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International Journal For Parasitology.... Aug 2023The nematode genome exhibits a vast array of Cys-loop receptors that are activated by a diverse set of neurotransmitters and anthelmintic drugs such as ivermectin and...
The nematode genome exhibits a vast array of Cys-loop receptors that are activated by a diverse set of neurotransmitters and anthelmintic drugs such as ivermectin and levamisole. While many Cys-loop receptors have been functionally and pharmacologically characterized, there remains a large subset of orphan receptors where the agonist remains unknown. We have identified an orphan Cys-loop receptor, LGC-39, from the parasitic nematode Haemonchus contortus that is a novel type of cholinergic-sensitive ligand-gated chloride channel. This receptor groups outside of the acetylcholine-gated chloride channel family, in the previously named GGR-1 (GABA/Glycine Receptor-1) group of Cys-loop receptors. We found that LGC-39 forms a functional homomeric receptor when expressed in Xenopus laevis oocytes and is activated by several cholinergic ligands including acetylcholine, methacholine and surprisingly, atropine with an EC for atropine on the low μM range. A homology model was generated which revealed some key features of the LGC-39 ligand-binding pocket that may explain some of the elements important for atropine recognition of the LGC-39 receptor. Overall these results suggest that the GGR-1 family (now called LGC-57) of Cys-loop receptors includes novel acetylcholine-gated chloride channel subtypes and may represent important future drug targets.
Topics: Animals; Chloride Channels; Acetylcholine; Haemonchus; Ligands; Receptors, GABA; Cysteine Loop Ligand-Gated Ion Channel Receptors; Ligand-Gated Ion Channels; Cholinergic Agents; Atropine Derivatives
PubMed: 37054482
DOI: 10.1016/j.ijpddr.2023.04.001 -
Respiratory Care Apr 2023Spirometry tests with a bronchodilator response (BDR) in FEV a methacholine concentration that produces a 20% drop in FEV (PC) ≤ 2 mg/mL, and a positive exercise test...
BACKGROUND
Spirometry tests with a bronchodilator response (BDR) in FEV a methacholine concentration that produces a 20% drop in FEV (PC) ≤ 2 mg/mL, and a positive exercise test have high specificity for the diagnosis of asthma in children. However, the value of forced expiratory flow during the middle half of the FVC maneuver (FEF) in spirometry has been questioned. The objective of this study was to relate the BDR in FEF of spirometry tests with normal FEV and FEV/FVC to airway hyper-responsiveness (AHR) to methacholine or exercise in children age 5-15 y with clinical suspicion of asthma.
METHODS
This was a cross-sectional study of spirometry tests performed between January 2017-December 2019 in children age 5-15 y with diagnostic suspicion of asthma who had a methacholine and/or exercise testing within a period not exceeding 60 d between exams.
RESULTS
The mean (± SD) age of the children was 9.04 ± 2.67 y, with a range of 5-15 y, and 56.17% were male. Of the 324 spirometry tests with normal FEV and FEV/FVC, 66 (20.4%) tests showed BDR in FEF. A total of 46.9% and 33.3% of the children with and without BDR in FEF, respectively, had a PC value ≤ 2 mg/mL and/or a positive exercise testing ( = .039).
CONCLUSIONS
Children with suspected asthma and normal spirometry, other than BDR in FEF, had greater AHR than those without BDR in FEF. BDR in FEF was not always accompanied by AHR to confirm the diagnosis of asthma, so this study suggests that assessment of FEF alone is not always reliable for ruling in or ruling out AHR in the setting of otherwise normal spirometry results in children with suspected asthma.
Topics: Humans; Male; Child; Child, Preschool; Adolescent; Female; Bronchodilator Agents; Methacholine Chloride; Cross-Sectional Studies; Asthma; Respiratory Function Tests; Spirometry; Forced Expiratory Volume
PubMed: 36963964
DOI: 10.4187/respcare.10177 -
The Senior Care Pharmacist Jan 2023To investigate potential reasons for unusually high incidence of negative Methacholine Challenge Tests (MCT), following standardized MCT medication-hold protocol, in...
