A Spatio-Temporal Ageing Atlas of the Proximal Femur

Osteoporosis is an age-associated disease characterised by low bone mineral density (BMD) and micro-architectural deterioration leading to enhanced fracture risk. Conventional dual-energy X-ray absorptiometry (DXA) analysis has facilitated our understanding of BMD reduction in specific regions of interest (ROIs) within the femur, but cannot resolve spatial BMD patterns nor reflect age-related changes in bone microarchitecture due to its inherent averaging of pixel BMD values into large ROIs. To address these limitations and develop a comprehensive model of involutional bone loss, this paper presents a fully automatic pipeline to build a spatio-temporal atlas of ageing bone in the proximal femur. A new technique, termed DXA region free analysis (DXA RFA), is proposed to eliminate morphological variation between DXA scans by warping each image into a reference template. To construct the atlas, we use unprocessed DXA data from Caucasian women aged 20-97 years participating in three cohort studies in Western Europe (n > 13 ,000). A novel calibration procedure, termed quantile matching regression, is proposed to integrate data from different DXA manufacturers. Pixel-wise BMD evolution with ageing was modelled using smooth quantile curves. This technique enables characterisation of spatially-complex BMD change patterns with ageing, visualised using heat-maps. Furthermore, quantile curves plotted at different pixel coordinates showed consistently different rates of bone loss at different regions within the femoral neck. Given the close relationship between spatio-temporal bone loss and osteoporotic fracture, improved understanding of the bone ageing process could lead to enhanced prognostic, preventive and therapeutic strategies for the disease

Disclosing intimate partner violence to health care clinicians - What a difference the setting makes: A qualitative study

<p>Abstract</p> <p>Background</p> <p>Despite endorsement by national organizations, the impact of screening for intimate partner violence (IPV) is understudied, particularly as it occurs in different clinical settings. We analyzed interviews of IPV survivors to understand the risks and benefits of disclosing IPV to clinicians across specialties.</p> <p>Methods</p> <p>Participants were English-speaking female IPV survivors recruited through IPV programs in Massachusetts. In-depth interviews describing medical encounters related to abuse were analyzed for common themes using Grounded Theory qualitative research methods. Encounters with health care clinicians were categorized by outcome (IPV disclosure by patient, discovery evidenced by discussion of IPV by clinician without patient disclosure, or non-disclosure), attribute (beneficial, unhelpful, harmful), and specialty (emergency department (ED), primary care (PC), obstetrics/gynecology (OB/GYN)).</p> <p>Results</p> <p>Of 27 participants aged 18–56, 5 were white, 10 Latina, and 12 black. Of 59 relevant health care encounters, 23 were in ED, 17 in OB/GYN, and 19 in PC. Seven of 9 ED disclosures were characterized as unhelpful; the majority of disclosures in PC and OB/GYN were characterized as beneficial. There were no harmful disclosures in any setting. Unhelpful disclosures resulted in emotional distress and alienation from health care. Regardless of whether disclosure occurred, beneficial encounters were characterized by familiarity with the clinician, acknowledgement of the abuse, respect and relevant referrals.</p> <p>Conclusion</p> <p>While no harms resulted from IPV disclosure, survivor satisfaction with disclosure is shaped by the setting of the encounter. Clinicians should aim to build a therapeutic relationship with IPV survivors that empowers and educates patients and does not demand disclosure.</p

The “Flexi-Chamber”: A Novel Cost-Effective In Situ Respirometry Chamber for Coral Physiological Measurements

Coral reefs are threatened worldwide, with environmental stressors increasingly affecting the ability of reef-building corals to sustain growth from calcification (G), photosynthesis (P) and respiration (R). These processes support the foundation of coral reefs by directly influencing biogeochemical nutrient cycles and complex ecological interactions and therefore represent key knowledge required for effective reef management. However, metabolic rates are not trivial to quantify and typically rely on the use of cumbersome in situ respirometry chambers and/or the need to remove material and examine ex situ, thereby fundamentally limiting the scale, resolution and possibly the accuracy of the rate data. Here we describe a novel low-cost in situ respirometry bag that mitigates many constraints of traditional glass and plexi-glass incubation chambers. We subsequently demonstrate the effectiveness of our novel "Flexi-Chamber" approach via two case studies: 1) the Flexi-Chamber provides values of P, R and G for the reef-building coral Siderastrea cf. stellata collected from reefs close to Salvador, Brazil, which were statistically similar to values collected from a traditional glass respirometry vessel; and 2) wide-scale application of obtaining P, R and G rates for different species across different habitats to obtain inter- and intra-species differences. Our novel cost-effective design allows us to increase sampling scale of metabolic rate measurements in situ without the need for destructive sampling and thus significantly expands on existing research potential, not only for corals as we have demonstrated here, but also other important benthic groups

Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole – of clinical importance?

Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; ‘FACE-trial'), clinicians have to make their choices today. On the basis of available evidence summarised here and until FACE-data become available, letrozole seems to be the best choice for the majority of breast cancer patients whenever a non-steroidal aromatase inhibitor has to be chosen in a clinical setting. The background for this recommendation is discussed in the following chapters

P2X7 receptors induce degranulation in human mast cells.

Mast cells play important roles in host defence against pathogens, as well as being a key effector cell in diseases with an allergic basis such as asthma and an increasing list of other chronic inflammatory conditions. Mast cells initiate immune responses through the release of newly synthesised eicosanoids and the secretion of pre-formed mediators such as histamine which they store in specialised granules. Calcium plays a key role in regulating both the synthesis and secretion of mast-cell-derived mediators, with influx across the membrane, in particular, being necessary for degranulation. This raises the possibility that calcium influx through P2X receptors may lead to antigen-independent secretion of histamine and other granule-derived mediators from human mast cells. Here we show that activation of P2X7 receptors with both ATP and BzATP induces robust calcium rises in human mast cells and triggers their degranulation; both effects are blocked by the P2X7 antagonist AZ11645373, or the removal of calcium from the extracellular medium. Activation of P2X1 receptors with αβmeATP also induces calcium influx in human mast cells, which is significantly reduced by both PPADS and NF 449. P2X1 receptor activation, however, does not trigger degranulation. The results indicate that P2X7 receptors may play a significant role in contributing to the unwanted activation of mast cells in chronic inflammatory conditions where extracellular ATP levels are elevated

Insulin-Like Growth Factors Promote Vasculogenesis in Embryonic Stem Cells

The ability of embryonic stem cells to differentiate into endothelium and form functional blood vessels has been well established and can potentially be harnessed for therapeutic angiogenesis. However, after almost two decades of investigation in this field, limited knowledge exists for directing endothelial differentiation. A better understanding of the cellular mechanisms regulating vasculogenesis is required for the development of embryonic stem cell-based models and therapies. In this study, we elucidated the mechanistic role of insulin-like growth factors (IGF1 and 2) and IGF receptors (IGFR1 and 2) in endothelial differentiation using an embryonic stem cell embryoid body model. Both IGF1 or IGF2 predisposed embryonic stem to differentiate towards a mesodermal lineage, the endothelial precursor germ layer, as well as increased the generation of significantly more endothelial cells at later stages. Inhibition of IGFR1 signaling using neutralizing antibody or a pharmacological inhibitor, picropodophyllin, significantly reduced IGF-induced mesoderm and endothelial precursor cell formation. We confirmed that IGF-IGFR1 signaling stabilizes HIF1α and leads to up-regulation of VEGF during vasculogenesis in embryoid bodies. Understanding the mechanisms that are critical for vasculogenesis in various models will bring us one step closer to enabling cell based therapies for neovascularization

Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies

The translation of in vitro findings to clinical outcomes is often elusive. Trauma/hemorrhagic shock (T/HS) results in hepatic hypoxia that drives inflammation. We hypothesize that in silico methods would help bridge in vitro hepatocyte data and clinical T/HS, in which the liver is a primary site of inflammation. Primary mouse hepatocytes were cultured under hypoxia (1% O 2) or normoxia (21% O2) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex™ technology. Statistical analysis and data-driven modeling were employed to characterize the main components of the cellular response. Statistical analyses, hierarchical and k-means clustering, Principal Component Analysis, and Dynamic Network Analysis suggested MCP-1/CCL2 and IL-1α as central coordinators of hepatocyte-mediated inflammation in C57BL/6 mouse hepatocytes. Hepatocytes from MCP-1-null mice had altered dynamic inflammatory networks. Circulating MCP-1 levels segregated human T/HS survivors from non-survivors. Furthermore, T/HS survivors with elevated early levels of plasma MCP-1 post-injury had longer total lengths of stay, longer intensive care unit lengths of stay, and prolonged requirement for mechanical ventilation vs. those with low plasma MCP-1. This study identifies MCP-1 as a main driver of the response of hepatocytes in vitro and as a biomarker for clinical outcomes in T/HS, and suggests an experimental and computational framework for discovery of novel clinical biomarkers in inflammatory diseases. © 2013 Ziraldo et al

Cellular distribution of vascular endothelial growth factor A (VEGFA) and B (VEGFB) and VEGF receptors 1 and 2 in focal cortical dysplasia type IIB

Members of the vascular endothelial growth factor (VEGF) family are key signaling proteins in the induction and regulation of angiogenesis, both during development and in pathological conditions. However, signaling mediated through VEGF family proteins and their receptors has recently been shown to have direct effects on neurons and glial cells. In the present study, we immunocytochemically investigated the expression and cellular distribution of VEGFA, VEGFB, and their associated receptors (VEGFR-1 and VEGFR-2) in focal cortical dysplasia (FCD) type IIB from patients with medically intractable epilepsy. Histologically normal temporal cortex and perilesional regions displayed neuronal immunoreactivity (IR) for VEGFA, VEGFB, and VEGF receptors (VEGFR-1 and VEGFR-2), mainly in pyramidal neurons. Weak IR was observed in blood vessels and there was no notable glial IR within the grey and white matter. In all FCD specimens, VEGFA, VEGFB, and both VEGF receptors were highly expressed in dysplastic neurons. IR in astroglial and balloon cells was observed for VEGFA and its receptors. VEGFR-1 displayed strong endothelial staining in FCD. Double-labeling also showed expression of VEGFA, VEGFB and VEGFR-1 in cells of the microglia/macrophage lineage. The neuronal expression of both VEGFA and VEGFB, together with their specific receptors in FCD, suggests autocrine/paracrine effects on dysplastic neurons. These autocrine/paracrine effects could play a role in the development of FCD, preventing the death of abnormal neuronal cells. In addition, the expression of VEGFA and its receptors in glial cells within the dysplastic cortex indicates that VEGF-mediated signaling could contribute to astroglial activation and associated inflammatory reactions