S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway.

INTRODUCTION: The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. METHOD: AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aß)-40, Aß42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. RESULTS: Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aß levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. CONCLUSION: The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.

Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis.

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Periostin: A Potential Biomarker and Therapeutic Target in Pulmonary Diseases.

Periostin is a matricellular, nonstructural protein belonging to the fasciclin family and is encoded by the POSTN gene in humans. Periostin plays an important role in maintaining a normal tissue matrix in the lungs. Despite the vital role as a structural mediator in tissue growth and repair, periostin is involved in the pathogenic mechanism during tissue remodeling and fibrosis. Periostin is a chemoattractant mediator, promotes eosinophil recruitment and adhesion on the airways sub-epithelial membrane of asthmatic patients. POSTN gene was identified as one of the highly expressed genes induced by interleukins IL-13, IL-5 and IL-4 - the key cytokines of Th2 immune responses in the bronchial tissues of asthmatic patients. This review highlights the potential role of periostin as a validated biomarker in respiratory disease progression and its candidacy to predict the response to treatments targeting Th-2 cytokines in bronchial asthma. In addition, its potential role in COPD, IPF, lung cancer and lung infection, is also speculated.   Keywords Periostin, Asthma, Pneumonia, COPD, Idiopathic pulmonary fibrosis, Biomarker.

S-nitrosoglutathione modulates HDAC2 and BDNF levels in the brain and improves cognitive deficits in experimental model of Alzheimer's disease in rats.

AIM: Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by cognitive deficits and abnormal memory formation. Histone acetylation is essential for hippocampal memory formation and improving the cognitive deficits, and histone deacetylase 2 (HDAC2) is increased in the hippocampus of AD patients. The present study evaluated the effects of the nitric oxide (NO) mimetics, L-arginine and the nitrosothiol NO donor, s-nitrosoglutathione (GSNO), on memory and brain HDAC2 levels in experimental animal model of sporadic Alzheimer's disease (sAD). METHODS: AD was induced experimentally in rats by intracerebroventricular injection of streptozotocin (STZ, 3 mg/kg). The effects of NO mimetics, GSNO and L-arginine, were assessed on STZ induced cognitive deficits in the Morris water maze (MWM) test, and, following this, the hippocampal homogenates were assayed for amyloid-ß, brain derived neurotropic factor (BDNF) and HDAC2 levels. The neurobehavioral and biochemical data of the drug treated groups were compared with those of experimental control group. RESULTS: The results showed that icv-STZ induced cognitive deficits were differentially attenuated by GSNO (50 µg/kg) and, to a lesser extent, L-arginine (100 mg/kg) with improvement in the spatial learning tasks in MWM test. These behavioral changes were associated with decreased levels of biochemical markers viz. amyloid ß, BDNF and HDAC2 levels in hippocampus. CONCLUSIONS: It is inferred that NO donors like GSNO could influence AD pathophysiology via epigenetic modification of HDAC2 inhibition.

Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can present with life-threatening lung-kidney syndromes. However, many controlled treatment trials excluded patients with diffuse alveolar hemorrhage or severely impaired glomerular filtration rates, and so the optimum treatment in these cases is unclear. In this retrospective cohort study, we report the outcomes of 64 patients with life-threatening disease treated with a combination regimen of rituximab, low-dose intravenous cyclophosphamide, oral glucocorticoids, and plasma exchange. At entry, the median estimated glomerular filtration rate was 9 mL/min, 47% of patients required dialysis, and 52% had diffuse alveolar hemorrhage. All patients received a minimum of seven plasma exchanges, and the median cumulative doses of rituximab, cyclophosphamide, and glucocorticoid were 2, 3, and 2.6 g, respectively, at six months. A total of 94% of patients had achieved disease remission (version 3 Birmingham Vasculitis Activity Score of 0) at this time point, and 67% of patients who required dialysis recovered independent kidney function. During long-term follow-up (median duration 46 months), overall patient survival was 85%, and 69% of patients remained free from end-stage kidney disease, which compares favorably to a historic cohort with severe disease treated with a conventional induction regimen. Combination treatment was associated with prolonged B cell depletion and low rates of relapse; 87% of patients were in continuous remission at month 36. The serious infection rate during total follow-up was 0.28 infections/patient/year, suggesting that combination treatment is not associated with an enduring risk of infection. Thus, we suggest that combination immunosuppressive therapy may permit glucocorticoid avoidance and provide rapid and prolonged disease control in patients with severe ANCA-associated vasculitis.

