RESUMO
Mutations in PTEN-induced kinase 1 (PINK1) contribute to autosomal recessive Parkinson's disease with cognitive and neuropsychiatric comorbidities. Disturbances in dendritic and spine architecture are hallmarks of neurodegenerative and neuropsychiatric conditions, but little is known of the impact of PINK1 on these structures. We used Pink1 -/- mice to study the role of endogenous PINK1 in regulating dendritic architecture, spine density, and spine maturation. Pink1 -/- cortical neurons of unknown sex showed decreased dendritic arborization, affecting both apical and basal arbors. Dendritic simplification in Pink1 -/- neurons was primarily driven by diminished branching with smaller effects on branch lengths. Pink1 -/- neurons showed reduced spine density with a shift in morphology to favor filopodia at the expense of mushroom spines. Electrophysiology revealed significant reductions in miniature EPSC (mEPSC) frequency in Pink1 -/- neurons, consistent with the observation of decreased spine numbers. Transfecting with human PINK1 rescued changes in dendritic architecture, in thin, stubby, and mushroom spine densities, and in mEPSC frequency. Diminished spine density was also observed in Golgi-Cox stained adult male Pink1 -/- brains. Western blot study of Pink1 -/- brains of either sex revealed reduced phosphorylation of NSFL1 cofactor p47, an indirect target of PINK1. Transfection of Pink1 -/- neurons with a phosphomimetic p47 plasmid rescued dendritic branching and thin/stubby spine density with a partial rescue of mushroom spines, implicating a role for PINK1-regulated p47 phosphorylation in dendrite and spine development. These findings suggest that PINK1-dependent synaptodendritic alterations may contribute to the risk of cognitive and/or neuropsychiatric pathologies observed in PINK1-mutated families.SIGNIFICANCE STATEMENT Loss of PINK1 function has been implicated in both familial and sporadic neurodegenerative diseases. Yet surprisingly little is known of the impact of PINK1 loss on the fine structure of neurons. Neurons receive excitatory synaptic signals along a complex network of projections that form the dendritic tree, largely at tiny protrusions called dendritic spines. We studied cortical neurons and brain tissues from mice lacking PINK1. We discovered that PINK1 deficiency causes striking simplification of dendritic architecture associated with reduced synaptic input and decreased spine density and maturation. These changes are reversed by reintroducing human PINK1 or one of its downstream mediators into PINK1-deficient mouse neurons, indicating a conserved function, whose loss may contribute to neurodegenerative processes.
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Espinhas Dendríticas , Doença de Parkinson , Humanos , Animais , Camundongos , Espinhas Dendríticas/metabolismo , Neurônios/fisiologia , Doença de Parkinson/metabolismo , Fosforilação , Proteínas Quinases/genética , PTEN Fosfo-Hidrolase/metabolismoRESUMO
Perturbations of the endolysosomal pathway have been suggested to play an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Specifically, VPS35 and the retromer complex play an important role in the endolysosomal system and are implicated in the pathophysiology of these diseases. A single missense mutation in VPS35, Asp620Asn (D620N), is known to cause late-onset, autosomal dominant familial PD. In this review, we focus on the emerging role of the PD-linked D620N mutation in causing retromer dysfunction and dissect its implications in neurodegeneration. Additionally, we will discuss how VPS35 and the retromer are linked to AD, amyotrophic lateral sclerosis, and primary tauopathies. Interestingly, reduced levels of VPS35 and other retromer components have been observed in post-mortem brain tissue, suggesting a role for the retromer in the pathophysiology of these diseases. This review will provide a comprehensive dive into the mechanisms of VPS35 dysfunction in neurodegenerative diseases. Furthermore, we will highlight outstanding questions in the field and the retromer as a therapeutic target for neurodegenerative disease at large.
