Distinguishing alpha1-antitrypsin deficiency from asthma

AbstractObjectiveTo explore the relations that exist between α1-antitrypsin deficiency (AATD) and asthma and to evaluate practices for screening patients with asthma for this genetically determined condition in the context of current guidelines.Data SourcesEnglish-language articles were selected from a PubMed search using combinations of the following search terms: alpha1-antitrypsin, screening, and asthma.Study SelectionsStudies to be included in this review were based on the authors' expert opinions.ResultsAsthma and AATD are 2 distinct conditions yet they can coexist. Although AATD has a variable symptomatology and some patients may be asymptomatic, many can present with symptoms that are similar to those of asthma, such as dyspnea, wheezing, cough, and mucus production, which can cause confusion at diagnosis. A simple genetic test exists for AATD, which is a single-gene disorder, and the American Thoracic Society and European Respiratory Society guidelines recommend the screening of patients with asthma who exhibit chronic airflow obstruction. Patients with AATD are seen by internal medicine, family medicine, allergy, and pulmonary clinicians, yet there is a generalized lack of awareness of testing among all specialties. This leads to a delayed diagnosis for patients with AATD, typically by 8.3 years.ConclusionA greater awareness of AATD among clinicians who regularly manage patients with asthma symptoms could increase diagnosis rates, thus optimizing interventions and management strategies to improve patient outcomes

Angiotensin I-Converting Enzyme Mutation (Trp1197Stop) Causes a Dramatic Increase in Blood ACE

BACKGROUND:Angiotensin-converting enzyme (ACE) metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases, including asthma. Previously, a molecular mechanism underlying a 5-fold familial increase of blood ACE was discovered: Pro1199Leu substitution enhanced the cleavage-secretion process. Carriers of this mutation were Caucasians from Europe (mostly Dutch) or had European roots. METHODOLOGY/PRINCIPAL FINDINGS:We have found a family of African-American descent whose affected members' blood ACE level was increased 13-fold over normal. In affected family members, codon TGG coding for Trp1197 was substituted in one allele by TGA (stop codon). As a result, half of ACE expressed in these individuals had a length of 1196 amino acids and lacked a transmembrane anchor. This ACE mutant is not trafficked to the cell membrane and is directly secreted out of cells; this mechanism apparently accounts for the high serum ACE level seen in affected individuals. A haplotype of the mutant ACE allele was determined based on 12 polymorphisms, which may help to identify other carriers of this mutation. Some but not all carriers of this mutation demonstrated airflow obstruction, and some but not all have hypertension. CONCLUSIONS/SIGNIFICANCE:We have identified a novel Trp1197Stop mutation that results in dramatic elevation of serum ACE. Since blood ACE elevation is often taken as a marker of disease activity (sarcoidosis and Gaucher diseases), it is important for clinicians and medical scientists to be aware of alternative genetic causes of elevated blood ACE that are not apparently linked to disease

Comprehensive Genetic Testing Identifies Targetable Genomic Alterations in Most Patients with Non-Small Cell Lung Cancer, Specifically Adenocarcinoma, Single Institute Investigation

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future

A Systematic Review of Digital vs Analog Drainage for Air Leak After Surgical Resection or Spontaneous Pneumothorax

Background The concerns regarding air leak after lung surgery or spontaneous pneumothorax include detection and duration. Prior studies have suggested that digital drainage systems permit shorter chest tube duration and hospital length of stay (LOS) by earlier detection of air leak cessation. We conducted a systematic review to assess the impact of digital drainage on chest tube duration and hospital LOS after pulmonary surgery and spontaneous pneumothorax. Methods Ovid MEDLINE, PubMed, Embase, the Cochrane Library, Scopus, and Google Scholar were searched from inception through January 2019. We included randomized controlled trials, cohort studies, and case series of adult patients, using digital or traditional drainage devices for air leaks of either postsurgical or spontaneous pneumothorax origin. Results Of 1,272 references reviewed, 23 articles were included. Nineteen articles addressed postoperative air leak, and four articles pertained to air leak after spontaneous pneumothorax. Thirteen studies were randomized controlled trials. Digital drainage resulted in significantly shorter chest tube duration in eight of 18 studies and shorter hospital LOS in six of 14 studies for postoperative air leak. For postpneumothorax air leak, digital drainage resulted in significantly shorter chest tube duration in two of three studies and hospital LOS in one of two studies with an analog control group. Conclusions Most studies show no significant differences in chest tube duration and hospital LOS with digital vs analog drainage systems for patients with air leak after pulmonary resection. For post-spontaneous pneumothorax air leak, the limited published evidence suggests shorter chest tube duration and hospital LOS with digital drainage systems

