The functionality of African-specific variants in the TGFB1 regulatory region and their potential role in HIVAN.

Background: Transcription of transforming growth factor beta-1 (TGF-β1) is regulated by a polymorphic promoter region containing African-specific single nucleotide polymorphisms (SNPs). Some of these SNPs have higher frequencies among Southern Africans compared to other African populations and their functionality has only been partially studied. Due to the high prevalence of HIV-associated nephropathy (HIVAN) in Africans we hypothesized that functional African TGFB1-promoter SNPs may contribute to HIVAN pathogenesis.

The African-387 C>T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis.

Although extraocular muscles are commonly affected by myasthenia gravis (MG) at presentation, a treatment-resistant ophthalmoplegic complication of MG (OP-MG) occurs in younger patients with African-genetic ancestry. In MG, pathogenic antibodies activate complement-mediated muscle damage and this may be potentiated in some OP-MG cases because of relative deficiency of decay-accelerating factor/CD55. Extending this argument, we hypothesized that OP-MG individuals may harbor African-specific polymorphisms in key genes influencing extraocular muscle remodeling.

The prevalence of pain at home and its consequences in children following two types of short stay surgery: a multicenter observational cohort study.

Background: The potential for pain at home in children following day case surgery has long been recognized. Pain has also been associated with behavioral disturbances and sleep disruption in children following surgery and may also impact negatively on recovery, parental and patient satisfaction, family life, healthcare use, and have an economic cost.

Aim: To investigate the prevalence of pain at home, and its consequences, in children following two types of short stay surgery across eight pediatric centers in the UK in an observational cohort study.

Non-negative matrix factorization for learning alignment-specific models of protein evolution.

Models of protein evolution currently come in two flavors: generalist and specialist. Generalist models (e.g.

Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5.

The optimization of a series of thiazolopyridine S1P1 agonists with limited activity at the S1P3 receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P1/S1P5 agonist with limited activity at S1P3 and no activity at S1P2/S1P4. Dosed orally at 0.

Discovery of a Potent, S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1).

Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge.

Benzofuran Derivatives as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead Molecule for MS.

We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species.

An antibody to IP-10 is a potent antagonist of cell migration in vitro and in vivo and does not affect disease in several animal models of inflammation.

IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC(50) of approximately 4 nM.

Prevalence of Chlamydophila psittaci in fecal droppings from feral pigeons in Amsterdam, The Netherlands.

In many cities, the feral rock dove is an abundant bird species that can harbor Chlamydophila psittaci. We determined the prevalence and genotype of C. psittaci in fresh fecal samples from feral pigeons in Amsterdam, The Netherlands.

Oxidative stress-induced perturbations of calcium homeostasis and cell death in cultured myocytes: role of extracellular calcium.

The role of extracellular calcium in the process of oxidative stress-induced calcium overload and cell death was investigated in cultured neonatal rat myocytes. Oxidative stress was induced by addition of cumene hydroperoxide (CHPO), a toxic organic hydroperoxide, in combination with varying extracellular calcium concentrations (1. normal calcium buffer: 2.

Properties of parametric photic entrainment of circadian rhythms in the rat.

Wistar rats were exposed to 24-h cycles of sinusoidal varying light intensity at various amplitudes (A) and mean intensity (I) levels. The cycle minimum was at least 0.1 lux.

Competition between fluoride-resistant and fluoride-sensitive Streptococcus mutans in rat dental plaque.

The experiments were designed to study the effects of fluoride on the competition between a fluoride-sensitive strain of Streptococcus mutans (C180-2) and a fluoride-resistant mutant (S. mutans C180-2FR) in rat dental plaque. Competition was induced either by superinfecting rats or by co-caging rats infected with either strain with non-infected rats.

Effects of T cycles of light/darkness and periodic forced activity on methamphetamine-induced rhythms in intact and SCN-lesioned rats: explanation by an hourglass-clock model.

