Search

Background Fall risk assessment in older people is of major importance for providing adequate preventive measures. Current predictive models are mainly focused on intrinsic risk factors and do not adjust for contextual exposure. The validity and utility of continuous risk scores have already been demonstrated in clinical practice in several diseases. In this study, we aimed to develop and validate an intrinsic-exposure continuous fall risk score (cFRs) for community-dwelling older people through standardized residuals. Methods Self-reported falls in the last year were recorded from 504 older persons (391 women: age 73.1 ± 6.5 years; 113 men: age 74.0 ± 6.1 years). Participants were categorized as occasional fallers (falls ≤1) or recurrent fallers (≥ 2 falls). The cFRs was derived for each participant by summing the standardized residuals (Z-scores) of the intrinsic fall risk factors and exposure factors. Receiver operating characteristic (ROC) analysis was used to determine the accuracy of the cFRs for identifying recurrent fallers. Results The cFRs varied according to the number of reported falls; it was lowest in the group with no falls (− 1.66 ± 2.59), higher in the group with one fall (0.05 ± 3.13, p p Conclusions The cFRs was shown to be a valid dynamic multifactorial fall risk assessment tool for epidemiological analyses and clinical practice. Moreover, the potential for the cFRs to become a widely used approach regarding fall prevention in community-dwelling older people was demonstrated, since it involves a holistic intrinsic-exposure approach to the phenomena. Further investigation is required to validate the cFRs with other samples since it is a sample-specific tool.

Background Falls in older adults are considered a major public health problem. Declines in cognitive and physical functions, as measured by parameters including reaction time, mobility, and dual-task performance, have been reported to be important risk factors for falls. The aim of this study was to investigate the effects of two multimodal programs on reaction time, mobility, and dual-task performance in community-dwelling older adults at risk of falling. Methods In this randomized controlled trial, fifty-one participants (75.4 ± 5.6 years) were allocated into two experimental groups (EGs) (with sessions 3 times per week for 24 weeks), and a control group: EG1 was enrolled in a psychomotor intervention program, EG2 was enrolled in a combined exercise program (psychomotor intervention program + whole-body vibration program), and the control group maintained their usual daily activities. The participants were assessed at baseline, after the intervention, and after a 12-week no-intervention follow-up period. Results The comparisons revealed significant improvements in mobility and dual-task performance after the intervention in EG1, while there were improvements in reaction time, mobility, and dual-task performance in EG2 (p ≤ 0.05). The size of the interventions’ clinical effect was medium in EG1 and ranged from medium to large in EG2. The comparisons also showed a reduction in the fall rate in both EGs (EG1: -44.2%; EG2: − 63.0%, p ≤ 0.05) from baseline to post-intervention. The interventions’ effects on reaction time, mobility, and dual-task performance were no longer evident after the 12-week no-intervention follow-up period. Conclusions The results suggest that multimodal psychomotor programs were well tolerated by community-dwelling older adults and were effective for fall prevention, as well as for the prevention of cognitive and physical functional decline, particularly if the programs are combined with whole-body vibration exercise. The discontinuation of these programs could lead to the fast reversal of the positive outcomes achieved. Trial registration ClinicalTrials.gov Identifier: NCT03446352. Date of registration: February 07, 2018.

Achyrocline satureioides (Lam.) DC is a plant in the Asteraceae family that is commonly known as macela or marcela. It has antidiarrheal, antispasmodic, analgesic, anti-inflammatory and antimicrobial properties. The species Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli are of great clinical importance, thus more evidence on the discovery of new compounds from plant species is required. The aim of this study was to evaluate the phytochemical profile and in vitro antimicrobial potential of essential oils from A. satureioides. A Minimal Inhibitory Concentration (MIC) test was performed using microdilution, and the chemical composition of the essential oil was analyzed using Gas Chromatography coupled to Mass spectrometry (GC / MS). Using the GC / MS analysis, we identified alpha-pinene and (E)-cariophilene as major phytoconstituents. We observed synergisms when the essential oil was combined with gentamicin and ampicillin against the S. aureus strain, as well as against E. coli when combined with gentamicin and norfloxacin. The results were promising, but further research is needed to assess the toxicity of A. satureioides oil and its potential for therapeutic use in humans.

Omeprazole is usually administered under an enteric coating. However, there is a Food and Drug Administration-approved strategy that enables its release in the stomach. When locally absorbed, omeprazole shows a higher efficacy and a cytoprotective effect, whose mechanism was still unknown. Therefore, we aimed to assess the effect of the absorption route on the gastric mucosa. 2D and 3D models of dipalmitoylphosphatidylcholine (DPPC) at different pH values (5.0 and 7.4) were used to mimic different absorption conditions. Several experimental techniques, namely, fluorescence studies, X-ray scattering methodologies, and Langmuir monolayers coupled with microscopy, X-ray diffraction, and infrared spectroscopy techniques, were combined with molecular dynamics simulations. The results showed that electrostatic and hydrophobic interactions between omeprazole and DPPC rearranged the conformational state of DPPC. Omeprazole intercalates among DPPC molecules, promoting domain formation with untilted phospholipids. Hence, the local release of omeprazole enables its action as a phospholipid-like drug, which can reinforce and protect the gastric mucosa.

We describe an X-linked syndrome in 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with intrauterine growth retardation, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. We performed genome sequencing in four individuals and identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. OTUD5 was considered as a candidate gene based on two previous missense variants detected in patients with intellectual disability. In conclusion, we define a syndrome associated with OTUD5 defects and add compelling evidence of genotype-phenotype association. This finding ended the long diagnostic odyssey of this family.

