A sthma is a chronic inflammatory disease which is accompanied by extensive changes in normal airway tissue architecture, termed remodeling (1, 2). Airway remodeling in asthma comprises epithelial dysfunction, hypertrophy of the mucus glands, subepithelial vascularization, and changes in extracellular matrix composition (2). In addition, airway smooth muscle (ASM) from people suffering with asthma exhibits enhanced proliferative (3) and migratory responses (4, 5), as well as increased secretion of a myriad of pro-inflammatory cytokines/ chemokines and growth factors (6). The mechanisms that underly the exaggerated function of ASM in asthma are unknown.Smooth muscle responses to diverse stimuli are controlled by changes in the concentration of free cytosolic Ca 2ϩ ([Ca 2ϩ ] i ). Elevation of [Ca 2ϩ ] i results from increased Ca 2ϩ influx across the plasma membrane following activation of Ca 2ϩ -permeable ion channels and the Na ϩ -Ca 2ϩ -exchanger (NCX, 3Na ϩ :1Ca 2ϩ ), and by release of stored Ca 2ϩ from the sarcoplasmic reticulum (SR), in turn triggered by inositol 1,4,5-triphosphate (IP 3 ) or ryanodine receptor (RyR) channels (7). Termination of the cytosolic Ca 2ϩ signal occurs by extracellular removal of cytosolic Ca 2ϩ by the NCX and by its rapid sequestration into SR stores by the sarco/endoplasmic reticulum Ca 2ϩ (SERCA) pump (7). Impaired replenishment of SR stores arising from reduced activity of the SERCA pump could impact on a wide range of Ca 2ϩ -dependent smooth muscle functions (8) and abnormal Ca 2ϩ handling by ASM has previously been proposed to be an important determinant of the airway hyperresponsiveness that is characteristically present in asthma (9, 10).There are 3 tissue-specific members of the mammalian SERCA family, SERCA1, SERCA2 and SERCA3, each encoded by a separate gene (ATP2A1, ATP2A2, and ATP2A3) (11), with SERCA2 being the most highly expressed in smooth muscle (12, 13). The function of the different isoforms of SERCA2 is similar (14). We have investigated if the secretory and hyperproliferative phenotype of ASM in asthma is associated with impaired SERCA isoform expression. Results SERCA2Expression. SERCA2 mRNA expression was reduced in ASM cells cultured from patients with moderate, but not mild asthma compared with cells derived from healthy subjects (P ϭ 0.04, Fig. 1A). Western immunoblot showed a single band for SERCA2 at the expected size (Ϸ110 kDa) in ASM lysates (Fig. 1). SERCA2 protein expression was correspondingly reduced in ASM cells from patients with moderate asthma (P ϭ 0.015, Fig. 1B). In contrast, IP 3 R1 mRNA and protein expression did not differ between asthmatics and controls ( Fig. 1 A and B), suggesting the change in SERCA2 was not the result of a reduction in total SR. Transcripts for SERCA1, and SERCA3 were not detected in ASM. Further experiments using SERCA2A, SERCA2B, and SERCA2C specific primers demonstrated that predominant isoform in ASM is SERCA2B with the other isoforms expressed at very low levels around the limit of detection. The pattern of ...

Both ceftazidime and avibactam penetrated dose-proportionally into ELF, with ELF exposure to both drugs ∼ 30% of plasma exposure.

Optic neuropathies are a group of optic nerve (ON) diseases caused by various insults including glaucoma, inflammation, ischemia, trauma, and genetic deficits, which are characterized by retinal ganglion cell (RGC) death and ON degeneration. An increasing number of genes involved in RGC intrinsic signaling have been found to be promising neural repair targets that can potentially be modulated directly by gene therapy, if we can achieve RGC specific gene targeting. To address this challenge, we first used adeno-associated virus (AAV)-mediated gene transfer to perform a low-throughput in vivo screening in both male and female mouse eyes and identified the mouse c-synuclein (mSncg) promoter, which specifically and potently sustained transgene expression in mouse RGCs and also works in human RGCs. We further demonstrated that gene therapy that combines AAV-mSncg promoter with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing can knock down pro-degenerative genes in RGCs and provide effective neuroprotection in optic neuropathies.

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The data support the hypothesis that asthmatic smokers develop neutrophilic inflammation of the airways propagated at least partly by smoke-induced production of IL-17A which together with smoke and other environmental stimuli acts on airways epithelial cells to induce neutrophil chemotaxins.

IntroductionBeta-lactams (BL) are the most frequently reported drug allergy, but the vast majority of patients are found not to be genuinely allergic after evaluation. Few studies have investigated the clinical predictors of genuine BL allergy, and the prevalence in hospitalized Chinese patients is unknown.MethodsPatients admitted to a tertiary hospital in Hong Kong (HK) were analyzed to identify the prevalence and factors associated with the presence of BL allergy labels among hospitalized Chinese patients. A combined cohort of patients having completed allergy investigation for suspected BL allergies in the United Kingdom (UK) and HK were analyzed to identify predictors of genuine allergy.ResultsThe prevalence of BL allergy labels in hospitalized HK Chinese was 5%, which was associated with female gender and concomitant non-BL antibiotic allergy labels. The rate of genuine BL allergy patients referred for suspected allergies in the UK and HK cohort was only 14%. History of anaphylaxis and interval of less than a year since the index reaction were independent clinical predictors of genuine BL allergy. The negative predictive value of penicillin skin testing was 90%, confirming the need for drug provocation testing after negative skin testing. There was a high rate of confirmed piperacillin-tazobactam allergy.DiscussionThe estimated true prevalence of genuine BL allergy in hospitalized HK Chinese is around 0.5%. This high rate of BL mislabeling highlights the need for comprehensive allergy evaluation and screening. History of anaphylaxis and duration since the index reaction are important predictors of genuine allergy. Piperacillin-tazobactam allergy may pose a unique challenge in this population with a high prevalence of suspected allergies, surging antibiotic resistance, and lack of testing available.

Background The outbreak of the COVID-19 pandemic facilitated a rapid transition to non-face-to-face models of care across the allergy services. Objective To describe the outcomes of the use of synchronous telemedicine for outpatient consultations in a tertiary adult allergy centre. Methods We retrospectively reviewed all non-face-to-face appointments during the second month of the pandemic in the UK. Results A total of 637 non-face-to-face appointments for unique patients were booked between 1 and 30 April 2020; 91% were new consultations. Most referrals (81.5%) were related to non-drug reactions. The overall ‘Did Not Attend’ rate was 15.7%. A total of 439 patients were assessed for non-drug reactions; 87% were new appointments. Food-related reactions (50.4%), urticaria/angioedema (23.2%) and rhinitis (18.1%) were the most common reasons for new referrals. Two hundred twenty-one (57.7%) of these patients required further allergy testing, primarily for suspected food allergy. More than 42% of the new patients, mainly referred for urticaria/angioedema, were discharged following their remote assessment. Less than 10% of the follow-up patients required additional testing. Ninety-seven new patients were assessed for a suspected drug reaction, predominantly to beta-lactam antibiotics (57.7%). Sixty-nine patients (71%) required further investigations, but a notable 29% did not require further allergy input. The overall experience was very good/good for most patients (85%). Conclusion Telemedicine can transform the current models of allergy care. Screening criteria for selecting suitable new patients are required. A telemedicine-based drug allergy service model can be more time- and cost-effective, and improve patient access to specialist care.

Backgroundp38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.ObjectivesThese studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.MethodsThe p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18–55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40–85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations.ResultsThe p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38β isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout.ConclusionAlthough p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.