HLA-DR4-associated T and B cell responses to specific determinants on the IA-2 autoantigen in type 1 diabetes.

Autoantibodies to IA-2 in type 1 diabetes are associated with HLA-DR4, suggesting influences of HLA-DR4-restricted T cells on IA-2-specific B cell responses. The aim of this study was to investigate possible T-B cell collaboration by determining whether autoantibodies to IA-2 epitopes are associated with T cell responses to IA-2 peptides presented by DR4. T cells secreting the cytokines IFN-γ and IL-10 in response to seven peptides known to elicit T cell responses in type 1 diabetes were quantified by cytokine ELISPOT in HLA-typed patients characterized for Abs to IA-2 epitopes. T cell responses were detected to all peptides tested, but only IL-10 responses to 841-860 and 853-872 peptides were associated with DR4. Phenotyping by RT-PCR of FACS-sorted CD45RO(hi) T cells secreting IL-10 in response to these two peptides indicated that these expressed GATA-3 or T-bet, but not FOXP3, consistent with these being Th2 or Th1 memory T cells rather than of regulatory phenotype. T cell responses to the same two peptides were also associated with specific Abs: those to 841-860 peptide with Abs to juxtamembrane epitopes, which appear early in prediabetes, and those to peptide 853-872 with Abs to an epitope located in the 831-862 central region of the IA-2 tyrosine phosphatase domain. Abs to juxtamembrane and central region constructs were both DR4 associated. This study identifies a region of focus for B and T cell responses to IA-2 in HLA-DR4 diabetic patients that may explain HLA associations of IA-2 autoantibodies, and this region may provide a target for future immune intervention to prevent disease.

Role of the paraventricular nucleus in the reflex diuresis to pulmonary lymphatic obstruction in rabbits.

The changes in urine flow and renal sympathetic nerve activity (RSNA) due to pulmonary lymphatic obstruction (PLO) were examined in anesthetized, artificially ventilated New Zealand white rabbits. PLO was produced by pressurizing an isolated pouch created in the right external jugular vein at the points of entry of the right lymphatic ducts. During this maneuver, urine flow increased from 8.5 ± 0.3 mL/10 min to 12 ± 0.5 mL/10 min (P < 0.0001) and RSNA increased from 24.0 ± 4 to 40.0 ± 5 µV·s (P < 0.0001). Bilateral lesioning of the paraventricular nucleus (PVN) of the hypothalamus or cervical vagotomy abolished these responses. PLO increased c-fos gene expression in the PVN. The increase in urine flow due to PLO was attenuated by muscimol and abolished by kynurenic acid microinjections into the PVN. The results show that (i) neurons in the PVN are an important relay site in the reflex arc, which is activated by PLO; and (ii) this activation is regulated by glutamatergic and partly by GABAergic input to the PVN.

Pharmacological and biochemical studies on the protective effects of melatonin during stress-induced behavioral and immunological changes in relation to oxidative stress in rats.

