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Clinical and Genetic Analysis of Children with Kartagener Syndrome
Get PDFPrimary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes' products. Our work calls the researcher's attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families.RP was funded by a PhD grant from the National Foundation for Science and Technology (FCT) (Ref.:
PD/BD/105767/2014). This work was also supported by the Institutions of the authors and in part by FCT/UMIB
(Pest-OE/SAU/UI0215/2014).info:eu-repo/semantics/publishedVersio
Lipid Antigen Presentation by CD1b and CD1d in Lysosomal Storage Disease Patients
Get PDFThe lysosome has a key role in the presentation of lipid antigens by CD1 molecules. While defects in lipid antigen presentation and in invariant Natural Killer T (iNKT) cell response were detected in several mouse models of lysosomal storage diseases (LSD), the impact of lysosomal engorgement in human lipid antigen presentation is poorly characterized. Here, we analyzed the capacity of monocyte-derived dendritic cells (Mo-DCs) from Fabry, Gaucher, Niemann Pick type C and Mucopolysaccharidosis type VI disease patients to present exogenous antigens to lipid-specific T cells. The CD1b- and CD1d-restricted presentation of lipid antigens by Mo-DCs revealed an ability of LSD patients to induce CD1-restricted T cell responses within the control range. Similarly, freshly isolated monocytes from Fabry and Gaucher disease patients had a normal ability to present α-Galactosylceramide (α-GalCer) antigen by CD1d. Gaucher disease patients' monocytes had an increased capacity to present α-Gal-(1-2)-αGalCer, an antigen that needs internalization and processing to become antigenic. In summary, our results show that Fabry, Gaucher, Niemann Pick type C, and Mucopolysaccharidosis type VI disease patients do not present a decreased capacity to present CD1d-restricted lipid antigens. These observations are in contrast to what was observed in mouse models of LSD. The percentage of total iNKT cells in the peripheral blood of these patients is also similar to control individuals. In addition, we show that the presentation of exogenous lipids that directly bind CD1b, the human CD1 isoform with an intracellular trafficking to the lysosome, is normal in these patients.This work was financed by Gaucher Generation Program, supported by Sanofi-Genzyme and by Norte-01-0145-FEDER-000012—Structured program on bioengineered therapies for infectious diseases and tissue regeneration, supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). BP-C was temporally supported by a grant from the American Portuguese Biomedical Research Fund (APBRF).info:eu-repo/semantics/publishedVersio
Tratamento de varizes retais de difícil controlo
Get PDFBackground: Rectal varices are portosystemic collaterals that arise as a complication of portal hypertension. Despite their significant prevalence among cirrhotic patients, clinically important bleeding occurs only in a minority. Various treatment options are available, with endoscopic therapies being widely used, and both interventional radiology and surgery being considered for refractory bleeding rectal varices.
Case: We report the case of a 61-year-old male with hepatic cirrhosis and bleedingrectal varices refractory to endoscopic therapy, successfully managed with a combination of transjugular intrahepatic portosystemic shunt (TIPS) and selective variceal embolization.
Conclusions: Radiological techniques are effective options for refractory bleeding. Adding embolization to TIPS implantation could represent a valid adjunctive measure for haemostasis of recurrent rectal variceal bleeding.Introdução: As varizes retais são colaterais portossistémicos que se formam como complicação da hipertensão portal. Apesar de serem frequentes em doentes com cirrose hepática, cursam com hemorragia apenas numa minoria dos casos. Entre as opções terapêuticas disponíveis, a endoscópica é a mais amplamente disponível e utilizada, sendo as intervenções da radiologia ou da cirurgia reservadas para casos de hemorragia refratária. Caso: Apresenta-se o caso de um homem de 61 anos com cirrose hepática e hemorragia com ponto de partida em varizes retais. Por refratariedade ao tratamento endoscópico, uma combinação de shunt portossistémico intrahepático transjugular e embolização seletiva das varizes retais foi necessária para uma hemóstase eficaz. Conclusão: A combinação do TIPS com a embolização seletiva das varizes retais é uma alternativa terapêutica na hemorragia por varizes retais refratárias a tratamento endoscópico.info:eu-repo/semantics/publishedVersio
Nutrição entérica pré-operatória e resultados pós-operatórios em adultos com doença de Crohn: revisão sistemática
Get PDFBackground and aim: Enteral nutrition (EN) is applicable to adult Crohn's disease (CD) in treating malnutrition and in inducing remission - here as a less effective alternative than corticosteroids. The purpose of this review is to determine whether preoperative EN impacts postoperative complications of adult CD, either by means of nutritional or therapeutic effects.
