Dental Caries: Early Intervention and the Role of the Pediatrician.

Despite improvements in oral morbidity levels and access to care among the pediatric population, there are still major disparities in the United States. Results of national surveys have documented a decrease in the number of children receiving either a dental examination or a cleaning. This finding is particularly concerning for toddlers and infants, as early preventive dental visits and the establishment of a dental home is cost-effective and leads to enhanced oral health outcomes over the life span. Many infants and toddlers do not visit a dentist, suggesting that the recommendations of the American Academy of Pediatrics and the American Academy of Pediatric Dentistry to establish a dental home are not appropriately adopted.

[Liver transplantation: development, learning curve and results after the first 300 cases]. / Trasplante hepático: evolución, curva de aprendizaje y resultados después de los primeros 300 casos.

BACKGROUND: Liver transplantation (LT) is an option for people with liver failure who cannot be cured with other therapies and for some people with liver cancer. AIM: To describe, and analyze the first 300 LT clinical results, and to establish our learning curve. MATERIAL AND METHODS: Retrospective cohort study with data obtained from a prospectively collected LT Program database. We included all LT performed at a single center from March 1994 to September 2017. The database gathered demographics, diagnosis, indications for LT, surgical aspects and postoperative courses. We constructed a cumulative summation test for learning curve (LC-CUSUM) using 30-day post-LT mortality. Mortality at 30 days, and actuarial 1-, and 5-year survival rate were analyzed. RESULTS: A total of 281 patients aged 54 (0-71) years (129 women) underwent 300 LT. Ten percent of patients were younger than 18 years old. The first, second and third indications for LT were non-alcoholic steatohepatitis, chronic autoimmune hepatitis and alcoholic liver cirrhosis, respectively. Acute liver failure was the LT indication in 51 cases (17%). The overall complication rate was 71%. Infectious and biliary complications were the most common of them (47 and 31% respectively). The LC-CUSUM curve shows that the first 30 patients corresponded to the learning curve. The peri-operative mortality was 8%. Actuarial 1 and 5-year survival rates were 82 and 71.4%, respectively. CONCLUSIONS: Outcome improvement of a LT program depends on the accumulation of experience after the first 30 transplants and the peri-operative mortality directly impacted long-term survival.

Overexpression of insulin like growth factor binding protein 5 reduces liver fibrosis in chronic cholangiopathy.

The ATP-binding cassette, sub-family B member 4 knock-out mouse (Abcb4(-/-)) is a relevant model for chronic cholangiopathy in man. Due to the lack of this P-glycoprotein in the canalicular membrane of hepatocytes, the secretion of phospholipids into bile is absent, resulting in increased bile toxicity. Expression of insulin like growth factor binding protein 5 (Igfbp5) increases in time in the livers of these mice. It is unclear whether this induction is a consequence of or plays a role in the progression of liver pathology. The aim of this study was therefore to investigate the effect of IGFBP5 induction on the progression of liver fibrosis caused by chronic cholangiopathy. IGFBP5 and, as a control, green fluorescent protein were overexpressed in the hepatocytes of Abcb4(-/-) mice, using an adeno-associated viral vector (AAV). Progression of liver fibrosis was studied 3, 6, and 12 weeks after vector injection by analyzing serum parameters, collagen deposition, expression of pro-fibrotic genes, inflammation and oxidative stress. A single administration of the AAV vectors provided prolonged expression of IGFBP5 and GFP in the livers of Abcb4(-/-) mice. Compared to GFP control, fractional liver weight, extracellular matrix deposition and amount of activated hepatic stellate cells significantly decreased in IGFBP5 overexpressing mice even 12 weeks after treatment. This effect was not due to a change in bile composition, but driven by reduced inflammation, oxidative stress, and proliferation. Overexpression of IGFBP5 seems to have a protective effect on liver pathology in this model for chronic cholangiopathy.

