Amyloid-β alters ongoing neuronal activity and excitability in the frontal cortex

The effects of amyloid-β on the activity and excitability of individual neurons in the early and advanced stages of the pathological progression of Alzheimer's disease remain unknown. We used in vivo intracellular recordings to measure the ongoing and evoked activity of pyramidal neurons in the frontal cortex of APPswe/PS1dE9 transgenic mice and age-matched nontransgenic littermate controls. Evoked excitability was altered in both transgenic groups: neurons in young transgenic mice displayed hypoexcitability, whereas those in older transgenic mice displayed hyperexcitability, suggesting changes in intrinsic electrical properties of the neurons. However, the ongoing activity of neurons in both young and old transgenic groups showed signs of hyperexcitability in the depolarized state of the membrane potential. The membrane potential of neurons in old transgenic mice had an increased tendency to fail to transition to the depolarized state, and the depolarized states had shorter durations on average than did controls. This suggests a combination of both intrinsic electrical and synaptic dysfunctions as mechanisms for activity changes at later stages of the neuropathological progression.     

Revisión de la legislación sobre la investigación clínica en el Sistema Nacional Salud y los servicios de farmacia hospitalaria

The call for public funding for the Spanish Health Care System clinical research with drugs for human use projects Subprogramme highlights the need for hospital pharmacy services to include the manufacture of investigational drugs which are the subject of a clinical trial, developed by either a researcher or a group of researchers, within its activities.This article discusses the legislation concerning the manufacture of investigational drugs and the requirements that the pharmacy services must meet in order to develop, distribute, or conceal an investigational drug in a clinical trial sponsored by a professional from the SHS.     

The development of neural correlates for memory formation

A growing body of literature considers the development of episodic memory systems in the brain; the majority are neuroimaging studies conducted during memory encoding in order to explore developmental trajectories in memory formation. This review considers evidence from behavioral studies of memory development, neural correlates of memory formation in adults, and structural brain development, all of which form the foundation of a developmental cognitive neuroscience approach to memory development. I then aim to integrate the current evidence from developmental functional neuroimaging studies of memory formation with respect to three hypotheses. First, memory development reflects the development in the use of memory strategies, linked to prefrontal cortex. Second, developmental effects within the medial temporal lobes are more complex, and correspond to current notions about the nature in which the MTL support the formation of memory. Third, neurocognitive changes in content representation influence memory. Open issues and current directions are discussed.     

Munc13-independent vesicle priming at mouse photoreceptor ribbon synapses

Munc13 proteins are essential regulators of exocytosis. In hippocampal glutamatergic neurons, the genetic deletion of Munc13s results in the complete loss of primed synaptic vesicles (SVs) in direct contact with the presynaptic active zone membrane, and in a total block of neurotransmitter release. Similarly drastic consequences of Munc13 loss are detectable in hippocampal and striatal GABAergic neurons. We show here that, in the adult mouse retina, the two Munc13-2 splice variants bMunc13-2 and ubMunc13-2 are selectively localized to conventional and ribbon synapses, respectively, and that ubMunc13-2 is the only Munc13 isoform in mature photoreceptor ribbon synapses. Strikingly, the genetic deletion of ubMunc13-2 has little effect on synaptic signaling by photoreceptor ribbon synapses and does not prevent membrane attachment of synaptic vesicles at the photoreceptor ribbon synaptic site. Thus, photoreceptor ribbon synapses and conventional synapses differ fundamentally with regard to their dependence on SV priming proteins of the Munc13 family. Their function is only moderately affected by Munc13 loss, which leads to slight perturbations of signal integration in the retina.     

