Centro Hospitalar do Porto
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Genotype-phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil
Get PDFBackground: Genetic heterogeneity and compound heterozygosis give rise to a continuous spectrum of phenylalanine hydroxylase deficiency and metabolic phenotypes in phenylketonuria (PKU). The most used parameters for evaluating phenotype in PKU are pretreatment phenylalanine (Phe) levels, tolerance for dietary Phe, and Phe overloading test. Phenotype can vary from a "classic" (severe) form to mild hyperphenylalaninemia, which does not require dietary treatment. A subset of patients is responsive to treatment by the cofactor tetrahydrobiopterin (BH4 ). Genotypes of PKU patients from Rio de Janeiro, Brazil, were compared to predicted and observed phenotypes. Genotype-based estimations of responsiveness to BH4 were also conducted.
Methods: Phenotype was defined by pretreatment Phe levels. A standard prediction system based on arbitrary assigned values was employed to measure genotype-phenotype concordance. Patients were also estimated as BH4 -responders according to the responsiveness previously reported for their mutations and genotypes.
Results: A 48.3% concordance rate between genotype-predicted and observed phenotypes was found. When the predicted phenotypes included those reported at the BIOPKU database, the concordance rate reached 77%. A total of 18 genotypes from 30 patients (29.4%) were estimated as of potential or probable BH4 responsiveness. Inconsistencies were observed in genotypic combinations including the common "moderate" mutations p.R261Q, p.V388M, and p.I65T and the mild mutations p.L48S, p.R68S, and p.L249F.
Conclusion: The high discordance rate between genotype-predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so-called "moderate" common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although our results of BH4 estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype-phenotype association studies are important in selecting patients to be offered a BH4 overload test, especially in low-resource settings like Brazil.Dr. Vieira Neto reports two public grants from Coordination for the Improvement of Higher Level Personnel (Capes) of the Ministry of Education, Brazil, and private grants from FBM Pharmaceutical Industry Ltd., Anápolis, Goiás, Brazil, and from Danone Ltd., São Paulo, Brazil, during the conduct of the study.info:eu-repo/semantics/publishedVersio
Phakic Intraocular Lens Implantation After Deep Anterior Lamellar Keratoplasty: Retrospective Case Series Analysis With Long-Term Follow-Up
Get PDFPurpose: To report outcomes of phakic intraocular lens (IOL) implantation after deep anterior lamellar keratoplasty (DALK) to correct high ametropia.
Setting: Centro Hospitalar Universitário do Porto, Portugal.
Methods: Retrospective case series with 11 eyes submitted to phakic IOL implantation after DALK. Main outcomes measured were uncorrected and corrected distance visual acuity (UDVA and CDVA), refractive error components, tomographic parameters and endothelial cell density (ECD). The minimum follow-up was 3 years for all cases.
Results: Mean ECD loss was 8.7±6.7% at 1 year, 13.1±8.6% at 3 years (n=11; p=0.016, p=0.007, respectively) and 14.0±20.4% at 5 years (n=5, p=0.212). Mean logMAR UDVA increased from 1.27±0.90logMAR preoperatively to 0.16±0.15logMAR postoperatively (p≤0.001) and no statistically significant differences were registered during follow-up. All patients gained at least 5 lines of UDVA. 54.5% of the eyes gained 1 line in CDVA postoperative and only one eye lost one CDVA line through follow-up. Efficacy and safety indexes at 1 and 3 years were 1.01-0.97 and 1.24-1.21, respectively. Mean spherical equivalent was reduced from -7.84±4.63 D preoperatively to -1.05±1.07 D postoperatively (p=0.001). Mean percentage of reduction in refractive cylinder and spherical error was 83.8±15.8% and 73.1±31.5%, respectively, p≤0.001 for both. In one eye there was a significantly gradual ECD loss over 5 years follow-up and the patient will be submitted to IOL explant.
Conclusion: Phakic IOLs were effective for correction high ametropia after DALK, showing high efficacy and safety indexes with stability over time. However, it was registered a continuing endothelial cell loss postoperatively, which assumed to be higher than those reported in eyes without DALK.info:eu-repo/semantics/publishedVersio
Ruptured Mitral Valve Aneurysm: A Rare Complication of Mitral Valve Endocarditis
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Development and validation of quick Acute Kidney Injury-score (q-AKI) to predict acute kidney injury at admission to a multidisciplinary intensive care unit
Get PDFAKI is associated with increased risk of death, prolonged length of stay and development of de-novo chronic kidney disease. The aim of our study is the development and validation of prediction models to identify the risk of AKI in ICU patients up to 7 days. We retrospectively recruited 692 consecutive patients admitted to the ICU at San Bortolo Hospital (Vicenza, Italy) from 1 June 2016 to 31 March 2017: 455 patients were treated as the derivation group and 237 as the validation group. Candidate variables were selected based on a literature review and expert opinion. Admission eGFR< 90 ml/min /1.73 mq (OR 2.78; 95% CI 1.78-4.35; p<0.001); SOFAcv ≥ 2 (OR 2.23; 95% CI 1.48-3.37; p<0.001); lactate ≥ 2 mmol/L (OR 1.81; 95% CI 1.19-2.74; p = 0.005) and (TIMP-2)•(IGFBP7) ≥ 0.3 (OR 1.65; 95% CI 1.08-2.52; p = 0.019) were significantly associated with AKI. For the q-AKI score, we stratified patients into different AKI Risk score levels: 0-2; 3-4; 5-6; 7-8 and 9-10. In both cohorts, we observed that the proportion of AKI patients was higher in the higher score levels.info:eu-repo/semantics/publishedVersio
Impact of physical activity in vascular cognitive impairment (AFIVASC): study protocol for a randomised controlled trial
Get PDFBackground: Cognitive impairment and cerebrovascular pathology are both frequent with ageing. Cognitive impairment due to vascular pathology of the brain, termed vascular cognitive impairment (VCI), is one of the most frequent causes of cognitive impairment in elderly subjects. Thus far, VCI has no specific pharmacological treatment. Recent observational studies have suggested a protective effect of physical activity in cognition, but adequate randomised controlled trials (RCT) are lacking.
Methods: AFIVASC is a multi-centre randomised controlled trial, with a 6-month intervention treatment and an additional follow-up of 6 months, that aims to estimate the impact of 6 months of moderate intensity physical activity on cognition (the primary outcome) at 6 and 12 months in subjects with VCI. Participants are community dwellers with criteria for VCI without dementia or who have had previous stroke or transient ischaemic attack (TIA). Patients may be self-referred or referred from a medical appointment. After confirming the inclusion criteria, a run-in period of 1 month is conducted to access adherence; only after that are subjects randomly assigned (using a computerised program blinded to clinical details) to two groups (intervention group and best practice usual care group). The intervention consists of three physical activity sessions of 60 min each (two supervised and one unsupervised) per week. The primary outcome is measured by the presence or absence of decline in cognitive status. Secondary outcomes include changes in neuro-cognitive measures, quality of life, and functional and motor status. Primary and secondary outcomes are evaluated at 6 and 12 months by investigators blinded to both intervention and randomisation. A required sample size of 280 subjects was estimated. Statistical analyses will include regression analysis with repeated measures. The study was approved by the Ethics Committee for Health of Centro Hospitalar de Lisboa Norte (ref. no. 1063/13) and by the Ethics Committee for Health of Centro Hospitalar do Porto CHP (ref. no. 2016.055(049-DEFI/048-CES)).
Discussion: We aim to show whether or not moderate physical activity has a beneficial impact on cognition, quality of life, motor, and functional status in people with vascular cognitive impairment, and to generate new insights on the applicability of implementing physical activity in this specific population.The authors disclose receipt of the following financial support for this research: FCT (FCT-PTDC/DTP-ES/3706/2014).info:eu-repo/semantics/publishedVersio
Effect of Hemodynamic Changes in Plasma Propofol Concentrations Associated with Knee-Chest Position in Spinal Surgery: A Prospective Study
Get PDFBackground: Anesthesia induction and maintenance with propofol can be guided by target-controlled infusion (TCI) systems using pharmacokinetic (Pk) models. Physiological variables, such as changes in cardiac output (CO), can influence propofol pharmacokinetics. Knee-chest (KC) surgical positioning can result in CO changes.
Objectives: This study aimed to evaluate the relationship between propofol plasma concentration prediction and CO changes after induction and KC positioning.
Methods: This two-phase prospective cohort study included 20 patients scheduled for spinal surgery. Two different TCI anesthesia protocols were administered after induction. In phase I (n = 9), the loss of consciousness (LOC) concentration was set as the propofol target concentration and CO changes following induction and KC positioning were quantified. In phase II (n = 11), based on data from phase I, two reductions in the propofol target concentration on the pump were applied after LOC and before KC positioning. Propofol plasma concentrations were measured at different moments in both phases: after induction and after KC positioning.
Results: Schnider Pk model showed a good performance in predicting propofol concentration after induction; however, after KC positioning, when a significant drop in CO occurred, the measured propofol concentrations were markedly underestimated. Intended reductions in the propofol target concentration did not attenuate HD changes. In the KC position, there was no correlation between the propofol concentration estimated by the Pk model and the measured concentration in plasma, as the latter was much higher (P = 0.013) while CO and BIS decreased significantly (P < 0.001 and P = 0.004, respectively).
Conclusions: Our study showed that the measured propofol plasma concentrations during the KC position were significantly underestimated by the Schnider Pk model and were associated with significant CO decrease. When placing patients in the KC position, anesthesiologists must be aware of pharmacokinetic changes and, in addition to standard monitoring, the use of depth of anesthesia and cardiac output monitors may be considered in high-risk patients.This work was partially funded by the Foundation for Science and Technology, FCT, through national (MEC) and European structural (FEDER) funds, in the scope of the research projects UID/MAT/04106/2019 (CIDMA/UA), UID/CEC/00127/2019 (IEETA/UA) and UID/MAT/00144/2019 (CMUP/UP). This work was also partially suported by Portugal 2020 under the Competitiveness and Internationalization Operational Program, and by the European Regional Development Fund through project SOCA-Smart Open Campus (CENTRO-01-0145-FEDER-000010), acknowledgements from Sonia Gouveia. Aura Silva also acknowledges the postdoctoral grant by FCT (ref. SFRH/BPD/75697/2011).info:eu-repo/semantics/publishedVersio
Carbidopa Alters Tryptophan Metabolism in Breast Cancer and Melanoma Cells Leading to the Formation of Indole-3-Acetonitrile, a Pro-Proliferative Metabolite
Get PDFCarbidopa is used for the treatment of Parkinson's disease (PD) as an inhibitor of DOPA decarboxylase, and PD patients taking carbidopa have a lower incidence of various tumors, except for breast cancer and melanoma. Recently, it was shown that carbidopa inhibits tryptophan-2,3-dioxygenase (TDO) and kynureninase enzymes. In the present study, the effect of carbidopa on the viability and metabolic profile of breast cancer MCF-7 and melanoma A375 cells was investigated. Carbidopa was not effective in inhibiting MCF-7 and A375 proliferation. Liquid chromatography and mass spectrometry revealed a new compound, identified as indole-3-acetonitrile (IAN), which promoted a concentration-dependent increase in the viability of both cell lines. The results suggest that treatment with carbidopa may alter tryptophan (Trp) metabolism in breast cancer and melanoma leading to the formation of a pro-proliferative Trp metabolite, which may contribute to its failure in reducing breast cancers and melanoma incidence in PD patients taking carbidopa.This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds
through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation (POCI),
Portugal 2020, and by Portuguese funds through FCT, in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274).” NV thanks FCT for IF position, Fundação Manuel António da Mota (FMAM, Portugal) for support. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT and FMAMinfo:eu-repo/semantics/publishedVersio
Ventilator-associated pneumonia diagnosis: a prioritization exercise based on multi-criteria decision analysis
Get PDFThe aim was to provide global experts ranking on priorities in diagnostic tools for VAP in clinical practice. A multiple criteria decision analysis (MCDA) was performed to identify diagnosis tools for VAP diagnosis. Priority factors were identified after literature review. An international, multidisciplinary expert panel reviewed variables and ranked diagnostic tools. Experts from ten European hospitals participated. Regarding bedside clinical practices, seven required chest X-ray use in all patients, whereas six reported the use of blood cultures and endotracheal aspirate in all patients. Invasive techniques were routinely performed in seven sites. CRP, PCT, and Gram stains were performed in all patients by 5, 2, and 8, respectively. Impact on patient outcomes, safety, and impact on the decision to start antibiotic therapy were ranked as the top three relevant concerns (7.7/10, 7/10, and 6.9/10, respectively). Chest X-ray was ranked as the most important imaging technique to diagnose VAP (score 251.7). Apart from blood cultures, endotracheal aspirate culture was identified as the main collection method for the microbiological testing (scores of 274.8 and 246.8, respectively). Mini-BAL was the preferred invasive technique with a score of 208. Top three biomarkers were CRP (score 184.3), PCT (181.3), and WBC (166.4). Gram stain (192.5) was prioritized among laboratory diagnostic techniques. Using MCDA, it is recommended to perform a combination of diagnostic techniques including images (chest X-ray), culture of clinical specimens (blood cultures and endotracheal aspirate), and biomarkers (CRP or PCT) for VAP diagnosis at the bedside. Gram stain was ranked as the preferred laboratory technique.info:eu-repo/semantics/publishedVersio
Ustekinumab no Tratamento de Psoríase Moderada a Grave: Experiência em 116 Doentes da Prática Clínica
Get PDFUstekinumab is a monoclonal antibody directed against the p40 subunit common to both IL-12 and IL-23 cytokines. Although the evidence of ustekinumab efficacy and safety in clinical trials is extensively recognized, data on its use in clinical practice is limited. Our objective is to report on the real-life experience of two Portuguese dermatology departments with ustekinumab in patients with moderate to severe psoriasis, and to identify the clinical characteristics associated with a weaker clinical response.Introdução:O ustekinumab é um anticorpo monoclonal dirigido contra a subunidade p40 presente nas IL-12 e 23. A evidência da sua eficácia e segurança em ensaios clínicos é amplamente conhecida. No entanto a evidência da sua utilização na prática clínica é relativamente limitada na população Portuguesa. O objetivo deste trabalho é relatar a experiência de dois serviços de dermatologia Portugueses no tratamento da psoríase moderada a grave com ustekinumab.
Material e Métodos:Foram avaliados os dados clínicos, demográficos, e de resposta terapêutica ao ustekinumab em 116 doentes com psoríase tratados entre novembro de 2009 e dezembro de 2015.
Resultados:Observou-se uma resposta terapêutica ≥ PASI75 em 67,2%, 85,3%, 89,6% e 88,7% dos doentes às semanas 4, 12, 24 e 52, respetivamente. O ustekinumab foi descontinuado em sete doentes (três por falências primárias, três por falências secundárias e um por evento adverso). Não foram observados eventos cardiovasculares nem reativações de infecções prévias (tuberculose, hepatite B). Em nove doentes foi utilizado em simultâneo metotrexato, e em catorze foi necessário otimizar a dose de ustekinumab.
Não foram observados efeitos colaterais nestes grupos. A resposta terapêutica foi superior nos doentes naïve a terapêuticas biológicas comparativamente com os doentes não-naïve. Observou-se uma tendência para resposta clínica inferior nos doentes com peso entre 90 – 100 kg.
Discussão e Conclusão:Este estudo confirma a segurança e eficácia de ustekinumab no tratamento da psoríase moderada a grave em doentes da prática clínica real, sustenta a eficácia mesmo nos doentes previamente expostos a terapêutica biológica e aponta para a possível necessidade de ajustar a dose a partir dos 90 kg.info:eu-repo/semantics/publishedVersio