Anticholinergic Exposure in Elderly Complex Chronic Patients: A Cross-Sectional Study.

BACKGROUND: Elderly patients with multiple chronic conditions are closely linked to polymedication, a condition that is also highly associated with the presence of adverse effects, such as those observed by anticholinergic activity. Anticholinergic burden is defined in a very variable way and is described inconsistently using different scores and providing different interpretations of the risk of suffering from anticholinergic adverse effects. OBJECTIVE: The objective is to analyse the anticholinergic risk exposure in elderly complex chronic patients. METHODS: A observational multicentre study was performed for a cohort of complex chronic patients over 65 years who received treatment with at least one drug with anticholinergic activity. Anticholinergic exposure was assessed using ten scales included in the Anticholinergic Burden Calculator. RESULTS: 473 patients were recruited, being 67.7% with excessive polypharmacy. 80 was the total number of anticholinergic drugs with any scale, with a median of 2 drugs with anticholinergic activity per patient (IQR=2). Three scales evaluated more than 70% of the patients (Chew: 79.1%; Drug Burden Index (DBI): 77.8%; Anticholinergic Cognitive Burden (ACB): 75.9%). The percentage of different drugs with anticholinergic properties evaluated ranged from 13.8% (Anticholinergic Burden Classification (ABC)) to 57.5% (DBI) and anticholinergic drugs prescriptions oscillated from 14% (Anticholinergic Risk Scale (ARS)) to 53.3% (DBI). 71.1% of patients were at risk (moderate and high risk) according to DBI vs. 9.7% by ARS at the opposite side. Important differences of anticholinergic risk in patients with excessive polypharmacy were in ACB, ABC and DBI scales. CONCLUSION: This study has highlighted clear differences between the scales used. DBI seems to be the scale that identifies a higher number of elderly chronic complex patients at risk of developing anticholinergic adverse effects.

Effectiveness of a nurse-led, face-to-face health coaching intervention in enhancing activation and secondary outcomes of primary care users with chronic conditions.

Prevalence of chronic diseases and multimorbidity is rising, and it remains unclear what the best strategy is for activating people with chronic conditions in their self-care. We designed a two-group quasi-experimental time series trial to examine the effectiveness of a nurse-led, face-to-face, individually-tailored health coaching (HC) intervention in improving patient activation and secondary outcomes (self-efficacy, quality of life, anxiety and depression symptoms, medication adherence, hospitalization and emergency visits) among primary care users with chronic conditions. A total of 118 people with chronic conditions were recruited through a primary care center and allocated to either the intervention group (IG) (n = 58) or control group (CG) (n = 60). The IG received a nurse-led individually-tailored HC intervention involving 4-6 face-to-face multicomponent sessions covering six core activation topics. The CG received usual primary care. Data were collected at baseline, after the intervention (6 weeks after baseline for controls) and at 6 and 12 months from baseline. Compared with controls, the IG had significantly higher patient activation scores after the intervention (73.29 vs. 66.51, p = .006). However, this improvement was not maintained at follow-up and there were no significant differences in secondary outcomes across the study period. HC may be an effective strategy for achieving short-term improvements in the activation of primary care users with chronic conditions. Further studies with different methodological approaches are needed to elucidate how HC may improve and sustain changes in patient activation.

Desarrollo de materiales educativos para pacientes crónicos y familiares / Development of educational materials for chronic patients and families

Un nivel bajo de alfabetización puede dificultar la comprensión de la información necesaria para tomar decisiones apropiadas en relación con la propia salud. Esta situación está relacionada con una peor adherencia a los tratamientos, un peor estado de bienestar y una mortalidad más elevada, sobre todo en personas de edad avanzada. Resulta esencial que la información pueda ser comprendida por el paciente y su familia. Este artículo tiene como objetivo presentar las recomendaciones internacionales existentes para el diseño y la elaboración de materiales o recursos educativos para pacientes crónicos y familiares. Se describen aspectos metodológicos que engloban la inclusión de los pacientes en distintos puntos durante el proceso de desarrollo del material, la adaptación del formato y el contenido al nivel de comprensión del paciente, así como su participación en una prueba piloto antes de la publicación de los mismos. Los materiales educativos que se han elaborado con la colaboración de los pacientes resultan más adaptados a su contexto y promueven cambios positivos en su salud

Low literacy can difficult the use of information needed to take appropriate decisions in healthcare. This situation is associated with poorer treatment adherence, lower health outcomes and higher mortality among the population and, specifically, the elderly. It is essential that information can be understood by patients and families. This article aims to present the existing international recommendations for the design and development of educational materials and resources to chronic patients and families. This process encompasses the involvement of patients at various levels during the development process of the materials, the adaptation of the format and content to the level of understanding of the patient as well as their participation in the evaluation process. Educational materials that have been developed in collaboration with patients are more adapted to their context and promote positive changes in their health

Gentamicin as Empirical Treatment in Hemodialysis Patients: Safety, Pharmacokinetics, and Pharmacodynamics.

