The recent Latin American and European guidelines published this year has proposed as a goal for blood pressure control in patients with diabetes type 2 a value similar or inferior to 140/90 mmHg. High blood pressure is the leading cause of cardiovascular diseases and deaths globally. Although once hypertension is detected, 80% of individuals are on a pharmacologic therapy only a minority is controlled. Diabetes also is a risk factor for other serious chronic diseases, including cardiovascular disease. Whether specifically targeting lower fasting glucose levels can reduce cardiovascular outcomes remains unknown. Hypertension is present in 20% to 60% of patients with type 2 diabetes, depending on age, ethnicity, obesity, and the presence of micro or macro albuminuria. High blood pressure substantially increases the risk of both macro and micro vascular complications, doubling the risk of all-cause mortality and stroke, tripling the risk of coronary heart disease and significantly hastening the progression of diabetic nephropathy, retinopathy, and neuropathy. Thus, blood pressure lowering is a major priority in preventing cardiovascular and renal events in patients with diabetes and hypertension. During many years the BP goals recommended in patients with diabetes were more aggressive than in patients without diabetes. As reviewed in this article many clinical trials have demonstrated not only the lack of benefits of lowering the BP below 130/80 mmHg, but also the J-shaped relationship in DM patients. Overall we discuss the importance of define the group of patients in whom significant BP reduction could be particularly dangerous and, on the other hand, those with a high risk of stroke who could benefit most from an intensive hypotensive therapy. In any case, the big challenge now is avoid the therapeutic inertia (leaving diabetic patients with BP values of 140/90 mmHg or higher) at all costs, as this would lead to an unacceptable toll in terms of human lives, suffering, and socioeconomic costs.
Hypertension; Diabetes; Guidelines; Blood pressure
The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM).
Methods and results
ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64–0.99; DM: HR: 1.16, 95% CI: 0.91–1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50–0.94; DM: HR: 1.64, 95% CI: 1.15–2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71–1.93; DM: HR: 2.39, 95% CI: 1.30–4.42; P = 0.07 for interaction).
This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.
Aliskiren; Diabetes; Outcomes; Post-discharge
About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients.
CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn’s post-test was used for comparisons between groups. Statistical significance was set at p < 0.05.
EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis.
Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-223) contains supplementary material, which is available to authorized users.
High-risk endometrial carcinomas; Circulating tumor cells; Epithelial to mesenchymal transition; Stem cell; ETV5
Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival.
Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed.
Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear β-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour-associated-stroma and components of the extracellular matrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and C:HR = 8.56(2.53-29.01); Dukes B,C and D:HR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma-subtype and the other tumor subtypes.
We have identified novel molecular subtypes in colon cancer with distinct biological and clinical behavior that are established from the initiation of the tumor. Tumor microenvironment is important for the classification and for the malignant power of the tumor. Differential gene sets and biological pathways characterize each tumor subtype reflecting underlying mechanisms of carcinogenesis that may be used for the selection of targeted therapeutic procedures. This classification may contribute to an improvement in the management of the patients with CRC and to a more comprehensive prognosis.
Colon cancer; Microarray gene expression; Molecular classification; Stroma; Survival
Autoimmune diseases with elevated circulating autoantibodies drive tissue damage and the onset of disease. The Fcγ receptors bind IgG subtypes modulating the clearance of circulating immune complexes (CIC). The inner ear damage in Ménière's disease (MD) could be mediated by an immune response driven by CIC. We examined single-nucleotide polymorphism (SNPs) in the CD16A and CD32 genes in patients with MD which may determine a Fcγ receptor with lower binding to CIC.
The functional CD16A (FcγRIIIa*559A > C, rs396991) and CD32A (FcγRIIa*519A > G, rs1801274) SNPs were analyzed using PCR-based TaqMan Genotyping Assay in two cohorts of 156 mediterranean and 112 Galicia patients in a case-control study. Data were analyzed by χ2 with Fisher's exact test and Cochran-Armitage trend test (CATT). CIC were measured by ELISA for C1q-binding CIC.
