Lafora disease offers a unique window into neuronal glycogen metabolism

Lafora disease (LD) is a fatal, autosomal recessive, glycogen-storage disorder that manifests as severe epilepsy. LD results from mutations in the gene encoding either the glycogen phosphatase laforin or the E3 ubiquitin ligase malin. Individuals with LD develop cytoplasmic, aberrant glycogen inclusions in nearly all tissues that more closely resemble plant starch than human glycogen. This Minireview discusses the unique window into glycogen metabolism that LD research offers. It also highlights recent discoveries, including that glycogen contains covalently bound phosphate and that neurons synthesize glycogen and express both glycogen synthase and glycogen phosphorylase

Characterisation of the Colour Fraction of Pedro Ximenez Andalusian Sweet Wines

Changes in colour fraction of commercially bottled Pedro Ximenez sweet wines, unaged and oxidatively agedin American oak casks and mostly produced in the Montilla-Moriles and Jerez-Xérès-Sherry Designations ofOrigin (Spain), have been studied. The total tannin content and the total polyphenol content (A280) increasedwith increased aging time, a trend clearly observed in the Jerez wines. Browning, as measured by the absorbanceat 420 nm, differed markedly between unaged and aged wines. Aged wines showed an increase in browning withtime and an increase in high molecular weight browning compounds, most probably Maillard compounds.Colour measurements based on the CIELab system showed a gradual decrease in hue and lightness with ageing

Eslicarbazepine acetate as monotherapy in clinical practice: Outcomes from Euro-Esli

OBJECTIVES: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) monotherapy in clinical practice in Europe. MATERIALS AND METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit) were assessed after 3, 6 and 12 months of ESL treatment and at last visit. Adverse events (AEs) and AEs leading to ESL discontinuation were assessed throughout follow-up. A subanalysis was conducted to assess outcomes for patients treated initially with ESL monotherapy and for patients treated at the last visit with ESL monotherapy. RESULTS: ESL was used as monotherapy in 88/2045 (4.3%) patients initially and in 229/1340 (17.1%) patients at the last visit. At 12 months, responder and seizure freedom rates were 94.1% and 88.2%, respectively, in patients treated initially with ESL monotherapy, and 93.2% and 77.4%, respectively, in patients treated at the last visit with ESL monotherapy. Corresponding values for patients treated initially with ESL adjunctive therapy were 74.8% and 39.0%, respectively; and for patients treated at the last visit with ESL adjunctive therapy, corresponding values were 70.4% and 25.9%, respectively. Safety and tolerability were generally comparable in patients treated with ESL as monotherapy or adjunctive therapy. The most commonly reported AEs (≥5% of patients in any group) were dizziness, somnolence, instability/ataxia, and fatigue. CONCLUSIONS: These clinical practice data support the use of ESL as monotherapy, as well as adjunctive therapy, for focal-onset seizures, complementing evidence from clinical trials.info:eu-repo/semantics/publishedVersio

Fundamentos científicos de la rehabilitación tras la sustitución intraarticular del ligamento cruzado anterior

Hay pocos aspectos de la rehabilitación en nuestra especialidad que sean tan complejos y controvertidos como la rehabilitación después de la sustitución intraarticular del ligamento cruzado anterior (LCA). La tendencia actual es utilizar protocolos de rehabilitación acelerada y rápido funcionalismo, todo lo cual está en relación directa con el avance en la investigación sobre el comportamiento biológico de los implantes, una mayor sofisticación en la técnica quirúrgica y los adelantos en las técnicas de rehabilitación. El objetivo de este trabajo es analizar no protocolos concretos, sino los problemas que plantea la cirugía del LCA y como minimizarlos en la medida de lo posible, protegiendo al mismo tiempo la plastia.There are few aspects of rehabilitation in our speciality which are so complex and controversial like rehabilitation after intraarticular replacement of the anterior cruciate ligament (ACL). Nowadays there is a trend to use protocols of accelerated rehabilitation and rapid functioning, and all this is related to the advances in research on the biological behavior of the grafts, a major sophistication in surgical technique and advances in rehabilitation techniques. The objective of this paper is not to analyze concrete protocols but rather the problems that state the surgery of the ACL, and how to diminish them to maximum, protecting at the same time the graft

Optimization of Xanthatin Extraction from Xanthium spinosum L. and its cytotoxic, anti-angiogenesis and antiviral properties

The aqueous extraction of the sesquiterpene lactone xanthatin from Xanthium spinosum L. favours the conversion of xanthinium to xanthatin via the loss of acetic acid. The cytotoxic (Hep-G2 and L1210 human cell lines) and antiviral activities of isolated xanthatin are established. This natural compound shows significant cytotoxicity against the Hep-G2 cell line and our experimental results reveal its strong anti-angiogenesis capacity in vitro. The structure of xanthatin is determined by spectroscopic methods and for the first time confirmed by X-ray diffraction

