Brugada Syndrome: Focus for the General Pediatrician

Brugada Syndrome is an "inherited" channelopathy characterized by a predisposition to syncope and sudden death. It typically presents in young adults but is also known to affect the pediatric population, even if the prevalence is low compared to the adult population. The diagnostic ECG pattern shows coved-type ST-segment elevation in the right precordial leads, occurring spontaneously or after provocative drug tests with IV administration of Class I antiarrhythmic drugs. However, the electrocardiographic findings may vary, and transient or concealed forms of the syndrome further complicate diagnosis, necessitating thorough evaluation and close clinical follow-up. The clinical presentation of Brugada Syndrome may range from asymptomatic individuals to patients who have experienced syncope or sudden cardiac arrest. The syndrome remains underdiagnosed due to its elusive symptoms and the absence of abnormal findings between episodes. Additionally, specific triggers such as fever, certain medications and alcohol consumption may unmask the electrocardiographic changes and provoke arrhythmias in susceptible individuals. Given its elusive nature, early diagnosis and risk stratification are crucial in identifying individuals who may benefit from an implantable cardioverter defibrillator, the mainstay of treatment for high-risk patients, or pharmacological interventions

Dopamine D3 receptor knockout mice exhibit increased hippocampal cAMP response element binding protein (CREB) following acquisition of passive avoidance memory

The dopamine D3 (D3R) receptor seems to be implicated in synaptic plasticity and memory-related processes as identified by several pharmacological and behavioral approaches (Laszy et al., 2005; Swant 2008). In a previous study we have shown that D3Rs mediate an inhibitory effect on learning, since D3R knockout (D3-/-) mice display enhanced cognitive performance in the single trial step-through passive avoidance task (PA) as compared to WTs (Micale et al., 2010; D’Amico et al., 2013). Formation of new memories is known to require de novo synthesis of proteins related to synaptic function, possibly through the activation of a number of signaling pathways including the mitogen-activated protein kinases (MAPKs), protein kinase B (namely Akt) and the activation of nuclear transcription factors such as the cAMP response element binding protein (CREB). However, no clear indications have yet been provided regarding the specific involvement of D3Rs in the activation of these signaling cascades after acquisition of PA. Therefore, in the present study we assessed whether activity/phosphorylation levels of several MAPKs, Akt and CREB were differentially affected by PA in both wild-type (WT) and D3-/- mice. Animals were divided into four groups: naive, unconditioned stimulus trained (USTA), conditioned stimulus trained (CSTA) and conditioned (CA) animals. Phosphorylation of MAPKs, including extracellular signal-regulated kinase 1/2 (ERK 1/2), c-Jun-N-terminal kinase (JNK) and p38, as well as of Akt and CREB were assessed by immunoblotting and immunohistochemical analyses. Results showed that acquisition of PA induced a significant increase in hippocampal pCREB levels both in WT and D3-/- mice. However, the extent of PA-driven increase in pCREB levels was significantly higher in mice lacking D3Rs. Similarly, hippocampal pERK 1/2 were further augmented in D3-/- mice subjected to PA as compared to trained WTs. JNK and p38 phosphorylation was not affected neither by PA nor by genetic background. Finally, a significantly increased Akt activation was observed only when comparing naïve WT and D3-/- mice, but not in response to PA acquisition. This result suggests that the Akt signaling cascade is influenced by the absence of the receptor, but only under basal conditions. In conclusion, the data here presented supports the notion that D3Rs might modulate CREB phosphorylation after acquisition of PA, probably via activation of the ERK signaling pathway

Dopamine D3 receptor modulates tissue type plasminogen activator (tPA) activity in mouse brain

Growing amount of evidence points to the dopamine D3 receptor (D3R) as an important mediator in the broad array of events that regulate memory function, perhaps through the modulation of molecular pathways involved in neurotrophic factor activation. Tissue type plasminogen activator (tPA) is a proteolytic enzyme that cleaves the precursor of brain derived neurotrophic factor (proBDNF) into the biologically active form of mature BDNF. However, whether D3Rs modulate tPA activity on BDNF in brain has not been ascertained yet. Here in the present study, using D3R knock-out (D3-/-) mice, we demonstrate that receptor inactivation is associated with increased tPA expression both in prefrontal cortex and, to a greater extent, in the hippocampus, two regions associated with memory processes. The heightened tPA levels observed in D3-/- mice inversely correlated with proBDNF protein expression, whereas they positively correlated with both BDNF mRNA and mature BDNF protein levels. In conclusion, our finding strongly suggest that D3Rs might modulate tPAmediated post-transcriptional processing of BDNF in brain regions critical to memory function

Neural network-derived perfusion maps: A model-free approach to computed tomography perfusion in patients with acute ischemic stroke

