[Infection due to Rothia mucilaginosa. A respiratory pathogen?]. / Infección por Rothia mucilaginosa. ¿Un patógeno respiratorio?

INTRODUCTION: To describe the spectrum of infections caused by Rothia mucilaginosa. METHODS: Retrospective study of 20 cases diagnosed with R. mucilaginosa from 2009 to 2012. RESULTS: Pulmonary infection was the most frequent clinical presentation (n=14, 70%): bronchiectasis infected (10), followed by pleural empyema (2), pneumonia (1) and acute bronchitis (1). Two episodes were of gastrointestinal origin: cholangitis secondary to biliary drainage and secondary peritonitis. Two episodes included bacteremia in patients with hematological malignancy. One patient had a surgical wound infection with bacteremia, and another had a bacteremic urinary tract infection in a patient with nephrostomy. DISCUSSION: R. mucilaginosa may be responsible for infections of the lower respiratory tract in predisposed patients.

Analysis of radio wave propagation for ISM 2.4 GHz Wireless Sensor Networks in inhomogeneous vegetation environments.

The use of wireless networks has experienced exponential growth due to the improvements in terms of battery life and low consumption of the devices. However, it is compulsory to conduct previous radio propagation analysis when deploying a wireless sensor network. These studies are necessary to perform an estimation of the range coverage, in order to optimize the distance between devices in an actual network deployment. In this work, the radio channel characterization for ISM 2.4 GHz Wireless Sensor Networks (WSNs) in an inhomogeneous vegetation environment has been analyzed. This analysis allows designing environment monitoring tools based on ZigBee and WiFi where WSN and smartphones cooperate, providing rich and customized monitoring information to users in a friendly manner. The impact of topology as well as morphology of the environment is assessed by means of an in-house developed 3D Ray Launching code, to emulate the realistic operation in the framework of the scenario. Experimental results gathered from a measurement campaign conducted by deploying a ZigBee Wireless Sensor Network, are analyzed and compared with simulations in this paper. The scenario where this network is intended to operate is a combination of buildings and diverse vegetation species. To gain insight in the effects of radio propagation, a simplified vegetation model has been developed, considering the material parameters and simplified geometry embedded in the simulation scenario. An initial location-based application has been implemented in a real scenario, to test the functionality within a context aware scenario. The use of deterministic tools can aid to know the impact of the topological influence in the deployment of the optimal Wireless Sensor Network in terms of capacity, coverage and energy consumption, making the use of these systems attractive for multiple applications in inhomogeneous vegetation environments.

Interaction of insulin and PPAR-α genes in Alzheimer's disease: the Epistasis Project.

Altered glucose metabolism has been described in Alzheimer's disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.

Monitoring complex secundum atrial septal defects percutaneous closure with real time three-dimensional echocardiography.

BACKGROUND: Atrial septal defect (ASD) is one of the most common congenital heart diseases. Nowadays, percutaneous closure is considered the treatment of choice in most of secundum ASDs. Assessment of the defect and procedure monitoring have been usually performed by angiographic balloon-sizing and/or two-dimensional (2D) transesophageal echocardiography. However, in complex ASDs these techniques might be inaccurate. METHODS: From January 2009 to January 2011 all adult patients with complex ASDs submitted for percutaneous closure were selected. Those defects, where shunts were present through a device previously implanted on the atrial septum or through multiperforated septums, were considered complex ASDs. Two-dimensional transesophageal echocardiography and real time three-dimensional (3D) echocardiography were performed simultaneously during the percutaneous closure procedure. Number of orifices, relationships between the defect, catheter, and device, as well as residual shunt were assessed. RESULTS: Seven patients were included. Five patients had a multiperforated septum and in two cases the defect in the septum was through a previously implanted device. In all cases, 3D echocardiography was superior to 2D echocardiography in relation to the assessment of the relationship between the defect and the catheter or the device. Mechanisms responsible for residual shunts through a device were also better assessed by 3D echocardiography. CONCLUSION: Three-dimensional echocardiography is a safe and useful technique when monitoring percutaneous closure of ASDs, showing relevant advantages over 2D echocardiography.

Detection of early Alzheimer's disease in MCI patients by the combination of MMSE and an episodic memory test.

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimer's disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia. METHODS: All patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI). RESULTS: A combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%. CONCLUSIONS: Pr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings.

