Pedro Horacio González

Myocardial Alterations in the Murine Model of Fabry Disease Can Be Reversed by Enzyme Replacement Therapy

BACKGROUND Fabry disease results from deficiency of alpha-galactosidase A (AGA), causing lysosomal storage of globotriaosylceramide in heart and other tissues. Since 2003, enzymatic replacement therapy with recombinant AGA agalsidase alfa (R-AGA) was approved for clinical use. METHODS We evaluated whether, in mice knocked out for AGA (FM, n = 31), the myocardium was altered with respect to the wild-type mice (WT, n = 25) and whether alterations were reversed in FM treated with intravenous R-AGA, 0.5 mg/kg every other week during 2 months (FM-AGA, n = 12). RESULTS Left ventricular (LV) contractility was depressed in FM, evaluated by LV ΔP/Δt (FM = 2832 ± 85 mm Hg/s, WT = 3179 ± 119 mm Hg/s; P < 0.05), papillary muscle contraction (FM = 39.8 ± 17.3 mg, WT = 67.5 ± 15.7 mg; P < 0.05), or shortening fraction measured by M-mode echocardiography (FM = 30% ± 6%, WT = 47% ± 2%; P < 0.05). LV stiffness (arrested hearts) decreased in FM (FM = 35.57 ± 3.5 mm Hg/20 μl; WT = 68.86 ± 6.12 mm Hg/20 μl; P < 0.05). FM myocytes showed augmented size, disorganized architecture, and intracytoplasmic vacuolization. Alterations reverted in FM-AGA: LV ΔP/Δt = 3281 ± 456 mm Hg/s and LV stiffness = 58.83 ± 2.15 mm Hg/20 μl, with normalization of myocyte architecture. No reversion was detected with AGA solvent. CONCLUSIONS The FM represent a mild, early stage of the disease, since myocardial alterations are not prominent and appear in nonhypertrophic hearts. Reversion of alterations in the FM-AGA suggests that enzymatic replacement therapy can be useful when administered in early stages of this disease.

Open lung biopsy for diffuse disease in patients with and without previously transplanted solid organs.

BACKGROUND Studies on whether surgical lung biopsy (SLB) modifies the treatment of patients with diffuse lung disease are conflicting, and information is limited on whether it alters treatment in solid-organ transplant recipients. Our objective was to determine and compare the rate of treatment change after SLB for diffuse lung disease in patients with and without a history of solid-organ transplantation. METHODS Patients undergoing SLB for diffuse lung disease between March 2004 and March 2009 were identified. A retrospective review was performed. RESULTS Sixty patients had SLB. Thirty-four patients (57%) had solid-organ transplantation. Twenty of 60 patients (33%) had a change in treatment as a result of the findings of the SLB. No significant differences in the treatment change rate were found between the transplant and nontransplant groups (10 of 34 versus 10 of 26; p = 0.46). Transplant patients were more likely to be on mechanical ventilation at the time of SLB (12 of 34 versus 3 of 26; p = 0.03). Mechanical ventilatory support at the time of SLB was associated with increased postoperative complications (odds ratio, 6.20; 95% confidence interval [CI], 1.70 to 22.66; p = 0.006) and in-hospital mortality (odds ratio, 9.75; 95% CI, 2.54 to 37.38; p = 0.001). Being on mechanical ventilation (hazard ratio, 3.91; 95% CI, 1.40 to 10.93; p = 0.009), a diagnosis of cancer (hazard ratio, 13.20; 95% CI, 2.87 to 60.78; p = 0.001), and a history of solid-organ transplantation (hazard ratio, 5.52; 95% CI, 1.08 to 28.14; p = 0.04) were independent predictors of survival. CONCLUSIONS Surgical lung biopsy changes treatment in one third of patients, with no significant difference between patients without transplantation and solid-organ transplant recipients. Patients who undergo SLB while on mechanical ventilation have a significantly increased risk of postoperative complications and death.

Densitometric quantitative analysis of intracoronary ultrasound images: anatomopathologic correlation

To establish if the video densitometric analysis (VDA) of the intracoronary ultrasound images (IVUS) can predict the qualitative and quantitative composition of the atherosclerotic coronary plaques, thirty-one patients with anatomopathologic study of directional coronary atherectomy (DCA) samples and pre and post intervention IVUS image were analyzed. The video IVUS images were digitized in a 512 x 512 matrix and analyzed for densitometric differences with an Automatic Image Analysis System (AIAS) (Vidas 2000, Zeiss Kontron). The components of the plaque were arbitrarily divided into three densitometric categories using a 256 gray scale: high density (HD) 121–255, medium (MD) 81–120 and low (LD) 30–80. The relative percentage of each component was automatically recorded. The DCA samples were microscopically examined and input in the AIAS. The components were divided into: collagenous tissue (CT); lipid-necrotic debris (LND); proliferative tissue (PT). The area of each component was expressed as a percentage of the total. Linear correlation analysis was applied. Comparison between the IVUS and the histological composition of the plaque showed that: HD corresponded to CT; MD to PT; LD to LND. The correlation between the percentage distribution of the densitometric categories and the anatomopathologic components showed a correlation coefficient r%equals;0.91 between HD and CT; r%equals;0.87 between MD and PT; r%equals;0.88 between LD and LND. The VDA of the IVUS can distinguish three basic components of the atherosclerotic plaque: fibrous, lipid-necrotic and proliferative tissue, allowing absolute and relative quantitative analysis. This capability may be of interest for device selection and histopathologic correlation.

The use of cyclophosphamide as an enhancer of the vaccine against foot-and-mouth disease

The immunization of biungulate animals with killed foot-and-mouth disease virus (FMDV) requires periodic vaccinations due to a low vaccine immunogenicity. Therefore, FMDV antigens need to be combined with adjuvants such as aluminum hydroxide, saponin or oil emulsions. Animal handling for periodic inoculations, and the repeated doses of vaccines that have to be administered increase the commercialization costs. Moreover, the use of adjuvants may induce adverse effects. In the present work we show that it is possible to increase the life span of neutralizing antibodies in serum when a single dose of cyclophosphamide (Cy) is administered four days before vaccination with aluminum hydroxidesaponin FMDV vaccine.