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Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Endossomos/metabolismo , Humanos , Mutação , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
AIMS: To evaluate the echocardiographic variable tricuspid annular plane systolic excursion normalised to body weight (TAPSEnorm) as a predictor of fluid responsiveness in hospitalised dogs with haemodynamic and tissue perfusion alterations and to investigate the association of left ventricular internal diameter in diastole normalised to body weight (LVIDdN) and aortic velocity time integral (VTIAo) with TAPSEnorm. METHODS: A single-centre, prospective study was carried out in a cohort of spontaneously breathing dogs, hospitalised for any reason, with severe haemodynamic and tissue perfusion alterations. The echocardiographic variables TAPSEnorm, LVIDdN, and VTIAO were measured. A bolus of 30â mL/kg of lactated Ringer's solution was administered and then VTIAo was subsequently remeasured. Patients were classified as fluid responsive if VTIAo increased by ≥15% after fluid expansion, or non-responsive if VTIAo increased by <15% after fluid expansion. The area under the receiver operating characteristic (AUROC) curve was generated to evaluate the ability of TAPSE to predict fluid responsiveness. Simple regression models were used to assess the linear relationship between TAPSEnorm and LVIDdN or VTIAO. RESULTS: TAPSEnorm was lower in fluid responsive dogs (mean 0.57 (95% CI = 0.50-0.64) cm/kg) compared to non-responsive dogs (mean 0.76 (95% CI = 0.62-0.90) cm/kg). The AUROC for TAPSEnorm was 0.827 (95% CI = 0.65-1.00). The optimal cut-off point was 0.76 with sensitivity of 80 (95% CI = 28.4-99.5)% and specificity of 86.7 (95% CI = 69.3-99.2)%, positive predictive value of 50 (95% CI = 15.7-84.3)% and negative predictive value of 96.3 (95% CI = 81-99.9)%. A monotonic linear relationship was observed between TAPSEnorm and LVIDdN (p<0.001) and between TAPSEnorm and VTIAo (p=0.001). CONCLUSIONS AND CLINICAL RELEVANCE: TAPSEnorm could be useful in determining those dogs that are likely to respond to a fluid bolus from those that are likely to be non-responsive. Additionally, a positive linear association between the LVIDdN and the TAPSEnorm suggests that TAPSEnorm decreases at lower preload values. The present study results suggest that TAPSEnorm could be a valuable tool for evaluating blood volume status and fluid responsiveness in hospitalised dogs.Abbreviations: AUROC: Area under the receiver operating characteristic; CO: Cardiac output; ICC: Intraclass correlation coefficient; LVIDd: Left ventricular internal diameter in diastole; LVIDdN: Left ventricular internal diameter in diastole normalised to body weight; TAPSE: Tricuspid annular plane systolic excursion; TAPSEnorm: Tricuspid annular plane systolic excursion normalised to body weight; VTIAo: Aortic velocity time integral.
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Ecocardiografia , Animais , Peso Corporal , Cães , Ecocardiografia/métodos , Ecocardiografia/veterinária , Humanos , Estudos Prospectivos , Curva ROC , Lactato de RingerRESUMO
AIMS: To evaluate associations between clinicopathological variables and hypercapnia measured in cats with decompensated chronic kidney disease (CKD) on admission to a veterinary hospital. METHODS: This is a retrospective, cross-sectional study of cats (n = 39) that presented to a tertiary veterinary hospital in Argentina between June 2015 and December 2017 with blood creatinine concentrations >140â µmol/L, and abdominal ultrasound results consistent with CKD. Data recorded included venous partial pressure of CO2 (PvCO2), blood pH, haematocrit and concentrations of glucose, potassium, sodium, corrected sodium (Na+c), and ionised calcium in blood. A logistic regression model was used to assess associations between the presence of hypercapnia (PvCO2 ≥ 44.7â mmHg) and the other clinicopathologic variables. The duration of hospitalisation was compared in cats with and without hypercapnia using the Wilcoxon Rank Sum test. RESULTS: The final study population comprised 39 cats. Eleven cats (28.2%) had hypercapnia. In the logistic regression model, two independent variables were associated with the presence of hypercapnia at admission in cats with CKD: the concentration of creatinine in blood (OR = 1.06 (95% CI = 1.016-1.108); p = 0.007) and Na+c (OR = 1.33 (95% CI = 1.08-1.63); p = 0.005). There were no statistically significant differences in the length of hospital stay between the two groups. CONCLUSIONS AND CLINICAL RELEVANCE: There appears to be an association between elevated concentrations of creatinine and Na+c in blood, and hypercapnia in cats with CKD, suggesting careful assessment of blood gas and electrolyte parameters during hospitalisation is required. Further prospective studies are needed to evaluate the mechanisms behind this association and the association of hypercapnia with disease outcome including mortality.
