Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy

One-third of patients with epilepsy continue to have seizures despite current treatments, indicating the need for better antiseizure medications with novel mechanisms of action. Ezogabine (retigabine) has recently been approved for adjunctive treatment of partial-onset seizures in adult patients with epilepsy. Ezogabine utilizes a novel mechanism of action, involving activation of specific potassium channels. The most common side effects of ezogabine are shared by most antiseizure medications and primarily consist of central nervous system (CNS) symptoms, such as somnolence, dizziness, confusion, and fatigue. In addition, a small percentage of patients on ezogabine experience a unique adverse effect affecting the bladder, which results in urinary hesitancy; thus, patients on ezogabine should be monitored carefully for potential urological symptoms. Overall, ezogabine appears to be well tolerated and represents a reasonable new option for treating patients with intractable epilepsy

Onset of Surface-Tension-Driven Benard Convection

Experiments with shadowgraph visualization reveal a subcritical transition to a hexagonal convection pattern in thin liquid layers that have a free upper surface and are heated from below. The measured critical Marangoni number (84) and observation of hysteresis (3%) agree with theory. In some experiments, imperfect bifurcation is observed and is attributed to deterministic forcing caused in part by the lateral boundaries in the experiment.Comment: 4 pages. The RevTeX file has a macro allowing various styles. The appropriate style is "mypprint" which is the defaul

Ideas in the Hispanic Caribbean in the nineteenth century: The antillanismo as emancipatory and integration ideal

En la compleja y conflictiva realidad del Caribe hispano del siglo XIX, emerge un conjunto de ideas que se organizan en torno de la voluntad de independencia, de libertad y autoafirmación política y cultural, de integración antillana y nuestroamericana. Ideas que pueden ser sintetizadas en el término antillanismo. Fueron esgrimidas en oposición al colonialismo y al imperialismo y fundamentadas desde posiciones filosóficas que abarcaron un amplio espectro, desde la ilustración al positivismo y el krausismo. Su originalidad radica en haber constituido una trama discursiva ligada dialécticamente a los acontecimientos de la situación social e histórica que buscaba comprender y transformar.In the Spanish Caribbean complex and conflicting realities of nineteenth–century, grows a set of ideas that are organized around the desire for independence, freedom, political and cultural self–assertion and integration. These ideas can be summarized in the term antillanismo. They were put forward in opposition to colonialism and imperialism and reasoned from philosophical positions that covered a wide spectrum, from illustration to positivism and krausism. Its originality lies in having formed a discursive frame dialectically linked to the events of the socio–historical situation that sought to understand and transform.Fil: Arpini, Adriana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Ciencias Humanas, Sociales y Ambientales; Argentin

The need for a network to establish and validate predictive biomarkers in cancer immunotherapy.

Immunotherapies have emerged as one of the most promising approaches to treat patients with cancer. Recently, the entire medical oncology field has been revolutionized by the introduction of immune checkpoints inhibitors. Despite success in a variety of malignancies, responses typically only occur in a small percentage of patients for any given histology or treatment regimen. There are also concerns that immunotherapies are associated with immune-related toxicity as well as high costs. As such, identifying biomarkers to determine which patients are likely to derive clinical benefit from which immunotherapy and/or be susceptible to adverse side effects is a compelling clinical and social need. In addition, with several new immunotherapy agents in different phases of development, and approved therapeutics being tested in combination with a variety of different standard of care treatments, there is a requirement to stratify patients and select the most appropriate population in which to assess clinical efficacy. The opportunity to design parallel biomarkers studies that are integrated within key randomized clinical trials could be the ideal solution. Sample collection (fresh and/or archival tissue, PBMC, serum, plasma, stool, etc.) at specific points of treatment is important for evaluating possible biomarkers and studying the mechanisms of responsiveness, resistance, toxicity and relapse. This white paper proposes the creation of a network to facilitate the sharing and coordinating of samples from clinical trials to enable more in-depth analyses of correlative biomarkers than is currently possible and to assess the feasibilities, logistics, and collated interests. We propose a high standard of sample collection and storage as well as exchange of samples and knowledge through collaboration, and envisage how this could move forward using banked samples from completed studies together with prospective planning for ongoing and future clinical trials

From START to FINISH : the influence of osmotic stress on the cell cycle

Peer reviewedPublisher PD

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.Fil: Ng, Bobby G.. Sanford Burnham Prebys Medical Discovery Institute; Estados UnidosFil: Eklund, Erik A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos. Lund University; SueciaFil: Shiryaev, Sergey A.. Sanford Burnham Prebys Medical Discovery Institute; Estados UnidosFil: Dong, Yin Y.. University of Oxford; Reino UnidoFil: Abbott, Mary Alice. University of Massachusetts Medical School; Estados UnidosFil: Asteggiano, Carla Gabriela. Universidad Católica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Bamshad, Michael J.. University of Washington; Estados UnidosFil: Barr, Eileen. University of Emory; Estados UnidosFil: Bernstein, Jonathan A.. University of Stanford; Estados UnidosFil: Chelakkadan, Shabeed. Monash Children's Hospital; AustraliaFil: Christodoulou, John. Sydney Medical School; Australia. University of Melbourne; AustraliaFil: Chung, Wendy K.. Columbia University; Estados UnidosFil: Ciliberto, Michael A.. University of Iowa; Estados UnidosFil: Cousin, Janice. National Human Genome Research Institute ; Estados UnidosFil: Gardiner, Fiona. University of Melbourne; AustraliaFil: Ghosh, Suman. University of Florida; Estados UnidosFil: Graf, William D.. University of Connecticut; Estados UnidosFil: Grunewald, Stephanie. University College London; Estados UnidosFil: Hammond, Katherine. University of Alabama at Birmingahm; Estados UnidosFil: Hauser, Natalie S.. Inova, Fairfax Hospital Falls Church; Estados UnidosFil: Hoganson, George E.. University Of Illinois At Chicago; Estados UnidosFil: Houck, Kimberly M.. Baylor College of Medicine; Estados UnidosFil: Kohler, Jennefer N.. University of Stanford; Estados UnidosFil: Morava, Eva. Mayo Clinic; Estados UnidosFil: Larson, Austin A.. University Of Colorado Anschutz Medical Campus.; Estados UnidosFil: Liu, Pengfei. Baylor Genetics; Estados Unidos. Baylor College Of Medicine; Estados UnidosFil: Madathil, Sujana. University of Iowa; Estados UnidosFil: McCormack, Colleen. University of Stanford; Estados UnidosFil: Meeks, Naomi J.L.. University Of Colorado Anschutz Medical Campus.; Estados UnidosFil: Papazoglu, Gabriela Magali. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentin

Crisis Standard of Care: Management of Infantile Spasms during COVID‐19

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156180/2/ana25792_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156180/1/ana25792.pd

A Mathematical Model of Mitotic Exit in Budding Yeast: The Role of Polo Kinase

Cell cycle progression in eukaryotes is regulated by periodic activation and inactivation of a family of cyclin–dependent kinases (Cdk's). Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins. Mitotic exit in budding yeast is known to involve the interplay of mitotic kinases (Cdk and Polo kinases) and phosphatases (Cdc55/PP2A and Cdc14), as well as the action of the anaphase promoting complex (APC) in degrading specific proteins in anaphase and telophase. To understand the intricacies of this mechanism, we propose a mathematical model for the molecular events during mitotic exit in budding yeast. The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains. The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network