Health care utilization and mortality for people with epilepsy during COVID-19: A population study.

OBJECTIVE: This study was undertaken to characterize changes in health care utilization and mortality for people with epilepsy (PWE) during the COVID-19 pandemic. METHODS: We performed a retrospective study using linked, individual-level, population-scale anonymized health data from the Secure Anonymised Information Linkage databank. We identified PWE living in Wales during the study "pandemic period" (January 1, 2020-June 30, 2021) and during a "prepandemic" period (January 1, 2016-December 31, 2019). We compared prepandemic health care utilization, status epilepticus, and mortality rates with corresponding pandemic rates for PWE and people without epilepsy (PWOE). We performed subgroup analyses on children (<18 years old), older people (>65 years old), those with intellectual disability, and those living in the most deprived areas. We used Poisson models to calculate adjusted rate ratios (RRs). RESULTS: We identified 27 279 PWE who had significantly higher rates of hospital (50.3 visits/1000 patient months), emergency department (55.7), and outpatient attendance (172.4) when compared to PWOE (corresponding figures: 25.7, 25.2, and 87.0) in the prepandemic period. Hospital and epilepsy-related hospital admissions, and emergency department and outpatient attendances all reduced significantly for PWE (and all subgroups) during the pandemic period. RRs [95% confidence intervals (CIs)] for pandemic versus prepandemic periods were .70 [.69-.72], .77 [.73-.81], .78 [.77-.79], and .80 [.79-.81]. The corresponding rates also reduced for PWOE. New epilepsy diagnosis rates decreased during the pandemic compared with the prepandemic period (2.3/100 000/month cf. 3.1/100 000/month, RR = .73, 95% CI = .68-.78). Both all-cause deaths and deaths with epilepsy recorded on the death certificate increased for PWE during the pandemic (RR = 1.07, 95% CI = .997-1.145 and RR = 2.44, 95% CI = 2.12-2.81). When removing COVID deaths, RRs were .88 (95% CI = .81-.95) and 1.29 (95% CI = 1.08-1.53). Status epilepticus rates did not change significantly during the pandemic (RR = .95, 95% CI = .78-1.15). SIGNIFICANCE: All-cause non-COVID deaths did not increase but non-COVID deaths associated with epilepsy did increase for PWE during the COVID-19 pandemic. The longer term effects of the decrease in new epilepsy diagnoses and health care utilization and increase in deaths associated with epilepsy need further research.

Epilepsy and the risk of COVID-19-related hospitalization and death: A population study.

OBJECTIVE: People with epilepsy (PWE) may be at an increased risk of severe COVID-19. It is important to characterize this risk to inform PWE and for future health and care planning. We assessed whether PWE were at higher risk of being hospitalized with, or dying from, COVID-19. METHODS: We performed a retrospective cohort study using linked, population-scale, anonymized electronic health records from the SAIL (Secure Anonymised Information Linkage) databank. This includes hospital admission and demographic data for the complete Welsh population (3.1 million) and primary care records for 86% of the population. We identified 27 279 PWE living in Wales during the study period (March 1, 2020 to June 30, 2021). Controls were identified using exact 5:1 matching (sex, age, and socioeconomic status). We defined COVID-19 deaths as having International Classification of Diseases, 10th Revision (ICD-10) codes for COVID-19 on death certificates or occurring within 28 days of a positive SARS-CoV-2 polymerase chain reaction (PCR) test. COVID-19 hospitalizations were defined as having a COVID-19 ICD-10 code for the reason for admission or occurring within 28 days of a positive SARS-CoV-2 PCR test. We recorded COVID-19 vaccinations and comorbidities known to increase the risk of COVID-19 hospitalization and death. We used Cox proportional hazard models to calculate hazard ratios. RESULTS: There were 158 (.58%) COVID-19 deaths and 933 (3.4%) COVID-19 hospitalizations in PWE, and 370 (.27%) deaths and 1871 (1.4%) hospitalizations in controls. Hazard ratios for COVID-19 death and hospitalization in PWE compared to controls were 2.15 (95% confidence interval [CI] = 1.78-2.59) and 2.15 (95% CI = 1.94-2.37), respectively. Adjusted hazard ratios (adjusted for comorbidities) for death and hospitalization were 1.32 (95% CI = 1.08-1.62) and 1.60 (95% CI = 1.44-1.78). SIGNIFICANCE: PWE are at increased risk of being hospitalized with, and dying from, COVID-19 when compared to age-, sex-, and deprivation-matched controls, even when adjusting for comorbidities. This may have implications for prioritizing future COVID-19 treatments and vaccinations for PWE.

Surgical re-excision vs. observation for histologically dysplastic naevi: a systematic review of associated clinical outcomes.

BACKGROUND: The management of histologically dysplastic naevi (HDN) with re-excision vs. observation remains controversial because of lack of evidence about associated melanoma outcomes. OBJECTIVES: To assess published data on the development of biopsy-site primary cutaneous melanoma among biopsy-proven HDN managed with either re-excision or observation. METHODS: A systematic review of all published data: a total of 5293 records were screened, 18 articles were assessed in full text and 12 studies met inclusion criteria. No controlled trials were identified. RESULTS: Most studies (11 of 12, 92%) were retrospective chart reviews, and one was both a cross-sectional and cohort study. Many studies (nine of 12, 75%) had no head-to-head comparison groups and either only reported HDN that were re-excised or observed. A total of 2673 (1535 observed vs. 1138 re-excised) HDN of various grades were included. Follow-up varied between 2 weeks and 30 years. Nine studies reported that no melanomas developed. Eleven biopsy-site melanomas developed across three of the studies, six among observed lesions (0·39%) and five among re-excised lesions (0·44%). CONCLUSIONS: Based upon the available evidence the rates of biopsy-site primary melanoma were similarly low among observed lesions and re-excised lesions. This suggests that HDNs can be observed with minimal adverse melanoma-associated outcomes. However, all included articles were of low quality and further prospective trials could better guide clinical decision making.

The Effect of MHC Antigen Matching Between Donors and Recipients on Skin Tolerance of Vascularized Composite Allografts.

The emergence of skin-containing vascularized composite allografts (VCAs) has provided impetus to understand factors affecting rejection and tolerance of skin. VCA tolerance can be established in miniature swine across haploidentical MHC barriers using mixed chimerism. Because the deceased donor pool for VCAs does not permit MHC antigen matching, clinical VCAs are transplanted across varying MHC disparities. We investigated whether sharing of MHC class I or II antigens between donors and recipients influences VCA skin tolerance. Miniature swine were conditioned nonmyeloablatively and received hematopoietic stem cell transplants and VCAs across MHC class I (n = 3) or class II (n = 3) barriers. In vitro immune responsiveness was assessed, and VCA skin-resident leukocytes were characterized by flow cytometry. Stable mixed chimerism was established in all animals. MHC class II-mismatched chimeras were tolerant of VCAs. MHC class I-mismatched animals, however, rejected VCA skin, characterized by infiltration of recipient-type CD8+ lymphocytes. Systemic donor-specific nonresponsiveness was maintained, including after VCA rejection. This study shows that MHC antigen matching influences VCA skin rejection and suggests that local regulation of immune tolerance is critical in long-term acceptance of all VCA components. These results help elucidate novel mechanisms underlying skin tolerance and identify clinically relevant VCA tolerance strategies.

Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria.

BACKGROUND: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30-1500 IU/mL) and bodyweight (30-150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). OBJECTIVES: To determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. METHODS: Data were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). RESULTS: Data for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria; other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV1 ) improved among above-range participants. There was no difference in response between above-range and within-range participants. Above-range participants due to either IgE alone or IgE and weight had similar improvements in ACQ-5, AQLQ and FEV1 . CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.

Myoferlin depletion elevates focal adhesion kinase and paxillin phosphorylation and enhances cell-matrix adhesion in breast cancer cells.

