Characteristics of Patients with Heart Failure and Advanced Chronic Kidney Disease (Stages 4-5) Not Undergoing Renal Replacement Therapy (ERCA-IC Study).

BACKGROUND: Despite the frequent coexistence of heart failure (HF) in patients with advanced chronic kidney disease (CKD), it has been understudied, and little is known about its prevalence and prognostic relevance. METHODS: A retrospective study of 217 patients with advanced CKD (stages 4 and 5) who did not undergo renal replacement therapy (RRT). The patients were followed up for two years. The primary outcome was all-cause death or the need for RRT. RESULTS: Forty percent of patients had a history of HF. The mean age was 78.2 ± 8.8 years and the mean eGFR was 18.4 ± 5.5 mL/min/1.73 m2. The presence of previous HF identified a subgroup of high-risk patients with a high prevalence of cardiovascular comorbidities and was significantly associated with the composite endpoint of all-cause hospitalization or need for RRT (66.7% vs. 53.1%, HR 95% CI 1.62 (1.04-2.52), p = 0.034). No differences were found in the need for RRT (27.6% vs. 32.2%, p = 0.46). Nineteen patients without HF at baseline developed HF during the follow-up and all-cause death was numerically higher (36.8 vs. 19.8%, p = 0.1). CONCLUSIONS: Patients with advanced CKD have a high prevalence of HF. The presence of previous HF identified a high-risk population with a worse prognosis that required close follow-up.

Increased Stiffness Downregulates Focal Adhesion Kinase Expression in Pancreatic Cancer Cells Cultured in 3D Self-Assembling Peptide Scaffolds.

The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that participates in integrin-mediated signal transduction and contributes to different biological processes, such as cell migration, survival, proliferation and angiogenesis. Moreover, FAK can be activated by autophosphorylation at position Y397 and trigger different signaling pathways in response to increased extracellular matrix stiffness. In addition, FAK is overexpressed and/or hyperactivated in many epithelial cancers, and its expression correlates with tumor malignancy and invasion potential. One of the characteristics of solid tumors is an over deposition of ECM components, which generates a stiff microenvironment that promotes, among other features, sustained cell proliferation and survival. Researchers are, therefore, increasingly developing cell culture models to mimic the increased stiffness associated with these kinds of tumors. In the present work, we have developed a new 3D in vitro model to study the effect of matrix stiffness in pancreatic ductal adenocarcinoma (PDAC) cells as this kind of tumor is characterized by a desmoplastic stroma and an increased stiffness compared to its normal counterpart. For that, we have used a synthetic self-assembling peptide nanofiber matrix, RAD16-I, which does not suffer a significant degradation in vitro, thus allowing to maintain the same local stiffness along culture time. We show that increased matrix stiffness in synthetic 3D RAD16-I gels, but not in collagen type I scaffolds, promotes FAK downregulation at a protein level in all the cell lines analyzed. Moreover, even though it has classically been described that stiff 3D matrices promote an increase in pFAKY397/FAK proteins, we found that this ratio in soft and stiff RAD16-I gels is cell-type-dependent. This study highlights how cell response to increased matrix stiffness greatly depends on the nature of the matrix used for 3D culture.

Efficacy of an accelerated double-dose hepatitis B vaccine regimen in patients with cirrhosis.

The hepatitis B (HBV) vaccine is recommended in unvaccinated adults with cirrhosis, despite its low efficacy. We aimed to evaluate the response to a double-dose/accelerated vaccine schedule in patients with cirrhosis admitted into a hepatology ward. All patients with cirrhosis admitted to the hepatology ward without exclusion criteria were offered the HBV HBVAXPRO 40mcg vaccine at months 0, 1 and 2. Non-responders received a second cycle. We evaluated 468 patients and only 19% were seroprotected against HBV. In 196 patients without exclusion criteria for HBV vaccination, the per protocol response rate (anti-HBs >10 U/ml) was 23% after a first cycle and 59% after a second cycle. The overall response per intention to treat was only 23%. We have not identified predictors of response. Only one patient had a mild adverse event. Most patients with cirrhosis admitted in the hepatology ward are unprotected against HBV. Although a second HBV vaccination cycle increases the response rate, the poor overall response reinforces the implementation of HBV vaccination before the development of cirrhosis.