Summary: A systematic review of English written full-text research articles published between January 1990 and November 2017, including adult patients undergoing abdominal surgery for complicated CD after EN, was performed. Four studies out of 22 were selected, all of which institutional, retrospective, case-control cohorts, one classified as "good quality" and three as "poor quality," as rated by the Newcastle-Ottawa Scale. The application of inclusion and exclusion criteria resulted in a non-intentional absence of studies referring to supplemental EN among those reviewed. The reduced number of heterogeneous eligible studies impeded meta-analysis. In all studies, exclusive EN (EEN) was used and well tolerated, allowing to defer or even avoid surgery altogether, improving patients' global state. The two studies with the greatest number of patients found preoperative EEN to be an independent factor against infectious and non-infectious complications in 219 patients and against anastomotic leaks or abscesses in 38 patients. Also, in univariate analysis, EEN was found to increase preop-erative immunosuppressant-free intervals and to protect against anastomotic dehiscences, intra-abdominal abscesses, surgical wound infections, ileus, stomas, and reoperations in the largest study; in another study it was related to fewer intra-abdominal septic complications.
Key messages: All reviewed studies are retrospective and, consequently, of limited relevance. Nonetheless, all of them call the attention of the scientific community to the potential benefits of preoperative EEN on postoperative outcomes in adult CD, calling for prospective multi-institutional studies and randomized controlled trials.Introdução e objetivo: No adulto com doença de Crohn (DC) a nutrição entérica (NE) é aplicável como terapêutica da desnutrição ou como alternativa, menos eficaz, aos corticoides, para indução de remissão. O objetivo desta revisão é determinar se a NE pré-operatória tem impacto nas complicações pós-operatórias, seja pelo efeito nutricional seja pelo terapêutico. Sumário: Foi realizada uma revisão sistemática dos artigos de investigação que incluíssem doentes adultos submetidos a cirurgia abdominal por DC complicada, após NE, redigidos em inglês e publicados entre janeiro de 1990 e novembro de 2017. De 22 estudos foram selecionados quatro institucionais e retrospetivos de coorte, um de “fraca qualidade” e três de “pobre qualidade” pela “Newcastle-Ottawa Scale”. Nos estudos revistos foi utilizada NE exclusiva (NEE) já que, não intencionalmente, os estudos com NE suplementar reuniram critérios de exclusão. O pequeno número e a heterogeneidade dos estudos elegíveis impossibilitaram uma meta-análise. A NEE foi utilizada e bem tolerada em todos os estudos, e permitiu melhorar o estado global dos doentes e protelar ou mesmo evitar a cirurgia. Nos dois estudos com maior número de doentes, a NEE pré-operatória foi um fator independente contra deiscências de sutura e abcessos em 219 doentes, e contra complicações infeciosas intra-abdominais em 38. Em análise univariada também se verificou que, no maior estudo, a NEE aumentou o intervalo pré-operatório livre de imunossupressores e foi protetora contra deiscências anastomóticas, abscessos intra-abdominais, infeções da ferida operatória, ileus, estomas e reoperações; noutro estudo menores correlacionou-se com menos complicações infeciosas intra-abdominais. Mensagens-chave: Todos os estudos revistos são retrospetivos e, consequentemente, de relevância limitada. No entanto, todos chamam a atenção da comunidade científica para os potenciais benefícios da NEE pré-operatória nos resultados pós-operatórios dos adultos com DC e para a necessidade de estudos prospetivos multi-institucionais e de ensaios clínicos randomizados.info:eu-repo/semantics/publishedVersio
Glycomacropeptide: long-term use and impact on blood phenylalanine, growth and nutritional status in children with PKU
Get PDFIn phenylketonuria, casein glycomacropeptide (CGMP) requires modification with the addition of some essential and semi essential amino acids to ensure suitability as a protein substitute. The optimal amount and ratio of additional amino acids is undefined.
