735 research outputs found
Falls in hospital settings: a longitudinal study
Get PDFThis study aims to assess the prevalence of falls, understand their consequences, identify causes and analyze intervention strategies to prevent them. This is a descriptive longitudinal study, from 2007 to 2009, in which nurses recorded patients' falls in a medicine ward, using a scale developed for this end. Most falls occurred with partially dependent patients, with a mean age ranging from 64 to 74 years. The bedroom was, in all of these years, the place where most of these falls occurred. Although most falls did not have consequences, they were observed in 36% of the cases. The number of falls increased throughout the years of the study. There was also a difference in the percentage of occurrences in the afternoon and night shifts (39% in 2007, 57% in 2008 and 64% in 2009). The identification of obstacles to referral and how to overcome them are analyzed here.Este estudio intenta evaluar la prevalencia de las caÃdas, conocer sus consecuencias, identificar causas y estudiar estrategias de intervención para prevenirlas. Es un estudio descriptivo longitudinal, realizado entre 2007 y 2009, donde los enfermeros registraron las caÃdas de enfermos en un servicio de medicina, de acuerdo con una escala elaborada para este propósito. La mayorÃa de las caÃdas ocurrió en enfermos parcialmente dependientes, cuyas edades variaban entre 64 y 74 años. La habitación fue, en todos los años, donde mayoritariamente estas ocurrieron. Aunque la mayorÃa de las caÃdas no hayan tenido consecuencias, se registraron en 36% de los casos. Este número aumentó a lo largo de los años del estudio. Se rebeló, igualmente, una diferencia en la proporcionalidad del número de registros para los turnos de la tarde/noche (39%, 2007, 57%, 2008 y 64%, 2009). Se analiza la identificación de las barreras a la referencia y como rebasar estas barreras.Este estudo visou avaliar a prevalência das quedas, conhecer as suas consequências, identificar as causas e estudar estratégias de intervenção para preveni-las. É um estudo descritivo longitudinal, de 2007 a 2009, com registro, pelos enfermeiros, das quedas dos doentes, num serviço de medicina, em escala construÃda para o efeito. A maioria das quedas ocorreu em doentes parcialmente dependentes, variando a idade entre 64 e 74 anos. O quarto foi, em todos os anos, o local onde maioritariamente ocorreram. Embora da maioria das quedas não houvesse resultado consequências, essas foram registradas em 36% dos casos. O número de quedas registrado aumentou ao longo dos anos do estudo. De igual modo se revelou diferença na proporcionalidade do número de registros para os turnos da tarde e noite (39% em 2007, 57% em 2008 e 64% em 2009). A identificação de barreiras à referenciação e como as ultrapassar são analisadas
Management of a South African family with retinitis pigmentosa—should potential therapy influence translational research protocols?
Get PDFMutation analysis of retinal candidate genes is performed as part of an ongoing research to identify the causative genetic defect in South African families with retinal degenerative disorders (RDDs). A translational research protocol has been established whereby probands are counseled and given their molecular genetic results to take back to other family members, who can then request individual diagnostic testing. A Thr17Met mutation of the rhodopsin gene was identified in a Caucasian South African family with autosomal dominant retinitis pigmentosa. Patients with this mutation appear to benefit from treatment using oral vitamin A supplementation. This family has been informed that a molecular diagnosis is available; however, one individual has refused testing and none of the younger generation has shown interest in receiving molecular results or genetic counseling. Adapting the established protocol for the translation of RDD research results and contacting mutation positive individuals may be justifiable in light of the potential benefit of therapy
The heat-shock response co-inducer arimoclomol protects against retinal degeneration in rhodopsin retinitis pigmentosa.
Get PDFRetinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to the progressive death of rod and cone photoreceptors in the retina. There are currently no effective treatments for RP. Inherited mutations in rhodopsin, the light-sensing protein of rod photoreceptor cells, are the most common cause of autosomal-dominant RP. The majority of mutations in rhodopsin, including the common P23H substitution, lead to protein misfolding, which is a feature in many neurodegenerative disorders. Previous studies have shown that upregulating molecular chaperone expression can delay disease progression in models of neurodegeneration. Here, we have explored the potential of the heat-shock protein co-inducer arimoclomol to ameliorate rhodopsin RP. In a cell model of P23H rod opsin RP, arimoclomol reduced P23H rod opsin aggregation and improved viability of mutant rhodopsin-expressing cells. In P23H rhodopsin transgenic rat models, pharmacological potentiation of the stress response with arimoclomol improved electroretinogram responses and prolonged photoreceptor survival, as assessed by measuring outer nuclear layer thickness in the retina. Furthermore, treated animal retinae showed improved photoreceptor outer segment structure and reduced rhodopsin aggregation compared with vehicle-treated controls. The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. Furthermore, the unfolded protein response (UPR), which is induced in P23H transgenic rats, was also enhanced in the retinae of arimoclomol-treated animals, suggesting that arimoclomol can potentiate the UPR as well as the HSR. These data suggest that pharmacological enhancement of cellular stress responses may be a potential treatment for rhodopsin RP and that arimoclomol could benefit diseases where ER stress is a factor
Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila
Get PDFThe most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (RhP23H). Unlike the wild-type Rh, mutant RhP23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded RhP23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that RhP23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1P37H (the equivalent of mammalian RhP23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1P37H retina. Despite this, Rh1P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1P37H retina. Pharmacological treatment of Rh1P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration
The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.