Ezetimibe: A biomarker for efficacy of liver directed UGT1A1 gene therapy for inherited hyperbilirubinemia.

As recently demonstrated in patients with factor IX deficiency, adeno-associated virus (AAV)-mediated liver-directed therapy is a viable option for inherited metabolic liver disorders. Our aim is to treat Crigler-Najjar syndrome type I (CN I), an inherited severe unconjugated hyperbilirubinemia, as a rare recessive inherited disorder. Because the number of patients eligible for this approach is small, the efficacy can only be demonstrated by a beneficial effect on the pathophysiology in individual patients. Serum bilirubin levels in potential candidates have been monitored since birth, providing an indication of their pathophysiology. Adjuvant phototherapy to prevent brain damage reduces serum unconjugated bilirubin (UCB) levels in CN I patients to the level seen in the milder form of the disease, CN type II. This therapy increases the excretion of UCB, thereby complicating the use of UCB and conjugated bilirubin levels in serum as biomarkers for the gene therapy we try to develop. Therefore, a suitable biomarker that is not affected by phototherapy is currently needed. To this end, we have investigated whether estradiol, ethinylestradiol or ezetimibe could be used as markers for uridine 5'-di-phospho-glucuronosyltransferase isoform 1A1 (UGT1A1) activity restored by AAV gene therapy in Gunn rats, a relevant animal model for CN I. Of these compounds, ezetimibe appeared most suitable because its glucuronidation rate in untreated control Gunn rats is low. Subsequently, ezetimibe glucuronidation was studied in both untreated and AAV-treated Gunn rats and the results suggest that it may serve as a useful serum marker for restored hepatic UGT1A1 activity.

Reliability of a digital system for models measurements in BBO grading: A pilot study.

INTRODUCTION: Currently, no method is considered effective for the evaluation of digital models in the Certification Examination of the Brazilian Board of Orthodontics (BBO), considering the parameters of the currently used manual method. OBJECTIVE: Thus, the aim of this study is to verify the reliability of an evaluation method for digital models that could be used in the BBO exam, compared to the gold standard. METHODS: Measurements were performed by five previously calibrated examiners. Samples of ten sets of plaster models of the final phase of orthodontic treatment were measured using a manual method (Objective Grading System, OGS). These models were digitized using a 3D scanner and exported to Geomagic Qualify software, in which the measurements were made with the proposed digital method. These measurements were repeated using five models, after fifteen days. The intra-examiner performance with this method was analyzed with a paired t-test, whereas the inter-examiner analysis was carried out with analysis of variance and Tukey's test. To compare the manual and digital methods, a paired t-test and Pearson's correlation analysis were performed. RESULTS: A statistically significant difference was found. The results showed that, when compared to the manual method, the digital method was effective in measuring the OGS in four of the seven variables studied: Marginal Ridge, Overjet, Occlusal Contact, and Interproximal Contact. The variables Alignment, BL inclination, and Occlusal Relationship showed a great amount of dispersion in the findings. CONCLUSION: Further studies are needed to develop an adequate digital methodology that can be used for all OGS variables.

Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology.

Huntington disease (HD) is a fatal, neurodegenerative genetic disorder with aggregation of mutant Huntingtin protein (mutHTT) in the brain as a key pathological mechanism. There are currently no disease modifying therapies for HD; however, HTT-lowering therapies hold promise. Recombinant adeno-associated virus serotype 5 expressing a microRNA that targets HTT mRNA (AAV5-miHTT) is in development for the treatment of HD with promising results in rodent and minipig HD models. To support a clinical trial, toxicity studies were performed in non-human primates (NHP, Macaca fascicularis) and Sprague-Dawley rats to evaluate the safety of AAV5-miHTT, the neurosurgical administration procedure, vector delivery and expression of the miHTT transgene during a 6-month observation period. For accurate delivery of AAV5-miHTT to the striatum, real-time magnetic resonance imaging (MRI) with convection-enhanced delivery (CED) was used in NHP. Catheters were successfully implanted in 24 NHP, without neurological symptoms, and resulted in tracer signal in the target areas. Widespread vector DNA and miHTT transgene distribution in the brain was found, particularly in areas associated with HD pathology. Intrastriatal administration of AAV5-miHTT was well tolerated with no clinically relevant changes in either species. These studies demonstrate the excellent safety profile of AAV5-miHTT, the reproducibility and tolerability of intrastriatal administration, and the delivery of AAV5-miHTT to the brain, which support the transition of AAV5-miHTT into clinical studies.

