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Introduction: Rare disorders that are genetically and clinically heterogeneous, such as mitochondrial diseases (MDs), have a challenging diagnosis. Nuclear genes codify most proteins involved in mitochondrial biogenesis, despite all mitochondria having their own DNA. The development of next-generation sequencing (NGS) technologies has revolutionized the understanding of many genes involved in the pathogenesis of MDs. In this new genetic era, using the NGS approach, we aimed to identify the genetic etiology for a suspected MD in a cohort of 450 Portuguese patients. Methods: We examined 450 patients using a combined NGS strategy, starting with the analysis of a targeted mitochondrial panel of 213 nuclear genes, and then proceeding to analyze the whole mitochondrial DNA. Results and Discussion: In this study, we identified disease-related variants in 134 (30%) analyzed patients, 88 with nuclear DNA (nDNA) and 46 with mitochondrial DNA (mtDNA) variants, most of them being pediatric patients (66%), of which 77% were identified in nDNA and 23% in mtDNA. The molecular analysis of this cohort revealed 72 already described pathogenic and 20 novel, probably pathogenic, variants, as well as 62 variants of unknown significance. For this cohort of patients with suspected MDs, the use of a customized gene panel provided a molecular diagnosis in a timely and cost-effective manner. Patients who cannot be diagnosed after this initial approach will be further selected for whole-exome sequencing. Conclusion: As a national laboratory for the study and research of MDs, we demonstrated the power of NGS to achieve a molecular etiology, expanding the mutational spectrum and proposing accurate genetic counseling in this group of heterogeneous diseases without therapeutic options.
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INTRODUCTION: Pain is a major nonmotor symptom of Parkinson's disease (PD), and central parkinsonian pain is the core feature of the putative Park pain subtype of PD. This study aimed to explore the cognitive and behavioral profile of PD patients with central parkinsonian pain. Material and Methods. A structured interview was used to identify and characterize pain in a cohort of 260 consecutive PD patients. The Ford classification of pain was applied. The Dementia Rating Scale-2 (DRS-2) and the Impulse Control Disorders in Parkinson's Disease Short Form (QUIP-S) were administered, and patients' smoking habits were recorded. The Unified Parkinson's Disease Rating Scale (UPDRS) was used to assess motor and nonmotor symptoms in off and on conditions. RESULTS: One hundred and eighty-eight patients (68%) reported pain; and in 41 (22%) of them, the pain was classified as central parkinsonian pain. PD patients with central parkinsonian pain had better cognitive performance in DRS-2 Initiation/Perseveration and Conceptualization subscales but reported more other compulsive behaviors (e.g., hobbyism, punding, and walkabout) and had more current smoking habits than those without pain or with non-central parkinsonian pain. Multiple logistic regression analyses revealed that the DRS-2 Conceptualization subscale, other compulsive behaviors, and smoking habits remained statistically associated with central parkinsonian pain even when other significant covariates were considered. Only patients with pain, regardless of type, had a gambling disorder. Discussion. The study results provide further evidence that pain revealed that patients with central parkinsonian pain are more likely to present compulsive or addictive behaviors, despite having more preserved cognitive performance. Patients with central parkinsonian pain appear to have a distinct phenotype of PD.
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INTRODUCTION: Sleep disturbances and pain are common non-motor symptoms in Parkinson's disease (PD). This study aimed to explore the association between these two symptoms in a cohort of patients with PD. MATERIALS AND METHODS: The Parkinson's Disease Sleep Scale (PDSS-2) was used to identify sleep disturbances in a series of 229 PD patients. The identification and characterization of pain was performed by a semi-structured interview and by the application of the Ford classification and the Brief Pain Inventory (BPI). The Unified Parkinson's Disease Rating Scale-III, Hoehn & Yahr (H&Y), and Schwab and England Independence Scale were used to assess motor symptoms and functional independence in off and on conditions. The Hospital Anxiety and Depression Scale (HADS) and SF-36 were applied to screen for anxiety and depression and to evaluate the quality of life. Non-parametric tests were used for group comparisons and logistic regressions were applied to explore predictors of sleep disturbances. RESULTS: Seventy-five (33%) patients had clinically relevant sleep disturbances (PDSS-2≥18) and 162 patients (71%) reported pain. Of those with pain, 38 (24%) had central parkinsonian pain. PD patients with sleep disturbances experienced more pain and had more severe motor symptoms, lower functional independence, more anxiety and depression symptoms, and worst quality of life. Among patients with pain, central parkinsonian pain was the subtype of pain with the highest odds of sleep disturbances, even when taking into account motor symptoms (H&Y off), motor fluctuations, intensity of pain (BPI), and symptoms of anxiety and depression (HADS). CONCLUSIONS: The association between pain and sleep disturbances in PD appears to be dependent on subtype of pain. The close relationship between central parkinsonian pain and sleep disturbances in PD raises the possibility of common pathophysiological mechanisms. A better understanding of the relationship between sleep disturbances and central parkinsonian pain may contribute to the development of new care strategies in PD patients.
