A framework for translating tauopathy therapeutics: Drug discovery to clinical trials.

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies.

Efficacy assessment of an active tau immunotherapy in Alzheimer's disease patients with amyloid and tau pathology: a post hoc analysis of the "ADAMANT" randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial.

Background: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available.

Methods: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis.

Body mass index trajectories among people with obesity and association with mortality: Evidence from a large Israeli database.

Objective: Previous studies using longitudinal weight data to characterize obesity are based on populations of limited size and mostly include individuals of all body mass index (BMI) levels, without focusing on weight changes among people with obesity. This study aimed to identify BMI trajectories over 5 years in a large population with obesity, and to determine the trajectories' association with mortality.

Methods: For inclusion, individuals aged 30-74 years at index date (1 January 2013) with continuous membership in Clalit Health Services from 2008 to 2012 were required to have ≥1 BMI measurement per year in ≥3 calendar years during this period, of which at least one was ≥30 kg/m.

A comprehensive descriptive assessment of obesity related chronic morbidity and estimated annual cost burden from a population-based electronic health record database.

Background: The growing prevalence of obesity and its complications pose a huge burden on the individual and health care systems worldwide. This study presents the frequency of multiple prevalent co-morbidities and estimated annual cost burden by body mass index (BMI) groups, age, and sex among the Israeli adult population to provide policy makers with further evidence to appropriately target interventions.

Methods: This cross-sectional study utilized population-based electronic medical records from the largest payer-provider health fund in Israel.

Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial.

Purpose Human epidermal growth factor receptor 2 ( HER2, ERBB2)-activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial. Patients and Methods Patients received ado-trastuzumab emtansine at 3.

Traditional graft preparation decreases physiologic responses, diminishes viscoelasticity, and reduces cellular viability of the conduit: A porcine saphenous vein model.

Traditional methods of intraoperative human saphenous vein preparation for use as bypass grafts can be deleterious to the conduit. The purpose of this study was to characterize acute graft preparation injury, and to mitigate this harm via an improved preparation technique. Porcine saphenous veins were surgically harvested (unprepared controls, UnP) and prepared using traditional (TraP) and improved preparations (ImP).

Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice.

Recent findings suggest that neurons can efficiently repair oxidatively damaged DNA, and that both DNA damage and repair are enhanced by activation of excitatory glutamate receptors. However, in pathological conditions such as ischemic stroke, excessive DNA damage can trigger the death of neurons. Oxidative DNA damage is mainly repaired by base excision repair (BER), a process initiated by DNA glycosylases that recognize and remove damaged DNA bases.

The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures.

The pleotrophic effects of insulin-like growth factor-I on human spinal cord neural progenitor cells.

Most stem cell therapies involve direct, intraparachymal placement of neural progenitor cells. These cells provide physical support to the endogenous neuronal population and may be engineered to provide in situ growth factor support. Insulin-like growth factor-I (IGF-I) has potent neurotrophic and neuroprotective properties and is expressed by human neural stem cells (hNSCs).

Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective loss of motor neurons (MNs). Twenty percent of familial ALS cases are associated with mutations in Cu(2+)/Zn(2+) superoxide dismutase (SOD1). To specifically understand the cellular mechanisms underlying mutant SOD1 toxicity, we have established an in vitro model of ALS using rat primary MN cultures transfected with an adenoviral vector encoding a mutant SOD1, G93A-SOD1.

Adverse effect of paroxetine on sperm.

Objective: To assess the effects of a selective serotonin reuptake inhibitor on semen parameters.

Design: Prospective study.

Setting: Academic medical center.

Bax and Bak do not exhibit functional redundancy in mediating radiation-induced endothelial apoptosis in the intestinal mucosa.

Purpose: To address in vivo the issue of whether Bax and Bak are functionally redundant in signaling apoptosis, capable of substituting for each other.

Methods And Materials: Mice were exposed to whole-body radiation, and endothelial cell apoptosis was quantified using double immunostaining with TUNEL and anti-CD31 antibody. Crypt survival was determined at 3.

New technology for examining the anterior segment by ultrasonic biomicroscopy.

Purpose: To compare the comfort levels and measurement accuracy of the open-shell technique and a bag/balloon technology (ClearScan, ESI) in anterior segment ultrasound biomicroscopy.