Elevated CIC were found in 7% of patients with MD during the intercrisis period. No differences were found in the allelic frequency for rs396991 or rs1801274 in controls subjects when they were compared with patients with MD from the same geographic area. However, the frequency of AA and AC genotypes of CD16A (rs396991) differed among mediterranean and Galicia controls (Fisher's test, corrected p = 6.9 × 10-4 for AA; corrected p = 0.02 for AC). Although genotype AC of the CD16A receptor was significantly more frequent in mediterranean controls than in patients, [Fisher's test corrected p = 0.02; OR = 0.63 (0.44-0.91)], a genetic additive effect for the allele C was not observed (CATT, p = 0.23). Moreover, no differences were found in genotype frequencies for rs396991 between patients with MD and controls from Galicia (CATT, p = 0.14). The allelic frequency of CD32 (rs1801274) was not different between patients and controls either in mediterranean (p = 0.51) or Galicia population (p = 0.11).
Elevated CIC are not found in most of patients with MD. Functional polymorphisms of CD16A and CD32 genes are not associated with onset of MD.
The optimal form of exercise for individuals with cancer has yet to be identified, but there is evidence that exercise improves their quality of life. The aim of this study is to assess the efficacy and efficiency of an innovative physical exercise programme, for individuals undergoing chemotherapy for breast, gastrointestinal or non-small cell lung tumours, for improving quality of life, reducing level of fatigue, and enhancing functional capacity over time.
We will conduct a clinical trial in 66 patients with stage IV breast, gastrointestinal or non-small cell lung cancer, recruited by the Department of Oncology of the referral hospital from 4 primary care health centres of the Basque Health Service (Osakidetza). These patients will be randomised to one of two groups. The treatment common to both groups will be the usual care for cancer: optimized usual drug therapies and strengthening of self-care; in addition, patients in the intervention group will participate in a 2-month exercise programme, including both aerobic and strength exercises, supervised by nurses in their health centre. The principal outcome variable is health-related quality of life, measured blindly with the 30-item European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire and Short Form-36 four times: at baseline, and 2, 6 and 12 months later. The secondary outcome variables are fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire), functional capacity (6-Minute Walk Test and cardiorespiratory test), muscle strength (hand-held dynamometry and sit-to-stand test), radiological response to treatment (Response Evaluation Criteria In Solid Tumors) and progression-free and overall survival. Age, sex, diagnosis, chemotherapy regimen, Eastern Cooperative Oncology Group performance status and smoking status will be considered as predictive variables. Data will be analysed on an intention-to-treat basis, comparing changes at each time point between groups, adjusting for baseline values by analysis of covariance.
As well as achieving the objectives set, this study will provide us with information on patient perception of the care received and an opportunity to develop a project based on collaborative action between the primary care and oncology professionals.
ClinicalTrials.gov Identifier: NCT01786122 Registration date: 02/05/2013.
Breast cancer; Colorectal cancer; Lung cancer; Metastasis; Physical exercise; Quality of life
A first analysis of the genome sequence of the common marmoset (Callithrix jacchus), assembled using traditional Sanger methods and Ensembl annotation, has permitted genomic comparison with apes and that old world monkeys and the identification of specific molecular features a rapid reproductive capacity partly due to may contribute to the unique biology of diminutive The common marmoset has prevalence of this dizygotic primate. twins. Remarkably, these twins share placental circulation and exchange hematopoietic stem cells in utero, resulting in adults that are hematopoietic chimeras.
