Clinical, Imaging and Neurogenetic Features of Patients with Gliomatosis Cerebri Referred to a Tertiary Neuro-Oncology Centre

Introduction: Gliomatosis cerebri describes a rare growth pattern of diffusely infiltrating glioma. The treatment options are limited and clinical outcomes remain poor. To characterise this population of patients, we examined referrals to a specialist brain tumour centre. Methods: We analysed demographic data, presenting symptoms, imaging, histology and genetics, and survival in individuals referred to a multidisciplinary team meeting over a 10-year period. Results: In total, 29 patients fulfilled the inclusion criteria with a median age of 64 years. The most common presenting symptoms were neuropsychiatric (31%), seizure (24%) or headache (21%). Of 20 patients with molecular data, 15 had IDH wild-type glioblastoma, with an IDH1 mutation most common in the remainder (5/20). The median length of survival from MDT referral to death was 48 weeks (IQR 23 to 70 weeks). Contrast enhancement patterns varied between and within tumours. In eight patients who had DSC perfusion studies, five (63%) had a measurable region of increased tumour perfusion with rCBV values ranging from 2.8 to 5.7. A minority of patients underwent MR spectroscopy with 2/3 (66.6%) false-negative results. Conclusions: Gliomatosis imaging, histological and genetic findings are heterogeneous. Advanced imaging, including MR perfusion, could identify biopsy targets. Negative MR spectroscopy does not exclude the diagnosis of glioma

Thalamic inputs to dorsomedial striatum are involved in inhibitory control: evidence from the five-choice serial reaction time task in rats

Rationale Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues. Objectives Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats. Methods The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 μl bilateral; 3 μM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively. Results We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field. Conclusions These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control

Rates of referable eye disease in the Scottish National Diabetic Retinopathy Screening Programme

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.Peer reviewedPublisher PD

Oligodendroglia Are Particularly Vulnerable to Oxidative Damage After Neurotrauma In Vivo.

In the paper "Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo," we determined the extent of oxidative damage to specific cellular subpopulations and structures within regions vulnerable to secondary degeneration and assessed the effect this had on oligodendroglial function. Comparative assessment of oxidative damage demonstrated selective vulnerability of oligodendroglia, specifically oligodendrocyte progenitor cells (OPCs) to DNA oxidation in vivo. Immunohistochemical fate mapping along the oligodendroglial lineage showed a transient susceptibility of these cells to DNA oxidation, protein nitration, and lipid peroxidation, with mature oligodendrocytes derived immediately after injury more vulnerable to DNA oxidation than their counterparts existing at the time of injury or later derived. In situ hybridization demonstrated a reduction in myelin regulatory factor (MyRF) messenger RNA (mRNA) fluorescence in newly derived mature oligodendrocytes, suggesting a compromise in the production and maintenance of the myelin sheath in these cells. The data imply a deficit in the normal differentiation of OPCs to myelinating oligodendrocytes, associated with a transient increase in oxidative damage, which may contribute to the dysmyelinating phenotype seen at chronic time points after injury. Identifying and understanding the sources of this oxidative damage is integral for the development of therapeutic interventions for neurotrauma

From ‘shallow’ to ‘deep’ policing:‘crash-for-cash’ insurance fraud investigation in England and Wales and the need for greater regulation

The policing of insurance fraud has traditionally been dealt with beyond the criminal justice system as a private matter between the claimant and the insurer with only a few iconic cases referred to the criminal justice system each year. The growth of insurance fraud, particularly ‘crash-for-cash’ fraud, and the disinterest of the police, has led to a change in the response of the insurance industry. This paper will argue that this response can be characterised as a shift from the traditional ‘shallow’ to a ‘deeper’ form of policing which sees greater focus upon criminal and quasi-criminal outcomes. This paper explores some of the private and innovative methods the industry has developed and illustrates what greater private criminal investigation might look like at a time when police privatisation has become a higher profile issue. The paper argues the shift to ‘deeper’ policing necessitates greater regulation of the private investigation of crime and outlines a number of proposals to address this gap which require further consideration and debate

Impairment of macroautophagy in dopamine neurons has opposing effects on Parkinsonian pathology and behavior

