Joana Saraiva

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

Several attempts have been made to discover the ideal vector for gene therapy in central nervous system (CNS). Adeno-associated viruses (AAVs) are currently the preferred vehicle since they exhibit stable transgene expression in post-mitotic cells, neuronal tropism, low risk of insertional mutagenesis and diminished immune responses. Additionally, the discovery that a particular serotype, AAV9, bypasses the blood-brain barrier has raised the possibility of intravascular administration as a non-invasive delivery route to achieve widespread CNS gene expression. AAV9 intravenous delivery has already shown promising results for several diseases in animal models, including lysosomal storage disorders and motor neuron diseases, opening the way to the first clinical trial in the field. This review presents an overview of clinical trials for CNS disorders using AAVs and will focus on preclinical studies based on the systemic gene delivery using AAV9.

Diabetes as an outcome predictor after heart transplantation

We aimed to compare post-transplantation morbidity and survival among heart transplant recipients with and without diabetes mellitus. A retrospective review of 141 adult patients submitted to heart transplantation from November 2003 to June 2009 (with a minimum follow-up of one year) was undertaken. The patients were divided into two groups: those with (29%) and those without (71%) pre-transplantation diabetes. Those with diabetes were older (57.6 ± 6.1 vs. 52.3 ± 11.1 years; P=0.020) and had lower creatinine clearance (53.6 ± 15.1 vs. 63.7 ± 22.1; P=0.029). Nine patients died in hospital (6.4%; P=non-significant). No significant differences in lipid profiles (diabetes vs. no diabetes) existed before transplantation or at one year afterwards. Patients with diabetes showed a significant deterioration in their one-year lipid profile (158 ± 43 vs.192 ± 38 mg/dl; P=0.001), although one-year fasting diabetic was lower than before (178 ± 80 vs. 138 ± 45 mg/dl; P=0.016). During the first year, 17 (17%) patients previously free of diabetes developed new-onset diabetes. No significant differences were seen in rejection at one year (14% vs. 20%), infection (31% vs. 33%), new-onset renal dysfunction (8% vs. 14%) or mortality (17% vs. 7%). One-year survival was not significantly different (83% vs. 94%), but there was a significant decrease in the survival of individuals with diabetes at three years (73% vs. 91%; P=0.020). No significant difference was found in one-year survival or in terms of higher morbidity in the heart transplant patients with diabetes, but a longer follow-up showed a significant decrease in survival. Nonetheless, the patients with diabetes benefited significantly from transplantation and should not be excluded from it.

Coronary artery bypass surgery in young adults: excellent perioperative results and long-term survival

OBJECTIVES To analyse perioperative results, long-term survival and freedom from complications after coronary artery bypass grafting (CABG) in young adults. METHODS A total of 163 patients, 40 years old or younger, had isolated CABG from January 1989 to December 2010. Pre- and perioperative demographic and clinical data were retrieved from a prospectively organised database. Follow-up data were obtained by letter or telephone interviews. The mean age of the patients was 37.6 ± 2.9 years and 146 were men (90%). Fifty-three patients (32.5%) had angina class III/IV; 106 (65.0%), previous myocardial infarction; and 23 (14.1%), impaired left ventricular function (ejection fraction <40%). Indication for surgery was 3-vessel disease in 101 cases (62.0%), 2-vessel disease in 30 (18.4%) and single-vessel disease in 32 (19.6%). The left main stem was affected in 16 patients (9.8%). The mean EuroSCORE II was 0.92 ± 0.71. A total of 417 grafts were constructed (mean 2.6 grafts/patient), 247 of which (59.2%) were arterial. RESULTS There were no in-hospital deaths. The mean hospital stay was 7.1 ± 4.0 days. Four patients (2.5%) were lost to follow-up, which extended from 3 to 25 years (mean 15.1 ± 5.5 years). There were 22 late deaths, 72.7% of cardiac or unknown origin. The 5-, 10- and 20-year survival rates were 98.7 ± 10.9, 95.2 ± 1.8 and 79.4 ± 4.4%, respectively. Twenty-six patients (18.1%) had non-fatal cardiac adverse complications (myocardial infarct, percutaneous re-revascularization or class III/IV angina), for 5-, 10- and 20-year freedom from complications of 97.9 ± 1.2, 91.9 ± 2.5 and 65.7 ± 7.1%, respectively. Twenty-two patients (17.5%) needed re-revascularization, for 5-, 10- and 20-year freedom from re-revascularization of 97.6 ± 1.4, 91.9 ± 2.6 and 69.5 ± 6.7%, respectively. CONCLUSIONS Despite the aggressive nature of coronary artery disease in young patients, perioperative death and morbidity rates are low, with good long-term survival and low rates of re-revascularization.OBJECTIVES To analyse perioperative results, long-term survival and freedom from complications after coronary artery bypass grafting (CABG) in young adults. METHODS A total of 163 patients, 40 years old or younger, had isolated CABG from January 1989 to December 2010. Pre- and perioperative demographic and clinical data were retrieved from a prospectively organised database. Follow-up data were obtained by letter or telephone interviews. The mean age of the patients was 37.6 ± 2.9 years and 146 were men (90%). Fifty-three patients (32.5%) had angina class III/IV; 106 (65.0%), previous myocardial infarction; and 23 (14.1%), impaired left ventricular function (ejection fraction <40%). Indication for surgery was 3-vessel disease in 101 cases (62.0%), 2-vessel disease in 30 (18.4%) and single-vessel disease in 32 (19.6%). The left main stem was affected in 16 patients (9.8%). The mean EuroSCORE II was 0.92 ± 0.71. A total of 417 grafts were constructed (mean 2.6 grafts/patient), 247 of which (59.2%) were arterial. RESULTS There were no in-hospital deaths. The mean hospital stay was 7.1 ± 4.0 days. Four patients (2.5%) were lost to follow-up, which extended from 3 to 25 years (mean 15.1 ± 5.5 years). There were 22 late deaths, 72.7% of cardiac or unknown origin. The 5-, 10- and 20-year survival rates were 98.7 ± 10.9, 95.2 ± 1.8 and 79.4 ± 4.4%, respectively. Twenty-six patients (18.1%) had non-fatal cardiac adverse complications (myocardial infarct, percutaneous re-revascularization or class III/IV angina), for 5-, 10- and 20-year freedom from complications of 97.9 ± 1.2, 91.9 ± 2.5 and 65.7 ± 7.1%, respectively. Twenty-two patients (17.5%) needed re-revascularization, for 5-, 10- and 20-year freedom from re-revascularization of 97.6 ± 1.4, 91.9 ± 2.6 and 69.5 ± 6.7%, respectively. CONCLUSIONS Despite the aggressive nature of coronary artery disease in young patients, perioperative death and morbidity rates are low, with good long-term survival and low rates of re-revascularization.

Pulmonary Peripheral Carcinoids after Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Tumorlets: Report of 3 Cases

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets are neuroendocrine cells proliferations smaller than 5 mm. The former confines to bronchial/bronchiolar wall, while the latter broke through epithelial basement membrane. The authors present 3 cases of DIPNECH and tumorlets associated with a typical peripheral carcinoid tumor without underlying lung disease. The patients presented with nonspecific pulmonary symptoms: 3 females, 60, 72, and 84 years old, whose CT-scans showed well-defined pulmonary nodules, 2.2, 1.6, and 1.4 cm, respectively; first patient was submitted to lobectomy and the others underwent surgical biopsy. Whitish/brownish lobulated tumors corresponded to typical carcinoids (less than 2 mitoses/2 mm2 and without necrosis); polygonal/elongated cells under lobular pattern expressed CD56, chromogranin A, synaptophysin, and CK7; Ki-67 positivity was between 1 and 3%. Bronchial/bronchiolar wall neuroendocrine cell hyperplasia and several neuroendocrine nodules under 5 mm, with identical morphologic and immunoexpression, were observed, without lung disease. Typical carcinoid associated with DIPNECH and tumorlets without other pulmonary diseases is rare. Sporadic cases may recall embryonal neuroendocrine differentiation potentiality to develop peripheral hyperplasia, most commonly in underoxygenated parenchyma. The described cases are elucidative of peripheral spectrum of neuroendocrine cell tumour evolution, reinforcing higher female incidence as in central carcinoids, still without a clear preneoplastic lesion.

Giant macroprolactinoma and pregnancy

Prolactinomas are a common cause of gonadal dysfunction and infertility. We present the case of a 38-year-old woman with history of amenorrhea and infertility. At seven weeks of pregnancy she presented neuro-ophthalmologic complaints of headaches, diplopia, and right ptosis. The work-up study revealed an invasive pituitary macroadenoma with a maximum diameter of 9 cm and serum prolactin of 25,800 ng/mL (3-20). At 12 weeks, she was referred to the Endocrinology Department of the Coimbra University Hospital and started therapy with bromocriptine, initially 5 mg/day and then at crescent doses. Hyperprolactinemia was rapidly and drastically reduced to 254 ng/mL three weeks after taking bromocriptine 15 mg/day. Tumoral volume was reduced and there was improvement of III pair paresis. At 38 weeks, a male healthy baby was born. This is a relevant clinical case that illustrates the efficacy and safety of bromocriptine therapy during pregnancy, even in severe cases like this one.

O papel da cirurgia na endocardite infeciosa está a modificar‐se?

When an editor of a journal is asked to write an editorial comment on an article in the acceptance of which he/she played an important part, he/she faces the dilemma of whether to highlight its strengths or to comment on its weaknesses. Some of the latter, of course, are overcome during the editorial process (the thoroughness of which readers are generally unaware), since what is eventually published is the final product of a wide-ranging review process. There are many reasons why an article may be accepted or rejected for publication. Acceptance of the article by Moreira et al. of the medical-surgical cardiology group at Santa Marta Hospital in Lisbon published in this issue of the Journal could very well be justified by the conclusion of one of the reviewers: ‘‘Informative, considering the scarcity of data about the disease in Portugal.’’ In fact, around four years ago, the São João Hospital group in Porto published a similar study in the Journal, but even so, a comparison between the experiences of two such geographically distant centers seems worthwhile. In the article by Moreira et al., the authors present a retrospective study of 233 cases of definite or likely infective endocarditis (IE) observed at a single center, which, in the

Readmission to an Adolescent Psychiatry Inpatient Unit: Readmission Rates and Risk Factors

INTRODUCTION Most mental disorders have a chronic evolution and therefore a certain amount of psychiatric readmissions are inevitable. Several studies indicate that over 25% of child and adolescent inpatients were readmitted within one year of discharge. Several risk factors for psychiatric readmissions have been reported in the literature, but the history of repeated readmissions is the most consistent risk factor. Our aim is to calculate the readmission rates at 30 days and 12 months after discharge and to identify associated risk factors. MATERIAL AND METHODS The authors consulted the clinical files of patients admitted to the Inpatient Unit between 2010 and 2013, in order to calculate the readmission rates at 30 days and at 12 months. The demographic and clinical characteristics of the readmitted patients were analyzed and compared with a second group of patients with no hospital readmissions, in order to investigate possible predictors of readmission. RESULTS A total of 445 patients were admitted to our inpatient unit between 2010 and 2013. Six adolescents were readmitted in a 30 days period (1.3%) and 52 were readmitted in a 12 month period after discharge (11.5%). Duration of the hospitalization and the previous number of mental health admissions were significant predictors of future hospital readmissions (p = 0.04 and p = 0.014). DISCUSSION The low readmission rates may reflect the positive clinical and sociofamilial support being provided after discharge. CONCLUSION Rehospitalisation is considered a fundamental target for intervention concerning prevention and intervention in mental healthcare. Thus, knowledge regarding their minimisation is crucial.

Descodificação dos comportamentos autolesivos sem intenção suicida - estudo qualitativo das funções e significados na adolescência

Os comportamentos autolesivos sem intenção suicida devem ser vistos como um modo de expressão de um conflito ou dificuldade vivencial do adolescente e, por isso, carecem de uma “descodificação” atenta. O presente estudo qualitativo teve como principal objetivo conhecer os significados e funções subjacentes a estes comportamentos numa amostra clínica de adolescentes. A amostra foi constituída por 25 participantes, recrutados na consulta externa do Serviço de Adolescência do Departamento de Psiquiatria da infância e da adolescência do Centro Hospitalar do Porto. A análise de conteúdo revelou a existência de funções intrapsíquicas e interpessoais, estando os comportamentos ao serviço de mais do que uma função, na maioria dos casos. Estas enquadraram-se em diferentes modelos explicativos teóricos, sendo possível identificar o predomínio de funções de alívio da tensão emocional e tentativa de fuga/retirada, ambas pertencentes ao modelo de Regulação emocional, e de funções interpessoais, enquadradas no modelo Ambiental. Embora exploratórios, estes resultados tendem a apoiar a investigação existente, apontando, contudo, para algumas especificidades. Evidenciam, ainda, a importância da avaliação atenta e compreensiva destes comportamentos de forma a aprimorar o seu tratamento.

Anterior descending coronary artery as a branch of the sinus node artery

Figure 1: (A) Angiographic left anterior oblique view showing the anterior descending artery originating from the sinus node artery (SNA), between the aorta and the superior vena cava. (B) Right anterior oblique view. In contrast to the classical anomalous origin from the right coronary artery, where the anterior descending artery crosses de infundibulum anteriorly, in this case the anterior descending artery ran in the transverse sinus behind the arterial pedicle, before reaching the superior portion of the interventricular groove. This was confirmed intraoperatively. Figure 2: Left oblique anterior view of the left coronary artery showing a very small anterior descendent, which runs parallel to the main anterior descendent artery branch of the de sinus node artery.

Anterior pituitary insufficiency and spontaneous fertility: case report

 Referenced due to Short stature.  Identification: PJON, ♂, DB 22.03.1981 Age: 7,63 years-old  Auxology: Height 108 cm (-2,86 SD) Predicted Adult Stature (PAS) 169.5 cm (-0.78 SD) Bone age 6 years (-2,82 SD) Growth velocity 2 cm  Past history of traumatic delivery; irrelevant familial history.  Cranial CT: intrasellar arachnoidocele. Daytime mean 0,2±0,28 ng/mL (max 1 ng/mL) Night mean 0,46 ±0,48 ng/ML (max 1,7 ng/mL)