Morin Hydrate Encapsulation and Release from Mesoporous Silica Nanoparticles for Melanoma Therapy.

Melanoma incidence, a type of skin cancer, has been increasing worldwide. There is a strong need to develop new therapeutic strategies to improve melanoma treatment. Morin is a bioflavonoid with the potential for use in the treatment of cancer, including melanoma. However, therapeutic applications of morin are restrained owing to its low aqueous solubility and limited bioavailability. This work investigates morin hydrate (MH) encapsulation in mesoporous silica nanoparticles (MSNs) to enhance morin bioavailability and consequently increase the antitumor effects in melanoma cells. Spheroidal MSNs with a mean size of 56.3 ± 6.5 nm and a specific surface area of 816 m2/g were synthesized. MH was successfully loaded (MH-MSN) using the evaporation method, with a loading capacity of 28.3% and loading efficiency of 99.1%. In vitro release studies showed that morin release from MH-MSNs was enhanced at pH 5.2, indicating increased flavonoid solubility. The in vitro cytotoxicity of MH and MH-MSNs on human A375, MNT-1 and SK-MEL-28 melanoma cell lines was investigated. Exposure to MSNs did not affect the cell viability of any of the cell lines tested, suggesting that the nanoparticles are biocompatible. The effect of MH and MH-MSNs on reducing cell viability was time- and concentration-dependent in all melanoma cell lines. The A375 and SK-MEL-28 cell lines were slightly more sensitive than MNT-1 cells in both the MH and MH-MSN treatments. Our findings suggest that MH-MSNs are a promising delivery system for the treatment of melanoma.

Portal cavernoma in type 1 neurofibromatosis: A fortuitous or causal association?

Neurofibromatosis type 1 (NF-1) is a multisystem genetic disorder affecting the NF1 tumor suppressor gene. Patients typically develop superficial (cutaneous) and internal (plexiform) neurofibromas. The latter may rarely involve the liver locating in the hilum and encasing the portal vessels, leading to portal hypertension. Vascular abnormalities (NF-I vasculopathy) are a well-recognized manifestation of NF-1. Although the pathogenesis is not well-known, NF-1 vasculopathy involves arteries of both peripheral and cerebral territories, with venous thrombosis being exceptionally reported. Portal venous thrombosis (PVT) is the leading cause of portal hypertension in childhood and has been associated with several risk factors. Nevertheless, predisposing conditions remain unknown in more than 50% of the cases. The treatment options are limited, and its management is nonconsensual in the pediatric age. We report the case of a 9-year-old boy with clinically and genetically confirmed NF-1, diagnosed with portal venous cavernoma after an episode of gastrointestinal bleeding. There were no identifiable risk factors for PVT and intrahepatic peri-hilar plexiform neurofibroma was excluded by MRI imaging. To the best of our knowledge, this is the first report of PVT in NF-1. We speculate that NF-1 vasculopathy may have been a pathogenic factor, or instead, it was a fortuitous association.

A Patient With Mental Disorder Wrongly Detained in a European Migrant Detention Centre.

The admission of undocumented migrants and refugees to detention centres (DC) has been systematically associated with several poor mental health outcomes. Much less is known about people with mental health disorders, non-migrants, who might be wrongfully committed to these facilities. This article draws on Dave's case, where a German citizen was detained in a migrant DC in Porto. The patient was later treated and diagnosed with schizophrenia. In light of another case report, we conceptualize the "Cornelia's phenomenon" by which a person with full citizenship rights but with a severe mental disorder is wrongly committed to a DC. We hypothesize that this worrisome phenomenon is underestimated, and we will discuss how pre-existent psychopathology might predispose vulnerable people to this situation. We will discuss the negative impact that detention might have on these patients, proposing solutions that might amend this worrisome phenomenon.

The animal's microbiome and cancer: A translational perspective.

Cancer is a substantial global health problem both in humans and animals with a consistent increase in mortality and incidence rate. The commensal microbiota has been involved in the regulation of several physiological and pathological processes, both within the gastrointestinal system and at distant tissue locations. Cancer is not an exception, and different aspects of the microbiome have been described to have anti- or pro-tumour effects. Using new techniques, for example high-throughput DNA sequencing, microbial populations of the human body have been largely described and, in the last years, studies more focused on companions' animals have emerged. In general, the recent investigations of faecal microbial phylogeny and functional capacity of the canine and feline gut have shown similarities with human gut. In this translational study we will review and summarize the relation between the microbiota and cancer, in humans and companion animals, and compare their resemblance in the type of neoplasms already studied in veterinary medicine: multicentric and intestinal lymphoma, colorectal tumours, nasal neoplasia and mast cell tumours. In the context of One Health, microbiota and microbiome integrative studies may contribute to the understanding of the tumourigenesis process, besides offering an opportunity to develop new diagnostics and therapeutic biomarkers both for veterinary and human oncology.