Stress is known to precipitate neuropsychiatric diseases, and depending upon its nature and intensity it can also influence the functioning of the immune system. Melatonin (N-acetyl-5-methoxy tryptamine) a pineal gland hormone and potent antioxidant is known to protect against many diseases. Effect of melatonin in stress-induced neuro-immunomodulation is not well elucidated. Therefore in the present study, the protective effects of melatonin were evaluated in restraint stress (RS)-induced behavioral and immunological changes in rats. RS for 1 h significantly reduces (i) percentage of open-arm entries and (ii) percentage of time spent on open-arm in elevated plus maze (EPM) test parameters (p < 0.01) and significant increase in MDA levels in brain homogenate when compared to non-RS control groups (p < 0.05). In immunological studies, both humoral and cell-mediated immune responses to antigen were significantly suppressed by RS for 1 h for 5 consecutive days, as evidenced by significant reduction in (i) anti-SRBC antibody titre, (ii) PFC counts, (iii) percentage change in paw volume, and (iv) Th1 (IFN-γ) and Th2 (IL-4) cytokine levels (p < 0.001 in all parameters). These RS-induced immunological changes were associated with significantly increased lipid peroxidation (MDA) levels in serum and significantly decreased activity of (i) SOD, (ii) CAT, and (iii) GSH levels in RS (X5)-exposed group (p < 0.02). Pretreatment with melatonin (10, 50, and 100 mg/kg) significantly reversed these RS-induced changes in EPM test parameters and humoral and cell-mediated immunological parameters, as well as oxidative stress markers in a dose-dependent manner by differential degrees (p < 0.001). Results are strongly suggestive of the involvement of free radicals during stress-induced neurobehavioral and immunological changes. These changes were significantly restored by melatonin pretreatment. We can conclude that melatonin may have a protective role during such stress-induced neuro-immunomodulation.

Cellular and molecular mechanisms of action of polyherbal preparation UNIM-352 in experimental models of bronchial asthma.

Bronchial asthma is a chronic inflammatory disorder of the airways and pharmacotherapy is dependent on anti-inflammatory and bronchodilator agents. However, adverse effects of these agents on chronic administration and sometimes non-responsiveness to these drugs have prompted the search for viable alternatives from medicinal plant sources. UNIM-352 is a polyherbal preparation traditionally used in the Unani system of Indian medicine for the treatment of bronchial asthma. The present study defines the possible cellular and molecular mechanisms of action of UNIM-352 in experimental models of bronchial asthma and validates the observed therapeutically beneficial effects. Wistar rats were immunized and challenged with ovalbumin, and blood and bronchoalveolar lavage (BAL) fluid were assayed for cytological and biochemical markers. UNIM-352 (200 and 400 mg/kg) markedly reduced the eosinophil and neutrophil counts in both blood and BAL compared to control. The polyherbal agent also attenuated the levels of TNF-α, IL-4, GM-CSF and NF-κB whereas histone deacetylase (HDAC) levels were elevated, in both blood and BAL fluid. All effects of UNIM-352 were comparable with the standard drug, prednisolone. The results demonstrated possible cellular and molecular mechanisms of UNIM-352 and thus explain its beneficial effects in bronchial asthma.

Differential neuromodulatory role of NO in anxiety and seizures: an experimental study.

Nitric oxide is a simple, ubiquitous, diatomic molecule with complex neuromodulatory functions. Anxiety and seizures are closely similar neurobehavioral disorders and are regulated by limbic system. The present study evaluated the regulatory roles of NO in these pathophysiological states in experimental models. In test for anxiety, aminophylline induced anxiogenic responses were assessed by the elevated plus maze (EPM) test, and a low dose of the drug (50 mg/kg) reduced both open arm entries and open arm time in rats. Pretreatment with the NO mimetic, L-arginine (500 and 1000 mg/kg) and melatonin (50 mg/kg) attenuated aminophylline induced anxiogenesis whereas the NO synthase inhibitors, L-NAME and 7-NI (30 mg/kg) aggravated the anxiogeneic response. Such aminophylline induced neurobehavioral suppression in the EPM activity was accompanied by increases in MDA levels and reductions in GSH and NOx activity in brain homogenates - changes which were reversed by L-arginine and melatonin pretreatments. In tests for seizures, aminophylline induced seizures and mortality at higher dose levels of the drug (300 mg/kg). Interestingly, such seizures and mortality in rats were antagonized by L-NAME and 7-NI pretreatments. On the other hand, L-arginine tended to potentiate seizures after sub-convulsive dose (100 mg/kg) of this methylxanthine. Aminophylline induced seizures were accompanied by greater elevations in brain MDA levels, whereas, GSH levels were consistently lowered. Unlike that seen during anxiety, NOx levels were increased in brain homogenates of these rats. The changes in oxidative stress markers were neutralized by NO synthase inhibitors. Synergistic anticonvulsant effect on aminophylline seizures was seen when L-NAME was combined with melatonin. These pharmacological and biochemical data indicate that aminophylline induced anxiety and seizures are differentially modulated by NO.

