Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Elevated intracranial pressure and cerebral edema following permanent MCA occlusion in an ovine model

INTRODUCTION: Malignant middle cerebral artery (MCA) stroke has a disproportionately high mortality due to the rapid development of refractory space-occupying cerebral edema. Animal models are essential in developing successful anti-edema therapies; however to date poor clinical translation has been associated with the predominately used rodent models. As such, large animal gyrencephalic models of stroke are urgently needed. The aim of the study was to characterize the intracranial pressure (ICP) response to MCA occlusion in our recently developed ovine stroke model. MATERIALS AND METHODS: 30 adult female Merino sheep (n = 8-12/gp) were randomized to sham surgery, temporary or permanent proximal MCA occlusion. ICP and brain tissue oxygen were monitored for 24 hours under general anesthesia. MRI, infarct volume with triphenyltetrazolium chloride (TTC) staining and histology were performed. RESULTS: No increase in ICP, radiological evidence of ischemia within the MCA territory but without space-occupying edema, and TTC infarct volumes of 7.9+/-5.1% were seen with temporary MCAO. Permanent MCAO resulted in significantly elevated ICP, accompanied by 30% mortality, radiological evidence of space-occupying cerebral edema and TTC infarct volumes of 27.4+/-6.4%. CONCLUSIONS: Permanent proximal MCAO in the sheep results in space-occupying cerebral edema, raised ICP and mortality similar to human malignant MCA stroke. This animal model may prove useful for pre-clinical testing of anti-edema therapies that have shown promise in rodent studies.Adam J. Wells, Robert Vink, Stephen C. Helps, Steven J. Knox, Peter C. Blumbergs, Renée J. Turne

The prevalence of rimmed vacuoles in biopsy-proven dermatomyositis

Vidya S. Limaye, Peter Blumberg

Idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies are a group of systemic autoimmune syndromes characterized by striated muscle inflammation. Here, we discuss the clinical features of this group of conditions and review the recent developments in the understanding of the pathogenesis and immunogenetics of the idiopathic inflammatory myopathies. The role of myositis-specific autoantibodies and their clinical significance and an overview of management are also provided.V. S. Limaye, P. Blumbergs and P. J. Roberts-Thomso

Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus

AimsThe long-terms complications of immunosuppressive and anti-inflammatory treatment in idiopathic inflammatory myositis (IIM) are unknown. We sought to determine the complications of these treatments in a large cohort of patients with biopsy-proven IIM.MethodsA South Australian database for patients with biopsy-proven IIM was established. Clinical details of patients including treatment received were recorded.ResultsForty-three patients with dermatomyositis (DM), 184 with polymyositis (PM) and 117 with inclusion body myositis (IBM) were registered on the database. The prevalence of hypertension and diabetes in this population was 62% and 29%, respectively, considerably higher than the background prevalence of 9.4% and 4%, making detection of treatment-related adverse effects difficult. Hypertension and ischemic heart disease were more likely to be present prior to the diagnosis of IIM rather than following it. Hypertension and diabetes occurred more frequently following the diagnosis of myositis, in patients with DM compared with PM or IBM.ConclusionsWe report a novel association of IIM with hypertension, diabetes and ischemic heart disease, indicating that a comprehensive assessment of vascular risk factors is essential in IIM.Vidya S. Limaye, Sue Lester, Peter Blumbergs and Peter J. Roberts-Thomso

Inflammatory myopathy with anti-SRP antibodies: case series of a South Australian cohort