Kaposi sarcoma in three pediatric liver transplantation recipients.

BACKGROUND: Kaposi sarcoma (KS) is an endothelial cell tumor, rare in children. It is 200 times more frequent after solid organ transplantation than in the general population. METHODS: We report three cases of pediatric patients who developed KS after liver transplantation (LT). RESULTS: Case 1, a 4-year-old boy undergoing LT due to familial intrahepatic cholestasis. Five months after LT, he presented with fever, dyspnea, and cough with enlarged lymph nodes and splenomegaly, anemia, thrombocytopenia, elevated liver enzymes, and positive EBV viral load. Lymph node biopsy diagnosed KS with an elevated HHV8 viral load. Case 2, a 4-year-old boy who underwent LT due to secondary biliary cirrhosis resulting from extrahepatic biliary atresia. Two years later, graft dysfunction was noticed with positive EBV viral load, thrombocytopenia, massive cervical lymph node enlargement, and splenomegaly. Lymph node biopsy diagnosed KS, Castleman's disease, and plasmablastic lymphoma related to HHV8 infection. Case 3, a 15-month-old girl, who received two LT due to biliary cirrhosis. Six months later, she presented with diarrhea, abdominal distension, anemia, thrombocytopenia, enlarged lymph nodes, splenomegaly, and positive CMV viral load. Axillary lymph node biopsy diagnosed KS and HHV8 infection was confirmed. In all three cases, tacrolimus was discontinued and, after diagnosis, sirolimus was started. All recovered without relapse and have a good graft function. CONCLUSIONS: Kaposi sarcoma is a rare disease post-LT in children. Recognizing keywords and early diagnosis is crucial for timely treatment and survival.

The human and animals' malignant melanoma: comparative tumor models and the role of microbiome in dogs and humans.

Currently, the most progressively occurring incident cancer is melanoma. The mouse is the most popular model in human melanoma research given its various benefits as a laboratory animal. Nevertheless, unlike humans, mice do not develop melanoma spontaneously, so they need to be genetically manipulated. In opposition, there are several reports of other animals, ranging from wild to domesticated animals, that spontaneously develop melanoma and that have cancer pathways that are similar to those of humans. The influence of the gut microbiome on health and disease is being the aim of many recent studies. It has been proven that the microbiome is a determinant of the host's immune status and disease prevention. In human medicine, there is increasing evidence that changes in the microbiome influences malignant melanoma progression and response to therapy. There are several similarities between some animals and human melanoma, especially between canine and human oral malignant melanoma as well as between the gut microbiome of both species. However, microbiome studies are scarce in veterinary medicine, especially in the oncology field. Future studies need to address the relevance of gut and tissue microbiome for canine malignant melanoma development, which results will certainly benefit both species in the context of translational medicine.

[Correction to the article "Medication Reconciliation During Admission to an Internal Medicine Department: A Pilot Study", Published as Ahead of Print on Acta Med Port 2022.] / Errata ao artigo "Reconciliação Terapêutica na Admissão de um Serviço de Medicina Interna: Estudo-Piloto", Publicado em Ahead of Print em Acta Med Port 2022.

Na página 9, Figura 2 onde se lê:73,53%Deverá ler-se:76,48%Artigo publicado com erros: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/16892.

Drug Delivery Systems and Flavonoids: Current Knowledge in Melanoma Treatment and Future Perspectives.

Melanoma is an aggressive form of skin cancer with a high prevalence in the population. An early diagnosis is crucial to cure this disease. Still, when this is not possible, combining potent pharmacological agents and effective drug delivery systems is essential to achieve optimal treatment and improve patients' quality of life. Nanotechnology application in biomedical sciences to encapsulate anticancer drugs, including flavonoids, in order to enhance therapeutic efficacy has attracted particular interest. Flavonoids have shown effectiveness against various types of cancers including in melanoma, but they show low aqueous solubility, low stability and very poor oral bioavailability. The utilization of novel drug delivery systems could increase flavonoid bioavailability, thereby potentiating its antitumor effects in melanoma. This review summarizes the potential of different flavonoids in melanoma treatment and the several nanosystems used to improve their biological activity, considering published information that reported improved biological and pharmacological properties of encapsulated flavonoids.

Immunohistochemical Expression of Platelet-Derived Growth Factor Receptor ß (PDGFR-ß) in Canine Cutaneous Peripheral Nerve Sheath Tumors: A Preliminary Study.

As in humans, the prevalence of tumors in companion animals is increasing dramatically and there is a strong need for research on new pharmacological agents particularly for the treatment of those tumors that are resistant to conventional chemotherapy agents such as soft tissue sarcomas (STS). Because malignant (MPNST) and benign peripheral nerve sheath tumors (BPNST) are relatively common STS in dogs, the aim of this retrospective study was to evaluate the immunohistochemical (IHC) expression of PDGFR-ß, contributing to its characterization as a potential target for their treatment. A total of 19 samples were included, 9 histologically classified as benign and the other 10 as malignant. The results showed diffuse immunoexpression in the cytoplasm of neoplastic cells. Six (66.7%) BPNST expressed the receptor in less than 25% of neoplastic cells and only three (33.3%) exhibited labelling in more than 25% of neoplastic cells. In contrast, all MPNST expressed PDGFR-ß, and in 8 (80%) of these samples, the receptor was expressed in more than 25% of neoplastic cells, and only 2 (20%) cases expressed the receptor in less than 25% of neoplastic cells. PDGFR-ß expression was significantly higher in MPNST and larger tumors, suggesting that drugs able to inhibit the activity of this tyrosine kinase receptor, such as toceranib, may be considered in the approach of unresectable tumors and/or in the context of adjuvant or neoadjuvant therapies.

Comprehensive In Silico Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy.

Transposable elements (TEs) are interspersed repetitive and mobile DNA sequences within the genome. Better tools for evaluating TE-derived sequences have provided insights into the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene but retention of its nearly perfect orthologue SMN2. Both genes are highly enriched in TEs. To establish a link between TEs and SMA, we conducted a comprehensive, in silico analysis of TE insertions within the SMN1/2 loci of SMA, carrier and healthy genomes. We found an Alu insertion in the promoter region and one L1 element in the 3'UTR that may play an important role in alternative promoter as well as in alternative transcriptional termination. Additionally, several intronic Alu repeats may influence alternative splicing via RNA circularization and causes the presence of new alternative exons. These Alu repeats present throughout the genes are also prone to recombination events that could lead to SMN1 exons deletions and, ultimately, SMA. TE characterization of the SMA genomic region could provide for a better understanding of the implications of TEs on human disease and genomic evolution.

[Medication Reconciliation During Admission to an Internal Medicine Department: A Pilot Study]. / Reconciliação Terapêutica na Admissão de um Serviço de Medicina Interna: Estudo-Piloto.

INTRODUCTION: The purpose of medication reconciliation is to promote patient safety by reducing medication errors and adverse events due to medication discrepancies in transition of care. The aim of this pilot study of medication reconciliation at the time of hospital admission was to identify the necessary resources for its implementation in clinical practice. MATERIAL AND METHODS: Pilot study with 100 patients admitted to an Internal Medicine department between October and December 2019, aged 18 and over, and chronically taking at least one medicine. The best possible medication history was obtained systematically, with subsequent identification, classification and resolution of the discrepancies. RESULTS: The study sample, in general characterized by polypharmacy and by having multiple long-term conditions, presented a mean age of 77.04 ± 13.74 years, being 67.0% male. Overall, 791 discrepancies were identified. Intentional discrepancies were 95.7% and 50.9% of them were documented. The difficulties encountered were mainly related with the access and quality of therapeutic information and communication problems between different healthcare professionals. The key priority resources that were identified were related with the process, tools, and personnel categories. CONCLUSION: The data revealed weaknesses in the clinical records available at the primary/hospital care interface. Optimization of data sources, standardization and informatization of the process, multidisciplinary approach and definition of priority groups were identified as opportunities for optimization.

