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In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients. [ABSTRACT FROM AUTHOR]

Background and objectives: Amyotrophic lateral sclerosis associated with mutations in SOD1 (SOD1-ALS) might be susceptible to specific treatment. The aim of the study is to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining SOD1-ALS phenotype may assist clinicians in identifying patients who should be prioritized for genetic testing. Methods: We performed an extensive literature research including original studies which reported the clinical features of SOD1-ALS and at least one of the following patient groups: C9ORF72 hexanucleotide repeat expansion (C9-ALS), TARDBP (TARDBP-ALS), FUS (FUS-ALS) or patients without a positive test for a major-ALS gene (N-ALS). A random effects meta-analytic model was applied to clinical data extracted encompassing sex, site and age of onset. To reconstruct individual patient survival data, the published Kaplan–Meier curves were digitized. Data were measured as odds ratio (OR) or standardized mean difference (SMD) as appropriate. Median survival was compared between groups. Results: Twenty studies met the inclusion criteria. We identified 721 SOD1-ALS, 470 C9-ALS, 183 TARDBP-ALS, 113 FUS-ALS and 2824 N-ALS. SOD1-ALS showed a higher rate of spinal onset compared with N-ALS and C9-ALS (OR = 4.85, 95% CI = 3.04–7.76; OR = 10.47, 95% CI = 4.32–27.87) and an earlier onset compared with N-ALS (SMD = − 0.45, 95% CI = − 0.72 to − 0.18). SOD1-ALS had a similar survival compared with N-ALS (p = 0.14), a longer survival compared with C9-ALS (p < 0.01) and FUS-ALS (p = 0.019) and a shorter survival compared with TARDBP-ALS (p < 0.01). Discussion: This study indicates the presence of a specific SOD1-ALS phenotype. Insights in SOD1-ALS clinical features are important in genetic counseling, disease prognosis and support patients' stratification in clinical trials. [ABSTRACT FROM AUTHOR]

Atrophy at the level of the dentate in I GRN i patients emerged also in comparison with I C9orf72 i patients (left dentate I p i = 0.019, right dentate I p i = 0.030). Indeed, in our cohort, I C9orf72 i patients showed quite symmetric bilateral frontotemporal involvement, while I GRN i patients presented a more lateralized left-sided pattern of atrophy. At the level of subcortical nuclei, the index patient showed a pattern of subcortical atrophy of the bilateral caudate, right hippocampus, and bilateral thalamus compared to controls, which was similar to that expressed by I C9orf72 i patients (left caudate and bilateral thalamus) and I GRN i patients (bilateral dentate and bilateral thalamus). I GRN i patients, instead, develop more frequently PPA, accompanied by severe brain atrophy, which is remarkably asymmetric and early involves parietal lobes [[5]] A few cases of patients with double FTLD-related mutations have been described, highlighting the necessity for full genetic screening in each individual case [[6]-[8]]. [Extracted from the article]

To investigate the prognostic role and the major determinants of serum phosphorylated neurofilament heavy -chain (pNfH) concentration across a large cohort of motor neuron disease (MND) phenotypes. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum pNfH concentration in 219 MND patients consecutively enrolled in our tertiary MND clinic. A multifactorial analysis was carried out to investigate the major clinical determinants of serum pNfH. Kaplan–Meier survival curves and Cox regression analysis were performed to explore the prognostic value of serum pNfH. Serum pNfH levels were not homogenous among MND phenotypes; higher concentrations in pyramidal, bulbar, and classic phenotypes were observed. C9orf72-MND exhibited higher pNfH concentrations compared to non-C9orf72 MND. Multiple linear regression analysis revealed mean MEP/cMAP and disease progression rate as the two major predictors of serum pNfH levels (R2 = 0.188; p ≤ 0.001). Kaplan–Meier curves showed a significant difference of survival among MND subgroups when divided into quartiles based on pNfH concentrations, log-rank X2 = 53.0, p ≤ 0.0001. Our study evidenced that higher serum pNfH concentration is a negative independent prognostic factor for survival. In Cox multivariate model, pNfH concentration showed the highest hazard ratio compared to the other factors influencing survival included in the analysis. pNfH differs among the MND phenotypes and is an independent prognostic factor for survival. This study provides supporting evidence of the role of pNfH as useful prognostic biomarker for MND patients. Neurofilament measurements should be considered in the future prognostic models and in clinical trials for biomarker-based stratification, and to evaluate treatment response. [ABSTRACT FROM AUTHOR]