Background: Lycium europaeum L. is a medicinal and edible Mediterranean halophyte spiny shrub. However, studies regarding its biological properties focused mainly on its aerial organs. Objective: The objective of the present work was to make a comparative evaluation of the in vitro antioxidant and enzyme inhibitory activities of ethanol extracts and fractions (chloroform, ethyl acetate, n-butanol and aqueous) from roots and leaves of L. europaeum, along with its total phenolic, flavonoid and tannin contents. Methods: The antioxidant activity was evaluated by the 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), superoxide radical, β-carotene bleaching, cupric reducing and ferric reducing activity methods Results: The n-butanol fraction from roots had the highest antioxidant activity in all the assays, and was also the most active against acetylcholinesterase, butyrylcholinesterase and urease (IC50 values of 92.63, 118.26 and 135.60 μgmL-1, respectively). This fraction showed a high level of total phenolic, flavonoid and tannin contents. Conclusion: The results suggest L. europaeum, especially its roots, as a candidate to be further explored as a source of bioactive products.

Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients’ phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.

Cystic fibrosis (CF) is a life-threatening autosomal recessive disease caused by more than 2100 mutations in the CF transmembrane conductance regulator (CFTR) gene, generating variability in disease severity among individuals with CF sharing the same CFTR genotype. Systems biology can assist in the collection and visualization of CF data to extract additional biological significance and find novel therapeutic targets. Here, we present the CyFi-MAP—a disease map repository of CFTR molecular mechanisms and pathways involved in CF. Specifically, we represented the wild-type (wt-CFTR) and the F508del associated processes (F508del-CFTR) in separate submaps, with pathways related to protein biosynthesis, endoplasmic reticulum retention, export, activation/inactivation of channel function, and recycling/degradation after endocytosis. CyFi-MAP is an open-access resource with specific, curated and continuously updated information on CFTR-related pathways available online at https://cysticfibrosismap.github.io/. This tool was developed as a reference CF pathway data repository to be continuously updated and used worldwide in CF research.

Background Falls and violence against older people might represent a joint public health problem, as both may result in injury, fear, social isolation, sedentary behavior and dependence or even death. The ESACA project “Aging safely in Alentejo - Understanding for action” was designed to promote the healthy aging of older people in Alentejo by preventing the occurrence of falls and violence. This study aimed to report the ESACA protocol and the preliminary outcomes. Methods The ESACA study has a twofold design as a cross-sectional study that included retrospective and prospective surveys. The participants were 508 community-dwelling older people. Assessments included falls, the risk of violence against older people, sociodemographic characteristics, health-related measurements, fear of falling, anthropometric measures and body composition, functional physical fitness, physical activity, and environmental hazards. Results Among the participants, 43% were fallers, 21% were recurrent fallers, and 22% were victims of one or more kinds of violence (psychological: 17.1%, physical: 5.6%, and patrimonial: 3.0%). Moreover, the cumulative results suggested high risk on several risk factors for falling (7 factors: 0.6% to 2 factors: 17.4%) and of violence (26.7%). Conclusions In the ESACA project, a wide range of potential influencing factors on falls and violence risk factors were measured, and comprehensive quality control measures were applied. Overall, the results suggest that for falls and violence prevention strategies to be effective, it is essential to evaluate, diagnose, and inform all stakeholders in a directed and useful way. Moreover, we believe that our project outcomes may help change mindsets and behaviors by involving people in active aging and well-being programs that promote exercise and avoid isolation.

Background Fall risk assessment and determination of older adults’ individual risk profiles are crucial elements in fall prevention. As such, it is essential to establish cutoffs and reference values for high and low risk according to key risk factor outcomes. This study main objective was to determine the key physical fitness, body composition, physical activity, health condition and environmental hazard risk outcome cutoffs and interval reference values for stratified fall risk assessment in community-dwelling older adults. Methods Five-hundred community-dwelling Portuguese older adults (72.2 ± 5.4 years) were assessed for falls, physical fitness, body composition, physical (in) activity, number of health conditions and environmental hazards, and sociodemographic characteristics. Results The established key outcomes and respective cutoffs and reference values used for fall risk stratification were multidimensional balance (low risk: score > 33, moderate risk: score 32–33, high risk: score 30–31, and very high: score 44 kg, moderate risk: 42–44 kg, high risk: 39–41 kg, and very high: 42%); total physical activity (low risk: > 2800 Met-min/wk., moderate risk: 2300–2800 Met-min/wk., high risk: 1900–2300 Met-min/wk., and very high: 5 h/day); health conditions (low risk: n n = 3, high risk: n = 4–5, and very high: n > 5); and environmental hazards (low risk: n n = 5, high risk: n = 6–8, and very high: n > 8). Conclusions Assessment of community-dwelling older adults’ fall risk should focus on the above outcomes to establish individual older adults’ fall risk profiles. Moreover, the design of fall prevention interventions should manage a person’s identified risks and take into account the determined cutoffs and respective interval values for fall risk stratification.