Breast cancer is the second leading cause of malignant death among women. A crucial feature of metastatic cancers is their propensity to lose adhesion to the underlying basement membrane as they transition to a motile phenotype and invade surrounding tissue. Attachment to the extracellular matrix is mediated by a complex of adhesion proteins, including integrins, signaling molecules, actin and actin-binding proteins, and scaffolding proteins. Focal adhesion kinase (FAK) is pivotal for the organization of focal contacts and maturation into focal adhesions, and disruption of this process is a hallmark of early cancer invasive potential. Our recent work has revealed that myoferlin (MYOF) mediates breast tumor cell motility and invasive phenotype. In this study we demonstrate that noninvasive breast cancer cell lines exhibit increased cell-substrate adhesion and that silencing of MYOF using RNAi in the highly invasive human breast cancer cell line MDA-MB-231 also enhances cell-substrate adhesion. In addition, we detected elevated tyrosine phosphorylation of FAK (FAK(Y397)) and paxillin (PAX(Y118)), markers of focal adhesion protein activation. Morphometric analysis of PAX expression revealed that RNAi-mediated depletion of MYOF resulted in larger, more elongated focal adhesions, in contrast to cells transduced with a control virus (MDA-231(LVC) cells), which exhibited smaller focal contacts. Finally, MYOF silencing in MDA-MB-231 cells exhibited a more elaborate ventral cytoskeletal structure near focal adhesions, typified by pronounced actin stress fibers. These data support the hypothesis that MYOF regulates cell adhesions and cell-substrate adhesion strength and may account for the high degree of motility in invasive breast cancer cells.

Kidney-induced cardiac allograft tolerance in miniature swine is dependent on MHC-matching of donor cardiac and renal parenchyma.

Kidney allografts possess the ability to enable a short course of immunosuppression to induce tolerance of themselves and of cardiac allografts across a full-MHC barrier in miniature swine. However, the renal element(s) responsible for kidney-induced cardiac allograft tolerance (KICAT) are unknown. Here we investigated whether MHC disparities between parenchyma versus hematopoietic-derived "passenger" cells of the heart and kidney allografts affected KICAT. Heart and kidney allografts were co-transplanted into MHC-mismatched recipients treated with high-dose tacrolimus for 12 days. Group 1 animals (n = 3) received kidney and heart allografts fully MHC-mismatched to each other and to the recipient. Group 2 animals (n = 3) received kidney and heart allografts MHC-matched to each other but MHC-mismatched to the recipient. Group 3 animals (n = 3) received chimeric kidney allografts whose parenchyma was MHC-mismatched to the donor heart. Group 4 animals (n = 3) received chimeric kidney allografts whose passenger leukocytes were MHC-mismatched to the donor heart. Five of six heart allografts in Groups 1 and 3 rejected <40 days. In contrast, heart allografts in Groups 2 and 4 survived >150 days without rejection (p < 0.05). These data demonstrate that KICAT requires MHC-matching between kidney allograft parenchyma and heart allografts, suggesting that cells intrinsic to the kidney enable cardiac allograft tolerance.

Treatment decisions and survival for people with small-cell lung cancer.

BACKGROUND: Chemotherapy improves survival for many patients with SCLC, and hence it is important to understand variations in practice and outcomes for this treatment strategy. METHODS: We used the National Lung Cancer Audit and Hospital Episodes Statistics to determine the proportion of patients who received chemotherapy for SCLC, and assess the effects of patient and organisational factors on the odds of receiving chemotherapy and of completing four cycles. We calculated median survival and used Cox regression to determine factors that predicted survival. RESULTS: Of 15 091 cases of SCLC, 70% received at least one cycle of chemotherapy. More deprived people were less likely to receive chemotherapy, but patients were more likely to receive chemotherapy, and to complete ≥ four cycles, if they were referred to the lung cancer team by their GP. Median survival for those treated with chemotherapy was 12.9 months for limited and 7.3 months for extensive stage disease. CONCLUSIONS: The Linked NLCA and HES data provide real-life measures of survival in people treated with chemotherapy and show how this is influenced by patient and tumour characteristics. These data show the characteristics of patients who are less likely to complete a full course of treatment, an adverse predictor of survival.

Activity and expression of histone acetylases and deacetylases in inflammatory phenotypes of asthma.