Objective: In this study, we investigate whether a Convolutional Neural Network (CNN) can generate informative parametric maps from the pre-processed CT perfusion data in patients with acute ischemic stroke in a clinical setting. Methods: The CNN training was performed on a subset of 100 pre-processed perfusion CT dataset, while 15 samples were kept for testing. All the data used for the training/testing of the network and for generating ground truth (GT) maps, using a state-of-the-art deconvolution algorithm, were previously pre-processed using a pipeline for motion correction and filtering. Threefold cross validation had been used to estimate the performance of the model on unseen data, reporting Mean Squared Error (MSE). Maps accuracy had been checked through manual segmentation of infarct core and total hypo-perfused regions on both CNN-derived and GT maps. Concordance among segmented lesions was assessed using the Dice Similarity Coefficient (DSC). Correlation and agreement among different perfusion analysis methods were evaluated using mean absolute volume differences, Pearson correlation coefficients, Bland-Altman analysis, and coefficient of repeatability across lesion volumes. Results: The MSE was very low for two out of three maps, and low in the remaining map, showing good generalizability. Mean Dice scores from two different raters and the GT maps ranged from 0.80 to 0.87. Inter-rater concordance was high, and a strong correlation was found between lesion volumes of CNN maps and GT maps (0.99, 0.98, respectively). Conclusion: The agreement between our CNN-based perfusion maps and the state-of-the-art deconvolution-algorithm perfusion analysis maps, highlights the potential of machine learning methods applied to perfusion analysis. CNN approaches can reduce the volume of data required by deconvolution algorithms to estimate the ischemic core, and thus might allow the development of novel perfusion protocols with lower radiation dose deployed to the patient

Generic pregabalin : current situation and implications for health authorities, generics and biosimilars manufacturers in the future

The manufacturer of pregabalin has a second use patent covering prescribing for neuropathic pain: its principal indication. The manufacturer has threatened legal action in the UK if generic pregabalin rather than Lyrica is prescribed for this indication. No problems exist for practitioners who prescribe pregabalin for epilepsy or generalized anxiety disorder. This has serious implications for health authorities. In Germany, however, generics could be legally prescribed for any approved indication once one indication loses its patent. We aim to establish the current situation with pregabalin among principally European countries. Personnel from 33 regional and national health authorities mainly from Europe, and nine from universities across Europe working as advisers to health authorities or with insight into their activities, were surveyed regarding four specific questions via email to shed light on the current situation with Lyrica and pregabalin in their country. The information collated from each country was subsequently checked for accuracy with each co-author by email and face-to-face contact and collated into five tables. The scenarios ranged from extending the patent life of Lyrica (e.g. France), endorsing the prescribing of Lyrica for neuropathic pain (e.g. Catalonia and South Korea), and current prescribing of pregabablin for all indications (e.g. Serbia and Germany). Little activity has taken place in European countries in which generic pregabalin is not yet reimbursed. The availability of generic pregabalin has prompted a number of different activities to be undertaken among the 33 countries and regions surveyed. The situation in Serbia and the historic situation in Germany provide examples of ways to maximize savings once a product loses its patent for at least one indication

Peptide nucleic acid molecular beacons for the detection of PCR amplicons in droplet-based microfluidic devices

The use of droplet-based microfluidics and peptide nucleic acid molecular beacons for the detection of polymerase chain reaction (PCR)-amplified DNA sequences within nanoliter-sized droplets is described in this work. The nanomolar–attomolar detection capabilities of the method were preliminarily tested by targeting two different singlestranded DNA sequences from the genetically modified Roundup Ready soybean and the Olea europaea genomes and detecting the fluorescence generated by peptide nucleic acid molecular beacons with fluorescence microscopy. Furthermore, the detection of 10 nM solutions of PCR amplicon of DNA extracted from leaves of O. europaea L. encapsulated in nanoliter-sized droplets was performed to demonstrate that peptide nucleic acid molecular beacons can discriminate O. europaea L. cultivar species carrying different singlenucleotide polymorphisms

Mercury and selenium intake by seafood from the Ionian Sea: A risk evaluation.

The subject of the present study is the evaluation of the concentrations of mercury (Hg) and selenium (Se) in fish and shellfish from the Gulf of Catania (Ionian Sea) and the assessment of related risk-based consumption limits per single contaminant in adults and children. In contrast to the potential harm from Hg, Se is an essential element that is normally found in high levels in seafood. If the amount of Hg is high enough, it could bind Se and irreversibly inhibit selenium-dependent enzymes. Thus, adequate levels of Se need to be available to replace the amount of Se lost to Hg sequestration, thereby maintaining normal selenoprotein synthesis. Hg analysis was conducted using a flow injection analysis system coupled with an atomic adsorption spectrometer, and Se analysis was conducted using an inductively coupled plasma mass spectrometry (ICP-MS). Of the trace elements investigated, only Hg has a limit set by the European Community for human consumption, and this was never exceeded. Nevertheless, based on Target Hazard Quotient (THQ) over 1, and on the Estimated Daily Intake per meal (EDIm) higher than the Provisional Tolerable Intake (PTI) suggested by the Joint FAO/WHO Expert Committee on Food Additive (JECFA), Hg oral exposure derived from consumption of the benthonic fish and of the bigger pelagic fish species analyzed, could follow the occurrence of systemic effects. Se was found always in molar excess respect to Hg in all pelagic fish and in the shellfish, nearly equimolar in the benthonic fish. Determining the evidence that foods, such as pelagic fish, with high molar excess of Se, could contribute to replace the amount of Se bound to Hg and thereby maintaining normal selenoprotein synthesis, is useful for a better understanding of the seafood safety

Potential role of probiotics on colorectal cancer prevention

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora.</p> <p>Discussion</p> <p>Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer prevention.</p> <p>Summary</p> <p>Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset. They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host’s immune response; anti-proliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase signaling pathways.</p

Summary of the Demographic, Clinical, and Neuroradiological Features of the Patients.

<p>SMA: supplementary motor area; SMG–AG: supramarginal gyrus-angular gyrus; WM: white matter.</p