Ankle-brachial index according to pulse pressure and microalbuminuria in hypertensive patients: a prospective study in family medicine.

INTRODUCTION: Microalbuminuria, as determined by the urinary albumin to creatinine (AC) ratio, is a marker of target organ damage (TOD) in hypertensive patients. Pulse pressure (PP) predicts arterial elasticity and the ankle-brachial index (ABI) is a marker of cardiovascular morbidity. TOD reduction should be achieved through improvements in these indices. OBJECTIVE: To determine whether ABI, calculated as the ratio between mean PP in the upper and lower limbs, is associated with a reduction in renal damage, as measured by the AC ratio. METHODS: This was a prospective interventional study based on an intention-to-treat analysis in an opportunity sample of patients treated by three specialists in family medicine, with three-monthly follow-up over a total of six months. Blood pressure was measured in arms and ankles, and PP was calculated and used to determine right and left ABI and mean overall ABI. The AC ratio was determined by urine dipstick test. Descriptive and inferential statistical analysis was performed. RESULTS: A sample of 75 patients were studied (42.4% women), of whom(42.4% women), of whom 27.6% were diabetic, 46.7% overweight/obese and 49.3% dyslipidemic. overweight/obese and 49 dyslipidemic. There were statistical differences for right ABI (as determined by PP) and for mean overall ABI (as determined by mean PP in lower and upper limbs). Bivariate correlation analysis showed that in the group with improved PP between the first and the third observations, n=23 (40%), there was a statistically significant reduction in AC ratio (r = -0.924, two-tailed p < 0.001); the opposite was observed in the group with reduced PP, in which the AC ratio increased. DISCUSSION: ABI determined by systolic blood pressure is an excellent predictor of hemodynamic alterations. Increased ABI, based on PP, was accompanied by improved urinary AC ratio. These results are in line with the international literature. CONCLUSIONS: An improvement in urinary AC ratio--a predictor of TOD--is observed when an improvement in the ankle PP/brachial PP ratio is achieved.

A Novel Organoid Model of Damage and Repair Identifies HNF4α as a Critical Regulator of Intestinal Epithelial Regeneration.

BACKGROUND & AIMS: Recent evidence has suggested that the intact intestinal epithelial barrier protects our body from a range of immune-mediated diseases. The epithelial layer has an impressive ability to reconstitute and repair upon damage and this process of repair increasingly is seen as a therapeutic target. In vitro models to study this process in primary intestinal cells are lacking. METHODS: We established and characterized an in vitro model of intestinal damage and repair by applying γ-radiation on small-intestinal organoids. We then used this model to identify novel regulators of intestinal regeneration. RESULTS: We identified hepatocyte nuclear factor 4α (HNF4α) as a pivotal upstream regulator of the intestinal regenerative response. Organoids lacking Hnf4a were not able to propagate in vitro. Importantly, intestinal Hnf4a knock-out mice showed impaired regeneration after whole-body irradiation, confirming intestinal organoids as a valuable alternative to in vivo studies. CONCLUSIONS: In conclusion, we established and validated an in vitro damage-repair model and identified HNF4α as a crucial regulator of intestinal regeneration. Transcript profiling: GSE141515 and GSE141518.

A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study.