Transcultural adaptation and validation of the patient empowerment in long-term conditions questionnaire.

BACKGROUND: Patient empowerment is a key element to improve the results in health, increase satisfaction amongst users and obtain higher treatment compliance. The main objective of this study is to validate the Spanish version of the questionnaire "Patient empowerment in long-term conditions" which evaluates the patients' level of empowerment of chronic diseases. The secondary objective is to identify factors which predict basal empowerment and changes (improvement or deterioration) in patients with Heart Failure (HF). METHODS: An observational and prospective design of psychometric type to validate a questionnaire (aim 1) and a prospective study of cohorts (aim 2). The study will include 121 patients with confirmed diagnosis of HF. Three measurements (basal, at 15 days and at 3 months) will be carried out: quality of life, self-care and empowerment. Descriptive and inferential analyses will be used. For the first aim of the study (validation), the test-retest reproducibility will be assessed through intraclass correlation coefficient; internal consistency will be assessed through Cronbach's alpha coefficient; construct validity through Pearson's correlation coefficient; and sensibility to change through effect size coefficient. DISCUSSION: Set a valid questionnaire to measure the level of empowerment of patients with chronic diseases could be an effective tool to assess the results from the provision of the health care services. It will also allow us to identify at an early stage, those groups of patients with a low level of empowerment. Hence, they could become a risk group due to poor management of the disease, with a high rate of decompensation and a higher use rate of the health system resources.

The role of striatal dopamine D2 receptors in the occurrence of extrapyramidal side effects: iodine-123-iodobenzamide single photon emission computed tomography study.

Levels above 75% of striatal dopamine 2 receptor occupancy (D2RO) have been associated with extrapyramidal symptoms (EPS). The aim of the present study is to investigate the relationship between D2RO and EPS in a sample of psychotic patients in current treatment with both typical and atypical antipsychotics. Brain iodine-123-iodobenzamide single photon emission computed tomography ((123)I-IBZM SPECT) was performed in 81 patients taking stable doses of haloperidol, risperidone, olanzapine, quetiapine, clozapine or ziprasidone. First, the degree of D2RO and Positive and Negative Syndrome Scale (PANSS) scores was compared between the group of patients who presented EPS and the group free of EPS. Afterwards, these variables were compared among the different antipsychotic medications. The group with EPS presented means of D2RO significantly higher than the group free of EPS. Significant differences in D2RO were found in clozapine, quetiapine and ziprasidone groups compared with the haloperidol group. No differences were observed between either olanzapine or risperidone and haloperidol. No quetiapine- or clozapine-treated patients developed EPS. Haloperidol and risperidone demonstrated a relationship between striatal D2RO and EPS. The findings suggest that higher D2RO is related to appearance of EPS. Occupancy in the group with EPS was in agreement with previous studies that suggested a high degree of D2RO is necessary for the occurrence of EPS.

Cannabis use and striatal D2 receptor density in untreated first-episode psychosis: an in vivo SPECT study.

The biological basis of the association between cannabis-induced dopamine dysregulation and psychosis remains poorly understood. This (123)I-IBZM SPECT study assessed striatal dopamine D2 receptor (D2R) binding in 37 untreated first-episode psychosis (FEP) subjects, and 18 healthy controls. The aim was to examine if there were differences between FEP subjects with (n=14) and without (n=23) cannabis use in uptake ratios in the D2R. Striatal/Frontal cortex (S/F) uptake ratios were obtained. Healthy controls showed the lowest D2R binding ratios. No differences were found in S/F ratios between users and non-users, suggesting similar dopaminergic mechanisms underlying psychotic symptoms in both groups.

Density of striatal D2 receptors in untreated first-episode psychosis: an I123-IBZM SPECT study.

