Implications of prenatal exposure to synthetic corticosteroid in the mesolimbic reward pathway

Tese de doutoramento em MedicinaIn the field of clinical obstetrics, glucocorticoids (GCs) have gained an important role in promoting fetal lung maturation, and are used in about 10% of risk pregnancies. The fetus is highly sensitive to perturbations of its chemical environment along critical developmental windows and, thus, it is not surprising that stress exposure or GC treatment during pregnancy cause notable changes in the physiology and behaviour of the offspring in adulthood. In fact, lifelong implications of sustained deleterious perinatal experiences, such as elevated GCs, include anxiety, mood and cognitive disorders as well as the development of addictive‐like behaviors. It seems that during these crucial periods, several brain regions might be programmed by prolonged stressful insults, such as exposure to high doses of GCs. However, less is known about the potential effects of shortterm therapies with these steroids during late gestation, a crucial stage of the neurodevelopment; as a consequence, very little is known about the underlying mechanisms of these detrimental effects. In this work we show that prenatal exposure to dexamethasone (DEX) at E18‐19 leads to the development of drug‐seeking behaviors in the adult progeny. DEX‐exposed animals displayed increased preference for the morphine‐paired compartment in the conditioned place preference teste (CPP, non‐contigent paradigm) and increased voluntary alcohol consumption (AC) using a two bottle free‐choice paradigm (contingent paradigm). These animals also displayed increased locomotor activity after morphine administration in the open field (OF) test, suggesting a hypersensitive behavioural response to drugs of abuse. Considering the importance of the dopaminergic mesolimbic system for the development of addiction, we performed herein an extensive structural, neurochemical and molecular analysis of the nucleus accumbens (NAcc) and the ventral tegmental area (VTA). At 3 days of postnatal life, we found a significant reduction in the rate of cell proliferation in DEX‐exposed animals in the NAcc and VTA. These changes seem to be sustained in time since in adulthood, DEX animals presented considerable reduced volume and cell numbers in the same brain regions. Because of well‐known plastic events in the central nervous system, we underwent a morphometric analysis of dendrites and synapses in adult offspring of DEX‐treated dams. We found significant changes in the number of spines and spine density of NAcc‐shell, most likely a compensatory mechanism, while in the NAcc core there was no sign of synaptic plasticity in DEX animals. The VTA also presented significant differences in the number of spines, spines density and dendritic branching. Our neurochemical analysis demonstrated that the dopaminergic input was de‐regulated in DEX‐exposed animals as they displayed significantly less dopamine and an impoverishment of dopaminergic fibers in the NAcc, while an increase in dopamine levels was observed in the VTA. In parallel, a significant up‐regulation of the dopamine receptor 2 (Drd2) in the NAcc of DEX‐exposed animals was found, which could reflect a compensation mechanism due to the lack of the ligand. Importantly, after a dopamine‐releasing stimulus (drug exposure), the levels of Drd2 were significantly reduced in DEX‐exposed animals. This phenomenon was associated with an increased methylation pattern of the promoter region of Drd2 in the NAcc. In an attempt to revert the hypodopaminergic status of DEX‐exposed animals in the NAcc, we administered L‐dopa/carbidopa by oral gavage. Interestingly, restoring dopamine levels in the NAcc had striking effects in the behavior of DEX‐exposed animals, since the behavioral phenotype was completely rescued, i.e., DEX animals no longer displayed increased conditioning in the CPP, increased AC or enhanced locomotor activity in the OF. Of notice, these effects were observed in short‐ and long‐term administration treatments and, at least for the long‐term treatment, the therapeutic effect was sustained in time. In summary, we show that prenatal DEX exposure programs the mesolimbic dopaminergic system at a morphological, neurochemical and molecular level and alters the threshold for the rewarding effects of drugs of abuse. Interestingly, the addictive‐like