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Doenças do Gato , Insuficiência Renal Crônica , Animais , Gatos , Estudos Transversais , Hospitalização , Hipercapnia/veterinária , Insuficiência Renal Crônica/veterinária , Estudos RetrospectivosRESUMO
The liver contains diploid and polyploid hepatocytes (tetraploid, octaploid, etc.), with polyploids comprising ≥90% of the hepatocyte population in adult mice. Polyploid hepatocytes form multipolar spindles in mitosis, which lead to chromosome gains/losses and random aneuploidy. The effect of aneuploidy on liver function is unclear, and the degree of liver aneuploidy is debated, with reports showing aneuploidy affects 5% to 60% of hepatocytes. To study relationships among liver polyploidy, aneuploidy, and adaptation, mice lacking E2f7 and E2f8 in the liver (LKO), which have a polyploidization defect, were used. Polyploids were reduced fourfold in LKO livers, and LKO hepatocytes remained predominantly diploid after extensive proliferation. Moreover, nearly all LKO hepatocytes were euploid compared with control hepatocytes, suggesting polyploid hepatocytes are required for production of aneuploid progeny. To determine whether reduced polyploidy impairs adaptation, LKO mice were bred onto a tyrosinemia background, a disease model whereby the liver can develop disease-resistant, regenerative nodules. Although tyrosinemic LKO mice were more susceptible to morbidities and death associated with tyrosinemia-induced liver failure, they developed regenerating nodules similar to control mice. Analyses revealed that nodules in the tyrosinemic livers were generated by aneuploidy and inactivating mutations. In summary, we identified new roles for polyploid hepatocytes and demonstrated that they are required for the formation of aneuploid progeny and can facilitate adaptation to chronic liver disease.
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Adaptação Fisiológica , Hepatócitos/metabolismo , Regeneração Hepática , Lesão Pulmonar/metabolismo , Poliploidia , Animais , Fator de Transcrição E2F7/deficiência , Técnicas de Silenciamento de Genes , Hepatócitos/patologia , Lesão Pulmonar/genética , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Proteínas Repressoras/deficiênciaRESUMO
The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well characterized; however, it is unclear whether diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid-only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (liver-specific E2f7/E2f8 knockout; LKO) were recently reported to have a polyploidization defect, but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20-fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function, but became highly tumorigenic when challenged with tumor-promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out-compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild-type (WT) mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. WT diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration (LR). Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. Conclusion: Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes.
Assuntos
Proliferação de Células/genética , Hepatócitos/citologia , Regeneração Hepática/genética , Poliploidia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenotype of dendritic shortening. As mitochondria play a major role in the rapid buffering of cytosolic calcium, we hypothesized that altered mitochondrial calcium handling contributes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations. In primary mouse cortical neurons, we observed increased depolarization-induced mitochondrial calcium uptake. We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitochondrial calcium uniporter (MCU) and the mitochondrial calcium uptake 1 protein (MICU1) with no change in levels of the mitochondrial calcium antiporter NCLX. Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased mitochondrial calcium uptake, and in postmortem brains of sporadic PD/PDD patients of both sexes. Transcriptional upregulation of MCU and MICU1 was caused by activation of the ERK1/2 (MAPK3/1) pathway. Inhibiting ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening. Pharmacological inhibitors or RNAi knockdown of MCU attenuated mitochondrial calcium uptake and dendritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mutant of NCLX that enhances calcium export from mitochondria was neuroprotective. These data suggest that an increased susceptibility to mitochondrial calcium dysregulation contributes to dendritic injury in mutant LRRK2 pathogenesis.SIGNIFICANCE STATEMENT Cognitive dysfunction and dementia are common features of Parkinson's disease (PD), causing significant disability. Mutations in LRRK2 represent the most common known genetic cause of PD. We found that PD-linked LRRK2 mutations increased dendritic and mitochondrial calcium uptake in cortical neurons and familial PD patient fibroblasts, accompanied by increased expression of the mitochondrial calcium transporter MCU. Blocking the ERK1/2-dependent upregulation of MCU conferred protection against mutant LRRK2-elicited dendrite shortening, as did inhibiting MCU-mediated calcium import. Conversely, stimulating the export of calcium from mitochondria was also neuroprotective. These results implicate increased susceptibility to mitochondrial calcium overload in LRRK2-driven neurodegeneration, and suggest possible interventions that may slow the progression of cognitive dysfunction in PD.
