PD-1 Blockade in Chronically HIV-1-Infected Humanized Mice Suppresses Viral Loads

An estimated 34 million people are living with HIV worldwide (UNAIDS, 2012), with the number of infected persons rising every year. Increases in HIV prevalence have resulted not only from new infections, but also from increases in the survival of HIV-infected persons produced by effective anti-retroviral therapies. Augmentation of anti-viral immune responses may be able to further increase the survival of HIV-infected persons. One strategy to augment these responses is to reinvigorate exhausted anti-HIV immune cells present in chronically infected persons. The PD-1-PD-L1 pathway has been implicated in the exhaustion of virus-specific T cells during chronic HIV infection. Inhibition of PD-1 signaling using blocking anti-PD-1 antibodies has been shown to reduce simian immunodeficiency virus (SIV) loads in monkeys. We now show that PD-1 blockade can improve control of HIV replication in vivo in an animal model. BLT (Bone marrow-Liver-Thymus) humanized mice chronically infected with HIV-1 were treated with an anti-PD-1 antibody over a 10-day period. The PD-1 blockade resulted in a very significant 45-fold reduction in HIV viral loads in humanized mice with high CD8+ T cell expression of PD-1, compared to controls at 4 weeks post-treatment. The anti-PD-1 antibody treatment also resulted in a significant increase in CD8+ T cells. PD-1 blockade did not affect T cell expression of other inhibitory receptors co-expressed with PD-1, including CD244, CD160 and LAG-3, and did not appear to affect virus-specific humoral immune responses. These data demonstrate that inhibiting PD-1 signaling can reduce HIV viral loads in vivo in the humanized BLT mouse model, suggesting that blockade of the PD-1-PD-L1 pathway may have therapeutic potential in the treatment of patients already infected with the AIDS virus

Single-center experience of stent retriever thrombectomy in acute ischemic stroke

Background and purpose Recently, positive data from several randomized controlled trials (RCTs) of endovascular therapy for acute ischemic stroke (AIS) has emerged. The aim of this retrospective study is to present our clinical experience in cerebral vessel occlusion treatment using retrievable intracranial stents. Methods Forty-three consecutive patients with ischemic stroke (median age 75, range 22–87) treated by stent retriever thrombectomy (Solitaire™ FR) between January 2013 and December 2015 were identified. We retrospectively assessed Thrombolysis in Cerebral Infarction (TICI) scale (2b–3 considered as successful recanalization), clinical outcome using modified Rankin scale (mRs) at 3 months (regarding score 0–2 as good clinical outcome), device-related complications and symptomatic intracranial hemorrhage (sICH; parenchymal hematoma Type 1 or 2 and National Institutes of Health Stroke Scale [NIHSS] score increment ≥4 points) rate. Results The mean NIHSS score on admission was 16.4 (median 16). The mean time from onset to groin puncture (time to treatment) was 290min (median 254min). Successful recanalization was achieved in 30 (69.8%) cases. The mean time from onset to successful reperfusion or procedure termination (time to reperfusion) was 394min (median 375min). Good outcome was observed in 17 (39.5%) patients and mortality was 27.9% (n=12). We found 2 (4,7%) sICHs, one (2,3%) thromboembolic event in different vascular territory and one (2,3%) groin hematoma. Conclusion Stent retriever thrombectomy for the treatment of ischemic stroke is safe, provides high rate of recanalization and good clinical outcomes in the setting of large vessel occlusion

8.1 Nieeksperymentalne metody aktywizujące w edukacji przyrodniczej w klasach IV–VIII szkoły podstawowej

Metody aktywizujące nie tylko pomagają wzbudzać zainteresowanie ucznia wykładanymprzedmiotem i ułatwiać mu przyswojenie treści nauczania. Przede wszystkim pozwalajądoskonalić umiejętności przydatne w codziennym życiu. Mamy tu na myśli takżeumiejętności, o których mowa w podstawie programowej kształcenia ogólnego w szkolepodstawowej (...)

Enaminone Modulators of Extrasynaptic α4β3δ γ-Aminobutyric AcidA Receptors Reverse Electrographic Status Epilepticus in the Rat After Acute Organophosphorus Poisoning

Seizures induced by organophosphorus nerve agent exposure become refractory to treatment with benzodiazepines because these drugs engage synaptic γ-aminobutyric acid-A receptors (GABAARs) that rapidly internalize during status epilepticus (SE). Extrasynaptic GABAARs, such as those containing α4β3δ subunits, are a putative pharmacological target to comprehensively manage nerve agent-induced seizures since they do not internalize during SE and are continuously available for activation. Neurosteroids related to allopregnanolone have been tested as a possible replacement for benzodiazepines because they target both synaptic and extrasynaptic GABAARs receptors. A longer effective treatment window, extended treatment efficacy, and enhanced neuroprotection represent significant advantages of neurosteroids over benzodiazepines. However, neurosteroid use is limited by poor physicochemical properties arising from the intrinsic requirement of the pregnane steroid core structure for efficacy rendering drug formulation problematic. We tested a non-steroidal enaminone GABAAR modulator that interacts with both synaptic and extrasynaptic GABAARs on a binding site distinct from neurosteroids or benzodiazepines for efficacy to control electrographic SE induced by diisopropyl fluorophosphate or soman intoxication in rats. Animals were treated with standard antidotes, and experimental therapeutic treatment was given following 1 h (diisopropyl fluorophosphate model) or 20 min (soman model) after SE onset. We found that the enaminone 2-261 had an extended duration of seizure termination (>10 h) in the diisopropyl fluorophosphate intoxication model in the presence or absence of midazolam (MDZ). 2-261 also moderately potentiated MDZ in the soman-induced seizure model but had limited efficacy as a stand-alone anticonvulsant treatment due to slow onset of action. 2-261 significantly reduced neuronal death in brain areas associated with either diisopropyl fluorophosphate- or soman-induced SE. 2-261 represents an alternate chemical template from neurosteroids for enhancing extrasynaptic α4β3δ GABAAR activity to reverse SE from organophosphorous intoxication

Cyberbiosecurity: A New Perspective on Protecting U.S. Food and Agricultural System

Our national data and infrastructure security issues affecting the “bioeconomy” are evolving rapidly. Simultaneously, the conversation about cyber security of the U.S. food and agricultural system (cyber biosecurity) is incomplete and disjointed. The food and agricultural production sectors influence over 20% of the nation's economy ($6.7T) and 15% of U.S. employment (43.3M jobs). The food and agricultural sectors are immensely diverse and they require advanced technologies and efficiencies that rely on computer technologies, big data, cloud-based data storage, and internet accessibility. There is a critical need to safeguard the cyber biosecurity of our bio economy, but currently protections are minimal and do not broadly exist across the food and agricultural system. Using the food safety management Hazard Analysis Critical Control Point system concept as an introductory point of reference, we identify important features in broad food and agricultural production and food systems: dairy, food animals, row crops, fruits and vegetables, and environmental resources (water). This analysis explores the relevant concepts of cyber biosecurity from food production to the end product user (such as the consumer) and considers the integration of diverse transportation, supplier, and retailer networks. We describe common challenges and unique barriers across these systems and recommend solutions to advance the role of cyber biosecurity in the food and agricultural sectors