phenotype seems to be dependent on dopamine levels and can be modulated by dopamine replacement, thus opening new perspectives in the treatment/prevention of addictive behaviors.Na clínica obstétrica, os glucocorticóides (GCs) são usados em cerca de 10% das gravidezes de risco de forma a promoverem a maturação pulmonar fetal. Existem períodos críticos de susceptibilidade do feto a perturbações do seu ambiente químico e, por isso, não é surpreendente que o stress ou tratamento com GCs durante a gravidez cause alterações na fisiologia e comportamento da descendência aquando adultos. Sabe‐se que experiências prenatais adversas tais como níveis de GCs elevados, estão associadas com uma maior propensão para a ansiedade, hiper‐emocionalidade e défices cognitivos, bem como com o desenvolvimento de comportamentos aditivos. Apesar de se supor que estas alterações comportamentais advém de uma “reprogramação” de determinadas áreas do cérebro por experiências nocivas, pouco se sabe acerca dos efeitos deletérios do tratamento com GCs no último trimestre da gravidez. Neste trabalho, demonstrámos que a exposição ao GC sintético dexametasona (DEX) no dia 18 e 19 de gestação, conduz ao aparecimento de comportamentos do tipo aditivo na prole adulta. Os animais DEX têm preferência aumentada para o compartimento associado à morfina no conditioned place preference test (CPP, paradigma não contingente) e aumento do consumo voluntário de álcool (AC, paradigma contingente). Estes mesmos animais também apresentam maior actividade locomotora no teste de open field (OF) após administração de morfina, sugerindo uma resposta exacerbada aos efeitos desta droga. Considerando a importância do sistema dopaminérgico mesolimbico para o desenvolvimento de comportamentos aditivos, nós efectuámos uma caracterização extensiva a nível estrutural, neuroquímico e molecular do nucleus accumbens (NAcc) e da área tegmental ventral (VTA). Aos 3 dias de vida pos‐natal, os animais DEX apresentam uma redução significativa da proliferação celular no NAcc e VTA. Estas alterações têm efeitos a longo prazo, uma vez que em adultos, estes animais têm uma hipotrofia volumétrica destas regiões. Devido à plasticidade conhecida do sistema nervoso central, efectuámos uma análise morfométrica das dendrites e sinapses nos animais adultos. Os animais DEX apresentam alterações no número e densidade de espinhas na subdivisão shell do NAcc, enquanto que o core não apresenta sinais de ter sofrido plasticidade sináptica. O número e densidade de espinhas, bem como o número de ramos dendríticos também se encontra alterado na VTA. A nossa análise neuroquímica mostra que o input dopaminérgico se encontra desregulado nos animais DEX, uma vez que eles apresentam uma diminuição de dopamina e uma redução de fibras dopaminérgicas no NAcc e uma elevação da dopamina na VTA. Em paralelo, encontrámos uma sobreexpressão do receptor de dopamina Drd2 no NAcc destes animais, sugerindo um potencial mecanismo de compensação devido à baixa quantidade de dopamina. De notar que, após um estímulo que induz a libertação de dopamina (exposição à morfina), os níveis de Drd2 estavam significativamente diminuídos nos animais DEX. Este fenómeno parece estar associado a um aumento do padrão de metilação na região promotora do Drd2 no NAcc. Numa tentativa de reverter o estado hipodopaminérgico dos animais DEX no NAcc, administramos L‐dopa/carbidopa por gavage oral. Ao repor os níveis de dopamina no NAcc, o fenótipo comportamental foi completamente revertido, i.e., os animais DEX deixam de apresentar condicionamento preferencial no CPP, aumento do consumo de álcool ou aumento da actividade locomotora no OF após administração de morfina. É importante referir que estes efeitos foram observados com regimes de tratamento de curta e longa duração, e que, pelo menos no caso do tratamento de longa duração com L‐dopa, os efeitos terapêuticos são mantidos durante 3 semanas. Em suma, nós demonstrámos que a exposição prenatal de DEX “reprograma” o sistema dopaminérgico mesolimbico a nível morfológico, neuroquímico e molecular; alterando também o limiar dos efeitos recompensadores das drogas de abuso. Importante mencionar que o comportamento aditivo parece ser dependente dos níveis de dopamina, e que pode ser modulado pela reposição de dopamina no NAcc, o que abre novas perspectivas para o tratamento/prevenção de comportamentos deste tipo