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Cálcio/metabolismo , Dendritos/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Doença por Corpos de Lewy/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Dendritos/genética , Dendritos/patologia , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/patologia , Mutação/genética , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , GravidezRESUMO
This work is a review on the basic aspects of the treatment of Helicobacter pylori, highlighting the causes of treatment failure and strategies exist to optimize the treatment according to the best evidence posted. Stands out the antimicrobial resistance as the main cause of treatment failure, as well as the different compartments where the microorganism is hosted. Shows major schemes currently available and how to choose therapies first, second, third line and rescue therapies.
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Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Inibidores da Bomba de Prótons/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/isolamento & purificação , Humanos , Falha de TratamentoRESUMO
The transplantation of rodent Schwann cells (SCs) provides anatomical and functional restitution in a variety of spinal cord injury (SCI) models, supporting the recent translation of SCs to phase 1 clinical trials for human SCI. Whereas human (Hu)SCs have been examined experimentally in a complete SCI transection paradigm, to date the reported behavior of SCs when transplanted after a clinically relevant contusive SCI has been restricted to the use of rodent SCs. Here, in a xenotransplant, contusive SCI paradigm, the survival, biodistribution, proliferation and tumorgenicity as well as host responses to HuSCs, cultured according to a protocol analogous to that developed for clinical application, were investigated. HuSCs persisted within the contused nude rat spinal cord through 6 months after transplantation (longest time examined), exhibited low cell proliferation, displayed no evidence of tumorigenicity and showed a restricted biodistribution to the lesion. Neuropathological examination of the CNS revealed no adverse effects of HuSCs. Animals exhibiting higher numbers of surviving HuSCs within the lesion showed greater volumes of preserved white matter and host rat SC and astrocyte ingress as well as axon ingrowth and myelination. These results demonstrate the safety of HuSCs when employed in a clinically relevant experimental SCI paradigm. Further, signs of a potentially positive influence of HuSC transplants on host tissue pathology were observed. These findings show that HuSCs exhibit a favorable toxicity profile for up to 6 months after transplantation into the contused rat spinal cord, an important outcome for FDA consideration of their use in human clinical trials.
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Regeneração Nervosa/fisiologia , Células de Schwann/fisiologia , Células de Schwann/transplante , Traumatismos da Medula Espinal/cirurgia , Adulto , Fatores Etários , Animais , Antígenos Nucleares/metabolismo , Proteínas de Ciclo Celular , Proliferação de Células/fisiologia , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Ratos , Ratos Nus , Receptor de Fator de Crescimento Neural/metabolismo , Traumatismos da Medula Espinal/mortalidade , Nervo Sural/citologia , Fatores de Tempo , Adulto JovemRESUMO
UNLABELLED: A defining feature of the mammalian liver is polyploidy, a numerical change in the entire complement of chromosomes. The first step of polyploidization involves cell division with failed cytokinesis. Although polyploidy is common, affecting â¼90% of hepatocytes in mice and 50% in humans, the specialized role played by polyploid cells in liver homeostasis and disease remains poorly understood. The goal of this study was to identify novel signals that regulate polyploidization, and we focused on microRNAs (miRNAs). First, to test whether miRNAs could regulate hepatic polyploidy, we examined livers from Dicer1 liver-specific knockout mice, which are devoid of mature miRNAs. Loss of miRNAs resulted in a 3-fold reduction in binucleate hepatocytes, indicating that miRNAs regulate polyploidization. Second, we surveyed age-dependent expression of miRNAs in wild-type mice and identified a subset of miRNAs, including miR-122, that is differentially expressed at 2-3 weeks, a period when extensive polyploidization occurs. Next, we examined Mir122 knockout mice and observed profound, lifelong depletion of polyploid hepatocytes, proving that miR-122 is required for complete hepatic polyploidization. Moreover, the polyploidy defect in Mir122 knockout mice was ameliorated by adenovirus-mediated overexpression of miR-122, underscoring the critical role miR-122 plays in polyploidization. Finally, we identified direct targets of miR-122 (Cux1, Rhoa, Iqgap1, Mapre1, Nedd4l, and Slc25a34) that regulate cytokinesis. Inhibition of each target induced cytokinesis failure and promoted hepatic binucleation. CONCLUSION: Among the different signals that have been associated with hepatic polyploidy, miR-122 is the first liver-specific signal identified; our data demonstrate that miR-122 is both necessary and sufficient in liver polyploidization, and these studies will serve as the foundation for future work investigating miR-122 in liver maturation, homeostasis, and disease. (Hepatology 2016;64:599-615).
