Rejected

Beyond the conventional mode of working of anti-inflammatory agents through enzyme inhibition, herein, COX-2 was provided with an alternate substrate. A proline-centered pentapeptide isoconformational to arachidonic acid, which exhibited appreciable selectivity for COX-2, overcoming acetic acid- and formalin-induced pain in rats to almost 80%, was treated as a substrate by the enzyme. Remarkably, COX-2 metabolized the pentapeptide into small fragments consisting mainly of di- and tripeptides that ensured the safe breakdown of the peptide under in vivo conditions. The kinetic parameter K/ K for COX-2-mediated metabolism of the peptide (6.3 × 10 M s) was quite similar to 9.5 × 10 M s for arachidonic acid. Evidenced by the molecular dynamic studies and the use of Y385F COX-2, it was observed that the breakage of the pentapeptide has probably been taken place through H-bond activation of the peptide bond by the side chains of Y385 and S530.

Coronary syndromes associated with conditions related to mast cell activation and inflammatory cell interaction, such as T-lymphocytes and macrophages, further inducing allergic or hypersensitivity and anaphylactic or anaphylactoid insults are referred today as Kounis syndrome. Kounis syndrome is caused by inflammatory mediators released during an allergic insult post inflammatory cell activation and interaction via multidirectional stimuli. A platelet subset, of 20%, with high and low affinity IgE surface receptors are also involved in this process. Kounis syndrome is not simply a single organ disease, but a complex multi-system and multi organ arterial clinical syndrome, affecting coronary, mesenteric and cerebral arteries accompanied by allergy-hypersensitivity-anaphylaxis, involving skin, respiratory and vascular systems in the context of anesthesia, surgery, radiology, oncology, or even dental and psychiatric medicine with significant influence on both morbidity and mortality. Kounis syndrome might be caused by numerous and continuously increasing causes accompanied with broadening clinical symptoms and signs via multi organ arterial system involvement, in patients of any age, demonstrating predominant anaphylaxis features in terms of a wide spectrum of mast cell-association disorders. Cardiac symptoms as chest pain, coronary vasospasm, angina pectoris, myocardial infarction, stent thrombosis, acute cardiac failure, and sudden cardiac death, associated with subclinical, clinical, acute or chronic allergic reactions constitute clinical manifestations of this syndrome. Since its first description, a common pathway between allergic and non allergic coronary events has been demonstrated. The hypothesis is based on the existence of a much higher mast cell degranulation degree at the sites of plaque erosion or rupture compared to adjacent areas or even to more distant segments in post acute myocardial infarction of non allergic etiology patients. Mast cell activation, differentiation and mediator release takes days or weeks, therefore mast cell degranulation could be performed just before any acute coronary event, further resulting in coronary artery vasoconstriction and atheromatous plaque rupture. It seems that medications and natural molecules stabilizing mast cell membrane as well as monoclonal antibodies by protecting mast cell surface could emerge as novel therapeutic modalities for acute coronary and cerebrovascular event prevention.

A concept elicitation, cognitive debriefing, and usability study was undertaken to: 1) ascertain the migraine experience with a particular focus on the impact on roles and daily functioning; 2) determine the comprehensiveness and comprehensibility of the Migraine-Specific Quality of Life Questionnaire version 2.1 electronic patient-reported outcome Role Function-Restrictive (MSQ v2.1 ePRO RFR) domain items, and the appropriateness and understanding of the recall period, response options, and instructions; and 3) assess the usability on an electronic tablet device.

Blind epidural catheter placement can lead to inadvertent misplacement. We present a case of intercostal misplacement of a thoracic epidural catheter.

Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive autoinflammatory condition. Recognised features include vasculitis predominantly affecting medium sized vessels, livedoid skin rash, central and peripheral nervous system involvement, variable degrees of immunodeficiency, and marrow failure, amongst other clinical presentations. We present the case of a six year old male with DADA2 who presented with acute testicular ischaemia secondary to vasculitis, the first such description in DADA2.

