Paroxysmal eye–head movements in Glut1 deficiency syndrome

Objective:To describe a characteristic paroxysmal eye–head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS).Methods:We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients.Results:A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually &lt;5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye movements were separated by clear intervals of fixation, usually ranging from 200 to 800 ms. The movements were consistent with eye–head gaze saccades. These movements can be distinguished from opsoclonus by the presence of a clear intermovement fixation interval and the association of a same-direction head movement.Conclusions:Paroxysmal eye–head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder.</jats:sec

Development of a Disposable Gold Electrodes-Based Sensor for Electrochemical Measurements of cDNA Hybridization

AbstractThis work deals with the development of a disposable electrochemical biosensor for the specific detection of short DNA sequences. The sensor is an amperometric transducer with three planar electrodes, comprising a working, a counter and a pseudo-reference electrode, all made of a gold layer over a polycarbonate substrate. For the development of the genosensor, the working electrode was modified using thiol-tethered 33-mer DNA probe by chemisorptions, in a concentration range from 0.1 μM to 5 μM. Immobilization of ssDNA on gold surface was monitored with electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV) in Fe(CN)64−/13− and Ruthenium(II)/(III) solutions. The time dependence of ssDNA probe immobilization was also studied. The hybridization detection is then compared with EIS and DPV measurements

Cell cycle progression or translation control is not essential for vesicular stomatitis virus oncolysis of hepatocellular carcinoma.

The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). Identifying key regulators in diverse transduction pathways that define VSV oncolysis in cancer cells represents a fundamental prerequisite to engineering more effective oncolytic viral vectors and adjusting combination therapies. After having identified defects in the signalling cascade of type I interferon induction, responsible for attenuated antiviral responses in human HCC cell lines, we have now investigated the role of cell proliferation and translation initiation. Cell cycle progression and translation initiation factors eIF4E and eIF2Bepsilon have been recently identified as key regulators of VSV permissiveness in T-lymphocytes and immortalized mouse embryonic fibroblasts, respectively. Here, we show that in HCC, decrease of cell proliferation by cell cycle inhibitors or siRNA-mediated reduction of G(1) cyclin-dependent kinase activities (CDK4) or cyclin D1 protein expression, do not significantly alter viral growth. Additionally, we demonstrate that translation initiation factors eIF4E and eIF2Bepsilon are negligible in sustaining VSV replication in HCC. Taken together, these results indicate that cellular proliferation and the initiation phase of cellular protein synthesis are not essential for successful VSV oncolysis of HCC. Moreover, our observations indicate the importance of cell-type specificity for VSV oncolysis, an important aspect to be considered in virotherapy applications in the future

Histological analysis of thrombi retrieved after acute ischemic stroke from large vessel occlusion: from research to clinical practice

Emergent reperfusion therapies have improved acute ischemic stroke prognosis, but many patients are still bound to bad clinical outcome, probably because of our incomplete knowledge of its pathophysiology. Thanks to mechanical thrombectomy, occluding material is available for histological analysis. Several studies investigated the possible relationship between thrombus composition and clinical, procedural, and radiological variables of acute ischemic stroke. The potential value of thrombus analysis as a tool for clinical practice and research is still not defined, as data from the literature are heterogeneous and sometimes conflicting. We propose a review of the existing literature regarding histological analysis of thrombi in acute ischemic stroke. We classified articles on clot composition according to the clinical variable explored in each study. We first distinguished articles about etiology, procedural, and radiological variables, and then we performed a subclassification for each group. This review could help both in the interpretation of thrombus analysis in clinical practice and in its usage for future researc

JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.

Background: cJun terminal kinase (JNK) is constitutively activated in most hepatocellular carcinomas (HCCs), yet its exact role in carcinogenesis remains controversial. While tumour necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) is known as a major mediator of acquired immune tumour surveillance, and is currently being tested in clinical trials as a novel cancer therapy, the resistance of many tumours to TRAIL and concerns about its toxicity in vivo represent obstacles to its clinical application. In this study we investigated whether JNK activity in HCC could contribute to the resistance to apoptosis in these tumours. Methods: The effect of JNK/Jun inhibition on receptormediated apoptosis was analysed by pharmacological inhibition or RNA interference in cancer cells and nontumour cells isolated from human liver or transgenic mice lacking a phosphorylation site for Jun. Results: JNK inhibition caused cell cycle arrest, enhanced caspase recruitment, and greatly sensitised HCC cells but not normal hepatocytes to TRAIL. TRAILinduced activation of JNK could be effectively interrupted by administration of the JNK inhibitor SP600125. Conclusions: Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL-mediated tumour surveillance. JNK inhibition might represent a novel strategy for specifically sensitising HCC cells to TRAIL thus opening promising therapeutic perspectives for safe and effective use of TRAIL in cancer treatment