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Hepatócitos/fisiologia , MicroRNAs/fisiologia , Poliploidia , Animais , Citocinese , Fígado/citologia , Fígado/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BACKGROUND: Although depression is a common problem among non-professional caregivers, only one trial has evaluated the efficacy of indicated prevention targeting this population and the long-term efficacy is unknown. The aim of this study was to evaluate the long-term efficacy of a brief intervention for the indicated prevention of depression in a sample of female caregivers. METHOD: A randomized controlled trial was conducted involving 173 participants (mean age 53.9 years) who were allocated to the intervention (n = 89) or the usual-care control group (n = 84). Blinded interviewers conducted assessments at 1, 3, 6 and 12 months of follow-up. The main outcome measure was the incidence of major depression and the secondary outcomes were compliance with treatment, depressive symptoms, emotional distress and caregiver burden. RESULTS: At the 12-month follow-up, a lower incidence of depression as evaluated using the Structured Clinical Interview for Axis I Disorders of the DSM-IV was found in the intervention group compared with the control group (10.1% v. 25.0%). The relative risk was 0.40 and statistically significant [χ2 = 6.68, degrees of freedom = 1, p = 0.010, 95% confidence interval (CI) 0.20-0.81], and the number needed to treat was 7 (95% CI 4-27). There was a significant delay in the onset of depression in the intervention group (p = 0.008). The good complier caregivers had a lower incidence of depression. The intervention effect on depressive symptoms, emotional distress and caregiver burden were maintained for 12 months. CONCLUSIONS: This is the first study to demonstrate that a brief problem-solving intervention can prevent the onset of depression among non-professional caregivers over the longer term.
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Cuidadores/psicologia , Transtorno Depressivo Maior/terapia , Psicoterapia/métodos , Adulto , Idoso , Transtorno Depressivo Maior/prevenção & controle , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resolução de Problemas , Método Simples-Cego , Fatores de Tempo , Resultado do TratamentoRESUMO
Scope: fructose consumption from added sugars correlates with the epidemic rise in MetS and CVD. Maternal fructose intake has been described to program metabolic diseases in progeny. However, consumption of fructose-containing beverages is allowed during gestation. Cholesterol is also a well-known risk factor for CVD. Therefore, it is essential to study Western diets which combine fructose and cholesterol and how maternal fructose can influence the response of progeny to these diets. Methods and results: a high-cholesterol (2%) diet combined with liquid fructose (10%), as a model of an unhealthy Western diet, was administered to descendants from control and fructose-fed mothers. Gene (mRNA and protein) expression and plasma, fecal and tissue parameters of cholesterol metabolism were measured. Interestingly, progeny from fructose-fed dams consumed less liquid fructose and cholesterol-rich chow than males from control mothers. Moreover, descendants of fructose-fed mothers fed a Western diet showed an increased cholesterol elimination through bile and feces than males from control mothers. Despite these mitigating circumstances to develop a proatherogenic profile, the same degree of hypercholesterolemia and severity of steatosis were observed in all descendants fed a Western diet, independently of maternal intake. An increased intestinal absorption of cholesterol, synthesis, esterification, and assembly into lipoprotein found in males from fructose-fed dams consuming a Western diet could be the cause. Moreover, an augmented GLP2 signalling seen in these animals would explain this enhanced lipid absorption. Conclusions: maternal fructose intake, through a fetal programming, makes a Western diet considerably more harmful in their descendants than in the offspring from control mothers.
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Colesterol , Dieta Ocidental , Frutose , Animais , Frutose/efeitos adversos , Frutose/administração & dosagem , Feminino , Masculino , Ratos , Dieta Ocidental/efeitos adversos , Gravidez , Colesterol/metabolismo , Colesterol/sangue , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Fenômenos Fisiológicos da Nutrição Materna , Fígado/metabolismo , Hipercolesterolemia/metabolismo , Hipercolesterolemia/etiologiaRESUMO
Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.
