Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies.

Neuropeptide Y (NPY) is one of the most abundant peptides in the central nervous system of mammals and is involved in several physiological processes through NPY Y1, Y2, Y4 and Y5 receptors. Of those, the Y2 receptor has particular relevance for its autoreceptor role in inhibiting the release of NPY and other neurotransmitters and for its involvement in relevant mechanisms such as feeding behaviour, cognitive processes, emotion regulation, circadian rhythms and disorders such as epilepsy and cancer. PET imaging of the Y2 receptor can provide a valuable platform to understand this receptor's functional role and evaluate its potential as a therapeutic target. In this work, we set out to refine the chemical and radiochemical synthesis of the Y2 receptor antagonist N-[11C]Me-JNJ31020028 for in vivo PET imaging studies. The non-radioactive reference compound, N-Me-JNJ-31020028, was synthesised through batch synthesis and continuous flow methodology, with 43% and 92% yields, respectively. N-[11C]Me-JNJ-31020028 was obtained with a radiochemical purity > 99%, RCY of 31% and molar activity of 156 GBq/µmol. PET imaging clearly showed the tracer's biodistribution in several areas of the mouse brain and gut where Y2 receptors are known to be expressed.

School engagement, school climate and youth externalizing behaviors: direct and indirect effects of parenting practices.

This research aimed to explore the direct and indirect effects of students' school engagement, school climate and parenting practices on youth's externalizing behaviors. A quantitative methodology with a sample of 183 Portuguese students, aged between 11 and 16 years old, was used. The main results suggested negative associations between externalizing behaviors and higher levels of school engagement and positive school climate. Poor parental supervision, inconsistent discipline and corporal punishment were positively related with externalizing behaviors, contrary to parental involvement and positive parenting that were associated with lower levels of externalizing behaviors. However, negative parenting practices were associated with lower levels of school engagement. Additionally, the results indicated that parenting practices might influence youth's externalizing behaviors through school engagement.

The clinical and translational prospects of microneedle devices, with a focus on insulin therapy for diabetes mellitus as a case study.

Microneedles have the clinical advantage of being able to deliver complex drugs across the skin in a convenient and comfortable manner yet haven't successfully transitioned to medical practice. Diabetes mellitus is a complicated disease, which is commonly treated with multiple daily insulin injections, contributing to poor treatment adherence. Firstly, this review determines the clinical prospect of microneedles, alongside considerations that ought to be addressed before microneedle technology can be translated from bench to bedside. Thereafter, we use diabetes as a case study to consider how microneedle-based-technology may be successfully harnessed. Here, publications referring to insulin microneedles were evaluated to understand whether insertion efficiency, angle of insertion, successful dose delivery, dose adjustability, material biocompatibility and therapeutic stability are being addressed in early stage research. Moreover, over 3,000 patents from 1970 to 2019 were reviewed with the search term '"microneedle" AND "insulin"' to understand the current status of the field. In conclusion, the reporting of early stage microneedle research demonstrated a lack of consistency relating to the translational factors addressed. Additionally, a more rational design, based on a patient-centred approach is required before microneedle-based delivery systems can be used to revolutionise the lives of people living with diabetes following regulatory approval.

PET Imaging of the Neuropeptide Y System: A Systematic Review.

Neuropeptide Y (NPY) is a vastly studied biological peptide with numerous physiological functions that activate the NPY receptor family (Y1, Y2, Y4 and Y5). Moreover, these receptors are correlated with the pathophysiology of several diseases such as feeding disorders, anxiety, metabolic diseases, neurodegenerative diseases, some types of cancers and others. In order to deepen the knowledge of NPY receptors' functions and molecular mechanisms, neuroimaging techniques such as positron emission tomography (PET) have been used. The development of new radiotracers for the different NPY receptors and their subsequent PET studies have led to significant insights into molecular mechanisms involving NPY receptors. This article provides a systematic review of the imaging biomarkers that have been developed as PET tracers in order to study the NPY receptor family.

Hypertonic saline for severe symptomatic hyponatraemia: real-world findings from the UK.