We observed positive selection or non-synonymous substitutions for genes encoding growth hormone / insulin-like growth factor (growth pathways), respiratory complex I (metabolic pathways), immunobiology, and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibit rapid sequence evolution. This New World monkey genome sequence enables significantly increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
Chronic obstructive pulmonary disease (COPD) is a complex heterogeneous disease, in which several factors combine to give the final clinical expression. Both early and more recent studies have shown that forced expiratory volume in one second (FEV1), despite being an extremely important parameter to predict the progression of the disease, is a poor surrogate marker for symptoms perception. Accordingly, patient-reported outcomes (PROs) have gained popularity as a measure of the impact of treatment from the patients’ perspective, since they represent the individuals’ perception of their health status, beyond any physiological limitations. Several such PROs, therefore, are currently included in multidimensional COPD evaluation. This multidimensional approach helps identify different patient types and individualize, up to a certain point, pharmacological treatment. In this multidimensional approach it is important to highlight the importance of long-acting bronchodilators in COPD treatment strategies. Long-acting bronchodilators are cost-effective and have been shown to achieve the greatest functional and clinical improvements in COPD. As a result, long-acting bronchodilators are now the main pharmacological treatment for COPD at all stages of the disease. Until recently, tiotropium was the leading bronchodilator for the treatment of COPD. The clinical development of this medication, unprecedented in inhaled therapy, involved tens of thousands of patients and yielded consistent outcomes in terms of lung function, symptoms, quality of life, exacerbations, and prognosis. However, new long-acting bronchodilators have recently been developed or are currently under development. In this review, we evaluate the effects of aclidinium bromide, a novel long-acting bronchodilator, on PROs in COPD. Aclidinium is a novel long-acting muscarinic antagonist with a good safety profile for the treatment of COPD, and has proven efficacy in both objective functional measurements and PROs. Comparison studies with tiotropium have shown it to have similar lung function improvement and a similar impact on PROs, including quality of life or symptom perception.
patient-reported outcomes; chronic obstructive pulmonary disease; bronchodilators; aclidinium
To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP). Also, to assess genotype-phenotype correlation and disease progression in 10 years by considering type of variants and age of onset.
A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD and 75 arRP.
Spanish families were analysed through a combination of ABCR400 genotyping microarray, denaturing High-Performance Liquid Chromatography (dHPLC) and High Resolution Melting (HRM) scanning. Direct sequencing was used as confirmation technique for the identified variants. Screening by Multiple Ligation Probe Analysis (MLPA) was used in order to detect possible large deletions or insertions in the ABCA4 gene. Selected families were further analysed by Next Generation Sequencing (NGS).
Main Outcome Measures
DNA sequence variants, mutation detection rates, haplotypes, age of onset, central or peripheral vision loss, night blindness.
Overall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was completely sequenced the detection rates reached 73.6% for STGD and 66.7% for CRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher to that in the general population. Moreover, in some families mutations in other known arRP genes segregated with the disease phenotype.
An increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and is also paramount in selecting patients for emerging clinical trials of therapeutic interventions. As ABCA4-associated diseases are evolving retinal dystrophies, assessment of age of onset, accurate clinical diagnosis and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with an RP-like phenotype often as a consequence of severe (null) mutations and/or in cases of long-term, advanced disease. Patients with “classical” arRP phenotypes, especially from the onset of the disease, should be first screened for mutations in known arRP genes and not ABCA4.
ABCA4; Stargardt disease; cone-rod dystrophy; genotype-phenotype correlation
The purpose of this study was to assess the genetic variation and differentiation of Blastocystis subtypes (STs) recovered from symptomatic children by analysing partial sequences of the small subunit rDNA gene region (SSUrDNA) and internal transcribed spacers (1 and 2) plus the 5.8S region (ITS, ITS1 + 5.8S + ITS2) and comparing with isolates from other countries.
Faecal samples from 47 Blastocystis-infected children with gastrointestinal symptoms and negative for pathogenic enterobacteria were analysed. PCR was performed on DNA from all the samples to identify Blastocystis STs, amplifying a fragment of SSUrDNA and the ITS region. The amplicons were purified and sequenced, and consensus sequences were submitted to GenBank; afterwards, SSUrDNA sequences were analysed for genetic diversity according to geographic area. Regarding the Blastocystis STs found, 51% were ST1, 23% ST2, 19% ST3 and 2% ST7. For ITS, a haplotype network tree and Bayesian inference revealed the presence of two novel variants of ST1, clustering some sequences into ST1A and ST1B. The values of nucleotide diversity (π) and haplotype polymorphism (θ) for ST1, ST2 and ST3 ranged from 0 to 1, whereas the ratio of genetic differentiation (FST)/migration index (Nm) showed the highest differentiation between Libya and Thailand-Philippines for ST2 (0.282/0.63). In contrast, a high flow gene was observed between Czech Republic-Denmark-Holland-Spain and USA-Mexico-Colombia for ST1 (0.003/84).
Our data on genetic differentiation and gene flow might explain the differences for the prevalence of Blastocystis STs. Moreover, the ITS region could be used as a genetic marker to assess genetic variation in this parasite.