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Biomarcadores Tumorais , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Mutação , Mieloma Múltiplo Latente , Humanos , Masculino , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Mieloma Múltiplo Latente/genética , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Idoso , Sequenciamento de Nucleotídeos em Larga Escala , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
This group is a product of the collaboration agreement signed by SOMIAMA (Sociedad de Medicina Intensiva de Madrid) and SAR MADRID (Sociedad de Anestesiología, Reanimación y Terapéutica del Dolor de Madrid) under which the organisations agreed to create joint working groups to improve critical patient care. Pain, discomfort, agitation, and delirium cause suffering, delay discharge, and can lead to serious complications in patients admitted to medical and surgical critical care units and post-anaesthesia care units. The main objectives in this type of unit include: Ensuring the comfort of patients suffering or recovering from a critical illness.Avoiding complications associated with the measures, particularly pharmacological, taken to ensure that comfort.
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Analgesia , Anestesia , Delírio , Humanos , Delírio/prevenção & controle , Unidades de Terapia Intensiva , DorRESUMO
Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended "nanotype" to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others.
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Few studies have mined social media platforms to assess environmental concerns. In this study, Twitter was scraped to obtain a ~140,000 tweet dataset related specifically to marine plastic pollution. The goal is to understand what kind of users profiles are tweeting and how and when they do it. In addition, topic modelling and graph theory techniques have allowed us to identify main concerns on this topic: i) impact on wildlife, ii) microplastics/water pollution, iii) estimates/reports, iv) legislation/protection, and v) recycling/cleaning initiatives. Results reveal a scarce influence of organizations involved in research and marine environmental awareness, so some guidelines are depicted that could help to adjust their communication plans. This is relevant to engage society through reliable information, change habits and reinforce sustainable behaviour. A visualization tool has been created to analyze the results over time.
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Plásticos , Mídias Sociais , Análise de Dados , Poluição Ambiental , Humanos , ReciclagemRESUMO
INTRODUCTION: Cognitive stimulation may be beneficial in slowing the progression of mild neurocognitive disorder (NCD), but the results of existing research are inconsistent. Furthermore, there are no long-term interventions nor individual (one-on-one) interventions applied by professionals. Objetive. The aim of this study was to assess the efficacy of a long-term individual cognitive stimulation intervention on people with mild NCD. PATIENTS AND METHODS: A pre-post test design with a non-equivalent control group was conducted. A total of 82 participants with mild NCD were assigned to a cognitive stimulation intervention group or to a control group. The intervention consisted of 88 individual format sessions of approximately 45 minutes, twice per week. Independent evaluators assessed cognition, depressive symptomatology and autonomy level in activities of daily living at pre-intervention, intra-intervention (6 months) and post-intervention (12 months). RESULTS: At intra- and post-intervention, significant improvement on cognition and depressive symptomatology in the intervention group compared to the control group were found. Younger participants and those with better cognitive function and status in pre-intervention achieved better results. Adherence to the intervention was high. CONCLUSIONS: Results suggest the efficacy of long-term individual cognitive intervention in people with mild NCD, which could delay the progression towards a major NCD.
TITLE: Efecto de la intervención de estimulación cognitiva individual de larga duración para personas con trastorno neurocognitivo leve.Introducción. La estimulación cognitiva puede ser beneficiosa para ralentizar la progresión del trastorno neurocognitivo (TNC) leve, pero los resultados de las investigaciones existentes son inconsistentes. Además, no existen intervenciones a largo plazo ni intervenciones individuales (uno a uno) aplicadas por profesionales. Objetivo. El objetivo de este estudio fue evaluar la eficacia de una intervención de estimulación cognitiva individual de larga duración para personas con TNC leve. Pacientes y métodos. Se llevó a cabo un diseño pretest-postest con un grupo control no equivalente. Un total de 82 participantes con TNC leve fueron asignados a un grupo de intervención de estimulación cognitiva o a un grupo control. La intervención consistió en 88 sesiones de formato individual de aproximadamente 45 minutos, dos veces por semana. Evaluadores independientes evaluaron la cognición, la sintomatología depresiva y el nivel de autonomía en las actividades de la vida diaria en la preintervención (línea base), la intraintervención (seis meses) y la postintervención (12 meses). Resultados. En la intra- y la postintervención, se encontró una mejora significativa en la cognición y la sintomatología depresiva en el grupo de intervención en comparación con el grupo control. Los participantes más jóvenes y los que tenían una mejor función y estado cognitivo en la preintervención obtuvieron mejores resultados. La adhesión a la intervención fue alta. Conclusiones. Los resultados sugieren la eficacia de una intervención cognitiva individual de larga duración para personas con TNC leve, que podría retrasar la progresión hacia un TNC mayor.
