Functional characterization of a single nucleotide polymorphism associated with Alzheimer's disease in a hiPSC-based neuron model.

Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer's disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear.

Uncovering specificity of endogenous TAU aggregation in a human iPSC-neuron TAU seeding model.

Tau pathobiology has emerged as a key component underlying Alzheimer's disease (AD) progression; however, human neuronal models have struggled to recapitulate tau phenomena observed . Here, we aimed to define the minimal requirements to achieve endogenous tau aggregation in functional neurons utilizing human induced pluripotent stem cell (hiPSC) technology. Optimized hiPSC-derived cortical neurons seeded with AD brain-derived competent tau species or recombinant tau fibrils displayed increases in insoluble, endogenous tau aggregates.

[Determination and hierarchy of clinical signs for early detection of cerebrotendinous xanthomatosis].

Background: Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene resulting in a decreased synthesis of bile acids. An early diagnosis and treatment would reduce the longterm complications observed in this disease.

Aim: To identify and hierarchize initial clinical signs of CTX to establish an early diagnostic suspicion index.

Compatibility of RUNX1/ETO fusion protein modules driving CD34+ human progenitor cell expansion.

Chromosomal translocations represent frequent events in leukemia. In t(8;21)+ acute myeloid leukemia, RUNX1 is fused to nearly the entire ETO protein, which contains four conserved nervy homology regions, NHR1-4. Furthermore RUNX1/ETO interacts with ETO-homologous proteins via NHR2, thereby multiplying NHR domain contacts.

ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.

The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A.

Stably integrated and expressed retroviral sequences can influence nuclear location and chromatin condensation of the integration locus.

The large-scale chromatin organization of retrovirus and retroviral gene vector integration loci has attracted little attention so far. We compared the nuclear organization of transcribed integration loci with the corresponding loci on the homologous chromosomes. Loci containing gamma-retroviral gene transfer vectors in mouse hematopoietic precursor cells showed small but significant repositioning of the integration loci towards the nuclear interior.

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease.

Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1).

Characterization of a protein phosphatase 2A holoenzyme that dephosphorylates the clathrin adaptors AP-1 and AP-2.

The AP-2 complex is a key factor in the formation of endocytic clathrin-coated vesicles (CCVs). AP-2 sorts and packages cargo membrane proteins into CCVs, binds the coat protein clathrin, and recruits numerous other factors to the site of vesicle formation. Structural information on the AP-2 complex and biochemical work have allowed understanding its function on the molecular level, and recent studies showed that cycles of phosphorylation are key steps in the regulation of AP-2 function.

Evaluation of the pharmacokinetics of dalteparin in patients with renal insufficiency.

The pharmacokinetics of the low-molecular weight heparin (LMWH), dalteparin, was evaluated after a single intravenous bolus injection of 50 IU anti-Xa/kg in 8 healthy volunteers, 8 patients with moderate/severe renal failure (Cl(crea) 13.1-56.5 ml/min) and 8 hemodialysis patients.

Endotherapy of Zenker's diverticulum using the needle-knife technique: long-term follow-up.

Background And Study Aims: Endotherapy of Zenker's diverticulum by mucomyotomy of the bridge between the diverticulum and the esophageal lumen has been introduced as a promising alternative to surgical techniques. However the data on long-term clinical outcome are limited. After poor results in four patients treated by argon plasma coagulation, we studied the efficacy and the long-term outcome of dissection using a needle-knife in a consecutive series of patients.

Pharmacokinetics of alpha-lipoic acid in subjects with severe kidney damage and end-stage renal disease.

In an open-label, parallel-group study involving 16 patients (8 with severely reduced renal function, 8 with end-stage renal disease needing hemodialysis), the effect of renal function on the pharmacokinetics, metabolism, and safety and of alpha-lipoic acid (thioctic acid) was evaluated by comparing the pharmacokinetic parameters with those of a reference group of 8 healthy subjects. Alpha-lipoic acid 600 mg was administered orally once daily for 4 days, and the pharmacokinetic parameters were measured on days 1 and 4. The mean percentage of the administered dose excreted in urine as parent compound was 0.

A randomized trial of unsedated transnasal small-caliber esophagogastroduodenoscopy (EGD) versus peroral small-caliber EGD versus conventional EGD.

Background And Study Aims: Unsedated esophagogastroduodenoscopy (EGD) has advantages over sedated EGD - e. g., prevention of side effects related to sedation, less patient monitoring, and less expense.

Long-term follow-up of percutaneous transhepatic therapy (PTT) in patients with definite benign anastomotic strictures after hepaticojejunostomy.

Background And Study Aims: Percutaneous transhepatic therapy (PTT) is a promising minimally invasive procedure for benign stenosis of the anastomosis after hepaticojejunostomy. In this prospective study, the effectiveness and safety of this technique were investigated.

Patients And Methods: Between October 1995 and May 2000 34 consecutive patients were referred for treatment of symptomatic cholestasis due to anastomotic strictures after hepaticojejunostomy.

[35-year-old patient with metastasized carcinoid of Vater's ampulla--case report and review of the literature].

We report the case of a 35-year-old female patient with a metastasized carcinoid of the papilla of Vater which is a rare lesion. 96 cases have been published in world literature previously. The carcinoid of the papilla of Vater appears typically as a hormone inactive tumor.

Induction by staurosporine of nitric oxide synthase expression in vascular smooth muscle cells: role of NF-kappa B, CREB and C/EBP beta.

1. The effect of different protein kinase inhibitors on the expression of the inducible isoform of nitric oxide (NO) synthase (iNOS) was investigated in cultured vascular smooth muscle cells (VSMC) isolated from the rat aorta. 2.

Inhibition by antioxidants of nitric oxide synthase expression in murine macrophages: role of nuclear factor kappa B and interferon regulatory factor 1.

1. In view of the potential deleterious effects of high amounts of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS) in inflammation, the prevention of the expression of this enzyme represents an important therapeutic goal. In cytokine-stimulated cells, activation of nuclear factor kappa B (NF-kappa B) is crucial for the increase in iNOS gene expression.

Antioxidants differentially affect nuclear factor kappa B-mediated nitric oxide synthase expression in vascular smooth muscle cells.

Increased 'oxidative stress' resulting in the activation of nuclear factor kappa B (NF-kappa B) is thought to play a crucial role in the cytokine-mediated expression of the inducible isoform of nitric oxide synthase (iNOS) in different cell types. Therefore, the effects of four different antioxidants, carbocromen, chrysin, 3,4-dichloroisocoumarin (DCI) and N-acetylserotonin (NAS), on iNOS expression were investigated in vascular smooth muscle cells (VSMC). All antioxidants strongly reduced the phorbol ester-stimulating superoxide anion formation in native VSMC.

Effects of aging on basal levels of serum gonadotropins, ovarian compensatory hypertrophy, and hypersecretion of gonadotropins after ovariectomy in female rats.

Young adult (four months old) and old (14 months old) female rats were used in a series of experiments to determine the effects of aging on serum gonadotropin levels and on ovarian compensatory hypertrophy. Basal levels of gonadotropins were similar for rats of both ages. On the day after hemiovariectomy, serum FSH levels were elevated in both old and young rats.