Background A slower reaction time (RT) performance is considered a risk factor for falls. Different approaches as a psychomotor intervention (involving neuromotor exercises) or the whole-body vibration (inducing neurophysiological changes) may reduce the risk of falls. Nevertheless, a combined program may promote greater gains. This study aimed to investigate the acceptability and the effect of two multimodal programs on RT in community-dwelling older adults fallers or balance-impaired. Methods A total of 37 participants (74.3 ± 5.2 years) were divided into two groups (3x/week): experimental group 1 (psychomotor intervention); experimental group 2 [EG2] (combined program: psychomotor intervention + whole-body vibration). The Deary-Liewald reaction time task assessed RT. Simple and choice reaction time [CRT] (ms) tasks were recorded under single and dual-task (DT) paradigms. DT cost was also computed. Results The attendance rate was 86.3%. Wilcoxon test comparisons revealed significant differences between baseline and post-intervention evaluations in the EG2. The improvement was observed in the variable ‘CRT-DT’, in which participants spent less time to perform the task (1026.0 ± 153.4 vs. 960.4 ± 160.9, P = 0.040). The correspondent effect size was medium (r = 0.33). The DT cost was also decreased in CRT-DT by 3.9%. No significant differences between groups were found. Conclusions This study demonstrated that both programs were safe and highly attended. The results suggest that a combined intervention (psychomotor intervention + whole-body vibration) should be privileged to improve RT and reduce the risk of falls. Trial Registration: ClinicalTrials.gov Identifier: NCT03446352. Funding: This study was supported by the ESACA Project (Grant ALT20-03-0145-FEDER-000007) and by FCT (SFRH/BD/147398/2019).

Tuberculosis (TB) remains a major health problem within the Community of Portuguese Language Speaking Countries (CPLP). Despite the marked variation in TB incidence across its member-states and continued human migratory flux between countries, a considerable gap in the knowledge on the Mycobacterium tuberculosis population structure and strain circulation between the countries still exists. To address this, we have assembled and analysed the largest CPLP M. tuberculosis molecular and drug susceptibility dataset, comprised by a total of 1447 clinical isolates, including 423 multidrug-resistant isolates, from five CPLP countries. The data herein presented reinforces Latin American and Mediterranean (LAM) strains as the hallmark of M. tuberculosis populational structure in the CPLP coupled with country-specific differential prevalence of minor clades. Moreover, using high-resolution typing by 24-loci MIRU-VNTR, six cross-border genetic clusters were detected, thus supporting recent clonal expansion across the Lusophone space. To make this data available to the scientific community and public health authorities we developed CPLP-TB (available at http://cplp-tb.ff.ulisboa.pt), an online database coupled with web-based tools for exploratory data analysis. As a public health tool, it is expected to contribute to improved knowledge on the M. tuberculosis population structure and strain circulation within the CPLP, thus supporting the risk assessment of strain-specific trends., Highlights • The Community of Portuguese Speaking Countries (CPLP) occupies a vast geographical area. • Three CPLP countries are shortlisted in the WHO's list of Top 30 high-burden countries. • Common Mycobacterium tuberculosis population structure denote historical strain flow. • Cross-border clusters suggest recent intercontinental tuberculosis transmission. • CPLP-TB: a novel strain database and framework for collaborative studies and strain tracing.

Introduction Falls are a common problem for older adults, and the identification of people at high risk of falling is a major challenge to health systems. Objective To evaluate the association between the history of falls and single-task Timed Up and Go Test (single TUG) or dual-task TUG variables. Methods Three hundred seventy seven community-dwelling older persons, with ages ranging from 65 and 92 years, participated in this cross-sectional study. Each participant performed two tests: single TUG and dual TUG. The cognitive task for dual TUG consisted of counting backward by one from 100 while performing the test. The number of cognitive errors, cognitive stops and motor stops were recorded. A new variable comprising time, errors and stops in the dual TUG was computed. Results The number of falls was significantly associated with mean single and dual TUG performance, mean cognitive errors, mean cognitive stops and mean motor stops. The score in the single TUG time was not able to significantly classify participants as fallers or non-fallers in any of the sexes. On the other hand, the variable “dual TUG time spent adding cognitive stops and cognitive errors” achieved the best ability to classify women as fallers or non-fallers, while “dual task cost” and “dual TUG time spent adding cognitive stops” were the best variables to classify men. Conclusions Dual TUG including cognitive stops and cognitive errors may be more capable than the single TUG to detect differences and accurately classify fallers and non-fallers in the elderly.

This work searched for the biotechnological potential and chemical characterisation of the medicinal halophyte Eryngium maritimum L. as source of bioactive natural products with enzymatic inhibitory properties and antioxidant capacity. With that aim, herbal formulations traditionally used in folk medicine, namely tisanes (infusions and decoctions) and tinctures, were prepared from four different anatomical organs (roots, stems, leaves and flowers) and assessed for in vitro inhibition of enzymes related with diabetes and for antioxidant potential. Phenolic fingerprinting and mineral contents were also assessed. Sea holly's tisanes, particularly from flowers and leaves, had the highest phenolic content although tinctures were comparatively richer considering the ingestion dosage. The main constituents identified were carvacrol, 2,3-dimethoxybenzoic acid, naringenin, catechin and t-cinnamic acid from the several compounds identified, naringin, naringenin and 2,3-dimethoxybenzoic acid are here firstly described in the genus and epicatechin and carvacrol in the species. In all extracts, sodium was the most abundant mineral, followed by potassium, calcium and magnesium, pointing to possible nutritional applications of these beverages/tinctures asmacronutrients supplementary source. Sea holly's tinctures (stems, leaves and flowers) were capable of inhibiting dietary carbohydrate digestive enzymes (alpha-glucosidase and alpha-amylase) and had in vitro antioxidant potential, particularly flowers. Altogether, results highlight that sea holly extracts, especially tinctures from stems, leaves and flowers, could be a novel source of alpha-glucosidase and alpha-amylase inhibitors, antioxidant compounds and also phenolic and mineral constituents, thus suggesting they may be interesting to further explore as potential health-promoting herbal beverages, food additives or other products. (c) 2018 Published by Elsevier B.V. on behalf of SAAB. Portuguese Foundation for Science and Technology - FCTPortuguese Foundation for Science and Technology [CCMAR/Multi/04326/2013] Portuguese National Budget MIUR, University of Chieti-Pescara "G. d'Annunzio", Chieti, Italy FCT Investigator Programme [IF/00049/2012] FCTPortuguese Foundation for Science and Technology [SFRH/BD/94407/2013, SFRH/BD/116604/2016]