The aim of this study was to describe the safety profile and pharmacokinetic/pharmacodynamic parameters in end-stage renal disease patients who received gentamicin as empirical treatment in catheter-related bacteremia when they showed infection signs, regardless of the timing of the next HD. Patients received gentamicin 3 mg/kg before blood culture extraction when they showed infection signs and regardless of the timing of next hemodialysis session. Serum concentrations were collected after the gentamicin administration (peak level) and before the next HD (trough level). Toxicities and adverse drug events were registered. The main pharmacokinetic/pharmacodynamic goal for Gram-negative infections was peak:minimum inhibitory concentration (MIC) ≥10. Sixteen patients were included. Nephrotoxicity was not assessed in this population, and no ototoxicity was found. According to microbial isolation and gentamicin susceptibility, the value of peak:MIC was 5.4 ± 2.0. The administration of gentamicin in these conditions was safe. Estimated pharmacokinetic values were consistent with previous studies and appropriate according to peak:MIC goal for Gram-negative organisms with MIC ≤1 mg/L.

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia.

The ubiquitin proteasome system (UPS) is a major regulator of protein processing, trafficking, and degradation. While protein ubiquitination is utilized for many cellular processes, one major function of this system is to target proteins to the proteasome for degradation. In schizophrenia, studies have found UPS transcript abnormalities in both blood and brain, and we have previously reported decreased protein expression of ubiquitin-associated proteins in brain. To test whether the proteasome is similarly dysregulated, we measured the protein expression of proteasome catalytic subunits as well as essential subunits from proteasome regulatory complexes in 14 pair-matched schizophrenia and comparison subjects in superior temporal cortex. We found decreased expression of Rpt1, Rpt3, and Rpt6, subunits of the 19S regulatory particle essential for ubiquitin-dependent degradation by the proteasome. Additionally, the α subunit of the 11S αß regulatory particle, which enhances proteasomal degradation of small peptides and unfolded proteins, was also decreased. Haloperidol-treated rats did not have altered expression of these subunits, suggesting the changes we observed in schizophrenia are likely not due to chronic antipsychotic treatment. Interestingly, expression of the catalytic subunits of both the standard and immunoproteasome were unchanged, suggesting the abnormalities we observed may be specific to the complexed state of the proteasome. Aging has significant effects on the proteasome, and several subunits (20S ß2, Rpn10, Rpn13, 11Sß, and 11Sγ) were significantly correlated with subject age. These data provide further evidence of dysfunction of the ubiquitin-proteasome system in schizophrenia, and suggest that altered proteasome activity may be associated with the pathophysiology of this illness.

Comparison of donkey hemogram using the LaserCyte hematology analyzer, an impedance system, and a manual method.

BACKGROUND: Donkeys are becoming increasingly important worldwide; therefore a reliable and accurate method of diagnosing disease is necessary. Flow cytometry-based hematologic analyzers are present in veterinary laboratories, but performance of LaserCyte has not been evaluated in donkeys. OBJECTIVES: The objective of the study was to compare the results of donkey blood obtained from the LaserCyte with impedance and manual methods. METHODS: Blood samples were collected from 84 healthy donkeys (1-20 years old) and measured with LaserCyte, Sysmex F-820 and manually. Agreement between methods was studied using Passing-Bablok test and Bland-Altman plots. Influence of blood abnormalities found on blood smears on LaserCyte counts was examined using Mann-Whitney or Kruskal-Wallis test. Intraassay precision was calculated. RESULTS: Hematologic variables obtained from the LaserCyte were significantly different from those obtained with impedance or manual methods; numerous values were flagged. Agreement between LaserCyte and manual method was poor for the majority of variables, but agreement between LaserCyte and impedance was only poor for HCT, MCH, and MCHC. LaserCyte had an intraassay precision < 10% for RBC and platelet variables, and > 10% for WBC variables. CONCLUSIONS: LaserCyte results were not interchangeable with results from other methods due to poor agreement. LaserCyte provided no additional hematologic variables or clinically relevant indices for donkey blood analysis. A large number of results were flagged, requiring the evaluation of blood smears. No benefits were found for the use of LaserCyte analyzer over the use of impedance or manual methods in this study. Specific software for LaserCyte for donkey blood would be beneficial.