Get PDFMitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex
LEDGF1-326 Decreases P23H and Wild Type Rhodopsin Aggregates and P23H Rhodopsin Mediated Cell Damage in Human Retinal Pigment Epithelial Cells
Get PDFP23H rhodopsin, a mutant rhodopsin, is known to aggregate and cause retinal degeneration. However, its effects on retinal pigment epithelial (RPE) cells are unknown. The purpose of this study was to determine the effect of P23H rhodopsin in RPE cells and further assess whether LEDGF(1-326), a protein devoid of heat shock elements of LEDGF, a cell survival factor, reduces P23H rhodopsin aggregates and any associated cellular damage.ARPE-19 cells were transiently transfected/cotransfected with pLEDGF(1-326) and/or pWT-Rho (wild type)/pP23H-Rho. Rhodopsin mediated cellular damage and rescue by LEDGF(1-326) was assessed using cell viability, cell proliferation, and confocal microscopy assays. Rhodopsin monomers, oligomers, and their reduction in the presence of LEDGF(1-326) were quantified by western blot analysis. P23H rhodopsin mRNA levels in the presence and absence of LEDGF(1-326) was determined by real time quantitative PCR.P23H rhodopsin reduced RPE cell viability and cell proliferation in a dose dependent manner, and disrupted the nuclear material. LEDGF(1-326) did not alter P23H rhodopsin mRNA levels, reduced its oligomers, and significantly increased RPE cell viability as well as proliferation, while reducing nuclear damage. WT rhodopsin formed oligomers, although to a smaller extent than P23H rhodopsin. Further, LEDGF(1-326) decreased WT rhodopsin aggregates.P23H rhodopsin as well as WT rhodopsin form aggregates in RPE cells and LEDGF(1-326) decreases these aggregates. Further, LEDGF(1-326) reduces the RPE cell damage caused by P23H rhodopsin. LEDGF(1-326) might be useful in treating cellular damage associated with protein aggregation diseases such as retinitis pigmentosa
Access to healthcare for children with Congenital Zika Syndrome in Brazil: perspectives of mothers and health professionals.
Get PDFThe Congenital Zika Syndrome (CZS) epidemic took place in Brazil between 2015 and 2017 and led to the emergence of at least 3194 children born with CZS. We explored access to healthcare services and activities in the Unified Health Service (Sistema Único de Saúde: SUS) from the perspective of mothers of children with CZS and professionals in the Public Healthcare Network. We carried out a qualitative, exploratory study, using semi-structured interviews, in two Brazilian states-Pernambuco, which was the epicentre of the epidemic in Brazil, and Rio de Janeiro, where the epidemic was less intense. The mothers and health professionals reported that healthcare provision was insufficient and fragmented and there were problems with follow-up care. There was a lack of co-ordination and an absence of communication between the various specialized services and between different levels of the health system. We also noted a public-private mixture in access to healthcare services, resulting from a segmented system and related to inequality of access. High reported household expenditure is an expression of the phenomenon of underfunding of the public system. The challenges that mothers and health professionals reported exposes contradictions in the health system which, although universal, does not guarantee equitable and comprehensive care. Other gaps were revealed through the outbreak. The epidemic provided visibility regarding difficulties of access for other children with disabilities determined by other causes. It also made explicit the gender inequalities that had an impact on the lives of mothers and other female caregivers, as well as an absence of the provision of care for these groups. In the face of an epidemic, the Brazilian State reproduced old fashioned forms of action-activities related to the transmitting mosquito and to prevention with an emphasis on the individual and no action related to social determinants
Rhodopsin Mutant P23H Destabilizes Rod Photoreceptor Disk Membranes
Get PDFMutations in rhodopsin cause retinitis pigmentosa in humans and retinal degeneration in a multitude of other animals. We utilized high-resolution live imaging of the large rod photoreceptors from transgenic frogs (Xenopus) to compare the properties of fluorescently tagged rhodopsin, Rho-EGFP, and RhoP23H-EGFP. The mutant was abnormally distributed both in the inner and outer segments (OS), accumulating in the OS to a concentration of ∼0.1% compared to endogenous opsin. RhoP23H-EGFP formed dense fluorescent foci, with concentrations of mutant protein up to ten times higher than other regions. Wild-type transgenic Rho-EGFP did not concentrate in OS foci when co-expressed in the same rod with RhoP23H-EGFP. Outer segment regions containing fluorescent foci were refractory to fluorescence recovery after photobleaching, while foci in the inner segment exhibited recovery kinetics similar to OS regions without foci and Rho-EGFP. The RhoP23H-EGFP foci were often in older, more distal OS disks. Electron micrographs of OS revealed abnormal disk membranes, with the regular disk bilayers broken into vesiculotubular structures. Furthermore, we observed similar OS disturbances in transgenic mice expressing RhoP23H, suggesting such structures are a general consequence of mutant expression. Together these results show that mutant opsin disrupts OS disks, destabilizing the outer segment possibly via the formation of aggregates. This may render rods susceptible to mechanical injury or compromise OS function, contributing to photoreceptor loss
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