Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease.

INTRODUCTION: Mycobacterium abscessus is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary M. abscessus disease, and examined heterogeneity of response to NO in vitro. METHODS: In the compassionate-use treatment, a 24-year-old CF patient with pulmonary M. abscessus was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. In vitro susceptibility tests were performed against patient's isolate and comparison clinical isolates and quantified by Hill's slopes calculated from time-kill curves. RESULTS: M. abscessus lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. In vitro susceptibility tests showed a dose-dependent NO effect on M. abscessus susceptibility and significant heterogeneity in response between M. abscessus clinical isolates. The patient's isolate was found to be the least susceptible strain in vitro. CONCLUSION: These results demonstrate heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

Quantitative dysmorphology assessment in Fabry disease.

PURPOSE: 1) To identify morphometric characteristics in hemizygous patients with Fabry disease a treatable lysosomal storage disorder caused by the deficiency of alpha-galactosidase A where morphological abnormalities have occasionally been mentioned, but have never been investigated systematically. 2) To devise a quantitative method to evaluate dysmorphic abnormalities in Fabry disease. METHOD: Cross-sectional, single center, independent dysmorphology assessment by a panel of three clinical geneticists, based on standardized medical photography. POPULATION: consecutive hemizygous patients with Fabry disease (N = 38) unselected for the features assessed, mean age 38 +/- 10.8 years (range: 10-60), recruited for neuropathic pain into enzyme replacement therapy trials. RESULTS: The following dysmorphic features were identified (in order of descending frequency): periorbital fullness, prominent lobules of the ears, bushy eyebrows, recessed forehead, pronounced nasal angle, generous nose/bulbous nasal tip, prominent supraorbital ridges, shallow midface, full lips, prominent nasal bridge, broad alar base, coarse features, posteriorly rotated ears, and prognathism. Extremity features included broad fingertips, short fingers, prominent superficial vessels of hands, 5 digit brachydactyly, and 5 digit clinodactyly. Narrow anterior-posterior chest diameter was noted. Ten core features were statistically defined. Cronbach's alpha measuring internal consistency was 0.62. Light's kappa for global inter-rater variability was 0.26 while Cohen's kappa allowing pair-wise rater comparison varied between 0.08-0.48. CONCLUSIONS: Patients with Fabry disease share common morphological characteristics of the face, trunk, and extremities. Some of these features are subtle as documented by the inter-rater variability. Awareness of these features may facilitate the diagnosis of patients with Fabry disease, and identification of affected family members.

Lack of susceptibility of cells from patients with Fabry disease to productive infection with R5 human immunodeficiency virus.

A lack of viral replication after HIV-1Ba-L (R5) but not HIV-1IIIB (X4) infection was found using in-vitro activated peripheral blood-derived mononuclear cells from patients with Fabry disease, who have a defect in the catabolism of globotriaosylceramide. CCR5, but not CD4 or CXCR4 expression levels, were lower and the surface expression of globotriaosylceramide was negligible on activated patients' cells. Our findings suggest a novel resistance mechanism to productive infection with R5 HIV-1 that potentially involves abnormal globotriaosylceramide catabolism.