Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure.

Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1, Elejalde), RAB27A (GS2) or MLPH (GS3) genes. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and hemophagocytic syndrome. We report here the diagnosis of GS2 in 3-year-old twin siblings, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death. Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. A homozygous nonsense mutation, C-T transition (c.550C>T), in the coding region of the RAB27A gene, which leads to a premature stop codon and prediction of a truncated protein (R184X), was found. In patient mononuclear cells, RAB27A mRNA levels were the same as in cells from the parents, but no protein was detected. In addition to the case report, we also present an updated summary on the exon/intron organization of the human RAB27A gene, a literature review of GS2 cases, and a complete list of the human mutations currently reported in this gene. Finally, we propose a flow chart to guide the early diagnosis of the GS subtypes and Chédiak-Higashi syndrome.

Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure

Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1, Elejalde), RAB27A (GS2) or MLPH (GS3) genes. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and hemophagocytic syndrome. We report here the diagnosis of GS2 in 3-year-old twin siblings, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death. Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. A homozygous nonsense mutation, C-T transition (c.550C>T), in the coding region of the RAB27A gene, which leads to a premature stop codon and prediction of a truncated protein (R184X), was found. In patient mononuclear cells, RAB27A mRNA levels were the same as in cells from the parents, but no protein was detected. In addition to the case report, we also present an updated summary on the exon/intron organization of the human RAB27A gene, a literature review of GS2 cases, and a complete list of the human mutations currently reported in this gene. Finally, we propose a flow chart to guide the early diagnosis of the GS subtypes and Chédiak-Higashi syndrome.

Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis.

OBJECTIVE: Hypofibrinolysis promotes atherosclerosis progression and recurrent ischemic events in premature coronary artery disease. We investigated the role of fibrin physical properties in this particular setting. METHODS AND RESULTS: Biomarkers of recurrent thrombosis and premature coronary artery disease (CAD) were measured in 33 young post-myocardial infarction patients with angiographic-proven CAD and in 33 healthy volunteers matched for age and sex. Ex vivo plasma fibrin physical properties were assessed by measuring fibrin rigidity and fibrin morphological properties using a torsion pendulum and optical confocal microscopy. The fibrinolysis rate was derived from continuous monitoring of the viscoelastic properties after addition of lytic enzymes. Young CAD patients had a significant increase in plasma concentration of fibrinogen, von Willebrand factor, plasminogen activator inhibitor type 1, and lipoprotein(a) as compared with controls (P<0.05). Fibrin of young CAD patients was stiffer (P=0.002), made of numerous (P=0.002) and shorter fibers (P=0.04), and lysed at a slower rate than that of controls (P=0.03). Fibrin stiffness was an independent predictor for both premature CAD and hypofibrinolysis. CONCLUSIONS: This first detailed study of clot properties in such a group of patients demonstrated that abnormal plasma fibrin architecture is an important feature of both premature CAD and fibrinolysis rate. The determinants of this particular phenotype warrant further investigation.

Inhaled nitric oxide: more than a selective pulmonary vasodilator.

Because of its high diffusing capacity through the alveolar-blood barrier and its high selectivity for the pulmonary vasculature, inhaled nitric oxide (NO) has been recently shown to be a viable and efficient approach to restore pulmonary NO deficiency. The most relevant applications of inhaled NO are in infants with primary pulmonary hypertension or hypoxia. In these patients, inhaled NO improves gas exchange and ventilation-perfusion matching, reduces the length of hospitalization and is without severe detrimental effects. The use of inhaled NO has also been extended to adults with pulmonary hypertension and the acute respiratory distress syndrome. In addition, recent clinical evidence supported by data from animal models, shows beneficial extra-pulmonary effects of inhaled NO, including protection against myocardial ischaemia-reperfusion injury.

Intravenous prostaglandin E1 reduces soluble vascular cell adhesion molecule-1 in peripheral arterial obstructive disease.

OBJECTIVES: Elevated levels of soluble (s) vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1, pointing to activation of cells involved in vascular inflammation, have been previously reported in peripheral arterial obstructive disease (PAOD). We tested the hypothesis that intravenous prostaglandin E(1) (PGE(1)) treatment, which produces clinical benefits in this condition, might decrease such levels. METHODS: Ten subjects (age range 58 +/- 10 years, 6 male, 4 female) with characterized Fontaine stage IIa to IV PAOD (ankle/arm pressure index <0.96) were entered into a treatment protocol with twice daily intravenous infusions of PGE(1) (alprostadil) at 120 microg per day, repeated for 10 consecutive days. Preinfusion and postinfusion plasma samples were stored for blind enzyme immunoassays of soluble adhesion molecules and the fibrinolytic marker tissue plasminogen activator, type-1 plasminogen-activator inhibitor, and D -dimer. RESULTS: Estimates of severity of pain at rest, consumption of analgesics, magnitude of trophic lesions, remission to lower Fontaine stages, and favorable changes in the venoarteriolar reflex documented significant beneficial effects of the treatment. Significant (P <.01) pretreatment and posttreatment reductions of in all soluble markers explored were found. Particularly, sVCAM-1 exhibited a significant decrease after each infusion, which was sustained at the last day of treatment (from 854 +/- 214 ng/mL to 775 +/- 215 ng/mL across the first infusion, from 773 +/- 146 ng/mL to 680 +/- 110 ng/mL across the last infusion). CONCLUSION: Thus a global decrease of vascular cell activation appears to occur as a result of PGE(1) administration and may contribute to the observed clinical benefits in PAOD.