Parkinson’s disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta (SNc) and accumulation of α-synuclein. Impaired autophagy has been implicated and activation of autophagy proposed as a treatment strategy. We generate a human α-synuclein-expressing mouse model of PD with macroautophagic failure in dopamine neurons to understand the interaction between impaired macroautophagy and α-synuclein. We find that impaired macroautophagy generates p62-positive inclusions and progressive neuron loss in the SNc. Despite this parkinsonian pathology, motor phenotypes accompanying human α-synuclein overexpression actually improve with impaired macroautophagy. Real-time fast-scan cyclic voltammetry reveals that macroautophagy impairment in dopamine neurons increases evoked extracellular concentrations of dopamine, reduces dopamine uptake, and relieves paired-stimulus depression. Our findings show that impaired macroautophagy paradoxically enhances dopamine neurotransmission, improving movement while worsening pathology, suggesting that changes to dopamine synapse function compensate for and conceal the underlying PD pathogenesis, with implications for therapies that target autophagy

Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma

Background: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca 2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca 2+ channel inhibitor Lomerizine (Lom), the Ca 2+ permeable AMPA receptor inhibitor YM872 and the P2X 7 receptor inhibitor oxATP. Results: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. Conclusions: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs

Mycobacterium ulcerans disease: experience with primary oral medical therapy in an Australian cohort

Mycobacterium ulcerans (MU) is responsible for disfiguring skin infections which are challenging to treat. The recommended treatment for MU has continued to evolve from surgery to remove all involved tissue, to the use of effective combination oral antibiotics with surgery as required. Our study describes the oral medical treatment utilised for consecutive cases of MU infection over a 15 month period at our institution, in Victoria, Australia. Managing patients primarily with oral antibiotics results in high cure rates and excellent cosmetic outcomes. The success with medical treatment reported in this study will aid those treating cases of MU infection, and will add to the growing body of knowledge about the relative roles of antibiotics and surgery for treating this infection

Outcomes of selective nonoperative management of civilian abdominal gunshot wounds: a systematic review and meta-analysis

Abstract Background Although mandatory laparotomy has been standard of care for patients with abdominal gunshot wounds (GSWs) for decades, this approach is associated with non-therapeutic operations, morbidity, and long hospital stays. This systematic review and meta-analysis sought to summarize outcomes of selective nonoperative management (SNOM) of civilian abdominal GSWs. Methods We searched electronic databases (March 1966–April 1, 2017) and reference lists of articles included in the systematic review for studies reporting outcomes of SNOM of civilian abdominal GSWs. We meta-analyzed the associated risks of SNOM-related failure (defined as laparotomy during hospital admission), mortality, and morbidity across included studies using DerSimonian and Laird random-effects models. Between-study heterogeneity was assessed by calculating I2 statistics and conducting tests of homogeneity. Results Of 7155 citations identified, we included 41 studies [n = 22,847 patients with abdominal GSWs, of whom 6777 (29.7%) underwent SNOM]. The pooled risk of failure of SNOM in hemodynamically stable patients without a reduced level of consciousness or signs of peritonitis was 7.0% [95% confidence interval (CI) = 3.9–10.1%; I2 = 92.6%, homogeneity p  0.99). In patients who failed SNOM, the pooled estimate of the risk of therapeutic laparotomy was 68.0% (95% CI = 58.3–77.7%; I2 = 91.5%; homogeneity p < 0.001). Risks of failure of SNOM were lowest in studies that evaluated patients with right thoracoabdomen (3.4%; 95% CI = 0–7.0%; I2 = 0%; homogeneity p = 0.45), flank (7.0%; 95% CI = 3.9–10.1%), and back (3.1%; 95% CI = 0–6.5%) GSWs and highest in those that evaluated patients with anterior abdomen (13.2%; 95% CI = 6.3–20.1%) GSWs. In patients who underwent mandatory abdominopelvic computed tomography (CT), the pooled risk of failure was 4.1% versus 8.3% in those who underwent selective CT (p = 0.08). The overall sample-size-weighted mean hospital length of stay among patients who underwent SNOM was 6 days versus 10 days if they failed SNOM or developed an in-hospital complication. Conclusions SNOM of abdominal GSWs is safe when conducted in hemodynamically stable patients without a reduced level of consciousness or signs of peritonitis. Failure of SNOM may be lower in patients with GSWs to the back, flank, or right thoracoabdomen and be decreased by mandatory use of abdominopelvic CT scans