Innovative Approaches To The Management of Acute Arterial Hypertension - Clevidipine Butyrate

Acute arterial hypertension is one of the major concerns in many clinical settings including but not limited to operating room, intensive care and emergency care units. Perioperative hypertension is one of the major reasons for cancellation of elective surgeries, and also increases the perioperative morbidity. We would like to discuss pathophysiology, evaluation of the patients with acute hypertension, management of these patients and future considerations of the current intravenous antihypertensive medications

Primary Decompressive Craniectomy: Effects on Neurocritical Care Management, Long-Term Neurologic Status and Mortality

Objectives: Decompressive craniectomy (DC) is a surgical therapy used to treat patients foreseen to be at risk for high intracranial pressure (ICP). In this retrospective case control study, mortality, ICP values, neurocritical care (NCC) management necessity, and long-term neurologic status were examined in patients treated with DC and in a matched control group. Methods: The primary end-points were all-cause mortality and functional status of NCC patients both at discharge and at a 6 month follow-up. Secondary end-points were ICP values at established time points and the use of advanced NCC therapies. Patients who underwent primary DC were matched with individuals with similar demographic and pre-intervention ICP values who had been treated with standard NCC management alone. Results Neurologic status outcome at discharge and the 6 month follow-up was significantly better in patients treated with DC compared to those in the control group: Glasgow Outcome Scale (GOS) 4-5 in 15 versus 5 patients; p = 0.033, and 16 versus 6 patients, p = 0.033. Mortality at 6 months was similar in the study groups (10 versus 16 patients; p = 0.212). ICP values were similar at NCC admission but were better controlled 24 hours after DC than in the control group. Fewer patients treated with DC needed advanced NCC medical therapies. Conclusions: DC is an effective way to normalize ICP levels while reducing the need for aggressive medical therapies. Survival rate and neurological outcome in patients treated with DC were found to be better than in those receiving only medical treatment

Multi-messenger observations of thunderstorm-related bursts of cosmic rays

We present the facilities of the Aragats Space Environmental Center in Armenia used during multi-year observations of the thunderstorm ground enhancements (TGEs) and corresponding environmental parameters. We analyze the characteristics of the scintillation detectors, operated on Aragats, and describe the coordinated detection of TGEs by the network of scintillation detectors, field meters, and environmental parameters. By using a fast synchronized data acquisition system we reveal correlations of the multivariate data on time scales from second to nanosecond which allow us to gain insight into the TGE and lightning origin and their interrelations

Thunderstorm ground enhancements: Multivariate analysis of 12 years of observations

We present a survey of more than a half-thousand thunderstorm ground enhancements (TGEs, fluxes of electrons, and gamma rays associated with thunderstorms) registered in 2008–2022 at Aragats space environmental center (ASEC). We analyze correlations between various measured parameters characterizing TGEs measured on Aragats. Two special cases of TGE events are considered: one, terminated by nearby lightning flashes, and another one—with a sufficiently large ratio of electrons to gamma rays. On the basis of the analysis, we summarize the most important results obtained during 12 years of TGE study, which include the following statements: (i) TGEs originated from multiple relativistic runaway electron avalanches starting with seed electrons from the ambient population of cosmic rays, which enter an extended region of the electric field with strength exceeding the critical value; (ii) quite frequently, TGEs occur prior to lightning flashes and are terminated by them; (iii) the energy spectra of avalanche electrons observed on Aragats indicate that the strong electric field region can extend very low above the ground covering a large area on the earth’s surface

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC

Oncolytic Adenoviruses Armed with Thymidine Kinase Can Be Traced by PET Imaging and Show Potent Antitumoural Effects by Ganciclovir Dosing

Replication-competent adenoviruses armed with thymidine kinase (TK) combine the concepts of virotherapy and suicide gene therapy. Moreover TK-activity can be detected by noninvasive positron emission-computed tomography (PET) imaging, what could potentially facilitate virus monitoring in vivo. Here, we report the generation of a novel oncolytic adenovirus that incorporates the Tat8-TK gene under the control of the Major Late Promoter in a highly selective backbone thus providing selectivity by targeting the retinoblastoma pathway. The selective oncolytic TK virus, termed ICOVIR5-TK-L, showed reduced potency compared to a non-selective counterpart. However the combination of ICOVIR5-TK-L with ganciclovir (GCV) induced a potent antitumoural effect similar to that of wild type adenovirus in a preclinical model of pancreatic cancer. Although the treatment with GCV provoked a reduction in the viral yield, both in vitro and in vivo, a two-cycle treatment of virus and GCV resulted in an enhanced antitumoral response that correlated with high TK-activity, based on microPET measurements. Thus, TK-expressing oncolytic adenoviruses can be traced by PET imaging providing real time information on the activity of the virus and its antitumoral potency can be optimized by GCV dosing

Imaging Long-Term Fate of Intramyocardially Implanted Mesenchymal Stem Cells in a Porcine Myocardial Infarction Model

The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [18F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [18F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33–35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC–associated [18F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [18F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI