Microvascular pathology in late-life depression.

Since the era of Gaupp who introduced the concept of atheroscletic depressive disorder, the concept of late-life depression has been correlated with cerebrovascular comorbidities, microvascular lesions, frontal cortical and subcortical gray and white matter hyperintensities. The predominant neuropsychological deficits concern the domains of planning, organization and abstraction, with executive dysfunction being the predominant finding. MRI studies reveal a higher prevalence of white matter lesions in elderly patients with depression. Molecular mechanisms underlying the disease still remain unclear. Hyperhomocysteinemia has been associated with depression through its toxicity to neurons and blood vessels. Endothelial dysfunction is another possible mechanism referring to the loss of vasodilatation capacity. Inflammatory phenomena, such as increased peripheral leucocytes, elevated CRP and cytokine levels, could play a role in endothelial dysfunction. In this review we will briefly combine findings from neurobiological, epidemiological, structural and post-mortem data. A more complex model in late-life depression combining different modalities could be an elucidating approach to the disease's etiopathogeny in the future.

Tendencias de la mortalidad por enfermedades cardiovasculares en Andalucía entre 1975 y 2004

Background: Cardiovascular diseases are ranked among the leading causes of death in the industrialized countries. This study is aimed at ascertaining the mortality trends by ischemic heart disease (IHD) and cerebrovascular diseases (CVD) in Andalusia within the 1975-2004 period. Method: Based on the official IHD and CVD death statistics and the related populations, the gross rates (GR) and age-adjusted rates (TS) and the Potential Years of Life Lost (PYLL) were calculated. To quantify the trends and their change points, a joinpoint regression analysis was made. Results: The number of IHD deaths for females rose from 2,086 deaths in 1975 to 3,336 in 2004, the TS having dropped from 74.29 to 50.94 deaths/100,000 females, the PYLL having dropped from 173.65 years to 90.56 years/100,000 females. The number of deaths for males rose from 2,854 deaths in 1975 to 4,085 in 2004, the TS having dropped from 147, 67 to 104.96 deaths /100,000 males. The PYLL showed a like behaviour from the first to the last year of the series, showing values of 716.46 and 460.04 years / 100,000 males. For the IHD in females, the number of deaths in absolute numbers dropped from 4,712 to 4,221, the TS having dropped from 166.00 to 62.08 deaths in females, and the PYLL from 338.08 to 87.63 years / 100,000 females. For males, the number of deaths dropped from 3,714 to 2,951, the TS from 206.88 deaths /100,000 males in 1975 to 76.12 /100,000 males in 2004, and the PYLL dropping from 533.12 to 182.38 years / 100,000 males. Conclusions: The trend in mortality due to IHD was not constant either among females or males, although it has always been a downward trend, the drop being statistically significant. The drop in the CVD has been such a major one that both the absolute numbers and the gross rates are lower for the most recent years that the first years in the series studied despite the aging of Andalusia’s population.

Frequency of Fabry disease in male and female haemodialysis patients in Spain

BACKGROUND: Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by a reduced activity of the lysosomal enzyme alpha-galactosidase A. The disorder ultimately leads to organ damage (including renal failure) in males and females. However, heterozygous females usually present a milder phenotype with a later onset and a slower progression. METHODS: A combined enzymatic and genetic strategy was used, measuring the activity of alpha-galactosidase A and genotyping the alpha-galactosidase A gene (GLA) in dried blood samples (DBS) of 911 patients undergoing haemodialysis in centers across Spain. RESULTS: GLA alterations were found in seven unrelated patients (4 males and 3 females). Two novel mutations (p.Gly346AlafsX347 and p.Val199GlyfsX203) were identified as well as a previously described mutation, R118C. The R118C mutation was present in 60% of unrelated patients with GLA causal mutations. The D313Y alteration, considered by some authors as a pseudo-deficiency allele, was also found in two out of seven patients. CONCLUSIONS: Excluding the controversial D313Y alteration, FD presents a frequency of one in 182 individuals (0.55%) within this population of males and females undergoing haemodialysis. Moreover, our findings suggest that a number of patients with unexplained and atypical symptoms of renal disease may have FD. Screening programmes for FD in populations of individuals presenting severe kidney dysfunction, cardiac alterations or cerebrovascular disease may lead to the diagnosis of FD in those patients, the study of their families and eventually the implementation of a specific therapy.