Dysfunction of the ubiquitin proteasome and ubiquitin-like systems in schizophrenia.

Protein expression abnormalities have been implicated in the pathophysiology of schizophrenia, but the underlying cause of these changes is not known. We sought to investigate ubiquitin and ubiquitin-like (UBL) systems (SUMOylation, NEDD8ylation, and Ufmylation) as putative mechanisms underlying protein expression abnormalities seen in schizophrenia. For this, we performed western blot analysis of total ubiquitination, free ubiquitin, K48- and K63-linked ubiquitination, and E1 activases, E2 conjugases, and E3 ligases involved in ubiquitination and UBL post-translational modifications in postmortem brain tissue samples from persons with schizophrenia (n=13) and comparison subjects (n=13). We studied the superior temporal gyrus (STG) of subjects from the Mount Sinai Medical Center brain collection that were matched for age, tissue pH, and sex. We found an overall reduction of protein ubiquitination, free ubiquitin, K48-linked ubiquitination, and increased K63 polyubiquitination in schizophrenia. Ubiquitin E1 activase UBA (ubiquitin activating enzyme)-6 and E3 ligase Nedd (neural precursor cell-expressed developmentally downregulated)-4 were decreased in this illness, as were E3 ligases involved in Ufmylation (UFL1) and SUMOylation (protein inhibitor of activated STAT 3, PIAS3). NEDD8ylation was also dysregulated in schizophrenia, with decreased levels of the E1 activase UBA3 and the E3 ligase Rnf7. This study of ubiquitin and UBL systems in schizophrenia found abnormalities of ubiquitination, Ufmylation, SUMOylation, and NEDD8ylation in the STG in this disorder. These results suggest a novel approach to the understanding of schizophrenia pathophysiology, where a disruption in homeostatic adaptation of the cell underlies discreet changes seen at the protein level in this illness.

The 3rd Schizophrenia International Research Society Conference, 14-18 April 2012, Florence, Italy: summaries of oral sessions.

The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.

Abnormalities of the Duo/Ras-related C3 botulinum toxin substrate 1/p21-activated kinase 1 pathway drive myosin light chain phosphorylation in frontal cortex in schizophrenia.

BACKGROUND: Recent studies on GTPases have suggested that reduced Duo and cell division cycle 42 (Cdc42) transcript expression is involved in dendritic spine loss in schizophrenia. In murine models, Duo and Cdc42 phosphorylate p21-activated kinase 1 (PAK1), which modifies the activity of regulatory myosin light chain (MLC) and cofilin by altering their phosphorylation. Therefore, we hypothesized that in schizophrenia abnormal Duo and Cdc42 expression result in changes in MLC and/or cofilin phosphorylation, which might alter actin cytoskeleton dynamics underlying dendritic spine maintenance. METHODS: We performed Western blot protein expression analysis in postmortem brains from patients diagnosed with schizophrenia and a comparison group. We focused our studies in the anterior cingulate cortex (ACC; n = 33 comparison group; n = 36 schizophrenia) and dorsolateral prefrontal cortex (DLPFC; n = 29 comparison group; n = 35 schizophrenia). RESULTS: In both ACC and DLPFC, we found a reduction of Duo expression and PAK1 phosphorylation in schizophrenia. Cdc42 protein expression was decreased in ACC but not in DLPFC. In ACC, we observed decreased PAK1 phosphorylation and increased MLC phosphorylation (pMLC), whereas in DLPFC pMLC remained unchanged. CONCLUSIONS: These data suggest a novel mechanism that might underlie dendritic spine loss in schizophrenia. The increase in pMLC seen in ACC might be associated with dendritic spine shrinkage. The lack of an effect on pMLC in DLPFC suggests that in schizophrenia PAK1 downstream pathways are differentially affected in these cortical areas.

Myosin II motor activity in the lateral amygdala is required for fear memory consolidation.