There is as yet no definite prognostic marker to determine whether a first-episode psychosis will become schizophrenia or not. The aim of the present study is to address whether the mechanism of sensitization of the subcortical dopaminergic pathway - yielding to an increase of the postsynaptic D2 receptors - may serve as a prognostic marker of clinical outcome in drug naïve patients with a first-episode psychosis, by means of a prospective and multicentric study with untreated first-episode psychosis patients (n=37). 123I-IBZM SPECT was performed at the time of the inclusion in the study, before antipsychotic medication was initiated. One year later, patients were assessed again so as to determine their diagnosis. There was a significant group effect at baseline in D2 Striatal/Frontal (S/F) ratios (F=10.2, p<0.001). Bonferroni posthoc comparisons attested significant differences between diagnosis (p=0.006), and between schizophrenia and control groups (p<0.001) but no differences between non-schizophrenia and control groups (p=0.9). The logistic regression model showed that D2R binding (p=0.02) and PAS (Premorbid Adjustment Scale) adulthood score (p=0.03) were predictive of the final diagnosis (schizophrenia/non-schizophrenia; Nagelkerke R(2)=0.59; X(2)=11.08, p=0.001). These findings replicate previous results on the usefulness of D2R binding as an objective prognostic parameter, together with the evaluation of premorbid adjustment, of the evolution of first-episode psychosis. In this regard, the results may provide a new view in the approach of early and personalized treatment in the debut of a psychosis.

Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes.

OBJECTIVE: To evaluate through early preclinical atherosclerosis assessment whether repeated episodes of hypoglycemia represent an aggravating factor for macrovascular disease in type 1 diabetes. RESEARCH DESIGN AND METHODS: After sample-size calculation, a case-control study of 25 patients with type 1 diabetes and repeated severe/nonsevere hypoglycemia (H-group) compared with 20 age- and sex-matched type 1 diabetes control subjects (C-group) was designed. Assessment of preclinical atherosclerosis consisted of flow-mediated brachial dilatation (FMD) and carotid and femoral intima-media thickness (IMT) studies. To consider hypoglycemia awareness, two different questionnaires and symptomatic response to an acute induction to hypoglycemia were used. Evaluation of the glycemic profile was obtained from continuous glucose monitoring. Endothelial function/inflammation markers were measured in euglycemia/hypoglycemia. A multivariate linear regression analysis was performed to test whether repeated hypoglycemia was independently associated with atherosclerosis. RESULTS: H-group subjects displayed hypoglycemia unawareness and presented a higher percentage of continuous glucose values and area under the curve <70 mg/dl compared with the C-group (14.2 ± 8.9 vs. 6.3 ± 7.1%, P < 0.02 and 2.4 ± 1.8 vs. 0.6 ± 1.0 mg/dl/day, P < 0.01). The percentage of maximal FMD was lower in the H-group than in the C-group (6.52 ± 2.92 vs. 8.62 ± 3.13%, P < 0.05). A significantly higher IMT was observed at both carotid and femoral sites in the H-group (carotid 0.53 ± 0.09 vs. 0.47 ± 0.08 mm, P < 0.05 and femoral 0.51 ± 0.17 vs. 0.39 ± 0.09 mm, P < 0.05). Baseline inflammation and endothelial function markers were higher in the H-group (leukocytes 7.0 ± 1.8 vs. 5.6 ± 1.4 × 10³/ml, von Willebrand factor 119 ± 29 vs. 93 ± 26%, fibrinogen 2.82 ± 0.64 vs. 2.29 ± 0.44 g/l, and soluble intercellular adhesion molecule-1 408 ± 224 vs. 296 ± 95 ng/ml; P < 0.05 for all). CONCLUSIONS: In addition to the induction of hypoglycemia unawareness and an increased risk for severe hypoglycemia, repeated hypoglycemia could be related to and considered an aggravating factor for preclinical atherosclerosis in type 1 diabetes. The precise mechanisms explaining this association remain to be clarified.