Phase II study of cisplatin, epirubicin, UFT, and leucovorin (PELUF) as first-line chemotherapy in metastatic gastric cancer

More than two-thirds of patients with gastric cancer present with metastatic disease and their curative options are limited. This phase II study assessed the efficacy and tolerability of cisplatin, epirubicin, tegafur-uracil (UFT) and leucovorin in patients with metastatic gastric cancer (MGC). Thirty-nine patients with previously untreated metastatic or unresectable gastric cancer received intravenous cisplatin 60 mg/m² and epirubicin 50 mg/m² on day 1 of a 28-day cycle; UFT 300 mg/m² was administered with oral leucovorin 30 mg/day in divided doses on days 1-22, followed by a 7-day rest. Two patients achieved a complete response, 13 had a partial response (overall response rate 38%; 95% confidence interval [CI] 24-52%) and 16 patients (41%) had stable disease. Median time to progression was 6.5 months (95% CI 5.5-7.5 months); overall survival was 9.5 months (95% CI 8.5-13.5 months). Grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 20%, 8%, and 3% of patients, respectively; two patients experienced febrile neutropenia. Grade 3 diarrhea occurred in three patients. The combination of cisplatin, epirubicin, UFT, and leucovorin has significant activity and tolerable toxicities in patients with MGC and represents a convenient treatment option for these patients.     

Mesenchymal stem cells protect from sub-chronic phencyclidine insult in vivo and counteract changes in astrocyte gene expression in vitro

Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine strategies in brain diseases. Experimental studies have shown that repeated administration of phencyclidine (PCP) leads to schizophrenia-like behavioral changes in mice. The aim of the present study was to explore the effectiveness of MSC transplantation into the hippocampus in attenuating PCP-induced social behavior deficits. PCP was administered subcutaneously to C57bl mice (10 mg/kg daily) for 2 weeks. On the first day of PCP administration, adult human MSCs were transplanted into the hippocampus. A week after the last PCP dose, the mice underwent social preference testing. MSC transplantation was associated with a significant reduction in the adverse social behavior induced by PCP. Immunohistochemical analysis revealed that the stem cells survived in the mouse brain, and hippocampal Western blot analysis revealed a statistical trend towards a decrease in cleaved caspase 3 protein levels in the stem cell treated group. Upon in vitro co-culture of astrocytes and MSCs, the MSCs, in the presence of PCP, positively regulated astrocyte expression of genes involved in glutamate metabolism and antioxidant defenses. These findings suggest that MSC transplantation into the hippocampus may serve as a novel neuroprotective tool for the treatment of the PCP-induced schizophrenia-like social endophenotype. The mechanism underlying the beneficial behavioral effect may involve modulation of host astrocyte functioning, including glutamate processing and antioxidant capacity.     

Perceived hardships at midlife: Prediction of long-term stroke mortality

Objectives

The objective of this study is to examine the association between perceived hardships and long-term stroke mortality among a large cohort of middle-aged men.

Background

Unlike cardiovascular morbidity and mortality, much less is known about the relationship between psychosocial factors and risk of stroke.

Methods

A cohort of 10,059 men aged ≥ 40 years at study inclusion that were tenured civil servants or municipal employees were followed for mortality over a median of 28.1 years (IQR 18.9–34.3). During follow-up 6528 (64.9%) men died, 665 of stroke and 1769 of coronary heart disease (CHD). A composite score of perceived hardships was calculated based on a structured psychosocial questionnaire filled at baseline, assessing domains of work, family, and finance. Cox proportional hazard models were used adjusting for traditional risk factors and socio-economic status.

Results

At baseline, subjects with higher hardship scores were slightly older, smoked more cigarettes, had higher prevalence of CHD, lower systolic blood pressure, higher anxiety levels and lower socio-economic status. Compared with the bottom tertile, the middle (HR 1.26, 95% CI 1.04–1.53) and top tertiles of the hardship score (HR 1.33, 95% CI 1.07–1.64) exhibited higher risk of stroke mortality (P for trend = 0.008), while no significant association was found with long-term mortality from CHD. The magnitude of the association was comparable to that of diabetes (HR 1.30, 95% CI 1.02–1.66).

Conclusion

Perceived hardships measured at midlife in a large cohort of apparently healthy men independently predict stroke mortality over long-term follow-up.