Intracranial pressure monitoring and treatment practices in severe traumatic brain injury between low-and middle-income countries and high-income countries: Data or dogma?

Background: Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Intracranial pressure (ICP) monitoring forms the cornerstone of most severe TBI (sTBI) management guidelines, yet treatment practices vary between high income countries (HIC) and low/middle-income countries (LMICs). We sought to find the reasons for variation in ICP monitoring and treatment practices between neurosurgeons in low- and high-income countries.

Discovery of BAY 2413555, First Selective Positive Allosteric Modulator of the M2 Receptor to Restore Cardiac Autonomic Balance.

Autonomic disbalance, i.e., sympathetic overactivation and parasympathetic withdrawal, is a causal driver of disease progression in heart failure.

Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell-engaging bispecific antibody targeting human claudin 6.

We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1.

The Brainstem Cavernoma Case Series: A Formula for Surgery and Surgical Technique.

: Cavernous malformations (CM) are vascular malformations with low blood flow. The removal of brainstem CMs (BS) is associated with high surgical morbidity, and there is no general consensus on when to treat deep-seated BS CMs. The aim of this study is to compare the surgical outcomes of a series of deep-seated BS CMs with the surgical outcomes of a series of superficially located BS CMs operated on at the Department of Neurosurgery, College of Tuebingen, Germany.

Metabolism and Excretion of Therapeutic Peptides: Current Industry Practices, Perspectives, and Recommendations.

Therapeutic peptides (TPeps) have expanded from the initial endogenous peptides to complex modified peptides through medicinal chemistry efforts for almost a century. Different from small molecules and large proteins, the diverse submodalities of TPeps have distinct structures and carry different absorption, distribution, metabolism, and excretion (ADME) properties. There is no distinct regulatory guidance for the industry on conducting ADME studies (what, how, and when) for TPeps.

Inability to phosphorylate Y88 of p27 enforces reduced p27 protein levels and accelerates leukemia progression.

The cyclin-dependent kinase (CDK) inhibitor p27 regulates cell proliferation. Phosphorylation of tyrosine residue 88 (Y88) converts the inhibitor into an assembly factor and activator of CDKs, since Y88-phosphorylation restores activity to cyclin E,A/CDK2 and enables assembly of active cyclin D/CDK4,6. To investigate the physiological significance of p27 tyrosine phosphorylation, we have generated a knock-in mouse model where Y88 was replaced by phenylalanine (p27-Y88F).

Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients.

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied as well as in healthy volunteers and in depressive disorder patients.

Stimulation of c-Jun/AP-1-Activity by the Cell Cycle Inhibitor p57.

p57 is a member of the Cip/Kip family of cell cycle inhibitors which restrict the eukaryotic cell cycle by binding to and inhibiting cyclin/CDK complexes. They are considered as tumor suppressors and inactivating genomic mutations of p57 are associated with human overgrowth disorders. Increasing evidence suggests that p57 controls additional cellular processes beyond cell cycle control such as apoptosis, cell migration or transcription.

Structure-Permeability Relationship of Semipeptidic Macrocycles-Understanding and Optimizing Passive Permeability and Efflux Ratio.

We herein report the first thorough analysis of the structure-permeability relationship of semipeptidic macrocycles. In total, 47 macrocycles were synthesized using a hybrid solid-phase/solution strategy, and then their passive and cellular permeability was assessed using the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assay, respectively. The results indicate that semipeptidic macrocycles generally possess high passive permeability based on the PAMPA, yet their cellular permeability is governed by efflux, as reported in the Caco-2 assay.

The CDK inhibitor p57 enhances the activity of the transcriptional coactivator FHL2.

The eukaryotic cell cycle is negatively regulated by cyclin-dependent kinase inhibitors (CKIs). p57 is a member of the Cip/Kip family of CKIs and frequently inactivated by genomic mutations associated with human overgrowth disorders. There is increasing evidence for p57 to control cellular processes in addition to cell cycle and CDK regulation including transcription, apoptosis, migration or development.

Feasibility and accuracy of a voxel-based neuronavigation system with 3D image rendering in preoperative planning and as a learning tool for young neurosurgeons, exemplified by the anatomical localization of the superior sagittal sinus.

