Higher incidence of death in multi-vessel coronary artery disease patients associated with polymorphisms in chromosome 9p21

Background: We investigated whether 9p21 polymorphisms are associated with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease (CAD) and preserved left ventricular function. Methods: The participants of the MASS II were genotyped for 9p21 polymorphisms (rs10757274, rs2383206, rs10757278 and rs1333049). Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, death from cardiac causes and myocardial infarction using a Cox proportional hazards survival model. Results: We observed significant differences between patients within each polymorphism genotype group for baseline characteristics. The frequency of diabetes was lower in patients carrying GG genotype for rs10757274, rs2383206 and rs10757278 (29.4%, 32.8%, 32.0%) compared to patients carrying AA or AG genotypes (49.1% and 39.2%, p = 0.01; 52.4% and 40.1%, p = 0.01; 47.8% and 37.9%, p = 0.04; respectively). Significant differences in genotype frequencies between double and triple vessel disease patients were observed for the rs10757274, rs10757278 and rs1333049. Finally, there was a higher incidence of overall mortality in patients with the GG genotype for rs2383206 compared to patients with AA and AG genotypes (19.5%, 11.9%, 11.0%, respectively; p = 0.04). Moreover, the rs2383206 was still significantly associated with a 1.75-fold increased risk of overall mortality (p = 0.02) even after adjustment of a Cox multivariate model for age, previous myocardial infarction, diabetes, smoking and type of coronary anatomy. Conclusions: Our data are in accordance to previous evidence that chromosome 9p21 genetic variation may constitute a genetic modulator in the cardiovascular system in different scenarios. In patients with established CAD, we observed an association between the rs2383206 and higher incidence of overall mortality and death from cardiac causes in patients with multi-vessel CAD.

Vascular dementia: Different forms of vessel disorders contribute to the development of dementia in the elderly brain

The diagnosis of vascular dementia (VaD) describes a group of various vessel disorders with different types of vascular lesions that finally contribute to the development of dementia. Most common forms of VaD in the elderly brain are subcortical vascular encephalopathy, strategic infarct dementia, and the multi infarct encephalopathy. Hereditary forms of VaD are rare. Most common is the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Sporadic forms of VaD are caused by degenerative vessel disorders such as atherosclerosis, small vessel disease (SVD) including small vessel arteriosclerosis, arteriolosclerosis, and lipohyalinosis, and cerebral amyloid angiopathy (CAA). Less frequently inflammatory vessel disorders and tumor-associated vessel lesions (e. g. angiocentric T-cell or angiotropic large cell lymphoma) can cause symptoms of dementia. Here, we review and discuss the impact of vessel disorders to distinct vascular brain tissue lesions and to the development of dementia in elderly individuals. The impact of coexisting neurodegenerative pathology in the elderly brain to VaD as well as the correlation between SVD and CAA expansion in the brain parenchyma with that of Alzheimer's disease (AD)-related pathology is highlighted. We conclude that "pure" VaD is rare and most frequently caused by infarctions. However, there is a significant contribution of vascular lesions and vessel pathology to the development of dementia that may go beyond tissue damage due to vascular lesions. Insufficient blood blow and alterations of the perivascular drainage mechanisms of the brain may also lead to a reduced protein clearance from extracellular space and subsequent increase of proteins in the brain parenchyma, such as the amyloid beta-protein, and foster, thereby, the development of AD-related neurodegeneration. As such, it seems to be important for clinical practice to consider treatment of potentially coexisting AD pathology in cognitively impaired patients with vascular lesions. (C) 2012 Elsevier Inc. All rights reserved.

The Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial: Clinical and angiographic profile at study entry

Background The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy. Methods A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients. Results The randomized cohort was 63.1 +/- 9.1 years old and 29% female, with a median diabetes duration of 10.2 +/- 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 +/- 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 +/- 1.7 mg/dL, 29% had low-density lipoprotein <70 mg/dL, and mean systolic blood pressure was 134 +/- 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts. Conclusions The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD. (Am Heart J 2012;164:591-9.)