Aim: A longitudinal, parallel, controlled study over 12 months evaluating a CGMP (CGMP-AA2) formulation compared with phenylalanine-free L-amino acid supplements (L-AA) on blood Phe, Tyr, Phe:Tyr ratio, biochemical nutritional status and growth in children with PKU. The CGMP-AA2 contained 36 mg Phe per 20 g protein equivalent.
Methods: Children with PKU, with a median age of 9.2 y (5-16y) were divided into 2 groups: 29 were given CGMP-AA2, 19 remained on Phe-free L-AA. The CGMP-AA2 formula gradually replaced L-AA, providing blood Phe concentrations were maintained within target range. Median blood Phe, Tyr, Phe:Tyr ratio and anthropometry, were compared within and between the two groups at baseline, 26 and 52 weeks. Nutritional biochemistry was studied at baseline and 26 weeks only.
Results: At the end of 52 weeks only 48% of subjects were able to completely use CGMP-AA2 as their single source of protein substitute. At 52 weeks CGMP-AA2 provided a median of 75% (30-100) of the total protein substitute with the remainder being given as L-AA. Within the CGMP-AA2 group, blood Phe increased significantly between baseline and 52 weeks: [baseline to 26 weeks; baseline Phe 270 μmol/L (170-430); 26 weeks, Phe 300 μmol/L (125-485) p = 0.06; baseline to 52 weeks: baseline, Phe 270 μmol/L (170-430), 52 weeks Phe 300 μmol/L (200-490), p < 0.001)]. However, there were no differences between the CGMP-AA2 and L-AA group for Phe, Tyr, Phe:Tyr ratio or anthropometry at any of the three measured time points. Within the CGMP-AA2 group only weight (p = 0.0001) and BMI z scores (p = 0.0001) increased significantly between baseline to 52 weeks. Whole blood and plasma selenium were significantly higher (whole blood selenium [p = 0.0002]; plasma selenium [p = 0.0007]) at 26 weeks in the CGMP-AA2 group compared L-AA. No differences were observed within the L-AA group for any of the nutritional markers.
Conclusions: CGMP-AA increases blood Phe concentrations and so it can only be used partly to contribute to protein substitute in some children with PKU. CGMP-AA should be carefully introduced in children with PKU and close monitoring of blood Phe control is essential.info:eu-repo/semantics/publishedVersio
Enzymatic vitreolysis for the treatment of tractional diabetic macular edema
Get PDFBackground: A new approach to address focal vitreomacular adhesion in patients with diabetic macular edema may control and stabilize diabetic macular edema with fewer anti-vascular endothelial growth factor injections.
Objectives: The aim of this study was to demonstrate that diabetic macular edema can be improved by inducing the release of a vitreomacular adhesion, with less than 2500 μm, with enzymatic vitreolysis.
Methods: From a retrospective analysis of clinical records from patients with diabetic retinopathy, patients with diabetic macular edema and vitreomacular adhesion <2500 μm were selected for a single-arm prospective study. The primary endpoint was to control diabetic macular edema with fewer anti-vascular endothelial growth factor injections after an observed vitreomacular adhesion release. A statistical subanalysis was performed for the following two groups: the group with vitreomacular adhesion release (group 1) and the group without vitreomacular adhesion release (group 2).