Caspase-1 genetic variation is not associated with Alzheimer's disease risk.

BACKGROUND: Interleukin (IL)-1beta is a potent proinflammatory cytokine markedly overexpressed in the brains of patients with Alzheimer's disease (AD), and also involved in development of atherosclerosis and coronary artery disease. Caspase-1 (CASP1), formerly called IL-1beta converting enzyme (ICE), mediates the cleavage of the inactive precursor of IL-1beta into the biologically active form. CASP1 genetic variation (G+7/in6A, rs501192) has been associated with susceptibility to myocardial infarction and cardiovascular death risk. We examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of CASP1 by genotyping haplotype tagging SNPs (htSNPs) (rs501192, rs556205 and rs530537) in a group of 628 Spanish AD cases and 722 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by age, gender or APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that CASP1 genetic variations are causally related to AD risk.

The dopamine ß-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.

BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine ß-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk.

Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.

Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease.

BACKGROUND: Chronic inflammation is a characteristic of Alzheimer's disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10). METHODS: We examined this interaction in the Epistasis Project, a collaboration of 7 AD research groups, contributing DNA samples from 1,757 cases of AD and 6,295 controls. RESULTS: We replicated the interaction. For IL6 rs2069837 AA x IL10 rs1800871 CC, the synergy factor (SF) was 1.63 (95% confidence interval: 1.10-2.41, p = 0.01), controlling for centre, age, gender and apolipoprotein E epsilon4 (APOEepsilon4) genotype. Our results are consistent between North Europe (SF = 1.7, p = 0.03) and North Spain (SF = 2.0, p = 0.09). Further replication may require a meta-analysis. However, association due to linkage disequilibrium with other polymorphisms in the regulatory regions of these genes cannot be excluded. CONCLUSION: We suggest that dysregulation of both IL-6 and IL-10 in some elderly people, due in part to genetic variations in the two genes, contributes to the development of AD. Thus, inflammation facilitates the onset of sporadic AD.

No association of CDK5 genetic variants with Alzheimer's disease risk.

BACKGROUND: As cyclin-dependent kinase 5 (CDK5) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of CDK5 by genotyping haplotype tagging SNPs (htSNPs) (rs9278, rs2069459, rs891507, rs2069454, rs1549759 and rs2069442) in a group of 408 Spanish AD cases and 444 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that CDK5 genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between CDK5 gene and AD risk in the Dutch population exists.

DYRK1A genetic variants are not linked to Alzheimer's disease in a Spanish case-control cohort.

BACKGROUND: As dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of DYRK1A by genotyping haplotype tagging SNPs (htSNPs) (rs11701483, rs2835740, rs1137600, rs2835761, rs2835762, rs2154545 and rs8132976) in a group of 634 Spanish AD cases and 733 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that DYRK1A genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between DYRK1A gene and AD risk in the Japanese population exists.

Genetic interaction between tau and the apolipoprotein E receptor LRP1 Increases Alzheimer's disease risk.

Abnormal tau hyperphosphorylation is one of the central events in the development of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD), and phosphorylation of tau is accelerated by the increase in the level of neuronal cholesterol. Apolipoprotein E (APOE) promotes the neuronal uptake of cholesterol via APOE receptors such as the low-density lipoprotein receptor-related protein 1 (LRP1), and the APOE epsilon4 allele is associated with an increase in NFT burden in AD brain. In a case-control study in 246 AD patients and 237 healthy controls, we examined whether the combined gene effects between tau (intron 9, rs2471738) polymorphism and LRP1 (exon 3, rs1799986) polymorphism might be responsible for susceptibility to AD, independently or in concert with the APOE epsilon4 allele. Subjects carrying both the tau (intron 9, rs2471738) T allele (CT and TT genotypes) and the LRP1 (exon 3, rs1799986) T allele (CT and TT genotypes) had a 6 times higher risk of developing AD than subjects without these risk genotypes (odds ration = 6.20, 95% confidence interval = 1.74-22.05, p = 0.005), and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. These data suggest that the synergistic effects (epistasis) between tau and LRP1 might modify the risk of AD in an APOE epsilon4 allele-independent fashion.

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aß, tau, immunity and lipid processing.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aß processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aß, tau, immunity and lipid processing.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interaction between CD14 and LXRbeta genes modulates Alzheimer's disease risk.

