Relación entre las cifras de presión arterial en la fase aguda del ictus medidas con monotorización ambulatoria de la presión arterial asi como mediante determinaciones casuales y la mortalidad total: deterioro funcional y neurológico a los siete dias, treinta días y seis meses

Tesis doctoral inedita leida en la Universidad Autonoma de Madrid, Facultad de Medicina, Departamento de Medicina Interna. Fecha de lectura: 4 de Febrero de 200

Revealing Adenosine A2A-Dopamine D2 Receptor Heteromers in Parkinson's Disease Post-Mortem Brain through a New AlphaScreen-Based Assay

Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human post-mortem brains. The AlphaScreen technology has been consistently used to quantify small analyte accumulation or depletion, bimolecular interactions, and post-translational modifications. The high signal-to-background, dynamic range and sensitivity exhibited by this technology support that it may be suitable to detect GPCR heteromers even under non-optimal conditions. Methods: Here, we describe the development of a new AlphaScreen assay to detect GPCR oligomers in human post-mortem brain. Results: Adenosine A2A-dopamine D2 receptor (A2AR/D2R) heteromer formation was monitored in caudate from healthy and Parkinson's disease (PD) subjects. The approach was first validated using striatal membranes from wild type and A2AR deficient mice. Secondly, we took advantage of the 6-hydroxydopamine hemiparkinsonian rat model to validate previous results. In addition, finally, A2AR/D2R heteromer formation was assessed in caudate membranes from human post-mortem brains. Importantly, our preliminary results revealed an increase in A2AR/D2R heteromer formation in PD brains. Conclusions: The new AlphaScreen assay allowed assessing GPCR heteromers in human post-mortem brains with high sensitivity

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases

YKL40 in sporadic amyotrophic lateral sclerosis: cerebrospinal fluid levels as a prognosis marker of disease progression

Abstract Amyotrophic lateral sclerosis (ALS) has variable clinical course and fatal outcome. Since inflammation plays a role in the pathogenesis of ALS, chitinase-3-like protein 1 or YKL40 has been assessed as putative biomarker of disease progression. YKL40 mRNA levels are increased in anterior horn of the spinal cord (P=0.004) in sporadic ALS (sALS) cases when compared with age-matched controls. These correlate with increased mRNA expression of microglial markers AIF1 and CD68 in the spinal cord in sALS (P=0.044 and P=0.000, respectively). YKL40 mRNA and protein expression had a tendency to increase in post-mortem frontal cortex area 8 (P=0.06 and P=0.08, respectively). Yet YKL40 immunoreactivity is restricted to a subpopulation of astrocytes in these regions. YKL40 protein levels, as revealed by enzyme-linked immunosorbent assay (ELISA), are significantly increased in the CSF in sALS (n=86) compared with age-matched controls (n=21) (P=0.045). Higher levels are found in patients with fast progression when compared with patients with slow and normal progression (P=0.008 and P=0.004, respectively), and correlates with ALS-FRS-R slope (P=0.000). Additionally, increased protein levels of neurofilament light chain (NF-L) are also found in sALS (P=0.000); highest values are found in patients with fast progression when compared with cases with slow and normal progression (P=0.005 and P=0.000, respectively), and also correlate with ALS-FRS-R slope (P=0.000). Pearson's correlation test linked positively the increased levels of YKL40 with increased NF-L levels (P=0.013). These data point to YKL40 and NF-L protein levels in the CSF as a good biomarker combination of disease progression in sALS

Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis

Abstract Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sAL

Awareness of Diagnosis in Persons with Early-Stage Alzheimer's Disease : An Observational Study in Spain

Limited information is available on people's experiences of living with Alzheimer's disease (AD) at earlier stages. This study assessed awareness of diagnosis among people with early-stage AD and its impact on different person-centered outcome measures. We conducted an observational, cross-sectional study in 21 memory clinics in Spain. Persons aged 50-90 years, diagnosed with prodromal or mild AD (NIA/AA criteria), a Mini Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5 or 1.0 were recruited. The Representations and Adjustment to Dementia Index (RADIX) was used to assess participants' beliefs about their condition and its consequences. A total of 149 persons with early-stage AD were studied. Mean (SD) age was 72.3 (7.0) years and 50.3% were female. Mean duration of AD was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1) and 87.2% had a CDR-GS score of 0.5. Most participants (n = 84, 57.5%) used a descriptive term related to specific AD symptoms (e.g., memory difficulties) when asked what they called their condition. Participants aware of their diagnosis using the term AD (n = 66, 45.2%) were younger, had more depressive symptoms, and poorer life satisfaction and quality of life compared to those without awareness of their specific diagnosis. Practical and emotional consequences RADIX scores showed a significant negative correlation with Quality of Life in Alzheimer's Disease score (rho = − 0.389 and − 0.413, respectively; p < 0.0001). Years of education was the only predictor of awareness of AD diagnosis [OR = 1.04 (95% CI 1.00-1.08); p = 0.029]. Awareness of diagnosis was a common phenomenon in persons with early-stage AD negatively impacting their quality of life. Understanding illness representations in earlier stages may facilitate implementing optimized care that supports improved quality of life and well-being