A novel angiotensin I-converting enzyme mutation (S333W) impairs N-domain enzymatic cleavage of the anti-fibrotic peptide, AcSDKP

BACKGROUND: Angiotensin I-converting enzyme (ACE) has two functional N- and C-domain active centers that display differences in the metabolism of biologically-active peptides including the hemoregulatory tetrapeptide, Ac-SDKP, hydrolysed preferentially by the N domain active center. Elevated Ac-SDKP concentrations are associated with reduced tissue fibrosis. RESULTS: We identified a patient of African descent exhibiting unusual blood ACE kinetics with reduced relative hydrolysis of two synthetic ACE substrates (ZPHL/HHL ratio) suggestive of the ACE N domain center inactivation. Inhibition of blood ACE activity by anti-catalytic mAbs and ACE inhibitors and conformational fingerprint of blood ACE suggested overall conformational changes in the ACE molecule and sequencing identified Ser333Trp substitution in the N domain of ACE. In silico analysis demonstrated S333W localized in the S 1 pocket of the active site of the N domain with the bulky Trp adversely affecting binding of ACE substrates due to steric hindrance. Expression of mutant ACE (S333W) in CHO cells confirmed altered kinetic properties of mutant ACE and conformational changes in the N domain. Further, the S333W mutant displayed decreased ability (5-fold) to cleave the physiological substrate AcSDKP compared to wild-type ACE. Conclusions and Significance A novel Ser333Trp ACE mutation results in dramatic changes in ACE kinetic properties and lowered clearance of Ac-SDKP. Individuals with this mutation (likely with significantly increased levels of the hemoregulatory tetrapeptide in blood and tissues), may confer protection against fibrosis

Expert Statement:Pneumothorax Associated with One-Way Valve Therapy for Emphysema: 2020 Update

For selected patients with advanced emphysema, bronchoscopic lung volume reduction with one-way valves can lead to clinically relevant improvements of airflow obstruction, hyperinflation, exercise capacity, and quality of life. The most common complication of this procedure is pneumothorax with a prevalence of up to +/- 34% of the treated patients. Patients who develop a pneumothorax also experience meaningful clinical benefits once the pneumothorax is resolved. Timely resolution of a post-valve treatment pneumothorax requires skilled and adequate pneumothorax management. This expert panel statement is an updated recommendation of the 2014 statement developed to help guide pneumothorax management after valve placement. Additionally, mechanisms for pneumothorax development, risk assessment, prevention of pneumothorax, and outcomes after pneumothorax are addressed. This recommendation is based on a combination of the current scientific literature and expert opinion, which was obtained through a modified Delphi method

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H(+) into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired.Fil: Riazanski, Vladimir. University of Chicago; Estados UnidosFil: Gabdoulkhakova, Aida G.. University of Chicago; Estados UnidosFil: Boynton, Lin S.. University of Chicago; Estados UnidosFil: Eguchi, Raphael R.. University of Chicago; Estados UnidosFil: Deriy, Ludmila V.. University of Chicago; Estados UnidosFil: Hogarth, D. Kyle. University of Chicago; Estados UnidosFil: Loaëc, Nadège. ManRos Therapeutics; FranciaFil: Oumata, Nassima. ManRos Therapeutics; FranciaFil: Galons, Hervé. Universite de Paris; FranciaFil: Brown, Mary E.. University of Chicago; Estados UnidosFil: Shevchenko, Pavel. University of Chicago; Estados UnidosFil: Gallan, Alexander J.. University of Chicago; Estados UnidosFil: Yoo, Sang Gune. University of Chicago; Estados UnidosFil: Naren, Anjaparavanda P.. Cincinnati Children’s Hospital Medical Center; Estados UnidosFil: Villereal, Mitchel L.. University of Chicago; Estados UnidosFil: Beacham, Daniel W.. Thermo Scientific; Estados UnidosFil: Bindokas, Vytautas P.. University of Chicago; Estados UnidosFil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Meijer, Laurent. ManRos Therapeutics; FranciaFil: Nelson, Deborah J.. University of Chicago; Estados Unido

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder