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.

Effects of 12 weeks of neuromuscular electrical stimulation of the quadriceps muscles on the function and physio-biochemical traits in functionally fit female nursing-home residents aged 75 + years: a pilot study.

PURPOSE: Muscular changes induced by neuromuscular electrical stimulation (NMES) are well recognized, but knowledge of how NMES influences the physio-biochemical traits of the oldest old is still limited. This study investigated the effect of NMES applied for 12 weeks to the quadriceps muscles of female nursing-home residents aged 75 + on their functional capability and inflammatory, bone metabolism, and cardiovascular traits. METHODS: Nineteen women regularly taking part in two body conditioning sessions per week were randomized into an electrical stimulation group (ES; n = 10; 30 min sessions, 3 times per week) or a control group (CON; n = 9). At baseline and study week 12, all women performed the 30 s chair stand test (30sCST), the 6-minute walk test (6MWT), and the instrumented timed up and go test (iTUG). Resting heart rates, blood pressure, and the blood concentrations of inflammatory and bone metabolism markers were also measured twice. RESULTS: NMES increased the strength of participants' quadriceps muscles and their performance on the 30sCST and 6MWT while lowering resting arterial blood pressure and inflammatory marker levels; osteoclast activity showed a tendency to decrease. Changes in the iTUG results were not observed. A multiple regression analysis found that the results of functional tests in the ES group were best correlated with pulse pressure (the 30sCST and iTUG tests) and diastolic blood pressure (the 6MWT test). CONCLUSION: Twelve weeks of NMES treatment improved participants' functional capacity and inflammatory, bone metabolism, and cardiovascular traits. The ES group participants' performance on functional tests was best predicted by hemodynamic parameters.

Electrical Stimulation in the Treatment of Pressure Injuries: A Systematic Review of Clinical Trials.

GENERAL PURPOSE: To provide information on evidence-based practice regarding the use of electrical stimulation for pressure injury management. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Apply clinical practice recommendations related to the use of electrical stimulation in the treatment of pressure injuries.2. Identify issues related to the use of electrical stimulation to treat pressure injuries.

To summarize evidence regarding the use of electrical stimulation for pressure injury (PI) management with a systematic review of randomized clinical trials. The authors searched scientific databases (PubMed, EBSCO, Medline, and Elsevier) and the online resources of gray publications for studies published between January 1, 1980, and June 20, 2021, using the keywords "electrostimulation," "electrical stimulation," "pressure ulcer," "pressure injury," "bedsore," and "decubitus ulcer." The search procedure generated 342 articles. Of these, 241 were disqualified after title screening, 52 after abstract screening, and 33 after full-text review; 16 articles were included in the review. Included articles were full-text reports of randomized clinical trials involving patients with PIs that had at least two patient groups, detailed how wounds healed, and were written in English. The authors extracted information about the purpose and design of each trial, patient inclusion and exclusion criteria, research methods, statistical analysis, findings, and conclusions. Researchers applied high-voltage monophasic pulsed current (HVMPC) in 10 trials, two trials used low-voltage monophasic pulsed current, three trials tested a low-voltage biphasic pulsed current, and one trial used low-intensity direct current. The effect of HVMPC in the treatment of PIs has been most thoroughly investigated in clinical trials. The results are consistent and indicate that HVMPC (twin-peak impulse, 50­154 µs, 100 pps, 45­60 min/d) is effective in PI treatment.

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.

