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To study systems able to sustain intramolecular proton-transfer, we have prepared a series of six aminofulvene aldimines including several labeled with (15)N and (2)H. These compounds show coupling constants through the hydrogen bond, (1h)J((15)N- (1)H) and (2h)J((15)N-(15)N). The position of the tautomeric equilibria, i.e., on what nitrogen atom is the proton, was determined in the solid state and in solution. The crystal structure of N[[5-[(phenylamino)methylene]-1,3-cyclopentadien-1-yl]methylene]pyrrole-1-amine (3) has been determined by X-ray analysis. In solution, both N-H and C-H tautomers were observed and their structures assigned by NMR spectroscopy. Particularly useful is the value of the (1)J((15)N-(1)H) coupling constant.

A new method for detecting hydrogen bonds in the solid state is presented. Using two-dimensional NMR correlation experiments, it is shown that a hydrogen-bond mediated J coupling can be observed in a powder under magic-angle spinning conditions, even though the J coupling is 2 orders of magnitude smaller than the dominant anisotropic interactions encountered in solid-state NMR. Specifically, the observation of a pair of peaks in a two-dimensional 15N-15N solid-state INADEQUATE experiment due to two nitrogens that have no covalent connectivity is attributed to the presence of a J coupling across a linking hydrogen bond.

Background: Gaucher disease is an autosomal recessive disorder resulting from mutations in the glucocerebrosidase gene (GBA). The lack of full genotype/phenotype correlation complicates counseling regarding clinical outcome and treatment recommendations., Subjects and Methods: Several mutations in the human beta-glucosidase gene associated with Gaucher disease in 16 Spanish families were identified utilizing a combination of methods: enzymatic restriction, PCR-SSCP, and sequence analyses. Expression studies were performed following the introduction of the mutagenized human acid beta-glucosidase cDNA into COS-1 cells, and the residual enzyme activities of the mutant protein were measured and compared with the normal cDNA., Results: The identified mutations and corresponding residual enzyme activities of the expressed protein are as follows: c.517A>C (T134P), 1%; c.721G>A (G202R), 17%; c.1090G>T (G325W), 13.9%; c.1093G>A (E326K), 26%; c.1208G>A (S364N), 4.1%; c.1226A>G (N370S), 17,8%; c.1246G>A (G377S), 17.6%; c.1289C>T (P391L), 8.5%; c.1448T>C (L444P), 3%; and c.1504C>T (R463C), 24.5%., Conclusions: Site-directed mutagenesis and expression in COS-1 cells are useful methods to increase our understanding of causality in Gaucher disease and the correlation between disease severity, gene defects, and residual enzyme activity. Our study demonstrates the functional consequences of the identified human beta-glucosidase mutations (T134P, S364N, G377S, P391L, and G325W) and provide evidence for the molecular and biochemical basis of Gaucher disease, among patients of Spanish ancestry., (Copyright 2001 Academic Press.)

Background: Chronic cor pulmonale (CPC) in patients with chronic obstructive pulmonary disease (COPD) is a predictor of mortality. ACE inhibitors (ACEIs) improve the symptoms and reduce mortality of left ventricular or congestive failure, however their long term use in patients with CPC has not been tested. The aim of this study is to assess the effect on exercise tolerance and cardiorespiratory function of long term administration of enalapril in patients with CPC., Methods: Placebo-controlled, double blind, randomized study. 28 patients (24 men and 4 women, mean age of 68.11 +/- 7.78, range 51-79) with CPC and without exacerbation of their respiratory symptoms at baseline were double blind randomised to receive enalapril or placebo for 6 months, added to their previous therapy. Respiratory function test, exercise tolerance ("six minutes walking test") and isotopic ventriculography were performed at baseline and at the end of the study., Results: At baseline there were no differences in FEV1, FVC, FEV1/FVC and exercise tolerance. Both placebo and enalapril were well tolerated. At the end of the study, patients taking enalapril increased their exercise tolerance an 8.9% (19 m) vs 4.7% (33 m) in the placebo group (p 0.44; 95 percent confidence interval, -41.10 to 91.99). RVEF improved a 6.4% with enalapril but worsened a 7.09% in placebo group (p 0.15; 95 percent confidence interval, -12.87 to 2.10)., Conclusions: Long term administration of enalapril do not improve neither exercise tolerance, nor right ventricular (RV) function, although given in increasingly doses is well tolerated and might prevent further worsening in RV systolic function.