Background There are a variety of intrinsic determinants which are key to understand the reasons for older people to stay (or not) active. Objectives To identify and analyse the factors underlying the physical activity engagement in older Portuguese living in a rural area. Methods A total of 504 community-dwelling older adults (aged ≥65 years) were enrolled in this cross-sectional study. Sociodemographic data, physical activity levels, physical fitness and body composition were analysed. Results Gender, age, income level, lower body strength, overweight, muscle mass and sedentarism (sitting time) were significantly associated with different physical activity levels. The multinomial logistic regression pointed out that dynamic balance, BMI and sitting time for moderate levels, as well as muscle mass for high levels, were the main independent factors that seem to influence the engagement in these levels compared to low physical activity levels. Additionally, classification tree analysis confirmed sitting time, dynamic balance and gender as discriminating factors for physical activity levels. Conclusion Physical fitness-related variables seem to mainly determine the levels of physical activity in the studied population. Thus, nursing care must promote the integration of physical activity into daily life routines of community-dwelling older adults, especially in rural areas. Implications for practice The diverse nature of factors influencing physical activity must be taken into account in primary health care, particularly in rural areas. Nursing care for older people must promote the integration of physical activity into daily life routines of community-dwelling older adults.

Background: The halophyte Lotus creticus L. (creta trefoil, Fabaceae) belongs to a family and genus containing several medicinal species, and is considered a promising crop for saline Mediterranean areas. However, to the best of our knowledge, information regarding the biological properties of this species that could increase its biotechnological value is particularly scarce. Objectives: We aimed to evaluate the potential use of creta trefoil collected in Southern Portugal (Algarve) as a source of bioactive products. Methods: Food-grade extracts (water, acetone, ethanol) were obtained by ultrasound-assisted extraction from aerial parts (stems and leaves) and fruits (pods), and evaluated for acute toxicity on mammalian cells. In vitro enzymatic inhibition was appraised on enzymes related to neurodegeneration (acetyl- and butyryl-cholinesterase: AChE and BuChE), type-2 diabetes (T2DM, α-glucosidase, and α-amylase), and hyperpigmentation/food browning (tyrosinase). In vitro, antioxidant activity included radical scavenging towards 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS), ferric-reducing antioxidant power (FRAP), and metal chelating activity on iron and copper. Chemical composition was established by liquid chromatography coupled with a diode array detector (LC-DAD-ESI-MS/MS). Results: Samples were not toxic and were active towards AChE (especially acetone extracts) and BuChE (particularly ethanol and acetone fruits’ extracts). Acetone and water fruit extracts and ethanol extract from aerial organs displayed significant inhibition on α-glucosidase, but low capacity towards amylase. All extracts exhibited a high capacity to inhibit tyrosinase, except water extract from aerial organs. Fruit extracts had, in general, the highest antioxidant capacity, especially ethanol. Fruits exhibited the highest diversity of polyphenols, especially flavonols, catechins, quercetin, myricetin, and its derivatives. Conclusions: Overall, our results suggested that creta trefoil should be further explored as a source of natural products for the management of T2DM, hyperpigmentation disorders, or food additive to prevent food oxidation and browning.

Recent studies suggest that temporoparietal junction (TPJ) modulation can influence attention and social cognition performance. Nevertheless, no studies have used multichannel transcranial direct current stimulation (tDCS) over bilateral TPJ to estimate the effects on these neuropsychological functions. The project STIPED is using optimized multichannel stimulation as an innovative treatment approach for chronic pediatric neurodevelopmental disorders, namely in children/adolescents with Autism Spectrum Disorder (ASD). In this pilot study, we aim to explore whether anodal multichannel tDCS coupled with a Joint Attention Task (JAT) influences social-cognitive task performance relative to sham stimulation, both in an Emotion Recognition Task (ERT) and in a Mooney Faces Detection Task (MFDT), as well as to evaluate this technique's safety and tolerability. Twenty healthy adults were enrolled in a randomized, single-blinded, sham-controlled, crossover study. During two sessions, participants completed the ERT and the MFDT before and after 20 min of sham or anodal tDCS over bilateral TPJ. No significant differences on performance accuracy and reaction time were found between stimulation conditions for all tasks, including the JAT. A significant main time effect for overall accuracy and reaction time was found for the MFDT. Itching was the most common side effect and stimulation conditions detection was at chance level. Results suggest that multichannel tDCS over bilateral TPJ does not affect performance of low-level emotional recognition tasks in healthy adults. Although preliminary safety and tolerability are demonstrated, further studies over longer periods will be pursued to investigate the clinical efficacy in children/adolescents with ASD, where social cognition impairments are preponderant.

