE: The aim of this study was to determine whether anodal and cathodal high-voltage monophasic pulsed currents (HVMPC) provided to the area of a pressure injury (PI) change the blood level of cytokines (interleukin [IL]-1ß, IL-10, and tumor necrosis factor [TNF]-α) and growth factors (insulin-like growth factor [IGF]-1 and transforming growth factor [TGF]-ß1) in patients with neurological injuries and whether the level of circulatory cytokines and growth factors correlates with PI healing progression. METHODS: This study was part of a randomized clinical trial on the effects of HVMPC on PI healing. All patients with neurological injuries (spinal cord injury, ischemic stroke, and blunt trauma to the head) and a stage 2, stage 3, or stage 4 PI of at least 4 weeks' duration hospitalized in one rehabilitation center were eligible to participate if older than 18 years of age and willing to consent to donating blood samples. Exclusion criteria included local contraindications to electrical stimulation (cancer, electronic implants, osteomyelitis, tunneling, necrotic wounds), PIs requiring surgical intervention, patients with poorly controlled diabetes mellitus (HbA1C > 7%), critical wound infection, and/or allergies to standard wound treatment. Participants were randomly assigned to 1 of 3 groups: anodal (AG) or cathodal (CG) HVMPC treatment (154 µs; 100 Hz; 360 µC/sec; 1.08 C/day) or a placebo (PG, sham) applied for 50 minutes a day, 5 days per week, for 8 weeks. TNF-α, IL-1ß, IL-10, TGF-ß1, and IGF-1 levels in blood serum were assessed using the immunoenzyme method (ELISA) and by chemiluminescence, respectively, at baseline and week 4. Wound surface area measurements were obtained at baseline and week 4 and analyzed using a digitizer connected to a personal computer. Statistical analyses were performed using the maximum-likelihood chi-squared test, the analysis of variance Kruskal-Wallis test, the Kruskal-Wallis post-hoc test, and Spearman's rank order correlation; the level of significance was set at P ≤.05. RESULTS: Among the 43 participants, 15 were randomized to AG (mean age 53.87 ± 13.30 years), 13 to CG (mean age 51.08 ± 20.43 years), and 15 to PG treatment (mean age 51.20 ± 14.47 years). Most PIs were located in the sacral region (12, 74.42%) and were stage 3 (11, 67.44%). Wound surface area baseline size ranged from 1.00 cm2 to 58.04 cm2. At baseline, none of the variables were significantly different. After 4 weeks, the concentration of IL-10 decreased in all groups (AG: 9.8%, CG: 38.54%, PG: 27.42%), but the decrease was smaller in the AG than CG group (P = .0046). The ratio of pro-inflammatory IL-10 to anti-inflammatory TNF-α increased 27.29% in the AG and decreased 26.79% in the CG and 18.56% in the PG groups. Differences between AG and CG and AG and PG were significant (AG compared to CG, P = .0009; AG compared to PG, P = .0054). Other percentage changes in cytokine and growth factor concentration were not statistically significant between groups. In the AG, the decrease of TNF-α and IL-1ß concentrations correlated positively with the decrease of PI size (P <.05). CONCLUSION: Anodal HVMPC elevates IL-10/TNF-α in blood serum. The decrease of TNF-α and IL-1ß concentrations in blood serum correlates with a decrease of PI wound area. More research is needed to determine whether the changes induced by anodal HVMPC improve PI healing and to determine whether and how different electrical currents affect the activity of biological agents responsible for specific wound healing phases, both within wounds and in patients' blood. In clinical practice, anodal HVMPC should be used to increase the ratio of anti-inflammatory IL-10 to pro-inflammatory TNF-α , which may promote healing.

Parainfluenza virus infection enhances NSAIDs-induced inhibition of PGE2 generation and COX-2 expression in human airway epithelial cells.