BACKGROUND: Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate gene expression, yet differences in the activity of these enzymes in the inflammatory phenotypes of asthma are unknown. We hypothesized that neutrophilic asthma (NA) would be associated with increased HAT and decreased HDAC activity. OBJECTIVE: To investigate total HAT/HDAC activity and gene expression in isolated blood monocytes and sputum macrophages from healthy and patients with asthma. METHODS: Peripheral blood and induced sputum were collected from adults with asthma (n = 52) and healthy controls (n = 9). Sputum inflammatory cell counts were performed and asthma inflammatory phenotypes were classified according to sputum eosinophil and neutrophil cut-off's of > 3% and > 61% respectively. Peripheral blood monocytes were isolated (n = 61) and sputum macrophages were isolated from a subgroup of patients with asthma (n = 14), using immunomagnetic cell separation. RNA and nuclear proteins were extracted and quantified. Enzyme activity was assessed using fluorescent assays and gene expression of EP300, KAT2B, CREBBP, and HDACs 1, 2 and 3 were measured by qPCR. RESULTS: There was a significant inverse association between blood monocyte HAT and HDAC activity (r = -0.58, P < 0.001). NA was associated with increased blood monocyte HAT enzyme activity (P = 0.02), decreased HDAC activity (P = 0.03), and increased HAT: HDAC ratio (P < 0.01) compared with eosinophilic asthma. There were no differences in gene expression of EP300, KAT2B, CREBBP, or HDACs 1, 2 and 3 in blood monocytes from subjects with asthma or inflammatory phenotypes of asthma. There was no effect of inhaled corticosteroid use, poor asthma control, or asthma severity on HAT/HDAC activities. Sputum macrophages had increased expression of KAT2B in eosinophilic compared with paucigranulocytic asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Neutrophilic airway inflammation is associated with increased HAT and reduced HDAC activity in blood monocytes, demonstrating further systemic manifestations relating to the altered inflammatory gene transcription profile of neutrophilic asthma.

Full blood count parameters for the detection of asthma inflammatory phenotypes.

BACKGROUND: In asthma, the airway inflammatory phenotype influences clinical characteristics and treatment response. Although induced sputum is the gold standard test for phenotyping asthma, a more accessible method is needed for clinical practice. OBJECTIVE: To investigate whether white blood cell counts and/or their derived ratios can predict sputum eosinophils or neutrophils in uncontrolled asthma. METHODS: This cross-sectional study evaluated 164 treated but uncontrolled asthmatic patients with sputum induction and blood collection. Receiver-operating characteristic (ROC) curves were used to assess the relationship between blood and sputum parameters. RESULTS: There was a significant positive relationship between blood eosinophil parameters and the percentage of sputum eosinophil count. A weak but significant correlation was found between sputum neutrophil percentage and blood neutrophil percentage (r = 0.219, P = 0.005). ROC curve analysis identified that blood eosinophil percentage count was the best predictor for eosinophilic asthma, with an area under the curve (AUC) of 0.907 (P < 0.001). The optimum cut-point for blood eosinophil percentage was 2.7%, and this yielded a sensitivity of 92.2% and a specificity of 75.8%. The absolute blood eosinophil count was also highly predictive with an AUC of 0.898 (P < 0.0001) at a blood eosinophil cut-off of 0.26 × 10(9) /L. The blood eosinophil/lymphocyte ratio (ELR) and eosinophil/neutrophil ratio (ENR) were increased in eosinophilic asthma, and the neutrophil/lymphocyte ratio (NLR) was increased in neutrophilic asthma. Neutrophilic asthma could also be detected by blood neutrophil percentages and NLR, but with less accuracy. CONCLUSIONS AND CLINICAL RELEVANCE: Blood eosinophil counts and derived ratios (ELR and ENR) can accurately predict eosinophilic asthma in patients with persistent uncontrolled asthma despite treatment. Blood neutrophil parameters are poor surrogates for the proportion of sputum neutrophils. Blood counts may be a useful aid in the monitoring of uncontrolled asthma.

Tunable mega-ampere electron current propagation in solids by dynamic control of lattice melt.

