Resistance of murine lung tumors to xenobiotic-induced cytotoxicity.

Studies were performed to test the hypothesis that urethane-induced murine lung tumors exhibit xenobiotic resistance and alterations in pulmonary cytochrome P-450 enzymes. 1,1-Dichloroethylene, naphthalene, and paraquat were administered to tumor-bearing and control mice to elicit acute lung cytotoxicity, and responses were evaluated in tumors (papillary and solid), uninvolved surrounding tissue, and untreated control lung. 1,1-Dichloroethylene (125 mg/kg, i.p.) and naphthalene (225 mg/kg, i.p.) caused preferential necrosis of Clara cells in control lungs and uninvolved tissue of tumor-bearing lungs. In contrast, papillary and solid tumors were both resistant to 1,1-dichloroethylene-induced cytotoxicity. Paraquat (10, 20 mg/kg, i.v.) elicited Clara cell damage in control lungs and uninvolved lung tissue of tumor-bearing mice, with minor disruption of the alveolar epithelium. Neither papillary nor solid tumors sustained any apparent cell damage from paraquat. Immunoblots of P-450 enzymes confirmed constitutive expression of CYP2B1 in control lung and uninvolved lung tissue of tumor-bearing mice, but this P-450 enzyme was not detected in either adenomas or carcinomas. Lung CYP1A1 was inducible by beta-naphthoflavone in non-tumor-bearing mice and uninvolved tissue of tumor-bearing mice; however, inducibility was decreased in adenomas and abolished in carcinomas. These results demonstrate resistance of lung tumor cells to chemically induced cytotoxicity and diminished expression of cytochrome P-450 enzymes in tumors.     

Pulmonary toxicity of trichloroethylene: induction of changes in surfactant phospholipids and phospholipase A2 activity in the mouse lung

Trichloroethylene (TCE) is a common organic solvent in use as a dry cleaning agent as well as an inhalant anesthetic. Nevertheless the effects of this material on the pulmonary surfactant which prevents alveolar collapse at maximal expiration is not known. Therefore, we have examined the effect of TCE on the intra- and extracellular surfactant pools and the activity of phospholipase A2, an enzyme which controls the remodeling of phosphatidylcholine to dipalmitoylphosphatidylcholine, the primary constituent of the pulmonary surfactant. Male CD-1 mice were treated ip with 2500 or 3000 mg/kg TCE. Twenty-four hours later mice were anesthetized and the lungs lavaged. Mice were then killed, the lungs perfused and excised, and subcellular fractions including lamellar bodies prepared. Some lungs were prepared for ultrastructural examination. Phospholipase A2 was assayed in all subcellular fractions. Phospholipid was assayed in the lavage (extracellular surfactant) and the lamellar bodies (intracellular surfactant). TCE (2500 mg/kg) caused selective exfoliation of Clara cells. However, only the dose of 3000 mg/kg TCE produced a significant decrease in the intracellular surfactant phospholipid. Minimal changes occurred in the phospholipid profiles. Phospholipase A2 specific activity was significantly decreased at both dosages within the lung microsomal fraction. In addition after treatment with 3000 mg/kg TCE the enzyme activity in the lamellar body fraction was significantly increased. These data suggest that inhalation of TCE may damage the enzymes which are responsible for synthesizing the pulmonary surfactant resulting in lower amounts of surfactant being stored and available for secretion into the alveolus.     

Exposure to trichloroethylene and its metabolites causes impairment of sperm fertilizing ability in mice.

Trichloroethylene (TCE) is a prevalent occupational and environmental contaminant that has been reported to cause a variety of toxic effects. Here, we have undertaken studies to test the hypothesis that TCE exposure adversely affects sperm function and fertilization. Sperm retrieved from mice exposed to TCE (1000 ppm) by inhalation for 1 to 6 weeks were incubated in vitro with eggs isolated from superovulated female mice. The number of sperm bound per egg was significantly decreased when mice were exposed to TCE for 2 and 6 weeks but not at exposures of 1 and 4 weeks. In vivo fertilization was also determined in superovulated female mice mated with males exposed to TCE for 2 to 6 weeks. The percentages of eggs fertilized, as assessed by the presence of two pronuclei, were significantly decreased after 2 and 6 weeks of TCE exposure. A slight but insignificant decrease was observed after 4 weeks of TCE exposure. The direct effects of TCE and its metabolites, chloral hydrate (CH) and trichloroethanol (TCOH), on in vitro sperm-egg binding were also investigated. Sperm-egg binding was significantly decreased when sperm were pretreated with CH (0.1-10 microg/mL). Significantly lower levels of sperm-egg binding were also detected with TCOH (0.1-10 microg/mL), although the decreases were not as pronounced as those for CH. These results showed that TCE exposure leads to impairment of sperm fertilizing ability, which may be attributed to TCE metabolites, CH, and TCOH.     