Possible role of nitric oxide (NO) in the regulation of gender related differences in stress induced anxiogenesis in rats.

Gender related differences in stress induced neurobehavioral disorders have been reported although the mechanisms involved are not yet clear. The present study investigated the role of nitric oxide, an important biomodulator in the sex related differences in stress induced anxiety like behavior in rats. Restraint stress (RS for 1 h) was used as the experimental stressor and the effects of NO modulators were assessed in the elevated plus maze (EPM) test in both male and female rats. No metabolites (NOx) and asymmetric dimethyl arginine (ADMA) were measured in brain homogenates of these rats for corroborative purposes. RS induced anxiogenesis in both male and female rats and such changes were greater in males as compared to females. The behavioral alterations were associated with enhanced levels of ADMA and reductions in levels of NOx in brain homogenates - the effects being greater in intensity in males as compared to females. Pretreatment with NO precursor L-arginine (500 mg/kg) reversed the RS induced behavioral and biochemical changes, while NO synthase inhibitor L-NAME (50 mg/kg) had opposite effects. Additionally, Formestane (50 mg/kg), an estrogen synthesis blocker, aggravated stress induced anxiogenesis with a corresponding increase in ADMA and decrease in NOx levels in the females. To our knowledge, this is the first report indicating the involvement of ADMA, an endogenous nitric oxide synthase inhibitor in stress induced neurobehavioral changes. Furthermore, it is also evident that nitric oxide and its interactions with estrogens play a crucial modulatory role in the differential anxiogenic response to stress among males and females.

Management of pneumothoraces detected on chest computed tomography: can anatomical location identify patients who can be managed expectantly?

BACKGROUND: Pneumothorax (PTX) can be readily detected by computed tomography (CT) or ultrasound. However, management of PTX in hemodynamically stable patients remains controversial. STUDY OBJECTIVES: We sought to investigate whether a distinct anatomical distribution of PTX along prespecified chest zones as detected by CT can be described in patients with or without subsequent chest tube thoracotomy (CTT), thus potentially allowing the extended focused assessment with sonography for trauma (EFAST) ultrasound examination to guide PTX management. METHODS: We performed a retrospective review of chest CT scans performed in the emergency department (ED) of a Level I trauma center. CT scans were analyzed for PTX distribution according to a chest zone model. Medical records of subjects with PTX were reviewed for subsequent CTT. RESULTS: Of 3636 chest CT scans performed, 183 PTX (156 patients) were detected without CTT at the time of CT scan (69% male, mean age 42 years). Of these, 66 subjects (40%) underwent CTT; 43 chest tubes (63%) were placed in the ED, 9 (13%) during hospitalization and 9 (13%) in the operating room. Median time to CTT was 140 min (interquartile range 52-199). Initial hemodynamic parameters, need for surgery, and need for mechanical ventilation were similar in both groups (p > 0.05 for all). Anatomical distribution and size of PTX were similar in the two groups. CONCLUSION: Although the majority of patients with traumatic PTX could be managed conservatively, we did not identify a characteristic anatomical PTX pattern, which could identify subjects who may not require CTT.

Modulation by Withania somnifera of stress-induced anxiogenesis and airway inflammation in rats.

OBJECTIVES: Stress is an aversive stimulus which disrupts the biological milieu of the organism and a variety of emotional and environmental stressors are known to influence allergic and immunological disorders like bronchial asthma but the pharmacological basis of such interactions is not clearly defined. Withania somnifera (ashwagandha) is a potent anti-stress agent used widely in Indian traditional medicine and the present experimental study evaluated the effects of W. somnifera extract (WSE) on chronic stress-induced neurobehavioral and immunological responses in an experimental model of allergic asthma in rats. METHODS: Wistar rats (200-250 g) were immunized and challenged with ovalbumin (OVA) and exposed to restraint stress (RS) and WSE treatments for 15 days. Following this, anxiety behavior was assessed by the elevated plus maze (EPM) test, and blood and BAL fluid samples were collected for measuring of inflammatory/immune markers by ELISA and biochemical assay. The data of the various treatment groups were analyzed by ANOVA and Tukey's test. RESULTS: Restraint stress (RS) induced anxiogenic behavior in the (EPM) test in OVA immunized rats, and this was attenuated by WSE (200 and 400 mg/kg), in a dose related manner. Examination of blood and BAL fluid in these RS exposed rats also resulted in elevations in IgE, TNF-α and IL-4 levels, which were also attenuated by WSE pretreatments. Further, WSE pretreatment neutralized the such RS induced changes in oxidative stress markers viz. elevated MDA and reduced GSH levels. CONCLUSIONS: The data pharmacologically validates role of stress in asthma and suggests that adaptogens like WSE could be a potential complementary agent for reducing anxiety as well as airway inflammation by a multi-targeted and holistic approach. The study also highlights the significance of integration of traditional and modern medical concepts in such chronic disorders.

Amelioration by Withania somnifera of neurobehavioural and immunological markers in time dependent sensitization induced post traumatic stress disorder in rats.

AIMS AND OBJECTIVES: Posttraumatic stress disorder (PTSD) is a complex neuropsychiatric pathophysiology with an unmet need for safe, effective, and sustainable therapeutic modalities. Thus, the present study evaluated the effects of Withaniasomnifera (WS, Ashwagandha) on an experimental model of PTSD in rats. MATERIALS AND METHODS: Wistar rats (200-250 g) were used and time-dependent sensitization (TDS) was used as the experimental model of PTSD. Standardized WS root extract (100 and 300 mg/kg, p.o. for 15 days) was administered with TDS and their effects were observed on neurobehavioral (anxiety) and brain cytokines, corticosterone, and oxidative stress markers. RESULTS: Exposure to TDS resulted in anxiogenic behavior in the elevated plus maze (EPM) test, i.e., reductions in open arm entries and open arm time, as compared to the control group. Pretreatment with WS extract (100 and 300 mg/kg × 14 days) attenuated the TDS-induced anxiogenic activity in a dose-related manner, and these WS effects were comparable to those seen after the comparator drug fluoxetine (10 mg/kg). Assay of brain homogenates showed that TDS also resulted in elevations in brain interleukin-6 and reduction in corticosterone levels in both the hippocampus and prefrontal cortex (PFC), which were reversed after WS pretreatments. Further, WS pretreatment also reversed the TDS-induced changes in brain oxidative stress markers, namely elevated malondialdehyde and reduced glutathione levels in both the hippocampus and PFC. CONCLUSION: These results suggest that WS could have potential as a therapeutic agent for treating PTSD by attenuating anxiogenesis, neuroimmune axis activation, and oxidative stress.

Plasma exchange as an adjunctive therapy in anti-neutrophil cytoplasm antibody-associated vasculitis.

