Molecular bases of diabetic nephropathy

The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.O principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-beta1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-beta1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes - e aditivos - na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)HC Instituto do Coração Unidade de HipertensãoUSP FMUniversidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM) Laboratório de NefrologiaFundação Universitária de Cardiologia Instituto de Cardiologia Laboratório de Cardiologia Molecular e CelularUNIFESP, EPM, Laboratório de NefrologiaSciEL

Temperature- and Touch-Sensitive Neurons Couple CNG and TRPV Channel Activities to Control Heat Avoidance in Caenorhabditis elegans

Background: Any organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding,35uC and also senses changes in its environmental temperature in the range between 15 and 25uC. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches. Methodology/Principal Findings: We show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicinsensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons. Conclusions/Significance: Our results identify distinct thermal responses mediated by a single neuron, but also show tha

Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Reinforcement Learning in Humans

Previous reports on the functional effects (i.e., gain or loss of function), and phenotypic outcomes (e.g., changes in addiction vulnerability and stress response) of a commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) have been inconsistent. Here we examine the effect of this polymorphism on implicit reward learning. We used a probabilistic signal detection task to determine whether this polymorphism impacts response bias to monetary reward in 63 healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes exhibited typical responding to the rewarded response—that is, their bias to the rewarded stimulus increased over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus compared to the AA homozygotes. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. Through comparison with other studies using this task, we suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning

Compassion: a scoping review of the healthcare literature

BACKGROUND: Recent concerns about suboptimal patient care and a lack of compassion have prompted policymakers to question the preparedness of clinicians for the challenging environment in which they practice. Compassionate care is expected by patients and is a professional obligation of clinicians; however, little is known about the state of research on clinical compassion. The purpose of this scoping review was to map the literature on compassion in clinical healthcare. METHODS: Searches of eight electronic databases and the grey literature were conducted to identify empirical studies published over the last 25 years. Eligible studies explored perceptions or interventions of compassionate care in clinical populations, healthcare professionals, and healthcare students. Following the title and abstract review, two reviewers independently screened full-texts articles, and extracted study data. A narrative approach to synthesizing and mapping the literature was used. RESULTS AND DISCUSSION: Of 36,637 records, 648 studies were retrieved and 44 studies were included in the review. Less than one third of studies included patients. Six themes emerged from studies that explored perceptions of compassionate care: nature of compassion, development of compassion, interpersonal factors related to compassion, action and practical compassion, barriers and enablers of compassion, and outcomes of compassion. Intervention studies included two compassionate care trials with patients and eight educational programs that aimed to improve compassionate care in clinicians and students. CONCLUSIONS: This review identifies the limited empirical understanding of compassion in healthcare, highlighting the lack of patient and family voices in compassion research. A deeper understanding of the key behaviors and attitudes that lead to improved patient-reported outcomes through compassionate care is necessary