Morbidity and prognostic factors in chronic chagasic cardiopathy

Chagas disease is a pleomorphic clinical entity that has several unique features. The aim of this study is to summarise some of the recent contributions from our research group to knowledge of the morbidity and prognostic factors in Chagas heart disease. A retrospective study suggested that ischaemic stroke associated with left ventricular (LV) apical thrombi is the first clinical manifestation of Chagas disease observed in a large proportion of patients. LV function and left atrial volume (LAV) are independent risk factors for ischaemic cerebrovascular events during follow-up of Chagas heart disease patients. Pulmonary congestion in Chagas-related dilated cardiomyopathy is common but usually mild. Although early right ventricular (RV) involvement has been described, we have shown by Doppler echocardiography that RV dysfunction is evident almost exclusively when it is associated with left ventricle dilatation and functional impairment. In addition, RV dysfunction is a powerful predictor of survival in patients with heart failure secondary to Chagas disease. We have also demonstrated that LAV provides incremental prognostic information independent of clinical data and conventional echocardiographic parameters that predict survival.

A prediction rule to identify low-risk patients with pulmonary embolism.

BACKGROUND: A simple prognostic model could help identify patients with pulmonary embolism who are at low risk of death and are candidates for outpatient treatment. METHODS: We randomly allocated 15,531 retrospectively identified inpatients who had a discharge diagnosis of pulmonary embolism from 186 Pennsylvania hospitals to derivation (67%) and internal validation (33%) samples. We derived our rule to predict 30-day mortality using classification tree analysis and patient data routinely available at initial examination as potential predictor variables. We used data from a European prospective study to externally validate the rule among 221 inpatients with pulmonary embolism. We determined mortality and nonfatal adverse medical outcomes across derivation and validation samples. RESULTS: Our final model consisted of 10 patient factors (age > or = 70 years; history of cancer, heart failure, chronic lung disease, chronic renal disease, and cerebrovascular disease; and clinical variables of pulse rate > or = 110 beats/min, systolic blood pressure < 100 mm Hg, altered mental status, and arterial oxygen saturation < 90%). Patients with none of these factors were defined as low risk. The 30-day mortality rates for low-risk patients were 0.6%, 1.5%, and 0% in the derivation, internal validation, and external validation samples, respectively. The rates of nonfatal adverse medical outcomes were less than 1% among low-risk patients across all study samples. CONCLUSIONS: This simple prediction rule accurately identifies patients with pulmonary embolism who are at low risk of short-term mortality and other adverse medical outcomes. Prospective validation of this rule is important before its implementation as a decision aid for outpatient treatment.

MR-based follow-up of the superior cerebellar artery after radiosurgery for trigeminal neuralgia.

Purpose: To study with a non invasive method any potential radiological change on the superior cerebellar artery (SCA) in patients treated radiosurgically for classic trigeminal neuralgia (CTN).Materials and methods: A retrospective measure of maximal dose received by SCA was performed analyzing the treatment planning in 55 consecutive patients treated by Gamma Knife radiosurgery for an CTN, then, a prospective study was designed using high resolution MR, with T2 SPIR, T1 without and with gadolinium enhancement, Proton density, 3D TONE and MIP reconstructions. Inclusion criteria were: patients followed at our institution, follow-up of one year or more, dose received by the SCA of 15 Gy or more and voluntary patient participation in the study. Patients with repeated Gamma Knife radiosurgery for failure or recurrence were excluded. The end points were: SCA occlusion, stenosis or infarction in the territory supplied by SCA.Results: Sixteen patients were studied, with a mean follow-up of 25.2 months (12-42 months). The mean maximal dose received by the SCA was 57.5 Gy. (15-87 Gy). Among these 16 patients studied, neither obstruction of the SCA nor infarction was demonstrated. In one patient a suspicion of asymptomatic SCA stenosis was visualized distant to the irradiation field.Conclusions: SCA can receive a high dose of irradiation during radiosurgical treatment for CTN. This study does not confirm any vascular damage to the SCA after radiosurgery for CTN. (C) 2011 Elsevier B.V. All rights reserved.

