PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism.

We analyzed the PINK1 gene in 58 patients with early-onset Parkinsonism and detected the homozygous mutation W437X in 1 patient. The clinical phenotype was characterized by early onset (22 years of age), good re- sponse to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinson’s disease and 3 further relatives were reported affected, according to an autosomal dominant transmission

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

<div><p>Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in <i>Cftr^F508del</i> homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the <i>F508del-CFTR</i> mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from <i>F508del</i> homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both <i>in vivo</i>, in mice, and <i>in vitro</i>, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 <i>F508del-CFTR</i> homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells <i>in vivo</i>, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of <i>TNF/TNF-alpha (tumor necrosis factor)</i> and <i>CXCL8</i> (<i>chemokine [C-X-C motif] ligand 8</i>) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the <i>F508del-CFTR</i> mutation.</p></div

A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells - 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells

The new glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol- 4-ylthio)hexanol (NBDHEX) is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines, i.e. CEM-VBL10, CEM-VBL100, and U-2 OS/DX580. The mechanism of cell death triggered by NBDHEX has been deeply investigated in leukemia cell lines. Kinetic data indicate a similar NBDHEX membrane permeability between multidrug resistance cells and their sensitive counterpart revealing that NBDHEX is not a substrate of the P-glycoprotein export pump. Unexpectedly, this molecule promotes a caspase-dependent apoptosis that is unusual in the P-glycoprotein-overexpressing cells. The primary event of the apoptotic pathway is the dissociation of glutathione S-transferase P1-1 from the complex with c-Jun N-terminal kinase. Interestingly, leukemia MDR1-expressing cells show lower LC50 values and a higher degree of apoptosis and caspase-3 activity than their drug-sensitive counterparts. The increased susceptibility of the multidrug resistance cells toward the NBDHEX action may be related to a lower content of glutathione S-transferase P1-1. Given the low toxicity of NBDHEX in vivo, this compound may represent an attractive basis for the selective treatment of MDR1 P-glycoproteinpositive tumors

The Framingham cardiovascular risk score in multiple sclerosis

Background and purpose: Cardiovascular risk factors can increase the risk of multiple sclerosis (MS) and modify its course. However, such factors possibly interact, determining a global cardiovascular risk. Our aim was to compare the global cardiovascular risk of subjects with and without MS with the simplified 10-year Framingham General Cardiovascular Disease Risk Score (FR) and to evaluate its importance on MS-related outcomes. Methods: Age, gender, smoking status, body mass index, systolic blood pressure, type II diabetes and use of antihypertensive medications were recorded in subjects with and without MS to estimate the FR, an individualized percentage risk score estimating the 10-year likelihood of cardiovascular events. Results: In total, 265 MS subjects were identified with 530 matched controls. A t test showed similar FR in cases and controls (P = 0.212). Secondary progressive MS presented significantly higher FR compared to relapsing-remitting MS (P < 0.001). Linear regression analysis showed a direct relationship between FR and Expanded Disability Status Scale (P < 0.001) and MS Severity Scale (P < 0.001). Conclusion: The FR, evaluating the global cardiovascular health by the interaction amongst different risk factors, relates to MS disability, severity and course

Contribution of the HMPID detector to the high-pT physics at LHC

The LHC will deliver unexplored energy regimes for proton-proton and heavy-ion collisions. As shown by the RHIC experiments, particle identification over a large momentum range is essential to disentangle physics processes, especially in the intermediate p$_T$ (1 $<p_{T}<5$ GeV/c) region. The novel design of the High-Momentum Particle Identification Detector (HMPID), based on large surface CsI photocathodes, is able to identify $\pi^{\pm}$, $K^{\pm}$, $p$ and $\bar{p}$ in the momentum region where bulk medium properties and hard scatterings interplay. Furthermore, measurement of resonance particles such as the $\phi \to K^+K^-$ could provide information on the system evolution. The HMPID layout and segmentation are optimized to study particle correlations at high momenta describing the early phase and the dynamical evolution of the collision. At LHC, the increased hard cross section will significantly be enhanced compared to RHIC. Jet reconstruction via Deterministic Annealing can address jet quenching and detailed measurements of jet properties. In this paper, we present these selected topics from the possible HMPID contributions to the physics goals of LHC.Comment: 6 pages, 7 figures, Contribution to QCD @ Work 2007: International Workshop on Quantum Chromodynamics Theory and Experiment, Martina Franca, Italy, 16-20 June 200

Nomenclature for renal replacement therapy and blood purification techniques in critically ill patients: practical applications

This article reports the conclusions of the second part of a consensus expert conference on the nomenclature of renal replacement therapy (RRT) techniques currently utilized to manage acute kidney injury and other organ dysfunction syndromes in critically ill patients. A multidisciplinary approach was taken to achieve harmonization of definitions, components, techniques, and operations of the extracorporeal therapies. The article describes the RRT techniques in detail with the relevant technology, procedures, and phases of treatment and key aspects of volume management/fluid balance in critically ill patients. In addition, the article describes recent developments in other extracorporeal therapies, including therapeutic plasma exchange, multiple organ support therapy, liver support, lung support, and blood purification in sepsis. This is a consensus report on nomenclature harmonization in extracorporeal blood purification therapies, such as hemofiltration, plasma exchange, multiple organ support therapies, and blood purification in sepsis