Gastrointestinal bleeding and pro-angiogenic shift in the angiopoietin axis with continuous flow left ventricular assist device implantation.

Background: Gastrointestinal bleeding (GIB) affects up to 40% of continuous-flow left ventricular assist device (CF-LVAD) recipients. A higher risk of GIB is seen in CF-LVAD recipients with lower device pulsatility without a known mechanism. One hypothesis is that the novel hemodynamics in CF-LVAD recipients affect angiogenesis signaling.

Assessment of the safety of the cationic arginine-rich peptides (CARPs) poly-arginine-18 (R18 and R18D) in models of mast cell degranulation and red blood cell hemolysis.

Our laboratory focuses on the development of novel neuroprotective cationic peptides, such poly-arginine-18 (R18: 18-mer of l-arginine; net charge +18) and its d-enantiomer R18D in stroke and other brain injuries. In the clinical development of R18/R18D, their cationic property raises potential safety concerns on their non-specific effects to induce mast cell degranulation and hemolysis. To address this, we first utilised primary human cultured mast cells (HCMCs) to examine anaphylactoid effects.

Impact of poly-arginine peptides R18D and R18 on alteplase and tenecteplase thrombolysis in vitro, and neuroprotective stability to proteolysis.

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.

Factitious Gastrointestinal Bleeding: A Case Series and Review.

Factitious gastrointestinal bleeding (GIB) is a manifestation of factitious disorder (FD) wherein patients feign GIB in the absence of external gain. As it can be a challenging diagnosis to make, factitious GIB often leads to multiple tests, exposure to contrast agents and radiation, invasive endoscopic and surgical procedures, an increased risk of iatrogenic complications, and increased healthcare costs. Patients who feign GIB often demonstrate characteristic behaviors that may go unnoticed unless they are explicitly addressed.

Comparative Assessment of the Proteolytic Stability and Impact of Poly-Arginine Peptides R18 and R18D on Infarct Growth and Penumbral Tissue Preservation Following Middle Cerebral Artery Occlusion in the Sprague Dawley Rat.

Poly-arginine peptides R18 and R18D have previously been demonstrated to be neuroprotective in ischaemic stroke models. Here we examined the proteolytic stability and efficacy of R18 and R18D in reducing infarct core growth and preserving the ischaemic penumbra following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. R18 (300 or 1000 nmol/kg), R18D (300 nmol/kg) or saline were administered intravenously 10 min after MCAO induced using a filament.

Adult polyglucosan body disease: an acute presentation leading to unmasking of this rare disorder.

Introduction: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy caused by abnormal intracellular accumulation of glycogen byproducts. This disorder is linked to a deficiency in glycogen branching enzyme-1 (GBE-1). Neurologic manifestations include upper and lower motor neuron signs, dementia, and peripheral neuropathy.

Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety.

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.

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with Zr-oxine PET-CT.

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 Zr-oxine labelling and PET-CT imaging as a potential clinical solution for non-invasively tracking MSCTRAIL biodistribution.

Assessment of therapeutic window for poly-arginine-18D (R18D) in a P7 rat model of perinatal hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) remains the leading cause of mortality and morbidity in neonates, with no available neuroprotective therapeutic agent. In the development of a therapeutic for HIE, we examined the neuroprotective efficacy of the poly-arginine peptide R18D (arginine 18 mer synthesised with D-arginine) in a perinatal model of hypoxia-ischaemia (HI; common carotid and external carotid occlusion + 8%O /92%N for 2.5 hr) in the P7 Sprague-Dawley rat.

Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs).

Perinatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality and morbidity in neonates, with survivors suffering significant neurological sequelae including cerebral palsy, epilepsy, intellectual disability and autism spectrum disorders. While hypothermia is used clinically to reduce neurological injury following HIE, it is only used for term infants (>36 weeks gestation) in tertiary hospitals and improves outcomes in only 30% of patients. For these reasons, a more effective and easily administrable pharmacological therapeutic agent, that can be used in combination with hypothermia or alone when hypothermia cannot be applied, is urgently needed to treat pre-term (≤36 weeks gestation) and term infants suffering HIE.

Association of Pulsatility with Gastrointestinal Bleeding in a Cohort of HeartMate II Recipients.

