Sodium bicarbonate reverts electrophysiologic cardiotoxicity of ropivacaine faster than lipid emulsions in a porcine model.

Ropivacaine has been described as a safer local anaesthetic (LA); however, serious cardiotoxic accidents have been reported. Intravenous-lipid-emulsion (ILE) therapy during LA intoxication seems to act as an antidote. Sodium bicarbonate is the standard treatment for sodium channel blocker drug toxicity.

Development of a Unique Rapid Test to Detect Anti-bodies Directed Against an Extended RBD of SARS-CoV-2 Spike Protein.

Serological testing for antibodies directed against SARS-CoV-2 in patients may serve as a diagnostic tool to verify a previous infection and as surrogate for an elicited humoral immune response, ideally conferring immunity after infection or vaccination. Here, we present the recombinant expression of an extended receptor binding domain (RBD) of the SARS-CoV-2 Spike protein used as capture antigen in a unique rapid immunoassay to detect the presence of RBD binding antibodies with high sensitivity and specificity. As currently available vaccines focus on the Spike RBD as target, the developed test can also be used to monitor a successful immune response after vaccination with an RBD based vaccine.

Lactic acidosis and hypoglycemia as markers of disease progression of multiple myeloma: A case report.

: A 64-year-old man was hospitalized in the intensive care unit with pneumonia, lactic acidosis, and hypoglycemia. Investigations revealed a kappa light chain multiple myeloma. The patient underwent chemotherapy by bortezomib, lenalidomide, and dexamethasone.

Efficacy and Safety of the Association of Nimodipine and Choline Alphoscerate in the Treatment of Cognitive Impairment in Patients with Cerebral Small Vessel Disease. The CONIVaD Trial.

Background: No approved treatment is available for patients with vascular cognitive impairment (VCI) due to cerebral small vessel disease (SVD).

Objective: The CONIVaD (Choline Alphoscerate and Nimodipine in Vascular Dementia) study aimed to investigate the feasibility, efficacy, and safety of a combined treatment with choline alphoscerate and nimodipine in patients with SVD and mild-to-moderate cognitive impairment.

Methods: Within this pilot, single-center (university hospital), double-blinded, randomized clinical trial, patients were randomized to two arms: 1-year treatment with nimodipine 30 mg three times a day (TID) plus choline alphoscerate 600 mg twice a day (BID) (arm 1) or nimodipine 30 mg TID plus placebo BID (arm 2).

Association Between Motor and Cognitive Performances in Elderly With Atrial Fibrillation: Strat-AF Study.

Growing evidence suggests a close relationship between motor and cognitive abilities, but possible common underlying mechanisms are not well-established. Atrial fibrillation (AF) is associated with reduced physical performance and increased risk of cognitive decline. The study aimed to assess in a cohort of elderly AF patients: (1) the association between motor and cognitive performances, and (2) the influence and potential mediating role of cerebral lesions burden.

4-(Difluoromethyl)-5-(4-((3,5)-3,5-dimethylmorpholino)-6-(()-3-methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders.

The mechanistic target of rapamycin (mTOR) pathway is hyperactivated in cancer and neurological disorders. Rapalogs and mTOR kinase inhibitors (TORKi) have recently been applied to alleviate epileptic seizures in tuberous sclerosis complex (TSC). Herein, we describe a pharmacophore exploration to identify a highly potent, selective, brain penetrant TORKi.

Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety.

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is a critical regulator of cell growth and is frequently hyperactivated in cancer. Therefore, PI3K inhibitors represent a valuable asset in cancer therapy. Herein we have developed a novel anticancer agent, the potent pan-PI3K inhibitor PQR514 (), which is a follow-up compound for the phase-II clinical compound PQR309 ().

Role of Biological Markers for Cerebral Bleeding Risk STRATification in Patients with Atrial Fibrillation on Oral Anticoagulants for Primary or Secondary Prevention of Ischemic Stroke (Strat-AF Study): Study Design and Methodology.

In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. Cerebral small vessel disease (SVD) represents the pathologic substrate for primary intracerebral hemorrhage and ischemic stroke. We hypothesize that biological markers-both circulating and imaging-based-and their possible interaction, might improve the prediction of bleeding risk in AF patients under treatment with any type of oral anticoagulant.

A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor.

The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conformational restriction approach to explore a novel chemical space for the generation of TORKi.

()-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like adenosine 5'-triphosphate-site PI3K/mTOR kinase inhibitor: ()-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound ), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels.

Comparative Effects of Sodium Bicarbonate and Intravenous Lipid Emulsions on Reversing Bupivacaine-Induced Electrophysiological Toxicity in a Porcine Experimental Model.

Background: Bupivacaine cardiotoxicity mainly manifests as inhibition of the cardiac sodium channel, which slows conduction, particularly at the ventricular level. Experimental studies have demonstrated that intravenous lipid emulsions (ILEs) can reduce the cardiotoxic effects of bupivacaine, but the extent of these effects is controversial. Sodium bicarbonate (B) represents the standard treatment of toxicity related to sodium channel-blocking drugs.