Results: A total of 23 eyes from 19 patients were included. A reduction of the median number of injections was achieved in group 1 (p = 0.006). Adverse events were mild and transitory.
Conclusion: Release of vitreomacular adhesion <2500 μm through enzymatic vitreolysis contributed to the control and stabilization of diabetic macular edema with fewer anti-vascular endothelial growth factor injections, reducing the burden and the risks related to these invasive and frequently chronic treatments.info:eu-repo/semantics/publishedVersio
Alteplase for Massive Pulmonary Embolism after Complicated Pericardiocentesis
Get PDFBackground: The occurrence of a high-risk pulmonary embolism (PE) within 48 hours of a complicated pericardiocentesis to remove a haemorrhagic pericardial effusion, is an uncommon clinical challenge.
Case summary: The authors report the case of a 75-year-old woman who presented with signs of imminent cardiac tamponade due to recurring idiopathic pericardial effusion. The patient underwent pericardiocentesis that was complicated by the loss of 1.5 litres of blood. Within 48 hours, the patient had collapsed with clear signs of obstructive shock. This was a life-threating situation so alteplase was administered after cardiac tamponade and hypertensive pneumothorax had been excluded. CT chest angiography later confirmed bilateral PE. The patient achieved haemodynamic stability less than an hour after receiving the alteplase. However, due to the high risk of bleeding, the medical team suspended the thrombolysis protocol and switched to unfractionated heparin within the hour. The cause of the PE was not identified despite extensive study, but after 1 year of follow-up the patient remained asymptomatic.
Discussion: Despite the presence of a contraindication, the use of thrombolytic therapy in obstructive shock after exclusion of hypertensive pneumothorax can be life-saving, and low-dose thrombolytic therapy may be a valid option in such cases.
Learning points: A quick and systematic approach to a collapsed patient with signs of shock is mandatory; understanding the type of shock may help narrow the differential diagnosis and help in therapeutic decisions.After exclusion of cardiac tamponade and hypertensive pneumothorax, life-saving thrombolytic therapy can be administered in obstructive shock due to probable massive pulmonary embolism.Contraindications for thrombolytic therapy originated as exclusion criteria for clinical trials but should not prevent the use of this therapy in life-threatening situations.info:eu-repo/semantics/publishedVersio
Abordagem diagnóstica e terapêutica da toxicidade gastrointestinal dos inibidores dos checkpoint imunológicos
Get PDFImmune checkpoint inhibitors have shown anti-tumour activity in cancers such as melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma, colorectal cancer, and Hodgkin's lymphoma. Though immune checkpoint inhibitors have revolutionized the treatment and prognosis of some advanced malignancies, they are also associated with a significant risk of immune-related adverse events. These adverse events can occur in any organ system, but gastrointestinal side effects are among the most commonly reported, with manifestations ranging from mild diarrhoea to severe colitis, sharing some features with inflammatory bowel disease. Anticipating a greater use of these drugs in the future, gastroenterologists should expect to be increasingly faced with gastrointestinal immune-related adverse events. Knowledge of these toxicities, as well as effective management algorithms, is essential to enable early diagnosis and treatment, decreasing morbidity and mortality. We reviewed the currently available literature on gastrointestinal toxicity induced by immune checkpoint inhibitors, namely the clinical features, diagnosis, and management.Os inibidores dos checkpoint imunológicos demonstraram atividade antitumoral em neoplasias como o melanoma, o carcinoma de células renais, o carcinoma pulmonar de não pequenas células, o carcinoma urotelial, o carcinoma colorretal e o linfoma de Hodgkin. Estes fármacos, embora tenham revolucionado o tratamento e o prognóstico de algumas neoplasias avançadas, também se associam a um risco considerável de efeitos adversos associadosao sistema imunitário. Qualquer órgão pode ser afetado, mas os efeitos adversos gastrointestinais estão entre os mais comumente relatados. As manifestações gastrointestinais variam desde diarreia ligeira a colite grave, a qual pode evidenciar características idênticas às da doença inflamatória intestinal. Antecipando uma maior utilização destes fármacos no futuro, os gastroenterologistas devem esperar confrontar-se cada vez mais com este tipo de efeitos adversos. O conhecimento dessas toxicidades, bem como dos algoritmos de abordagem destes doentes é fundamental para um diagnóstico e tratamento precoces, diminuindo desta forma a morbilidade e a mortalidade. Os autores pretenderam rever a literatura mais atual sobre a toxicidade gastrointestinal induzida pelos inibidores dos checkpoint imunológicos, nomeadamente apresentação clínica, abordagem diagnóstica e terapêutica.info:eu-repo/semantics/publishedVersio
Digital Versus Conventional Rehabilitation After Total Hip Arthroplasty: A Single-Center, Parallel-Group Pilot Study
Get PDFBackground: The demand for total hip arthroplasty (THA) is rising. In the face of rapidly increasing health care costs, ensuring widespread, cost-effective rehabilitation is a priority. Technologies allowing independent home-based rehabilitation may be the key to facilitate access, improve effectiveness, and lower costs of care.