Distinct phenotypes of multisystem inflammatory syndrome in children: a cohort study

To characterize the clinical features and outcomes of childhood-onset primary Sjögren’s syndrome (pSS). Patients less than 18 years old who were diagnosed with pSS by paediatric rheumatologists were included, and all patients were applied the 2002 American-European Consensus Group (ACEG) criteria, the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for pSS, or the 1999 proposed juvenile pSS criteria. The electronic medical records of patients with pSS from 2013 to 2020 were collected and analysed. Thirty-nine patients were included. Of them, 27 (69.2%), 38 (97.4%) and 35 (89.7%) patients fulfilled the AECG criteria, ACR/EULAR criteria and proposed juvenile pSS criteria, respectively. The female:male ratio was 3.9:1. The median ages at first signs or symptoms and at diagnosis were 9.2 (4.7, 14.5) years and 10.9 (6.3, 15.0) years, respectively. The main clinical manifestations were rash or purpura (20, 51.3%), followed by fever (12, 30.8%), glandular enlargement/recurrent parotitis (10, 25.6%), and dry mouth and/or dry eyes (9, 23.1%). Twenty-eight (56.4%) patients had systemic damage, the most common of which was haematological involvement (14, 35.9%), followed by hepatic (13, 33.3%) and renal involvement (8, 20.5%). Thirty-eight (97.4%) patients underwent labial minor salivary gland biopsy, and all exhibited focal lymphocytic sialadenitis. All patients had a global ESSDAI score ≥ 1 at diagnosis, and the median total score at diagnosis was 8 (2, 31). Thirty-six (92.3%) patients were followed up for a median time of 23.6 (7.9, 79.5) months, and three patients developed systemic lupus erythematosus (SLE) at follow-up times of 13.3, 38.8 and 63.8 months. The presentation of childhood-onset pSS is atypical, and extraglandular manifestations and systemic involvement are more common than in adult-onset pSS. Labial salivary gland biopsy is vital for patients with probable pSS. Some patients may develop SLE over time.     

Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation

OBJECTIVES: Current criteria use FEV(1) to assess bronchodilator responsiveness, despite its insensitivity and inability to predict improvement in symptoms or exercise tolerance. Response in lung volumes remains largely unexplored even though volume parameters, such as inspiratory capacity (IC), closely correlate with functional improvements. Therefore, we assessed the response of lung volumes (i.e., by IC, total lung capacity [TLC], functional residual capacity [FRC], residual volume [RV], and FVC) to salbutamol and the relationship of these changes to improvements in the spirometry in these patients. DESIGN: A retrospective review of data extracted from a large database of patients who were undergoing spirometry and static lung volume measurements before and after the administration of 200 microg salbutamol. PATIENTS: Patients with an FEV(1)/FVC ratio of < 85% of predicted values were defined as being severely hyperinflated (SH) if TLC was > 133% of predicted and as being moderately hyperinflated (MH) if TLC was 115 to 133% of predicted. RESULTS: Two hundred eighty-one SH patients and 676 MH patients were identified. Salbutamol significantly reduced the mean (+/- SEM) TLC (SH patients, 222 +/- 23 mL; MH patients, 150 +/- 10 mL; p < 0.001), FRC (SH patients, 442 +/- 26 mL; MH patients, 260 +/- 39 mL; p < 0.001), and RV (SH patients, 510 +/- 28 mL; MH patients, 300 +/- 14 mL; p < 0.001) and increased both the IC (SH patients, 220 +/- 15 mL; MH patients, 110 +/- 11 mL; p < 0.001) and FVC (SH patients, 336 +/- 21 mL; MH patients, 204 +/- 13 mL; p < 0.001). FEV(1) improved in a minority of patients (SH patients, 33%; MH patients, 26%), but if lung volume measurements are also considered, the overall bronchodilator response may improve to up to 76% of the SH group and up to 62% of the MH group. Changes in volumes correlated poorly with changes in maximal airflows. CONCLUSIONS: Bronchodilators reduce hyperinflation. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness.     

The effect of vagal stimulation on the distribution of inspired gas in the lungs.