A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). CD14 and LXRbeta are receptors involved in the regulation of inflammatory responses of microglia in response to bacterial infection or lipopolysaccharide stimulation. In a case-control study in 266 AD patients and 273 healthy controls, we examined whether the combined gene effects between CD14 (-260) polymorphism and LXRbeta (intron 5) polymorphism might be responsible for susceptibility to AD. Subjects carrying both the CD14 (-260) C/C and the LXRbeta (intron 5) G/G genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR 0.16, 95% CI 0.04-0.67, p=0.01). These data support a role for innate immune response genes in risk for AD.

14-3-3 zeta and tau genes interactively decrease Alzheimer's disease risk.

Abnormal tau hyperphosphorylation has been suggested as being one of the central events in the development of neurofibrillary tangles, which are one of the characteristic neuropathological lesions found in Alzheimer's disease (AD) brains. 14-3-3 zeta protein is associated with tau in brain and stimulates tau phosphorylation. In a case-control study in 293 AD patients and 396 healthy controls, we examined whether the combined gene effects between 14-3-3 zeta (intron 4, rs 983583) polymorphism and tau (intron 9, rs 2471738) polymorphism might be responsible for susceptibility to AD. Subjects carrying both the 14-3-3 zeta (intron 4, rs 983583) AA and the tau (intron 9, rs 2471738) CC genotypes had a two and a half times lower risk of developing AD than subjects without these risk genotypes (OR = 0.4, 95% CI = 0.2-0.8, p = 0.016). Considering synergistic effects between polymorphisms in tau phosphorylation related genes may help in determining the risk profile for AD.

Deficiency of CARD8 is associated with increased Alzheimer's disease risk in women.

NF-kappaB, a major transcription factor controlling inflammation, is activated in Alzheimer's disease (AD) brains. CARD8 protein has been implicated in the suppression of NF-kappaB activity, but a truncating polymorphism (p.C10X, rs2043211) renders a non-functional CARD8 protein that gives rise to a more active NF-kappaB and an amplification of the inflammatory process. Apolipoprotein E (ApoE) epsilon4 allele, the major genetic risk factor of AD, is associated with hyperactivation of NF-kappaB and enhanced brain inflammation. In a case-control study in 300 AD patients and 300 healthy controls, we examined whether the CARD8 (p.C10X) polymorphism, independently or in concert with the ApoE epsilon4 allele, might predispose to AD. Women, but not men, carrying the CARD8 AA genotype (truncated protein) had a 2.39-fold higher risk of developing AD than subjects with the CARD8 TT genotype (full-length protein). This association with susceptibility to AD was independent of the ApoE epsilon4 allele.

Synergistic effect of heme oxygenase-1 and tau genetic variants on Alzheimer's disease risk.

Oxidative stress plays a role in tau hyperphosphorylation and the development of neurofibrillary tangles (NFT). In Alzheimer's disease (AD) brain, accumulation of hyperphosphorylated tau in NFT is associated with the induction of heme oxygenase-1 (HO-1), a potent antioxidant that downregulates the production of tau. In a case-control study of 300 AD patients and 360 healthy controls, we examined whether the combined gene effects between HO-1 (-413, rs2071746) and tau (5' of exon 1, rs242557) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the HO-1 (-413) TT and the tau (5' of exon 1) AA genotypes had a more than 6.5-time higher risk of developing AD than subjects without these risk genotypes (OR = 6.65, 95% CI 1.12-39.29; p = 0.037). These data support a role for tau-related genes in the risk of AD.

No association of genetic variants of liver X receptor-beta with Alzheimer's disease risk.

Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

Poly (ADP-ribose) polymerase-1 (PARP-1) genetic variants are protective against Parkinson's disease.

Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in crucial pathogenic events in Parkinson's disease (PD). We studied the effect of promoter variations of PARP-1 gene on the risk for PD in a case-control association study comprising 146 PD patients and 161 controls from Northern Spain. Three polymorphisms from the promoter region of PARP-1 gene were analyzed: -410C/T, -1672G/A, and a (CA)n microsatellite. A protective effect against PD was found for heterozygosity at (-410) (OR 0.44) and (CA)n microsatellite (OR 0.53) polymorphisms, and heterozygosity at (-1672) polymorphism delayed by 4 years on the onset age of PD. Variations in the regulatory region of PARP-1 gene might modify the risk for PD.