Explore the vast range of titles available.

Using cortical neuronal cultures and glutamic acid excitotoxicity and oxygen-glucose deprivation (OGD) stroke models, we demonstrated that poly-arginine and arginine-rich cell-penetrating peptides (CPPs), are highly neuroprotective, with efficacy increasing with increasing arginine content, have the capacity to reduce glutamic acid-induced neuronal calcium influx and require heparan sulfate preotoglycan-mediated endocytosis to induce a neuroprotective effect. Furthermore, neuroprotection could be induced with immediate peptide treatment or treatment up to 2 to 4 hours before glutamic acid excitotoxicity or OGD, and with poly-arginine-9 (R9) when administered intravenously after stroke onset in a rat model. In contrast, the JNKI-1 peptide when fused to the (non-arginine) kFGF CPP, which does not rely on endocytosis for uptake, was not neuroprotective in the glutamic acid model; the kFGF peptide was also ineffective. Similarly, positively charged poly-lysine-10 (K10) and R9 fused to the negatively charged poly-glutamic acid-9 (E9) peptide (R9/E9) displayed minimal neuroprotection after excitotoxicity. These results indicate that peptide positive charge and arginine residues are critical for neuroprotection, and have led us to hypothesize that peptide-induced endocytic internalization of ion channels is a potential mechanism of action. The findings also question the mode of action of different neuroprotective peptides fused to arginine-rich CPPs.

Cationic arginine-rich peptides represent a novel class of peptides being developed as neuroprotective agents for stroke and other acute and chronic neurological disorders. As a group, cationic arginine-rich peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds. At present, while many neuroprotective cationic arginine-rich peptides have been examined in preclinical animal neuroprotection studies, few have been assessed in human safety studies. Despite this, the safety of the prototypical cationic arginine-rich peptide, protamine, which has been in clinical use for over 70 years to reverse the anticoagulant effects of heparin and as an excipient in certain insulin preparations, is well established. In addition, the poly-arginine peptide R9 (ALX40-4C) was developed as an anti-human inmmunodeficiency virus therapeutic in the mid-1990s, and more recently, the neuroprotective cationic arginine-rich peptides TAT-NR2B9c (NA-1), CN-105 and RD2 are being evaluated for the treatment of ischaemic stroke, haemorrhagic stroke and Alzheimer’s disease, respectively. Based on the available clinical data, cationic arginine-rich peptides as a group appear to be safe when administered at therapeutic doses by a slow intravenous infusion. While protamine, owing to its isolation from salmon milt and homology with human sperm protamine, can trigger anaphylactic and anaphylactoid reactions in a small proportion of patients previously exposed to the peptide (e.g. diabetic patients), who are allergic to fish or have undergone a vasectomy, such reactions are unlikely to be triggered in individuals exposed to non-protamine cationic arginine-rich peptides.