Remote Ischemic Preconditioning and Contrast-Induced Acute Kidney Injury in Patients Undergoing Elective Percutaneous Coronary Intervention: A Randomized Clinical Trial.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a common cause of hospital-acquired AKI and a serious complication of percutaneous coronary intervention. OBJECTIVE: The aim of the present study was to assess whether remote ischemic preconditioning (RIPC) reduces the incidence of CI-AKI. METHODS: We conducted a prospective, randomized, sham-controlled clinical study. The study included 101 patients admitted to the Intensive Cardiac Therapy Clinic of Medical University of Lodz for elective percutaneous coronary intervention. The participants were randomly assigned in a 1:1 ratio to either a control group (n = 51) or an RIPC group (n = 50). In the latter, RIPC was achieved before percutaneous coronary intervention by 4 cycles of 5-minute inflation of a cuff on the left upper arm to 200 mm Hg followed by 5-minute deflation. In the control group, a deflated cuff was placed on the left arm for 40 minutes. Serum creatinine concentration was measured to check for the presence of CI-AKI within 48 to 72 hours of percutaneous coronary intervention. Serum neutrophil gelatinase-associated lipocalin level was also measured within 3 hours. RESULTS: CI-AKI occurred in 2 patients from the RIPC group (4%) and 3 patients from the control group (5.9%), but the difference was not significant (P = 0.98). The patients who developed CI-AKI also demonstrated increased serum neutrophil gelatinase-associated lipocalin concentrations (the area under the receiver operator characteristic curve = 0.97; 95% CI, 0.938-1.00; P < 0.00) and the optimal cutoff point value was 118.9 ng/mL. CONCLUSIONS: The use of RIPC before elective percutaneous coronary intervention was not found to prevent CI-AKI. ClinicalTrials.gov identifier: NCT03761368. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Desensitization to biological agents used in rheumatology.

Biological agents such as monoclonal antibodies and fusion proteins are widely used for the treatment of patients with various rheumatic disorders, influencing the quality of life, disability and even mortality in patients. However, biological agents can evoke adverse reactions of different grades of severity. Although drug avoidance remains a gold standard in the care of patients hypersensitive to medication, in certain clinical situations the culprit drug is the drug of choice and cannot be replaced by another equally effective compound. In such cases, desensitization can allow the patient to be treated within current guidelines and with the most effective treatment. The authors searched Medline and Scopus databases for English-language sources using the following key words: hypersensitivity, desensitization, biologicals, adalimumab, etanercept, adalimumab, certolizumab, golimumab, rituximab, infliximab, ixekizumab, tocilizumab, anakinra and canakinumab. The aim of our review is to present the current knowledge about desensitization to biological agents and some guidelines according to patient inclusion, contraindications, procedures, and safety requirements. Drug desensitization is a new issue in rheumatology, and the solution to the problem of allergic reactions to biological drugs, which gives patients with rheumatic diseases the opportunity to extend and prolong their therapy. The present article is one of the first widely discussing this topic in the biological treatment of rheumatic diseases.

Expression of PIM kinases in Reed-Sternberg cells fosters immune privilege and tumor cell survival in Hodgkin lymphoma.

Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (cHL) express multiple immunoregulatory proteins that shape the cHL microenvironment and allow tumor cells to evade immune surveillance. Expression of certain immunoregulatory proteins is modulated by prosurvival transcription factors, such as NFκB and STATs. Because these factors also induce expression of the oncogenic PIM1/2/3 serine/threonine kinases, and as PIMs modulate transcriptional activity of NFκB and STATs, we hypothesized that these kinases support RS cell survival and foster their immune privilege. Here, we investigated PIM1/2/3 expression in cHL and assessed their role in developing RS cell immune privilege and survival. PIM1/2/3 were ubiquitously expressed in primary and cultured RS cells, and their expression was driven by JAK-STAT and NFκB activity. Genetic or chemical PIM inhibition with a newly developed pan-PIM inhibitor, SEL24-B489, induced RS cell apoptosis. PIM inhibition decreased cap-dependent protein translation, blocked JAK-STAT signaling, and markedly attenuated NFκB-dependent gene expression. In a cHL xenograft model, SEL24-B489 delayed tumor growth by 95.8% (P = .0002). Furthermore, SEL24-B489 decreased the expression of multiple molecules engaged in developing the immunosuppressive microenvironment, including galectin-1 and PD-L1/2. In coculture experiments, T cells incubated with SEL24-B489-treated RS cells exhibited higher expression of activation markers than T cells coincubated with control RS cells. Taken together, our data indicate that PIM kinases in cHL exhibit pleiotropic effects, orchestrating tumor immune escape and supporting RS cell survival. Inhibition of PIM kinases decreases RS cell viability and disrupts signaling circuits that link these cells with their niches. Thus, PIM kinases are promising therapeutic targets in cHL.

Rhinovirus Species-Specific Antibodies Differentially Reflect Clinical Outcomes in Health and Asthma.