O direito de greve no serviço público e a constitucionalidade do Decreto Nº 7.777, de 24 de julho de 2012

O direito de greve dos servidores públicos foi pela primeira vez previsto no ordenamento jurídico pela Constituição da República de 1988, como um direito social instrumental de defesa coletiva de seus interesses frente ao poderio da Administração. O dispositivo constitucional que trouxe essa prerrogativa, contudo, é uma norma de eficácia limitada, que não recebeu do legislador normatividade suficiente para sua aplicação. Após anos de desregulamentação, para minorar os efeitos da omissão legislativa, o Supremo Tribunal Federal aplicou a lei regulamentadora da greve na seara privada aos servidores públicos, com algumas adaptações. A atuação da Suprema Corte possibilitou, contudo, uma efetivação apenas precária do direito de greve dos servidores públicos, tendo em vista que o regramento a eles ajustado acabou subtraindo o desejo normativo do constituinte. Tanto é que, vinte e quatro anos após a promulgação da Constituição, sem que o Congresso Nacional tivesse editado lei específica destinada a regulamentar o direito, foi publicado o Decreto nº 7.777/12, cuja finalidade primordial era de dar continuidade aos serviços públicos durante as greves pelo compartilhamento da execução das atividades ou por meio da adoção de procedimentos simplificados necessários à  manutenção dos serviços paralisados. O objetivo deste trabalho é, pois, verificar se a adoção dessas medidas serviu, de algum modo, como instrumento de pressão temerário à  greve, tendo em vista que o Decreto nº 7.777/12 permitiu que a problemática desse direito, que é a não prestação do serviço, fosse, em tese, solucionada. Para tanto, foi feita uma retrospectiva histórica do direito de greve dos servidores públicos no Brasil e realizado um estudo sobre o controle de constitucionalidade. Por fim, foram explorados os dispositivos do Decreto para verificar se estes incorreram em algum vício procedimental ou de competência para seu ingresso no mundo jurídico, bem como se foi contrário a alguma norma substantiva da Constituição, seja ela uma regra ou um princípio. Da análise de constitucionalidade do Decreto nº 7.777/12, verificou-se que este não observou o procedimento legislativo adequado  sua finalidade (contratação temporária de pessoal), ao meio utilizado (compartilhamento dos serviços paralisados por meio de convênios) e à  sua consequência (aumento de despesas), razão pela qual se entende que o diploma legal incorreu em vícios formais de constitucionalidade. Outrossim, conclui-se que, por ter desnaturado a essência da greve - que, sem paralisação, deixa de existir - e servido como instrumento formal de pressão aos grevistas, o Decreto nº 7.777/12 impediu a resolução do conflito originador do movimento e limitou a eficácia do exercício do direito de greve dos servidores públicos

Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC. Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. Conclusions: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials

Brain Mechanisms Underlying Human Communication

Human communication has been described as involving the coding-decoding of a conventional symbol system, which could be supported by parts of the human motor system (i.e. the “mirror neurons system”). However, this view does not explain how these conventions could develop in the first place. Here we target the neglected but crucial issue of how people organize their non-verbal behavior to communicate a given intention without pre-established conventions. We have measured behavioral and brain responses in pairs of subjects during communicative exchanges occurring in a real, interactive, on-line social context. In two fMRI studies, we found robust evidence that planning new communicative actions (by a sender) and recognizing the communicative intention of the same actions (by a receiver) relied on spatially overlapping portions of their brains (the right posterior superior temporal sulcus). The response of this region was lateralized to the right hemisphere, modulated by the ambiguity in meaning of the communicative acts, but not by their sensorimotor complexity. These results indicate that the sender of a communicative signal uses his own intention recognition system to make a prediction of the intention recognition performed by the receiver. This finding supports the notion that our communicative abilities are distinct from both sensorimotor processes and language abilities

Marginal deformation of N=4 SYM and Penrose limits with continuum spectrum

We study the Penrose limit about a null geodesic with 3 equal angular momenta in the recently obtained type IIB solution dual to an exactly marginal $\gamma$-deformation of N=4 SYM. The resulting background has non-trivial NS 3-form flux as well as RR 5- and 3-form fluxes. We quantise the light-cone Green-Schwarz action and show that it exhibits a continuum spectrum. We show that this is related to the dynamics of a charged particle moving in a Landau plane with an extra interaction induced by the deformation. We interpret the results in the dual N=1 SCFT.Comment: 26 pages, 2 figures; v2: typos corrected, field theory interpretation extende