Objective: The aim of this study was to assess the feasibility of a novel artificial intelligence-powered digital biofeedback system following THA and compare the clinical outcomes against supervised conventional rehabilitation.
Methods: This was a single-center, parallel-group pilot study, with an 8-week intervention program. Patients were assessed at baseline, during the program (at 4 and 8 weeks), and 3 and 6 months after surgery. The primary outcome was the Timed Up and Go (TUG) score and secondary outcomes were the Hip dysfunction and Osteoarthritis Outcome Scale (HOOS; a patient-reported outcome) and hip range of motion (ROM).
Results: A total of 66 patients were included: 35 digital physiotherapy (PT) versus 31 conventional. There were no differences at baseline between groups except for lower HOOS quality of life (QoL) subscale scores in the digital PT group. Clinically relevant improvements were noted in both groups at all time points. The digital PT group showed a retention rate of 86% (30/35). Per-protocol analysis revealed a superiority of the digital PT group for all outcome measures. Intention-to-treat analysis revealed the superiority of the digital PT group at all time points for TUG (change between baseline and 4 and 8 weeks: P<.001; change between baseline and 3 and 6 months: P=.001 and P=.005, respectively), with a difference between median changes of -4.79 seconds (95% CI -7.24 to -1.71) at 6 months post-THA. Between baseline and month 6, results were also superior in the digital PT group for the HOOS sports and QoL subscales and all ROM except for standing flexion.
Conclusions: This study demonstrates this novel solution holds promise in rehabilitation after THA, ensuring better clinical outcomes than conventional rehabilitation while reducing dependence on human resources.info:eu-repo/semantics/publishedVersio
Long-Term Growth in Phenylketonuria: A Systematic Review and Meta-Analysis
Get PDFThere is an ongoing debate regarding the impact of phenylketonuria (PKU) and its treatment on growth. To date, evidence from studies is inconsistent, and data on the whole developmental period is limited. The primary aim of this systematic review was to investigate the effects of a phenylalanine (Phe)-restricted diet on long-term growth in patients with PKU. Four electronic databases were searched for articles published until September 2018. A total of 887 results were found, but only 13 articles met eligibility criteria. Only three studies had an adequate methodology for meta-analysis. Although the results indicate normal growth at birth and during infancy, children with PKU were significantly shorter and had lower weight for age than reference populations during the first four years of life. Impaired linear growth was observed until the end of adolescence in PKU. In contrast, growth impairment was not reported in patients with mild hyperphenylalaninemia, not requiring dietary restriction. Current evidence indicates that even with advances in dietary treatments, "optimal" growth outcomes are not attained in PKU. The majority of studies include children born before 1990s, so further research is needed to show the effects of recent dietary practices on growth in PKU.info:eu-repo/semantics/publishedVersio