Objective: To evaluate 'real-world' safety and efficacy of the European Society of Endocrinology guidelines for the treatment of severe symptomatic hyponatraemia using hypertonic saline (HTS). Design: Retrospective, observational, cohort study, examining the use of HTS for severe symptomatic hyponatraemia at Sheffield Teaching Hospitals between 2017 and 2020. Methods: Patients were identified from pharmacy records and demographic, clinical, and treatment data extracted. Results: Out of 112 patients (females:males = 61:51), the mean age ± s.d. was 66.3± 16.0 years and mean pre-treatment serum sodium ± s.d. was 113.8 ± 6.4 mmol/L. Overall, overcorrection rates at 24 and 48 h (>10 and >18 mmol/L) were 44.9 and 19.6%, respectively, while 19.6% of patients were treated for overcorrection. Above-target rise in sodium (>5 mmol/L) after first and second boluses was noted in 22.6 and 34.6% of patients, respectively. In-hospital and 12-month mortality was 7.1 and 18.7%, respectively, with no cases of osmotic demyelination. The mean venous blood gas (VBG) sodium was 1.9 mmol/L lower than paired serum sodium (n = 36) (113.6 ± 6.6 vs 115.7 ± 7.8 mmol/L). Conclusion: We report real-world data demonstrating that a significant number of patients overcorrected using current guidelines. Also, several patients had above-target rise in sodium after one bolus of HTS, and sodium measurement should be considered before the second bolus unless ongoing severe symptoms persist. A point of care VBG sodium concentration was useful for this purpose. In addition to careful monitoring, a cautious but anticipatory overcorrection prevention strategy should be considered in the first 24 h.

Virulence and Reproductive Fitness of Meloidogyne paranaensis Field Populations in Coffee Genotypes.

The aim of this study was to characterize Meloidogyne paranaensis populations collected from infested coffee crops. Methodologies used to characterize the 11 studied populations from municipalities in Paraná and Minas Gerais States involved the morphological analysis of perineal patterns, biochemical analysis by isozyme electrophoresis, sequencing of internal transcribes spacer 1 (ITS-1) and D2/D3 ribosomal DNA (rDNA) regions, reproductive fitness, and virulence characterization in coffee genotypes. Morphological evaluations showed the existence of variation between populations, although the majority of them showed typical perineal patterns. The biochemical identification was based on α-esterase isozyme analyses and resulted in the appearance of three distinct profiles: P1 (typical), P2 (atypical), and a nondescribed profile, P2b. BLAST of the ITS-1 and D2/D3 rDNA regions indicated homology (>95%) with other sequences deposited in GenBank. For reproductive fitness and virulence characterization, 13 coffee genotypes (5 Coffea arabica and 8 C. canephora) were inoculated with 11 M. paranaensis populations. Variation in the reproductive fitness of populations was observed for cultivar Mundo Novo, a genotype without resistance genes, and variation in the virulence of populations was observed in genotypes carrying resistance genes. Three populations exhibited virulence combined with high reproductive fitness, while one showed virulence with low reproductive fitness. Some hosts were resistant to 11 populations, while one of the hosts was resistant to only one population, indicating the presence of different resistance genes. Nevertheless, no relationship was observed between the origin of population and their variations in perineal patterns, esterase profiles, phylogeny, or reproductive fitness in coffee genotypes, or between the different characterizations, although differences were observed within each characteristic.

Optical coherence tomography angiography in herpetic leucoma.

BACKGROUND: Herpes simplex virus (HSV) keratitis remains a leading infectious cause of blindness worldwide. Although all forms of HSV keratitis are commonly recurrent, the risk is greatest in stromal keratitis, which is the most likely to result in corneal scarring, thinning, and neovascularization. Recent studies showed the ability of Optical Coherence Tomography Angiography (OCTA) to detect and study vascular abnormalities in the anterior segment, including abnormal corneal vessels. This study intends to investigate the potential of OCTA device to image and describe quantitatively the vascularization in eyes diagnosed with herpetic leucoma and to discuss and review the usefulness of this technique in this pathology. METHODS: A Cross-sectional study was made, including 17 eyes of 15 patients with leucoma secondary to herpetic keratitis. All eyes underwent anterior segment Slit-Lamp photography (SLP), and OCTA with en-face, b-scans and c-scans imaging. The vessel density (VD) was analyzed in the inferior, nasal and temporal corneal margin in all patients, and in the central area, in eyes with central corneal neovascularization (CoNV). The measurements were calculated after binarization with ImageJ software, using OCTA scans with 6 × 6 mm in a depth of 800 µm. RESULTS: Patients included had a mean age 53.267 ± 21.542 (years ± SD). The mean total vessel area was 50.907% ± 3.435%. VD was higher in the nasal quadrant (51.156% ± 4.276%) but there were no significant differences between the three analyzed areas (p = 0.940). OCTA was able to identify abnormal vessels when SLP apparently showed no abnormal vessels; OCTA was able to distinguish between larger and smaller vessels even in central cornea; OCTA scans allowed the investigation of several corneal planes and the relation of them with clinical findings. CONCLUSIONS: OCTA can be useful in both qualitative and quantitative follow-up of patients and may become a non-invasive alternative to objectively monitor treatment response in eyes with corneal vascularization due to herpetic infection.