Improvement of pain management strategies after arthroscopic surgery by multimodal analgesia may include the use of long-acting amide local anesthetics. Among these anesthetics, the low molecular weight local anesthetic agent bupivacaine (BUP) is attractive for use in postoperative pain management. However, it has a relatively short duration of action and imposes a higher risk of systemic toxicity at relatively large bolus doses. Bupivacaine encapsulation in lipid-based delivery systems is an attractive strategy for prolonging its local anaesthetic effect and reducing the associated undesirable systemic side effects. Here, we discuss the potential development of liquid crystalline nanocarriers for delivering BUP by using a binary lipid mixture of citrem and soy phosphatidylcholine (SPC) at different weight ratios. The produced safe-by-design family of citrem/SPC nanoparticles is attractive for use in the development of nanocarriers owing to the previously reported hemocompatibility. BUP encapsulation efficiency (EE), depending on the lipid composition, was in the range of 65-77%. In this study, nanoparticle tracking analysis (NTA) and synchrotron small-angle X-ray scattering (SAXS) were employed to gain insight into the effect of BUP solubilization and lipid composition on the size and structural characteristics of the produced citrem/SPC nanodispersions. BUP loading led to a slight change in the mean sizes (diameters) and size distributions of citrem/SPC nanoparticles. However, we found that BUP accommodation into the self-assembled interiors of nanoparticles, triggers significant structural alterations in BUP concentration- and lipid composition-dependent manners, which involve vesicle-cubosome and vesicle-hexosome transitions. The structural tunability of citrem/SPC nanoparticles and the implications for potential applications in intra-articular BUP delivery are discussed.

We report an unusual case of a dural arteriovenous fistula (dAVF) presenting as acute neck pain and quadripareis in a 55-year-old previously healthy man. Imaging was suspicious for cervicomedullary venous thrombosis and angiography failed to show evidence of arteriovenous malformation or dAVF. The patient was started on warfarin for a presumed cervicomedullary venous thrombosis and there was a significant clinical improvement. However, 3 weeks later, the symptoms recurred and repeat angiography revealed a dAVF fed by a posterior branch of the left middle meningeal artery draining into the posterior fossa vein. We postulated that warfarin caused recanalisation of the previously thrombosed venous pouch allowing for angiographic discovery and treatment of the dAVF. The dAVF was embolised with onyx resulting in the complete obliteration of the dAVF and symptomatic improvement. Although rare, some dAVF can be concealed or disappear on angiography due to thrombosis of the draining vein and warfarin can lead to recanalisation.

Brucellosis epididymo-orchitis (BEO) is extremely rare in non-endemic areas such as Australia. While epididymo-orchitis is relatively common in adolescent men, when presented with a significant travel history, consideration should be given to rare causes such as this. Here, we present a case of BEO in a young 18-year-old man who recently migrated from Greece, with symptoms of acute scrotal pain, swelling and persistent fever. was isolated in the blood culture and confirmed with PCR. We suspect transmission was related to ingestion of unpasteurised goat dairy products. He made a full recovery after 7 days of intravenous gentamicin and 6 weeks of oral doxycycline. BEO should be considered in those who present with acute scrotal pain and fever after a recent history of travel to or from a brucellosis- endemic area.

Pelvic fragility fractures (PFF) are common in older people and associated with a significant burden of mortality and morbidity. This is related to the challenges of appropriate pain control and early mobilisation. The current standard for treatment of PFF is non-surgical management. Minimally invasive surgical techniques for sacral fracture stabilisation have been shown to improve outcomes in terms of pain control and mobility, and they are safe. Randomised controlled trials are required before recommendations can be made for surgical management of PFF to become the new standard of care. This feasibility study will explore several uncertainties around conducting such a trial.

Autophagy is a physiological process that helps maintain a balance between the manufacture of cellular components and breakdown of damaged organelles and other toxic cellular constituents. Changes in autophagic markers are readily detectable in the spinal cord and brain following neurotrauma, including traumatic spinal cord and brain injury (SCI/TBI). However, the role of autophagy in neurotrauma remains less clear. Whether autophagy is good or bad is under debate, with strong support for both a beneficial and detrimental role for autophagy in experimental models of neurotrauma. Emerging data suggest that autophagic flux, a measure of autophagic degradation activity, is impaired in injured central nervous systems (CNS), and interventions that stimulate autophagic flux may provide neuroprotection in SCI/TBI models. Recent data demonstrating that neurotrauma can cause lysosomal membrane damage resulting in pathological autophagosome accumulation in the spinal cord and brain further supports the idea that the impairment of the autophagy-lysosome pathway may be a part of secondary injury processes of SCI/TBI. Here, we review experimental work on the complex and varied responses of autophagy in terms of both the beneficial and detrimental effects in SCI and TBI models. We also discuss the existing and developing therapeutic options aimed at reducing the disruption of autophagy to protect the CNS after injuries.