The influence of lattice-melt-induced resistivity gradients on the transport of mega-ampere currents of fast electrons in solids is investigated numerically and experimentally using laser-accelerated protons to induce isochoric heating. Tailoring the heating profile enables the resistive magnetic fields which strongly influence the current propagation to be manipulated. This tunable laser-driven process enables important fast electron beam properties, including the beam divergence, profile, and symmetry to be actively tailored, and without recourse to complex target manufacture.

Lung cancer survival in England: trends in non-small-cell lung cancer survival over the duration of the National Lung Cancer Audit.

BACKGROUND: In comparison with other European and North American countries, England has poor survival figures for lung cancer. Our aim was to evaluate the changes in survival since the introduction of the National Lung Cancer Audit (NLCA). METHODS: We used data from the NLCA to identify people with non-small-cell lung cancer (NSCLC) and stratified people according to their performance status (PS) and clinical stage. Using Cox regression, we calculated hazard ratios (HRs) for death according to the year of diagnosis from 2004/2005 to 2010; adjusted for patient features including age, sex and co-morbidity. We also assessed whether any changes in survival were explained by the changes in surgical resection rates or histological subtype. RESULTS: In this cohort of 120,745 patients, the overall median survival did not change; but there was a 1% annual improvement in survival over the study period (adjusted HR 0.99, 95% confidence interval (CI) 0.98-0.99). Survival improvement was only seen in patients with good PS and early stage (adjusted HR 0.97, 95% CI 0.95-0.99) and this was partly accounted for by changes in resection rates. CONCLUSION: Survival has only improved for a limited group of people with NSCLC and increasing surgical resection rates appeared to explain some of this improvement.

Annular fast electron transport in silicon arising from low-temperature resistivity.

Fast electron transport in Si, driven by ultraintense laser pulses, is investigated experimentally and via 3D hybrid particle-in-cell simulations. A transition from a Gaussian-like to an annular fast electron beam profile is demonstrated and explained by resistively generated magnetic fields. The results highlight the potential to completely transform the beam transport pattern by tailoring the resistivity-temperature profile at temperatures as low as a few eV.

The risk of congenital malformations, perinatal mortality and neonatal hospitalisation among pregnant women with asthma: a systematic review and meta-analysis.

BACKGROUND: There is conflicting literature on the effect of maternal asthma on congenital malformations and neonatal outcomes. OBJECTIVES: This review and meta-analysis sought to determine if maternal asthma is associated with an increased risk of adverse neonatal outcomes. SEARCH STRATEGY: We searched electronic databases for: (asthma or wheeze) and (pregnan* or perinat* or obstet*). SELECTION CRITERIA: Cohort studies published between 1975 and March 2012 reporting at least one perinatal outcome of interest (congenital malformations, neonatal complications, perinatal mortality). DATA COLLECTION AND ANALYSIS: In all, 21 studies met inclusion criteria in pregnant women with and without asthma. Further analysis was conducted on 16 studies where asthmatic women were stratified by exacerbation history, corticosteroid use, bronchodilator use or asthma severity. MAIN RESULTS: Maternal asthma was associated with a significantly increased risk of congenital malformations (relative risk [RR] 1.11, 95% confidence interval [95% CI] 1.02-1.21, I(2)  = 59.5%), cleft lip with or without cleft palate (RR 1.30, 95% CI 1.01-1.68, I(2)  = 65.6%), neonatal death (RR 1.49, 95% CI 1.11-2.00, I(2)  = 0%), and neonatal hospitalisation (RR 1.50, 95% CI 1.03-2.20, I(2)  = 64.5%). There was no significant effect of asthma on major malformations (RR 1.31, 95% CI 0.57-3.02, I(2)  = 70.9%) or stillbirth (RR 1.06, 95% CI 0.9-1.25, I(2)  = 35%). Exacerbations and use of bronchodilators and inhaled corticosteroids were not associated with congenital malformation risk. AUTHORS' CONCLUSIONS: Despite limitations related to the observational nature of the primary studies, this review demonstrates a small increased risk of neonatal complications among pregnant women with asthma. Further investigations into mechanisms and potential preventive interventions to improve infant outcomes are required.

COVID-19 vaccination uptake in people with epilepsy in wales.

