Structural identification of oxidized acyl-phosphatidylcholines that induce platelet activation

Oxidation of low-density lipoprotein (LDL) generates proinflammatory and prothrombotic mediators that may play a crucial role in cardiovascular and inflammatory diseases. In order to study platelet-activating components of oxidized LDL 1-stearoyl-2-arachidonoyl-sn-glycero-3- phosphocholine, a representative of the major phospholipid species in LDL, the 1-acyl-phosphatidylcholines (PC), was oxidized by CuCl2 and H2O2. After separation by high-performance liquid chromatography, three compounds were detected which induced platelet shape change at low micromolar concentrations. Platelet activation by these compounds was distinct from the pathways stimulated by platelet-activating factor, lysophosphatidic acid, lyso-PC and thromboxane A(2), as evidenced by the use of specific receptor antagonists. Further analyses of the oxidized phospholipids by electrospray ionization mass spectrometry structurally identified them as 1-stearoyl-2-azelaoyl-sn-glycero-3-phosphocholine (m/z 694; SAzPC), 1-stearoyl-2-glutaroyl-snglycero-3- phosphocholine (m/z 638; SGPC), and 1-stearoyl-2-( 5-oxovaleroyl)-sn-glycero-3-phosphocholine (m/z 622; SOVPC). These observations demonstrate that novel 1-acyl-PC which had previously been found to stimulate interaction of monocytes with endothelial cells also induce platelet activation, a central step in acute thrombogenic and atherogenic processes. Copyright (C) 2005 S. Karger AG, Basel

A Standardised Procedure for Evaluating Creative Systems: Computational Creativity Evaluation Based on What it is to be Creative

Computational creativity is a flourishing research area, with a variety of creative systems being produced and developed. Creativity evaluation has not kept pace with system development with an evident lack of systematic evaluation of the creativity of these systems in the literature. This is partially due to difficulties in defining what it means for a computer to be creative; indeed, there is no consensus on this for human creativity, let alone its computational equivalent. This paper proposes a Standardised Procedure for Evaluating Creative Systems (SPECS). SPECS is a three-step process: stating what it means for a particular computational system to be creative, deriving and performing tests based on these statements. To assist this process, the paper offers a collection of key components of creativity, identified empirically from discussions of human and computational creativity. Using this approach, the SPECS methodology is demonstrated through a comparative case study evaluating computational creativity systems that improvise music

Surgical Management of Inguinal Hernias at Bugando Medical Centre in Northwestern Tanzania: Our Experiences in a Resource-Limited Setting.

Inguinal hernia repair remains the commonest operation performed by general surgeons all over the world. There is paucity of published data on surgical management of inguinal hernias in our environment. This study is intended to describe our own experiences in the surgical management of inguinal hernias and compare our results with that reported in literature. A descriptive prospective study was conducted at Bugando Medical Centre in northwestern Tanzania. Ethical approval to conduct the study was obtained from relevant authorities before the commencement of the study. Statistical data analysis was done using SPSS software version 17.0. A total of 452 patients with inguinal hernias were enrolled in the study. The median age of patients was 36 years (range 3 months to 78 years). Males outnumbered females by a ratio of 36.7:1. This gender deference was statistically significant (P=0.003). Most patients (44.7%) presented late (more than five years of onset of hernia). Inguinoscrotal hernia (66.8%) was the commonest presentation. At presentation, 208 (46.0%) patients had reducible hernia, 110 (24.3%) had irreducible hernia, 84 (18.6%) and 50(11.1%) patients had obstructed and strangulated hernias respectively. The majority of patients (53.1%) had right sided inguinal hernia with a right-to-left ratio of 2.1: 1. Ninety-two (20.4%) patients had bilateral inguinal hernias. 296 (65.5%) patients had indirect hernia, 102 (22.6%) had direct hernia and 54 (11.9%) had both indirect and direct types (pantaloon hernia). All patients in this study underwent open herniorrhaphy. The majority of patients (61.5%) underwent elective herniorrhaphy under spinal anaesthesia (69.2%). Local anaesthesia was used in only 1.1% of cases. Bowel resection was required in 15.9% of patients. Modified Bassini's repair (79.9%) was the most common technique of posterior wall repair of the inguinal canal. Lichtenstein mesh repair was used in only one (0.2%) patient. Complication rate was 12.4% and it was significantly higher in emergency herniorrhaphy than in elective herniorrhaphy (P=0.002). The median length of hospital stay was 8 days and it was significantly longer in patients with advanced age, delayed admission, concomitant medical illness, high ASA class, the need for bowel resection and in those with surgical repair performed under general anesthesia (P<0.001). Mortality rate was 9.7%. Longer duration of symptoms, late hospitalization, coexisting disease, high ASA class, delayed operation, the need for bowel resection and presence of complications were found to be predictors of mortality (P<0.001). Inguinal hernias continue to be a source of morbidity and mortality in our centre. Early presentation and elective repair of inguinal hernias is pivotal in order to eliminate the morbidity and mortality associated with this very common problem

Sexual Abuse-Current Medico-legal, Forensic and Psychiatric Aspects

Abstract Violence against women and minors is a worldwide problem that has not yet been sufficiently acknowledged. There are many obstacles especially when sexual abuses have to be evaluated. These problems are present both when victims of sexual abuse are evaluated and when sex offenders are dealt with, especially when the offenders are juvenile sex offenders (JSO). These issues give cause for great concern about prognosis, and the resulting psychosocial implications, and call for a special effort from the scientific community in identifying appropriate prevention and treatment methods. This chapter is divided into two parts. The first part deals with the forensic and psychiatric features, such as diagnostic and therapeutic/rehabilitative strategies for JSO, while the second part analyzes the legal–medicine aspects related to rape/sexual assault in a European context