In this study intact and suprachiasmatic nuclei (SCN)-lesioned female rats were treated with chronic methamphetamine (MA) via the drinking water. Body temperature, feeding, drinking and wheel-running activity were continuously and automatically recorded. The rats were subjected to light-dark (LD) cycles with period T = 23 hr for 4 months and subsequently T = 25 hr for 3 months.

Effects of time of feeding on recovery of food-entrained rhythms during subsequent fasting in SCN-lesioned rats.

Rats subjected to Eat-Fast (EF) cycles show food-anticipatory rhythms independent from the suprachiasmatic nuclei (SCN). These rhythms do not persist during subsequent ad lib feeding (EE). There are indications for a recovery of rhythmicity during fasting (FF) using a 'memory' paradigm in which FF sessions are alternated with EE.

[Tapeworms in the Netherlands].

Scientists have been discussing the nature of helminths, and particularly tapeworms, for ages. A synopsis of the ancient literature and literature of the Middle-Ages concerned with this subject is presented. Even today a number of remarkable stories about tapeworms is being told.

Myeloperoxidase is more efficient than eosinophil peroxidase in the in vitro killing of newborn larvae of Trichinella spiralis.

Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) catalyse the formation of hypochlorite (OCl-) from chloride ions (OCl-) and hydrogen peroxide (H2O2). OCl- proved to be highly toxic for Trichinella spiralis newborn larvae (NBL) in in vitro assays. Using purified human MPO and EPO it was found that even at neutral pH both enzymes under appropriate conditions are able to kill NBL.

[Immunologic defense and inflammation in parasitic infections. The role of eosinophilic granulocytes].

The origin, kinetics and role of eosinophilic granulocytes in immune defense and inflammatory response in parasitism are reviewed. Particular attention was paid to the toxic action of eosinophilic granulocytes on parasites and the biochemical reactions which are of importance in these cases. Reference was also made to the regulatory role of eosinophilic granulocytes in inflammatory reactions, particularly in regard to mast cells.

The athymic nude rat. IV. Immunocytochemical study to detect T-cells, and immunological and histopathological reactions against Trichinella spiralis.

The anti-parasite response was investigated after oral infection of athymic nude (rnu/rnu) rats and heterozygous (+/rnu) littermates with 1000 muscle larvae of Trichinella spiralis. No IgM, IgG and IgE antibodies were detected in serum of rnu/rnu rats. Expulsion of adult worms from the small intestine was prolonged (worms were nearly all expelled at days 14 and 91 in +/rnu and rnu/rnu rats respectively).

Rat mononuclear cells and neutrophils are more effective than eosinophils in antibody-mediated stage-specific killing of Trichinella spiralis in vitro.

The capacity of non-infected rat total, eosinophil-enriched and eosinophil-depleted fractions of peritoneal exudate and bone marrow cells to adhere to and kill Trichinella spiralis newborn larvae with immune rat serum has been studied in vitro. The eosinophil-depleted peritoneal exudate cell fraction contained mainly mononuclear cells, whereas the corresponding bone marrow cell fraction consisted of a considerable number of neutrophils. All cell types either originating from the peritoneal cavity or the bone marrow, showed adherence and killing properties to the Trichinella newborn larvae.

Corynebacterium parvum: antibodies measured with the enzyme-linked immunosorbent assay (ELISA) in normal human sera and sera from cancer patients undergoing treatment.

An enzyme-linked immunosorbent assay (ELISA) was developed to monitor the antibody response to Corynebacterium parvum during cancer immunotherapy. Firstly, in sera from 176 clinically healthy individuals not treated with C. parvum, elevated ELISA extinction values were observed from the age of 11 years onwards for both sexes; these high values were probably due to preexisting antibodies to C.

The killing of newborn larvae of Trichinella spiralis by eosinophil peroxidase in vitro.

Helminth infections in mammals are characterized by a high level of eosinophils in parasitized tissues and blood, and it has recently been suggested that these cells have a direct parasiticidal effect. Newborn larvae of Trichinella spiralis can be killed within 20 min by incubation at room temperature in a cell-free system, including purified human eosinophil peroxidase (EPO), H2O2 and chloride at pH 5.5.