To investigate potential reasons for unusually high incidence of negative Methacholine Challenge Tests (MCT), following standardized MCT medication-hold protocol, in older people with physician-diagnosed asthma. An analysis of a longitudinal observational parent study of asthma. Community-dwelling participants were evaluated in an outpatient clinic and at home. Screening inclusion criteria for the parent study included 60 years of age or older, physician diagnosis of asthma, and a positive response to at least one of six asthma screening questions. Participants were enrolled in the study if they also demonstrate either: (1) a postbronchodilator administration response showing an increase of at least 12% and 200 mL in forced expiratory volume or an increase of at least 12% and 200 mL in forced vital capacity, or (2) an MCT result of PC20 ≤ 16 mg/mL (indicating bronchial hyper-responsiveness, MCT positive). Exclusion criteria included diagnosis of cognitive impairment or dementia, residing in a long-term care facility, more than 20 pack/ year smoking history or a history of smoking within the previous five years, inability to perform pulmonary function testing maneuvers, and a Prognostic Index score of greater than 10. Analysis of participant data for non-medication- and medication-exposure factors for association with negative MCT results. Anticholinergic burden and statin use were positively associated with negative MCT. Medications not accounted for in medication-hold protocols, and concurrently in use, may impact clinical tests and outcomes.
Topics: Humans; Aged; Methacholine Chloride; Polypharmacy; Asthma; Bronchial Provocation Tests; Forced Expiratory Volume
PubMed: 36751917
DOI: 10.4140/TCP.n.2023.29 -
Respirology (Carlton, Vic.) May 2023
Topics: Humans; Respiratory Function Tests; Asthma; Bronchi; Bronchial Provocation Tests; Methacholine Chloride; Bronchial Hyperreactivity; Forced Expiratory Volume
PubMed: 36722470
DOI: 10.1111/resp.14463 -
Klinische Padiatrie Mar 2023Chronic cough is one of the most common symptoms in childhood. Making a definite diagnosis is a challenge for all pediatricians especially in patients when cough is...
BACKGROUND
Chronic cough is one of the most common symptoms in childhood. Making a definite diagnosis is a challenge for all pediatricians especially in patients when cough is without an organic cause like in habit cough.
PATIENTS AND METHODS
In this retrospective analysis, all electronic outpatient charts of the Division of Allergology and Pneumology, between January 1, 2010 and December 31, 2019 were reviewed in order to study all children with potential habit cough. All children underwent the following diagnostic algorithms, skin prick test (SPT), measurement of fractional exhaled nitric oxide (FeNO), spirometry and methacholine challenge test (MCT). The value of a normal MCT and FeNO measurement for diagnosing habit cough was investigated.
RESULTS
The chart review revealed 482 patients with chronic cough>4 weeks. Of these, 99 (20.5%) with suspected habit cough were collected. 13 patients had to be excluded for other diagnosis and a complete data set was available in 55 patients. 33 (60.0%) of 55 patients were SPT negative and 22 (40.0%) had sensitization to common allergens. Five patients had elevated FeNO≥20 ppb and three showed severe bronchial hyperresponsiveness<0.1 mg methacholine, challenging the diagnosis of habit cough.
CONCLUSION
A normal FeNO and MCT can help confirm the clinical diagnosis of habit cough. However, in patients with positive MCT and/or elevated FeNO habit cough can be present. Especially in patients with elevated FeNO and severe BHR cough variant asthma and eosinophilic bronchitis have to be ruled out.
Topics: Child; Humans; Methacholine Chloride; Cough; Fractional Exhaled Nitric Oxide Testing; Retrospective Studies; Nitric Oxide; Chronic Disease; Breath Tests
PubMed: 36720225
DOI: 10.1055/a-2004-3477 -
British Journal of Sports Medicine Apr 2023To compare the performance of various diagnostic bronchoprovocation tests (BPT) in the assessment of lower airway dysfunction (LAD) in athletes and inform best clinical... (Meta-Analysis)
Meta-Analysis
Diagnostic approach to lower airway dysfunction in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus on 'acute respiratory illness in the athlete'.
OBJECTIVES
To compare the performance of various diagnostic bronchoprovocation tests (BPT) in the assessment of lower airway dysfunction (LAD) in athletes and inform best clinical practice.
DESIGN
Systematic review with sensitivity and specificity meta-analyses.
DATA SOURCES
PubMed, EBSCOhost and Web of Science (1 January 1990-31 December 2021).
ELIGIBILITY CRITERIA
Original full-text studies, including athletes/physically active individuals (15-65 years) who underwent assessment for LAD by symptom-based questionnaires/history and/or direct and/or indirect BPTs.