Cannabinoid Hyperemesis Syndrome: A Case Report of an Underdiagnosed Condition.

Cannabinoid hyperemesis syndrome (CHS) is characterized by episodic bursts of nausea, vomiting and abdominal pain, affecting chronic cannabis users. The clinical picture mimics an acute abdomen, usually leading to multiple assessments in the emergency department. Several complementary diagnostic examinations are performed with non-specific results, making differential diagnosis puzzling. We present a case of a 42-year-old man, who has been admitted multiple times to the emergency department in the last 3 months for abdominal pain, nausea and vomiting, without triggering factors and improving only with hot water baths. He was evaluated by different specialties, the various complementary diagnostic tests performed showed no significant results, and no definitive diagnosis was obtained. Treatment resulted only in a partial and transient resolution of symptoms. A more detailed medical history revealed cannabis use for more than 5 years, with a recent increase in the amount consumed. After psychoeducation, explaining the risks associated with consumption and its relationship with the clinical symptoms, which resulted in complete suspension of cannabis, there have been no new symptomatic episodes since then. We present an illustrative case of a poorly reported clinical entity despite having a probable significant prevalence, raising awareness in order that clinicians identify and properly manage these cases.

A Síndrome Hiperemética dos Canabinóides cursa com crises episódicas de náuseas, vómitos e dor abdominal que acometem consumidores crónicos de cannabis. O quadro clínico mimetiza o de um abdómen agudo, condicionando habitualmente múltiplas avaliações no Serviço de Urgência (SU) que levam à realização de vários exames complementares de diagnóstico (ECD), cujos resultados tendem a ser inespecíficos, dificultando o diagnóstico diferencial. Apresentamos o caso de um homem de 42 anos de idade, sem antecedentes psiquiátricos conhecidos, que nos últimos 3 meses foi admitido por múltiplas vezes no SU Hospitalar por dor abdominal, náuseas e vómitos aliviados com banhos de água quente. Vários exames auxiliares de diagnóstico e avaliação por diferentes especialidades foram realizados, sem que se obtivesse um diagnóstico definitivo. A terapêutica sintomática instituída resultou apenas numa resolução parcial e transitória dos sintomas. Uma história clínica mais detalhada revelou um consumo de cannabis há mais de 5 anos, com incremento recente da quantidade consumida. Após psicoeducação ao doente, explicando os riscos do consume de canabinóides e a sua relação com a sintomatologia apresentada resultou na suspensão completa no consume de cannabis, não se tendo verificado novos episódios sintomáticos desde então. Este é um caso ilustrativo de uma entidade clínica recente, cuja prevalência está a aumentar, tendo em conta o aumento do consumo de cannabis. A adequada identificação desta patologia é fundamental para um tratamento adequado e eficaz, evitando o uso desnecessário de métodos complementares de diagnóstico e medicação.

Portuguese parental beliefs and attitudes towards vaccination.

INTRODUCTION: Portugal has one of the highest vaccine coverage rates among European countries, associated with excellent vaccine convenience and confidence levels. Considering both the high rate of pediatric vaccination in Portugal and the excellent indicators of vaccine convenience established, an analysis of confidence and complacency indicators could help understand this positive example. This study aimed to characterize parental beliefs according to the intention to vaccinate a next child and identify cognitive and demographic predictors of that intention in a Portuguese sample. METHODS: We measured perceptions of vaccines' safety and efficacy, perceptions of the severity of vaccine-preventable diseases, beliefs related to conspiracy theories, attitudes towards immunization requirements, perceptions of social norms as predictors of the intention to vaccinate a subsequent child. We also inquired if parents had previously refused a recommended vaccine. The authors disseminated the questionnaire online to reach a diverse population of parents of 0-12 years old children. The final sample included 1,118 parents, 96.9% reported their intention to vaccinate the next child, and 3.6% had previously refused a vaccine. Two additional open-ended questions regarding motives to vaccinate or refuse a future baby's vaccination were answered by 886 parents. RESULTS: All the evaluated parental cognitive dimensions were significantly different between the group of parents who would vaccinate a next child and those who expressed the intention not to vaccinate. Beliefs about the safety and efficacy of vaccines and having fewer children were significant predictors of that intention. CONCLUSION: The vast majority of parents reported attitudes and beliefs favorable to pediatric vaccination with high consistency in all cognitive dimensions assessed. Concerns regarding pediatric vaccines' safety need to be sensitively and actively addressed by health providers to maintain excellent vaccination coverage rates.

