Optimal duration of anticoagulation of venous thromboembolism

The optimal duration of anticoagulation after venous thromboembolism (VTE) is determined according to the risk of recurrent VTE after stopping anticoagulant therapy and the risk of anticoagulant-related bleeding while on antivitamin K. Clinical risk factors appears to be determinant to predict the risk of recurrence whereas the influence of biochemical and morphological tests is uncertain. The risk of recurrent venous thromboembolism is low when the initial episode was provoked by a reversible major risk factor (surgery): 3 months of anticoagulation is optimal. Conversely, this risk is high when venous thromboembolism was unprovoked or associated with persistent risk factor (cancer): 6 months or more prolonged anticoagulation is warranted. After this first estimation, the duration of anticoagulation may be modulated according to the presence of additional minor risk factors (major thrombophilia, chronic pulmonary hypertension, massive pulmonary embolism): 6 months if VTE was provoked and 12 to 24 months if VTE was unprovoked. If the risk of anticoagulant related bleeding is high, the duration of anticoagulation should be shortened (3 months if VTE was provoked and 6 or 3 months if it was unprovoked). Lastly, if VTE occurred in the setting of a cancer, anticoagulation should be conducted for 6 months or more while cancer is active or on ongoing treatment. Despite an increasing knowledge of the risk factors of recurrent VTE, a number of issues remain unresolved; randomised trial comparing different duration of anticoagulation are needed.     

Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure

OBJECTIVES: We studied whether direct assessment of the hemodynamic response to exercise could improve the prognostic evaluation of patients with heart failure (HF) and identify those in whom the main cause of the reduced functional capacity is related to extracardiac factors. BACKGROUND: Peak exercise oxygen consumption (VO2) is one of the main prognostic variables in patients with HF, but it is influenced also by many extracardiac factors. METHODS: Bicycle cardiopulmonary exercise testing with hemodynamic monitoring was performed, in addition to clinical evaluation and radionuclide ventriculography, in 219 consecutive patients with chronic HF (left ventricular ejection fraction, 22 +/- 7%; peak VO2, 14.2 +/- 4.4 ml/kg/min). RESULTS: During a follow-up of 19 +/- 25 months, 32 patients died and 6 underwent urgent transplantation with a 71% cumulative major event-free 2-year survival. Peak exercise stroke work index (SWI) was the most powerful prognostic variable selected by Cox multivariate analysis, followed by serum sodium and left ventricular ejection fraction, for one-year survival, and peak VO2 and serum sodium for two-year survival. Two-year survival was 54% in the patients with peak exercise SWI < or = 30 g x m/m2 versus 91% in those with a SWI >30 g x m/m2 (p < 0.0001). A significant percentage of patients (41%) had a normal cardiac output response to exercise with an excellent two-year survival (87% vs. 58% in the others) despite a relatively low peak VO2 (15.1 +/- 4.7 ml/kg/min). CONCLUSIONS: Direct assessment of exercise hemodynamics in patients with HF provides additive independent prognostic information, compared to traditional noninvasive data.     

Lack of tolerance development during chronic ibopamine administration to patients with congestive heart failure

Summary Beta-adrenergic agonists can progressively lose their efficacy during chronic therapy in patients with heart failure. Ibopamine is a new dopamine derivative, active on dopaminergic and beta-adrenergic receptors, whose hemodynamic activity has been acutely demonstrated. To assess whether any attenuation of its efficacy occurs, the variations of the cardiac output induced during chronic therapy were monitored by impedance cardiography in 15 patients with dilated cardiomyopathy who showed a significant increase of the cardiac output (20.7 ± 10.0%) after acute ibopamine administration. The efficacy of ibopamine was also assessed after 6 and 12 months of therapy by echocardiography, exercise testing, and 24-hour dynamic electrocardiogram (EKG) monitoring.The cardiac output response to ibopamine did not show any significant attenuation (range 15% to 19%) in the evaluations at 1, 2, 3, 4, 8, and 12 months of therapy. No significant change, was noted, after 6 and 12 months, in the exercise capacity (505 vs. 602 and 604 seconds) and the fractional shortening (16.2 vs. 18.3 and 18.5) without any change of the diastolic diameter. Ventricular arrhythmias were significantly reduced after 6, but not 12, months of therapy. No significant change in the New York Heart Association (NYHA) functional class was noted at 6 and 12 months of therapy (2.4 ± 5 vs. 2.3 ± 7 and 2.4 ± 0.6, respectively). Our results show that ibopamine can maintain its hemodynamic activity even during chronic therapy.     

