83 research outputs found
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 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
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
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: LoaĂ«c, Nadège. ManRos Therapeutics; FranciaFil: Oumata, Nassima. ManRos Therapeutics; FranciaFil: Galons, HervĂ©. 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 CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - La Plata. Instituto de Investigaciones BiotecnolĂłgicas. Universidad Nacional de San MartĂn. Instituto de Investigaciones BiotecnolĂłgicas; ArgentinaFil: Meijer, Laurent. ManRos Therapeutics; FranciaFil: Nelson, Deborah J.. University of Chicago; Estados Unido
Alcohol devaluation has dissociable effects on distinct components of alcohol behaviour
Rationale Substance-related behaviour is often viewed as an appetitive behaviour, motivated by the reinforcing effects of the drug. However, there are various indices of substance motivation (e.g. attentional bias, behavioural economic demand, craving) and it is unclear how these are related or whether they play an important role in all types of substance-related behaviour. Objectives (1) To determine the effect of alcohol devaluation on several indices of alcohol motivation and goal-directed and cue-elicited alcohol behaviour. (2) To investigate which components of motivation mediate any effect of devaluation on behaviour. Methods Sixty-two social drinkers gave baseline measures of alcohol craving, behavioural economic demand and choice for alcohol vs. soft drink. Participants tasted alcohol which was either unadulterated (control) or adulterated with a bitter solution (devaluation) before craving and demand were measured again. Alcohol choice was assessed in several phases: extinction (evaluating goal-directed behaviour), in the presence of drink cues (Pavlovian-to-instrumental transfer (PIT, cue-elicited behaviour)), and reacquisition. Attentional bias (AB) was measured by tracking eye movements towards the drink cues during novel PIT trials where both cues were presented. Finally, consumption was evaluated in a taste test. Results Alcohol devaluation reduced alcohol-related demand, AB, alcohol choice in all phases, and consumption. Alcohol cues presented during PIT increased alcohol choice above baseline irrespective of devaluation. AB and demand for alcohol fully mediated the effect of devaluation on alcohol choice during extinction, AB fully mediated the effect on cue-elicited (specific PIT) alcohol choice and alcohol consumption. Conclusions Alcohol behaviour in social drinkers is largely sensitive to devaluation, i.e. governed by current motivational value of the drug (suggesting goal-directed behaviour). However, a dissociable form of stimulus control can also drive alcohol-seeking independently of drug value (specific PIT). Mediation analyses suggests that AB may play a paradoxical role in both forms of alcohol seeking and consumption
Interstitial lung disease and gastroesophageal reflux disease: key role of esophageal function tests in the diagnosis and treatment
- …