Aneurysmal bone cyst of medial end of clavicle: a rare case report

Aneurysmal bone cyst is a benign, but locally aggressive benign tumor. The clavicle being a rare site of tumors and very few cases of aneurysmal bone cyst of clavicle have been reported in literature. Due to its rarity of location of its presentation we hereby report a rare case of aneurysmal bone cyst of medial end of clavicle in a 20-year-old female which was treated by wide local resection and reconstruction

Prioritizing a sequence of short-duration groups as the standardized pathway for chronic noncancer pain at an Australian tertiary multidisciplinary pain service: preliminary outcomes

Objective: To describe implementation and report preliminary outcomes of a resource-efficient, standardized group pathway for chronic noncancer pain. Design: Descriptive cross-sectional study of a group-based pain management pathway in comparison with an Australasian benchmarking data set. Setting: An Australian tertiary multidisciplinary pain service. Subjects: Patients with chronic noncancer pain actively participating in the group pathway in 2016. Methods: Referred patients were prioritized to a short-duration group-based standardized pain management pathway linking education, assessment, and treatment groups. Measures of pain, mood, self-efficacy, and catastrophizing and reduction in daily opioid use were collated from the Australasian data set. Results: In 2016, 928 patients were actively engaged with the pain service. More patients were prioritized to receive treatment in a group format in comparison with other Australasian services (68.4% vs 22%). A greater percentage of patients attended their first clinical contact within 3 months of referral (81.4%) compared with the Australasian average (68.6%). Comparable improvements in average pain intensity, pain interference, depression, anxiety, stress, pain catastrophizing, and self-efficacy were observed. There was significantly greater reduction in opioid use, including for those taking more than 40 mg of oral morphine equivalent daily dose. Conclusion: Implementation of a sequence of short-duration groups as the default clinical pathway resulted in shorter waiting times and noninferior outcomes in key areas for patients completing the program, compared with Australasian averages. Given the resource efficiencies of the group process, this finding has implications for service design

The fork protection complex recruits FACT to reorganize nucleosomes during replication

Chromosome replication depends on efficient removal of nucleosomes by accessory factors to ensure rapid access to genomic information. Here, we show this process requires recruitment of the nucleosome reorganization activity of the histone chaperone FACT. Using single-molecule FRET, we demonstrate that reorganization of nucleosomal DNA by FACT requires coordinated engagement by the middle and C-terminal domains of Spt16 and Pob3 but does not require the N-terminus of Spt16. Using structure-guided pulldowns, we demonstrate instead that the N-terminal region is critical for recruitment by the fork protection complex subunit Tof1. Using in vitro chromatin replication assays, we confirm the importance of these interactions for robust replication. Our findings support a mechanism in which nucleosomes are removed through the coordinated engagement of multiple FACT domains positioned at the replication fork by the fork protection complex

Treatment With Naringenin Elevates the Activity of Transcription Factor Nrf2 to Protect Pancreatic β-Cells From Streptozotocin-Induced Diabetes in vitro and in vivo

Chronic hyperglycemia and unusually high oxidative stress are the key contributors for diabetes in humans. Since nuclear factor E2-related factor 2 (Nrf2) controls the expression of antioxidant- and detoxification genes, it is hypothesized that targeted activation of Nrf2 using phytochemicals is likely to protect pancreatic β-cells, from oxidative damage, thereby mitigates the complications of diabetes. Naringenin is one such activator of Nrf2. However, it is currently not known whether the protective effect of naringenin against streptozotocin (STZ) induced damage is mediated by Nrf2 activation. Hence, the potential of naringenin to activate Nrf2 and protect pancreatic β-cells from STZ-induced damage in MIN6 cells is studied. In MIN6 cells, naringenin could activate Nrf2 and its target genes GST and NQO1, thereby inhibit cellular apoptosis. In animals, administration of 50 mg/kg body weight naringenin, for 45 days, significantly decreased STZ-induced blood glucose levels, normalized the lipid profile, and augmented the levels of antioxidants in pancreatic tissues. Immunohistochemical analysis measuring the number of insulin-positive cells in pancreas showed restoration of insulin expression similar to control animals. Furthermore, naringenin promoted glycolysis while inhibiting gluconeogenesis. In conclusion, naringenin could be a good anti-diabetic agent, which works by promoting Nrf2 levels and by decreasing cellular oxidative stress

Altered synaptobrevin-II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder

textabstractFollowing exocytosis, synaptic vesicles (SVs) have to be reformed with the correct complement of proteins in the correct stoichiometry to ensure continued neurotransmission. Synaptophysin is a highly abundant, integral SV protein necessary for the efficient retrieval of the SV SNARE protein, synaptobrevin II (sybII). However the molecular mechanism underpinning synaptophysin-dependent sybII retrieval is still unclear. We recently identified a male patient with severe intellectual disability, hypotonia, epilepsy and callosal agenesis who has a point mutation in the juxtamembrane region of the fourth transmembrane domain of synaptophysin (T198I). This mutation had no effect on the activity-dependent retrieval of synaptophysin that was tagged with the genetically-encoded pH-sensitive reporter (pHluorin) in synaptophysin knockout hippocampal cultures. This suggested the mutant has no global effect on SV endocytosis, which was confirmed when retrieval of a different SV cargo (the glutamate transporter vGLUT1) was examined. However neurons expressing this T198I mutant did display impaired activity-dependent sybII retrieval, similar to that observed in synaptophysin knockout neurons. Interestingly this impairment did not result in an increased stranding of sybII at the plasma membrane. Screening of known human synaptophysin mutations revealed a similar presynaptic phenotype between T198I and a mutation found in X-linked intellectual disability. Thus this novel human synaptophysin mutation has revealed that aberrant retrieval and increased plasma membrane localisation of SV cargo can be decoupled in human disease

Intraplaque haemorrhages as the trigger of plaque vulnerability

Atherothrombosis remains one of the main causes of morbidity and mortality in the western countries. Human atherothrombotic disease begins early in life in relation to circulating lipid retention in the inner vascular wall. Risk factors enhance the progression towards clinical expression: dyslipidaemia, diabetes, smoking, hypertension, ageing, etc. The evolution from the initial lipid retention in the arterial wall to clinical events is a continuum of increasingly complex biological processes. Current strategies to fight the consequences of atherothrombosis are orientated either towards the promotion of a healthy life style1 and preventive treatment of risk factors, or towards late interventional strategies.2 Despite this therapeutic arsenal, the incidence of clinical events remains dramatically high,3 dependent, at least in part, on the increasing frequency of type 2 diabetes and ageing. But some medical treatments, focusing only on prevention of the metabolic risk, have failed to reduce cardiovascular mortality, thus illustrating that our understanding of the pathophysiology of human atherothrombosis leading to clinical events remain incomplete. New paradigms are now emerging which may give rise to novel experimental strategies to improve therapeutic efficacy and prediction of disease progression. Recent studies strengthen the concept that the intraplaque neovascularization and bleeding (Figure 1, upper panel) are events that could play a major role in plaque progression and leucocyte infiltration, and may also serve as a measure of risk for the development of future events. The recent advances in our understanding of IntraPlaque Hemorrhage as a critical event in triggering acute clinical events have important implications for clinical research and possibly future clinical practice. Figure 1Macroscopic view and schematic representation of the detrimental consequences of intraplaque haemorrhages on plaque biology and stability

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Evolution based statistical optimization technique to design the smart structural system for large aerospace structures

A numerical approach for genetics based statistical optimization technique is used to design the smart structural system for aerospace structures. An evolutionary based optimization technique like genetic algorithm (GA) has come into prominence. The reason for developing evolution based algorithm for optimization is for its robustness and randomness. Other numerical tools that are used for optimization are generally gradient based algorithm, where there is possibility of occurrence for a local optimum value. The GA developed is a niche-micro GA, where termination criteria are set in order to restart the algorithm. Stage-wise multiple objective functions and multiple termination criteria are incorporated to improve the computational effort. The current approach is very much robust to design a smart structural system through optimization for its maximum structural performance. In order to achieve maximum structural performance for the smart structural system, it is necessary to appropriately position the active elements. Here the genetic algorithm is amalgamated with finite element to perform a statistical based optimization to locate the position and size of active structural elements i.e. actuators/sensors. Majorly, nowadays the actuators and sensors that are preferred for smart structures design (i.e. Piezo patches, Piezo composite, SMA wire, SMA composite etc) develop induced strain under an external applied field. It becomes necessary to optimize the smart structures using the following parameters such as static strains, modal dynamic strains, size of the actuators/sensors, induced strain etc. A scaled T-Tail model is taken as an illustration to carry out the GA analysis for the location and sizing of PZT actuator/sensor. The structural parameters such as static strains, modal dynamic strains and geometry details are taken from NASTRAN and then interfaced with MATLAB to perform the statistical optimization analysis