PURPOSE: People with epilepsy (PWE) are at increased risk of severe COVID-19. Assessing COVID-19 vaccine uptake is therefore important. We compared COVID-19 vaccination uptake for PWE in Wales with a matched control cohort. METHODS: We performed a retrospective, population, cohort study using linked, anonymised, Welsh electronic health records within the Secure Anonymised Information Linkage (SAIL) Databank (Welsh population=3.1 million).We identified PWE in Wales between 1st March 2020 and 31st December 2021 and created a control cohort using exact 5:1 matching (sex, age and socioeconomic status). We recorded 1st, 2nd and booster COVID-19 vaccinations. RESULTS: There were 25,404 adults with epilepsy (127,020 controls). 23,454 (92.3%) had a first vaccination, 22,826 (89.9%) a second, and 17,797 (70.1%) a booster. Comparative figures for controls were: 112,334 (87.8%), 109,057 (85.2%) and 79,980 (62.4%).PWE had higher vaccination rates in all age, sex and socioeconomic subgroups apart from booster uptake in older subgroups. Vaccination rates were higher in older subgroups, women and less deprived areas for both cohorts. People with intellectual disability and epilepsy had higher vaccination rates when compared with controls with intellectual disability. CONCLUSIONS: COVID-19 vaccination uptake for PWE in Wales was higher than that for a matched control group.

Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth.

Although estrogen receptor alpha (ERα) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3 or 24 h. IGF-I regulated mRNA of five to tenfold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors, for example, B-cell linker (BLNK), were down-regulated by IGF-I and E2. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ERα. However, repression by IGF-I or E2 required common kinases, such as PI3K and MEK, suggesting downstream convergence of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and, for some genes, the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ERα and IGF-IR signaling may require co-targeting of both pathways.

Characterization of innate immune signalling receptors in virus-induced acute asthma.

BACKGROUND: The role of toll-like receptors (TLRs) and innate immune activation in clinical asthma exacerbations and their relationship to virus infection are unclear. OBJECTIVE: This study aimed to characterize TLR expression and innate immune activity during virus infection in acute asthma. METHODS: Subjects with acute asthma, stable asthma and healthy controls were recruited and underwent spirometry and sputum induction with isotonic saline. Selected sputum was dispersed with dithiothreitol and total and differential leucocyte counts were performed. Selected sputum was also used for quantitative real-time PCR for TLR2, TLR3, TLR4, IL-10 and IP-10mRNA expression. Sputum supernatant was used for the measurement of innate immune markers, including IL-8, matrix metalloproteinase-9 and neutrophil elastase activity. Viruses were detected using real-time and gel-based PCR. RESULTS: Sputum TLR2 mRNA expression was up-regulated in both acute and stable asthma compared with healthy controls and decreased 4-6 weeks after acute exacerbation. Sputum TLR2 mRNA expression was elevated in viral, compared with non-viral, acute asthma. Sputum TLR3 mRNA expression was similar in controls, stable and acute asthma. However, in acute asthma, subjects with virus-induced acute asthma had significantly higher sputum TLR3 mRNA expression. Induced sputum gene expression for IP-10 and IL-10 were increased in viral, compared with non-viral, acute asthma. In virus-induced acute asthma, levels of IP-10 and IL-10 mRNA expression were correlated with the mRNA expression of TLR2 and TLR3. CONCLUSIONS AND CLINICAL RELEVANCE: Virus-induced acute asthma leads to specific induction of TLR2, TLR3, IP-10 and IL-10, suggesting that signalling via TLRs may play an important role in mediating airway inflammation, via both innate and adaptive pathways, in virus-induced exacerbations. These mediators may provide potential treatment targets for virus-induced asthma. They may also be useful in diagnosing the nature of acute asthma exacerbations and monitoring treatment responses, which would be useful in the clinical management of asthma exacerbations.

A meta-analysis of adverse perinatal outcomes in women with asthma.

