Fibronectin attenuates process outgrowth in oligodendrocytes by mislocalizing MMP-9 activity

The extension of multiple oligodendroglial branched processes towards axons is an important event during the early stages of myelination that likely requires remodeling of the extracellular matrix (ECM) microenvironment via matrix metalloproteinases (MMPs). Here we investigated whether fibronectin-mediated inhibition of myelin sheet formation in oligodendrocytes correlated with an altered MMP activity. Our data reveal that fibronectin enhanced, in a PKC-dependent manner, the net activity of MMP-9, but not its expression, in conditioned medium of oligodendrocytes. Residual cellular MMP-9 activity on fibronectin was confined to the cell body, whereas MMP-9 activity on laminin-2 was localized along extending processes of oligodendrocytes. The mislocalization of MMP-9 activity on fibronectin correlated with a perturbed outgrowth of oligodendroglial processes. In conclusion, our findings suggest that ECM molecules influence both the net activity of secreted MMP and the spatial distribution of cell-associated MMP activity, and thereby morphological oligodendrocyte differentiation.     

Vascular pathology in patients with idiopathic Parkinson's disease

To study the impact of brain vessel pathology on the clinical status of Parkinson's disease (PD), in 57 consecutive patients the clinical and neuropsychological data were compared with clinical MRI signs of vascular impairment and with the ultrasound brain vessel investigations. There was a significant correlation between clinical and cognitive status and intimomedial thickness, which is an indicator of large vessel impairment. Cognitive status was significantly related to the pulsatility index (an indicator of small vessel impairment). This study provides evidence that subclinical vascular pathology could influence the clinical status by contributing to motor and cognitive dysfunction in PD.     

Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma

RATIONALE: The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma. Objective: We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies. METHODS: The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9. RESULTS: AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883. CONCLUSIONS: Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.     

Novel mutations in the NF1 gene in Czech patients with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is one of the most common inherited human disorders, with an estimated incidence of 1 per 3500 births. In most cases, the disease is caused either by mutation in the NF1 gene, or by a particular or complete deletion of the NF1 gene. The NF1 gene exhibits one of the highest mutation rates of any human disorder. In this experimental study of the NF1 gene, we screened the mutational spectrum of 22 unrelated patients from the Czech Republic using the denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) methods. We found NF1 mutations in 17 patients: 15 causal mutations were detected with the use of the DHPLC method (15/20, 75%). With the MPLA method, we also confirmed and specified two large deletions that were previously genotyped by microsatellite markers. Twelve of the above-mentioned mutations were newly found: c.1_2delATinsCC, c.1185+1G>C, c.1757_1760delCTAG, c.1642-7A>G, c.2329 T>G, c.2816delA, c.3738_3741delGTTT, c.4733 C>T, c.5220delT, c.6473_6474insGAAG, ex14_49del, ex28_49del. We present this study as a first effectual step in the routine diagnosis of the NF1 in patients from the Czech Republic.     

Immune response of mice with alveolar echinococcosis to therapy with transfer factor, alone and in combination with albendazole

The effect of dialysable leucocyte extract (transfer factor TF) on immune response of mice infected with Echinococcus multilocularis and treated with albendazole (ABZ) was observed. TF administration increased the parasite-suppressed proliferative response of T and B lymphocytes of infected mice from weeks 8 to 12 or 14 post infection (p.i.), respectively, with the most stimulative effect after TF+ABZ therapy. The CD4 T cell presence in the spleen of infected mice with TF or TF+ABZ therapy was increased from weeks 6 to 12 or 14 p.i., respectively. The production of IFN-γ (Th1 cytokine) after TF or TF+ABZ therapy was significantly higher from weeks 6 to 12 p.i., and during this time, the significantly inhibited IL-5 synthesis (Th2 cytokine) was detected, particularly after TF+ABZ therapy. The superoxide anion (O₂⁻) production in peritoneal macrophages of infected mice treated with TF or TF+ABZ was stimulated from weeks 8 to 18 p.i. The immunomodulative effect of TF reduced the growth of larval cysts till week 14 p.i. with a comparable intensity to the anthelmintic drug ABZ. Combined therapy TF+ABZ resulted in the greatest parasite restriction and reduced the cyst development till the end of the experiment.     

507 A Novel Mechanism of Fas Signaling Suppression by PMLRARα in Acute Promyelocytic Leukemia

Presence of potential inhibitors of Fas could block Fas signaling and explain cancer cells resistance to apoptosis. In this study, we found that PMLRARα binds to Fas and blocks Fas-mediated apoptosis through recruiting c-FLIP in APL. Targeting tissue-specific inhibitors of Fas such as PMLRARα would improve cancer therapy.

Full Abstract

Fas plays a critical role in cell proliferation and in the selective killing of autoreactive lymphocytes and abnormal cells, including infected cells. To explain the common expression of Fas and the resistance to the Fas-induced apoptosis observed in some normal and cancer cells, we have screened cells for potential regulators of the Fas death receptor. By using mass spectrometry analysis of Fas-associated proteins, we identified peptides derived from promyelocytic leukemia (PML).PML enhances

     

On the involvement of H2S in nitroso signaling and other mechanisms of H2S action

Both endogenously produced and exogenously administered H2S exert numerous biological effects. However, the molecular mechanisms underlying these effects are not fully understood. This review surveys the biological effects of H2S and summarizes the molecular mechanisms of H2S action. It focuses on the role of H2S/HS--induced NO release from nitroso compounds, modulation of ion channels and the antioxidant and radical properties of H2S in the molecular mechanism of its effects. The potential involvement of H2S in nitroso signaling underlying its diverse biological effects is also discussed.     

Effect of Fire on Pools of Mercury in Forest Soil,Central Europe

In year 2006, 17.9 ha of forest was burned during a forest fire at the Bohemian Switzerland National Park found in northern part of Czech Republic (CR), central Europe. Complete combustion of organic soil (4,039 t) on the burned area caused volatilization of 1.34 ± 0.07 kg of Hg. Thus Hg emissions due to fire amounted to 75.1 g ha⁻¹. The average burned forested areas in CR for the period 2000–2006 were reported at 356 ha with estimated Hg emissions at 26.7 kg year⁻¹, while the average anthropogenic emissions in the same period amounted to 3 t year⁻¹. Thus estimated mean emissions of Hg from burned forest soil in the period 2000–2006 reached 1% of the annual anthropogenic Hg emissions.