Introdução: A reconciliação terapêutica visa promover a segurança do doente por meio da redução de erros de medicação e eventos adversos decorrentes de discrepâncias de medicação na transição de cuidados. Foi nosso objetivo realizar um estudo-piloto de reconciliação terapêutica no momento da admissão hospitalar para, a partir dele, identificarmos os recursos necessários para a sua implementação na prática clínica.Material e Métodos: Estudo-piloto com 100 doentes admitidos num serviço de Medicina Interna entre outubro e dezembro de 2019, com mais de 18 anos e a tomar cronicamente pelo menos um medicamento. A melhor história farmacoterapêutica possível foi obtida sistematicamente, com posterior identificação, classificação e resolução das discrepâncias.Resultados: A amostra em estudo, em geral polimedicada e com múltiplas morbilidades, apresentou uma média de idades de 77,04 ± 13,74 anos, sendo 67,0% do sexo masculino. Foram identificadas 791 discrepâncias e as intencionais (95,7%) estavam documentadas em 50,9% das situações. As dificuldades encontradas relacionaram-se principalmente com o acesso e a qualidade da informação terapêutica e com a dificuldade de comunicação entre os diversos profissionais de saúde. Os principais recursos prioritários identificados relacionaram-se com as categorias de processo, ferramentas e pessoal.Conclusão: Os dados revelaram fragilidades nos registos clínicos disponíveis na interface dos cuidados primários/hospitalares. A otimização das fontes de dados, normalização e informatização do processo, atuação multidisciplinar e definição de grupos prioritários foram identificadas como oportunidades de otimização.

Reduced Motivation in Perinatal Fluoxetine-Treated Mice: A Hypodopaminergic Phenotype.

Early life is a sensitive period, in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor (SSRI), fluoxetine, affects motivation, and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task. Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.SIGNIFICANCE STATEMENT The developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here, we show that exposure to the SSRI fluoxetine during a restricted period in early life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.

Perinatal interference with the serotonergic system affects VTA function in the adult via glutamate co-transmission.

Serotonin and dopamine are associated with multiple psychiatric disorders. How they interact during development to affect subsequent behavior remains unknown. Knockout of the serotonin transporter or postnatal blockade with selective serotonin reuptake inhibitors (SSRIs) leads to novelty-induced exploration deficits in adulthood, potentially involving the dopamine system. Here, we show in the mouse that raphe nucleus serotonin neurons activate ventral tegmental area dopamine neurons via glutamate co-transmission and that this co-transmission is reduced in animals exposed postnatally to SSRIs. Blocking serotonin neuron glutamate co-transmission mimics this SSRI-induced hypolocomotion, while optogenetic activation of dopamine neurons reverses this hypolocomotor phenotype. Our data demonstrate that serotonin neurons modulate dopamine neuron activity via glutamate co-transmission and that this pathway is developmentally malleable, with high serotonin levels during early life reducing co-transmission, revealing the basis for the reduced novelty-induced exploration in adulthood due to postnatal SSRI exposure.

Primary Aortoesophageal Fistula: Is a High Level of Suspicion Enough?

Aortoenteric fistula (AEF) is a rare condition with a high mortality rate. AEFs are classified according to their primary and secondary causes, the former being less frequent. Primary AEFs occur in a native aorta and their causes include aneurysms, foreign bodies, tumours, radiotherapy and infection. The classic triad of aortoesophageal fistulas, a subtype of AEFs, are mid-thoracic pain and sentinel haemorrhage, followed by massive bleeding after a symptom-free interval. We present the case of a 41-year-old male patient who presented in the emergency room after successive episodes of abundant haematemesis. He was hypovolemic, hypothermic and acidotic at presentation. His medical history included an emergency room visit the week before with chest pain but no relevant anomalies on work-up, active intravenous drug use and chronic hepatitis. Esophagogastroduodenoscopy (EGD) showed a bulging ulcerated lesion suspicious for aortoesophageal fistula, confirmed by computed tomography (CT) angiography, which revealed a saccular aortic aneurysm with a bleeding aortoesophageal fistula. The patient underwent urgent thoracic endovascular aortic repair. The sentinel chest pain, leucocytosis and CT findings hinted at the presence of a mycotic aneurysm, despite the negative blood cultures. It was most likely caused by a septic embolus due to the patient's risk factors. While a high level of suspicion for aortoesophageal fistula is needed to prompt a fast diagnosis, EGD and CT findings were crucial to establish it and allow a life-saving intervention. We conclude that chest pain cannot be disregarded in a patient aged 41 years with multiple comorbidities, despite normal work-up, to prevent a fatal outcome. LEARNING POINTS: Aortoesophageal fistula is a rare cause of severe upper gastrointestinal haemorrhage with a high mortality rate.Computed tomography angiography is diagnostic in most cases but a high level of suspicion is essential.Chest pain, a characteristic clinical symptom of aortoesophageal fistula, cannot be disregarded in a patient with multiple comorbidities, even in the presence of a normal electrocardiogram and chest x-ray.