PURPOSE: Respiratory viral infection and nonsteroidal anti-inflammatory drugs (NSAIDs) may affect arachidonic acid (AA) metabolism in the airway epithelium, however their joint effect has not been studied. We hypothesized, that alternations of AA metabolism in human airway epithelial cells (ECs) - induced by Parainfluenza virus type 3 (PIV3) - may be modified by concomitant treatment with NSAIDs. MATERIALS AND METHODS: Nasal (RPMI 2650) and bronchial (BEAS-2B) epithelial cells were cultured into confluence and then infected with PIV3. Prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (15-HETE) levels in cell supernatants were measured by ELISA and expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) mRNA in cells was evaluated after reverse transcription with real-time polymerase chain reactions. RESULTS: PGE2 generation was decreased by PIV3 infection in the upper airway epithelial cells, and increased in the lower airway epithelial cells. Both naproxen and celecoxib induced significant reduction in PGE2 release in both infected and non-infected upper and lower airway epithelial cells. However, in PIV3-infected epithelial cells celecoxib inhibited PGE2 release and COX-2 expression to significantly higher degree as compared to non-infected cells. 15-HETE generation or COX-1, 5-LO and 15-LO expression were not affected by the virus infection or by NSAIDs. CONCLUSION: Virus infection in airway epithelial cells enhances inhibitory effect of NSAIDs on prostaglandin E2 generation.

The effect of unloader knee braces on medial meniscal strain.

BACKGROUND:: A medial meniscal tear is a common knee injury, especially following an anterior cruciate ligament injury. Decreasing the compressive force on the medial meniscus during dynamic activities using an unloader knee brace could reduce meniscal strain, effectively reducing injury risk and/or severity. OBJECTIVES:: To investigate the efficacy of two unloader knee braces on medial meniscus strain during dynamic activities in intact & deficient anterior cruciate ligament states. STUDY DESIGN:: Combined in vivo/in vitro study. METHODS:: In vivo knee kinematics and muscle force profiles from a healthy individual performing single/doubleleg squats and walking motions were simulated on 10 cadaveric specimens using a dynamic knee simulator system. Simulations were performed on knees in unbraced and braced scenarios, with and without the anterior cruciate ligament. Anterior and posterior medial meniscal strains were measured. RESULTS:: Two different braces each showed a significant reduction in the posteromedial meniscal strain ( p ⩽ 0.01) in an intact anterior cruciate ligament state. Neither brace mirrored this result for the anteromedial strain ( p > 0.05). In the deficient anterior cruciate ligament state, the braces had no significant effect on strain ( p > 0.05). CONCLUSION:: Two unloader knee braces effectively reduced strain in the medial meniscus with an intact anterior cruciate ligament during dynamic activities. Neither brace made a significant reduction in strain for anterior cruciate ligament-deficient knees. CLINICAL RELEVANCE: Unloader knee braces could be used to reduce the medial meniscus strain following meniscal surgery and during rehabilitation in patients with an isolated medial meniscus injury. However, these braces cannot be recommended for this purpose in patients with an anterior cruciate ligament deficiency.

Complex calculation or quick glance? Mean platelet volume - new predictive marker for pulmonary embolism.

BACKGROUND: Wells and Geneva scores are widely used in the assessment of pretest probability of pulmonary embolism (PE). OBJECTIVE: The objective of this study was to examine the hypothesis that mean platelet volume (MPV) may better predict PE than the clinical prediction rules. METHODS: A study was performed among patients with PE. Baseline characteristics and complete blood counts including MPV were prospectively recorded upon admission. To assess clinical probability in patients with PE risk, we used Wells and Geneva scores. RESULTS: Data records of 136 patients (males: 44%) with median age of 66 years (interquartile range [IQR] 57.5-78.0) diagnosed with PE at the Intensive Cardiac Therapy Clinic in Lodz (Poland) were analyzed. Baseline characteristics indicate that patients suffered from arterial hypertension (65%), obesity (32%), and diabetes mellitus (24%). Furthermore, they reported active smoking (21%), prolonged immobilization (20%), major surgery (21%), pregnancy (4%), and oral contraceptives (9%). Patients presented with various symptoms. The MPV, plateletcrit, and D-dimer values on admission were respectively as follows: 10.71 (IQR 3.29-13.67), 0.2 (IQR 0.15-0.24), and 9.23 (IQR 8.5-9.85). The study revealed that Wells score correlated significantly with an elevated MPV value (P<0.05) per contra to Geneva score (P>0.05). According to our results, there is a lack of coherence between Wells and Geneva scores (P>0.05). Finally, we determined that the optimum MPV level cutoff point for PE on admission with reference to the original Wells score is 9.6 fL. CONCLUSION: MPV may be considered useful as an adjunctive or independent predictive marker for PE used in lieu of clinical prediction rules.