We investigated the direct effects of efferent vagal activity on the distribution of inspired gas by stimulating the vagus nerve of one lung and measuring the topographic distribution of a radioactive tracer (133Xe) to both lungs. The distribution of inspired (133Xe) boli was measured with NaI scintillation detectors placed apex-base over each posterior lung of intubated, paralyzed, anesthetized dogs. In 7 supine dogs vagal stimulation reduced the distribution of rapidly insufflated 133Xe boli (flow greater than 2.5 L/s) to the test lung (P less than 0.02), but not when boli were insufflated slowly (flow less than 0.5 L/s), suggesting that vagal stimulation affects pulmonary gas distribution primarily by increasing airway resistance and not through changes in lung compliance. The effect of vagal stimulation on the regional apex-base distribution of inspired gas (greater than 2.5 L/s) was measured in 7 supine and 5 upright dogs. In the supine position, vagal stimulation did not change the uniform apex-base bolus distribution, whereas in the upright position less of the bolus was distributed to the middle and lower lung regions (P less than 0.043), compared to control measurements. This indicates that the regional effects of vagal stimulation on the distribution of inspired gas are uniform in the supine position, but that vagal stimulation alters the distribution of inspired gas when the apex-base pleural pressure gradient is increased.     

Multivariate dynamic prediction of ischemic infarction and tissue salvage as a function of time and degree of recanalization

Benefit of endovascular recanalization beyond established treatment time windows likely exists in select stroke patients. However, there is currently no imaging model that predicts infarction adjusting for elapsed time between the pathologic snapshot of admission imaging until endovascular recanalization. We trained and cross validated a multivariate generalized linear model (GLM) that uses computer tomography perfusion and clinical data to quantify patient-specific dynamic change of tissue infarction depending on degree and time of recanalization. Multicenter data of 161 patients with proximal anterior circulation occlusion undergoing endovascular therapy were included. Multivariate voxelwise infarct probability was calculated within the GLM. The effect of increasing time to treatment and degree of recanalization on voxelwise infarction was calculated in each patient. Tissue benefit of successful relative to unsuccessful recanalization was shown up to 15 hours after onset in individual patients and decreased nonlinearly with time. On average, the relative reduction of infarct volume at the treatment interval of 5 hours was 53% and this salvage effect decreased by 5% units per hour to <5% after 10 additional hours to treatment. Treatment time-adjusted multivariate prediction of infarction by perfusion and clinical status may identify patients who benefit from extended time to recanalization therapy.     

Flock Worker's Lung Disease: Natural History of Cases and Exposed Workers in Kingston,Ontario

BackgroundThe natural history of flock worker's lung (FWL) and longitudinal lung function changes in nylon flock-exposed workers have not been well characterized.MethodsSymptoms, pulmonary function testing, and chest radiographs from five index cases, subsequent case referrals, and screened employees of a flocking plant in Kingston, Ontario, Canada, were compared and analyzed for changes over time (variable follow-up intervals between 1991 and 2011).ResultsNine cases and 30 flock-exposed workers without FWL were identified. Four cases had persistent interstitial lung disease despite three having left the workplace. Two developed hypoxemic respiratory failure and secondary pulmonary hypertension and died of complications 18 and 20 years after diagnosis, respectively. Five cases resolved after leaving the workplace. Compared with resolved cases, persistent cases had lower diffusing capacity of the lung for carbon monoxide at presentation (P < .05) and follow-up (P < .05). Among exposed workers employed for 14.5 ± 4.7 years, five had abnormal chest radiographs vs none at baseline (P = .001) over 14.8 ± 4.6 years of follow-up. The prevalence of wheeze increased (P = .001), and FEV₁/FVC decreased (P < .001). FEV₁ % predicted was significantly lower at follow-up (P = .05). Average FEV₁ decline was 46 mL/year (range, ?27 to 151 mL/y). Seventy-seven percent of exposed workers were current or former smokers.ConclusionsThe natural history of FWL includes the following patterns: complete resolution of symptoms; radiographic and pulmonary function abnormalities; permanent, but stable symptoms and restrictive pulmonary function deficits; and progressive decline in pulmonary function, causing death from respiratory failure and secondary pulmonary hypertension. A low baseline diffusing capacity of the lung for carbon monoxide is associated with the persistence and progression of FWL.     

Interregional gas mixing and gas transport during high frequency oscillations

We investigated gas mixing between lung regions and its relationship to gas transport out of the lungs during high frequency oscillation (HFO) in eight, healthy male volunteers. Gas mixing within the lung during HFO was assessed by measuring changes in the regional concentration of 133Xenon with scintillation detectors positioned over the posterior chest, 5, 15 and 25 cm below each lung apex. Gas transport out of the lungs was assessed by measuring changes in 133Xenon concentration at the mouth during HFO. Mixing between topographic lung regions from the apex to base was increased by both the stroke volume (P less than 0.05) and the frequency (P less than 0.05) of HFO. This mixing correlated best with the product of f X SV1.5 (r = 0.99 P less than 0.001). Changes in regional gradient with HFO showed a strong positive correlation with changes in mouth concentration (r = 0.94, P less than 0.025). We conclude that gas mixing between lung regions in man is increased more by stroke volume than frequency during HFO. This mixing is closely related to gas transport out of the lungs.