Context- and Subgroup-Specific Language Changes in Individuals Who Develop PTSD After Trauma.

Post-traumatic stress disorder (PTSD) is a very common condition with more than 3 million new cases per year in the US alone. The right diagnosis in a timely manner is key to ensuring a prompt treatment that could lead to a full recovery. Unfortunately, avoidance of trauma reminders, social stigma, self-presentation, and self-assessment biases often prevent individuals from seeking timely evaluation, leading to delays in treatment and suboptimal outcomes. Previous studies show that various mental health conditions are associated with distinct patterns of language use. Analyzing language use may also help to avoid response bias in self-reports. In this study, we analyze text data from online forum users, showing that language use differences between PTSD sufferers and controls. In all groups of PTSD sufferers, the usage of singular first-person pronouns was higher and that of plural first-person pronouns was lower than in control groups. However, the analysis of other word categories suggests that subgroups of people with the same mental health disorder (here PTSD) may have salient differences in their language use, particularly in word usage frequencies. Additionally, we show that word usage patterns may vary depending on the type of the text analyzed. Nevertheless, more studies will be needed to increase precision by further examine a variety of text types and different comorbidities. If properly developed, such tools may facilitate earlier PTSD diagnosis, leading to timely support and treatment, which are associated with better outcomes.

Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism.

Mental health disorders are manifested in families, yet cannot be fully explained by classical Mendelian genetics. Changes in gene expression via epigenetics present a plausible mechanism. Anxiety often leads to avoidant behaviors which upon repetition may become habitual, maladaptive and resistant to extinction as observed in obsessive compulsive disorders (OCD). Psychophysical models of OCD propose that anxiety (amygdala) and habits (dorsolateral striatum, DLS) may be causally linked. The amygdala activates spiny projection neurons in the DLS. Repetitive amygdala terminal stimulation in the DLS elicits long term OCD-like behavior in mice associated with circuitry changes and gene methylation-mediated decrease in the activity of protein phosphatase 1 (PP1). Treatment of OCD-like grooming behavior in Slitrk5, SAPAP3, and laser-stimulated mice with one dose of RG108 (DNA methyltransferase inhibitor), lead to marked symptom improvement lasting for at least one week as well as complete reversal of anomalous changes in circuitry and PP1 gene methylation.

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms.

Recent studies demonstrated the existence in vivo of various functional DNA structures that differ from the double helix. The G-quadruplex (G4) and intercalated motif (I-motif or IM) DNA structures are formed as knots where, correspondingly, guanines or cytosines on the same strand of DNA bind to each other. There are grounds to believe that G4 and IM sequences play a significant role in regulating gene expression considering their tendency to be found in or near regulatory sites (such as promoters, enhancers, and telomeres) as well as the correlation between the prevalence of G4 or IM conformations and specific phases of cell cycle. Notably, G4 and IM capable sequences tend to be found on the opposite strands of the same DNA site with at most one of the two structures formed at any given time. The recent evidence that K+, Mg2+ concentrations directly affect IM formation (and likely G4 formation indirectly) lead us to believe that these structures may play a major role in synaptic plasticity of neurons, and, therefore, in a variety of central nervous system (CNS) functions including memory, learning, habitual behaviors, pain perception and others. Furthermore, epigenetic mechanisms, which have an important role in synaptic plasticity and memory formation, were also shown to influence formation and stability of G4s and IMs. Our hypothesis is that non-canonical DNA and RNA structures could be an integral part of neuroplasticity control via gene expression regulation at the level of transcription, translation and splicing. We propose that the regulatory activity of DNA IM and G4 structures is modulated by DNA methylation/demethylation of the IM and/or G4 sequences, which facilitates the switch between canonical and non-canonical conformation. Other neuronal mechanisms interacting with the formation and regulatory activity of non-canonical DNA and RNA structures, particularly G4, IM and triplexes, may involve microRNAs as well as ion and proton fluxes. We are proposing experiments in acute brain slices and in vivo to test our hypothesis. The proposed studies would provide new insights into fundamental neuronal mechanisms in health and disease and potentially open new avenues for treating mental health disorders.