Blastocystis spp; Internal transcribed spacers; Blastocystis subtypes; Genetic variation
Objective. To compare the modifications in lipids between patients with rheumatoid arthritis (RA) receiving etanercept plus methotrexate (ETA + MTX) versus methotrexate (MTX) and their relationship with serum levels of tumor necrosis factor-alpha (TNF-α). Methods. In an observational cohort study, we compared changes in lipid levels in patients receiving ETA + MTX versus MTX in RA. These groups were assessed at baseline and at 4 and 24 weeks, measuring clinical outcomes, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and TNF-α. Results. Baseline values for lipid levels were similar in both groups. HDL-C levels increased significantly only in the ETA + MTX group (from 45.5 to 50.0 mg/dL at 4 weeks, a 10.2% increase, P < 0.001, and to 56.0 mg/dL at 24 weeks, a 25.1% increase, P < 0.001), while other lipids underwent no significant changes. ETA + MTX also exhibited a significant increase in TNF-α (44.8 pg/mL at baseline versus 281.4 pg/mL at 24 weeks, P < 0.001). The MTX group had no significant changes in lipids or TNF-α. Significant differences in HDL-C between groups were observed at 24 weeks (P = 0.04) and also in TNF-α (P = 0.01). Conclusion. HDL-C levels increased significantly following treatment with ETA + MTX, without a relationship with decrease of TNF-α.
Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging effects of the regimen in patients with operable PDA.
Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine.
A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine.
These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.
PDA; stroma; nab-paclitaxel; CAF
Acute colonic pseudo-obstruction (ACPO) is an uncommon condition that occasionally develops in hospitalized patients with serious underlying ailments. Its early recognition is essential to reduce life-threatening complications. Few low-powered randomized clinical trials (RCTs) have confirmed the effectiveness of neostigmine for treatment.
To analyse the effectiveness and main side effects of neostigmine in the treatment of ACPO.
A literature search was performed for all published RCTs, reporting on neostigmine as treatment for ACPO.
Four studies fulfilled the inclusion criteria, evaluating 127 patients: treatment group = 65, control group = 62. Neostigmine effectiveness to resolve ACPO with only one dose was 89.2% versus 14.65% (P < 0.001, NNT = 1 [95% CI 1–2]).
Neostigmine is a safe and effective option for patients with ACPO who failed to respond to conservative management.
Neostigmine; Acute colonic pseudo-obstruction; Side effects
The induction of polyploidy is considered the reproductive end of cells, but there is evidence that polyploid giant cancer cells (PGCCs) contribute to cell repopulation during tumor relapse. However, the role of these cells in the development, progression and response to therapy in colon cancer remains undefined. Therefore, the main objective of this study was to investigate the generation of PGCCs in colon cancer cells and identify mechanisms of formation. Treatment of HCT-116 and Caco-2 colon cancer cells with the hypoxia mimic CoCl2 induced the formation of cells with larger cell and nuclear size (PGCCs), while the cells with normal morphology were selectively eliminated. Cytometric analysis showed that CoCl2 treatment induced G2 cell cycle arrest and the generation of a polyploid cell subpopulation with increased cellular DNA content. Polyploidy of hypoxia-induced PGCCs was confirmed by FISH analysis. Furthermore, CoCl2 treatment effectively induced the stabilization of HIF-1α, the differential expression of a truncated form of p53 (p47) and decreased levels of cyclin D1, indicating molecular mechanisms associated with cell cycle arrest at G2. Generation of PGCCs also contributed to expansion of a cell subpopulation with cancer stem cells (CSCs) characteristics, as indicated by colonosphere formation assays, and enhanced chemoresistance to 5-fluorouracil and oxaliplatin. In conclusion, the pharmacological induction of hypoxia in colon cancer cells causes the formation of PGCCs, the expansion of a cell subpopulation with CSC characteristics and chemoresistance. The molecular mechanisms involved, including the stabilization of HIF-1 α, the involvement of p53/p47 isoform and cell cycle arrest at G2, suggest novel targets to prevent tumor relapse and treatment failure in colon cancer.
