We evaluated tolerance, safety, and effects on lung function and bronchial responsiveness of BAL (4 × 50 ml) combined with BB (three to five specimens) performed without premedication in 13 mild and ...stable asthmatics and eight healthy volunteers. All subjects tolerated bronchoscopy procedures well and without serious side effects. During procedures, no supplemental oxygen was administered and no ECG abnormalities were noted. The PEFR was measured before and immediately after bronchoscopy and at 5-min intervals up until recovery. The maximal percentage fall in PEFR after bronchoscopy was significantly greater in asthmatics (23.1 ± 13.9 percent) compared to normal subjects (7.8 ± 8.2 percent, p<0.01). Changes in PEFR returned to baseline values within 120 min in all asthmatics. The tcPo2 was recorded at baseline, during and after bronchoscopy. In both groups, a significant change in tcPo2 was measured during the infusion of BAL aliquots, and persisted throughout the procedure. A significant difference in asthmatics compared to healthy subjects was evident during BB and at the end of the procedure (p<0.05). In asthmatics, M challenge was performed on three different days over a three-week period prior to bronchoscopy, and was repeated at intervals of 2, 6, and 24 h following procedure. The PC20 M values measured before bronchoscopy were found to have a very high reproducibility (intraclass correlation coefficient = 0.93). The PC20 values measured during experiment times after bronchoscopy were not significantly different from baseline values. These data demonstrate that in mild and stable asthmatics, BAL combined with BB can be safely performed following administration of only local anesthesia. In carefully selected asthmatic subjects, transient bronchoconstriction and a lowering of oxygen tension can be induced by BAL and BB, whereas changes in bronchial responsiveness are more unlikely to occur.
In this study, we tested the hypothesis that walking capacity, assessed by the 6-min walk test (6MWT), could be related to the effect of flight simulation at sea level obtained by the ...hypoxia-altitude simulation test (HAST) in patients with chronic respiratory disease.
There were 15 patients with interstitial lung disease and 15 patients with chronic obstructive pulmonary disease who were recruited. Their baseline SpO2 values ranged from 88 to 98%. All patients performed the 6MWT and HAST according to standardized methods.
Patients covered a walking distance ranging from 185 to 592 m without stopping while experiencing no to severe dyspnea. No correlation was found between dyspnea perception during walking, walking distance, and oxygen desaturation during HAST. The oxygen desaturation induced by the 6MWT was related to that after HAST (r = 0.52, p < 0.01). The bias and limits of agreement between the oxygen desaturation after the 6MWT and after the HAST were 0.8 and -6.6 to 8.2%, respectively. The baseline SpO2 could reliably predict the oxygen desaturation during HAST (r2 = 0.51).
Our results showed that measurement of SpO2 during 6MWT can provide useful information for the preflight assessment and the in-flight oxygen prescription of patients with chronic respiratory disease.
Pleural involvement in systemic disorders Aiello, Marina; Chetta, Alfredo; Marangio, Emilio ...
Current drug targets. Inflammation & allergy
3, Številka:
4
Journal Article
The collagen vascular diseases are a heterogeneous group of immunologically-mediated inflammatory disorders. Frequently, these diseases affect organ systems outside the thorax as their primary ...manifestation, but may involve the pleura as a single presenting feature, as part of multisystem involvement, or as an isolated manifestation of a disease that is otherwise quiescent. In this article, we review the manifestations of respiratory disease caused by rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis/dermatomyositis, mixed connective tissue disease, Sjogren's syndrome, Wegener's granulomatosis, and sarcoidosis.
To assess the impact of long-term treatment with topical timolol on bronchial reactivity in healthy individuals.
Twenty-one otherwise healthy individuals with high-pressure primary open-angle ...glaucoma were enrolled in a randomized controlled clinical trial. Eleven patients underwent 3 years of topical 0.5% timolol treatment followed by a 1-year washout period; 10 patients underwent primary argon laser trabeculoplasty. Functional variables and bronchial reactivity (forced expiratory volume in 1 second and metacholine challenge test results) were assessed in both groups at enrollment and after 3 and 4 years of follow-up.
After 3 years, a measurable response to metacholine challenge was recorded in 6 of 11 otherwise symptom-free individuals treated with 0.5% timolol twice daily. A detectable response to metacholine challenge was still present in half of these individuals (3 of 6) when further washed out for 1 year from the topical beta-blocker. No significant variation in bronchial reactivity was measured in the laser-treated group during 4 years of follow-up.
Healthy individuals who undergo long-term topical application of a nonselective beta-blocker (0.5% timolol) can develop a subclinical increase in bronchial reactivity. This phenomenon may not be completely reversible on withdrawal of the beta-blocker.
Various pleuro-pulmonary abnormalities are known to complicate vascular collagen diseases, particularly, rheumatoid arthritis. Each component of the respiratory system is affected, either separately ...or in combination. Although most pulmonary complications appear in an established case of collagen vascular disease, in certain conditions, the lung disease precedes the more typical manifestation. While some complications are asymptomatic and tend to be resolved spontaneously (for e.g. pleuritis and rheumatoid nodules), others may cause severe or fatal conditions (interstitial pneumonia and constrictive bronchiolitis). The incidence of interstitial lung disease is increasing in vascular collagen disease. This may be mainly attributed to the increase use of invasive techniques such as bronchoscopy and video-assisted thoracoscopic surgery and in part due to the use of high resolution computed tomography, and functional pulmonary tests.
A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic ...castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119–mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7–driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.
Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. ...Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.
Inactivating mutations of the multiple endocrine neoplasia 1 (
) gene cause MEN1 syndrome, characterized by primary hyperparathyroidism (pHPT), and parathyroid and gastro-entero-pancreatic pituitary ...tumors. At present, only 14 cases of malignant parathyroid tumor have been associated with the syndrome, with 6 cases carrying an inactivating mutation of the
gene. The present study presents the case of a 48-year-old female who presented with multigland pHPT and multiple pancreatic lesions. The patient underwent surgery several times for the excision of parathyroid hyperplasia, carcinoma and adenoma. The
gene was screened, revealing three variants (in cis) at the intron/exon 3 boundary (IVS2-3G>C, c.497A>T and c.499G>T) detected on the DNA of the proband, not shared by her relatives. RNA sequencing revealed that the IVS2-3C>G variant caused the skipping of the exon 3. Therefore, the present study reports on a novel rare association of MEN1 syndrome and parathyroid carcinoma. The reported splicing mutation was previously identified in subjects who always developed malignant lesions; thus, a possible genotype-phenotype association may be considered.
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