A combined DTI-fMRI approach for optimizing the delineation of posteromedial vs. anterolateral entorhinal cortex

In the entorhinal cortex (EC), attempts have been made to identify the human homologue regions of the medial (MEC) and lateral (LEC) subdivision using either functional magnetic resonance imaging (fMRI) or diffusion tensor imaging (DTI). However, there are still discrepancies between entorhinal subdivisions depending on the choice of connectivity seed regions and the imaging modality used. While DTI can be used to follow the white matter tracts of the brain, fMRI can identify functionally connected brain regions. In this study, we used both DTI and resting-state fMRI in 103 healthy adults to investigate both structural and functional connectivity between the EC and associated cortical brain regions. Differential connectivity with these regions was then used to predict the locations of the human homologues of MEC and LEC. Our results from combining DTI and fMRI support a subdivision into posteromedial (pmEC) and anterolateral (alEC) EC and reveal a discrete border between the pmEC and alEC. Furthermore, the EC subregions obtained by either imaging modality showed similar distinct connectivity patterns: While pmEC showed increased connectivity preferentially with the default mode network, the alEC exhibited increased connectivity with regions in the dorsal attention and salience networks. Optimizing the delineation of the human homologues of MEC and LEC with a combined, cross-validated DTI-fMRI approach allows to define a likely border between the two subdivisions and has implications for both cognitive and translational neuroscience research

Structural connectivity-based segmentation of the human entorhinal cortex

The medial (MEC) and lateral entorhinal cortex (LEC), widely studied in rodents, are well defined and characterized. In humans, however, the exact locations of their homologues remain uncertain. Previous functional magnetic resonance imaging (fMRI) studies have subdivided the human EC into posteromedial (pmEC) and anterolateral (alEC) parts, but uncertainty remains about the choice of imaging modality and seed regions, in particular in light of a substantial revision of the classical model of EC connectivity based on novel insights from rodent anatomy. Here, we used structural, not functional imaging, namely diffusion tensor imaging (DTI) and probabilistic tractography to segment the human EC based on differential connectivity to other brain regions known to project selectively to MEC or LEC. We defined MEC as more strongly connected with presubiculum and retrosplenial cortex (RSC), and LEC as more strongly connected with distal CA1 and proximal subiculum (dCA1pSub) and lateral orbitofrontal cortex (OFC). Although our DTI segmentation had a larger medial-lateral component than in the previous fMRI studies, our results show that the human MEC and LEC homologues have a border oriented both towards the posterior-anterior and medial-lateral axes, supporting the differentiation between pmEC and alEC

Antibodies to cyclic citrullinated protein and erythrocyte sedimentation rate predict hand bone loss in patients with rheumatoid arthritis of short duration: a longitudinal study

Introduction Radiographic progression in rheumatoid arthritis (RA) has in several studies been shown to be predicted by serological markers widely used in daily clinical practice. The objective of this longitudinal study was to examine if these serological markers also predict hand bone mineral density (BMD) loss in patients with RA of short disease duration. Methods 163 patients with RA of short disease duration (2.4 years) were included and followed longitudinally. Antibodies to cyclic citrullinated protein (anti-CCP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed from baseline blood-samples. Hand BMD was measured by digital X-ray radiogrammetry (DXR) based on hand and wrist radiographs obtained at baseline and 1, 2 and 5-year follow-up. Results During the study period, DXR-BMD decreased by median (inter quartile range) 1.7% (4.1 to 0.4), 2.8% (5.3 to 0.9) and 5.6% (11.7 to 2.3) after 1, 2 and 5 years, respectively. Elevated baseline anti-CCP, RF, ESR and CRP levels were in univariate linear regression analyses consistently associated with DXR-BMD change at all time-points. Anti-CCP and ESR were independently associated with hand DXR-BMD in multivariate linear regression analyses. Elevated anti-CCP levels were consistent and independent predictors of loss in cortical hand bone during the study period, with the odds ratios (95% confidence interval) 2.2 (1.0 to 4.5), 2.6 (1.1 to 6.2) and 4.9 (1.4 to 16.7) for the 1, 2, and 5-year follow-up periods, respectively. Conclusions Anti-CCP and ESR were found to be independent predictors of early localised BMD loss. This finding adds to the understanding of anti-CCP and ESR as important predictors of bone involvement in RA

UK Healthcare Workers' Experiences of Major System Change in Elective Surgery During the COVID-19 Pandemic: Reflections on Rapid Service Adaptation

Background: The coronavirus disease 2019 (COVID-19) pandemic disrupted the delivery of elective surgery in the United Kingdom. The majority of planned surgery was cancelled or postponed in March 2020 for the duration of the first wave of the pandemic. We investigated the experiences of staff responsible for delivering rapid changes to surgical services during the first wave of the pandemic in the United Kingdom, with the aim of developing lessons for future major systems change (MSC). Methods: Using a rapid qualitative study design, we conducted 25 interviews with frontline surgical staff during the first wave of the pandemic. Framework analysis was used to organise and interpret findings. Results: Staff discussed positive and negative experiences of rapid service organisation. Clinician-led decision-making, the flexibility of individual staff and teams, and the opportunity to innovate service design were all seen as positive contributors to success in service adaptation. The negative aspects of rapid change were inconsistent guidance from national government and medical bodies, top-down decisions about when to cancel and restart surgery, the challenges of delivering emergency surgical care safely and the complexity of prioritising surgical cases when services re-started. Conclusion: Success in the rapid reorganisation of elective surgical services can be attributed to the flexibility and adaptability of staff. However, there was an absence of involvement of staff in wider system-level pandemic decisionmaking and competing guidance from national bodies. Involving staff in decisions about the organisation and delivery of MSC is essential for the sustainability of change processes

The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats

<p>Abstract</p> <p>Background</p> <p>Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats.</p> <p>Methods</p> <p>Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed.</p> <p>Results</p> <p>Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate.</p> <p>Conclusions</p> <p>The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.</p

Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone

<p>Abstract</p> <p>Background</p> <p>All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats.</p> <p>Methods</p> <p>Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied.</p> <p>Results</p> <p>The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1.</p> <p>Conclusion</p> <p>We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.</p