Cardiovascular (CV) toxicity is nowadays recognized as a class effect of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs). However, their mechanisms of cardiotoxicity are not yet well understood, since different compounds with similar action mechanisms exhibit distinct cardiotoxicity. For instance, diclofenac (DIC) is among the most cardiotoxic compounds, while naproxen (NAP) is associated with low CV risk. In this sense, this study aimed to unravel the role of drug-lipid interactions in NSAIDs-induced cardiotoxicity. For that, DIC and NAP interactions with lipid bilayers as model systems of cell and mitochondrial membranes were characterized by derivative spectrophotometry, fluorometric leakage assays, and synchrotron X-ray scattering. Both DIC and NAP were found to have the ability to permeabilize the membrane models, as well as to alter the bilayers&rsquo, structure. The NSAIDs-induced modifications were dependent on the lipid composition of the membrane model, the three-dimensional structure of the drug, as well as the drug:lipid molar ratio tested. Altogether, this work supports the hypothesis that NSAIDs-lipid interactions, in particular at the mitochondrial level, may be another key step among the mechanisms underlying NSAIDs-induced cardiotoxicity.

Background Vici syndrome is a severe inherited multisystem disease caused by mutations in the EPG5 gene. The diagnosis depends on the constellation of cardinal features of agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency followed by confirmation by genetic testing. We report an Egyptian infant with Vici syndrome carrying a homozygous splice site variant (c.1252+1G>T; NM_020964.2) in the EPG5 gene, detailed clinical description, outcome, and differential diagnosis of inherited hypopigmentation disorders associated with neurological manifestations. Case presentation The infant initially presented with oculocutaneous hypopigmentation, agenesis of the corpus callosum, and immunodeficiency. A few months later, a diagnosis of dilated cardiomyopathy was made. Family history revealed 2 deceased siblings phenotypically matching our index infant. He died at the age of 15 months with acute respiratory failure. Conclusion The accurate diagnosis of such rare diseases with genetic confirmation is vital for proper clinical decision-making, genetic counseling of the affected families, and future genotype-phenotype correlation studies.

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features., Association Française contre les Myopathies (AFM); Deutsche Forschungsgemeinschaft; GENMED Laboratory of Excellence on Medical Genomics, Agence Nationale de la Recherche; Institut National de la Santé et de la Recherche Médicale (INSERM); Aix-Marseille University (AMU) by the RAREMED Amidex Project

WOS: 000456899500016, PubMed: 30529825, In this study, ethyl acetate, acetone, ethanol and water extracts from flowers, stems and roots of Cistanche phelypaea (L.) Cout were appraised for radical scavenging activity (RSA) towards 1,1-diphenyl-2-picrylhydrazyl,2,2-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) and superoxide free radicals, and for metal chelating activities on iron and copper ions. The water extracts had the highest antioxidant activity, especially those from roots and flowers, and were further appraised for in vitro inhibition of enzymes implicated on the onset of human ailments, namely acetyl- (AChE) and butyrylcholinesterase (BuChE) for Alzheimer's disease, alpha-glucosidase and alpha-amylase for diabetes, and tyrosinase for skin hyper-pigmentation disorders. The extracts had a higher activity towards BuChE, and the roots extract had the highest capacity to inhibit tyrosinase. Samples showed a low capacity to inhibit carbohydrate hydrolysing enzymes, except for the root extract with a good inhibition on glucosidase. Samples were then characterized by NMR (1D and 2D): the main metabolites identified in the flowers extract were iridoid glycosides, in particular gluroside and bartsioside. In stems, phenylehanoid glycosides (PhGs) and iri doids were detected, especially acteoside. In roots were detected essentially PhGs, mainly echinacoside and tubuloside A. Docking studies were performed on the identified compounds. A favorable binding energy of tubuloside A to tyrosinase was calculated, and indicated this compound as a possible competitive inhibitor of alpha-glucosidase and tyrosinase. Our results suggest that C. phelypeae is a promising source of biologically-active compounds with health promoting properties for pharmaceutical and biomedical applications. (C) 2018 Elsevier B.V. All rights reserved., Foundation for Science and Technology (FCT, Portugal)Portuguese Foundation for Science and Technology; Portuguese National Budget funding through the CCMAR project [CCMAR/Multi/04326/2013]; FCTPortuguese Foundation for Science and Technology [IF/00049/2012, SFRH/BD/94407/2013, SFRH/BD/116604/2016], This work was supported by the Foundation for Science and Technology (FCT, Portugal) and by the Portuguese National Budget funding through the CCMAR/Multi/04326/2013 project. Luisa Custodio was supported by FCT Investigator Programme (IF/00049/2012). Catarina Guerreiro Pereira and Maria Joao Rodrigues acknowledges FCT for the PhD grants SFRH/BD/94407/2013 and SFRH/BD/116604/2016, respectively.

We implemented a collaborative diagnostic program in Lahore (Pakistan) aiming to establish the genetic diagnosis, and to asses diagnostic yield and clinical impact in patients with suspected genetic diseases. Local physicians ascertained pediatric patients who had no previous access to genetic testing. More than 1586 genetic tests were performed in 1019 individuals (349 index cases, 670 relatives). Most frequently performed tests were exome/genome sequencing (ES/GS, 284/78 index cases) and specific gene panels (55 index cases). In 61.3% of the patients (n = 214) a genetic diagnosis was established based on pathogenic and likely pathogenic variants. Diagnostic yield was higher in consanguineous families (60.1 vs. 39.5%). In 27 patients, genetic diagnosis relied on additional biochemical testing, allowing rapid assessment of the functional effect of the variants. Remarkably, the genetic diagnosis had a direct impact on clinical management. Most relevant consequences were therapy related such as initiation of the appropriated treatment in a timely manner in 51.9% of the patients (n = 111). Finally, we report 12 candidate genes among 66 cases with no genetic diagnosis. Importantly, three of these genes were validated as ‘diagnostic’ genes given the strong evidence supporting causality derived from our data repository (CAP2-dilated cardiomyopathy, ITFG2-intellectual disability and USP53-liver cholestasis). The high diagnostic yield, clinical impact, and research findings demonstrate the utility of genomic testing, especially when used as first-line genetic test. For patients with suspected genetic diseases from resource-limited regions, ES can be considered as the test of choice to achieve genetic diagnosis.