The relationship between selected body fatness indices and the level of blood interleukin-6 in female nursing home residents aged 80+ years without inflammation: A pilot study.

BACKGROUND: Interleukin-6 (IL-6) production facilitates a shift from acute to chronic inflammation that may induce the development of some diseases and aging. Several studies have suggested that adiposity is closely related to serum IL-6 level, but their authors examined relatively young older adults (aged 60-80 years), so it is not clear whether this association would also occur in people at a more advanced age. OBJECTIVE: to assess whether in elderly women without inflammation the widely used anthropometric obesity indices are associated with serum IL-6 level and, if so, to determine the best anthropometric predictor of this inflammatory biomarker. METHODS: The sample consisted of 12 women (85.1 ±â€¯3.9 years; 58.1 ±â€¯8.7 kg; 151.9 ±â€¯6.3 cm), the residents of nursing homes, who did not use anti-inflammatory drugs, statins or diuretics and whose blood C-reactive protein (CRP) concentration was lower than 3 mg/l. To determine CRP and IL-6 concentrations, venous blood samples were collected in the morning in a fasted state. The following anthropometric measurements were made in all participants: body weight, body height, the circumferences of waist, hip and neck. Body fat percentage and visceral fat rating (VFR) were determined by bioelectrical impedance analysis. The measurements were then used to calculate body mass index (BMI), body fat mass index (BFMI), body adiposity index (BAI), the waist-hip ratio (WHR) and the waist-height ratio (WHtR). In the statistical analysis, Pearson's correlation coefficients and stepwise multiple regression analysis with backward elimination were used. RESULTS: A direct relationship was established between IL-6 and CRP levels (r = 0.639; p < 0.05). Moreover, IL-6 significantly and positively correlated with hip and neck circumferences, BMI, BFMI, and BAI, as well as with VFR (r range 0.597-0.704; p < 0.05). The multiple regression analysis for IL-6 showed that the neck circumference was the only statistically significant independent variable (r2 = 0.496; p < 0.05; SEE = 0.554 pg/ml). CONCLUSIONS: The results suggest that of all popular indices of adiposity neck circumference is the best predictor of serum IL-6 concentration in the oldest old women without inflammation.

Microenvironment-induced PIM kinases promote CXCR4-triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration.

Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment-dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first-line treatment. In primary CLL cells, inhibition of PIM kinases with a pan-PIM inhibitor, SEL24-B489, decreased PIM-specific substrate phosphorylation and induced dose-dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24-B489 was similar in TP53-mutant and TP53 wild-type cells. Finally, inhibition of PIM kinases decreased CXCR4-mediated cell chemotaxis in two related mechanisms-by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4-triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12-triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment-modulated PIM expression, their pro-survival function and a role of PIMs in CXCR4-induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease.

Contribution of repeated infections in asthma persistence from preschool to school age: Design and characteristics of the PreDicta cohort.

