p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21.Methodsp21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay.ResultsWe show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis.ConclusionThe novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy

Perceptions towards aqua-based exercise among older adults with osteoarthritis who have discontinued participation in this exercise mode

Aim: This study aimed to investigate reasons for ceasing participation in aqua-based exercise among older adults with osteoarthritis (OA). Methods: Eleven adults over 60 years of age with OA participated in one of two focus groups, during which they discussed barriers to aqua-based exercise and the potential benefits of this exercise mode. Each focus group was audiotaped, transcribed and then analysed using the general inductive thematic approach. The investigators reached a consensus on all coding categories and then identified themes. Results: Key barriers identified were: a lack of suitable classes; insufficient instructor knowledge, which often led to increased pain; cold water and the changing facilities. Key perceived benefits included increased physical ability in water and social interaction. Conclusions: A greater understanding of reasons for ceasing participation in aqua-based exercise among older adults with OA may help facilitate development of suitable exercise programs that minimise barriers for this group

Adherence support strategies for exercise interventions in people with mild cognitive impairment and dementia: a systematic review

Exercise-based therapy may improve health status for people with Mild Cognitive Impairment (MCI) or dementia but cannot work without adherence, which has proven difficult. This review aimed to evaluate strategies to support adherence among people with MCI or Dementia and was completed in Nottingham/UK in 2017. A narrative synthesis was used to investigate the effectiveness or usefulness of adherence support strategies. Fifteen adherence support strategies were used including theoretical underpinning (programmes based on behavior change theories), individual tailoring, worksheets and exercise booklets, goal setting, phone calls or reminders, newsletters, support to overcome exercise barriers, information, adaptation periods, individual supervision, support for clinicians, group setting, music, accelerometers/pedometers and emphasis on enjoyable activities. Music was the only strategy that was investigated in a comparative design but was found to be effective only for those who were generally interested in participating in activities. A wide range of adherence support strategies are being included in exercise interventions for people with MCI or dementia, but the evidence regarding their effectiveness is limited

Severity of chronic Lyme disease compared to other chronic conditions: a quality of life survey

Overview. The Centers for Disease Control and Prevention (CDC) health-related quality of life (HRQoL) indicators are widely used in the general population to determine the burden of disease, identify health needs, and direct public health policy. These indicators also allow the burden of illness to be compared across different diseases. Although Lyme disease has recently been acknowledged as a major health threat in the USA with more than 300,000 new cases per year, no comprehensive assessment of the health burden of this tickborne disease is available. This study assesses the HRQoL of patients with chronic Lyme disease (CLD) and compares the severity of CLD to other chronic conditions.Methods. Of 5,357 subjects who responded to an online survey, 3,090 were selected for the study. Respondents were characterized as having CLD if they were clinically diagnosed with Lyme disease and had persisting symptoms lasting more than 6 months following antibiotic treatment. HRQoL of CLD patients was assessed using the CDC 9-item metric. The HRQoL analysis for CLD was compared to published analyses for the general population and other chronic illnesses using standard statistical methods.Results. Compared to the general population and patients with other chronic diseases reviewed here, patients with CLD reported significantly lower health quality status, more bad mental and physical health days, a significant symptom disease burden, and greater activity limitations. They also reported impairment in their ability to work, increased utilization of healthcare services, and greater out of pocket medical costs.Conclusions. CLD patients have significantly impaired HRQoL and greater healthcare utilization compared to the general population and patients with other chronic diseases. The heavy burden of illness associated with CLD highlights the need for earlier diagnosis and innovative treatment approaches that may reduce the burden of illness and concomitant costs posed by this illness

Continuing evolution of Burkholderia mallei through genome reduction and large-scale rearrangements

