Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau.

The interneuronal propagation of aggregated tau is believed to play an important role in the pathogenesis of human tauopathies. It requires the uptake of seed-competent tau into cells, seeding of soluble tau in recipient neurons and release of seeded tau into the extracellular space to complete the cycle. At present, it is not known which tau species are seed-competent.

Hypoxia Affects Neprilysin Expression Through Caspase Activation and an APP Intracellular Domain-dependent Mechanism.

While gene mutations in the amyloid precursor protein (APP) and the presenilins lead to an accumulation of the amyloid β-peptide (Aβ) in the brain causing neurodegeneration and familial Alzheimer's disease (AD), over 95% of all AD cases are sporadic. Despite the pathologies being indistinguishable, relatively little is known about the mechanisms affecting generation of Aβ in the sporadic cases. Vascular disorders such as ischaemia and stroke are well established risk factors for the development of neurodegenerative diseases and systemic hypoxic episodes have been shown to increase Aβ production and accumulation.

Electrophysiological characterization of human and mouse sodium-dependent citrate transporters (NaCT/SLC13A5) reveal species differences with respect to substrate sensitivity and cation dependence.

The citric acid cycle intermediate citrate plays a crucial role in metabolic processes such as fatty acid synthesis, glucose metabolism, and β-oxidation. Citrate is imported from the circulation across the plasma membrane into liver cells mainly by the sodium-dependent citrate transporter (NaCT; SLC13A5). Deletion of NaCT from mice led to metabolic changes similar to caloric restriction; therefore, NaCT has been proposed as an attractive therapeutic target for the treatment of obesity and type 2 diabetes.

Identifying factors of activities of daily living important for cost and caregiver outcomes in Alzheimer's disease.

Background: We aimed to obtain a better understanding of how different aspects of patient functioning affect key cost and caregiver outcomes in Alzheimer's disease (AD).

Methods: Baseline data from a prospective observational study of community-living AD patients (GERAS) were used. Functioning was assessed using the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale.

Relationship of insight with medication adherence and the impact on outcomes in patients with schizophrenia and bipolar disorder: results from a 1-year European outpatient observational study.

Background: Many patients with schizophrenia and bipolar disorder have impaired insight and low medication adherence. The aim of this post hoc analysis was to explore the relationship between insight and medication adherence.

Methods: We included 903 patients with schizophrenia or bipolar disorder who participated in an observational study conducted in Europe on the outcomes of patients treated with two oral formulations of olanzapine over a 1-year period.

α7 and β2 Nicotinic Acetylcholine Receptor Subunits Form Heteromeric Receptor Complexes that Are Expressed in the Human Cortex and Display Distinct Pharmacological Properties.

The existence of α7β2 nicotinic acetylcholine receptors (nAChRs) has recently been demonstrated in both the rodent and human brain. Since α7-containing nAChRs are promising drug targets for schizophrenia and Alzheimer's disease, it is critical to determine whether α7β2 nAChRs are present in the human brain, in which brain areas, and whether they differ functionally from α7 nAChR homomers. We used α-bungarotoxin to affinity purify α7-containing nAChRs from surgically excised human temporal cortex, and found that α7 subunits co-purify with β2 subunits, indicating the presence of α7β2 nAChRs in the human brain.

Pharmacological Characterisation of Nicotinic Acetylcholine Receptors Expressed in Human iPSC-Derived Neurons.

Neurons derived from human induced pluripotent stem cells (iPSCs) represent a potentially valuable tool for the characterisation of neuronal receptors and ion channels. Previous studies on iPSC-derived neuronal cells have reported the functional characterisation of a variety of receptors and ion channels, including glutamate receptors, γ-aminobutyric acid (GABA) receptors and several voltage-gated ion channels. In the present study we have examined the expression and functional properties of nicotinic acetylcholine receptors (nAChRs) in human iPSC-derived neurons.

Determinants of societal costs in Alzheimer's disease: GERAS study baseline results.

Background: To identify the main factors associated with societal costs of Alzheimer's disease (AD) in community-dwelling patients across three European countries.

Methods: Baseline cost data from a prospective, observational study were used. Assessments included patients' cognition, activities of daily living (ADLs) and behavioral symptoms, and caregiver burden.

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

Objective: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning.

Method: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009.

Clinical and Economic Characteristics of Milestones along the Continuum of Alzheimer's Disease: Transforming Functional Scores into Levels of Dependence.

Background: Because Alzheimer's disease (AD) is characterized by a gradual decline, it can be difficult to identify distinct clinical milestones that signal disease advancement. Adapting a functional scale may be a useful way of staging disease progression that is more informative for healthcare systems.

Objectives: To adapt functional scale scores into discrete levels of dependence as a way of staging disease progression that is more informative to care providers and stakeholders who rely on the functional impact of diseases to determine access to supportive services and interventions.

Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid-β of Peptides in Cerebrospinal Fluid Specimens from Alzheimer’s Disease Studies.

The aim of this study was to validate assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF)specimens according to regulatory guidance and demonstrate their utility with measurements in specimens from Alzheimer’s disease (AD) studies. Methods based on INNOTEST(®)β-AMYLOID(1-42) and prototype INNOTEST(®)β-AMYLOID(1-40) ELISAkits were developed involving pre-analytical sample treatment with Tween-20 for reliable analyte recovery.Validation parameters were evaluated by repeated testing of CSF pools collected and stored in the same manner as clinical specimens.