Strategies for Multivessel Revascularization in Patients with Diabetes

BACKGROUND In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease. METHODS In this randomized trial, we assigned patients with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescribed currently recommended medical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure, and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. RESULTS From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients' mean age was 63.1 +/- 9.1 years, 29% were women, and 83% had three-vessel disease. The primary outcome occurred more frequently in the PCI group (P=0.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03). CONCLUSIONS For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke. (Funded by the National Heart, Lung, and Blood Institute and others; FREEDOM ClinicalTrials.gov number, NCT00086450.)

Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies

The association of RASopathies [Noonan syndrome (NS) and Noonan-related syndromes] and autoimmune disorders has been reported sporadically. However, a concomitant evaluation of autoimmune diseases and an assessment of multiple autoantibodies in a large population of patients with molecularly confirmed RASopathy have not been performed. The clinical and laboratory features were analyzed in 42 RASopathy patients, the majority of whom had NS and five individuals had Noonan-related disorders. The following autoantibodies were measured: Anti-nuclear antibodies, anti-double stranded DNA, anti-SS-A/Ro, anti-SS-B/La, anti-Sm, anti-RNP, anti-Scl-70, anti-Jo-1, anti-ribosomal P, IgG and IgM anticardiolipin (aCL), thyroid, anti-smooth muscle, anti-endomysial (AE), anti-liver cytosolic protein type 1 (LC1), anti-parietal cell (APC), anti-mitochondrial (AM) antibodies, anti-liver-kidney microsome type 1 antibodies (LKM-1), and lupus anticoagulant. Six patients (14%) fulfilled the clinical criteria for autoimmune diseases [systemic lupus erythematous, polyendocrinopathy (autoimmune thyroiditis and celiac disease), primary antiphospholipid syndrome (PAPS), autoimmune hepatitis, vitiligo, and autoimmune thyroiditis]. Autoimmune antibodies were observed in 52% of the patients. Remarkably, three (7%) of the patients had specific gastrointestinal and liver autoantibodies without clinical findings. Autoimmune diseases and autoantibodies were frequently present in patients with RASopathies. Until a final conclusion of the real incidence of autoimmunity in Rasopathy is drawn, the physicians should be alerted to the possibility of this association and the need for a fast diagnosis, proper referral to a specialist and ultimately, adequate treatment. (c) 2012 Wiley Periodicals, Inc.

Association between UCP2 A55V polymorphism and risk of cardiovascular events in patients with multi-vessel coronary arterial disease

Background UCP2 (uncoupling protein 2) plays an important role in cardiovascular diseases and recent studies have suggested that the A55V polymorphism can cause UCP2 dysfunction. The main aim was to investigate the association of A55V polymorphism with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease and preserved left ventricular function. Methods The participants of the MASS II were genotyped for the A55V polymorphism using allele-specific PCR assay. Survival curves were calculated with the Kaplan–Meier method and evaluated with the log-rank statistic. The relationship between baseline variables and the composite end-point of cardiac death, acute myocardial infarction (AMI), refractory angina requiring revascularization and cerebrovascular accident were assessed using a Cox proportional hazards survival model. Results There were no significant differences for baseline variables according genotypes. After 2 years of follow-up, dysglycemic patients harboring the VV genotype had higher occurrence of AMI (p=0.026), Death+AMI (p=0.033), new revascularization intervention (p=0.009) and combined events (p=0.037) as compared with patients carrying other genotypes. This association was not evident in normoglycemic patients. Conclusions These findings support the hypothesis that A55V polymorphism is associated with UCP2 functional alterations that increase the risk of cardiovascular events in patients with previous coronary artery disease and dysglycemia.