Sanfilippo syndrome or mucopolysaccharidosis III (MPS III), includes a group of four autosomal recessive lysosomal storage disorders caused by deficient activity of enzymes involved in the catabolism of heparan sulfate. The four types of MPS III are recognized in accordance with the deficient enzyme, resulting in the accumulation of heparan sulfate with particularly deleterious effects in the central nervous system. The incidence of MPS III remains to be established in Latin American countries. We describe the journey of a patient with MPS IIIB whom, even in the presence of speech delay and deterioration, behavioral problems and motor incoordination, showed unaltered urinary glycosaminoglycans (GAGs) levels. An investigation for MPS was undertaken and enzyme analysis indicated a deficiency of alpha-N-acetylglucosaminidase, leading to the diagnosis of MPS IIIB. With the correct diagnosis, the patient’s symptoms could be properly managed, and the parents received appropriate genetic counseling. The present case report reinforces the need of investigating MPS III in patients with language delay and/or regression, neurological impairment and behavioral alterations, even when urinary GAGs are within normal range. A definitive diagnosis ends the diagnostic journey and enables the medical team and family to provide a better care for the child.

Several Apiaceae species, used as both food and in complementary and alternative medicine, represents a rich source of potential valuable phytopharmaceuticals which necessitates scientific contemplation. In the present study, the antioxidant, enzyme inhibitory, antimicrobial, and cytotoxic properties of methanol extracts of seven Apiaceae species, (Chaerophyllum macrospermum (Willd. ex Spreng.) Fisch. & C.A.Mey. ex Hohen, Ferula rigidula Fisch. ex DC., Ferula orientalis L., Prangos ferulacea Lindl., Prangos peucedanifolia Fenzl., Ferulago setifolia K. Koch, and Pimpinella anthriscoides Boiss.) were evaluated. Species belonging to the Prangos genus exhibited the highest total phenolic content, namely P. peucedanifolia and P. ferulacea, with values of 47.90 and 44.44 mg gallic acid equivalent/g extract, respectively. P. peucedanifolia also displayed the highest radical scavenging capacity (81.53 and 102.70 mg Trolox equivalent [TE]/g extract for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS), respectively) and reducing power (165.87 and 100.09 mg TE/g extract for cupric reducing antioxidant capacity (CUPRAC) and ferric reducing antioxidant power (FRAP), respectively). C. macrospermum showed the most potent inhibition against Alzheimer's disease related enzymes, namely acetylcholinesterase (4.53 mg galantamine equivalent [GALAE]/g extract) and butyrylcholinesterase (3.22 mg GALAE/g extract). P. ferulacea (131.94 mg kojic acid (KAE) equivalent/g extract) and P. peucedanifolia (4.97 mmol acarbose equivalent (ACAE)/g extract) were potent inhibitors of tyrosinase and a-glucosidase, respectively. In general, studied species were able to reduce cellular viabilities. P. peucedanifolia possessed promising antibacterial potential against Bacillus cereus (Minimum inhibition concentration (MIC): 0.37 mg/mL), L. monocytogenes (MIC: 0.56 mg/mL), P. aeruginosa and Escherichia coli (MIC: 0.27 mg/mL), Salmonella typhimurium and Enterobacter cloacae (MIC: 0.75 mg/mL). F. rigidula showed the highest antifungal effect against Aspergillus ochraceus and Trichoderma viride (MIC: 0.10 mg/mL). The present findings could be the scientific starting point towards the pharmaceutical and/or commercial utilization of these Apiaceae species. Ministry of Education, Science and Technological Development, Republic of Serbia [451-03-68/2020-14/200007] info:eu-repo/semantics/publishedVersion

Background and objectives: Peritoneal dialysis (PD) patients are expected to present lower levels of physical activity, unhealthy changes at the body composition level, and low levels of strength. Firstly, this study aimed to report the sex differences in physical activity, body composition and muscle strength and the relations among these variables. Secondly, we analyze the relationship between physical activity and biochemical parameters. Materials and Methods: Thirty-four patients (13 women and 21 men) participated in this study. Body composition was assessed by bioimpedance and dual-energy X-ray absorptiometry (DXA), and maximum isokinetic unilateral strength, analytical parameters and physical activity levels were evaluated. Results: The men showed higher values for weight, height, lean body mass, bone mineral content, bone mineral density (BMD) and total body water, while women showed higher values for the percentage of fat mass and hydration of lean body mass (p &lt, 0.05). No differences between the sexes were found in different levels of physical activity, however, males registered significantly higher values for isokinetic strength variables except for knee extensor strength. BMD was positively related to sedentary activity and negatively related to moderate and vigorous activity (r = 0.383 and r = −0.404, respectively). Light physical activity was negatively correlated with albumin (r = −0.393) and total protein (r = −0.410) levels, while moderate/vigorous activity was positively correlated with urea distribution volume (r = 0.446) and creatinine clearance (r = 0.359) and negatively correlated with the triglyceride level (r = −0.455). Conclusions: PD patients with higher levels of physical activity present better results in terms of body composition and biochemical parameters. Additional studies should be conducted to clarify the relation between physical activity level and BMD.