Gastrointestinal bleeding (GIB) is common in patients with continuous-flow left ventricular assist devices (CF-LVADs) possibly because of changes in blood flow. We aimed to test the hypothesis that a low pulsatility index (PI) is associated with an increased hazard of overt GIB in patients with CF-LVADs. We conducted a retrospective cohort study of patients who had a HeartMate II (HMII) CF-LVAD implanted at our center.

Poly-arginine R18 and R18D (D-enantiomer) peptides reduce infarct volume and improves behavioural outcomes following perinatal hypoxic-ischaemic encephalopathy in the P7 rat.

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/92%N for 2.5 h).

Assessment of R18, COG1410, and APP96-110 in Excitotoxicity and Traumatic Brain Injury.

Cationic arginine-rich and poly-arginine peptides (referred to as CARPs) have potent neuroprotective properties in in vitro excitotoxicity and in vivo models of stroke. Traumatic brain injury (TBI) shares many pathophysiological processes as stroke, including excitotoxicity. Therefore, we evaluated our lead peptide, poly-arginine R18, with the COG1410 and APP96-110 peptides, which have neuroprotective actions following TBI.

Modification to the Rice-Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48hours.

Background: The Rice-Vannucci model of hypoxic-ischaemic encephalopathy (HIE) has been associated with a high degree of variability with respect to the development of cerebral infarction and infarct lesion volume. For this reason, we examined the occurrence of communicational blood flow within the common carotid (CCA), internal (ICA), and external (ECA) carotid arteries following CCA occlusion as a source of variability in the model.

New Method: We propose a novel modification to the Rice-Vannucci model, whereby both the CCA and ECA are permanently ligated; mitigating communicational blood flow.

Assessment of the Neuroprotective Effects of Arginine-Rich Protamine Peptides, Poly-Arginine Peptides (R12-Cyclic, R22) and Arginine-Tryptophan-Containing Peptides Following In Vitro Excitotoxicity and/or Permanent Middle Cerebral Artery Occlusion in Rats.

We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke.

Pit Latrine Fecal Sludge Resistance Using a Dynamic Cone Penetrometer in Low Income Areas in Mzuzu City, Malawi.

Pit latrines can provide improved household sanitation, but without effective and inexpensive emptying options, they are often abandoned once full and may pose a public health threat. Emptying techniques can be difficult, as the sludge contents of each pit latrine are different. The design of effective emptying techniques (e.

The Neuroprotective Peptide Poly-Arginine-12 (R12) Reduces Cell Surface Levels of NMDA NR2B Receptor Subunit in Cortical Neurons; Investigation into the Involvement of Endocytic Mechanisms.

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.

Characterisation of neuroprotective efficacy of modified poly-arginine-9 (R9) peptides using a neuronal glutamic acid excitotoxicity model.

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).

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties.

Several recent studies have demonstrated that TAT and other arginine-rich cell penetrating peptides (CPPs) have intrinsic neuroprotective properties in their own right. Examples, we have demonstrated that in addition to TAT, poly-arginine peptides (R8 to R18; containing 8-18 arginine residues) as well as some other arginine-rich peptides are neuroprotective in vitro (in neurons exposed to glutamic acid excitotoxicity and oxygen glucose deprivation) and in the case of R9 in vivo (after permanent middle cerebral artery occlusion in the rat). Based on several lines of evidence, we propose that this neuroprotection is related to the peptide's endocytosis-inducing properties, with peptide charge and arginine residues being critical factors.

Perfusion imaging in the 3-hour time window predicts a tPA-associated hemorrhage in acute ischemic stroke.

Perfusion imaging is being evaluated in acute ischemic stroke patients to identify those who may benefit from reperfusion therapies beyond the standard thrombolytic time window but limited data are available on its utility in patients presenting within the standard thrombolytic time window. We report a case of a patient presenting within the 3-hour time window where computerized tomographic perfusion imaging before intravenous thrombolysis identified a large volume of severely ischemic tissue and where intravenous tissue plasminogen activator administration subsequently resulted in a fatal intracerebral hemorrhage. Whether perfusion imaging can predict an increased risk of tissue plasminogen activator-associated symptomatic hemorrhage in patients presenting within the standard thrombolytic time window requires further study.

Poly-arginine and arginine-rich peptides are neuroprotective in stroke models.

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.