Advances in the automated synthesis of 6-[18F]Fluoro-L-DOPA.

The neurotracer 6-[18F] FDOPA has been, for many years, a powerful tool in PET imaging of neuropsychiatric diseases, movement disorders and brain malignancies. More recently, it also demonstrated good results in the diagnosis of other malignancies such as neuroendocrine tumours, pheochromocytoma or pancreatic adenocarcinoma.The multiple clinical applications of this tracer fostered a very strong interest in the development of new and improved methods for its radiosynthesis. The no-carrier-added nucleophilic 18F-fluorination process has gained increasing attention, in recent years, due to the high molar activities obtained, when compared with the other methods although the radiochemical yield remains low (17-30%). This led to the development of several nucleophilic synthetic processes in order to obtain the product with molar activity, radiochemical yield and enantiomeric purity suitable for human PET studies.Automation of the synthetic processes is crucial for routine clinical use and compliance with GMP requirements. Nevertheless, the complexity of the synthesis makes the production challenging, increasing the chance of failure in routine production. Thus, for large-scale clinical application and wider use of this radiopharmaceutical, progress in the automation of this complex radiosynthesis is of critical importance.This review summarizes the most recent developments of 6-[18F]FDOPA radiosynthesis and discusses the key issues regarding its automation for routine clinical use.

Hydration methods and physiological potential of sweet corn seeds / Métodos de hidratação e potencial fisiológico de sementes de milho doce

The evaluation of the physiological potential of sweet corn seeds is fundamental in the production process, because the germination and vigor reflect the potential for storage, commercialization and use of these seeds. The choice of vigor tests with an adequate and efficient analysis methodology is fundamental to obtaining reliable results. In this sense, the objective of this study was to assess the physiological potential of sweet corn seeds after hydration using different moistening methods to increase water content to 20%. First, the lot of seeds was characterized as to its moisture content and initial physiological potential. Subsequently, two experiments were conducted, both under a completely randomized design. In the first experiment, different volumes of water on the filter paper sheets were assessed for seed hydration a method that uses a wet substrate. In the second, four hydration methods were evaluated: wet substrate (WS), humid atmosphere (HU), immersion in water (IW) and addition of the required amount of water (WR). A constant temperature of 25ºC was used in both experiments and then the moisture content and physiological potential of seeds were determined. The humid atmosphere method reduces the physiological quality of sweet corn seeds because it favors the deterioration and hence is unsuitable for the hydration of seeds of this species. The wet substrate method, in an amount equivalent to 2.5 times the paper mass, increased the water content of sweet corn seeds to 20%, achieving the desired degree of moisture without altering their physiological potential.

A avaliação do potencial fisiológico de sementes de milho doce é fundamental no processo de produção, pois a germinação e o vigor refletem o potencial de armazenamento, comercialização e utilização dessas sementes. A escolha de testes de vigor com uma metodologia de análise adequada e eficiente é fundamental para a obtenção de resultados confiáveis. Nesse sentido, o objetivo deste estudo foi avaliar o potencial fisiológico de sementes de milho doce após hidratação sob diferentes métodos de umedecimento, visando elevar o teor de água para 20%. O lote de sementes foi caracterizado quanto a umidade e o potencial fisiológico inicial. Posteriormente, foram conduzidos dois experimentos, ambos sob delineamento inteiramente casualizado. No primeiro, foram avaliadas diferentes quantidades de água no papel para hidratação das sementes pelo método do substrato úmido. No segundo, foram avaliados quatro métodos de umedecimento: substrato úmido (WS), atmosfera úmida (HU), imersão em água (IW) e adição da quantidade de água requerida (WR). Em ambos experimentos foi utilizada temperatura constante de 25ºC e, posteriormente, foram determinados a umidade e o potencial fisiológico das sementes. O método da atmosfera úmida reduz a qualidade fisiológica das sementes de milho doce pois favorece a deterioração, sendo inadequado para a hidratação de sementes desta espécie. O método do substrato úmido, na proporção de 2,5 vezes a massa do papel em água, mostrou-se adequado para a elevação do teor de água de sementes de milho doce para 20%, por permitir a obtenção do grau de umidade desejado sem alterar o potencial fisiológico.

Improving the quality of insulin prescribing for people with diabetes being discharged from hospital.

Medication errors involving insulin in hospital are common, and may be particularly problematic at the point of transfer of care. Our aim was to improve the safety of insulin prescribing on discharge from hospital using a continuous improvement methodology involving cycles of iterative change. A multidisciplinary project team formulated locally tailored insulin discharge prescribing guidance. After baseline data collection, three 'plan-do-study-act' cycles were undertaken over a 3-week period (September/October 2018) to introduce the guidelines and improve the quality of discharge prescriptions from one diabetes ward at the hospital. Discharge prescriptions involving insulin from the ward during Monday to Friday of each week were examined, and their adherence to the guidance measured. After the introduction of the guidelines in the form of a poster, and later a checklist, the adherence to guidelines rose from an average of 50% to 99%. Qualitative data suggested that although it took pharmacists slightly longer to clinically verify discharge prescriptions, the interventions resulted in a clear and helpful reminder to help improve discharge quality for the benefit of patient safety. This project highlights that small iterative changes made by a multidisciplinary project team can result in improvement of insulin discharge prescription quality. The sustainability and scale of the intervention may be improved by its integration into the electronic prescribing system so that all users may access and refer to the guidance when prescribing insulin for patients at the point of discharge.

Major duodenal diverticular bleeding / Hemorragia de divertículo duodenal

No disponible

Novel insights into the antioxidant role of tauroursodeoxycholic acid in experimental models of Parkinson's disease.

Impaired mitochondrial function and generation of reactive oxygen species are deeply implicated in Parkinson's disease progression. Indeed, mutations in genes that affect mitochondrial function account for most of the familial cases of the disease, and post mortem studies in sporadic PD patients brains revealed increased signs of oxidative stress. Moreover, exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor, leads to clinical symptoms similar to sporadic PD. The bile acid tauroursodeoxycholic acid (TUDCA) is an anti-apoptotic molecule shown to protect against MPTP-induced neurodegeneration in mice, but the mechanisms involved are still incompletely identified. Herein we used MPTP-treated mice, as well as primary cultures of mice cortical neurons and SH-SY5Y cells treated with MPP+ to investigate the modulation of mitochondrial dysfunction by TUDCA in PD models. We show that TUDCA exerts its neuroprotective role in a parkin-dependent manner. Overall, our results point to the pharmacological up-regulation of mitochondrial turnover by TUDCA as a novel neuroprotective mechanism of this molecule, and contribute to the validation of TUDCA clinical application in PD.

Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the cause of PD remains elusive, mitochondrial dysfunction and severe oxidative stress are strongly implicated in the cell death that characterizes the disease. Under oxidative stress, the master regulator of cellular redox status, nuclear factor erythroid 2 related factor 2 (Nrf2), is responsible for activating the transcription of several cytoprotective enzymes, namely glutathione peroxidase (GPx) and heme oxygenase-1 (HO-1). Nrf2 is a promising target to limit reactive oxygen species (ROS)-mediated damage in PD. Here, we show that tauroursodeoxycholic acid (TUDCA) prevents both 1-methyl-4-phenylpyridinium (MPP+)- and α-synuclein-induced oxidative stress, through Nrf2 activation, in SH-SY5Y cells. Additionally, we used C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to elucidate the effect of TUDCA in this in vivo model of PD. In vivo, TUDCA treatment increases the expression of Nrf2, Nrf2 stabilizer DJ-1, and Nrf2 downstream target antioxidant enzymes HO-1 and GPx. Moreover, we found that TUDCA enhances GPx activity in the brain. Altogether, our results suggest that TUDCA is a promising agent to limit ROS-mediated damage, in different models of PD acting, at least in part, through modulation of the Nrf2 signaling pathway. Therefore, TUDCA should be considered a promising therapeutic agent to be implemented in PD.