Assessment of brain-derived extracellular vesicle enrichment for blood biomarker analysis in age-related neurodegenerative diseases: An international overview.

Introduction: Brain-derived extracellular vesicles (BEVs) in blood allows for minimally-invasive investigations of central nervous system (CNS) -specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols.

Proteomic comparison between non-purified cerebrospinal fluid and cerebrospinal fluid-derived extracellular vesicles from patients with Alzheimer's, Parkinson's and Lewy body dementia.

Dementia is a leading cause of death worldwide, with increasing prevalence as global life expectancy increases. The most common neurodegenerative disorders are Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). With this study, we took an in-depth look at the proteome of the (non-purified) cerebrospinal fluid (CSF) and the CSF-derived extracellular vesicles (EVs) of AD, PD, PD-MCI (Parkinson's disease with mild cognitive impairment), PDD and DLB patients analysed by label-free mass spectrometry.

Assessment of brain-derived extracellular vesicle enrichment for blood biomarker analysis in age-related neurodegenerative diseases: An international overview.

Introduction: Brain-derived extracellular vesicles (BEVs) in blood allows for minimally- invasive investigations of CNS-specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols.

Characterising extracellular vesicles from individual low volume cerebrospinal fluid samples, isolated by SmartSEC.

Extracellular vesicles (EVs) are suggested to have a role in the progression of neurodegeneration, and are able to transmit pathological proteins from one cell to another. One of the biofluids from which EVs can be isolated is cerebrospinal fluid (CSF). However, so far, few studies have been performed on small volumes of CSF.

Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With Tuberous Sclerosis Complex: Final Analysis Results.

The TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety substudy that assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) receiving everolimus for its licensed indications in the European Union (EU). This substudy also aimed to address TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility. Eligible patients were enrolled from 39 sites across 11 countries in the EU.

Biofluid Markers for Prodromal Parkinson's Disease: Evidence From a Catecholaminergic Perspective.

Parkinson's disease (PD) is the most frequent of all Lewy body diseases, a family of progressive neurodegenerative disorders characterized by intra-neuronal cytoplasmic inclusions of α-synuclein. Its most defining features are bradykinesia, tremor, rigidity and postural instability. By the time PD manifests with motor signs, 70% of dopaminergic midbrain neurons are lost, and the disease is already in the middle or late stage.

Altered age-linked regulation of plasma DYRK1A in elderly cognitive complainers (INSIGHT-preAD study) with high brain amyloid load.

Introduction: An effective therapy has not yet been developed for Alzheimer's disease (AD), in part because pathological changes occur years before clinical symptoms manifest. We recently showed that decreased plasma DYRK1A identifies individuals with mild cognitive impairment (MCI) or AD, and that aged mice have higher DYRK1A levels.

Methods: We assessed DYRK1A in plasma in young/aged controls and in elderly cognitive complainers with low (L) and high (H) brain amyloid load.

Real-world Effectiveness and Safety of Pazopanib in Patients With Intermediate Prognostic Risk Advanced Renal Cell Carcinoma.

Introduction: The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778).

Patients And Methods: Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety.

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study).

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC).

Subjects, Materials, And Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible.

Multiple-dose pharmacokinetics confirm no accumulation and dose proportionality of the novel promotile drug tegaserod (HTF 919).

Objective: To evaluate the steady-state pharmacokinetics (PK) and dose proportionality of the selective 5-HT4 receptor partial agonist tegaserod (HTF 919) in healthy subjects.

Methods: Eighteen subjects were given 2, 6, or 12-mg doses of tegaserod twice daily (b.i.

Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin.

Objective: Nateglinide, a new short-acting D-phenylalanine derivative for treating type 2 diabetes, reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. This study evaluated the pharmacokinetic and pharmacodynamic interactions of nateglinide and metformin in subjects with type 2 diabetes.

Research Design And Methods: A total of 12 type 2 diabetic subjects with the following baseline characteristics were enrolled: age, 56 +/- 13 years; BMI, 28.

Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis.

This single-dose, open-label, parallel-group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis and 8 matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half-lives were comparable.

In vitro and in situ permeability of a 'second generation' hydroxypyridinone oral iron chelator: correlation with physico-chemical properties and oral activity.

Purpose: The in vitro and in situ transport of CGP 65015 ((+)-3-hydroxy-1-(2-hydroxyethyl)-2-hydroxyphenyl-methyl-1H-pyridin-4-on e), a novel oral iron chelator, is described. The predictive power of these data in assessing intestinal absorption in man is described.

Methods: Caco-2 epithelial monolayer and in situ rat jejunum perfusion intestinal permeability models were utilized.