The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27±4.90) than patients with 249V/V genotype (67.65±7.42; diff −25.49 months 95%CI [−42.79,−8.18]; p = 0.004; adj-p = 0.018). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff = −29.78 months; 95%CI [−49.42,−10.14]; p = 0.003). The same effects were also observed in the spinal sALS patients with 249I–280M haplotype (diff = −27.02 months; 95%CI [−49.57, −4.48]; p = 0.019). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% [1.32, 5.07]; p = 0.006; adj-p = 0.027). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease's symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.
Candida tropicalis ranks between third and fourth among Candida species most commonly isolated from clinical specimens. Invasive candidiasis and candidemia are treated with amphotericin B or echinocandins as first-line therapy, with extended-spectrum triazoles as acceptable alternatives. Candida tropicalis is usually susceptible to all antifungal agents, although several azole drug-resistant clinical isolates are being reported. However, C. tropicalis resistant to amphotericin B is uncommon, and only a few strains have reliably demonstrated a high level of resistance to this agent. The resistance mechanisms operating in C. tropicalis strains isolated from clinical samples showing resistance to azole drugs alone or with amphotericin B cross-resistance were elucidated. Antifungal drug resistance was related to mutations of the azole target (Erg11p) with or without alterations of the ergosterol biosynthesis pathway. The antifungal drug resistance shown in vitro correlated very well with the results obtained in vivo using the model host Galleria mellonella. Using this panel of strains, the G. mellonella model system was validated as a simple, nonmammalian minihost model that can be used to study in vitro-in vivo correlation of antifungals in C. tropicalis. The development in C. tropicalis of antifungal drug resistance with different mechanisms during antifungal treatment has potential clinical impact and deserves specific prospective studies.
Introduction and Objective
This paper provides an overview of the DUQuE (Deepening our Understanding of Quality Improvement in Europe) project, the first study across multiple countries of the European Union (EU) to assess relationships between quality management and patient outcomes at EU level. The paper describes the conceptual framework and methods applied, highlighting the novel features of this study.
DUQuE was designed as a multi-level cross-sectional study with data collection at hospital, pathway, professional and patient level in eight countries.
Setting and Participants
We aimed to collect data for the assessment of hospital-wide constructs from up to 30 randomly selected hospitals in each country, and additional data at pathway and patient level in 12 of these 30.
Main outcome measures
A comprehensive conceptual framework was developed to account for the multiple levels that influence hospital performance and patient outcomes. We assessed hospital-specific constructs (organizational culture and professional involvement), clinical pathway constructs (the organization of care processes for acute myocardial infarction, stroke, hip fracture and deliveries), patient-specific processes and outcomes (clinical effectiveness, patient safety and patient experience) and external constructs that could modify hospital quality (external assessment and perceived external pressure).
Data was gathered from 188 hospitals in 7 participating countries. The overall participation and response rate were between 75% and 100% for the assessed measures.
This is the first study assessing relation between quality management and patient outcomes at EU level. The study involved a large number of respondents and achieved high response rates. This work will serve to develop guidance in how to assess quality management and makes recommendations on the best ways to improve quality in healthcare for hospital stakeholders, payers, researchers, and policy makers throughout the EU.
quality management systems; clinical indicators; clinical effectiveness; quality of healthcare; hospitals; cross-national research; patient outcomes
Environmental and genetic factors may modify or contribute to the phenotypic differences observed in multigenic and monogenic diseases, such as cystic fibrosis (CF). An analysis of modifier genes can be helpful for estimating patient prognosis and directing preventive care. The aim of this study is to determine the association between seven genetic variants of four modifier genes and CF by comparing their corresponding allelic and genotypic frequencies in CF patients (n = 81) and control subjects (n = 104). Genetic variants of MBL2 exon 1 (A, B, C and D), the IL-8 promoter (−251 A/T), the TNFα promoter (TNF1/TNF2), and SERPINA1 (PI*Z and PI*S) were tested in CF patients and control subjects from northeastern Mexico by PCR-RFLP.
The TNF2 allele (P = 0.012, OR 3.43, 95% CI 1.25–9.38) was significantly associated with CF under the dominant and additive models but was not associated with CF under the recessive model. This association remained statistically significant after adjusting for multiple tests using the Bonferroni correction (P = 0.0482). The other tested variants and genotypes did not show any association with the disease.