Anal herpes

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Mucinous carcinomatosis: A rare association between an ovarian tumor and an E-GIST

Pseudomyxoma peritonei (PMP) and extragastrointestinal stromal tumors (E-GISTs) are both rare entities. Most of the time, PMP is associated with an appendiceal tumor. An ovarian mucinous tumor can mimic appendiceal metastases. E-GIST is a mesenchymal tumor that can arise from the omentum, retroperitoneum, mesentery, or pleura. We present a case of an 87-year-old woman with mucinous carcinomatosis and acute intestinal occlusion submitted to an emergency laparotomy. She has found to have a borderline mucinous tumor of the ovary from the intestinal type with several lesions of pseudomyxoma peritonei and an E-GIST from the epiploons retrocavity (intermediated risk). In the literature, no relation was found between these two rare tumors. E-GIST was an incidental finding in the context of a mucinous carcinomatosis.info:eu-repo/semantics/publishedVersio

Enterocutaneous fistula: a novel video-assisted approach

Video-assisted anal fistula treatment (VAAFT) is a novel minimally invasive and sphincter-saving technique to treat complex anal fistulas described by Meinero in 2006. An enterocutaneous fistula is an abnormal communication between the bowel and the skin. Most cases are secondary to surgical complications, and managing this condition is a true challenge for surgeons. Postoperative fistulas account for 75-85% of all enterocutaneous fistulas. The aim of paper was to devise a minimally invasive technique to treat enterocutaneous fistulas. We used the same principles of VAAFT applied to other conditions, combining endoluminal vision of the tract with colonoscopy to identify the internal opening. We present a case of a 78-year-old woman who was subjected to a total colectomy for cecum and sigmoid synchronous adenocarcinoma. The postoperative course was complicated with an enterocutaneous fistula, treated with conservative measures, which recurred during follow-up. We performed video-assisted fistula treatment using a fistuloscope combined with a colonoscope. Once we identified the fistula tract, we performed cleansing and destruction of the tract, applied synthetic cyanoacrylate and sealed the internal opening with clips through an endoluminal approach. The patient was discharged 5 days later without complications. Two months later the wound was completely healed without evidence of recurrence. This procedure represents an alternative treatment for enterocutaneous fistula using a minimally invasive technique, especially in selected patients not able to undergo major surgery.(undefined)info:eu-repo/semantics/publishedVersio

Developing an individualized survival prediction model for colon cancer

In this work a 5-year survival prediction model was developed for colon cancer using machine learning methods. The model was based on the SEER dataset which, after preprocessing, consisted of 38,592 records of colon cancer patients. Survival prediction models for colon cancer are not widely and easily available. Results showed that the performance of the model using fewer features is close to that of the model using a larger set of features recommended by an expert physician, which indicates that the first may be a good compromise between usability and performance. The purpose of such a model is to be used in Ambient Assisted Living applications, providing decision support to health care professionals.info:eu-repo/semantics/publishedVersio

Epigastric pain: incarceration or rotation?

Introduction: Acute intrathoracic gastric volvulus occurs when the stomach has a twist mesenteroaxial/organoaxial or chest cavity resulting in a dilatation or rupture of the diaphragmatic hiatus or diaphragmatic hernia. The purpose of this work is to show a interesting case of gastric volvulus in a patient with several comorbidities. Case Report: A 77-year-old female with past history of hiatal hernia and mental disease associated with diabetes and atrial fibrillation. Patient went to the emergency department due to vomiting associated with blood. Analytical parameters (WBC, HGB, PCR, metabolic panel and liver function), showed no significant alterations. Thoracic X-ray revealed an enlarged mediastinum due to herniation of the stomach. A computed tomography (CT) scan confirmed intrathoracic localization of the gastric antrum with twist. Patient’s symptoms were relieved by nasogastric intubation and analgesia. After six months, the patient is still asymptomatic. Conclusion: In general, the treatment of an acute gastric volvulus requires an emergent surgical repair. In patients who are not surgical candidates (with comorbidities or an inability to tolerate anesthesia), endoscopic reduction should be attempted. Chronic gastric volvulus may be treated non-emergently, and surgical treatment is increasingly being performed using a laparoscopic approach. In this case, it is a chronic form that was solved with the placement of the nasogastric tube. A nasogastric decompression is an option in the chronic form of hiatal hernia associated to gastric volvulus in patients with serious comorbidities

A reasoning module for distributed clinical decision support systems

One of the main challenges in distributed clinical decision support systems is to ensure that the flow of information is kept. The failure of one or more components should not bring down an entire system. Moreover, it should not impair any decision processes that are taking place in a functioning component. This work describes a decision module that is capable of managing states of incomplete information which result from the failure of communication between components or delays in making the information available. The framework is also capable of generating scenarios for situations in which there are information gaps. The proposal is described through an example about colon cancer staging.This work is part-funded by ERDF-European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the FCT-Fundacao para a Ciencia e a Tecnologia (Portuguese Foundation for Science and Technology) within project FCOMP-01-0124-FEDER-028980 and project scope UID/CEC/00319/2013. The work of Tiago Oliveira is supported by a FCT grant with the reference SFRH/BD/85291/2012.info:eu-repo/semantics/publishedVersio

Early Inflammatory Biomarkers as Predictive Factors for Freedom from Infection after Colorectal Cancer Surgery: A Prospective Cohort Study

Different biomarkers are useful in diagnosing infections. The aim of this work was to clarify the relation between different inflammatory biomarkers (white blood cell [WBC] count, C-reactive protein [CRP], procalcitonin [PCT], and C-reactive protein-to-albumin ratio [CAR]) and early infectious complications after colorectal surgery.info:eu-repo/semantics/publishedVersio

Anatomy Teaching at the School of Health Sciences of University of Minho

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