Assuntos
Disfunção Cognitiva/terapia , Jogos Recreativos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Atenção , Disfunção Cognitiva/psicologia , Depressão/etiologia , Depressão/terapia , Progressão da Doença , Função Executiva , Feminino , Jogos Recreativos/psicologia , Humanos , Idioma , Masculino , Memória , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Autonomia PessoalRESUMO
The benefits of the food industry compared to other sectors are much lower, which is why producers are tempted to commit fraud. Although it is a bad practice committed with a wide variety of foods, it is worth noting the case of olive oil because it is a product of great value and with a high percentage of fraud. It is for all these reasons that the authenticity of olive oil has become a major problem for producers, consumers, and legislators. To avoid such fraud, it is necessary to develop analytical techniques to detect them. In this review, we performed a complete analysis about the available instrumentation used in olive fraud which comprised spectroscopic and spectrometric methodology and analyte separation techniques such as liquid chromatography and gas chromatography. Additionally, other methodology including protein-based biomolecular techniques and analytical approaches like metabolomic, hhyperspectral imaging and chemometrics are discussed.
RESUMO
BACKGROUND AND GOAL OF THE STUDY: The goal of the study was to compare the incidence of complications, technical difficulty of intubation and physiologic pre-intubation status between the first intubation and reintubation performed on the same patient in an ICU. MATERIALS AND METHODS: The study was approved by the ethics committee of Galicia (Santiago-Lugo, code No. 2015-012). Due to the observational, noninterventional, and noninvasive design of this study, the need for written consent was waived by the ethics committee of Galicia. Patients requiring tracheal intubation and reintubation in the ICU were included in this prospective observational study. Main endpoint was to compare the incidence of complications, physiologic pre-intubation status, and the rate of technical difficulty of intubation between the first intubation and reintubation performed on the same patient in an ICU. RESULTS AND DISCUSSION: 504 patients were intubated in our ICU during the study period, and 82 (16%) required reintubation. There was no difference between the first intubation and reintubation regarding number of total complication (35% vs 33%; P = ,86), hypotension (24% vs 24%; P = 1), hypoxia (26% vs 26%; P = 1), esophageal intubation (1% vs 1%; P = 1), and bronchoaspiration (2% vs 1%; P = ,86). Physiologic pre-intubation status and technical difficulty of intubation did not differ between the first intubation and reintubation. CONCLUSIONS: In our ICU patients requiring tracheal reintubation, incidence of complications, physiologic pre-intubation status, and technical difficulty of intubation did not differ between the first intubation and reintubation.
Assuntos
Hipotensão , Intubação Intratraqueal , Humanos , Hipotensão/epidemiologia , Unidades de Terapia Intensiva , Intubação Intratraqueal/efeitos adversos , Estudos Prospectivos , TraqueiaRESUMO
BACKGROUND: After using propofol for a decade, pain on injection had been considered routine by patients and medical personnel. When given propofol from a different manufacturer, patients did not complain. Two preparations of propofol were compared. METHODS: A comparative, double-blind, randomized study was conducted in 22 adult patients undergoing pain relief procedures; they received sedation by an intravenous injection of 1.7 mg/kg of propofol and then were treated with paravertebral injections. Pain on injection was assessed by verbal complaint, movement of the extremity, of the whole body and recollection of pain at induction, when discharged. Propofol from Baxter Laboratories, mixed with either 5 ml of 2% lidocaine or 5 ml of NaCl 0.9%, was compared with propofol Laboratorios Gray, which was similarly mixed. Injections were randomly administered four times, blindly, to each of 22 patients. Statistical analysis was conducted using the analysis of variance method. RESULTS: A total of 352 propofol injections were given. Each of the four propofol solutions was administered 88 times; of patients receiving Baxter propofol+saline, 74 (84%) had pain; when mixed with 2% lidocaine 45 (50.2%) complained. After propofol Gray with NaCl 0.9% was given, two patients (2.2%) experienced pain. Propofol Gray with 2% lidocaine produced no pain. None of the latter group remembered having pain, whereas, those given propofol Baxter 54 (61.3%) and 26 (29.5%) remembered experiencing pain at injection. Pain on injection was prevented and statistically reduced (<0.01) with the propofol from Laboratorios Gray. CONCLUSIONS: By changing the formulation (size of molecules and their dispersion) of propofol, pain on injection was avoided.