Burkholderia mallei (Bm), the causative agent of the predominately equine disease glanders, is a genetically uniform species that is very closely related to the much more diverse species Burkholderia pseudomallei (Bp), an opportunistic human pathogen and the primary cause of melioidosis. To gain insight into the relative lack of genetic diversity within Bm, we performed whole-genome comparative analysis of seven Bm strains and contrasted these with eight Bp strains. The Bm core genome (shared by all seven strains) is smaller in size than that of Bp, but the inverse is true for the variable gene sets that are distributed across strains. Interestingly, the biological roles of the Bm variable gene sets are much more homogeneous than those of Bp. The Bm variable genes are found mostly in contiguous regions flanked by insertion sequence (IS) elements, which appear to mediate excision and subsequent elimination of groups of genes that are under reduced selection in the mammalian host. The analysis suggests that the Bm genome continues to evolve through random IS-mediated recombination events, and differences in gene content may contribute to differences in virulence observed among Bm strains. The results are consistent with the view that Bm recently evolved from a single strain of Bp upon introduction into an animal host followed by expansion of IS elements, prophage elimination, and genome rearrangements and reduction mediated by homologous recombination across IS elements

Biochemical and Molecular Aspects of Vascular Adrenergic Regulation of Blood Pressure in the Elderly

Hypertension, orthostatic hypotension, arterial insufficiency, and atherosclerosis are common disorders in the elderly that lead to significant morbidity and mortality. One common factor to these conditions is an age-related decline in vascular beta-adrenergic receptor-mediated function and subsequent cAMP generation. Presently, there is no single cellular factor that can explain this age-related decline, and thus, the primary cause of this homeostatic imbalance is yet to be identified. However, the etiology is clearly associated with an age-related change in the ability of beta-adrenergic receptor to respond to agonist at the cellular level in the vasculature. This paper will review what is presently understood regarding the molecular and biochemical basis of age-impaired beta-adrenergic receptor-mediated signaling. A fundamental understanding of why β-AR-mediated vasorelaxation is impaired with age will provide new insights and innovative strategies for the management of multiple clinical disorders

INFRAESTRUTURA VERDE NO CONTEXTO DA INFRAESTRUTURA AMBIENTAL URBANA E DA GESTÃO DO MEIO AMBIENTE

The increasing quantity of research about the green infrastructure concept in Brazil and some performed concrete experiments reflect the need for progress on issues related to its integration in the context of environmental infrastructure necessary for large urban agencies and environmental land management. The intense range of solutions proposed by this concept presents interfaces with many other urban infrastructures and especially with different scales and actors of land management.Thus, this article intends to contribute to this debate by presenting a preliminary approach on the nature of the environmental management of urbanized areas and where the locus of those actions, connected to the concept of green infrastructure, will be. Concomitantly to this target, it will be presented the initial formulation of a concept of urban environmental management¹, which seeks to comprise the sphere of management of all structures that establish the use and consumption of natural resources in a more effective way, i.e., either relating to the ground, as well as to water and vegetation. _____________________¹ Urban environmental management meaning the urbanization of the territory, including rural and intra-urban areas, so that the whole sphere of municipal action and those which should expand to the state sphere, especially in cases of large urbanized regions, i.e., the case of metropolitan regions. It involves the insertion of the territory context used by the city, which extrapolates, partially, the limits of its urban areas and its municipal boundaries.O crescente número de pesquisas acerca do conceito de infraestrutura verde no Brasil e de algumas experiências concretas realizadas já reflete a necessidade de se avançar nas questões referentes à sua inserção no contexto da infraestrutura ambiental necessária aos grandes organismos urbanos e da gestão ambiental do território. A intensa gama de soluções propostas por esse conceito apresenta interfaces com muitas outras infraestruturas urbanas e, sobretudo, com diferentes escalas e atores da gestão do território.Neste sentido, este artigo pretende contribuir para essa reflexão, apresentando uma abordagem preliminar sobre a natureza da gestão ambiental do território urbanizado e onde estará o lócus das ações vinculadas ao conceito de infraestrutura verde. Concomitante a esse objetivo, apresenta-se a formulação inicial de um conceito de gestão ambiental urbana¹, o qual busca abranger a esfera de gestão de todas as estruturas que estabelecem o uso e o consumo dos recursos naturais de forma mais direta, ou seja, tanto em relação ao solo, como à água e à vegetação. ________________¹ Gestão ambiental urbana com o sentido da urbanização do território, incluindo as áreas rurais e intra-urbanas, assim, toda a esfera de ação municipal e naquilo que deverá se expandir para a estadual, em especial nos casos das grandes regiões urbanizadas, ou seja, o caso das regiões metropolitanas. Trata-se de inserir o contexto do território utilizado pela cidade, que extrapola, em parte, os limites de suas áreas urbanas e dos seus limites municipais

