Wine, alcohol, polyphenols and cardiovascular disease

Abstract. Excessive alcohol consumption is associated with increased morbidity and mortality as well as with labour and traffic accidents. However, current evidence suggests beneficial effects of moderate drinking on cardiovascular events including coronary heart disease, ischaemic stroke, peripheral arterial disease and congestive heart failure. The underlying mechanisms to explain these protective effects against coronary heart disease include an increase in high-density lipoprotein cholesterol and an increase in insulin sensitivity, and a decrease in platelet aggregation and circulating concentrations of fibrinogen. However, there are discrepancies regarding the specific effects of different types of beverages on the cardiovascular system, and also whether the possible protective effects of alcoholic beverages are due to their alcohol component (ethanol) or non-alcoholic products containing, mainly polyphenols. Recent randomised clinical trials have shown that wine, a polyphenol-rich alcoholic beverage, provides higher antioxidant and anti-inflammatory effects than some spirits such as gin, a polyphenol-free alcoholic beverage. In addition, dealcoholized red wine decreases blood pressure through a nitric oxide mediated mechanism, suggesting a protective effect of polyphenols on vascular function. Other studies performed in women have observed that daily doses of 1520 g of alcohol as red wine are sufficient to elicit protective effects similar to those observed in men who consumed higher doses of wine. In conclusion, moderate consumption of wine exerts a protective effect on biomarkers related to the progression and development of atherosclerosis due to its alcoholic (ethanol) and non-alcoholic (polyphenols) content. Women are more sensitive to the beneficial effects of wine.

Lymphocyte populations in liver biopsy specimens from patients with chronic liver disease

The characterisation of lymphocytes from liver biopsies indicates that 'activated' T lymphocytes are present in the liver in alcohol induced hepatitis, chronic active hepatitis (HBS+ve and -ve), and in primary biliary cirrhosis but not in inactive cirrhosis, chronic persistent hepatitis, extrahepatic and drug induced cholestasis. A greater percentage of lymphocytes bear Fc-receptors in chronic active hepatitis than in alcohol induced hepatitis or cholestatic liver disease. The concentration of 'activated' T cells in the peripheral blood in all groups studied was within the normal range, suggesting that the 'activated' T cells found in the liver were reacting to either native or foreign antigens within the liver. The data on Fc-receptor bearing cells are consistent with the involvement of antibody assisted K cell mediated cytotoxicity in chronic active hepatitis.

Eficàcia de les intervencions infermeres per a l'autocontrol de la tensió arterial en persones hipertenses

Fonaments: La hipertensió és una malaltia crònica amb alta prevalença al món. Els estils de vidasaludables es relacionen directament amb aquesta patologia pel que el rol de la infermeria és clauen el desenvolupament d'eines i intervencions per millorar l'autocontrol dels pacients hipertensosmitjançant l'educació sanitària.Objectiu: És valorar l'eficàcia de les intervencions en consultes d'infermera per a l'autocontrol dela tensió arterial en pacients amb hipertensió arterial respecte al seguiment habitual d'aquestspacients en consultes mèdiques.Mètode: S'estudiaran a 34 adults hipertensos mitjançant un assaig clínic aleatoritzat en dos grupsde 17 pacients hipertensos. El grup experimental serà objecte d'unes intervencions educativessobre la hipertensió i la repercussió dels estils de vida pel control d'aquesta patologia per partd'infermeria, a més a més, d'un control rutinari mèdic. Mentre que el grup control solamentassistirà als controls rutinaris mèdics sobre la hipertensió i no rebrà intervencions infermeres. Enl'avaluació de les dades es tindran en compte les variables de la mesura de la tensió arterial, ladieta, l'exercici físic i el seguiment del tractament, a més de diferents variablessociodemogràfiques com són l'edat, el gènere i el nivell socioeconòmic. Les dades s'analitzaranmitjançant Chi Cuadrat per a les variables qualitatives, la Correlació de Pearson i la de Spearmanper a les variables quantitatives i, finalment, la T de Student per a la comparació de la mitja de lesdues mostres independents.Conclusió: Amb l'assaig clínic es pretés demostrar que les intervencions d’infermeria en consultesmilloren l'autocontrol dels pacients amb hipertensió arterial, és a dir, són eficaces.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Rapid improvement of canine cognitive dysfunction with immunotherapy designed for Alzheimer's disease