Introduction Performing a dual-task (DT), mainly while walking and performing another task simultaneously, is seen as determinants factors for falls and injuries in older adults. A psychomotor intervention relying on the prevention of sensorimotor and neurocognitive deterioration may prevent falls. The whole-body vibration (WBV) promotes the increase of agility, reducing the risk of falling. However, an intervention that combines both methods can lead to additional benefits, particularly as regards DT. Objectives To evaluate the feasibility and the effect of two multimodal programs designed for community-dwelling older adults, fallers or at high risk of falling, on DT performance ability. Methodology Thirty-seven participants (74.3±5.2 years) were randomly assigned into experimental group 1 [EG1] (psychomotor intervention); or experimental group 2 [EG2] (psychomotor intervention + WBV). DT performance (TUGcog) was assessed by the Timed Up and Go Test (s) performed simultaneously with the counting backward cognitive task. Results Adherence rate was 86.3%. Wilcoxon test comparisons showed improvements from baseline to post-intervention on EG1 (time (s): 10.1±2.7 vs. 9.0±2.7, p = 0.001; cognitive stops (n): 0.9±1.0 vs. 0.2±0.4, p = 0.012; motor stops (n): 0.3±0.5 vs. 0.0±0.0, p = 0.025), corresponding to an effect size (cohen’s d) ranging from 0.41 (small) to 0.92 (medium) and on EG2 (time (s): 9.9±2.5 vs. 8.5±1.8, p = 0.010; cognitive stops (n): 1.1±0.7 vs. 0.4±0.5, p = 0.004), corresponding to a d ranging from 0.64 (medium) to 1.15 (medium). There were no significant differences between groups. Conclusion These preliminary results suggested that the multimodal programs were feasible and effective in reducing the risk of falling by improving the determinant risk factor DT performance. Trial Registration: ClinicalTrials.gov Identifier: NCT03446352. Funding: This study was funded by ESACA Project (Grant ALT20-03-0145-FEDER-000007) and by FCT (SFRH/BD/147398/2019).

Introduction With the world, population ageing falls become a problem. Portugal follows this tendency, particularly in Alentejo. Ecological models evidence that biological, behaviour and socioeconomic factors explain falls. However, the role of socioeconomic and health-related factors on the risk of falls is not well known. Objectives To analyse the association of socioeconomic and health-related factors with fall risk on community-dwelling older adults from Alentejo. Methodology This observational study involved 384 community-dwelling older adults (73.6 ± 6.0 years), the minimal sample size calculated by Open Epi Online program, of whom 40.6% fell at least once in the previous year. Sociodemographic characteristics (age, gender, marital status, schooling, retirement age, living alone and yield) and health-related factors (number of health conditions, cognitive state, fat mass %, physical activity, and depression index) were accessed. Results Univariate Regression Logistic showed that gender was the only sociodemographic characteristics which significantly explains falls occurrence, in which to be woman increases the likelihood of falling on 96% (OR: 1.96, p < 0.05). As regard health-related factors, results show that for each additional health condition the likelihood of falling increased 17%, for each additional 1% on fat mass this likelihood increased 4%, and for each additional point on depression index this likelihood increased 15.1% (OR: 1.04 to 1.17, p < 0.05). Conclusion Health-related factors showed to be more preponderant in the occurrence of falls compared to socio-demographic characteristics. Women with more chronic conditions increased fat mass, and high depression index will be the most susceptible to falls. Thus, preventive measures should play particular attention to these persons.

Introduction For dual-task paradigms, the timed up and go (TUG) test along with other cognitive or motor tasks has been used to evaluate and predict the risk of falling in older adults. However, the interference between motor-cognitive tasks can differ by the cognitive task. Objective To evaluate the performance of the TUG test under a single task condition and two dual-task conditions in older adults and to explore the effect of educational level on task performance. Methods A total of 418 older adults (328 females) voluntarily participated in this study. The TUG test was administered as a single task and a dual task with one secondary simultaneous task: counting aloud backward from 100 or naming animals. Comparisons were performed to determine the interference caused by each cognitive task on the motor task, and correlation analysis was performed to explore the role of educational level. Results The animal task led to a poorer TUG performance and a higher dual-task cost than did the counting task. Furthermore, the motor task led to a higher percentage of errors and cognitive stops in the animal task. Educational level plays a significant role in the interaction between tasks. Conclusions Between-task interference differs by the type of cognitive task performed and the educational level of the participants. The results of the present study should be considered when dual-task assessments are planned for older adults.

Background Falls and fall-related injuries along with fear of falling (FoF) seem to restrict activities of daily living (ADL), resulting in physical dependence. However, it is still unclear how falls and related injuries or FoF by themselves explain general and specific ADL dependence. Objectives To investigate the relationships between falls and related injuries, FoF and physical dependence on ADL in community-dwelling older adults, controlling for age, gender, physical activity and physical fitness as confounders. Methods This cross-sectional descriptive study assessed 588 community-dwelling older adults. Falls and fall-related injuries, ADL dependence on basic, instrumental and advanced activities, FoF, demographic characteristics and health conditions were assessed through a questionnaire. Physical activity was measured through the International Physical Activity Questionnaire. Physical fitness was assessed by the Senior Fitness Test and the Fullerton Advanced Balance Scale. Body composition was measured through bioimpedance. Results Severe injuries occurrence increased the likelihood of moderate and high physical dependence by 3 and 6 times, while FoF increased this likelihood by 3 and 7 times, respectively. Also, the occurrence of previous falls, resulting in severe injuries, increased the likelihood of dependence in two instrumental ADL (3 and 4 times), while FoF increased this likelihood in numerous basic, instrumental and advanced ADL (2-3 times). The FoF was shown to explain overall physical functioning dependence, by itself, representing a constraint on the performance of most basic, instrumental and advanced ADL. Conclusion The FoF showed to be a greater threat to ADL dependence than falls and related injuries. Assessment guidelines for older adults living in the community should include the FoF in clinical evaluation. Implications for practice Understand the isolated interplay of FoF and previous falls and injuries on ADL dependence among older adults allows healthcare professionals to perform more accurate clinical evaluations and develop more successful interventions to prevent further dependence.