Patients with thrombophilia and/or a history of venous thromboembolism (VTE) exhibit a high risk of thrombosis during pregnancy. The present multicentre study prospectively assessed a prophylaxis strategy, based on a risk score, in pregnancies with increased risk of VTE. Among 286 patients included in the study, 183 had a personal history of VTE (63.98%) and 191 patients (66.8%) had a thrombophilia marker. Eighty nine (46.6%) thrombophilic women had a personal history of VTE. Patients were assigned to one of three prophylaxis strategies according to the risk scoring system. In postpartum, all patients received low molecular weight heparin (LMWH) prophylaxis for at least 6 weeks. In antepartum, LMWH prophylaxis was prescribed to 61.8% of patients with high risk of VTE. Among them, 37.7% were treated in the third trimester only and 24.1% were treated throughout pregnancy. In this cohort, one antepartum-related VTE (0.35%) and two postpartum-related VTE (0.7%) occurred. No case of pulmonary embolism was observed during the study period. The rate of serious bleeding was 0.35%. There was no evidence of heparin-induced thrombocytopenia or osteoporosis. The use of a risk score may provide a rational decision process to implement safe and effective antepartum thromboprophylaxis in pregnant women at high risk of VTE.

Towards liver-directed gene therapy for Crigler-Najjar syndrome.

Crigler-Najjar (CN) syndrome is a recessive inherited disorder caused by deficiency of uridine diphospho-glucuronosyl transferase 1A1. This hepatic enzyme catalyzes the glucuronidation of bilirubin, an essential step in excretion into bile of this neurotoxic compound. As a result, CN patients suffer from severe unconjugated hyperbilirubinemia and are at risk of bilirubin encephalopathy. Over the last decades ex vivo and in vivo gene therapy using viral and non-viral vectors has been used to correct hyperbilirubinemia in the relevant animal model for CN syndrome, the Gunn rat. Several of these approaches did result in long-term correction of serum bilirubin levels in this animal model. However, none have been translated into a clinical trial. In this review we will recapitulate the strategies used and discuss their suitability for clinical application in the near future. We will also address specific safety measures in the gene therapy protocol needed to prevent adverse effects such as bilirubin toxicity. Since CN seems an ideal model for other monogenetic inherited metabolic liver disorders, development of liver-directed gene-therapy has relevance beyond this rare disease.

Enhanced Factor IX Activity following Administration of AAV5-R338L "Padua" Factor IX versus AAV5 WT Human Factor IX in NHPs.

Gene therapy for severe hemophilia B is advancing and offers sustained disease amelioration with a single treatment. We have reported the efficacy and safety of AMT-060, an investigational gene therapy comprising an adeno-associated virus serotype 5 capsid encapsidating the codon-optimized wild-type human factor IX (WT hFIX) gene with a liver-specific promoter, in patients with severe hemophilia B. Treatment with 2 × 1013 gc/kg AMT-060 showed sustained and durable FIX activity of 3%-13% and a substantial reduction in spontaneous bleeds without T cell-mediated hepatoxicity. To achieve higher FIX activity, we modified AMT-060 to encode the R338L "Padua" FIX variant that has increased specific activity (AMT-061). We report the safety and increased FIX activity of AMT-061 in non-human primates. Animals (n = 3/group) received intravenous AMT-060 (5 × 1012 gc/kg), AMT-061 (ranging from 5 × 1011 to 9 × 1013 gc/kg), or vehicle. Human FIX protein expression, FIX activity, and coagulation markers including D-dimer and thrombin-antithrombin complexes were measured. At equal doses, AMT-060 and AMT-061 resulted in similar human FIX protein expression, but FIX activity was 6.5-fold enhanced using AMT-061. Both vectors show similar safety and transduction profiles. Thus, AMT-061 holds great promise as a more potent FIX replacement gene therapy with a favorable safety profile.

