Non-classic cystic fibrosis associated with D1152H CFTR mutation.

BACKGROUND: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. METHODS: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Phenotypic characteristics were compared with those of pancreatic insufficient (PI) and pancreatic sufficient (PS) cystic fibrosis (CF) subjects in the Registry (CF cohort). RESULTS: Forty-two subjects with D1152H alleles were identified. Features leading to diagnosis included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2). Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Estimated rates of decline in forced expiratory volume in 1 s (FEV(1)) were lower in D1152H subjects vs PI CF subjects (p < 0.05). None of the D1152H subjects identified since 1999 had died or required lung transplantation. CONCLUSIONS: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival.

Factors associated with mucoid transition of Pseudomonas aeruginosa in cystic fibrosis patients.

Although the mucoid form of Pseudomonas aeruginosa (Pa) is largely responsible for the progression of lung disease in cystic fibrosis (CF), the relationship between factors relating daily-care regimes to mucoidy acquisition are as yet poorly investigated. Fifty-two CF patients registered at the CF centre of Dijon, France, were retrospectively evaluated from the date of Pa colonization either to the first positive sputum culture for mucoid Pa (n = 26) or to the last culture in which the Pa remained non-mucoid (n = 26). All clinical, pathological and therapeutic events were recorded. The association between the parameters collected and mucoid transition of Pa was assessed in a Cox model with time-dependant covariables. The mean follow-up was 4.7 + or - 4.3 years. Three independent parameters were associated with the higher risk of mucoid transition of Pa: persistence of Pa in sputum (OR 7.89; p <0.01), use of inhaled bronchodilators (OR 3.40; p = 0.04), and the use of inhaled colimycin (OR 4.04; p = 0.02). Isolation of Staphylococcus aureus, Haemophilus influenzae or Streptococcus pneumoniae in sputum was associated with a lower risk (OR 0.24; p < 0.01). Mucoid transition of Pa was associated with variables that reflected the severity of both lung disease and Pa colonization. Although they do not lead to prophylactic measures, these results corroborate the need to avoid Pa persistence.

Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes.

We determined the number and functional status of CD4+ CD25(high) regulatory T cells (Treg) in blood samples from patients with metastatic carcinoma, and evaluated their sensitivity to a single intravenous infusion of cyclophosphamide. Treg numbers were significantly higher in 49 patients with metastatic cancer (9.2% of CD4+ T cells) compared to 24 healthy donors (7.1%). These cells expressed the transcription factor forkhead box P3 (FoxP3), glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) and intracellular CD152, and demonstrated a suppressive activity in vitro against CD4+ CD25- autologous proliferation. At a single intravenous infusion, cyclophosphamide failed, in association with a non-specific immunotherapy by intratumoral bacille Calmette-Guérin (BCG), to modulate significantly Treg numbers or function. Metastatic cancer is associated with an expansion of peripheral blood CD4+ CD25(high) FoxP3+ GITR+ CD152+ Treg cells whose immunosuppressive properties do not differ from those of healthy subjects. Moreover, cyclophosphamide administration may not represent an optimal therapy to eliminate Treg, which further underlines the need to identify specific agents that would selectively deplete these cells.

[Leak monitoring in noninvasive ventilation]. / Monitorización de las fugas en ventilación no invasiva.

Nasal mask ventilation has been shown to be effective, but outcomes do not always match expectations because of mouth leaks, patient-ventilator asynchrony, or decreased upper airway patency. These developments are detected when they lead ultimately to circuit leaks that lower the effectiveness of ventilation through pressure loss, poor inspiratory triggering, and prolonged inspiratory time. The quality of sleep is affected, and adverse effects and treatment intolerance may arise. A number of ways to detect leaks and their practical consequences are proposed in this article. We applied 310 leak-detection procedures to 177 patients who had disappointing clinical, gasometric, or polysomnographic outcomes of ventilation. The leak-detection procedures varied according to the type of ventilation and the supposed underlying pathophysiological mechanism. Significant leaks were detected in 132 patients (76%); therapeutic changes were then prescribed to optimize outcomes. We present a practical method to apply in patients with suboptimal ventilation outcomes. If leaks can be detected during treatment, the probable cause of treatment failure can sometimes be established and possible pathophysiological mechanisms better understood. With this knowledge, it may be possible to improve ventilation.

Monitorización de las fugas en ventilación no invasiva / Leak monitoring in noninvasive ventilation

La ventilación por mascarilla nasal ha dado sobradas pruebas de su eficacia. Sin embargo, en ciertos casos los resultados no son los esperados. Tres mecanismos pueden explicar estos fallos: apertura bucal, desincronización paciente-respirador y disminución de la permeabilidad de la vía respiratoria superior. Éstos pueden detectarse por su manifestación última: las fugas en el circuito, que reducen la eficacia de la ventilación (fallo de presurización, disfunción del trigger inspiratorio y prolongación del tiempo inspiratorio), alteran la calidad del sueño y producen efectos adversos e intolerancia al tratamiento. Proponemos aquí varias técnicas de detección de fugas y sus consecuencias prácticas. Se sometió a 177 pacientes, con resultados de la ventilación inferiores a los esperados (clínicos, gasométricos o poligráficos), a 310 procedimientos de detección de fugas, con montajes que variaron según la modalidad ventilatoria y el mecanismo fisiopatológico juzgado como responsable. Se detectaron fugas significativas en 132 pacientes (76 por ciento), lo cual impuso modificaciones terapéuticas para optimizar los resultados. Presentamos un método de aplicación práctica en casos en que se asista a resultados insuficientes de la ventilación. La detección de fugas bajo tratamiento ofrece la posibilidad de establecer la causa probable del fracaso, comprender el mecanismo fisiopatológico potencialmente responsable e intervenir en consecuencia (AU)