Immunotherapy against amyloid-β(Aβ) may improve rodent cognitive function by reducing amyloid neuropathology and is being validated in clinical trials with positive preliminary results. However, for a complete understanding of the direct and long-term immunization responses in the aged patient, and also to avoid significant side effects, several key aspects remain to be clarified. Thus, to investigate brain Aβ clearance and Th2 responses in the elderly, and the reverse inflammatory events not found in the immunized rodent, better Alzheimer"s disease (AD) models are required. In the aged familiar canine with a Cognitive Dysfunction Syndrome (CDS) we describe the rapid effectiveness and the full safety profile of a new active vaccine candidate for human AD prevention and treatment. In these aged animals, besidesa weak immune system, the antibody response activated a coordinated central and peripheral Aβ clearance, that rapidly improved their cognitive function in absence of any side effects. Our results also confirm the interest to use familiar dogs to develop innovative and reliable therapies for AD.

Educación de Enfermería para el autocuidado y control de la Hipertensión Arterial (HTA) en personas con HTA Crónica

La Hipertensión Arterial (HTA) es uno de los principales factores de riesgo de morbilidad y mortalidad cardíaca y cerebrovascular, que afecta mundialmente, por lo que conlleva a un problema de salud pública universal. Es por ello que, el JNC7 recomienda una serie de actividades de autocuidado (AC), que se dividen en el tratamiento farmacológico y no-farmacológico, en el que deberá intervenir el personal sanitario, entre ellos, enfermería, para lograr el control de la enfermedad y evitar complicaciones.

Ischemic heart disease and primary care: identifying gender-related differences. An observational study

Background: Gender-related differences are seen in multiple aspects of both health and illness. Ischemic heart disease (IHD) is a pathology in which diagnostic, treatment and prognostic differences are seen between sexes, especially in the acute phase and in the hospital setting. The objective of the present study is to analyze whether there are differences between men and women when examining associated cardiovascular risk factors and secondary pharmacological prevention in the primary care setting. Methods: Retrospective descriptive observational study from January to December of 2006, including 1907 patients diagnosed with ischemic heart disease in the city of Lleida, Spain. The clinical data were obtained from computerized medical records and pharmaceutical records of medications dispensed in pharmacies with official prescriptions. Data was analyzed using bivariate descriptive statistical analysis as well as logistic regression. Results: There were no gender-related differences in screening percentages for arterial hypertension, diabetes, obesity, dyslipemia, and smoking. A greater percentage of women were hypertensive, obese and diabetic compared to men. However, men showed a tendency to achieve control targets more easily than women, with no statistically significant differences. In both sexes cardiovascular risk factors control was inadequate, between 10 and 50%. For secondary pharmaceutical prevention, the percentages of prescriptions were greater in men for anticoagulants, beta-blockers, lipid-lowering agents and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, with age group variations up to 10%. When adjusting by age and specific diagnoses, differences were maintained for anticoagulants and lipid-lowering agents. Conclusion: Screening of cardiovascular risk factors was similar in men and women with IHD. Although a greater percentage of women were hypertensive, diabetic or obese, their management of risk factors tended to be worse than men. Overall, a poor control of cardiovascular risk factors was noted. Taken as a whole, more men were prescribed secondary prevention drugs, with differences varying by age group and IHD diagnosis.

Association study of lipoprotein(a) genetic markers, traditional risk factors, and coronary heart disease in HIV-1-infected patients.

Objectives: General population studies have shown associations between copy number variation (CNV) of the LPA gene Kringle-IV type-2 (KIV-2) coding region, single-nucleotide polymorphism (SNP) rs6415084 in LPA and coronary heart disease (CHD). Because risk factors for HIV-infected patients may differ from the general population, we aimed to assess whether these potential associations also occur in HIV-infected patients. Methods: A unicenter, retrospective, case-control (1:3) study. Eighteen HIV-patients with confirmed diagnosis of acute myocardial infarction (AMI) were adjusted for age, gender, and time since HIV diagnosis to 54 HIV-patients without CHD. After gDNA extraction from frozen blood, both CNV and SNP genotyping were performed using real-time quantitative PCR. All genetic and non-genetic variables for AMI were assessed in a logistic regression analysis. Results: Our results did not confirm any association in terms of lipoprotein(a) LPA structural genetic variants when comparing KIV-2 CNV (p = 0.67) and SNP genotypes (p = 0.44) between AMI cases and controls. However, traditional risk factors such as diabetes mellitus, hypertension, and CD4(+) T cell count showed association (p < 0.05) with CHD. Conclusion: Although significant associations of AMI with diabetes, hypertension and CD4(+) T cell count in HIV-patients were found, this study could not confirm the feasibility neither of KIV-2 CNV nor rs6415084 in LPA as genetic markers of CHD in HIV-infected patients.Highlights:● Individuals with HIV infection are at higher risk of coronary heart disease (CHD) than the non-infected population.● Our results showed no evidence of LPA structural genetic variants associated with CHD in HIV-1-infected patients.● Associations were found between diabetes mellitus, arterial hypertension, CD4(+) T cell count, and CHD.● The clinical usefulness of these biomarkers to predict CHD in HIV-1-infected population remains unproven.● Further studies are needed to assess the contribution of common genetic variations to CHD in HIV-infected individuals.

Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease

Chronic obstructive pulmonary disease (COPD) is a lethal progressive lung disease culminating in permanent airway obstruction and alveolar enlargement. Previous studies suggest CTL involvement in COPD progression; however, their precise role remains unknown. Here, we investigated whether the CTL activation receptor NK cell group 2D (NKG2D) contributes to the development of COPD. Using primary murine lung epithelium isolated from mice chronically exposed to cigarette smoke and cultured epithelial cells exposed to cigarette smoke extract in vitro, we demonstrated induced expression of the NKG2D ligand retinoic acid early tran - script 1 (RAET1)as well as NKG2D-mediated cytotoxicity. Furthermore, a genetic model of inducible RAET1 expression on mouse pulmonary epithelial cells yielded a severe emphysematous phenotype characterized by epithelial apoptosis and increased CTL activation, which was reversed by blocking NKG2D activation. We also assessed whether NKG2D ligand expression corresponded with pulmonary disease in human patients by staining airway and peripheral lung tissues from never smokers, smokers with normal lung function, and current and former smokers with COPD. NKG2D ligand expression was independent of NKG2D receptor expression in COPD patients, demonstrating that ligand expression is the limiting factor in CTL activation. These results demonstrate that aberrant, persistent NKG2D ligand expression in the pulmonary epithelium contributes to the development of COPD pathologies.

Differential methylation of TCF7L2 promoter in peripheral blood DNA in newly diagnosed, drug-naïve patients with type 2 diabetes

TCF7L2 is the susceptibility gene for Type 2 diabetes (T2D) with the largest effect on disease risk that has been discovered to date. However, the mechanisms by which TCF7L2 contributes to the disease remain largely elusive. In addition, epigenetic mechanisms, such as changes in DNA methylation patterns, might have a role in the pathophysiology of T2D. This study aimed to investigate the differences in terms of DNA methylation profile of TCF7L2 promoter gene between type 2 diabetic patients and age- and Body Mass Index (BMI)- matched controls. We included 93 type 2 diabetic patients that were recently diagnosed for T2D and exclusively on diet (without any pharmacological treatment). DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Type 2 diabetic patients were more insulin resistant than their matched controls (mean HOMA IR 2.6 vs 1.8 in controls, P<0.001) and had a poorer beta-cell function (mean HOMA B 75.7 vs. 113.6 in controls, P<0.001). Results showed that 59% of the CpGs analyzed in TCF7L2 promoter had significant differences between type 2 diabetic patients and matched controls. In addition, fasting glucose, HOMA-B, HOMA-IR, total cholesterol and LDL-cholesterol correlated with methylation in specific CpG sites of TCF7L2 promoter. After adjustment by age, BMI, gender, physical inactivity, waist circumference, smoking status and diabetes status uniquely fasting glucose, total cholesterol and LDL-cholesterol remained significant. Taken together, newly diagnosed, drug-naïve type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to age- and BMI-matched controls. Methylation in TCF7L2 promoter is further correlated with fasting glucose in peripheral blood DNA, which sheds new light on the role of epigenetic regulation of TCF7L2 in T2D.

Hipertensión arterial y enfermedad de Alzheimer

Hypertension (HT) is the most prevalent cardiovascular risk factor associated with dementia and Alzheimer disease (AD). The evidence about the association within hight blood pressure (BP) level in the middle age and dementia and Alzheimer’s disease incidence in the advanced age has increased. Longitudinal studies show that in the previous years of onset AD, BP is similar or lower in the patients who develop AD with regard to those who not develop. When patients has developed AD the case is the same that the previous one. Most studies show that BP reduction is beneficious to prevent cognitive impairment, dementia and AD. Is spite of some discordant studies, health authorities recommend to treat isolated systolic HT with an ‘A’ evidence degree, level 1, to prevent AD. Animal experimentation prove different ways to act of antihypertensive drugs in the AD prevention and has established the pathophysiological bases in this relation, until now only showed through various clinical studies

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.