Myopathy associated with anti-signal recognition particle (SRP) antibodies is a rare form of myopathy, which is thought to be distinct from classic polymyositis.We sought to determine the demographic, clinical and histopathological features of patients with anti-SRP antibodies. Hence we undertook an audit of patients with histologically-confirmed myositis who had anti-SRP antibodies. Of 144 patients with inflammatory myositis tested for myositis-specific and myositis-associated antibodies between 2007 and 2011 inclusive, five with anti-SRP antibodies were identified. All five were male, four had severe proximal weakness, one was asymptomatic and three had dysphagia. None had cardiovascular involvement. All patients showed isolated anti-SRP positivity and absence of antinuclear antibodies. Muscle histopathology showed variable myofibre necrosis, and most had an inflammatory infiltrate. Majority showed a favorable response to combination immunosuppressive therapy. Myopathy associated with anti-SRP antibodies is clinically heterogeneous in presentation. Muscle histopathology shows a mixture of necrotic and inflammatory features.Sajini K Basnayake, Peter Blumbergs, Ju Ann Tan, Peter J Roberts-Thompson, Vidya Limay

Experimental Characterization of the Properties of Double-Lap Needled and Hybrid Joints of Carbon/Epoxy Composites

The effect of through-thickness reinforcement by thin 1 mm steel needles (z-pins) on the static tensile strength of double-lap joints of a carbon/epoxy composite was investigated. Two types of joints—z-pinned and hybrid (including glued ones)—were considered. The joints were reinforced in the overlap region with 9, 25, or 36 z-pins. Comparing mechanical properties of the double-lap joints with the corresponding characteristics of their unpinned counterparts, the z-pins were found to be highly effective: the strength and stiffness of the pinned joints increased up to 300% and 280%, respectively. These improvements were due to a transition in the failure mechanism from debonding of the joint in the absence of z-pins to pullout or shear rupture of z-pins or to the tensile failure of laminate adherends, depending on the volume content of the pins

Model experiments using slag during CdO recovery

A new method of production of cadmium from shredded cadmium-containing batteries using electroslag remelting was proposed, investigated theoretically and experimentally. The reduction of cadmium from cadmium oxide with carbon occurs in electroslag remelting equipment in a liquid slag bath. The resulting molten cadmium is collected in a crucible under a layer of molten flux. The intensity of the reduction process is affected by the liquid flux movement. This movement is caused by thermal convection and also by the electrical current interacting with the magnetic field. The work explores the possibility of intensifying the process using the external magnetic field. Magnetic fields are induced by different configurations of permanent magnet systems located outside the bath

Mortality and its predominant causes in a large cohort of patients with biopsy-determined inflammatory myositis

BACKGROUND: There is a paucity of literature on the patterns and predictors of mortality in idiopathic inflammatory myopathies (IIM). AIMS: To determine the patterns and predictors of mortality in a South Australian cohort of patients with biopsy-proven IIM. METHODS: The living/ deceased status (and for deceased patients the causes of death) of patients with histologically-determined IIM was determined from the Births, Deaths and Marriages Registry. Standardized mortality ratios (SMR) were generated compared with the age/gender matched South Australian population. The effect of presence/ absence of the components of the Bohan and Peter criteria on risk ratios (RR) for mortality were determined. The effect of comorbidities and autoantibodies on mortality were investigated. RESULTS: The SMR for mortality in IIM was 1.75 and was significantly increased in all disease subgroups, being highest in patients with dermatomyositis (2.40). Dominant causes of death were cardiovascular disease (31%), infections (22%) and malignancy (11%). Risk factors for death were age at time of biopsy (hazard ratio 1.05), ischemic heart disease (RR 2.97, p < 0.0001), proximal weakness at diagnosis (RR 1.8, p = 0.03), definite diagnosis of IIM per the Bohan and Peter criteria (RR 2.14, p < 0.0001), and the absence of autoantibodies (Risk ratio 1.9, p < 0.001). CONCLUSIONS: Patients with IIM are at 75% increased risk for mortality, and cardiovascular diseases account for the commonest causes of death. This study suggests a thorough cardiovascular evaluation of these patients is indicated, and raises the possibility that targeted interventions such as the use of aspirin or statins may improve outcomes in IIM.Vidya Limaye, Paul Hakendorf, Richard J. Woodman, Peter Blumbergs and Peter Roberts-Thomso