A cost-effectiveness analysis of aspirin versus oral anticoagulants after acute myocardial infarction in Italy -- equivalence of costs as a possible case for oral anticoagulants.

AIMS: The recent publication of two large trials of secondary prevention of coronary artery disease with oral anticoagulants (WARIS and ASPECT) has caused a revival of the interest for this antithrombotic therapy in a clinical setting where the use of aspirin is common medical practice. Despite this, the preferential use of aspirin has been supported by an American cost-effectiveness analysis (JAMA 1995; 273: 965). METHODS AND RESULTS: Using the same parameters used in that analysis and incidence of events from the Antiplatelet Trialists Collaboration and the ASPECT study, we re-evaluated the economic odds in favor of aspirin or oral anticoagulants in the Italian Health System, which differs significantly in cost allocation from the United States system and is, conversely, similar to other European settings. Recalculated costs associated with each therapy were 2,150 ECU/ patient/year for oral anticoagulants and 2,187 ECU/patient/year for aspirin. In our analysis, the higher costs of oral anticoagulants versus aspirin due to a moderate excess of bleeding (about 10 ECU/ patient/year) and the monitoring of therapy (168 ECU/ patient/year) are more than offset by an alleged savings for recurrent ischemic syndromes and interventional procedures (249 ECU/ patient/year). CONCLUSIONS: Preference of aspirin vs. oral anticoagulants in a pharmaco-economical perspective is highly dependent on the geographical situation whereupon calculations are based. On a pure cost-effectiveness basis, and in the absence of data of direct comparisons between aspirin alone versus I.N.R.-adjusted oral anticoagulants, the latter are not more expensive than aspirin in Italy and, by cost comparisons, in other European countries in the setting of post-myocardial infarction.

[Anticoagulant or antiaggregant therapy in the secondary prevention of myocardial infarct?]. / Terapia anticoagulante o antiaggregante nella prevenzione secondaria dell'infarto miocardico?

The recent publication of the results of two large trials of secondary prevention of myocardial infarction with oral anticoagulants is causing a revival of interest for oral anticoagulants in this clinical setting. On the basis of these data, oral anticoagulants should be considered not only an effective preventive strategy, but, probably, more effective than antiplatelet agents, currently the standard therapy in the prevention of thrombosis in acute myocardial infarction. There are advantages and disadvantages for both these treatments, and an adequate balancing of expected risks and benefits has to be performed in each single patient. The present review summarizes rationales and main clinical results in the prevention of reinfarction with antiplatelet agents and with oral anticoagulants, and analyzes the reasoning to prefer the formers or the latters in daily clinical practice of secondary prevention of coronary artery disease. Also, an analysis of the benefit/risk ratio of antiplatelet agents (aspirin) and oral anticoagulants in the Italian health system is synthetically presented. Such an analysis can be useful for the formulation of general guidelines and may suggest a modification of currently established and widely popular therapeutic habits in the management of coronary artery disease in Italy.

[n-3 fatty acids and cardiovascular diseases: update to 1996]. / Acidi grassi n-3 e malattie cardiovascolari: un aggiornamento al 1996.

n-3 Fatty acids (mostly eicosapentaenoic and docosahexaenoic acid) continue to elicit research interest as dietary or pharmacological agents able to prevent or retard the progression of atherosclerosis and its clinical manifestations. Significant advances have occurred over the past five years in understanding their mechanism of action, including anti-atherogenic, anti-thrombotic and anti-arrhythmic properties. In parallel, clinical studies have continued the evaluation of these compounds in the prevention of cardiovascular disease. Recent epidemiological studies have in general confirmed the hypothesis of a relevant anti-atherogenic effect, although this has not necessarily translated into clinical benefits in selected, relatively low-risk populations. Recent negative studies in trials of restenosis prevention after coronary angioplasty have tempered the initial enthusiasm as a possible preventive strategy in this subset, although reasons for discrepancies among past trials still await conclusive explanations. A recent dietary intervention trial in post-myocardial infarction patients has renewed the interest for alpha-linolenic acid, both as the metabolic precursor of eicosapentaenoic and docosahexaenoic acid, and as a fatty acid with direct specific properties.