Effect of nutritional status on clinical outcome in a population of geriatric rehabilitation patients

BACKGROUND AND AIMS: In a geriatric patient, nutritional status (NS), particularly in the case of malnutrition (M), may influence not only clinical results but also achievement of targets expected by geriatric rehabilitation. The aim of this study was to evaluate the effect of nutritional status (NS) on the occurrence of Adverse Clinical Events (ACE) and on mortality in geriatric rehabilitation patients. METHODS: We retrospectively examined the clinical records of 278 elderly subjects (154 women, 124 men), admitted to a geriatric hospital between September 2000 and December 2001 and evaluated for clinical, functional, cognitive and NS within the first 48 hours of admission. Clinical outcomes (ACE, mortality) were recorded during follow-up. Logistic regression analysis estimated models having mortality or the occurrence of ACE as outcome variables. RESULTS: Malnutrition was detected upon admission in 56.1% of the sample population. Incidence of ACE in malnourished subjects was higher than that in well-nourished patients (28.2 vs 13.1%). Equally, mortality among malnourished subjects was higher than among those whose NS was normal (23.1 vs 9.8%). The logistic regression models were able to predict: 1) mortality from comorbidity (OR 1.43; 95% CI 1.16-1.78; p=0.001) and NS (OR 2.64; 95% CI 1.29-5.4; p=0.008), and 2) occurrence of ACE from comorbidity (OR 1.69; 95% CI 1.36-2.1; p=0.000), cognitive (OR 1.22; 95% CI 1.11-1.35; p=0.000) and nutritional status (OR 2.38; 95% CI 1.19-4.8; p=0.015). CONCLUSIONS: NS emerged as the main independent predictor of both mortality and occurrence of ACE. Although most patients fell into the category of mild/moderate (energy) malnutrition (148/156), a mild deterioration of NS, for instance, reduction in triceps skinfold thickness (TSF) seemed to be sufficient to cause an increase in the incidence of ACE and in mortality.     

Smoking and suicidal behaviors in the National Comorbidity Survey: Replication

Controversy exists about the role of mental disorders in the consistently documented association between smoking and suicidal behavior. This controversy is addressed here with data from the nationally representative National Comorbidity Survey-Replication (NCS-R). Assessments were made of 12-month smoking, suicidal behaviors (ideation, plans, attempts), and DSM-IV disorders (anxiety, mood, impulse-control, and substance use disorders). Statistically significant odds ratios (2.9-3.1) were found between 12-month smoking and 12-month suicidal behaviors. However, the associations of smoking with the outcomes became insignificant with controls for DSM-IV mental disorders. Although clear adjudication among contending hypotheses about causal mechanisms cannot be made from the cross-sectional NCS-R data, the results make it clear that future research on smoking and suicidal behaviors should focus more centrally than previous research on mental disorders either as common causes, markers, or mediators.     