INTRODUCTION:Capsule endoscopy (CE) is indicated in the evaluation of suspected Crohn's disease (CD) when ileocolonoscopy and radiographic studies are negative or inconclusive. However, it should be recognized that mucosal breaks or ulcers alone are not always diagnostic of CD.CASE DESCRIPTION/METHODS:A 55 year-old man from India who immigrated to the US as a child was admitted to an outside hospital with 6 months of bilateral lower quadrant abdominal pain and iron-deficiency anemia. After normal upper endoscopy and colonoscopy, CE showed an ulcer and inflamed mucosa in the ileum. On this basis he was diagnosed with CD and treated with prednisone. The next month he was admitted to our institution with ongoing abdominal pain and unintentional weight loss but no diarrhea or hematochezia. On exam his vital signs and body mass index were normal. His abdomen was soft without organomegaly or palpable mass. He was tender to palpation in the bilateral lower quadrants. Stool was brown. Laboratory results were Hgb 8.3 g/dL, iron studies consistent with iron-deficiency, albumin 2.8 g/dL, C-reactive protein 150 mg/L, and erythrocyte sedimentation rate 45 mm/hr. CT enterography showed wall thickening of the mid-ileum with mucosal enhancement and mesenteric root adenopathy. Retrograde double balloon enteroscopy 90 cm into the ileum revealed a 15 mm shallow ulcer 80 cm proximal to the ileocecal (IC) valve and a similar ulcer 15 cm proximal to the IC valve. Biopsies showed ulcerated mucosa with infiltrating atypical cells that stained positive for ERG, a highly specific endothelial marker, and negative for other immunostains, leading to a diagnosis of primary intestinal angiosarcoma.DISCUSSION:Primary intestinal angiosarcoma is a rare soft tissue sarcoma that may present with abdominal pain, GI bleeding, obstruction, or weight loss. Tumors, detected on 2-4% of CEs, are in the differential diagnosis for small bowel CD along with infection, ischemia, vasculitis, lymphoma, Behcet disease, radiation enteritis, and drug-induced enteritis. In suspected CD, there is no reference standard or uniform criteria for diagnosis by CE. And, many of the lesions that lead to a diagnosis of CD are non-specific with the specificity of CE for CD as low as 53% and the positive predictive value <60% in some studies. Thus, findings of CE should be interpreted with an adequate degree of skepticism and a broad differential diagnosis considered to minimize mimics being mistaken for CD.

The perceived threat of 'transnational organized crime' to Western societies has been of huge interest to politicians, policy makers and social scientists over the last decade. This book considers the origins of this crime, how it has been defined and measured and the appropriateness of governments' policy responses. The contributors argue that while serious harm is often caused by transnational criminal activity - for example, the trafficking in human beings - the construction of that criminal activity as an external threat obscures the origins of these crimes in the markets for illicit goods and services within the 'threatened' societies. As such, the authors question the extent to which global crime can be controlled through law enforcement initiatives, and alternative policy initiatives are considered. The authors also question whether transnational organised crime will retain its place on the policy agendas of the United Nations and European Union in the wake of the 'War on Terror'. Part 1: Origins of the Concept Part 2: Measurements and Interpretations Part 3: Case Studies Part 4: Current and Prospective Responses Adam Edwards is Senior Lecturer in the Department of Social Sciences at Nottingham Trent University. Peter Gill is Reader in Politics and Security at the School of Social Science, Liverpool John Moores University. 'A significant contribution in the field of criminology.' - Global Crime

Aims: There are high rates of Neurodevelopmental Disorders (NDD) and mental health needs in young people who engage in offending behaviours. Incompletely assessed development can be a factor in engaging with legal proceedings and with those involved in their care. Young people open to the three Gwent Youth Offending Services (YOS) and Tier 3 Gwent Forensic Child & Adolescent Mental Health Service (FCAMHS) have previously been identified as having traits indicative of an underlying NDD. No specific ND assessment pathways exist within YOS for suspected Autism Spectrum Disorder (ASD) and/or Attention Deficit Hyperactivity Disorder (ADHD); those requiring assessment are referred to the CAMHS ND Team. Some cases are Not in Education, Employment or further Training (NEET), may not reside with family, and can struggle to engage in typical referral pathways. An evaluation is taking place regarding the use of existing Gwent CAMHS and YOS resources for piloting a Tier 3 Gwent Forensic CAMHS Neurodevelopmental Assessment Pathway (FCAMHS NDAP). Methods: Gwent FCAMHS is a small Multidisciplinary Team (MDT): One part-time Consultant Forensic Child & Adolescent Psychiatrist. Four Psychiatric Nurses. One part-time Forensic Psychologist. Between December 2023–December 2024 the number of YOS cases referred for and receiving ND assessment were logged. Assessment outcomes were considered with ongoing discussions with each of the YOS to ascertain ongoing roll-out of a pilot FCAMHS NDAP. Results: Between December 2023–December 2024: 7 cases were referred (5 for possible ADHD, 2 for ASD). 6 of the referrals were not in mainstream education or NEET. 6 ND assessments were completed. 5 resulted in an NDD diagnosis (ADHD=4, ASD=1). 2 cases necessitated ADOS-2 assessment and 1 case was assessed using the Qb Test protocol. Upon diagnosis, 2 elected to trial ADHD medication. Referrals originated from all three YOS in Gwent: Newport (2), Blaenau Gwent-Caerphilly (4) and Monmouthshire-Torfaen (1). Conclusion: Cases were diverted from the CAMHSND waiting list to FCAMHS. YOS support in case engagement and obtaining information was vital for the assessments. YOS managers recognise the role an FCAMHS NDAP has for some cases in the Gwent YOS who would struggle to engage in the typical pathway. Requests have been received for YOS staff training in NDD. A formal roll-out of a Gwent FCAMHS NDAP pilot with specific inclusion criteria has been agreed with the YOS teams and Gwent FCAMHS, commencing January 2025. Quality Improvement methodology is utilised and training packages for YOS staff are being developed.