Chromatic discrimination losses in multiple sclerosis patients with and without optic neuritis using the Cambridge Colour Test

We assessed chromatic discrimination in multiple sclerosis (MS) patients both with (ON) and without (no ON) a history of optic neuritis using the Cambridge color test (CCT). Our goal was to determine the magnitude and chromatic axes of any color vision losses in both patient groups, and to evaluate age-related changes in chromatic discrimination in both patient groups compared to normals. Using the CCT, we measured chromatic discrimination along the protan, deutan and tritan axes in 35 patients with MS (17 ON eyes) and 74 age matched controls. Color thresholds for both patient groups were significantly higher than controls` along the protan and tritan axes (P < 0.001). In addition, the ON and no-ON groups differed significantly along all three-color axes (p < 0.001). MS patients presented a progressive color discrimination impairment with age (along the deutan and tritan axes) that was almost two times faster than controls, even in the absence of ON. These findings suggest that demyelinating diseases reduce sensitivity to color vision in both red-green and blue-yellow axes, implying impairment in both parvocellular and koniocellular visual pathways. The CCT is a useful tool to help characterize vision losses in MS and the relationship between these losses and degree of optic nerve involvement.

Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma

Despite the good response of stem cell transplant (SCT) in the treatment of multiple myeloma (MM), most patients relapse or do not achieve complete remission, suggesting that additional treatment is needed. We assessed the impact of thalidomide in maintenance after SCT in untreated patients with MM. A hundred and eight patients (<70 years old) were randomized to receive maintenance with dexamethasone (arm A; n = 52) or dexamethasone with thalidomide (arm B; n = 56; 200 mg daily) for 12 months or until disease progression. After a median follow-up of 27 months, an intention to treat analysis showed a 2-year progression-free survival (PFS) of 30% in arm A (95% CI 2238) and 64% in arm B (95% CI 5771; P = 0.002), with median PFS of 19 months and 36 months, respectively. In patients who did not achieve at least a very good partial response, the PFS at 2 years was significantly higher when in use of thalidomide (19 vs. 59%; P = 0.002). Overall survival at 2 years was not significantly improved (70 vs. 85% in arm A and arm B, respectively; P = 0.27). The addition of thalidomide to dexamethasone as maintenance improved the PFS mainly in patients who did not respond to treatment after SCT. Am. J. Hematol. (c) 2012 Wiley Periodicals, Inc.

Human telomere disease due to disruption of the CCAAT box of the TERC promoter

Mutations in the coding region of telomerase complex genes can result in accelerated telomere attrition and human disease. Manifestations of telomere disease include the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia, acute myeloid leukemia, liver cirrhosis, and pulmonary fibrosis. Here, we describe a mutation in the CCAAT box (GCAAT) of the TERC gene promoter in a family in which multiple members had typical features of telomeropathy. The genetic alteration in this critical regulatory sequence resulted in reduced reporter gene activity and absent binding of transcription factor NF-Y, likely responsible for reduced TERC levels, decreased telomerase activity, and short telomeres. This is the first description of a pathogenic mutation in the highly con-served CCAAT box and the first instance of a mutation in the promoter region of TERC producing a telomeropathy. We propose that current mutation-screening strategies should include gene promoter regions for the diagnosis of telomere diseases. This clinical trial was registered at www.clinicaltrials.gov as #NCT00071045. (Blood. 2012;119(13):3060-3063)

A comparative transcriptome analysis reveals expression profiles conserved across three Eimeria spp. of domestic fowl and associated with multiple developmental stages

Coccidiosis of the domestic fowl is a worldwide disease caused by seven species of protozoan parasites of the genus Eimeria. The genome of the model species, Eimeria tenella, presents a complexity of 55-60 MB distributed in 14 chromosomes. Relatively few studies have been undertaken to unravel the complexity of the transcriptome of Eimeria parasites. We report here the generation of more than 45,000 open reading frame expressed sequence tag (ORESTES) cDNA reads of E. tenella, Eimeria maxima and Eimeria acervulina, covering several developmental stages: unsporulated oocysts, sporoblastic oocysts, sporulated oocysts, sporozoites and second generation merozoites. All reads were assembled to constitute gene indices and submitted to a comprehensive functional annotation pipeline. In the case of E. tenella, we also incorporated publicly available ESTs to generate an integrated body of information. Orthology analyses have identified genes conserved across different apicomplexan parasites, as well as genes restricted to the genus Eimeria. Digital expression profiles obtained from ORESTES/EST countings, submitted to clustering analyses, revealed a high conservation pattern across the three Eimeria spp. Distance trees showed that unsporulated and sporoblastic oocysts constitute a distinct clade in all species, with sporulated oocysts forming a more external branch. This latter stage also shows a close relationship with sporozoites, whereas first and second generation merozoites are more closely related to each other than to sporozoites. The profiles were unambiguously associated with the distinct developmental stages and strongly correlated with the order of the stages in the parasite life cycle. Finally, we present The Eimeria Transcript Database (http://www.coccidia.icb.usp.br/eimeriatdb), a website that provides open access to all sequencing data, annotation and comparative analysis. We expect this repository to represent a useful resource to the Eimeria scientific community, helping to define potential candidates for the development of new strategies to control coccidiosis of the domestic fowl. (C) 2011 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Number of recent sexual partners among blood donors in Brazil: associations with donor demographics, donation characteristics, and infectious disease markers

