Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with either Sporadic or Familial Alzheimer's Disease

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinson's disease (PD) patients as well as several animal models of AD and PD. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show that both sporadic AD (sAD) and PSEN1 fibroblasts share the same impairment of mitochondrial membrane potential and alterations in mitochondrial morphology. Mitochondrial respiration, however, was decreased in sAD fibroblasts and increased in PSEN1 fibroblasts. Morphological changes seen in AD fibroblasts include reduced mitochondrial number and increased mitochondrial clustering around the cell nucleus as well as an increased number of long mitochondria. We show here for the first time in AD patient tissue that treatment with UDCA increases mitochondrial membrane potential and respiration as well as reducing the amount of long mitochondria in AD fibroblasts. In addition we show reductions in Dynamin-related protein 1 (Drp1) level; particularly the amount localised to mitochondria in both sporadic AD and familial patient fibroblasts. Drp1 protein amount and localization were increased after UDCA treatment. The restorative effects of UDCA are abolished when Drp1 is knocked down. This paper highlights the potential use of UDCA as a treatment for neurodegenerative disease

Glial repair in an insect central nervous system: effects of selective glial disruption

In vivo application of ethidium bromide to cockroach central nervous connectives caused extensive disruption of the neuroglia within 24 hr. Axonal conduction persisted following treatment with the glial toxin. A consistent feature of glial damage and repair was the prominent involvement of granule-containing cells. These cells (which were never seen in control cords) shared a number of cytological features with hemocytes that were seen adhering to and penetrating the neural lamella, in the early stages of glial damage. The granule-containing cells appear to serve dual functions: phagocytosis and structural repair. After 48 hr, granule-containing cells, or their processes, formed layers at the periphery of the connectives. By 4 to 6 days after treatment, the peripheral cells had assumed the morphological characteristics of normal perineurial cells and by 28 days were indistinguishable, ultrastructurally, from those of the perineurium of normal, untreated animals. These structural changes paralleled the re-establishment of the normal permeability properties of the blood-brain interface revealed by the exclusion of an extracellular tracer, ionic lanthanum, and electrophysiological observations

Landsat TM analysis of fracture patterns: a case study from the Coastal Cordillera of northern Chile

Cretaceous rocks on the continental margin of northern Chile record a complex geodynamic evolution. Cycles of transtensional and transpressional deformation and of extrusive and intrusive magmatism are linked to the development of crustal-scale lineaments. The Landsat Thematic Mapper is used here as a tool to define these structural features. Geocorrected data were digitally enhanced and lineaments plotted directly from a hard copy image, thereby excluding artificial or non-geological features that might degrade the subsequent structural analysis. The lineaments were then digitised and analysed using a Weighted Moving Average (WMA) technique to suppress noise and to enhance azimuthal variation. Statistical analysis of the data reveals three lineament populations. The first is a set of NNE-trending lineaments that belong to the margin-parallel, sinistral Atacama Fault System. The second is a series of NW-trending lineaments with a similar orientation to large-scale structures identified across the South American continental plate. The third is a widely spaced set of NE-trending lineaments. The key result of this study is that lineaments identified from remotely sensed data may have orientation patterns that differ considerably from those identified by traditional geological mapping and that full structural analysis of structurally complex crustal regions will likely be incomplete without a comprehensive analysis of remotely sensed data. Although the NW-trending structures are numerically dominant on the Landsat image, they are seldom recorded at map scale and are under-represented on published geological maps. Of the 275 faults marked on the published geological map sheets, 89 are N to NNE-trending and only 88 are NW-trending. By contrast, of 841 lineaments identified from the satellite image, 455 are NW-trending and 178 are N- to NNE-trending. The lack of prior recognition of the NW-trending structures means that their importance has been underestimated in reconstructions of the geodynamic evolution of the region. In addition, as major ore deposits in the region are frequently located at intersections between two fracture systems, the recognition here of the NW-trending set of structures should illuminate future mineral exploration programmes

Health professionals and students encounter multi-level barriers to implementing high-value osteoarthritis care: a multi-national study

Objective: Consistent evidence-practice gaps in osteoarthritis (OA) care are observed in primary care settings globally. Building workforce capacity to deliver high-value care requires a contemporary understanding of barriers to care delivery. We aimed to explore barriers to OA care delivery among clinicians and students. Design: A cross-sectional, multinational study sampling clinicians (physiotherapists, primary care nurses, general practitioners (GPs), GP registrars; total possible denominator: n = 119,735) and final-year physiotherapy and medical students (denominator: n = 2,215) across Australia, New Zealand and Canada. Respondents answered a survey, aligned to contemporary implementation science domains, which measured barriers to OA care using categorical and free-text responses. Results: 1886 clinicians and 1611 students responded. Items within the domains ‘health system’ and ‘patient-related factors’ represented the most applicable barriers experienced by clinicians (25–42% and 20–36%, respectively), whereas for students, ‘knowledge and skills’ and ‘patient-related factors’ (16–24% and 19–28%, respectively) were the most applicable domains. Meta-synthesis of qualitative data highlighted skills gaps in specific components of OA care (tailoring exercise, nutritional/overweight management and supporting positive behaviour change); assessment, measurement and monitoring; tailoring care; managing case complexity; and translating knowledge to practice (especially among students). Other barriers included general infrastructure limitations (particularly related to community facilities); patient-related factors (e.g., beliefs and compliance); workforce-related factors such as inconsistent care and a general knowledge gap in high-value care; and system and service-level factors relating to financing and time pressures, respectively. Conclusions: Clinicians and students encounter barriers to delivery of high-value OA care in clinical practice/training (micro-level); within service environments (meso-level); and within the health system (macro-level)