Current opinion in pulmonary medicine
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Cystic fibrosis is characterized by a wide variability of clinical expression. The cloning of the cystic fibrosis transmembrane conductance regulator gene and the identification of its mutations has promoted extensive research into the association between genotype and phenotype. Several studies showed that there are mutations, such as delta F508 (the most common mutation worldwide), that are associated with a severe phenotype: early age at diagnosis, pancreatic insufficiency, poor nutritional status, high incidence of meconium ileus, and high sweat chloride levels; lung disease, however, is variable. ⋯ In vitro studies of cystic fibrosis transmembrane conductance regulator function suggested that different mutations cause different defects of protein production and function. Five mechanisms by which mutations disrupt cystic fibrosis transmembrane conductance regulator function have been suggested: class I mutations cause defective protein production, class II mutations are associated with defective protein processing, class III mutations are associated with defective regulation, class IV mutations are associated with defective conductance, and class V mutations include mutations affecting the level of normal messenger RNA transcript and protein required for normal function. This class might include mutations affecting correct splicing of pre-messenger RNA transcripts by either exon skipping or by inclusion of extra cryptic exons.
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In recent years, several functions of the cystic fibrosis transmembrane conductance regulator have been discovered, yet the pathophysiology of the pulmonary disease in cystic fibrosis remains unclear. At the cellular level, functions of this protein include regulation of chloride and sodium transport at the cell membrane and in intracellular organelles, regulation of protein trafficking, and posttranslational processing of glycoconjugates. ⋯ Current evidence suggests that defects in the cystic fibrosis transmembrane conductance regulator lead to alterations in periciliary fluid homeostasis, mucus hydration, mucin secretion, and apical membrane protein structure. In turn, these alterations impair mucociliary clearance and promote bacterial infection, which then leads to chronic airway inflammation and the development of bronchiectasis.
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Cystic fibrosis has only been recognized as a distinct clinical entity for less than 60 years. In that period of time, the median survival has improved from a few months to 29 years. ⋯ The discussion includes how the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator, produces lung disease; the relationship between genotype and phenotype; the factors that determine prognosis in cystic fibrosis; new treatment modalities for cystic fibrosis; lung transplantation; and the prospects for gene therapy in cystic fibrosis. With rapid advances in our clinical and genetic understanding of cystic fibrosis, it is projected that individuals born with cystic fibrosis today will live into their 40s.
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Pulmonary disorders in systemic lupus erythematosus involve a variety of clinical presentations and pathologic patterns, which can be difficult to diagnose due to systemic dysfunction, infection, or complications of therapy. The causes of dyspnea in systemic lupus erythematosus are multifactorial, and the clinical manifestations of lung disease widely vary. Biopsy is frequently relied on to evaluate and diagnose pulmonary disease in systemic lupus erythematosus. The patient who has systemic lupus erythematosus-associated lung disease is effectively treated with various immunosuppressive drugs, in conjunction with careful evaluation of the patient's systemic involvement, drug-induced complications, and the ever-present threat of infection.
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Pulmonary lymphangioleiomyomatosis is an uncommon chronic debilitating disorder of unknown etiology afflicting women of childbearing age, characterized histologically by proliferation of atypical smooth muscle cells in the lung. The clinical features of lymphangioleiomyomatosis can be typical, with airflow limitation, diffuse pulmonary infiltrates on chest radiograph, and numerous lung cysts on computed tomogram of the chest. ⋯ Hormonal manipulation therapy had beneficial effects on chylothorax or chylous ascites, whereas pulmonary parenchymal changes appeared to be stationary or progressive. Several prognostic factors were reported among pulmonary function data and histologic findings of open lung biopsy specimens.