Rationale: Rhinoviruses (RVs) are major triggers of common cold and acute asthma exacerbations. RV species A, B, and C may have distinct clinical impact; however, little is known regarding RV species-specific antibody responses in health and asthma.Objectives: To describe and compare total and RV species-specific antibody levels in healthy children and children with asthma, away from an acute event.Methods: Serum samples from 163 preschool children with mild to moderate asthma and 72 healthy control subjects from the multinational Predicta cohort were analyzed using the recently developed PreDicta RV antibody chip.Measurements and Main Results: RV antibody levels varied, with RV-C and RV-A being higher than RV-B in both groups. Compared with control subjects, asthma was characterized by significantly higher levels of antibodies to RV-A and RV-C, but not RV-B. RV antibody levels positively correlated with the number of common colds over the previous year in healthy children, and wheeze episodes in children with asthma. Antibody levels also positively correlated with asthma severity but not with current asthma control.Conclusions: The variable humoral response to RV species in both groups suggests a differential infectivity pattern between RV species. In healthy preschoolers, RV antibodies accumulate with colds. In asthma, RV-A and RV-C antibodies are much higher and further increase with disease severity and wheeze episodes. Higher antibody levels in asthma may be caused by a compromised innate immune response, leading to increased exposure of the adaptive immune response to the virus. Importantly, there is no apparent protection with increasing levels of antibodies.

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.

FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal-dependent diffuse large B-cell lymphomas.

Inhibition of spleen tyrosine kinase (SYK) in tonic B-cell receptor (BCR) signal-dependent diffuse large B-cell lymphomas (DLBCLs) inhibits cellular proliferation, decreases cholesterol biosynthesis, and triggers apoptosis, at least in part via a mechanism involving decreased activity of phosphatidylinositol 3-kinase/AKT axis. Because forkhead box O1 (FOXO1) is a major effector of this pathway, we investigated the role of FOXO1 in toxicity of BCR pathway inhibition. Inhibition of SYK in DLBCL cells with tonic BCR signaling decreased phospho-AKT and phospho-FOXO1 levels and triggered FOXO1-driven gene expression. Introduction of constitutively active FOXO1 mutant triggered cell cycle arrest and apoptosis, indicating that increased FOXO1 activity is toxic to these DLBCL cells. Depletion of FOXO1 with short hairpin RNA led to almost complete resistance to chemical SYK inhibitor R406, demonstrating that FOXO1 is also required for R406-induced cell death. FOXO1 in these cells is also involved in regulation of expression of the critical master regulator of cholesterol biosynthesis, SREBP1. Because HRK is the key effector of SYK inhibition, we characterized a mechanism linking FOXO1 activation and HRK induction that involves caspase-dependent cleavage of HRK's transcriptional repressor DREAM. Because AKT in lymphoma cells can be regulated by other signals than BCR, we assessed the combined effects of the AKT inhibitor MK-2206 with R406 and found markedly synergistic FOXO1-dependent toxicity. In primary DLBCLs, FOXO1 expression was present in 80% of tumors, correlated with SYK activity, and was associated with longer overall survival. These results demonstrate that FOXO1 is required for SYK and AKT inhibitor-induced toxicity.

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".

Toll-Like Receptor Agonists Modulate Wound Regeneration in Airway Epithelial Cells.

BACKGROUND: Impaired regeneration of airway epithelium may lead to persistence of inflammation and remodelling. Regeneration of injured epithelium is a complex phenomenon and the role of toll-like receptors (TLRs) in the stimulation of respiratory virus products in this process has not been established. OBJECTIVE: This study was undertaken to test the hypothesis that the wound repair process in airway epithelium is modulated by microbial products via toll-like receptors. METHODS: Injured and not-injured bronchial epithelial cells (ECs) (BEAS-2B line) were incubated with the TLR agonists poly(I:C), lipopolisacharide (LPS), allergen Der p1, and supernatants from virus-infected epithelial cells, either alone or in combination with TLR inhibitors. Regeneration and immune response in injured and not-injured cells were studied. RESULTS: Addition of either poly(I:C) or LPS to ECs induced a marked inhibition of wound repair. Supernatants from RV1b-infected cells also decreased regeneration. Preincubation of injured and not-injured ECs with TLR inhibitors decreased LPS and poly(I:C)-induced repair inhibition. TGF-ß and RANTES mRNA expression was higher in injured ECs and IFN-α, IFN-ß, IL-8, and VEGF mRNA expression was lower in damaged epithelium as compared to not-injured. Stimulation with poly(I:C) increased IFN-α and IFN-ß mRNA expression in injured cells, and LPS stimulation decreased interferons mRNA expression both in not-injured and injured ECs. CONCLUSION: Regeneration of the airway epithelium is modulated by microbial products via toll-like receptors.