Reliability of a digital system for models measurements in BBO grading: A pilot study

ABSTRACT Introduction: Currently, no method is considered effective for the evaluation of digital models in the Certification Examination of the Brazilian Board of Orthodontics (BBO), considering the parameters of the currently used manual method. Objective: Thus, the aim of this study is to verify the reliability of an evaluation method for digital models that could be used in the BBO exam, compared to the gold standard. Methods: Measurements were performed by five previously calibrated examiners. Samples of ten sets of plaster models of the final phase of orthodontic treatment were measured using a manual method (Objective Grading System, OGS). These models were digitized using a 3D scanner and exported to Geomagic Qualify software, in which the measurements were made with the proposed digital method. These measurements were repeated using five models, after fifteen days. The intra-examiner performance with this method was analyzed with a paired t-test, whereas the inter-examiner analysis was carried out with analysis of variance and Tukey's test. To compare the manual and digital methods, a paired t-test and Pearson's correlation analysis were performed. Results: A statistically significant difference was found. The results showed that, when compared to the manual method, the digital method was effective in measuring the OGS in four of the seven variables studied: Marginal Ridge, Overjet, Occlusal Contact, and Interproximal Contact. The variables Alignment, BL inclination, and Occlusal Relationship showed a great amount of dispersion in the findings. Conclusion: Further studies are needed to develop an adequate digital methodology that can be used for all OGS variables.

RESUMO Introdução: Ainda não há um método considerado eficaz para análise dos modelos digitais no exame do Board Brasileiro de Ortodontia (BBO), considerando-se os parâmetros do método manual atual. Objetivo: Assim, o presente estudo objetiva verificar a confiabilidade de um método de avaliação em modelos digitais para o exame do BBO, comparando com o padrão-ouro. Métodos: As medições foram realizadas por 5 examinadores, previamente calibrados. A amostra de 10 pares de modelos de gesso da fase final do tratamento ortodôntico foi medida no método manual (Sistema Objetivo de Avaliação, SOA). Os modelos foram digitalizados por meio de um scanner 3D e exportados para o software Geomagic Qualify, onde foram feitas as medidas no método digital proposto. As medidas foram refeitas em 5 modelos após 15 dias. A análise intraexaminador desse método foi realizada por meio do teste t pareado; já a interexaminadores, feita com ANOVA e teste de Tukey, sendo encontrada diferença estatisticamente significativa. Para a comparação dos métodos manual e digital, foram utilizados o teste t pareado e a correlação de Pearson. Resultados: Uma diferença estatisticamente significativa foi encontrada. Os resultados mostraram que, comparada ao método manual, a metodologia digital mostrou-se eficaz para medição do SOA em quatro das sete variáveis estudadas: Margem interproximal, Sobressaliência, Contato oclusal e Contato interproximal. As variáveis Alinhamento, Inclinação V-L e Relação oclusal mostraram muita dispersão nos achados. Conclusão: Mais estudos são necessários para o desenvolvimento de uma metodologia digital adequada em todas as variáveis do SOA.

A protocol for lentiviral transduction and downstream analysis of intestinal organoids.

Intestinal crypt-villus structures termed organoids, can be kept in sustained culture three dimensionally when supplemented with the appropriate growth factors. Since organoids are highly similar to the original tissue in terms of homeostatic stem cell differentiation, cell polarity and presence of all terminally differentiated cell types known to the adult intestinal epithelium, they serve as an essential resource in experimental research on the epithelium. The possibility to express transgenes or interfering RNA using lentiviral or retroviral vectors in organoids has increased opportunities for functional analysis of the intestinal epithelium and intestinal stem cells, surpassing traditional mouse transgenics in speed and cost. In the current video protocol we show how to utilize transduction of small intestinal organoids with lentiviral vectors illustrated by use of doxycylin inducible transgenes, or IPTG inducible short hairpin RNA for overexpression or gene knockdown. Furthermore, considering organoid culture yields minute cell counts that may even be reduced by experimental treatment, we explain how to process organoids for downstream analysis aimed at quantitative RT-PCR, RNA-microarray and immunohistochemistry. Techniques that enable transgene expression and gene knock down in intestinal organoids contribute to the research potential that these intestinal epithelial structures hold, establishing organoid culture as a new standard in cell culture.

Trasplante hepático: evolución, curva de aprendizaje y resultados después de los primeros 300 casos / Liver transplantation: development, learning curve and results after the first 300 cases

Background: Liver transplantation (LT) is an option for people with liver failure who cannot be cured with other therapies and for some people with liver cancer. Aim: To describe, and analyze the first 300 LT clinical results, and to establish our learning curve. Material and Methods: Retrospective cohort study with data obtained from a prospectively collected LT Program database. We included all LT performed at a single center from March 1994 to September 2017. The database gathered demographics, diagnosis, indications for LT, surgical aspects and postoperative courses. We constructed a cumulative summation test for learning curve (LC-CUSUM) using 30-day post-LT mortality. Mortality at 30 days, and actuarial 1-, and 5-year survival rate were analyzed. Results: A total of 281 patients aged 54 (0-71) years (129 women) underwent 300 LT. Ten percent of patients were younger than 18 years old. The first, second and third indications for LT were non-alcoholic steatohepatitis, chronic autoimmune hepatitis and alcoholic liver cirrhosis, respectively. Acute liver failure was the LT indication in 51 cases (17%). The overall complication rate was 71%. Infectious and biliary complications were the most common of them (47 and 31% respectively). The LC-CUSUM curve shows that the first 30 patients corresponded to the learning curve. The peri-operative mortality was 8%. Actuarial 1 and 5-year survival rates were 82 and 71.4%, respectively. Conclusions: Outcome improvement of a LT program depends on the accumulation of experience after the first 30 transplants and the peri-operative mortality directly impacted long-term survival.

Peripheral blood pressure by Dinamap and central blood pressure by applanation tonometry in outpatient general practice.

INTRODUCTION: Central blood pressure (CBP) is the pressure exerted by the blood column at any given moment on the aortic and carotid artery walls, which is a close proxy for the blood pressure inside the brain and the heart, and is thus a better marker of cardiovascular morbidity and mortality than peripheral blood pressure (PBP). OBJECTIVE: To assess how the augmentation index (AI), peripheral pulse pressure (pPP), central pulse pressure (cPP) and subendocardial viability ratio (SEVR) vary in hypertensive patients according to level of control of CBP and PBP. METHODS: We performed an observational, cross-sectional study in a convenience sample from a general practice in Central Portugal over a period of four days in May 2010. Measurements were taken after a four-minute resting period. The following values were considered to reflect controlled pressures: PBP <140/90 mmHg, CBP <130/80 mmHg, pPP <55 mmHg and cPP <45 mmHg. RESULTS: The sample included 92 patients, 38 male (41.3%), mean age 62.3±11.1 years, with no significant difference in gender distribution. PBP was controlled in 55 (59.8%), and CBP in 53 (57.6%). Both PBP and CBP were controlled in 50 patients (54.3%) and neither was controlled in 34 (37.9%). pPP and cPP were significantly lower in those with controlled PBP (p<0.001) and CBP (p<0.001). AI was non-significantly lower in those with controlled PBP (78±9 vs. 80.7) and those with controlled CBP (78±9 vs.81±7) (p=0.02). SEVR was within the desirable range in 92 patients (92.2%). 78.4% of individuals were taking drugs acting on the renin angiotensin aldosterone system (RAAS). CONCLUSIONS: In a convenience sample of 92 patients, PBP and CBP were controlled in 59.8% and 57.6%, respectively. Those with controlled PBP had significantly better peripheral systolic and diastolic blood pressure, CBP, pPP and cPP; the same was true of those with controlled CBP, who also had a significantly better AI. The percentage of the cardiac cycle in diastole had a desirable value for 92,2% of the subjects.

Polyinosinic acid blocks adeno-associated virus macrophage endocytosis in vitro and enhances adeno-associated virus liver-directed gene therapy in vivo.

Adeno-associated virus serotype 8 (AAV8) has been demonstrated to be effective for liver-directed gene therapy in humans. Although hepatocytes are the main target cell for AAV8, there is a loss of the viral vector because of uptake by macrophages and Kupffer cells. Reducing this loss would increase the efficacy of viral gene therapy and allow a dose reduction. The receptor mediating this uptake has not been identified; a potential candidate seems the macrophage scavenger receptor A (SR-A) that is involved in the endocytosis of, for instance, adenovirus. In this study we show that SR-A can mediate scAAV8 endocytosis and that blocking it with polyinosinic acid (poly[i]) reduces endocytosis significantly in vitro. Subsequently, we demonstrate that blocking this receptor improves scAAV-mediated liver-directed gene therapy in a model for inherited hyperbilirubinemia, the uridine diphospho-glucuronyl transferase 1A1-deficient Gunn rat. In male rats, preadministration of poly[i] increases the efficacy of a low dose (1×10¹¹ gc/kg) but not of a higher dose (3×10¹¹ gc/kg) scAAV8-LP1-UT1A1. Administration of poly[i] just before the vector significantly increases the correction of serum bilirubin in female rats. In these, the effect of poly[i] is seen by both doses but is more pronounced in the females receiving the low vector, where it also results in a significant increase of bilirubin glucuronides in bile. In conclusion, this study shows that SR-A mediates the endocytosis of AAV8 in vitro and in vivo and that blocking this receptor can improve the efficacy of AAV-mediated liver-directed gene therapy.

Adeno-associated viral vector serotype 5 poorly transduces liver in rat models.

Preclinical studies in mice and non-human primates showed that AAV serotype 5 provides efficient liver transduction and as such seems a promising vector for liver directed gene therapy. An advantage of AAV5 compared to serotype 8 already shown to provide efficient correction in a phase 1 trial in patients suffering from hemophilia B, is its lower seroprevalence in the general population. Our goal is liver directed gene therapy for Crigler-Najjar syndrome type I, inherited severe unconjugated hyperbilirubinemia caused by UGT1A1 deficiency. In a relevant animal model, the Gunn rat, we compared the efficacy of AAV 5 and 8 to that of AAV1 previously shown to be effective. Ferrying a construct driving hepatocyte specific expression of UGT1A1, both AAV8 and AAV1 provided an efficient correction of hyperbilirubinemia. In contrast to these two and to other animal models AAV5 failed to provide any correction. To clarify whether this unexpected finding was due to the rat model used or due to a problem with AAV5, the efficacy of this serotype was compared in a mouse and two additional rat strains. Administration of an AAV5 vector expressing luciferase under the control of a liver specific promoter confirmed that this serotype poorly performed in rat liver, rendering it not suitable for proof of concept studies in this species.

Perfil dos pacientes e contexto das consultas em que se fez pela primeira vez o diagnóstico de depressão no Centro de Saúde de Eiras, durante o ano de 2011 / Patient's profile and the context of consultations in which the diagnose of depression was made for the first time in Eiras Health Centre in 2011 / Perfil de losusuarios y contexto de las consultas en que se hizoel primer diagnóstico de depresiónenel Centro de Salud de Eiras durante elaño de 2011

