Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension.

For chronic thromboembolic pulmonary hypertension not amenable to pulmonary endarterectomy, effective medical therapy is desired. In an open-label uncontrolled clinical trial, 104 patients (mean +/- sem age 62 +/- 11 yrs) with inoperable chronic thromboembolic pulmonary hypertension were treated with 50 mg sildenafil t.i.d. At baseline, patients had severe pulmonary hypertension (pulmonary vascular resistance 863 +/- 38 dyn.s.cm(-5)) and a 6-min walking distance of 310 +/- 11 m. Eight patients were in World Health Organization functional class II, 76 in class III and 20 in class IV. After 3 months' treatment, there was significant haemodynamic improvement, with reduction of pulmonary vascular resistance to 759 +/- 62 dyn.s.cm(-5). The 6-min walking distance increased significantly to 361 +/- 15 m after 3 months' treatment, and to 366 +/- 18 m after 12 months' treatment. A subset of 67 patients received a single dose of 50 mg sildenafil during initial right heart catheterisation. The acute haemodynamic effect of this was not predictive of long-term outcome. In this large series of patients with inoperable chronic thromboembolic pulmonary hypertension, open-label treatment with sildenafil led to significant long-term functional improvement. The acute effect of sildenafil may not predict the long-term outcome of therapy.     

Neuroinvasion of prions: insights from mouse models

The prion was defined by Stanley B. Prusiner as the infectious agent that causes transmissible spongiform encephalopathies. A pathological protein accumulating in the brain of scrapie-infected hamsters was isolated in 1982 and termed prion protein (PrPSc). Its cognate gene Prnp was identified more than a decade ago by Charles Weissmann, and shown to encode the host protein PrP(C). Since the latter discovery, transgenic mice have contributed many important insights into the field of prion biology, including the understanding of the molecular basis of the species barrier for prions. By disrupting the Prnp gene, it was shown that an organism that lacks PrP(C) is resistant to infection by prions. Introduction of mutant PrP genes into PrP-deficient mice was used to investigate the structure-activity relationship of the PrP gene with regard to scrapie susceptibility. Ectopic expression of PrP in PrP knockout mice proved a useful tool for the identification of host cells competent for prion replication. Finally, the availability of PrP knockout mice and transgenic mice overexpressing PrP allows selective reconstitution experiments aimed at expressing PrP in neurografts or in specific populations of haemato- and lymphopoietic cells. The latter studies have allowed us to clarify some of the mechanisms of prion spread and disease pathogenesis.     

Engagement of adenosine receptors inhibits hydrogen peroxide (H2O2-) release by activated human neutrophils

Adenosine and its analogs, acting at specific cell surface receptors, inhibit generation of superoxide anion by neutrophils. Since it has been suggested that hydrogen peroxide (H2O2) release may not be contingent upon superoxide anion release, we studied the effects of 2-chloroadenosine, a potent adenosine receptor agonist, on the formation of H2O2 by neutrophils exposed to various stimuli: n-formyl-methionyl-leucyl-phenylalanine (FMLP), concanavalin A, phorbol myristate acetate (PMA), serum-treated zymosan particles (STZ), and immune complexes. 2-Chloroadenosine (0.01-10 microM) inhibited formation of H2O2 by neutrophils exposed to FMLP, concanavalin A, and STZ particles. As we have found with O2- generation, 2-chloroadenosine failed to inhibit H2O2 release by neutrophils stimulated by either phorbol myristate acetate or immune complexes. The data show that whereas adenosine and its analogs inhibit neutrophil release of H2O2 and superoxide anion in response to most ligands, they fail to inhibit activation of neutrophils by immune complexes. Nor do they inhibit neutrophil activation by PMA, an agent which bypasses cell surface receptors by direct activation of protein kinase C. Surprisingly, we found that adenosine deaminase activity was adsorbed onto zymosan particles during opsonization and enhanced release of H2O2 by neutrophils exposed to STZ. These studies with yeast cell walls suggest that if microorganisms adsorb adenosine deaminase from serum, then the intracellular microbicidal activity of neutrophils is enhanced.     

The Defect in the Hurler and Scheie Syndromes: Deficiency of α-L-Iduronidase

Skin fibroblasts cultured from patients affected with the Hurler or Scheie syndromes (mucopoly-saccharidoses I or V, respectively) have a functional deficiency of a protein required for catabolism of sulfated mucopolysaccharide that has been designated the "Hurler corrective factor." We now show Hurler factor purified from normal human urine to be associated with alpha-L-iduronidase activity. Cell lines deficient in Hurler corrective factor have no detectable activity of alpha-L-iduronidase (less than 3% of that found in cells from individuals of other genotypes). Such correspondence indicates that Hurler corrective factor and alpha-L-iduronidase are the same entity. Correction of deficient cells is accompanied by an efficient uptake of alpha-L-iduronidase from the medium.     

Chagasic meningoencephalitis: case report of a recently included AIDS-defining illness in Brazil

Recently, reactivation of Chagas disease (meningoencephalitis and/or myocarditis) was included in the list of AIDS-defining illnesses in Brazil. We report a case of a 52-year-old patient with no history of previous disease who presented acute meningoencephalitis. Direct examination of blood and cerebrospinal fluid (CSF) showed Trypanosoma cruzi. CSF culture confirmed the diagnosis. Serological assays for T. cruzi and human immunodeficiency virus (HIV) were positive. Despite treatment with benznidazol and supportive measures, the patient died 24 hours after hospital admission. In endemic areas, reactivation of Chagas disease should always be considered in the differential diagnosis of meningoencephalitis among HIV-infected patients, and its presence is indicative of AIDS.     

Inhaled iloprost reverses vascular remodeling in chronic experimental pulmonary hypertension

RATIONALE: Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH. OBJECTIVES: The present study was designed to investigate chronic antiremodeling effects of inhaled iloprost in monocrotaline (MCT)-induced PAH in rats. Methods: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost at a dose of 6 microg . kg(-1) . day(-1), or underwent sham nebulization with saline. RESULTS: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase-2 and -9 activities and tenascin-C expression was suppressed. CONCLUSIONS: We conclude that the inhalation of iloprost reverses PAH and vascular structural remodeling in MCT-treated rats. This regimen suggests the possibility of an antiremodeling therapy in PAH.