The poly-arginine peptides R18D and R18 represent novel potential neuroprotective treatments for acute ischaemic stroke. Here we examined whether R18D and R18 had any significant effects on the thrombolytic activity of alteplase (tPA) and tenecteplase (TNK) on clots formed from whole blood in an in vitro thrombolysis plate assay. R18D and R18 were examined at concentrations of 0.25, 0.5, 1, 2, 4, 8 and 16 µM during the 1-h thrombolytic assay. We also included the well-characterised neuroprotective NA-1 peptide as a control. R18D, R18 and NA-1 all reduced tPA or TNK percentage clot lysis by 0–9.35%, 0–3.44% and 0–4.8%, respectively. R18D, R18 and NA-1 had a modest and variable effect on the lag time, increasing the time to the commencement of thrombolysis by 0–9.9 min, 0–5.53 min and 0–7.16 min, respectively. Lastly, R18 and NA-1 appeared to increase the maximal activity of the thrombolysis reaction. In addition, the in vitro anti-excitotoxic neuroprotective efficacy of R18D and R18 was not affected by pre-incubation for 1–2 h or overnight with tPA or TNK, whereas only R18D retained high anti-excitotoxic neuroprotective efficacy when pre-incubated in a synthetic trypsin (TrypLE Express). The present in vitro findings suggest that neither R18D or R18 when co-administered with the thrombolytic inducing agents tPA or TNK are likely to have a significant impact when used clinically during clot thrombolysis and confirm the superior proteolytic stability of the R18D peptide.

We have previously reported that cationic poly-arginine and arginine-rich cell-penetrating peptides display high-level neuroprotection and reduce calcium influx following in vitro excitotoxicity, as well as reduce brain injury in animal stroke models. Using the neuroprotective peptides poly-arginine R12 (R12) and the NR2B9c peptide fused to the arginine-rich carrier peptide TAT (TAT-NR2B9c; also known as NA-1), we investigated the mechanisms whereby poly-arginine and arginine-rich peptides reduce glutamate-induced excitotoxic calcium influx. Using cell surface biotin protein labeling and western blot analysis, we demonstrated that R12 and TAT-NR2B9c significantly reduced cortical neuronal cell surface expression of the NMDA receptor subunit NR2B. Chemical endocytic inhibitors used individually or in combination prior to glutamate excitotoxicity did not significantly affect R12 peptide neuroprotective efficacy. Similarly, pretreatment of neurons with enzymes to degrade anionic cell surface proteoglycans, heparan sulfate proteoglycan (HSPG), and chondroitin sulfate proteoglycan (CSPG), as well as sialic acid residues, did not significantly affect peptide neuroprotective efficacy. While the exact mechanisms responsible for R12 peptide-mediated NMDA receptor NR2B subunit cell surface downregulation were not identified, an endocytic process could not be ruled out. The study supports our hypothesis that arginine-rich peptides reduce excitotoxic calcium influx by reducing the levels of cell surface ion channels.