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The development of physiologically based (PB) models to support safety assessments in the field of nanotechnology has grown steadily during the last decade. This review reports on the availability of PB models for toxicokinetic (TK) and toxicodynamic (TD) processes, including in vitro and in vivo dosimetry models applied to manufactured nanomaterials (MNs). In addition to reporting on the state-of-the-art in the scientific literature concerning the availability of physiologically based kinetic (PBK) models, we evaluate their relevance for regulatory applications, mainly considering the EU REACH regulation. First, we performed a literature search to identify all available PBK models. Then, we systematically reported the content of the identified papers in a tailored template to build a consistent inventory, thereby supporting model comparison. We also described model availability for physiologically based dynamic (PBD) and in vitro and in vivo dosimetry models according to the same template. For completeness, a number of classical toxicokinetic (CTK) models were also included in the inventory. The review describes the PBK model landscape applied to MNs on the basis of the type of MNs covered by the models, their stated applicability domain, the type of (nano-specific) inputs required, and the type of outputs generated. We identify the main assumptions made during model development that may influence the uncertainty in the final assessment, and we assess the REACH relevance of the available models within each model category. Finally, we compare the state of PB model acceptance for chemicals and for MNs. In general, PB model acceptance is limited by the absence of standardised reporting formats, psychological factors such as the complexity of the models, and technical considerations such as lack of blood:tissue partitioning data for model calibration/validation.
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Objetivou-se avaliar os efeitos de inclusão da casca da mandioca (CM) sobre a composição centesimal e de ácidos graxos do músculo Longíssimus de cordeiros. Foram utilizados 32 cordeiros mestiços Santa Inês, machos não castrados, peso corporal médio de 21 ± 1,5kg. Os tratamentos foram distribuídos em delineamento inteiramente ao acaso aos animais, cujo os níveis de inclusão da CM foram (0, 10, 20, 30%) baseado na matéria seca da dieta. Utilizou-se como volumoso o feno da parte aérea de mandioca, e a relação volumoso:concentrado foi de 48:52. O experimento teve duração de 70 dias. Logo após, os cordeiros passaram por um jejum sólido de 16h e, depois, foram abatidos. A carcaça foi conduzida à câmara fria, permanecendo por 24h, a uma temperatura de 4°C. Na carcaça fria, foi retirada uma amostra do músculo Longíssimus, a qual foi congelada (4°C), até o início das análises. Os resultados de umidade, cinzas e proteína não foram influenciados pela CM, observando-se efeito linear decrescente para os teores de lipídeos. Com relação à composição de ácidos graxos, houve efeito linear para o C15:0 e efeito quadrático para C14:0, C18:0 e C22:0. Nos monoinsaturados, observou-se efeito linear para C16:1, C18:1-9c e C22:1-9c e efeito quadrático para C15:1, C17:1 e C20:1; já nos poli-insaturados, foi observado efeito linear para CLA, C20:3n-6, C20:4n-6, C20:5n-3 e C22:6n-3, e quadrático para C20:2 e C18:3n-6. Assim, conclui-se que a composição centesimal e de ácidos graxos apresenta variações em razão da inclusão da CM, porém não compromete a qualidade da carne.(AU)
This study sought to evaluate the effects of the inclusion of cassava peel on the centesimal composition and fatty acids of the Longissimus muscle of lambs. We used 32 uncastrated crossbred Santa Inês lambs, with average body weight of 21 ± 1.5 kg. Treatments were in a completely randomized design, with the inclusion of cassava peel (0, 10, 20, 30%) in the diet dry matter. Hay from the cassava shoot has been used as forage and the forage:concentrate ratio was 48:52. The experiment lasted 70 days and then the lambs underwent a fast for 16 hours, were slaughtered, and their carcasses remained at a temperature of 4°C for 24 hours. In cold carcass the Longissimus muscle were taken and frozen (4°C) until the analysis. The results for moisture, ashes and protein were not influenced by cassava peel, and a decreasing linear effect was observed for the lipids levels. In composition of unsaturated fatty acids, there was a linear effect for C15:0 and a quadratic effect for C14:0, C18:0 and C22:0. Regarding the monounsaturated fatty acids, a linear effect has been observed for C16:1, C18:1-9c and C22:1-9c, and a quadratic effect for C15:1, C17:1 and C20:1. With the polyunsaturated fatty acids, a linear effect was observed for CLA, C20:3n-6, C20:4n-6, C20:5n-3 and C22:6n-3, and a quadratic effect was seen for C20:2 and C18:3n-6. Thus, it is concluded that the centesimal and fatty acid composition varies depending on the inclusion of cassava peel, however, it does not compromise the quality of the meat.(AU)