Dynamic arterial elastance to predict arterial pressure response to volume loading in preload-dependent patients

INTRODUCTION Hemodynamic resuscitation should be aimed at achieving not only adequate cardiac output but also sufficient mean arterial pressure (MAP) to guarantee adequate tissue perfusion pressure. Since the arterial pressure response to volume expansion (VE) depends on arterial tone, knowing whether a patient is preload-dependent provides only a partial solution to the problem. The objective of this study was to assess the ability of a functional evaluation of arterial tone by dynamic arterial elastance (Ea(dyn)), defined as the pulse pressure variation (PPV) to stroke volume variation (SVV) ratio, to predict the hemodynamic response in MAP to fluid administration in hypotensive, preload-dependent patients with acute circulatory failure. METHODS We performed a prospective clinical study in an adult medical/surgical intensive care unit in a tertiary care teaching hospital, including 25 patients with controlled mechanical ventilation who were monitored with the Vigileo(®) monitor, for whom the decision to give fluids was made because of the presence of acute circulatory failure, including arterial hypotension (MAP ≤65 mmHg or systolic arterial pressure <90 mmHg) and preserved preload responsiveness condition, defined as a SVV value ≥10%. RESULTS Before fluid infusion, Ea(dyn) was significantly different between MAP responders (MAP increase ≥15% after VE) and MAP nonresponders. VE-induced increases in MAP were strongly correlated with baseline Ea(dyn) (r(2) = 0.83; P < 0.0001). The only predictor of MAP increase was Ea(dyn) (area under the curve, 0.986 ± 0.02; 95% confidence interval (CI), 0.84-1). A baseline Ea(dyn) value >0.89 predicted a MAP increase after fluid administration with a sensitivity of 93.75% (95% CI, 69.8%-99.8%) and a specificity of 100% (95% CI, 66.4%-100%). CONCLUSIONS Functional assessment of arterial tone by Ea(dyn), measured as the PVV to SVV ratio, predicted arterial pressure response after volume loading in hypotensive, preload-dependent patients under controlled mechanical ventilation.

Intratracheal suctioning in sick preterm infants: prevention of intracranial hypertension and cerebral hypoperfusion by muscle paralysis.

In a prospective nonrandomized study, using each baby as his or her own control, we compared intracranial pressure (anterior fontanel pressure as measured with the Digilab pneumotonometer), cerebral perfusion pressure, BP, heart rate, transcutaneous Po2, and transcutaneous Pco2 before, during, and after endotracheal suctioning, with and without muscle paralysis, in 28 critically ill preterm infants with respiratory distress syndrome. With suctioning, there was a small but significant increase in intracranial pressure in paralyzed patients (from 13.7 [mean] +/- 4.4 mm Hg [SD] to 15.8 +/- 5.2 mm Hg) but a significantly larger (P less than .001) increase when they were not paralyzed (from 12.5 +/- 3.6 to 28.5 +/- 8.3 mm Hg). Suctioning led to a slight increase in BP with (from 45.3 +/- 9.1 to 48.0 +/- 8.7 mm Hg) and without muscle paralysis (from 45.1 +/- 9.4 to 50.0 +/- 11.7 mm Hg); but there was no significant difference between the two groups. The cerebral perfusion pressure in paralyzed infants did not show any significant change before, during, and after suctioning (31.5 +/- 9.1 mm Hg before v 32.0 +/- 8.7 mm Hg during suctioning), but without muscle paralysis cerebral perfusion pressure decreased (P less than .001) from 32.8 +/- 9.7 to 21.3 +/- 13.1 mm Hg. Suctioning induced a slight decrease in mean heart rate and transcutaneous Po2, but pancuronium did not alter these changes. There was no statistical difference in transcutaneous Pco2 before, during, and after suctioning with and without muscle paralysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference.