RESULTS
In 26 studies containing data for quantitative meta-analyses on BPT diagnostic performance (n=2624 participants; 33% female); 22% had physician diagnosed asthma and 51% reported LAD symptoms. In athletes with symptoms of LAD, eucapnic voluntary hyperpnoea (EVH) and exercise challenge tests (ECTs) confirmed the diagnosis with a 46% sensitivity and 74% specificity, and 51% sensitivity and 84% specificity, respectively, while methacholine BPTs were 55% sensitive and 56% specific. If EVH was the reference standard, the presence of LAD symptoms was 78% sensitive and 45% specific for a positive EVH, while ECTs were 42% sensitive and 82% specific. If ECTs were the reference standard, the presence of LAD symptoms was 80% sensitive and 56% specific for a positive ECT, while EVH demonstrated 65% sensitivity and 65% specificity for a positive ECT.
CONCLUSION
In the assessment of LAD in athletes, EVH and field-based ECTs offer similar and moderate diagnostic test performance. In contrast, methacholine BPTs have lower overall test performance.
PROSPERO REGISTRATION NUMBER
CRD42020170915.
Topics: Humans; Female; Male; Methacholine Chloride; Bronchoconstriction; Consensus; Bronchial Provocation Tests; Athletes; Asthma, Exercise-Induced; Forced Expiratory Volume
PubMed: 36717213
DOI: 10.1136/bjsports-2022-106059 -
PloS One 2023Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the...
INTRODUCTION
Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the bio-diversity of early microbial exposure. This study aims to evaluate the effect of early-life farm exposure on airway hyperresponsiveness and cough hypersensitivity in an allergic airway inflammation rabbit model.
METHOD
A specific environment was applied to pregnant rabbits and their offspring until six weeks after birth. Rabbits were housed in a pathogen-free zone for the control group and a calf barn for the farm group. At the end of the specific environmental exposure, both groups were then housed in a conventional zone and then sensitized to ovalbumin. Ten days after sensitization, the rabbit pups received ovalbumin aerosols to provoke airway inflammation. Sensitization to ovalbumin was assessed by specific IgE assay. Cough sensitivity was assessed by mechanical stimulation of the trachea, and bronchial reactivity was assessed by methacholine challenge. The farm environment was characterized by endotoxin measurement.
RESULTS
A total of 38 rabbit pups were included (18 in the farm group). Endotoxin levels in the farm environment varied from 30 to 1854 EU.m-3. There was no significant difference in specific IgE values to ovalbumin (p = 0.826) between the two groups. The mechanical threshold to elicit a cough did not differ between the two groups (p = 0.492). There was no difference in the number of cough (p = 0.270) or the intensity of ventilatory responses (p = 0.735). After adjusting for age and weight, there was no difference in respiratory resistance before and after methacholine challenge.
CONCLUSION
Early exposure to the calf barn did not affect cough sensitivity or bronchial reactivity in ovalbumin-sensitized rabbits. These results suggest that not all farm environments protect against asthma and atopy. Continuous exposure to several sources of microbial diversity is probably needed.
Topics: Animals; Rabbits; Cough; Methacholine Chloride; Bronchial Hyperreactivity; Dust; Farms; Ovalbumin; Inflammation; Bronchi; Immunoglobulin E; Endotoxins; Bronchoalveolar Lavage Fluid
PubMed: 36706084
DOI: 10.1371/journal.pone.0279498 -
International Journal of Medical... 2023Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER) breast cancer patients, a significant number of patients still develop metastasis or...
Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase () might play essential roles in the recurrence of tamoxifen-resistant ER patients. increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how regulates the tumor microenvironment for tamoxifen-resistant ER breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of , which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
Topics: Female; Humans; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Fulvestrant; Gene Expression Regulation, Neoplastic; Glutamate-Ammonia Ligase; MicroRNAs; Tamoxifen; Tumor Microenvironment
PubMed: 36619229
DOI: 10.7150/ijms.75625 -
Chest Apr 2023The purpose of this study was to investigate physiological phenotypes of asthma in obesity.
BACKGROUND
The purpose of this study was to investigate physiological phenotypes of asthma in obesity.
RESEARCH QUESTION
Do physiological responses during bronchoconstriction distinguish different groups of asthma in people with obesity, and also differentiate from responses simply related to obesity?
STUDY DESIGN AND METHODS
Cross-sectional study of people with obesity (31 with asthma and 22 without lung disease). Participants underwent methacholine challenge testing with measurement of spirometry and respiratory system impedance by oscillometry.
RESULTS
Participants had class III obesity (BMI, 46.7 ± 6.6 kg/m in control subjects and 47.2 ± 8.2 kg/m in people with asthma). Most participants had significant changes in peripheral airway impedance in response to methacholine: in control subjects, resistance at 5 Hz measured by oscillometry increased by 45% ± 27% and area under the reactance curve (AX) by 268% ± 236% in response to 16 mg/mL methacholine; in people with asthma, resistance at 5 Hz measured by oscillometry increased by 52% ± 38% and AX by 361% ± 295% in response to provocation concentration producing a 20% fall in FEV dose of methacholine. These responses suggest that obesity predisposes to peripheral airway reactivity. Two distinct groups of asthma emerged based on respiratory system impedance: one with lower reactance (baseline AX, 11.8; interquartile range, 9.9-23.4 cm HO/L) and more concordant bronchoconstriction in central and peripheral airways; the other with high reactance (baseline AX, 46.7; interquartile range, 23.2-53.7 cm HO/L) and discordant bronchoconstriction responses in central and peripheral airways. The high reactance asthma group included only women, and reported significantly more gastroesophageal reflux disease, worse chest tightness, more wheeze, and more asthma exacerbations than the low reactance group.
INTERPRETATION
Peripheral airway reactivity detected by oscillometry is common in obese control subjects and obese people with asthma. There is a subgroup of obese asthma characterized by significant peripheral airway dysfunction by oscillometry out of proportion to spirometric airway dysfunction. This peripheral dysfunction represents clinically significant respiratory disease not readily assessed by spirometry.
Topics: Female; Humans; Methacholine Chloride; Cross-Sectional Studies; Asthma; Respiratory System; Spirometry; Bronchial Provocation Tests; Obesity; Airway Resistance; Forced Expiratory Volume
PubMed: 36610669
DOI: 10.1016/j.chest.2022.12.030 -
Biology of Sex Differences Jan 2023Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of...
RATIONALE
Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of oral contraceptives decreased the onset of asthma in women of reproductive age. In the current study, we hypothesized that steady-state levels of estrogen would reduce airway inflammation and airway hyperresponsiveness to methacholine challenge.
METHODS
Ovariectomized BALB/c mice (Ovx) were implanted with subcutaneous hormone pellets (estrogen, OVX-E2) that deliver consistent levels of estrogen [68 ± 2 pg/mL], or placebo pellets (OVX-Placebo), followed by ovalbumin sensitization and challenge. In conjunction with methacholine challenge, immune phenotyping was performed to correlate inflammatory proteins and immune populations with better or worse pulmonary outcomes measured by invasive pulmonary mechanics techniques.
RESULTS
Histologic analysis showed an increase in total cell infiltration and mucus staining around the airways leading to an increased inflammatory score in ovarectomized (OVX) animals with steady-state estrogen pellets (OVX-E2-OVA) as compared to other groups including female-sham operated (F-INTACT-OVA) and OVX implanted with a placebo pellet (OVX-Pl-OVA). Airway resistance (Rrs) and lung elastance (Ers) were increased in OVX-E2-OVA in comparison to F-INTACT-OVA following aerosolized intratracheal methacholine challenges. Immune phenotyping revealed that steady-state estrogen reduced CD3+ T cells, CD19+ B cells, ILC2 and eosinophils in the BAL across all experiments. While these commonly described allergic cells were reduced in the BAL, or airways, we found no changes in neutrophils, CD3+ T cells or CD19+ B cells in the remaining lung tissue. Similarly, inflammatory cytokines (IL-5 and IL-13) were also decreased in OVX-E2-OVA-treated animals in comparison to Female-INTACT-OVA mice in the BAL, but in the lung tissue IL-5, IL-13 and IL-33 were comparable in OVX-E2-OVA and F-INTACT OVA mice. ILC2 were sorted from the lungs and stimulated with exogenous IL-33. These ILC2 had reduced cytokine and chemokine expression when they were isolated from OVX-E2-OVA animals, indicating that steady-state estrogen suppresses IL-33-mediated activation of ILC2.
CONCLUSIONS
Therapeutically targeting estrogen receptors may have a limiting effect on eosinophils, ILC2 and potentially other immune populations that may improve asthma symptoms in those females that experience perimenstrual worsening of asthma, with the caveat, that long-term use of estrogens or hormone receptor modulators may be detrimental to the lung microenvironment over time.
Topics: Female; Animals; Mice; Interleukin-33; Estradiol; Immunity, Innate; Interleukin-13; Methacholine Chloride; Allergens; Airway Resistance; Interleukin-5; Bronchoalveolar Lavage Fluid; Lymphocytes; Lung; Asthma; Cytokines; Estrogens
PubMed: 36609358
DOI: 10.1186/s13293-022-00483-7