The performance of laminin-containing cryogel scaffolds in neural tissue regeneration

Currently, there are no effective therapies to restore lost brain neurons, although rapid progress in stem cell biology and biomaterials development provides new tools for regeneration of central nervous system. Here we describe neurogenic properties of bioactive scaffolds generated by cryogelation of dextran or gelatin linked to laminin - the main component of brain extracellular matrix. We showed that such scaffolds promoted differentiation of human cord blood-derived stem cells into artificial neural tissue in vitro. Our experiments revealed that optimal range of scaffolds' pore size for neural tissue engineering was 80-100 microns. We found that scaffold seeded with undifferentiated, but not neutrally committed stem cells, gave optimal cell adhesion and proliferation in "niche"-like structures. Subsequent differentiation resulted in generation of mature 3D networks of neurons (MAP2+) and glia (S100beta+) cells. We showed that cryogel scaffolds could be transplanted into the brain tissue or organotypic hippocampal slices in a rat models. The scaffolds did not induced inflammation mediated by microglial cells (ED1-, Ox43-, Iba1-) and prevented formation of glial scar (GFAP-). Contrary, laminin-rich scaffolds attracted infiltration of host's neuroblasts (NF200+, Nestin+) indicating high neuroregeneration properties.     

Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes

Barth syndrome is an X-linked recessive disorder caused by the tafazzin (TAZ) gene mutations and includes dilated cardiomyopathy (DCM) with left ventricular non-compaction, neutropenia, skeletal myopathy, abnormal mitochondria and 3-methylglutaconic aciduria. Dilated cardiomyopathy with left ventricular non-compaction transmitted as an autosomal dominant condition has also been associated with LIM domain-binding 3 (LDB3) gene defects. We describe a family in which the 12-year-old proband had left ventricular non-compaction and DCM. His mother had five miscarriages, two other sons who died in infancy, and a healthy son and daughter. The proband showed left ventricular non-compaction-DCM, skeletal myopathy, recurrent oral aphthous ulcers and cyclic neutropenia. The DCM progressively improved with age; medical therapy was discontinued at 5 years of age. At present, left ventricular function is normal and arrhythmias are absent. Magnetic resonance imaging documented left ventricular non-compaction. However, oral aphthous ulcers and cyclic neutropenia have recurred. In the proband we identified two novel mutations, one of maternal origin in the TAZ gene (p.[Glu202ValfsX15]) and one of paternal origin in the LDB3 gene (p.[Thr350Ile]). The mother, brother and father are healthy; although the latter two show prominent left ventricle trabeculation without dysfunction. Expression studies of TAZ and LDB3 genes were conducted in family members and controls. In the proband, brother and father, LDB3 expression was similar to control cases. TAZ and LDB3 expression progressively declined with age in control both blood and myocardial samples. However, an endomyocardial biopsy performed in the proband at 6 months of age, showed significantly lower TAZ and LDB3 expression than in age-matched myocardial controls. We believe that the clinical, genetic and expression data support the hypothesis that tafazzins are essential during fetal and early post-natal life.     

Methyl substitution on the piperidine ring of N-[omega-(6-methoxynaphthalen-1-yl)alkyl] derivatives as a probe for selective binding and activity at the sigma(1) receptor

The N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl and N-(6-methoxynaphthalen-1-yl)propyl derivatives as well as their upper homologous butyl derivatives of various methylpiperidines were prepared. The piperidine moiety bearing monomethyl or geminal dimethyl groups was employed as a probe to explore sigma-subtype affinities and selectivities by radioligand binding assays at sigma(1) and sigma(2) receptors and the Delta(8)-Delta(7) sterol isomerase (SI) site. 4-Methyl derivative 31 was the most potent sigma(1) ligand (K(i)=0.030 nM) with a good selectivity profile (597-fold and 268-fold relative to sigma(2) receptor and SI site, respectively), whereas 3,3-dimethyl derivative 26 (K(i)=0.35 nM) was the most selective (680-fold) relative to the sigma(2) receptor. Both compounds can be proposed as tools for PET experiments. Furthermore, the naphthalene compounds 26, 28, 31, and 33 demonstrated antiproliferative activity in rat C6 glioma cells (EC(50) = 15.0 microM for 33), revealing a putative sigma(1) antagonist activity and opening a useful perspective in tumor research and therapy.