In a recent study, we highlighted the importance of cationic charge and arginine residues for the neuroprotective properties of poly-arginine and arginine-rich peptides. In this study, using cortical neuronal cultures and an in vitro glutamic acid excitotoxicity model, we examined the neuroprotective efficacy of different modifications to the poly-arginine-9 peptide (R9). We compared an unmodified R9 peptide with R9 peptides containing the following modifications: (i) C-terminal amidation (R9-NH2); (ii) N-terminal acetylation (Ac-R9); (iii) C-terminal amidation with N-terminal acetylation (Ac-R9-NH2); and (iv) C-terminal amidation with d -amino acids (R9D-NH2). The three C-terminal amidated peptides (R9-NH2, Ac-R9-NH2, and R9D-NH2) displayed neuroprotective effects greater than the unmodified R9 peptide, while the N-terminal acetylated peptide (Ac-R9) had reduced efficacy. Using the R9-NH2 peptide, neuroprotection could be induced with a 10 min peptide pre-treatment, 1–6 h before glutamic acid insult, or when added to neuronal cultures up to 45 min post-insult. In addition, all peptides were capable of reducing glutamic acid-mediated neuronal intracellular calcium influx, in a manner that reflected their neuroprotective efficacy. This study further highlights the neuroprotective properties of poly-arginine peptides and provides insight into peptide modifications that affect efficacy.

We examined the neuroprotective efficacy of the poly-arginine peptide R18 and its D-enantiomer R18D in a perinatal hypoxic-ischaemic (HI) model in P7 Sprague-Dawley rats. R18 and R18D peptides were administered intraperitoneally at doses of 30, 100, 300 or 1000 nmol/kg immediately after HI (8% O 2 /92%N 2 for 2.5 h). The previously characterised neuroprotective JNKI-1-TATD peptide at a dose of 1000 nmol/kg was used as a control. Infarct volume and behavioural outcomes were measured 48 h after HI. For the R18 and R18D doses examined, total infarct volume was reduced by 25.93% to 43.80% ( P  = 0.038 to < 0.001). By comparison, the JNKI-1-TATD reduced lesion volume by 25.27% ( P  = 0.073). Moreover, R18 and R18D treatment resulted in significant improvements in behavioural outcomes, while with JNKI-1-TATD there was a trend towards improvement. As an insight into the likely mechanism underlying the effects of R18, R18D and JNKI-1-TATD, the peptides were added to cortical neuronal cultures exposed to glutamic acid excitotoxicity, resulting in up to 89, 100 and 71% neuroprotection, respectively, and a dose dependent inhibition of neuronal calcium influx. The study further confirms the neuroprotective properties of poly-arginine peptides, and suggests a potential therapeutic role for R18 and R18D in the treatment of HIE.

Background MSCTRAIL is a cell-based therapy consisting of human allogeneic umbilical cord-derived MSCs genetically modified to express the anti-cancer protein TRAIL. Though cell-based therapies are typically designed with a target tissue in mind, delivery is rarely assessed due to a lack of translatable non-invasive imaging approaches. In this preclinical study, we demonstrate 89 Zr-oxine labelling and PET-CT imaging as a potential clinical solution for non-invasively tracking MSCTRAIL biodistribution. Future implementation of this technique should improve our understanding of MSCTRAIL during its evaluation as a therapy for metastatic lung adenocarcinoma. Methods MSCTRAIL were radiolabelled with 89 Zr-oxine and assayed for viability, phenotype, and therapeutic efficacy post-labelling. PET-CT imaging of 89 Zr-oxine-labelled MSCTRAIL was performed in a mouse model of lung cancer following intravenous injection, and biodistribution was confirmed ex vivo . Results MSCTRAIL retained the therapeutic efficacy and MSC phenotype in vitro at labelling amounts up to and above those required for clinical imaging. The effect of 89 Zr-oxine labelling on cell proliferation rate was amount- and time-dependent. PET-CT imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer up to 1 week post-injection, validated by in vivo bioluminescence imaging, autoradiography, and fluorescence imaging on tissue sections. Conclusions 89 Zr-oxine labelling and PET-CT imaging present a potential method of evaluating the biodistribution of new cell therapies in patients, including MSCTRAIL. This offers to improve understanding of cell therapies, including mechanism of action, migration dynamics, and inter-patient variability.