Setting: Department of Ophthalmology and Visual Science, Robert Cizik Eye Clinic, University of Texas Medical School at Houston, Houston, Texas, USA.

Methods: In this prospective investigation, 20 subjects stated their preference and rated comfort (0 best to 5 worst) for the open-shell technique versus the bag/balloon technology.

Mouse models of diabetic neuropathy.

Diabetic neuropathy (DN) is a debilitating complication of type 1 and type 2 diabetes. Rodent models of DN do not fully replicate the pathology observed in human patients. We examined DN in streptozotocin (STZ)-induced [B6] and spontaneous type 1 diabetes [B6Ins2(Akita)] and spontaneous type 2 diabetes [B6-db/db, BKS-db/db].

Apoptosis and proliferation of cultured mesangial cells isolated from kidneys of rosiglitazone-treated pregnant diabetic rats.

Background: The peroxisome proliferator activating nuclear receptors (PPAR) are activated in the context of inflammation, diabetes or normal pregnancy. Renal mesangial cells express PPAR-gamma which upon activation are capable of exerting anti-inflammatory effects. We investigated the effect of in vivo treatment by rosiglitazone on angiotensin II (A-II) stimulated manifestations of inflammation in cultured renal mesangial cells, such as proliferation, apoptosis, TGF-beta1 production and nuclear factor kappaB (NF-kappaB) activation, in the situation of pregnancies, complicated or not with diabetes.

Interferon gamma-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells.

Background: Interferon gamma-inducible protein 10 (IP-10) has antitumor effects in various murine models. The IP-10 receptor has two distinct splice variants, CXCR3A and CXCR3B, that have paradoxical effects after ligand-receptor interaction.

Methods: To characterize the putative antiangiogenic effects of IP-10, we measured proliferation rates and apoptosis in human umbilical vein endothelial cells (HUVECs), fibroblasts, and A375 melanoma or WIDR adenocarcinoma cell lines after exposure to the recombinant protein.

Identification of candidate drugs for the treatment of ALS.

A consortium of investigators interested in neurodegenerative diseases collaborated to screen 1040 drugs in multiple neurodegenerative disease assays. One model of amyotrophic lateral sclerosis (ALS) pathogenesis in particular incorporated glutamate exposure in enriched primary rat motor neuron cultures. In this model 78 compounds decreased motor neuron death caused by 100 microM glutamate.

Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP).

Akt negatively regulates apoptotic pathways at a premitochondrial level through phosphorylation and modulation of proteins such as Bad, Forkhead proteins, and GSK-3beta. Akt has also been shown to protect cell death at a post-mitochondrial level, although its downstream targets have not been well documented. Here, we demonstrate that Akt, including AKT1 and AKT2, interacts with and phosphorylates X-linked inhibitor of apoptosis protein (XIAP) at residue serine-87 in vitro and in vivo.

The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice.

Purpose: The purpose of this research was to evaluate theinfluence of the combination of the vitamin D(3) analogue EB 1089 with fractionated radiation on growth and apoptosis of MCF-7 tumor xenografts in athymic mice.

Experimental Design: Four to six-week-old ovariectomized mice were injected s.c.

High glucose-induced oxidative stress and mitochondrial dysfunction in neurons.

The current study examines the association between glucose induction of reactive oxygen species (ROS), mitochondrial (Mt) depolarization, and programmed cell death in primary neurons. In primary dorsal root ganglion (DRG) neurons, 45 mM glucose rapidly induces a peak rise in ROS corresponding to a 50% increase in mean Mt size at 6 h (P<0.001).

Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin.

Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin.

Comparison of glucose concentrations in blood samples obtained with a marginal ear vein nick technique versus from a peripheral vein in healthy cats and cats with diabetes mellitus.

Objective: To compare blood glucose (BG) concentrations measured with a portable blood glucose meter in blood samples obtained with a marginal ear vein (MEV) nick technique, from a peripheral venous catheter, and by direct venipuncture in healthy cats and cats with diabetes mellitus.

Design: Prospective study.

Animals: 1 0 healthy cats and 11 cats with diabetes mellitus.

Neurons undergo apoptosis in animal and cell culture models of diabetes.

Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed.