The evidence-based role of catecholaminergic PET tracers in Neuroblastoma. A systematic review and a head-to-head comparison with mIBG scintigraphy.

BACKGROUND: Molecular imaging is pivotal in staging and response assessment of children with neuroblastoma (NB). [123I]-metaiodobenzylguanidine (mIBG) is the standard imaging method; however, it is characterised by low spatial resolution, time-consuming acquisition procedures and difficult interpretation. Many PET catecholaminergic radiotracers have been proposed as a replacement for [123I]-mIBG, however they have not yet made it into clinical practice. We aimed to review the available literature comparing head-to-head [123I]-mIBG with the most common PET catecholaminergic radiopharmaceuticals. METHODS: We searched the PubMed database for studies performing a head-to-head comparison between [123I]-mIBG and PET radiopharmaceuticals including meta-hydroxyephedrine ([11C]C-HED), 18F-18F-3,4-dihydroxyphenylalanine ([18F]DOPA) [124I]mIBG and Meta-[18F]fluorobenzylguanidine ([18F]mFBG). Review articles, preclinical studies, small case series (< 5 subjects), case reports, and articles not in English were excluded. From each study, the following characteristics were extracted: bibliographic information, technical parameters, and the sensitivity of the procedure according to a patient-based analysis (PBA) and a lesion-based analysis (LBA). RESULTS: Ten studies were selected: two regarding [11C]C-HED, four [18F]DOPA, one [124I]mIBG, and three [18F]mFBG. These studies included 181 patients (range 5-46). For the PBA, the superiority of the PET method was reported in two out of ten studies (both using [18F]DOPA). For LBA, PET detected significantly more lesions than scintigraphy in seven out of ten studies. CONCLUSIONS: PET/CT using catecholaminergic tracers shows superior diagnostic performance than mIBG scintigraphy. However, it is still unknown if such superiority can influence clinical decision-making. Nonetheless, the PET examination appears promising for clinical practice as it offers faster image acquisition, less need for sedation, and a single-day examination.

Spontaneous Remission of High-Grade Non-Hodgkin Lymphoma After SARS-CoV-2 Infection: A Case Report.

ABSTRACT: Despite extensive research into COVID-19 since its emergence in late 2019, there is still much not fully understood about its long-term effects. When infected with SARS-CoV-2, cancer patients have been reported to be at higher risk for unfavorable outcomes. Nevertheless, evidence suggests that viruses may exhibit an antitumor effect in some cases, which has recently been anecdotally reported with SARS-CoV-2. We present the case of a patient with a recent high-grade non-Hodgkin lymphoma diagnosis and without any cancer-specific therapy, in whom a complete metabolic response on 2-[ 18 F]FDG PET/CT was observed after COVID-19.

Beyond the Bones: A Case Report of Extraosseous Ewing Sarcoma.

Ewing sarcoma (ES) is primarily recognized as a primary bone tumor; however, its extraosseous variant is exceptionally rare and presents unique clinical challenges. In this article, we report the case of a 22-year-old male who initially presented with abdominal swelling. Diagnostic tests included abdominal imaging and a CT scan, revealing a solid liver mass. A thorough evaluation confirmed it to be an extraosseous ES, supported by liver biopsy and immunohistochemistry demonstrating positive expression for AE1/AE3 and CD-99, along with genetic analysis revealing a rearrangement of the EWSR1 gene (translocation 22q12). The patient's treatment involved a multimodal approach, including perioperative chemotherapy, surgery, and postoperative chemotherapy, following which the patient remained in complete remission after 24 months. This case emphasizes the importance of considering rare malignancies such as ES in differential diagnoses for young patients with liver masses. It also accentuates the pivotal role of family physicians in early detection and holistic patient care, underscoring the need for comprehensive investigations when encountering persistent symptoms.

Triple Therapy for Cystic Fibrosis (Elexacaftor, Tezacaftor, and Ivacaftor): Desensitization After Skin Rash.

Cystic fibrosis (CF) is an autosomal recessive disorder of the CF transmembrane conductance regulator (CFTR) gene. CFTR modulators are novel approved therapies, and triple therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is the current gold standard for patients with at least one F508del mutation. CFTR modulators are usually well-tolerated, but some adverse effects may occur, including skin rash. We report a case of a female patient who developed a severe skin rash after initiating treatment with ELX/TEZ/IVA. Modulator therapy and contraception were discontinued, and consequently, there was a drop in lung function and reappearance of respiratory symptoms. After rash resolution, a gradual reintroduction of ELX/TEZ/IVA was started, and this is the protocol the authors have summarized. Triple therapy with CFTR modulators has a significant impact on lung function and the quality of life of CF patients who have at least one F508del mutation, justifying its reintroduction and desensitization even after a severe adverse effect.

Nanofiber Carriers of Therapeutic Load: Current Trends.

The fast advancement in nanotechnology has prompted the improvement of numerous methods for the creation of various nanoscale composites of which nanofibers have gotten extensive consideration. Nanofibers are polymeric/composite fibers which have a nanoscale diameter. They vary in porous structure and have an extensive area. Material choice is of crucial importance for the assembly of nanofibers and their function as efficient drug and biomedicine carriers. A broad scope of active pharmaceutical ingredients can be incorporated within the nanofibers or bound to their surface. The ability to deliver small molecular drugs such as antibiotics or anticancer medications, proteins, peptides, cells, DNA and RNAs has led to the biomedical application in disease therapy and tissue engineering. Although nanofibers have shown incredible potential for drug and biomedicine applications, there are still difficulties which should be resolved before they can be utilized in clinical practice. This review intends to give an outline of the recent advances in nanofibers, contemplating the preparation methods, the therapeutic loading and release and the various therapeutic applications.

New Advances in Biomedical Application of Polymeric Micelles.

In the last decade, nanomedicine has arisen as an emergent area of medicine, which studies nanometric systems, namely polymeric micelles (PMs), that increase the solubility and the stability of the encapsulated drugs. Furthermore, their application in dermal drug delivery is also relevant. PMs present unique characteristics because of their unique core-shell architecture. They are colloidal dispersions of amphiphilic compounds, which self-assemble in an aqueous medium, giving a structure-type core-shell, with a hydrophobic core (that can encapsulate hydrophobic drugs), and a hydrophilic shell, which works as a stabilizing agent. These features offer PMs adequate steric protection and determine their hydrophilicity, charge, length, and surface density properties. Furthermore, due to their small size, PMs can be absorbed by the intestinal mucosa with the drug, and they transport the drug in the bloodstream until the therapeutic target. Moreover, PMs improve the pharmacokinetic profile of the encapsulated drug, present high load capacity, and are synthesized by a reproducible, easy, and low-cost method. In silico approaches have been explored to improve the physicochemical properties of PMs. Based on this, a computer-aided strategy was developed and validated to enable the delivery of poorly soluble drugs and established critical physicochemical parameters to maximize drug loading, formulation stability, and tumor exposure. Poly(2-oxazoline) (POx)-based PMs display unprecedented high loading concerning water-insoluble drugs and over 60 drugs have been incorporated in POx PMs. Among various stimuli, pH and temperature are the most widely studied for enhanced drug release at the site of action. Researchers are focusing on dual (pH and temperature) responsive PMs for controlled and improved drug release at the site of action. These dual responsive systems are mainly evaluated for cancer therapy as certain malignancies can cause a slight increase in temperature and a decrease in the extracellular pH around the tumor site. This review is a compilation of updated therapeutic applications of PMs, such as PMs that are based on Pluronics®, micelleplexes and Pox-based PMs in several biomedical applications.

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn's Disease Patients: The SUSTAIN Study.

BACKGROUND: Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn's disease (CD) patients in real-world clinical practice. METHODS: A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. RESULTS: A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). CONCLUSIONS: Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice.

This large retrospective study demonstrated the short- and long-term effectiveness and safety of ustekinumab in patients with Crohn's disease in real-world clinical practice, including those with refractory disease.

Identification of new targets of S-nitrosylation in neural stem cells by thiol redox proteomics.

Nitric oxide (NO) is well established as a regulator of neurogenesis. NO increases the proliferation of neural stem cells (NSC), and is essential for hippocampal injury-induced neurogenesis following an excitotoxic lesion. One of the mechanisms underlying non-classical NO cell signaling is protein S-nitrosylation. This post-translational modification consists in the formation of a nitrosothiol group (R-SNO) in cysteine residues, which can promote formation of other oxidative modifications in those cysteine residues. S-nitrosylation can regulate many physiological processes, including neuronal plasticity and neurogenesis. In this work, we aimed to identify S-nitrosylation targets of NO that could participate in neurogenesis. In NSC, we identified a group of proteins oxidatively modified using complementary techniques of thiol redox proteomics. S-nitrosylation of some of these proteins was confirmed and validated in a seizure mouse model of hippocampal injury and in cultured hippocampal stem cells. The identified S-nitrosylated proteins are involved in the ERK/MAPK pathway and may be important targets of NO to enhance the proliferation of NSC.

Impacto de um programa de competências parentais no stress e competências de atenção plena / Impacto de un programa de competencias parentales en el estrés y en competencias de atención plena / Effects of a parenting education program on parenting skills, parenting stress, and mindfulness skills

Resumo Objetivo: Analisar o impacto da frequência do Adults and Children Together Raising Safe Kids (ACT-RSK) Programe nas competências parentais, no stress parental e nas competências de atenção plena, de um grupo de pais de crianças. Métodos: Realizou-se uma investigação-ação, utilizando um pré e pós-teste, tendo por referência a implementação do programa ACT-RSK, em 8 sessões de 90 minutos com periodicidade semanal, numa amostra de 22 pais da região Centro de Portugal. Utilizaram-se os questionários do Programa ACT-RSK, o Índice de Stress Parental, a Escala de Mindfulness Interpessoal na Parentalidade e um questionário sociodemográfico. A análise descritiva e inferencial ( Wilcoxon ) foi realizada com recurso ao Statistical Package fos Social Sciences (SPSS - IBM 24), com grau de confiança de 95%. Resultados: Os participantes melhoraram, do pré para pós-teste, nas 4 dimensões do programa: estilos parentais (M=36.32±6.61 vs. M=48.50±4.31; p<0.01); meios de comunicação (M=24.73±3.90 vs. M=30.73±2.90; p≤0.01); desenvolvimento infantil (M=55.18±11.82 vs. M=73.55±4.04; p≤0.01); e comportamento dos pais (M=34.23±7.83 vs. M=43.05±2.81; p≤0.01). Destacam-se, igualmente, melhorias consideráveis nos resultados da Escala de Mindfulness Interpessoal na Parentalidade (Z=-3.929, p=0.000) e no stress parental, que desceu do nível muito elevado (91.59) para o nível médio (74.45). Conclusão: Constata-se o impacto positivo do ACT-RSK na melhoria das variáveis estudadas.

Resumen Objetivo: Analizar el impacto de la frecuencia del Adults and Children Together Raising Safe Kids (ACT-RSK) Programe en las competencias parentales, en el estrés parental y en las competencias de atención plena de un grupo de padres de niños. Métodos: Se realizó una investigación-acción utilizando un pretest y postest en la implementación del programa ACT-RSK, en 8 sesiones de 90 minutos con frecuencia semanal, en una muestra de 22 padres de la región Centro de Portugal. Se utilizaron los cuestionarios del programa ACT-RSK, el Índice de Estrés Parental, la Escala de Mindfulness Interpersonal en la Paternidad y un cuestionario sociodemográfico. El análisis descriptivo e inferencial ( Wilcoxon ) fue realizado con el Statistical Package for Social Sciences (SPSS - IBM 24), con nivel de confianza de 95 %. Resultados: Del pretest al postest, los participantes demostraron una mejora en las cuatro dimensiones del programa: estilos parentales (M=36,32±6,61 vs. M=48,50±4,31; p<0,01); medios de comunicación (M=24,73±3,90 vs. M=30,73±2,90; p≤0,01); desarrollo infantil (M=55,18±11,82 vs. M=73,55±4,04; p≤0,01); y comportamiento de los padres (M=34,23±7,83 vs. M=43,05±2,81; p≤0,01). Además, se destacan mejoras considerables en los resultados de la Escala de Mindfulness Interpersonal en la Paternidad (Z=-3,929, p=0,000) y el en estrés parental, que se redujo de un nivel muy elevado (91,59) a un nivel medio (74,45). Conclusión: Se verifica un impacto positivo del ACT-RSK en la mejora de las variables estudiadas.

Abstract Objective: To analyze the impact of the Adults and Children Together Raising Safe Kids (ACT-RSK) Program in parenting skills, parenting stress, and mindfulness skills in a group of parents and children. Methods: This investigative intervention was based on the application of a pre-test and a post-test before and after the implementation of the ACT-RSK Program. The program consisted of eight weekly 90-minute sessions conducted with a sample of 22 parents from Central Portugal. The ACT-RSK Program questionnaires, Parenting Stress Index (PSI), Interpersonal Mindfulness in Parenting (IM-P) scale, and a socio-demographic questionnaire were used. A descriptive and inferential analysis (Wilcoxon) was conducted using the Statistical Package for Social Sciences (IBM SPSS, v. 24) with a 95% confidence interval. Results: Participants showed improvement from pre-test to post-test in all four program dimensions: Parenting Style (M=36.32±6.61 vs. M=48.50±4.31; p<0.01); Electronic Media (M=24.73±3.90 vs. M=30.73±2.90; p≤0.01); Child Development (M=55.18±11.82 vs. M=73.55±4.04; p≤0.01); and Parental Behavior (M=34.23±7.83 vs. M=43.05±2.81; p≤0.01). Likewise, significant improvement was seen in the Interpersonal Mindfulness in Parenting (IM-P) scale's results (Z=-3.929, p=0.000) and in parenting stress, which decreased from a very high (91.59) to a medium level (74.45). Conclusion: Data show the ACT-RSK had a positive effect and improved study variables.

S-Nitrosylation of Ras Mediates Nitric Oxide-Dependent Post-Injury Neurogenesis in a Seizure Model.

AIMS: Nitric oxide (NO) is involved in the upregulation of endogenous neurogenesis in the subventricular zone and in the hippocampus after injury. One of the main neurogenic pathways activated by NO is the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway, downstream of the epidermal growth factor receptor. However, the mechanism by which NO stimulates cell proliferation through activation of the ERK/MAPK pathway remains unknown, although p21Ras seems to be one of the earliest targets of NO. Here, we aimed at studying the possible neurogenic action of NO by post-translational modification of p21Ras as a relevant target for early neurogenic events promoted by NO in neural stem cells (NSCs). RESULTS: We show that NO caused S-nitrosylation (SNO) of p21Ras in Cys118, which triggered downstream activation of the ERK/MAPK pathway and proliferation of NSC. Moreover, in cells overexpressing a mutant Ras in which Cys118 was replaced by a serine-C118S-, cells were insensitive to NO, and no increase in SNO, in ERK phosphorylation, or in cell proliferation was observed. We also show that, after seizures, in the presence of NO derived from inducible nitric oxide synthase, there was an increase in p21Ras cysteine modification that was concomitant with the previously described stimulation of proliferation in the dentate gyrus. INNOVATION: Our work identifies p21Ras and its SNO as an early target of NO during signaling events that lead to NSC proliferation and neurogenesis. CONCLUSION: Our data highlight Ras SNO as an early event leading to NSC proliferation, and they may provide a target for NO-induced stimulation of neurogenesis with implications for brain repair. Antioxid. Redox Signal. 28, 15-30.

Caffeine Reverts Memory But Not Mood Impairment in a Depression-Prone Mouse Strain with Up-Regulated Adenosine A2A Receptor in Hippocampal Glutamate Synapses.

Caffeine prophylactically prevents mood and memory impairments through adenosine A2A receptor (A2AR) antagonism. A2AR antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 ± 7 %) and GABAergic (vGAT; -23 ± 8 %) markers in the hippocampus. HM displayed higher A2AR density (72 ± 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A2AR agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 ± 8 % vs. 21 ± 5 % in controls) that was restored to control levels (30 ± 10 %) by the A2AR antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A2AR controlling synaptic glutamatergic function.

[Relationship between smoking and anxiety and depression in primary care]. / Relação do tabagismo com ansiedade e depressão nos cuidados de saúde primários.

INTRODUCTION: Smoking prevalence in Portugal is estimated to be 19.7% (2005). Smoking is prevalent in anxiety disorders. Studies report that 60% of smokers have a history of depression. The Fagerström scale can be used to assess smoke dependence. The Hospital Anxiety and Depression Scale allows an estimate of anxiety and depression. Our goal was to find whether there is a relationship between smoking and anxiety / depression in eight clinics within primary care practice. MATERIAL AND METHODS: We designed an observational, descriptive, cross-sectional, analytical study. Anonymous survey. We considered as inclusion criteria the over 18 years of age and literate clinic users and as exclusion criteria the under 18 years old users or incomplete surveys. We defined as variables: Fagerström, Hospital Anxiety and Depression Scale, age, marital status, gender, profession, schooling. RESULTS: We obtained a total of 608 valid surveys of which there were 64% women and 21% smokers. We found no differences in the prevalence of anxiety or depression when comparing non-smokers, ex-smokers and smokers. We found that the degree of nicotine addiction varies directly with anxiety and depression, however, the only statistically significant relationship observed was in women, even after correcting the effect of age. DISCUSSION: There is a relationship between nicotine dependence and the severity of symptoms of anxiety and depression, most relevant in women. LIMITATION: selection bias. CONCLUSION: This study supplies information regarding psychological factors associated with tobacco consumption, allowing for its inclusion in treatment options for nicotine dependence.

Introdução: A prevalência de tabagismo em Portugal é estimada em 19,7% (2005). O tabagismo é prevalente nas perturbações da ansiedade. Alguns estudos referem que 60% dos fumadores tem história de depressão. A dependência tabágica pode ser avaliada pela escala de Fagerström. A Escala de Ansiedade e Depressão Hospitalar permite estimar a ansiedade e depressão. O objectivo deste trabalho foi procurar a existência de relação entre tabagismo e ansiedade/depressão em utentes de oito unidades de cuidados primários.Material e Métodos: Foi desenhado um estudo observacional, descritivo, transversal, analítico. Inquérito anónimo. Foram considerados como critérios de inclusão os utilizadores das unidades, maiores de 18 anos e alfabetizados e de exclusão os menores de 18 anos ou erros no preenchimento dos inquéritos. As variáveis consideradas foram: Fagerström, Escala de Ansiedade e Depressão Hospitalar, idade, estado civil, género, profissão, escolaridade.Resultados: Foram considerados no estudo um total de 608 indivíduos, sendo 64% do género feminino e 21% de fumadores. Não verificámos diferenças em termos de ansiedade ou depressão na comparação entre não fumadores, ex-fumadores e fumadores. Verificámos que o grau de dependência da nicotina varia directamente com a ansiedade e depressão embora só se encontre relação estatisticamente significativa no género feminino, mesmo após correcção do efeito da idade.Discussão: Existe relação entre dependência da nicotina e gravidade de sintomas de ansiedade e depressão, sobretudo no género feminino. Limitação: viés de selecção.Conclusão: Este estudo fornece informação relativa aos factores psicológicos associados ao consumo de tabaco, podendo ser útil no tratamento da dependência de nicotina.

Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia.

A chronic stress paradigm comprising exposure to predation, tail suspension and restraint induces a depressive syndrome in C57BL/6J mice that occurs in some, but not all, animals. Here, we sought to extend our behavioural studies to investigate how susceptibility (sucrose preference<65%) or resilience (sucrose preference>65%) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes. All chronically stressed animals, displayed increased level of anxiety, but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions. These changes were not present in resilient or acutely stressed animals. Compared to resilient animals, susceptible mice showed elevated expression of tumour necrosis factor alpha (TNF) and the 5-HT transporter (SERT) in the pre-frontal area. Enhanced expression of 5HT(2A) and COX-1 in the pre-frontal area was observed in all stressed animals. In turn, indoleamine-2,3-dioxygenase (IDO) was significantly unregulated in the raphe of susceptible animals. At the cellular level, increased numbers of Iba-1-positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals. Consequently, the susceptible animals display a unique molecular profile when compared to resilient, but anxious, animals. Unexpectedly, this altered profile provides a rationale for exploring anti-inflammatory, and possibly, TNF-targeted therapy for major depression.

Estimation of the collective dose in the Portuguese population due to medical procedures in 2010.

In a wide range of medical fields, technological advancements have led to an increase in the average collective dose in national populations worldwide. Periodic estimations of the average collective population dose due to medical exposure is, therefore of utmost importance, and is now mandatory in countries within the European Union (article 12 of EURATOM directive 97/43). Presented in this work is a report on the estimation of the collective dose in the Portuguese population due to nuclear medicine diagnostic procedures and the Top 20 diagnostic radiology examinations, which represent the 20 exams that contribute the most to the total collective dose in diagnostic radiology and interventional procedures in Europe. This work involved the collaboration of a multidisciplinary taskforce comprising representatives of all major Portuguese stakeholders (universities, research institutions, public and private healthcare providers, administrative services of the National Healthcare System, scientific and professional associations and private service providers). This allowed us to gather a comprehensive amount of data necessary for a robust estimation of the collective effective dose to the Portuguese population. The methodology used for data collection and dose estimation was based on European Commission recommendations, as this work was performed in the framework of the European wide Dose Datamed II project. This is the first study estimating the collective dose for the population in Portugal, considering such a wide national coverage and range of procedures and consisting of important baseline reference data. The taskforce intends to continue developing periodic collective dose estimations in the future. The estimated annual average effective dose for the Portuguese population was of 0.080±0.017 mSv caput(-1) for nuclear medicine exams and of 0.96±0.68 mSv caput(-1) for the Top 20 diagnostic radiology exams.