Impact of low-level laser therapy on the dynamics of pressure ulcer-induced changes considering an infectious agent and cathelicidin LL-37 concentration: a preliminary study.

INTRODUCTION: Low-level laser therapy is used in managing chronic wounds including pressure ulcers. Less is known about its impact on the healing process if an inhibitive agent e.g. bacterial infection takes place. Modulating non-specific immunity processes might eliminate bacteria if laser therapy is applied. AIM: To investigate the impact of low-level laser therapy on pressure ulcer dynamics considering an infectious agent and cathelicidin LL-37 concentration. MATERIAL AND METHODS: The study comprised 6 patients with pressure ulcers ranging from stage II to III in Torrance classification and 12 patients without pressure ulcers. Venous blood sample and decubitus wound swab were taken - in study groups A at baseline and after 2 weeks; in control group B once - at a specific point of time. The swabs served for species identification. Drug susceptibility of isolated pathogens and cathelicidin LL-37 in serum concentration were measured. RESULTS: In study group A, the following bacteria predominantly occurred: S. aureus, E. faecalis, P. mirabilis, P. aeruginosa, while in control group B, excluding one MRSA case, S. hominis, S. epidermidis, D. nishinomiyaensis, A. haemolyticus (physiological flora) were present. HLGR resistance mechanisms were detected when analyzing drug susceptibility panels. Study group A findings demonstrated a statistically significant difference between the levels of cathelicidin LL-37 concentration at baseline and at the end. CONCLUSIONS: There is insufficient information to accurately determine the effect of LLLT on pressure ulcer dynamics considering an infectious agent. These effects may occur if innate immunity processes are modulated so that laser therapy might eliminate bacteria indirectly.

Aging effect on the instrumented Timed-Up-and-Go test variables in nursing home women aged 80-93 years.

Although the total "Timed-Up-and Go" test (TUG) performance time can characterize an age-related decline of general mobility, this result alone doesn't give any detailed information about the test subtasks. The primary objective of the study was to identify in nursing home women a variable extracted from instrumented TUG (iTUG) that is the best predictor of age. The secondary objective was to assess whether this variable is associated with the results of the isometric knee extension peak torque (IKEPT); lower limb strength measured by the 30-s chair stand test (30sCST), and walking capacity measured by the 6-min walk test (6MWT). Twenty-six women (mean ± SD: age-85.8 ± 3.6 years; body weight-59.4 ± 12.3 kg; body height-151.0 ± 7.3 cm; BMI-26.0 ± 4.9 kg/m2) performed iTUG (while wearing a body-fixed inertial sensor) and functional tests. Total iTUG performance time significantly correlated with age (r = 0.484; p < 0.05), 30sCST (r = -0.593; p < 0.01), and 6MWT (r = -0.747; p < 0.001) but not with absolute nor relative IKEPT (p > 0.05). Additionally, the subjects' age correlated with 30sCST (r = -0.422; p < 0.05), 6MWT (r = -0.482; p < 0.05), IKEPT (r = -0.392; p < 0.05) and IKEPT/FFM (r = -0.407; p < 0.05). Five out of 16 analyzed iTUG variables were significantly related to age, and multiple regression analysis showed the best correlation with the sit-to-stand vertical acceleration range (STSVAR) (r2 = 0.430; SEE = 3.041; ß = -0.544 ± 0.245; B = -1.204 ± 0.543; p < 0.05). Moreover, STSVAR was significantly associated with %Fat (r = 0.415; p < 0.05), 30sCST (r = 0.519; p < 0.01), 6MWT (r = 0.585; p < 0.01) but not with absolute nor relative IKEPT (p > 0.05). The obtained results suggest that in the oldest old group of nursing home women an age-related decline in TUG performance is mainly associated with a reduction of "explosive" strength of lower limb muscles.