Striatum and entorhinal cortex atrophy in AD mouse models: MRI comprehensive analysis.

Alzheimer's disease is experimentally modeled in transgenic (Tg) mice overexpressing mutated forms of the human amyloid precursor protein either alone or combined with mutated presenilins and tau. In the present study, we developed a systematic approach to compare double (TASTPM) and triple (APP/PS2/Tau) Tg mice by serial magnetic resonance imaging and spectroscopy analysis from 4 to 26 months of age to define homologous biomarkers between mice and humans. Hippocampal atrophy was found in Tg mice compared with WT.

Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.

Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients.

Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain.

Background: Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis.

Systematic literature review and meta-analysis of diagnostic test accuracy in Alzheimer's disease and other dementia using autopsy as standard of truth.

Background: Early diagnosis of Alzheimer's disease (AD) is crucial to implement the latest treatment strategies and management of AD symptoms. Diagnostic procedures play a major role in this detection process but evidence on their respective accuracy is still limited.

Objective: To conduct a systematic literature on the sensitivity and specificity of different test modalities to identify AD patients and perform meta-analyses on the test accuracy values of studies focusing on autopsy-confirmation as the standard of truth.

Macro- and microvascular outcomes in patients with type 2 diabetes treated with rapid-acting insulin analogues or human regular insulin: a retrospective database analysis.

To investigate the risk of macro- and microvascular complications in patients with type 2 diabetes receiving rapid-acting insulin analogues (IA) or human regular insulin (HI).General practice diabetes patients with continuous prescription of any IA or HI for ≥3 years were selected from the German Disease Analyzer database (IMS Health). Logistic and Cox regression models were applied to analyze the incidence and time to onset of vascular outcomes (IA vs.

Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary.

Objective: Major depressive disorder (MDD) is a significant public health concern and challenges health care providers to intervene with appropriate treatment. This article provides an overview of efficacy and safety information for duloxetine 60 mg/day in the treatment of MDD, including its effect on painful physical symptoms (PPS).

Design: A literature search was conducted for articles and pooled analyses reporting information regarding the use of duloxetine 60 mg/day in placebo-controlled trials.

The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post-marketing adverse event reports.

Purpose: To assess the safety of duloxetine with regards to bleeding-related events in patients who concomitantly did, versus did not, use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin.

Methods: Safety data from all placebo-controlled trials of duloxetine conducted between December 1993 and December 2010, and post-marketing reports from duloxetine-treated patients in the US Food and Drug Administration Adverse Event Reporting System (FAERS), were searched for bleeding-related treatment-emergent adverse events (TEAEs). The percentage of patients with bleeding-related TEAEs was summarized and compared between treatment groups in all the placebo-controlled studies.

Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment.

Cortical bone, the dominant component of the human skeleton by volume, plays a key role in protecting bones from fracture. We analyzed the cortical bone effects of teriparatide treatment in postmenopausal women with osteoporosis who had previously received long-term alendronate (ALN) therapy or were treatment naïve (TN). Tetracycline-labeled paired iliac crest biopsies obtained from 29 ALN-pretreated and 16 TN women were evaluated for dynamic histomorphometric parameters of bone formation at the periosteal, endocortical and intracortical bone compartments, before and after 24months of teriparatide treatment.

Pharmacological profiling of the TRPV3 channel in recombinant and native assays.

Background And Purpose: Transient receptor potential vanilloid subtype 3 (TRPV3) is implicated in nociception and certain skin conditions. As such, it is an attractive target for pharmaceutical research. Understanding of endogenous TRPV3 function and pharmacology remains elusive as selective compounds and native preparations utilizing higher throughput methodologies are lacking.

Treatment persistence and changes in fracture risk, back pain, and quality of life amongst patients treated with teriparatide in routine clinical care in France: results from the European Forsteo Observational Study.

Objectives: The European Forsteo Observational Study assessed the clinical fracture incidence, back pain, quality of life (QoL), and treatment persistence amongst post-menopausal women, who were prescribed teriparatide in routine care in eight European countries. We present the results for France, with health-insurance reimbursement criteria channel teriparatide to women with severe disease and limit treatment to 18 months.

Methods: A representative sample of women initiating teriparatide in France was followed in routine care for 36 months.

Patient satisfaction with psychotropic drugs: Validation of the PAtient SAtisfaction with Psychotropic (PASAP) scale in patients with bipolar disorder.

Purpose: The PAtient SAtisfaction with Psychotropic (PASAP) scale is a self-completed questionnaire measuring satisfaction with psychotropic medication. The aim of the study was to describe its development in French and its psychometric properties.

Materials And Methods: Scale construction was based on an extensive search of the literature.

Which somatic symptoms are associated with an unfavorable course in Asian patients with major depressive disorder?

Objective: To investigate the impact of somatic symptoms on the severity and course of depression in Asian patients treated for an acute episode of major depressive disorder (MDD).

Methods: Three-month prospective observational study of 917 patients with MDD in psychiatric care settings of which 909 had complete main baseline data. Depression severity was assessed using the physician-rated Clinical Global Impression of Severity (CGI-S) and 17-item Hamilton Depression Rating Scale (HAMD17), and somatic symptoms were assessed using the patient-rated 28-item Somatic Symptom Inventory (SSI).