An analysis of seven genetic variants of four modifier genes showed that one variant, the TNF2 allele, appears to be significantly associated with CF in Mexican patients.
Seven Klebsiella pneumoniae isolates from dogs and cats in Spain were found to be highly resistant to aminoglycosides, and ArmA methyltransferase was responsible for this phenotype. All isolates were typed by multilocus sequence typing (MLST) as ST11, a human epidemic clone reported worldwide and associated with, among others, OXA-48 and NDM carbapenemases. In the seven strains, armA was borne by an IncR plasmid, pB1025, of 50 kb. The isolates were found to coproduce DHA-1 and SHV-11 β-lactamases, as well as the QnrB4 resistance determinant. This first report of the ArmA methyltransferase in pets illustrates their importance as a reservoir for human multidrug-resistant K. pneumoniae.
We investigated the association between adolescent depressive symptoms and components of executive functioning (EF), including planning (Tower of London), set-shifting (Wisconsin Card Sorting Task), and inhibition (Stop Signal Task) in a community sample of 12–14 year olds. Further, EF was tested as a moderator of motivation (as operationalized by revised Reinforcement Sensitivity Theory) effects on depressive symptoms. Results suggested that planning ability was associated with depressive symptoms. Furthermore, planning ability moderated the relationship between motivation (fight-flight- freeze system; FFFS) and depressive symptoms, such that among adolescents with poor planning ability the FFFS positively predicted depressive symptoms, but among adolescents with strong planning ability the FFFS negatively predicts depressive symptoms. Neither set-shifting nor inhibition was associated with depressive symptoms. Findings highlight the need to consider multiple components of EF and to integrate motivational and executive dysfunction models to the study of depression.
Entamoeba histolytica, the protozoan responsible for human amoebiasis, exhibits a great genome plasticity that is probably related to homologous recombination events. It contains the RAD52 epistasis group genes, including Ehrad51 and Ehrad54, and the Ehblm gene, which are key homologous recombination factors in other organisms. Ehrad51 and Ehrad54 genes are differentially transcribed in trophozoites when DNA double-strand breaks are induced by ultraviolet-C irradiation. Moreover, the EhRAD51 recombinase is overexpressed at 30 min in the nucleus. Here, we extend our analysis of the homologous recombination mechanism in E. histolytica by studying EhRAD51, EhRAD54, and EhBLM expression in response to DNA damage. Bioinformatic analyses show that EhRAD54 has the molecular features of homologous proteins, indicating that it may have similar functions. Western blot assays evidence the differential expression of EhRAD51, EhRAD54, and EhBLM at different times after DNA damage, suggesting their potential roles in the different steps of homologous recombination in this protozoan.
DNA double-strand break repair; Homologous recombination; Amoebiasis
Although B cells and antibodies are the central effectors of humoral immunity, B cells can also produce and secrete cytokines and present antigen to helper T cells. The uptake of antigen is mainly mediated by endocytosis; thus, antigens are often presented by MHC-II molecules. However, it is unclear if B cells can present these same antigens via MHC-I molecules. Recently, Salmonella bacteria were found to infect B cells, allowing possible antigen cross-processing that could generate bacterial peptides for antigen presentation via MHC-I molecules. Here, we will discuss available knowledge regarding Salmonella antigen presentation by infected B cell MHC-I molecules and subsequent inhibitory effects on CD8+ T cells for bacterial evasion of cell-mediated immunity.
B cells; Salmonella; CD8 T cells; cross-presentation; PD-L1
We propose and demonstrate the use of spatial multiplexing as a means to reduce the costs of distributed sensing networks. We propose a new scheme in which remote power-by-light switching is deployed to scan multiple branches of a distributed sensing network based on Brillouin Optical Time Domain Analysis (BOTDA) sensors. A proof-of-concept system is assembled with two 5-km sensor fiber branches that are alternatively monitored using a fast remotely controlled and optically powered optical switch. The multiplexed distributed sensor fibers were located 10 km away from the interrogation unit and a Raman pump is used to remotely power the switch. Furthermore, the deployed BOTDA unit uses an alternative configuration that can lead to simplified setups.
BOTDA sensor; remote sensing; optical switch; sensor network