Inverted stress- induced cardiomyopathy as a unusual variant of acute heart failure after cesarean delivery- a case report.

BACKGROUND: Stress- induced cardiomyopathy is acute, reversible left ventricle mainly apical dysfunction in patients with normal coronary angiography. Rarely it regards basal segments, therefore defined as "inverted stress- induced cardiomyopathy". While classic form mostly affects postmenopausal women, inverted variant occurs essentially in younger females, always triggered by stress. It can also develop after medical procedures and surgery. Herein we report such unique case of 36- year old woman after cesarean delivery. CASE PRESENTATION: A 36- year- old white woman at 40 week of gestation was admitted to hospital for elective repeated cesarean delivery. During caesarean delivery under spinal anaesthesia a previously healthy woman became hypotensive, requiring ephedrine to maintain her blood pressure. Three hours after delivery the patient presented acute heart failure and pulmonary oedema. Due to low blood pressure she demanded the administration of inotropic agents. Owing to respiratory failure and gradual deterioration of consciousness, mechanical ventilation was applied. Results of additional tests finally excluded pulmonary thromboembolism and acute coronary syndrome. The transthoracic echocardiography revealed severe left ventricular systolic dysfunction, ejection fraction 30 % with hypokinesis of the mid and basal segments of posterior, anterior and lateral wall with preserved contractility of the apical segments. The diagnosis of inverted stress- induced cardiomyopathy was set upon the overall clinical data. Both echocardiography and magnetic resonance imaging performed on the fifth day showed complete recovery of myocardial function. The patient was discharged after 15 days in good overall condition. At 12- month follow- up she remained asymptomatic with no echocardiographic abnormalities. CONCLUSIONS: Inverted stress- induced cardiomyopathy may occur in postpartum period, especially in combination with spinal anesthesia and adrenergic stimulants administration. The clinical awareness and multimodality imaging of possible diagnosis and further management of this unexpected variant of acute heart failure after caesarean delivery is required.

Clinical benefits of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease are not related to urinary eicosanoid release and are accompanied with decreased urine creatinine.

BACKGROUND: Treatment with acetylsalicylic acid (ASA) after desensitization may be a therapeutic option in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD). The mechanisms that lead to improvement in rhinosinusitis and asthma symptoms remain unknown. AIM: To attribute the documented clinical effects of ASA treatment of chronic rhinosinusitis and/or asthma to the release of eicosanoid metabolites in urine. METHODS: Fourteen patients with NERD were successfully desensitized, and, eventually, eight patients were treated with 650 mg of ASA daily for 3 months. In addition to clinical assessments, nuclear magnetic resonance imaging and smell test were performed before and after treatment with ASA. Venous blood and urine were collected before desensitization and after 1 and 3 months of treatment. The levels of urinary leukotrienes (LT) (cysteinyl LT and LTE4) and tetranor PGDM (metabolite of prostaglandin D2) were measured by enzyme-linked immunosorbent assay. RESULTS: Treatment with ASA after desensitization alleviated symptoms of rhinosinusitis, improved nasal patency (mean, 50% decrease in peak nasal inspiratory flow) and sense of smell (fourfold increase in smell test score) in as early as 4 weeks. Clinical improvements were not accompanied by any change in sinonasal mucosa thickness as assessed with nuclear magnetic resonance. Urinary cysteinyl LTs, LTE4, and prostaglandin D2 metabolite remained relatively stable during ASA treatment and did not correlate with clinical improvements. Desensitization was associated with a progressive decrease of urinary creatinine. CONCLUSION: Clinical improvement in rhinosinusitis and/or asthma after ASA desensitization was not related to concentrations of urinary eicosanoid metabolites. A decrease of urinary creatinine requires further study to determine the renal safety of long-term treatment with ASA after desensitization.

Evaluation of the Healing Progress of Pressure Ulcers Treated with Cathodal High-Voltage Monophasic Pulsed Current: Results of a Prospective, Double-blind, Randomized Clinical Trial.