Learning induces dynamic changes to the actin cytoskeleton that are required to support memory formation. However, the molecular mechanisms that mediate filamentous actin (F-actin) dynamics during learning and memory are poorly understood. Myosin II motors are highly expressed in actin-rich growth structures including dendritic spines, and we have recently shown that these molecular machines mobilize F-actin in response to synaptic stimulation and learning in the hippocampus. In this study, we report that Myosin II motors in the rat lateral amygdala (LA) are essential for fear memory formation. Pretraining infusions of the Myosin II inhibitor, blebbistatin (blebb), disrupted long term memory, while short term memory was unaffected. Interestingly, both post-training and pretesting infusions had no effect on memory formation, indicating that Myosin II motors operate during or shortly after learning to promote memory consolidation. These data support the idea that Myosin II motor-force generation is a general mechanism that supports memory consolidation in the mammalian CNS.

Glutamate receptor abnormalities in schizophrenia: implications for innovative treatments.

Schizophrenia is a devastating psychiatric illness that afflicts 1% of the population worldwide, resulting in substantial impact to patients, their families, and health care delivery systems. For many years, schizophrenia has been felt to be associated with dysregulated dopaminergic neurotransmission as a key feature of the pathophysiology of the illness. Although numerous studies point to dopaminergic abnormalities in schizophrenia, dopamine dysfunction cannot completely account for all of the symptoms seen in schizophrenia, and dopamine-based treatments are often inadequate and can be associated with serious side effects. More recently, converging lines of evidence have suggested that there are abnormalities of glutamate transmission in schizophrenia. Glutamatergic neurotransmission involves numerous molecules that facilitate glutamate release, receptor activation, glutamate reuptake, and other synaptic activities. Evidence for glutamatergic abnormalities in schizophrenia primarily has implicated the NMDA and AMPA subtypes of the glutamate receptor. The expression of these receptors and other molecules associated with glutamate neurotransmission has been systematically studied in the brain in schizophrenia. These studies have generally revealed region- and molecule-specific changes in glutamate receptor transcript and protein expression in this illness. Given that glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, recent drug development efforts have targeted the glutamate system. Much effort to date has focused on modulation of the NMDA receptor, although more recently other glutamate receptors and transporters have been the targets of drug development. These efforts have been promising thus far, and ongoing efforts to develop additional drugs that modulate glutamatergic neurotransmission are underway that may hold the potential for novel classes of more effective treatments for this serious psychiatric illness.

Regulation of synapse structure and function by distinct myosin II motors.

Ongoing synaptic function and rapid, bidirectional plasticity are both controlled by regulatory mechanisms within dendritic spines. Spine actin dynamics maintain synapse structure and function, and cytoskeletal rearrangements in these structures trigger structural and functional plasticity. Therefore, proteins that interact with actin filaments are attractive candidates to regulate synaptic actin dynamics and, thus, synapse structure and function. Here, we have cloned the rat isoform of class II myosin heavy chain MyH7B in brain. Unexpectedly, this isoform resembles muscle-type myosin II rather than the ubiquitously expressed nonmuscle myosin II isoforms, suggesting that a rich functional diversity of myosin II motors may exist in neurons. Indeed, reducing the expression of MyH7B in mature neurons caused profound alterations to dendritic spine structure and excitatory synaptic strength. Structurally, dendritic spines had large, irregularly shaped heads that contained many filopodia-like protrusions. Neurons with reduced MyH7B expression also had impaired miniature EPSC amplitudes accompanied by a decrease in synaptic AMPA receptors, which was linked to alterations of the actin cytoskeleton. MyH7B-mediated control over spine morphology and synaptic strength was distinct from that of a nonmuscle myosin, myosin IIb. Interestingly, when myosin IIb expression and MyH7B expression were simultaneously knocked-down in neurons, a third, more pronounced phenotype emerged. Together, our data provide evidence that distinct myosin II isoforms work together to regulate synapse structure and function in cultured hippocampal neurons. Thus, myosin II motor activity is emerging as a broad regulatory mechanism for control over complex actin networks within dendritic spines.

Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation.

