Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report

Background: Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although Parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity), namely on what concerns genetic variation in Parkinson's disease (PD) associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNAGln T4336C). Case presentation: Patient 1 is a 40 year-old female (onset at 30 years of age), initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother). Patient 2 is a 38 year-old male (onset at 33 years of age), presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father). Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients. Conclusions: The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD

Role of IL-1 Beta in the Development of Human TH17 Cells: Lesson from NLPR3 Mutated Patients

T helper 17 cells (T(H)-17) represent a lineage of effector T cells critical in host defence and autoimmunity. In both mouse and human IL-1β has been indicated as a key cytokine for the commitment to T(H)-17 cells. Cryopyrin-associated periodic syndromes (CAPS) are a group of inflammatory diseases associated with mutations of the NLRP3 gene encoding the inflammasome component cryopyrin. In this work we asked whether the deregulated secretion of IL-1β secondary to mutations characterizing these patients could affect the IL-23/IL-17 axis.A total of 11 CAPS, 26 systemic onset juvenile idiopathic arthritis (SoJIA) patients and 20 healthy controls were analyzed. Serum levels of IL-17 and IL-6 serum were assessed by ELISA assay. Frequency of T(H)17 cells was quantified upon staphylococcus enterotoxin B (SEB) stimulation. Secretion of IL-1β, IL-23 and IL-6 by monocyte derived dendritic cells (MoDCs), were quantified by ELISA assay. A total of 8 CAPS and 11 SoJIA patients were also analysed before and after treatment with IL-1β blockade. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of T(H)17 compared to control subjects. On the contrary, SoJIA patients displayed a frequency of T(H)17 similar to normal donors, but were found to have significantly increased serum level of IL-6 when compared to CAPS patients or healthy donors. Remarkably, decreased IL-17 serum levels and T(H)17 frequency were observed in CAPS patients following in vivo IL-1β blockade. On the same line, MoDCs from CAPS patients exhibited enhanced secretion of IL-1β and IL-23 upon TLRs stimulation, with a reduction after anti-IL-1 treatment.These findings further support the central role of IL-1β in the differentiation of T(H)17 in human inflammatory conditions

A Survey of Avian Influenza in Tree Sparrows in China in 2011

Tree sparrows (Passer montanus) are widely distributed in all seasons in many countries. In this study, a survey and relevant experiments on avian influenza (AI) in tree sparrows were conducted. The results suggested that the receptor for avian influenza viruses (AIVs), SAα2,3Gal, is abundant in the respiratory tract of tree sparrows, and most of the tree sparrows infected experimentally with two H5 subtype highly pathogenic avian influenza (HPAI) viruses died within five days after inoculation. Furthermore, no AIVs were isolated from the rectum eluate of 1300 tree sparrows, but 94 serological positives of AI were found in 800 tree sparrows. The serological positives were more prevalent for H5 subtype HPAI (94/800) than for H7 subtype AI (0/800), more prevalent for clade 2.3.2.1 H5 subtype HPAI (89/800) than for clade 2.3.4 (1/800) and clade 7.2 (4/800) H5 subtype HPAI, more prevalent for clade 2.3.2.1 H5 subtype HPAI in a city in southern China (82/800) than in a city in northern China (8/800). The serological data are all consistent with the distribution of the subtypes or clades of AI in poultry in China. Previously, sparrows or other passerine birds were often found to be pathogenically negative for AIVs, except when an AIV was circulating in the local poultry, or the tested passerine birds were from a region near waterfowl-rich bodies of water. Taken together, the data suggest that tree sparrows are susceptible to infection of AIVs, and surveys targeting sparrows can provide good serological data about the circulation of AIVs in relevant regions

Amyotrophic Lateral Sclerosis Multiprotein Biomarkers in Peripheral Blood Mononuclear Cells

Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms

BAG3: a multifaceted protein that regulates major cell pathways

Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110–124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression

Characteristics of the Mesophotic Megabenthic Assemblages of the Vercelli Seamount (North Tyrrhenian Sea)

The biodiversity of the megabenthic assemblages of the mesophotic zone of a Tyrrhenian seamount (Vercelli Seamount) is described using Remotely Operated Vehicle (ROV) video imaging from 100 m depth to the top of the mount around 61 m depth. This pinnacle hosts a rich coralligenous community characterized by three different assemblages: (i) the top shows a dense covering of the kelp Laminaria rodriguezii; (ii) the southern side biocoenosis is mainly dominated by the octocorals Paramuricea clavata and Eunicella cavolinii; while (iii) the northern side of the seamount assemblage is colonized by active filter-feeding organisms such as sponges (sometimes covering 100% of the surface) with numerous colonies of the ascidian Diazona violacea, and the polychaete Sabella pavonina. This study highlights, also for a Mediterranean seamount, the potential role of an isolated rocky peak penetrating the euphotic zone, to work as an aggregating structure, hosting abundant benthic communities dominated by suspension feeders, whose distribution may vary in accordance to the geomorphology of the area and the different local hydrodynamic conditions

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Search for neutral MSSM Higgs bosons decaying to a pair of tau leptons in pp collisions

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Measurement of top quark–antiquark pair production in association with a W or Z boson in pp collisions at √s=8 TeV

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