WOS: 000510521700008, The halophyte species Carpobrotus edulis (L.) N.E. Br, also known as Hottentot-fig, is one of the 20 most aggressive invasive species of coastal areas worldwide. It is native to South Africa, where it is used in traditional medicine for the treatment of several diseases, including tuberculosis and acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV). Aiming at a sustainable use of its biomass as a value-added product, this work reports for the first time the in vitro antioxidant, anti-microbial, enzymatic inhibitory properties and toxicity of peel and flesh extracts of Hottentot-fig mature fruits. The extracts' chemical composition was also determined by spectrophotometric methods (total contents of phenolics: TPC; flavonoids: TFC and tannins: TTC), and by high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS/MS). The peels' extracts had generally the highest TPC, TFC and TTC, especially the ethanol ones (TPC: 272.82 mg gallic acid equivalents (GAE)/g dry weight (DW), TFC: 1.58 mg quercetin equivalents (QE)/g DW and TTC: 20.3 mg catechin equivalents (CE)/g DW). The peels' extracts also had the highest diversity of compounds, mostly phenolic acids, flavonoids, and coumarins, as identified by HPLC-ESI-MS/MS. Some molecules were specific to a particular fruit part, for example, coumaric acid and uvaol in the peel, and vanillin and kaempferol-O-(rhamnosyl)hexosylhexoside in the flesh. Some compounds are here described for the first time in Hottentot-fig, such as azelaic acid and emodin. The peel's extracts had the highest anti radical activity, especially the ethanol and acetone towards 2,2-diphenyl-1-picrylhydrazyl (DPPH) (half maximal inhibitory concentration (IC50) values of 0.59 and 0.88 mg/mL, respectively), and the acetone extract against 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) (IC50 = 0.56 mg/mL). Samples had nil capacity to chelate iron, a low copper chelation potential, but a significant capacity to reduce iron, especially the ethanol (IC50 = 0.09 mg/mL) and the acetone extracts of peels (IC50 = 0.10 mg/mL) and flesh (IC50 = 0.11 mg/mL) and also the water peel's extracts (IC50 = 0.18 mg/mL). Samples had nil to low activity towards the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), alpha-amylase and alpha-glucosidase, but displayed a strong inhibition of tyrosinase, especially the ethanol peel's extracts (29.55 mg kojic acid equivalents (KAE)/g). Samples had nil to low in vitro toxicity towards human keratinocytes. All together our results suggests possible novel biotechnological applications of Hottentot-fig fruits as sources of innovative bioactive ingredients for the food, cosmetic, agriculture and/or pharmaceutical industries., Foundation for Science and Technology (FCT)Portuguese Foundation for Science and Technology; Portuguese National Budget [CCMAR/Multi/04326/2019, UID/DTP/04138/2019]; GreenVet project [ALG-01-0145-FEDER-028876]; FCTPortuguese Foundation for Science and Technology [SFRH/BD/116604/2016, CEECIND/00425/2017], Work supported by the Foundation for Science and Technology (FCT) and the Portuguese National Budget (CCMAR/Multi/04326/2019 project), UID/DTP/04138/2019 and GreenVet project (ALG-01-0145-FEDER-028876). Joao Rodrigues acknowledge FCT for the PhD grant SFRH/BD/116604/2016. Luisa Cust6dio was supported by the FCT Scientific Employment Stimulus (CEECIND/00425/2017).

The main objective of this study was to clarify the topical mechanisms underlying diclofenac-induced gastric toxicity by considering for the first time both ionization states of this nonsteroidal anti-inflammatory drug. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes were the model system chosen to mimic the protective phospholipid layers of the gastric mucosa and to describe the interactions with diclofenac, considering the pH gradient found in the gastric mucosa (3 < pH < 7.4). Complementary experimental techniques were combined to evaluate the drug's affinity for DMPC bilayers, as well as to assess the drug's effects on the structural properties of the phospholipid bilayer. The diclofenac-DMPC interactions were clearly dependent on the drug's ionization state. Neutral diclofenac displayed greater affinity for DMPC bilayers than anionic diclofenac. Moreover, the protonated/neutral form of the drug induced more pronounced and/or distinct alterations in the structure of the DMPC bilayer than the deprotonated/ionized form, considering similar membrane concentrations. Therefore, neutral diclofenac-induced changes in the structural properties of the external phospholipid layers of the gastric mucosa may constitute an additional toxicity mechanism of this worldwide-used drug, which shall be considered for the development of safer therapeutic strategies. SIGNIFICANCE STATEMENT: Neutral or anionic diclofenac exerted distinct alterations in phosphatidylcholine bilayers, which are used in this work as models for the protective phospholipid layers of the gastric mucosa. Remarkable changes were induced by neutral diclofenac in the structural properties of the phospholipid bilayer, suggesting that both ionized and neutral states of nonsteroidal anti-inflammatory drugs must be considered to clarify their mechanisms of toxicity and to ultimately develop safer anti-inflammatory drugs.