OBJECTIVE: To investigate the effectiveness of high-voltage monophasic pulsed current (HVMPC) as an adjunct to a standard wound care for the treatment of Stage II and III pressure ulcers (PrUs). DESIGN: Prospective, randomized, double-blind, controlled clinical study. SETTING: Two nursing and care centers. PATIENTS: Patients with PrUs that did not respond to previous treatment for at least 4 weeks were randomly assigned to the electrical stimulation (ES) group (25 patients; mean age of 79.92 ± 8.50 years; mean wound surface area [WSA] of 10.58 ± 10.57 cm) or to the control group (24 patients; mean age of 76.33 ± 12.74 years; mean WSA of 9.71 ± 6.70 cm). INTERVENTIONS: Both the ES and control groups received standard wound care and respectively, cathodal HVMPC (154 microseconds; 100 pulses per second; 0.24 A; 250 µ/s) applied continuously for 50 minutes once a day, 5 times a week, or sham HVMPC. MAIN OUTCOME: Percentage area reduction over 6 weeks of intervention. MAIN RESULTS: In the ES group, there was a statistically significant decrease in WSA after 1 week of treatment (35% ± 30.5%) compared with 17.07% ± 34.13% in the control group (P = .032). After treatment, at week 6, percentage area reduction in the ES group was 80.31% ± 29.02% versus 54.65% ± 42.65% in the control group (P = .046). CONCLUSIONS: Cathodal HVMPC reduces the WSA of Stage II and III PrUs. The results are consistent with the results of other researchers who used HVMPC to treat PrUs.

Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy.

BACKGROUND: The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1. OBJECTIVES: Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1. METHODS: Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product. RESULTS: Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability. CONCLUSION: The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.

Hypersensitivity to Aspirin and other NSAIDs: Diagnostic Approach in Patients with Chronic Rhinosinusitis.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) associated with chronic rhinosinusitis (CRS) and/or asthma comprises a distinct clinical syndrome referred to as NSAIDs exacerbated respiratory disease (NERD). Patients with NERD tend to have more severe course of both upper (CRS and nasal polyps) and lower airway (asthma) diseases and are usually recalcitrant to conventional treatment modalities. Diagnosing and phenotyping of patients with NERD are critical for prevention of drug-induced adverse reactions and open novel options for management of underlying chronic airway inflammatory diseases. Diagnosis of NERD is based on detailed clinical history confirmed by challenge with aspirin, but new diagnostic approaches are currently being developed. This review article focuses on the diagnostic approach to a patient with CRS and hypersensitivity to NSAIDs, emphasizing the importance of diagnosis for proper patient's management.

IgE-mediated 15-hydroxyeicosatetraenoic acid (15-HETE) generation by peripheral blood leukocytes: its association with basophil activation.

INTRODUCTION: Allergen-induced basophil activation has been associated with the release of several mediators and with an increased expression of CD203c molecules on basophils. AIM: To assess the influence of specific allergens on the generation of 15-hydroxyeicosatetraenoic (15-HETE) from peripheral blood leukocytes in relation to basophil activation, on the basis of CD203c molecule expression and histamine release. MATERIAL AND METHODS: The study included 15 patients with clinical symptoms of birch pollen allergy confirmed by a positive skin prick test with the birch allergen, and 6 healthy controls. Leukocytes isolated from peripheral blood were incubated with 3 concentrations of the birch pollen allergen (Bet v 1), anti-IgE or with ionophore A23187. RESULTS: In vitro challenge of leukocytes from allergic patients with 1 ng/ml of allergen induced a significant increase in 15-HETE generation. An increase above 30% was observed in almost half the allergic patients, with mean values ranging from 40% to 46%, but not in healthy controls. Anti-IgE antibodies increased 15-HETE generation in 5 patients (termed IgE+), and the allergen induced a significant increase in 15-HETE in all patients who reacted to anti-IgE. The mean CD203c expression on basophils of the allergic patients increased after allergen challenge, but a significant increase (> 30%) was observed only in patients who demonstrated an increased expression after anti-IgE exposure. A significant correlation was seen between 15-HETE generation and histamine release induced by the highest concentration of the allergen (r = 0.95; p < 0.01). CONCLUSIONS: Allergen-induced, IgE-mediated activation of basophils is associated with a significant increase in 15-HETE generation.