Bilateral Dorsal Cochlear Nucleus Lesions Prevent Acoustic-Trauma Induced Tinnitus in an Animal Model

Animal experiments suggest that chronic tinnitus (“ringing in the ears”) may result from processes that overcompensate for lost afferent input. Abnormally elevated spontaneous neural activity has been found in the dorsal cochlear nucleus (DCN) of animals with psychophysical evidence of tinnitus. However, it has also been reported that DCN ablation fails to reduce established tinnitus. Since other auditory areas have been implicated in tinnitus, the role of the DCN is unresolved. The apparently conflicting electrophysiological and lesion data can be reconciled if the DCN serves as a necessary trigger zone rather than a chronic generator of tinnitus. The present experiment used lesion procedures identical to those that failed to decrease pre-existing tinnitus. The exception was that lesions were done prior to tinnitus induction. Young adult rats were trained and tested using a psychophysical procedure shown to detect tinnitus. Tinnitus was induced by a single unilateral high-level noise exposure. Consistent with the trigger hypothesis, bilateral dorsal DCN lesions made before high-level noise exposure prevented the development of tinnitus. A protective effect stemming from disruption of the afferent pathway could not explain the outcome because unilateral lesions ipsilateral to the noise exposure did not prevent tinnitus and unilateral lesions contralateral to the noise exposure actually exacerbated the tinnitus. The DCN trigger mechanism may involve plastic circuits that, through loss of inhibition, or upregulation of excitation, increase spontaneous neural output to rostral areas such as the inferior colliculus. The increased drive could produce persistent pathological changes in the rostral areas, such as high-frequency bursting and decreased interspike variance, that comprise the chronic tinnitus signal

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study

INTRODUCTION: We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. METHODS: In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to--or had contraindications for--non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). RESULTS: At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P &lt; 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. CONCLUSIONS: Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. TRIAL REGISTRATION: clinicaltrials.gov: NCT00798369

Disruption of Nrf2, a Key Inducer of Antioxidant Defenses, Attenuates ApoE-Mediated Atherosclerosis in Mice

Background: Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Nrf2 is a redox-sensitive transcription factor that upregulates a battery of antioxidative genes and cytoprotective enzymes that constitute the cellular response to oxidative stress. Our previous studies have shown that disruption of Nrf2 in mice (Nrf2-/-) causes increased susceptibility to pulmonary emphysema, asthma and sepsis due to increased oxidative stress and inflammation. Here we have tested the hypothesis that disruption of Nrf2 in mice causes increased atherosclerosis. Principal Findings: To investigate the role of Nrf2 in the development of atherosclerosis, we crossed Nrf2-/- mice with apoliporotein E-deficient (ApoE-/- mice. ApoE-/- and ApoE-/- Nrf2-/- mice were fed an atherogenic diet for 20 weeks, and plaque area was assessed in the aortas. Surprisingly, ApoE-/- Nrf2-/- mice exhibited significantly smaller plaque area than ApoE-/- controls (11.5% vs 29.5%). This decrease in plaque area observed in ApoE-/- Nrf2-/- mice was associated with a significant decrease in uptake of modified low density lipoproteins (AcLDL) by isolated macrophages from ApoE-/- Nrf2-/- mice. Furthermore, atherosclerotic plaques and isolated macrophages from ApoE-/- Nrf2-/- mice exhibited decreased expression of the scavenger receptor CD36. Conclusions: Nrf2 is pro-atherogenic in mice, despite its antioxidative function. The net pro-atherogenic effect of Nrf2 may be mediated via positive regulation of CD36. Our data demonstrates that the potential effects of Nrf2-targeted therapies on cardiovascular disease need to be investigated.9 page(s

Exploiting unexpected situations in the mathematics classroom

The professional development of mathematics teachers needs to support teachers in orchestrating the mathematics classroom in ways that enable them to respond flexibly and productively to the unexpected. When a situation arises in the classroom which is not connected in an obvious way to the mathematical learning intentions of the lesson, it can be challenging for the teacher to improvise so as to craft this situation into an opportunity for doing and learning mathematics. In this study, as teacher-researcher I maintained a record of unexpected situations as they arose in my own secondary mathematics classroom. Details are given of four unexpected situations which I found ways to exploit mathematically, and these are analysed to highlight factors which may enhance a mathematics teacher’s preparedness for dealing with the unexpected. The results of this study indicate that deviating from the intended lesson to exploit an unexpected situation in which students have shown some interest can lead them into enjoyable and worthwhile mathematical engagement

Ethical Considerations in Crowdfunding

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A Role for VEGFR2 Activation in Endothelial Responses Caused by Barrier Disruptive OxPAPC Concentrations

Introduction: Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) differentially modulate endothelial cell (EC) barrier function in a dose-dependent fashion. Vascular endothelial growth factor receptor-2 (VEGFR2) is involved in the OxPAPC-induced EC inflammatory activation. This study examined a role of VEGFR2 in barrier dysfunction caused by high concentrations of OxPAPC and evaluated downstream signaling mechanisms resulting from the effect of OxPAPC in EC from pulmonary and systemic circulation