Association of nimodipine and choline alphoscerate in the treatment of cognitive impairment in patients with cerebral small vessel disease: study protocol for a randomized placebo-controlled trial-the CONIVaD trial.

Background: Vascular cognitive impairment (VCI) is an extremely disabling condition that includes post-stroke dementia and VCI caused by cerebral small vessel disease (SVD). Currently, there is no approved treatment for this condition. Drugs active on the cholinergic pathway have been tested in VCI patients showing positive but limited efficacy.

Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.

Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel.

The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy.

The mTOR signaling pathway has emerged as a possible therapeutic target for epilepsy. Clinical trials have shown that mTOR inhibitors such as everolimus reduce seizures in tuberous sclerosis complex patients with intractable epilepsy. Furthermore, accumulating preclinical data suggest that mTOR inhibitors may have anti-seizure or anti-epileptogenic actions in other types of epilepsy.

Radiological study to evaluate the spreading of two volumes (10 vs. 20ml) of radiological contrast in the block of cutaneous branches of intercostal nerves in medial axillary line (BRILMA) in a porcine experimental model.

Objective: Interfascial blocks of the thoracic wall are being developed as an alternative to central blocks in breast surgery. However, there are few studies that have evaluated the anatomical extension of the local anaesthetic. The objective of this study was to analyse, using fluoroscopy, the spreading of two volumes (10 vs.

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.

Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays.

Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.

BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors.

Proven Epstein-Barr encephalitis with negative EBV-DNA load in cerebrospinal fluid after allogeneic hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia.

We report a case of EBV encephalitis in a seven-yr-old child with Ph+ ALL. Two months after an allogeneic HSCT from his HLA mismatched mother, the patient showed an altered sensorium, generalized seizures, and a left hemiparesis. Brain MRI demonstrated multiple lesions highly suggestive for viral encephalitis.

Intracranial hemangiopericytoma--our experience in 30 years: a series of 43 cases and review of the literature.

Objective: Meningeal hemangiopericytoma (HPC) is a rare, aggressive central nervous system tumor that tends to invade locally and to metastasize, and has a high rate of recurrence.

Methods: This study presents a retrospective review of patients managed for intracranial HPC at Rome University Hospital.

Results: A total of 43 patients with intracranial HPC were treated from 1980 to 2010.

Cardiovascular and cerebrovascular events pre- and post-earthquake of 6 April 2009: the Abruzzo's experience.

Background: On 6 April 2009, an earthquake occurred in Abruzzo, a small region in the middle-east of Italy. Its chief town, L'Aquila, was the epicenter. We carried out an observational analysis to evaluate the potential association between the earthquake and the rate of cardiovascular and cerebrovascular admissions of the residents in the province of L'Aquila.

Motor-evoked potentials (MEP) during brainstem surgery to preserve corticospinal function.

Background: Brainstem surgery bears a risk of damage to the corticospinal tract (CST). Motor-evoked potentials (MEPs) are used intraoperatively to monitor CST function in order to detect CST damage at a reversible stage and thus impede permanent neurological deficits. While the method of MEP is generally accepted, warning criteria in the context of brainstem surgery still have to be agreed on.

Preservation of chicken breast meat treated with thyme and balm essential oils.

The present study evaluated the effects of thyme and balm essential oils on the 3-wk storage of fresh chicken breast meat at 4 °C. Thyme and, to a lesser extent, balm essential oils reduced DPPH (2,2-diphenyl-1-picrylhydrazyl) radical formation in the meat (25% to 30% and 20%, respectively). Treatment with the 2 essential oils also limited lipid peroxidation and the deterioration of sarcoplasmic proteins, helping to preserve the meat even after 2 wk of storage.

Intracranial extra-axial cavernous angioma of the cerebellar falx.

Introduction: Intracranial cavernous hemangiomas are benign vascular malformations that can be divided into intra-axial and extra-axial types. Extra-axial cavernous angiomas (or hemangiomas) are rare lesions; intracranially, they arise in relation to the dura mater or at a spinal level mimicking meningiomas. They are very rarely reported in the posterior cranial fossa.

Blunt abdominal aortic disruption (BAAD) in shear fracture of the adult thoraco-lumbar spine: case report and literature review.

To present a rare case of association of abdominal aorta rupture and flexion-distraction fracture of thoracolumbar spine and to review the literature on this condition. In non-penetrating abdominal traumatic injuries with flexion-distraction fractures of the thoracolumbar spine, rupture of the abdominal aorta is an extremely rare occurrence but its outcome is potentially lethal. This association of skeletal and vascular lesions mainly affects young patients and involves the thoraco-lumbar junction and the portion of the aorta that lies in front of it.