Oral absorption of CGS-20625, an insoluble drug, in dogs and man.

Oral bioavailability of highly water-insoluble drugs is often quite limited and variable, requiring the development of improved formulations. Animal models are an essential aspect of the design and testing of such formulations designed to improve absorption in man. The present report compares the absorption of CGS-20625, an insoluble drug, in dog and man after oral administration of the drug as a powder, a solid dispersion capsule, and after gastric and duodenal administration in PEG 400 solution.

Molecular basis of cardiac troponin T isoform heterogeneity in rabbit heart.

In the rabbit heart, multiple isoforms of cardiac troponin T (cTnT1 through cTnT5, from largest in size to smallest), a protein essential for calcium-regulated myofibrillar ATPase activity, have been identified, and a correlation has been found between these isoforms and myofilament sensitivity to calcium. We have sought to establish the molecular basis of this diversity. Restriction-digest analysis of genomic DNA has indicated that the rabbit cTnT gene is a single-copy gene.

Effect of tracer and intravenous fat emulsion on the measurement of reticuloendothelial system function.

Since the addition of lipid to intravenous feeding formulas, animal and human studies have shown impairment of the reticuloendothelial system (RES) due to slow rates of clearance and gradual accumulation of long chain triglycerides (LCT) in the liver. Medium chain triglycerides (MCT) accumulate only minimally in the liver and do not impair the RES. However, results from animal studies using technetium sulfur colloid (TSC) to assess RES function have been inconclusive.

Short-term TPN containing n-3 fatty acids ameliorate lactic acidosis induced by endotoxin in guinea pigs.

We evaluated the effect of total parenteral nutrition (TPN) enriched with n-3 fatty acids on the physiologic response to endotoxin in guinea pigs. Animals were randomly assigned to receive TPN differing only in lipid source for 3.5 d.

The response to endotoxin in guinea pigs after intravenous black currant seed oil.

The influence on the metabolic response to endotoxin of three days of total parenteral nutrition with lipids high in gammalinolenic acid (18:3 omega 6, GLA) compared to soy oil (SO) was examined in acute operatively stressed guinea pigs. GLA is the precursor of dihomogammalinolenic acid (DHLA), the substrate for synthesis of "1" series prostaglandins such as PGE1, which have previously been shown to be protective in endotoxin lung injury and traumatic shock. Guinea pigs fed an intravenous diet containing black currant seed oil (BCO) emulsion (20% GLA) or soy oil emulsion (0% GLA) for 2.

The effects of chronic fish oil feeding in rats on protein catabolism induced by recombinant mediators.

The influence of dietary lipid manipulation with menhaden or safflower oil on changes in protein metabolism in rats receiving recombinant interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha/cachectin (TNF), or both combined (COINF) was examined. Whole-body protein kinetics, energy expenditure, nitrogen excretion, and liver and muscle protein synthesis were studied using tracer quantities of L-[1-14C]-leucine. Rats fed menhaden oil, high in omega-3 fatty acids, had significantly lower rates of leucine oxidation compared to safflower-fed rats after monokine infusion (P less than .

Glycolytic support of adenine nucleotides in rat liver flush-preserved with UW or Collins' II. Importance of donor nutritional status.

Correlation of hepatocellular adenine nucleotides in donor liver with clinical posttransplant outcome has recently been reported. Our earlier work with rats has shown that pretreatment of donors with glucose effectively retards hepatocellular ATP losses in livers preserved in Collins' II solution through potentiation of their glycolytic capacity. The primary substrate--i.

Serum fatty acid profiles after intravenous medium chain triglyceride administration.

The serum fatty acid profiles of patients receiving either intravenous medium or long chain triglycerides were studied. Seventeen hospitalized patients, dependent on total parenteral nutrition, were randomly enrolled into a prospective study. The total parenteral nutrition (TPN) delivered amino acids and glucose and either a 75% medium chain triglyceride and 25% long chain triglyceride (MCT group) physical mixture or all long chain triglyceride (LCT group), as the respective fat sources.

Decreased loss of liver adenosine triphosphate during hypothermic preservation in rats pretreated with glucose: implications for organ donor management.

Recent studies of human donor livers indicate an association between ex vivo hepatocellular adenosine triphosphate and posttransplant graft function. To test the hypothesis that prior glucose loading of donor liver would optimize its adenosine triphosphate production and adenylate energy charge during ex vivo organ preservation, adult male rats were randomized to receive either intravenous dextrose or saline for 44 h. After this infusion, a liver lobe was exposed and freeze-clamped (time 0).