BACKGROUND: The PreDicta cohort was designed to prospectively evaluate wheeze/asthma persistence in preschoolers in association with viral/microbial exposures and immunological responses. We present the cohort design and demographic/disease characteristics and evaluate unsupervised and predefined phenotypic subgroups at inclusion. METHODS: PreDicta is a 2-year prospective study conducted in five European regions, including children 4-6 years with a diagnosis of asthma as cases and healthy age-matched controls. At baseline, detailed information on demographics, asthma and allergy-related disease activity, exposures, and lifestyle were recorded. Lung function, airway inflammation, and immune responses were also assessed. Power analysis confirmed that the cohort is adequate to answer the initial hypothesis. RESULTS: A total of 167 asthmatic children (102 males) and 66 healthy controls (30 males) were included. Groups were homogeneous in respect to most baseline characteristics, with the exception of male gender in cases (61%) and exposure to tobacco smoke. Comorbidities and number and duration of infections were significantly higher in asthmatics than controls. 55.7% of asthmatic children had at least one positive skin prick test to aeroallergens (controls: 33.3%, P = .002). Spirometric and exhaled nitric oxide values were within normal limits; only baseline FEV0.5 and FEV1 reversibility values were significantly different between groups. Viral infections were the most common triggers (89.2%) independent of severity, control, or atopy; however, overlapping phenotypes were also common. Severity and control clustered together in an unsupervised analysis, separating moderate from mild disease. CONCLUSIONS: The PreDicta cohort presented no differences in non-asthma related measures; however, it is well balanced regarding key phenotypic characteristics representative of "preschool asthma".

A Randomized, Controlled Clinical Study to Assess the Effect of Anodal and Cathodal Electrical Stimulation on Periwound Skin Blood Flow and Pressure Ulcer Size Reduction in Persons with Neurological Injuries.

The use of electrical stimulation (ES) should be considered for treating nonhealing pressure ulcers (PUs), but optimal ES wound treatment protocols have yet to be established. A randomized, controlled, double-blind clinical study was conducted to evaluate the effects of cathodal and anodal high-voltage monophasic pulsed current (HVMPC) on periwound skin blood flow (PSBF) and size reduction of Stage 2 to Stage 4 PUs of at least 4 weeks' duration. Persons >18 years of age, hospitalized with neurological injuries, at high risk for PU development (Norton scale <14 points; Waterlow scale >15 points), and with at least 1 Stage 2 to Stage 4 PU were eligible to participate in the study. Persons with necrotic wounds, osteomyelitis, electronic or metal implants in the PU area, PUs in need of surgical intervention, acute wound inflammation, diabetes (HBA1c >7%), diabetic neuropathy, cancer, and/or allergies to standard wound treatments were excluded. Patients were randomly assigned to 1 of 3 groups: anodal (AG), cathodal (CG), or placebo (PG) ES. All groups received individualized PU prevention and standard wound care. In the PG, sham ES was applied; the AG and CG were treated with anodal and cathodal HVMPC, respectively (154 µs 100 Hz; 360 µC/second; 1.08 C/day), 50 minutes per day, 5 days per week, for a maximum of 8 weeks. PSBF was measured using laser Doppler flowmetry at baseline, week 2, and week 4, and wound surface area measurements were obtained and analyzed using a digitizer connected to a personal computer. Data analysis utilized the maximum-likelihood chi-squared test, the analysis of variance Kruskal-Wallis test, the Kruskal-Wallis post-hoc test, and Spearman's rank order correlation. Nonlinear approximation based on exponential function was used to calculate treatment time needed to reduce the wound area by 50%. In all tests, the level of significance was set at P ≤.05. Of the 61 participating patients, 20 were in the AG (mean age 53.2 ± 13.82 years), 21 in the CG (mean age 55.67 ± 17.83 years), and 20 in the PG (mean age 52.5 ± 13.18 years). PUs (baseline size range 1.01 cm2 to 59.57 cm2; duration 4 to 48 weeks) were most frequently located in the sacral region (73.77%) and classified as Stage 3 (62.29%). PSBF at week 2 was significantly higher in the AG and CG than in the PG (P <.05). Week 4 differences were not statistically significant. Wound percentage area reduction calculated at week 8 for the AG (64.10% ± 29.22%) and CG (74.06% ± 23.23%) were significantly different from PG ulcers (41.42% ± 27.88%; P = .0391 and P = .0024, respectively). In both ES groups, PSBF at week 4 and percent wound surface area reductions between weeks 4 and 8 were positively correlated, but only the AG correlation was statistically significant (P = .049). In this study, both ES modalities improved blood flow and wound area reduction rate. Studies examining optimal ES treatment times for healing to occur, the effect of comorbidities and baseline wound variables on ES outcomes, and the nature of the relationship between blood flow and healing are necessary.