IDIOPATHIC PARTIAL EPILEPSY WITH AUDITORY FEATURES (IPEAF): A CLINICAL AND GENETIC STUDY OF 53 SPORADIC CASES

The purpose of our study was to describe the clinical characteristics of sporadic (S) cases of partial epilepsy with auditory features (PEAF) and pinpoint clinical, prognostic and genetic differences with respect to previously reported familial (F) cases of autosomal dominant partial epilepsy with auditory features (ADPEAF). We analysed 53 patients (24 females and 29 males) with PEAF diagnosed according to the following criteria: partial epilepsy with auditory symptoms, negative family history for epilepsy and absence of cerebral lesions on NMR study. All patients underwent a full clinical, neuroradiological and neurophysiological examination. Forty patients were screened for mutations in LGI1/epitempin, which is involved in ADPEAF. Age at onset ranged from 6 to 39 years (average 19 years). Secondarily generalized seizures were the most common type of seizures at onset (79%). Auditory auras occurred either in isolation (53%) or associated with visual, psychic or aphasic symptoms. Low seizure frequency at onset and good drug responsiveness were common, with 51% of patients seizure-free. Seizures tended to recur after drug withdrawal. Clinically, no major differences were found between S and F patients with respect to age at onset, seizure frequency and response to therapy. Analysis of LGI1/epitempin exons failed to disclose mutations. Our data support the existence of a peculiar form of non-lesional temporal lobe epilepsy closely related to ADPEAF but without a positive family history. This syndrome, here named IPEAF, has a benign course in the majority of patients and could be diagnosed by the presence of auditory aura. Although LGI1 mutations have been excluded, genetic factors may play an aetiopathogenetic role in at least some of these S cases

Accuracy of prenatal culture in predicting intrapartum group B streptococcus colonization status

Objective: To evaluate the positive predictive value (PPV) of group B Streptococcus (GBS) cultures at 35–37 weeks of gestation relative to GBS colonization status at delivery. Methods: Rectovaginal swabs from 221 women at labor in four Lisbon hospitals were collected for GBS screening according to the CDC guidelines. Results: The PPV was 24.4%. IAP was administered to 100% of prenatally GBS positive women. There was no case of early onset GBS disease (EOD). Conclusions: Poor accuracy of prenatal cultures in identifying true candidates for IAP highlights the need for Portuguese clinical and laboratory guidelines to prevent EOD and antibiotic overtreatment of pregnant women

Biomimetic Construction of the Hydroquinoline Ring System. Diastereodivergent Enantioselective Synthesis of 2,5-Disubstituted cis-Decahydroquinolines

The straightforward enantioselective construction of the hydroquinoline ring system from 1,5-polycarbonyl derivatives, using (R)-phenyglycinol as a chiral latent form of ammonia, is reported. The process mimics the key steps believed to occur in nature in the biosynthesis of amphibian decahydroquinoline alkaloids. Diastereodivergent routes to enantiopure cis-2,5-disubstituted decahydroquinolines, including the alkaloid pumiliotoxin C (cis-195A), are developed

Poly-glutamic dendrimer-based conjugates for cancer vaccination - a computational design for targeted delivery of antigens

© 2017 Taylor & Francis. This is an accepted manuscript of an article published by Taylor & Francis in Journal of Drug Targeting on 10 Aug 2017, available online: https://doi.org/10.1080/1061186X.2017.1363213.Computational techniques are useful to predict interaction models and molecular properties for the design of drug delivery systems, such as dendrimers. Dendrimers are hyperbranched macromolecules with repetitive building blocks, defined architecture and functionality. This work evaluated the impact of surface modifications of mannosamine-conjugated multifunctional poly (glutamic acid) (PG)-dendrimers as nanocarriers of the tumor associated antigens (TAA) MART-1, gp100:44 and gp100:209. Their potential to target antigen presenting cells through molecular interactions with mannose receptor (MR1) to promote an efficient and selective antitumor immunotherapeutic effect was also evaluated. Molecular dynamics (MD) simulations and docking studies were performed. Results showed that nitrobenzoxadiazole (NBD)-PG-G4-dendrimer displayed 64 carboxylic groups, however the frontier molecular orbital theory study has indicated that only 32 of those carboxylic groups present on the backbone were available to form covalent bonds with either mannosamine or TAA. No differences in the gap energy of HOMO of conjugated NBD-PG-G4-dendrimer and LUMO of conjugating agents were observed while increasing conjugation loading. When the number of mannosamines conjugated to dendrimer was increased from 16 to 32, the conjugated dendrimer interacted with the receptor with higher affinity. However, due to absence of available carboxylic end groups of backbone chain for further conjugation in a dendrimer with 32 mannosamine, the 16 mannosamines-NBD-PG-G4-dendrimer was chosen to conjugate TAA for added functionality. Docking results showed that the majority of TAA-conjugated NBD-PG-G4-dendrimer demonstrated a favorable interaction with mannosamine binding site on MR1, thus constituting a promising tool for the targeted delivery of TAA. Our in silico approach effectively narrows down the selection of the best candidates for the synthesis of functionalized PG-dendrimers with desired functionalities. The results of this study will significantly reduce the time and efforts required to experimentally obtain modified dendrimers for optimal controlled delivery of antigens to targeted DC.Peer reviewedFinal Accepted Versio