INTRODUCTION: We summarize evidence for the role of therapeutic plasma exchange (TPE) in the treatment of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). TPE rapidly removes ANCA IgG, complement and coagulation factors important in the pathogenesis of AAV. TPE has been used in patients with rapidly deteriorating renal function to achieve early disease control, allowing time for immunosuppressive agents to prevent resynthesis of ANCA. The PEXIVAS trial challenged the utility of TPE in AAV, as it did not show benefit of adjunctive TPE on a combined end point of end stage kidney disease (ESKD) and death. AREAS COVERED: We analyze data from PEXIVAS and other trials of TPE in AAV, an up-to-date meta-analysis, and recently published large cohort studies. EXPERT OPINION: There remains a role for the use of TPE in AAV in certain groups of patients, in particular those with severe renal involvement (Cr >500 µmol/L or dialysis-dependent). It should be considered in patients with Cr >300 µmol/L and rapidly deteriorating function, or with life-threatening pulmonary hemorrhage. A separate indication is patients double positive for anti-GBM antibodies and ANCA. TPE may have the greatest benefit as part of steroid-sparing immunosuppressive treatment strategies.

Modulation of Immunological, Biochemical, and Histopathological Changes of Airway Remodeling by Withania somnifera in an Experimental Model of Allergic Asthma in Rats.

Objectives: Airway remodeling in asthma involves chronic inflammation associated with structural changes, which result in severe airflow limitation and very few therapeutic options. Thus, the present study was designed to experimentally evaluate the ameliorative effects of Withania somnifera (WS) root extract against Ovalbumin (OVA)-induced airway remodeling in a rat model of asthma. Methods: Wistar rats were immunized (i.p) and challenged (aerosol) with ovalbumin (OVA), and the effects of WS extract were investigated on the development and progress of airway remodeling by assessing immunological, biochemical, and histological changes in these rats. Results: OVA-immunization and challenge in rats resulted in significant increases in the levels of IL-13, 8-OhdG, TGF-ß, hydroxyproline, and periostin in bronchoalveolar lavage fluid (BALF) and serum/lung homogenate compared to normal control (saline only) rats, and these changes were attenuated after WS extract (200 and 400 mg/kg), as well as dexamethasone (DEX, 1 mg/kg) pretreatments. Further, WS extract attenuated histopathological changes and maintained lung integrity. In herb-drug interactions, sub-threshold doses of WS extract and DEX showed synergistic effects on all parameters studied as compared to either form of monotherapy. Conclusion: These results indicated that WS exerted significant protective effects against airway remodeling in the experimental model by modulating inflammatory and fibrotic cytokines, and could have the potential for developing a therapeutic alternative/adjunct for the treatment of airway remodeling of bronchial asthma.

Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. METHODS: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. RESULTS: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. CONCLUSION: These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.

Anatomical distribution of traumatic pneumothoraces on chest computed tomography: implications for ultrasound screening in the ED.

OBJECTIVES: We sought to assess the anatomical distribution of traumatic pneumothoraces (PTXs) on chest computed tomography (CT) to develop an optimized protocol for PTX screening with ultrasound in the emergency department (ED). METHODS: We performed a retrospective review of all chest CTs performed in one ED between January 2005 and December 2008 according to presence, location, and size of PTX. Pneumothoraces were then measured and categorized into 14 anatomical regions for each hemithorax. RESULTS: A total of 277 (3.8%) PTXs were identified, with 26 bilateral PTX, on 3636 chest CTs performed during the study period. Etiology was blunt (85%) or penetrating trauma (15%). Eighty-three (45%) PTXs were radiographically occult on initial chest x-ray. One hundred eighty-three (66%) PTX had no chest tube at the time of CT. For both hemithoraces, the distribution demonstrated increasing PTX frequency and size from lateral to medial and from superior to inferior. Region 12 (parasternal, intercostal spaces [ICS] 7-8) was involved in 68% of PTX on either side; region 9 (parasternal, ICS 5-6), in 67% on the left and in 52% on the right; and region 11 (lateral to midclavicular line, ICS 7-8), in 46% on the left and in 53% on the right. The largest anterior-to-posterior PTX dimension was seen in region 12. CONCLUSIONS: Our results indicate that 80.4% of right- and 83.7% of left-sided traumatic PTXs would be identified by scanning regions 9, 11, and 12. These findings suggest that a standardized protocol for PTX screening with ultrasound should include these regions.