Análise estratégica do relevo e planejamento territorial urbano: compartimentos ambientais estruturantes na macrometrópole de São Paulo

The great urban spreading occurred in metropolitan areas worldwide, still in intense movement of urban expansion on old rural areas, evidenced that the environmental problems, which most affect the territories nowadays, are the result of intensive urbanization processes. In this sense, the decision about where and how to occupy a territorial area must pass through a different analysis on the topography, not anymore as just as static and passive element, which conforms to the several urban uses requested for a strategic approach linked to the urban territorial and environmental planning. By highlighting the main lines and environmental structuring compartments of a landscape under the topographic aspect and the processes of its geomorphologic form, it is possible to better glimpse the relationships urban processes and imposed infrastructures establish with these strategic landscape portions, which allow to define ways of use and land occupancy more suitable to urban and natural processes, aiming the selection of the main topographic sectors designated to environmental services for preservation of spaces of natural processes occurrence.O grande espalhamento urbano ocorrido nas regiões metropolitanas mundiais, ainda em intenso movimento de expansão urbana sobre antigos territórios rurais, colocou em evidência que os problemas ambientais que mais impactam os territórios, hoje, são os decorrentes dos processos de urbanização intensiva. Nesse sentido, a decisão sobre onde e como ocupar um território deve perpassar uma outra análise sobre o relevo, não mais apenas como um elemento estático e passivo, que se amolda aos diversos usos urbanos solicitados, mas com uma abordagem estratégica vinculada ao planejamento territorial e ambiental urbano. Ao destacar as principais linhas e compartimentos ambientais estruturantes de uma paisagem, sob o aspecto do relevo e dos processos de sua esculturação, pode-se entrever melhor as relações que os processos urbanos e suas infraestruturas impostas estabelecem com essas porções estratégicas da paisagem, podendo direcionar, assim, formas de uso e de ocupação do relevo mais condizentes com os processos urbanos e naturais, objetivando a eleição dos principais setores do relevo destinados aos serviços ambientais da preservação dos espaços de ocorrência dos processos naturais

Tibio-femoral joint constraints for bone pose estimation during movement using multi-body optimization

The financial support of the Universita'Italo-Francese (Call Vinci) and of the Department of Human Movement and Sport Sciences of the University of Rome ''Foro Italico'' is gratefully acknowledged. The authors wish to acknowledge Dr. Sophie Lacoste for her technical support and John McCamley for his contribution to the refinement of the manuscriptWhen using skin markers and stereophotogrammetry for movement analysis, bone pose estimation may be performed using multi-body optimization with the intent of reducing the effect of soft tissue artefacts. When the joint of interest is the knee, improvement of this approach requires defining subject-specific relevant kinematic constraints. The aim of this work was to provide these constraints in the form of plausible values for the distances between origin and insertion of the main ligaments (ligament lengths), during loaded healthy knee flexion, taking into account the indeterminacies associated with landmark identification during anatomical calibration. Ligament attachment sites were identified through virtual palpation on digital bone templates. Attachments sites were estimated for six knee specimens by matching the femur and tibia templates to low-dose stereoradiography images. Movement data were obtained using stereophotogrammetry and pin markers. Relevant ligament lengths for the anterior and posterior cruciate, lateral collateral, and deep and superficial bundles of the medial collateral ligaments (ACL, PCL, LCL, MCLdeep, MCLsup) were calculated. The effect of landmark identification variability was evaluated performing a Monte Carlo simulation on the coordinates of the origin-insertion centroids. The ACL and LCL lengths were found to decrease, and the MCLdeep length to increase significantly during flexion, while variations in PCL and MCLsup length was concealed by the experimental indeterminacy. An analytical model is given that provides subject-specific plausible ligament length variations as functions of the knee flexion angle and that can be incorporated in a multi-body optimization procedure