BACKGROUND: Brazilian blood centers ask candidate blood donors about the number of sexual partners in the past 12 months. Candidates who report a number over the limit are deferred. We studied the implications of this practice on blood safety. STUDY DESIGN AND METHODS: We analyzed demographic characteristics, number of heterosexual partners, and disease marker rates among 689,868 donations from three Brazilian centers between July 2007 and December 2009. Donors were grouped based on maximum number of partners allowed in the past 12 months for each center. Chi-square and logistic regression analysis were conducted to examine associations between demographic characteristics, number of sex partners, and individual and overall positive markers rates for human immunodeficiency virus (HIV), human T-lymphotropic virus Types 1 and 2, hepatitis B virus, hepatitis C virus, and syphilis. RESULTS: First-time, younger, and more educated donors were associated with a higher number of recent sexual partners, as was male sex in Sao Paulo and Recife (p < 0.001). Serologic markers for HIV and syphilis and overall were associated with multiple partners in Sao Paulo and Recife (p < 0.001), but not in Belo Horizonte (p = 0.05, p = 0.94, and p = 0.75, respectively). In logistic regression analysis, number of recent sexual partners was associated with positive serologic markers (adjusted odds ratio [AOR], 1.2-1.5), especially HIV (AOR, 1.9-4.4). CONCLUSIONS: Number of recent heterosexual partners was associated with HIV positivity and overall rates of serologic markers of sexually transmitted infections. The association was not consistent across centers, making it difficult to define the best cutoff value. These findings suggest the use of recent heterosexual contacts as a potentially important deferral criterion to improve blood safety in Brazil.

Multiple Intravenous Administrations of Human Umbilical Cord Blood Cells Benefit in a Mouse Model of ALS

Background: A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) is the use of cell-based therapies that can protect motor neurons and thereby retard disease progression. We recently showed that a single large dose (25x10(6) cells) of mononuclear cells from human umbilical cord blood (MNC hUCB) administered intravenously to pre-symptomatic G93A SOD1 mice is optimal in delaying disease progression and increasing lifespan. However, this single high cell dose is impractical for clinical use. The aim of the present pre-clinical translation study was therefore to evaluate the effects of multiple low dose systemic injections of MNC hUCB cell into G93A SOD1 mice at different disease stages. Methodology/Principal Findings: Mice received weekly intravenous injections of MNC hUCB or media. Symptomatic mice received 10(6) or 2.5x10(6) cells from 13 weeks of age. A third, pre-symptomatic, group received 10(6) cells from 9 weeks of age. Control groups were media-injected G93A and mice carrying the normal hSOD1 gene. Motor function tests and various assays determined cell effects. Administered cell distribution, motor neuron counts, and glial cell densities were analyzed in mouse spinal cords. Results showed that mice receiving 10(6) cells pre-symptomatically or 2.5x10(6) cells symptomatically significantly delayed functional deterioration, increased lifespan and had higher motor neuron counts than media mice. Astrocytes and microglia were significantly reduced in all cell-treated groups. Conclusions/Significance: These results demonstrate that multiple injections of MNC hUCB cells, even beginning at the symptomatic disease stage, could benefit disease outcomes by protecting motor neurons from inflammatory effectors. This multiple cell infusion approach may promote future clinical studies.

Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients

We have described that MMP-9 C- T-1562 and (CA)(n) polymorphisms contribute to multiple sclerosis (MS). Here, we evaluate whether plasma MMP-9 levels are related to disease severity, drug therapy resistance and polymorphisms. For sub-study 1, 36 patients with MS and 35 controls were recruited. For sub-study 2, 88 individuals (53 patients and 35 controls) were included in a cross-sectional analysis. MS patients presented higher MMP-9 activity (1.4 +/- 0.18 versus 0.93 +/- 0.18 A.U. for control, P<0.05). Drug-therapy resistant individuals exhibited increased MMP-9 activity (1.96 +/- 0.25 versus 1.21 +/- 0.09 A.U. for non-resistant patients). EDSS score was also related to MMP-9 levels. The CT + TT and HH genotypes had higher MMP-9 levels as compared to patients carrying the CC and LL Drug therapy resistance, disease severity. MMP-9 plasma activity and polymorphisms are associated with MS. (C) 2012 Elsevier B.V. All rights reserved.

Religious/spiritual coping in people with chronic kidney disease undergoing hemodialysis

The objective of the present study is to investigate the use of religious/spiritual coping mechanisms in patients with chronic kidney disease undergoing hemodialysis, by means of interviews using a sociodemographic questionnaire and the religious/spiritual coping scale. Data analysis was performed using descriptive statistics and multiple linear regression. A total of 123 individuals were interviewed, 79.6% of whom presented a high score for religious/spiritual coping and none of whom presented low or irrelevant scores. The variables that affected the religious/spiritual coping behavior were: gender, age group, treatment time, family income, and religious practice. In conclusion, the participants used religious/spiritual coping mechanisms as a strategy to cope with the disease, particularly women with a higher family income who attend church every week.

Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis

Objective: Early treatment in sepsis may improve outcome. The aim of this study was to evaluate how the delay in starting resuscitation influences the severity of sepsis and the treatment needed to achieve hemodynamic stability. Design: Prospective, randomized, controlled experimental study. Setting: Experimental laboratory in a university hospital. Subjects: Thirty-two anesthetized and mechanically ventilated pigs. Interventions: Pigs were randomly assigned (n = 8 per group) to a nonseptic control group or one of three groups in which fecal peritonitis (peritoneal instillation of 2 g/kg autologous feces) was induced, and a 48-hr period of protocolized resuscitation started 6 (Delta T-6 hrs), 12 (Delta T-12 hrs), or 24 (Delta T-24 hrs) hrs later. The aim of this study was to evaluate the impact of delays in resuscitation on disease severity, need for resuscitation, and the development of sepsis-associated organ and mitochondrial dysfunction. Measurements and Main Results: Any delay in starting resuscitation was associated with progressive signs of hypovolemia and increased plasma levels of interleukin-6 and tumor necrosis factor-alpha prior to resuscitation. Delaying resuscitation increased cumulative net fluid balances (2.1 +/- 0.5 mL/kg/hr, 2.8 +/- 0.7 mL/kg/hr, and 3.2 +/- 1.5 mL/kg/hr, respectively, for groups.T-6 hrs, Delta T-12 hrs, and.T-24 hrs; p < .01) and norepinephrine requirements during the 48-hr resuscitation protocol (0.02 +/- 0.04 mu g/kg/min, 0.06 +/- 0.09 mu g/kg/min, and 0.13 +/- 0.15 mu g/kg/min; p = .059), decreased maximal brain mitochondrial complex II respiration (p = .048), and tended to increase mortality (p = .08). Muscle tissue adenosine triphosphate decreased in all groups (p < .01), with lowest values at the end in groups Delta T-12 hrs and.T-24 hrs. Conclusions: Increasing the delay between sepsis initiation and resuscitation increases disease severity, need for resuscitation, and sepsis-associated brain mitochondrial dysfunction. Our results support the concept of a critical window of opportunity in sepsis resuscitation. (Crit Care Med 2012; 40:2841-2849)