Neuroimaging with diffusion-weighted imaging is routinely used for clinical diagnosis/prognosis. Its quantitative parameter, the apparent diffusion coefficient (ADC), is thought to reflect water mobility in brain tissues. After injury, reduced ADC values are thought to be secondary to decreases in the extracellular space caused by cell swelling. However, the physiological mechanisms associated with such changes remain uncertain. Aquaporins (AQPs) facilitate water diffusion through the plasma membrane and provide a unique opportunity to examine the molecular mechanisms underlying water mobility. Because of this critical role and the recognition that brain AQP4 is distributed within astrocytic cell membranes, we hypothesized that AQP4 contributes to the regulation of water diffusion and variations in its expression would alter ADC values in normal brain. Using RNA interference in the rodent brain, we acutely knocked down AQP4 expression and observed that a 27% AQP4-specific silencing induced a 50% decrease in ADC values, without modification of tissue histology. Our results demonstrate that ADC values in normal brain are modulated by astrocytic AQP4. These findings have major clinical relevance as they suggest that imaging changes seen in acute neurologic disorders such as stroke and trauma are in part due to changes in tissue AQP4 levels.

Perinatal Hypoxia Enhances Cyclic Adenosine Monophosphate-mediated BKCa Channel Activation in Adult Murine Pulmonary Artery.

Exposure to perinatal hypoxia results in alteration of the adult pulmonary circulation, which is linked among others to alterations in K channels in pulmonary artery (PA) smooth muscle cells. In particular, large conductance Ca-activated K (BKCa) channels protein expression and activity were increased in adult PA from mice born in hypoxia compared with controls. We evaluated long-term effects of perinatal hypoxia on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway-mediated activation of BKCa channels, using isoproterenol, forskolin, and dibutyryl-cAMP. Whole-cell outward current was higher in pulmonary artery smooth muscle cells from mice born in hypoxia compared with controls. Spontaneous transient outward currents, representative of BKCa activity, were present in a greater proportion in pulmonary artery smooth muscle cells of mice born in hypoxia than in controls. Agonists induced a greater relaxation in PA of mice born in hypoxia compared with controls, and BKCa channels contributed more to the cAMP/PKA-mediated relaxation in case of perinatal hypoxia. In summary, perinatal hypoxia enhanced cAMP-mediated BKCa channels activation in adult murine PA, suggesting that this pathway could be a potential target for modulating adult pulmonary vascular tone after perinatal hypoxia.

Vertebral artery occlusion after chemotherapy

We present a patient who experienced a stroke due to vertebral artery occlusion after chemotherapy

Implication of the endocannabinoid system in the locomotor hyperactivity associated with congenital hypothyroidism

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB(1)) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB(1) receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB(1) receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.

Fungal co-culture as a new source of antifungal metabolites

Background: Over the last two decades, mortality from coronary heart disease (CHD) and cerebrovascular disease (CVD) declined by about 30% in the European Union (EU). Design: We analyzed trends in CHD (X ICD codes: I20-I25) and CVD (X ICD codes: I60-I69) mortality in young adults (age 35-44 years) in the EU as a whole and in 12 selected European countries, over the period 1980-2007. Methods: Data were derived from the World Health Organization mortality database. With joinpoint regression analysis, we identified significant changes in trends and estimated average annual percent changes (AAPC). Results: CHD mortality rates at ages 35-44 years have decreased in both sexes since the 1980s for most countries, except for Russia (130/100,000 men and 24/100,000 women, in 2005-7). The lowest rates (around 9/100,000 men, 2/100,000 women) were in France, Italy and Sweden. In men, the steepest declines in mortality were in the Czech Republic (AAPC = -6.1%), the Netherlands (-5.2%), Poland (-4.5%), and England and Wales (-4.5%). Patterns were similar in women, though with appreciably lower rates. The AAPC in the EU was -3.3% for men (rate = 16.6/100,000 in 2005-7) and -2.1% for women (rate = 3.5/100,000). For CVD, Russian rates in 2005-7 were 40/100,000 men and 16/100,000 women, 5 to 10-fold higher than in most western European countries. The steepest declines were in the Czech Republic and Italy for men, in Sweden and the Czech Republic for women. The AAPC in the EU was -2.5% in both sexes, with steeper declines after the mid-late 1990s (rates = 6.4/100,000 men and 4.3/100,000 women in 2005-7). Conclusions: CHD and CVD mortality steadily declined in Europe, except in Russia, whose rates were 10 to 15-fold higher than those of France, Italy or Sweden. Hungary and Poland, and also Scotland, where CHD trends were less favourable than in other western European countries, also emerge as priorities for preventive interventions.