Reorganization of the actin cytoskeleton is essential for synaptic plasticity and memory formation. Presently, the mechanisms that trigger actin dynamics during these brain processes are poorly understood. In this study, we show that myosin II motor activity is downstream of LTP induction and is necessary for the emergence of specialized actin structures that stabilize an early phase of LTP. We also demonstrate that myosin II activity contributes importantly to an actin-dependent process that underlies memory consolidation. Pharmacological treatments that promote actin polymerization reversed the effects of a myosin II inhibitor on LTP and memory. We conclude that myosin II motors regulate plasticity by imparting mechanical forces onto the spine actin cytoskeleton in response to synaptic stimulation. These cytoskeletal forces trigger the emergence of actin structures that stabilize synaptic plasticity. Our studies provide a mechanical framework for understanding cytoskeletal dynamics associated with synaptic plasticity and memory formation.

Cortical DNA methylation maintains remote memory.

A behavioral memory's lifetime represents multiple molecular lifetimes, suggesting the necessity for a self-perpetuating signal. One candidate is DNA methylation, a transcriptional repression mechanism that maintains cellular memory throughout development. We found that persistent, gene-specific cortical hypermethylation was induced in rats by a single, hippocampus-dependent associative learning experience and pharmacologic inhibition of methylation 1 month after learning disrupted remote memory. We propose that the adult brain utilizes DNA methylation to preserve long-lasting memories.

Infective endocarditis in patients receiving chronic hemodialysis: clinical features and outcome.

BACKGROUND AND AIM OF THE STUDY: Patients undergoing chronic hemodialysis are at increased risk of infective endocarditis (IE), and mortality is high in this group. The study aim was to determine clinical features and outcome of IE in patients with chronic renal failure and receiving hemodialysis. METHODS: Between 1987 and 2002, all consecutive patients with infective endocarditis treated at the authors' institution who were not intravenous drug abusers were selected prospectively. A comparative analysis was performed of patients undergoing hemodialysis and other patients in the series. RESULTS: A total of 241 cases of IE was diagnosed, and 14 patients (6%) were receiving hemodialysis. A lower frequency of known predisposing heart disease (14% versus 74%, p <0.01) and prosthetic valve endocarditis (0% versus 35%, p <0.05) and a higher rate of negative blood cultures (21% versus 12%, p <0.05) were detected in hemodialysis patients. Early surgery was performed in 50% of patients in both groups. The frequency of complications was similar in both groups, but early (43% versus 16%, p = 0.03) and late (22% versus 9%, p <0.05) mortality were higher in hemodialysis patients. CONCLUSION: Patients with IE who are undergoing hemodialysis have a lower frequency of predisposing heart disease and higher rates of negative blood cultures. Although patient groups were similarly treated, early and late mortality was significantly higher among those receiving dialysis.

[Pulmonary atresia with intact ventricular septum associated with severe aortic stenosis]. / Atresia pulmonar con septo integro asociada a estenosis aórtica severa.

Pulmonary atresia with intact ventricular septum is the complete obstruction of the right ventricular outflow tract due to pulmonary valve atresia in the absence of ventricular septal defect. Pulmonary flow is dependent on the ductus arteriosus. Other morphological anomalies are also present. Aortic stenosis in association with pulmonary atresia with intact ventricular septum is extremely infrequent, and very few cases have been described. We report a 19-year-old primiparous woman in whom the fetal echocardiogram showed pulmonary atresia with intact ventricular septum. The neonate had low oxygen saturation and a systolic murmur originating in the aorta. An echocardiogram showed pulmonary atresia with intact ventricular septum and a bicuspid, thickened, stenotic aortic valve. Low cardiac output ensued and could not be controlled, and the infant died.

Atresia pulmonar con septo íntegro asociada a estenosis aórtica severa / Pulmonary atresia with intact ventricular septum associated with severe aortic stenosis

La atresia pulmonar con septo íntegro es la obstrucción completa del tracto de salida del ventrículo derecho por la válvula pulmonar atrésica, sin defecto septal interventricular y con un flujo pulmonar dependiente de un ductus. Se acompaña de otras anomalías morfológicas. La asociación a estenosis aórtica es extremadamente infrecuente y los casos publicados son excepcionales. Presentamos el caso de una primípara de 19 años en la que un ecocardiograma fetal evidenció atresia pulmonar con septo íntegro. La recién nacida presentó desaturación y soplo sistólico en el foco aórtico. Un ecocardiograma mostró una atresia pulmonar con el septo íntegro y una válvula aórtica bicúspide engrosada y estenótica. Evolucionó hacia el bajo gasto sistémico, incontrolable y mortal (AU)