Short Introduction: Gaucher's disease (GD) is an autosomal recessive disease produced by mutations of the Glucocerebrosidase gene. Carriers are considered to be healthy subjects because there is no manifestation of the disease, but they show signs of macrophage disfunction. The aim of the study was to determine if GD patients and non affected carriers risk suffering other diseases when compared to healthy non-carrier relatives., Design: Epidemiologic study of historic cohorts. The fact that they have one or two mutated alleles has been considered to be the risk factor leading to other conditions (Dementia, Parkinson disease, Ischemic stroke, Ischemic heart disease, Non rheumatic valvular disease, Cancer hematological and non-hematological, Pulmonary fibrosis, Tuberculosis, Gallstones and Schizophrenia). All people, patients, carriers and healthy controls shared the same genetical background and environmental influence. - Patients and relatives enrolled on the Spanish Gaucher Disease Registry were evaluated., Statistics: For the Relative-Risk calculation the Mantel-Haenszel test was applied. Yates' correction was used when size sample was too small. A value of p <0.05 was accepted for statistical significance., Results: 370 people, from 79 different families, were surveyed. We received evaluable information from 45 families (56%), totalling 258 people (69%): 59 healthy subjects (Mean age 32. 20, RANGE: 10-85; M 57.63%/F 42.37%), 132 carriers (Mean age 35.91, RANGE: 1-79; M 56.82%/F 43.18%) and 67 patients (Mean age 32.16, Range: 1-76; M 44.78%/F 55.22%. - Relative Risk of suffering any disease with regard to Gaucher's status: Patient vs Healthy 9.69 (95% Confidence interval [CI] 2.00-63.99; p 0.0006). Patient vs Carrier 3.74 (CI 1.53-9.27; p 0.001); Carrier vs Healthy 2.59 (CI 0. 52-12.50; p 0.21). Relative Risk of suffering any disease with regard to sex was 3.96 for female patients (CI 1.01-16.75; p 0.02) and 1.34 for female carriers (CI 0.27-6.75; p = 0.68)., Conclusion: As a group, Gaucher's patients seem to have a greater risk of suffering other common unrelated diseases than carriers or healthy relatives. This excess of risk is particularly higher among female patients and can not be explained in terms of differences in age. Carrier status doesn't seem to highten the risk of suffering other diseases.

Background: Gaucher's disease is the most common lysosomal storage disorder, caused by deficiency of glucocerebrosidase resulting from homozygosity for any of several mutations of the glucocerebrosidase gene locus. Affected people have decreased concentrations of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). We assessed the association between mutations in the glucocerebrosidase locus and hypo-alpha-lipoproteinaemia., Methods: We studied 258 people from 43 unrelated Spanish families. 57 participants were affected, 137 were non-affected carriers, and 64 were non-carriers. We determined glucocerebrosidase genotypes and measured plasmid lipids, apolipoproteins A-I, B, and E, and leucocyte glucocerebrosidase activity., Findings: The most common glucocerebrosidase mutations were N370S (45%), L444P (23%), and G377S (5%). Deletions and recombinants accounted for another 5%, and point mutations in exons 5, 6, 9, and 10 were present in 12%. Affected participants had lower LDL-C and HDL-C concentrations than non-affected carriers (p<0.001) and non-carriers (p<0.001). HDL-C values were also significantly different between the non-affected carriers and non-carriers. Mutations at this locus may account for as much as 19.5% of the genetic variability in HDL-C in the population studied., Interpretation: Heterozygosity for these mutations at the glucocerebrosidase locus does not result in clinical expression of Gaucher's disease but can decrease HDL-C concentrations. Given the high frequency of these mutations, the glucocerebrosidase locus might lead to familial low alpha-lipoproteinaemia in up to 2% of the general population and be one of the most common known genetic causes of HDL-C.

Transesophageal echocardiographic and computed tomographic imaging in a patient with lipomatous hypertrophy of the interatrial septum and advanced left bundle branch block are presented. Transesophageal echocardiography demonstrated a thickening of the atrial septum sparing the fossa ovalis region. Computed tomographic scan at the level of the interatrial septum showed a mass of fat density, and the HIS bundle electrogram showed an advanced infra-his block after intravenous ajmaline. We stress the utility of transesophageal echocardiography in this disorder, and the possible relationship between lipomatous hypertrophy of the interatrial septum and conduction disturbances.

We have prospectively studied 48 patients previously diagnosed of systemic lupus erythematosus over a mean follow up period of 5.8 years of which 28 presented 36 episodes of infection and 20 did not develop infections. Urinary infections were the most frequent kind of infection followed by pneumonia and bacteriemia; the most frequently isolated microorganism responsible for those infections were E. colii, staphylococcus aureu and P. mirabillis. We have found a risk factors that and impared renal function an steroid treatment over 20 mg/day were significantly associated with a increasing number of infectious precesses. On the contrary, we have observed that only a bad and critical clinical situation had prognostic value and was significantly associated with an increased mortality.