Pyruvate Dehydrogenase Complex Deficiency: Updating the Clinical, Metabolic and Mutational Landscapes in a Cohort of Portuguese Patients

Background: The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results: The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion: The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.info:eu-repo/semantics/publishedVersio

Enhancing Volumetric Bouligand-Minkowski Fractal Descriptors by using Functional Data Analysis

This work proposes and study the concept of Functional Data Analysis transform, applying it to the performance improving of volumetric Bouligand-Minkowski fractal descriptors. The proposed transform consists essentially in changing the descriptors originally defined in the space of the calculus of fractal dimension into the space of coefficients used in the functional data representation of these descriptors. The transformed decriptors are used here in texture classification problems. The enhancement provided by the FDA transform is measured by comparing the transformed to the original descriptors in terms of the correctness rate in the classification of well known datasets

Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe

Preliminary Integrated Chronostratigraphy of the AND-1B Core, ANDRILL McMurdo Ice Shelf Project, Antarctica

Chronostratigraphic data available for the preliminary age model for the upper 700 m for the AND-1B drill core include diatom biostratigraphy, magnetostratigraphy, 40Ar/39Ar ages on volcanic material, 87Sr/86Sr ages on calcareous fossil material, and surfaces of erosion identifi ed from physical appearance and facies relationships recognised in the AND-1B drill core. The available age data allow a relatively well-constrained age model to be constructed for the upper 700 m of the drill core. Available diatom biostratigraphic constraints and 40Ar/39Ar ages allow a unique correlation of ~70% of the AND- 1B magnetic polarity stratigraphy with the Geomagnetic Polarity Time Scale (GPTS). Unique correlation is not possible in several coarse diamictite intervals with closely spaced glacial surfaces of erosion and sparse microfl ora. However, the age model indicates relatively rapid (up to 1 m/k.y.) and continuous accumulation of intervening fi ner grained diatomaceous intervals punctuated by several half- to millionyear hiatuses representing more than half of the last 7 m.y. in the AND-1B record. The mid- to late Pleistocene is represented by superimposed diamictite units separated from upper Pliocene alternating diamictites/diatomites by a ~1 m.y. hiatus co-incident with a regionally correlated seismic reflection surface. A c. 100 m-thick diatomite represents a signifi cant portion of the early Pliocene record in the AND-1B drill core. Strata below ~620 m are late Miocene in age; however, biostratigraphic constraints are absent below 586 m and correlation with the GPTS is relatively unconstrained. At the time of writing, the only chronostratigraphic data available below 700 mbsf include three 40Ar/39Ar ages on volcanic clasts from near 1280 mbsf affording a maximum depositional age of 13.57 Ma for the base of the AND-1B drill core

Association of knowledge, preventive counseling and personal health behaviors on physical activity and consumption of fruits or vegetables in community health workers

Abstract\ud \ud Background\ud There is evidence that if a health professional is active and has a healthy diet, he/she is more likely to advise patients about the benefits of physical activity and healthy eating The aims of this study were to: (1) describe the personal physical activity, consumption of fruits and vegetables behaviors and nutritional status of community health workers; (2) evaluate the association between knowledge, delivery of preventive counseling and personal behaviors among community health workers.\ud \ud \ud Methods\ud This was a cross-sectional study conducted in a nationally sample of health professionals working in primary health care settings in Brazil in 2011. This survey was part of the second phase of the Guide for Useful Interventions for Activity in Brazil and Latin America project, and data were collected through telephone interviews of 269 community health workers from the Unified Health Care system of Brazil. We applied questionnaires about personal reported behaviors, knowledge and preventive counseling in physical activity and consumption of fruits and vegetables. We calculated the prevalence and associations between the variables with logistic regression.\ud \ud \ud Results\ud The proportion of community health workers that practiced 150 minutes per week of physical activity in leisure time or transportation was high (64.9%). Half of community health workers were overweight and only 26.2% reported consuming five portions/day of fruits or vegetables. Most community health workers reported counseling about physical activity for more than six months (59.7%), and most were not knowledgeable of the fruits and vegetables and physical activity recommendations. Meeting the fruits and vegetables recommendations was associated with correct knowledge (OR = 4.5; CI95% 1.03;19.7), with reporting 150 minutes or more of physical activity per week (OR = 2.0; CI95% 1.03;3.7) and with reporting physical activity in leisure time (OR = 2.0; CI95% 1.05;3.6). Regular physical activity counseling was associated with reporting 10–149 minutes per week (OR = 3.8; CI95% 1.1;13.3) and with more than 150 minutes of physical activity per week (OR = 4.9; CI95% 1.5;16.5).\ud \ud \ud Conclusion\ud Actions to promote physical activity and healthy eating and to improve knowledge among community health workers within the health care system of Brazil could have a potential positive influence on delivery of preventive counseling to patients on this topic