Functional opposition between N-methyl- d-aspartate and 5-HT2A receptors may be a neural mechanism supporting cognitive functions. These systems converge on an intracellular signaling pathway that involves protein kinase A-dependent phosphorylation of different proteins including cyclic adenosine monophosphate response element binding (CREB). Thus, we tested whether selective 5-HT2A receptor antagonist, M100907, might abolish phencyclidine (PCP)-induced attentional performance deficit by preventing its effects on transduction mechanisms leading to CREB phosphorylation. Using the five-choice serial reaction time task, the ability of subcutaneous injections of 2.5 and 10 µg/kg of M100907 to abolish the effects of an intraperitoneal injection of 1.5 mg/kg PCP on attentional performance as measured by accuracy (percentage of correct responses) and anticipatory and perseverative responding was assessed in DBA/2 mice. The effects of PCP, M100907, and their combination on S133-CREB and T34-DARPP32 phosphorylation in the dorsal striatum and prefrontal cortex (PFC) of behaviorally naïve mice were examined using Western blotting technique. PCP reduced accuracy and increased anticipatory and perseverative responses as well as it increased S133-CREB phosphorylation in the dorsal striatum but not in the PFC. Ten μg/kg M100907 abolished the PCP-induced attentional performance deficits and the increase in S133-CREB but not T34-DARPP32 phosphorylation. By itself, M100907 had no effect on attentional performance or phospho-S133-CREB and phospho-T34-DARPP32. Interestingly, the effect of PCP on phospho-S133-CREB but not on phospho-T34-DARPP32 was dependent on endogenous 5-HT. The data indicate that blockade of 5-HT2A receptors may exert beneficial effects on cognitive deficits through a mechanism linked to striatal S133-CREB phosphorylation. [ABSTRACT FROM AUTHOR]

This paper presents a methodology for automatically designing Instruction-Set Extensions in embedded processors. Many commercially available CPUs now offer the possibility of extending their instruction set for a specific application. Their tool chains typically support manual experimentations, but algorithms that can define the set of customised functional units most beneficial for a given applications are missing. Only a few algorithms exist but are severely limited in the type and size of operation clusters they can choose and hence reduce significantly the effectiveness of specialisation. A more general algorithm is presented here which selects maximal-speedup convex subgraphs of the application dataflow graph under fundamental microarchitectural constraints, and which improves significantly on the state of the art. [ABSTRACT FROM AUTHOR]

Shows that the stimulatory effect of caffeine on motor activity in mice was greatly reduced following genetic deletion of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of relative molecular mass (DARPP-32). Involvement of DARPP-32 in the behavioral response to blockade of adenosine A[sub 2A] receptors; Expression of striato-pallidal neurons; Determination of adenosine A[sub 1] receptor binding.

Transgenic nice were produced in which human HLA-Cw4 is stably integrated, behaves as a single Mendelian trait, and, being under the transcriptional control of human CD2, is selectively and efficiently expressed in T lymphocytes. These mice were used as a model system to dtermine whether HLA-type C molecules can be exposed on the surface of activated lymphocytes as free heavy chains, non-associated with β2-microglobulin (βm). In our transgenic mice we could identify HLA-Cw4 molecules either as free chains or as βm-associated molecules by the use of monoclonal antibodies specific for either conformation of HLA class I and nonreactive to mouse H2 molecules. Resting mouse lymphocytes were shown by western transfer analysis to contain sizeable amounts of HLA-Cw4 free chains, but they exposed on thier surface HLA-Cw4 only in association with β2m,a s indicated by flow cytometric measurements. Conversely, where the content of total HLA-Cw4 was increased, lectin-activated mouse lymphocytes exposed on thier outer cell membrane HLA-Cw4 molecules in both conformation, namely, also as free heavy chains, Isoelectrofocusing analysis confirmed the presence of both HLA-Cw4 molecular conformations in activated T cells and indicated that HLA-Cw4 heavy chains can bind to mouse βm with the same low affinity displayed for human βm. The results of our experiments led us to conclude that (1) association with βm is not necessary for the exposure of HLA-C on the surface of activated T lymphocytes and (2)o cell activation affects the balance between the two conformation forms of HLA-C. [ABSTRACT FROM AUTHOR]

Transgenic mice were produced containing a 33 kilobase (kb) DNA fragment encompassing the five exons and all the known regulatory regions of the class II HLA-DRA gene. The transgene displayed regulated expression [constitutive and interferon-γ (IFN)-γ induced] of the human products in most mouse tissues. The tissue distribution of the DRA transgene products more closely resembled that of their mouse homologues, the endogenous H-2 Ea products, than the wider distribution of DRA products in humans. This was evident in several tissues (endothelia of small vessels, especially those of glomerular capillaries, Kupffer cells, and epithelial cells lining the gastrointestinal tract), known to differentially express class II molecules in the two species. Thus, the wider human specific pattern of expression requires an exact cis/trans complementation which is incompletely reconstituted in transgenic mice, suggesting that human specific cis-acting elements may have arisen during evolution to direct the expression of class II genes to those anatomical regions which usually lack them in the mouse. The only example of aberrant expression of the DRA gene in the present series of transgenic mice was in the dendritic and/or epithelial cells of the thymic cortex, which displayed greately reduced DRA levels in spite of a normal expression of the endogenous Ea molecules. [ABSTRACT FROM AUTHOR]