ECFS standards of care on CFTR-related disorders: Diagnostic criteria of CFTR dysfunction.

The spectrum of disorders involving CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction correlates with a continuous gradient of CFTR function defined by the combination of two allelic CFTR variants. CFTR-related disorders are clinical entities with features of cystic fibrosis (CF) and evidence for presence of CFTR dysfunction but not meeting criteria for diagnosis of CF. Individuals with CFTR-RDs demonstrate a wide range of CFTR activity and are still under-recognized or misclassified. The level of CFTR dysfunction may be measured in vivo (sweat testing, nasal potential difference measurements) and/or by ex vivo tests (intestinal current measurement), or indirectly indicated by CFTR variants, as alteration in sequence of the CFTR gene translates into CFTR dysfunction. CFTR bioassays can aid in the diagnosis of individuals with CF, but we lack parameters to differentiate CF from CFTR-RD. In the era of the CFTR modulators and their potential clinical benefit, it is of utmost importance to diagnose CFTR-RD as unambiguously as possible. We therefore propose the following to define compatible CFTR dysfunction in a person with a suspected diagnosis of CFTR-RD : (1) evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (2) One CFTR variant known to reduce CFTR function and evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (3) Two CFTR variants shown to reduce CFTR function, with at most one CF-causing variant.

Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease.

RATIONALE: Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects. OBJECTIVES: We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy. METHODS: An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks. MEASUREMENTS AND MAIN RESULTS: Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased. CONCLUSIONS: Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF.

Acute chlorpyrifos poisoning in pregnancy: a case report.

BACKGROUND: Pesticide exposures and poisoning are common and generally under-reported in poorly resourced countries where women are mainly involved in agricultural work. Cases of organophosphate poisoning in pregnancy are unusual. CASE REPORT: A 22-year-old woman in her 29th week of pregnancy presented to King Edward VIII Hospital, Durban, South Africa having had multiple generalized tonic-clonic seizures at home. An initial presumptive diagnosis of eclampsia was made and treatment using intravenous MgSO(4) was initiated. Signs of OP toxicity included a garlic odor; vomiting, diarrhea, fecal incontinence; hypersecretions with airway compromise, diffuse rhonchi; pinpoint pupils; and muscle weakness and fasciculations. The patient responded to intravenous doses of atropine; oximes were not available. Although the mother survived, the infant was born prematurely and died two days after birth without showing any OP signs. CONCLUSIONS: Organophosphate poisoning may mimic acute complications in pregnancy, such as eclampsia and seizures. Immediate management includes general supportive measures and use of specific pharmacological agents such as atropine and oximes. Poisoning during pregnancy may result in serious adverse effects for both mother and the fetus or neonate. Prompt diagnosis and treatment are necessary to avoid adverse outcomes.

Low levels of persistent organic pollutants raise concerns for future generations.

Bans and regulation in many countries have reduced the environmental levels of many persistent organic pollutants (POPs). Despite these declines, there is still evidence of exposures in a range associated with adverse health effects. This seeming paradox is a result of the realisation that levels once presumed safe can cause subtle but important health effects. For example, levels of PCBs now shown to affect human brain development are nearly one million-fold lower than levels previously believed safe. These findings add urgency to efforts to globally eliminate these chemicals, and carry lessons for persistent pollutants that are still in widespread use today, such as the polybrominated diphenyl ethers (PBDEs) and synthetic musks.

Risk and incidence of asthma attributable to occupational exposure among HMO members.

Occupational asthma may account for a significant proportion of adult-onset asthma, but incidence estimates from surveillance of physician reports and workers' compensation data (0.9 to 15/100,000) are lower than expected from community-based cross-sectional studies of asthma patients. We conducted a prospective cohort study of 79,204 health maintenance organization members between the ages of 15 and 55 at risk for asthma. Computerized files, medical records, and telephone interviews were used to identify and characterize asthma cases. Evidence for asthma attributable to occupational exposure was determined from work-related symptoms and workplace exposure. The annual incidence of clinically significant, new-onset asthma was 1.3/1,000, and increased to 3.7/1,000 when cases with reactivation of previously quiescent asthma were included. Criteria for onset of clinically significant asthma attributable to occupational exposure were met by 21% (95% CI 12-32%) of cases giving an incidence of 71/100,000 (95% CI 43-111). Physicians documented asking about work-related symptoms in 15% of charts, and recorded suggestive symptoms in three cases, but did not obtain occupational medicine consultation, diagnose occupational asthma, report to the state surveillance program, or bill workers' compensation for any of them. These data suggest that the incidence of asthma attributable to occupational exposures is significantly higher than previously reported, and accounts for a sizable proportion of adult-onset asthma.

Stillbirth after occupational exposure to N-methyl-2-pyrrolidone. A case report and review of the literature.

N-methyl-2-pyrrolidone is a solvent that is increasingly used in a variety of industries, including petroleum refining, microelectronics, pesticide formulation, and veterinary medicine. Animal studies have demonstrated fetotoxic effects after maternal exposure to doses that have minimal to no adverse effect on the mothers. The fetotoxicity comprises resorption, stillbirth, and low birthweight and delayed ossification in surviving young. We report a human case of intrauterine growth retardation followed by fetal demise at 31 weeks gestation. The mother was a laboratory worker with no other apparent risk factors, who sustained occupational exposure to N-methyl-2-pyrrolidone throughout the first trimester of pregnancy. Laboratory work and solvent exposure have both previously been associated with adverse reproductive outcomes. Laboratories and other industries that use suspected reproductive toxins should have reproductive health policies in place that allow for decision-making based on toxicologic review, exposure assessment, and medical evaluation. These policies should allow for voluntary removal of prospective parents until environmental assessment and controls are instituted.