BACKGROUND: Asthma is a common condition during pregnancy and may be associated with adverse perinatal outcomes. OBJECTIVE: This meta-analysis sought to establish if maternal asthma is associated with an increased risk of adverse perinatal outcomes, and to determine the size of these effects. SEARCH STRATEGY: Electronic databases were searched for the following terms: (asthma or wheeze) and (pregnan* or perinat* or obstet*). SELECTION CRITERIA: Cohort studies published between 1975 and March 2009 were considered for inclusion. Studies were included if they reported at least one perinatal outcome in pregnant women with and without asthma. DATA COLLECTION AND ANALYSIS: A total of 103 articles were identified, and of these 40 publications involving 1,637,180 subjects were included. Meta-analysis was conducted with subgroup analyses by study design and active asthma management. MAIN RESULTS: Maternal asthma was associated with an increased risk of low birthweight (RR 1.46, 95% CI 1.22-1.75), small for gestational age (RR 1.22, 95% CI 1.14-1.31), preterm delivery (RR 1.41, 95% CI 1.22-1.61) and pre-eclampsia (RR 1.54, 95% CI 1.32-1.81). The relative risk of preterm delivery and preterm labour were reduced to non-significant levels by active asthma management (RR 1.07, 95% CI 0.91-1.26 for preterm delivery; RR 0.96, 95% CI 0.73-1.26 for preterm labour). AUTHOR'S CONCLUSIONS: Pregnant women with asthma are at increased risk of perinatal complications, including pre-eclampsia and outcomes that affect the baby's size and timing of birth. Active asthma management with a view to reducing the exacerbation rate may be clinically useful in reducing the risk of perinatal complications, particularly preterm delivery.

Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer.

INTRODUCTION: Accumulating evidence suggests that both levels and activity of the estrogen receptor (ER) and the progesterone receptor (PR) are dramatically influenced by growth-factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in breast cancer. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity and intrinsic molecular subtype. METHODS: We defined two independent molecular signatures of the PI3K pathway: a proteomic (reverse-phase proteomic array) PI3K signature, based on protein measurement for PI3K signaling intermediates, and a PI3K transcriptional (mRNA) signature based on the set of genes either induced or repressed by PI3K inhibitors. By using these signatures, we scored each ER+ breast tumor represented in multiple independent expression-profiling datasets (four mRNA, n = 915; one protein, n = 429) for activation of the PI3K pathway. Effects of PI3K inhibitor BEZ-235 on ER expression and activity levels and cell growth were tested by quantitative real-time PCR and cell proliferation assays. RESULTS: Within ER+ tumors, ER levels were negatively correlated with the PI3K activation scores, both at the proteomic and transcriptional levels, in all datasets examined. PI3K signature scores were also higher in ER+ tumors and cell lines of the more aggressive luminal B molecular subtype versus those of the less aggressive luminal A subtype. Notably, BEZ-235 treatment in four different ER+ cell lines increased expression of ER and ER target genes including PR, and treatment with IGF-I (which signals via PI3K) decreased expression of ER and target genes, thus further establishing an inverse functional relation between ER and PI3K. BEZ-235 had an additional effect on tamoxifen in inhibiting the growth of a number of ER+ cell lines. CONCLUSIONS: Our data suggest that luminal B tumors have hyperactive GFR/PI3K signaling associated with lower ER levels, which has been correlated with resistance to endocrine therapy. Targeting PI3K in these tumors might reverse loss of ER expression and signaling and restore hormonal sensitivity.

Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction.

Abnormal humoral responses toward motor end plate constituents in muscle induce myasthenia gravis (MG). To study the etiology of this disease, and whether it could be induced by host defense molecules, we examined the consequences of interferon (IFN) gamma production within the neuromuscular junction of transgenic mice. The transgenic mice exhibited gradually increasing muscular weakness, flaccid paralysis, and functional disruption of the neuromuscular junction that was reversed after administration of an inhibitor of acetylcholinesterase, features which are strikingly similar to human MG. Furthermore, histological examination revealed infiltration of mononuclear cells and autoantibody deposition at motor end plates. Immunoprecipitation analysis indicated that a previously unidentified 87-kD target antigen was recognized by sera from transgenic mice and also by sera from the majority of human MG patients studied. These results suggest that expression of IFN-gamma at motor end plates provokes an autoimmune humoral response, similar to human MG, thus linking the expression of this factor with development of this disease.