Lacosamide monotherapy in clinical practice: A retrospective chart review

Objective: To assess effectiveness and tolerability of first-line and conversion to lacosamide monotherapy for focal seizures. Materials and Methods: Retrospective, non-interventional chart review of lacosamide monotherapy patients aged ≥16 years in Europe. Outcomes included retention rate at observational point (OP) 3 (12 ± 3 months), seizure freedom rates at OP2 (6 ± 3 months) and OP3 and adverse drug reactions (ADRs). Results: A total of 439 patients were included (98 first-line and 341 conversion to monotherapy; 128 aged ≥65 years [25 first-line and 103 conversion to monotherapy]). First-line and conversion to monotherapy retention rates were 60.2% (59/98; 95% confidence interval [CI] 49.8%-70.0%) and 62.5% (213/341; 57.1%-67.6%), respectively. Kaplan-Meier estimates of 12-month retention rates were 81.2% and 91.4% for first-line and conversion to monotherapy, respectively. First-line and conversion to monotherapy retention rates in patients aged ≥65 years were 60.0% (38.7%-78.9%) and 68.9% (59.1%-77.7%), respectively. At OP2, 66.3% of first-line and 63.0% of conversion to monotherapy patients were seizure free. At OP3, 60.2% of first-line and 52.5% of conversion to monotherapy patients were seizure free. In the ≥65 years subgroup, seizure freedom rates at OP2 were 72.0% and 68.0% for first-line and converted to monotherapy, respectively, and at OP3, 68.0% and 56.3%, respectively. Overall, 52 of 439 (11.8%) patients reported ADRs (16.4% in ≥65 years subgroup), most commonly dizziness (5.0%), headache (2.1%) and somnolence (1.6%). Conclusions: Lacosamide was effective and well tolerated as first-line or conversion to monotherapy in a clinical setting in adult and elderly patients with focal seizuresThis study was supported by UCB Pharm

Generalised median of a set of correspondences based on the hamming distance.

A correspondence is a set of mappings that establishes a relation between the elements of two data structures (i.e. sets of points, strings, trees or graphs). If we consider several correspondences between the same two structures, one option to define a representative of them is through the generalised median correspondence. In general, the computation of the generalised median is an NP-complete task. In this paper, we present two methods to calculate the generalised median correspondence of multiple correspondences. The first one obtains the optimal solution in cubic time, but it is restricted to the Hamming distance. The second one obtains a sub-optimal solution through an iterative approach, but does not have any restrictions with respect to the used distance. We compare both proposals in terms of the distance to the true generalised median and runtime

Antiepileptogenesis after Stroke - Trials and Tribulations: Methodological Challenges and Recruitment Results of a Phase II Study with Eslicarbazepine Acetate.

There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicentre, randomised, double-blind, placebo-controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral haemorrhage or acute ischaemic stroke were randomised to receive ESL 800 mg/day or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is occurrence of a first unprovoked seizure within 6 months after randomisation ('failure rate'). Secondary efficacy assessments include occurrence of a first unprovoked seizure during 12 months after randomisation and during the entire study; functional outcomes (Barthel Index original 10-item version; National Institutes of Health Stroke Scale); post-stroke depression (Patient Health Questionnaire-9; PHQ-9); and overall survival. Safety assessments include evaluation of treatment-emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behaviour (PHQ-9 question 9). The protocol aimed to randomise approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID-19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomised. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol

Childhood Absence Epilepsy with Tonic-Clonic Seizures and Electroencephalogram 3–4-Hz Spike and Multispike–Slow Wave Complexes: Linkage to Chromosome 8q24

SummaryChildhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%–15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected–pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3–4-Hz spike– and multispike–slow wave complexes were considered to be affected. Significant P values of .00000–.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval

MicroRNA-200, associated with metastatic breast cancer, promotes traits of mammary luminal progenitor cells

MicroRNAs are critical regulators of gene networks in normal and abnormal biological processes. Focusing on invasive ductal breast cancer (IDC), we have found dysregulated expression in tumor samples of several microRNAs, including the miR-200 family, along progression from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b and miR-7 in IDC patients with regional or distant metastases relative to patients with primary node-negative tumors. Forced expression of miR-200s in MCF10CA1h mammary cells induced an enhanced epithelial program, aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization in vivo. MiR-200s also induced the constitutive activation of the PI3K-Akt signaling through downregulation of PTEN, and the enhanced mammosphere growth and ALDH activity induced in MCF10CA1h cells by miR-200s required the activation of this signaling pathway. Interestingly, the morphology of tumors formed in vivo by cells expressing miR-200s was reminiscent of metaplastic breast cancer (MBC). Indeed, the epithelial components of MBC samples expressed significantly higher levels of miR-200s than their mesenchymal components and displayed a marker profile compatible with luminal progenitor cells. We propose that microRNAs of the miR-200 family promote traits of highly proliferative breast luminal progenitor cells, thereby exacerbating the growth and metastatic properties of transformed mammary epithelial cells