Objetivo: Este estudo pretendeu conhecer aspectos dos utentes e consultas em que se fez pela primeira vez o diagnóstico de depressão. Métodos: Estudo observacional, transversal e descritivo. População obtida por aplicação de critérios de exclusão aos utentes que, em consulta durante 2011, tiveram em "Avaliação" a codificação "Perturbações depressivas". Pela análise do registro da consulta, estudaram-se as variáveis: idade, sexo, mês, tipo de consulta, consulta presencial/não presencial, sinais/sintomas depressivos anotados e/ou codificados, prescrição de psicofármacos, prescrição pela primeira vez/renovação de receituário. No caso de prescrição pela primeira vez: psicofármacos segundo grupo farmacológico e Denominação Comum Internacional, prescrição de antidepressivo na dose terapêutica e referência ao tempo de tratamento antidepressivo. Resultados: População de 105 indivíduos. Consultas maioritariamente presenciais (79%). Maior codificação de sinais/sintomas depressivos que anotação apenas ou que anotação e codificação. O sinal/sintoma mais codificado foi "Sensação de depressão" (28%). Houve prescrição de ansiolíticos isoladamente e um caso de prescrição subterapêutica do antidepressivo. Quanto à duração do tratamento antidepressivo, em 13,7% das receitas houve menção de que o tratamento deveria prolongar-se no mínimo por 6 meses. Conclusão: A obtenção de uma população pequena e possíveis vieses de informação foram limitações encontradas. Achamos curioso que o sinal/sintoma depressivo mais codificado fosse "Sensação de depressão". É necessário melhorar os registros clínicos e prescrição na depressão.

Objective: This investigation intended to know about aspects about patients and consultations in which depression was diagnosed for the first time. Methods: Observational, cross-sectional and descriptive study. Population obtained through the application of exclusion criteria in patients that during 2011 were in "Evaluation" with the codification "Depressive disturbance". Through the analysis of the consultation, we studied the variables: age, sex, month, type of consultation, consultation in the presence of the patient/patient not attending, depressive signs/symptoms noted and/or coded, prescription of psychiatric medication, if it was prescribed for the first time/renewed. In case it is prescribed for the first time: group of medication and name of the drug. If antidepressant was prescribed for the first time: therapeutic dosage/not and mention the time of treatment. Results: Population of 105 individuals. The consultations were mainly in the presence of the patient (79%). More encoding of depressive signs/symptoms than annotation only or than annotation and codification. The most coded depressive sign/symptom was "Sensation of depression" (28%). There was prescription of isolated anxiolytics and a case of under-therapeutic prescription of antidepressant. 13.7% of the prescription had the reference that the antidepressive treatment should last at least 6 months. Conclusion: Obtainment of a small population and possible information bias were limitations encountered. It is worthy to mention that the most coded depressive sign/symptom was "Sensation of depression". We must improve our clinical records and the prescription in depression.

Objetivo: Este estudio se destinó a comprender los aspectos de los usuarios y las consultas en que se hizo el primer diagnóstico de depresión. Métodos: Se realizó un estudio observacional, transversal y descriptivo. Población obtenida mediante la aplicación de criterios de exclusión a los usuarios que en consulta durante 2011, tuvieran la codificación "trastornos depresivos". Por el análisis de registros de consulta, se estudiaron las variables: edad, sexo, mes, tipo de consulta, consulta presencial/no, signos/síntomas depresivos anotados y/o codificados, la prescripción psicotrópica, si esa prescripción fue por la primera vez/renovación de la prescripción. En el caso de la prescripción por la primera vez: los psicotrópicos según grupo farmacológico y las denominaciones comunes internacionales, referencia, en la prescripción de terapia antidepresiva, a la dosis y tiempo del tratamiento. Resultados: Población de 105 individuos. Sobre todo consultas presenciales (79%). Más codificación de señales/síntomas depresivos que la anotación sola o que anotación y codificación. El signo/síntoma que se codificó más fue "Sentirse deprimido" (28%). Fueron prescritos ansiolíticos aislados y hubo un caso de prescripción sub-terapéutica de antidepresivo. En cuanto a duración del tratamiento antidepresivo, en 13,7% de las prescripciones se mencionaba que el tratamiento debía extenderse por lo menos 6 meses. Conclusión: La obtención de una pequeña población y los posibles sesgos de información fueron limitaciones encontradas. Fue curioso el hecho de que la señal/síntoma más codificada fue "Sentirse deprimido". Es necesario mejorar las historias clínicas y la prescripción en depresión.