Medical help-seeking intentions among patients with early Alzheimer’s disease

BackgroundLimited information is available on the active process of seeking medical help in patients with Alzheimer’s disease (AD) at early stages. The aim of this study was to assess the phenomenon of medical help-seeking in early AD and to identify associated factors.MethodsA multicenter, non-interventional study was conducted including patients of 50–90 years of age with prodromal or mild AD (National Institute on Aging/Alzheimer’s Association criteria), a Mini-Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5–1.0. A multivariate logistic regression analysis was conducted.ResultsA total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years, 50.3% were female, and 87.2% had a CDR-GS score of 0.5. Mean disease duration was 1.4 (1.8) years. Ninety-four (63.1%) patients sought medical help, mostly from neurologists. Patients with help-seeking intentions were mostly female (60.6%) with a CDR-GS score of 0.5 (91.5%) and had a greater awareness of diagnosis, poorer quality of life, more depressive symptoms, and a more severe perception of their condition than their counterparts. Lack of help-seeking intentions was associated with male sex (p = 0.003), fewer years of education (p = 0.005), a low awareness of diagnosis (p = 0.005), and a low emotional consequence of the condition (p = 0.016).ConclusionUnderstanding the phenomenon of active medical help-seeking may facilitate the design of specific strategies to improve the detection of cognitive impairment, especially in patients with a lower level of educational attainment and poor awareness of their condition

Rationale and methods of the multicenter randomised trial of a heart failure management programme among geriatric patients (HF-Geriatrics)

<p>Abstract</p> <p>Background</p> <p>Disease management programmes (DMPs) have been shown to reduce hospital readmissions and mortality in adults with heart failure (HF), but their effectiveness in elderly patients or in those with major comorbidity is unknown. The Multicenter Randomised Trial of a Heart Failure Management Programme among Geriatric Patients (HF-Geriatrics) assesses the effectiveness of a DMP in elderly patients with HF and major comorbidity.</p> <p>Methods/Design</p> <p>Clinical trial in 700 patients aged ≥ 75 years admitted with a primary diagnosis of HF in the acute care unit of eight geriatric services in Spain. Each patient should meet at least one of the following comorbidty criteria: Charlson index ≥ 3, dependence in ≥ 2 activities of daily living, treatment with ≥ 5 drugs, active treatment for ≥ 3 diseases, recent emergency hospitalization, severe visual or hearing loss, cognitive impairment, Parkinson's disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), anaemia, or constitutional syndrome. Half of the patients will be randomly assigned to a 1-year DMP led by a case manager and the other half to usual care. The DMP consists of an educational programme for patients and caregivers on the management of HF, COPD (knowledge of the disease, smoking cessation, immunizations, use of inhaled medication, recognition of exacerbations), diabetes (knowledge of the disease, symptoms of hyperglycaemia and hypoglycaemia, self-adjustment of insulin, foot care) and depression (knowledge of the disease, diagnosis and treatment). It also includes close monitoring of the symptoms of decompensation and optimisation of treatment compliance. The main outcome variables are quality of life, hospital readmissions, and overall mortality during a 12-month follow-up.</p> <p>Discussion</p> <p>The physiological changes, lower life expectancy, comorbidity and low health literacy associated with aging may influence the effectiveness of DMPs in HF. The HF-Geriatrics study will provide direct evidence on the effect of a DMP in elderly patients with HF and high comorbidty, and will reduce the need to extrapolate the results of clinical trials in adults to elderly patients.</p> <p>Trial registration</p> <p>(ClinicalTrials.gov number, <a href="http://www.clinicaltrials.gov/ct2/show/NCT01076465">NCT01076465</a>).</p

Incidence, clinical characteristics and management of inflammatory bowel disease in Spain: large-scale epidemiological study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD—Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)—during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100, 000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31–56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery. © 2021 by the authors. Licensee MDPI, Basel, Switzerland