It is essential for a neurosurgeon to know individual anatomy and the corresponding anatomical landmarks before starting a surgery. Continuous training, especially of young neurosurgeons, is crucial for understanding complex neuroanatomy. In this study, we used a neuronavigation system with 3D volumetric image rendering to determine the anatomical relationship between the sagittal suture and the superior sagittal sinus (SSS) in patients with intracranial lesions.

Review of first clinical experiences with a 1.5 Tesla ceiling-mounted moveable intraoperative MRI system in Europe.

High-field intraoperative MRI (iMRI) systems provide excellent imaging quality and are used for resection control and update of image guidance systems in a number of centers. A ceiling-mounted intraoperative MRI system has several advantages compared to a conventional iMRI system. In this article, we report on first clinical experience with using such a state-of-the-art, the 1.

Temporarily increased TGFβ following radon spa correlates with reduced pain while serum IL-18 is a general predictive marker for pain sensitivity.

Sustained pain relief following radon spa therapy in patients suffering from chronic painful diseases has been well described. But still, the underlying mechanisms are not fully understood. We conducted the prospective and explorative RAD-ON01 study which included 103 patients who suffered from chronic painful musculoskeletal disorders of the spine and/or joints and present here the data of the examination of pro- and anti-inflammatory cytokines in the serum of the patients before and at weeks 6, 12 and 30 after therapy.

Optimized two-dimensional gel electrophoresis in an alkaline pH range improves the identification of intracellular CFDA-cisplatin-protein adducts in ovarian cancer cells.

Intracellular binding of cisplatin to proteins has been associated with acquired resistance to chemotherapy. In our previous study we established an analytical method for the identification of intracellular cisplatin-binding proteins. The method used a fluorescent carboxyfluorescein-diacetate-labeled cisplatin analogue (CFDA-cisplatin), two-dimensional gel electrophoresis (2DE) and mass spectrometry, which allows detecting and identifying intracellular CFDA-cisplatin-containing protein adducts in the acidic pH range (pH 4-7).

Cold-inducible RNA-binding protein (CIRP) induces translation of the cell-cycle inhibitor p27Kip1.

The CDK inhibitor p27Kip1 plays a central role in controlling cell proliferation and cell-cycle exit. p27Kip1 protein levels oscillate during cell-cycle progression and are regulated by mitogen or anti-proliferative signaling. The abundance of the protein is frequently determined by post-transcriptional mechanisms including ubiquitin-mediated proteolysis and translational control.

Ultrasound-guided placement of ventricular catheters in first-time pediatric VP shunt surgery.

Purpose: Ventriculo-peritoneal (VP) shunts are effective for treatment of hydrocephalus in all age groups; however, they are associated with complications, a common one being ventricular catheter (VC) obstruction. VC position is likely to influence VC survival; however, most VCs are positioned freehand without guidance. This paper describes the accuracy of ultrasound guidance for VC placement and the impact of tip location on VC occlusion rate.

Transcutaneous glomerular filtration rate measurement in a canine animal model of chronic kidney disease.

Introduction: Quantitative assessment of renal function by measurement of glomerular filtration rate (GFR) is an important part of safety and efficacy evaluation in preclinical drug development. Existing methods are often time consuming, imprecise and associated with animal burden. Here we describe the comparison between GFR determinations with sinistrin (PS-GFR) and fluorescence-labelled sinistrin-application and its transcutaneous detection (TD-GFR) in a large animal model of chronic kidney disease (CKD).

A fluorescent oxaliplatin derivative for investigation of oxaliplatin resistance using imaging techniques.

Oxaliplatin is the backbone of chemotherapy for advanced colorectal cancer and undergoes clinical trials for treatment of other tumour entities. However, acquired resistance is a major hurdle. Confocal microscopy is a useful tool to get an insight into the mechanisms of resistance but it requires fluorescent compounds.

Evaluation of the Predictive Value of Intraoperative Changes in Motor-Evoked Potentials of Caudal Cranial Nerves for the Postoperative Functional Outcome.

Objective: The predictive value of changes in intraoperatively acquired motor-evoked potentials (MEPs) of the lower cranial nerves (LCN) IX-X (glossopharyngeal-vagus nerve) and CN XII (hypoglossal nerve) on operative outcomes was investigated.

Methods: MEPs of CN IX-X and CN XII were recorded intraoperatively in 63 patients undergoing surgery of the posterior cranial fossa. We correlated the changes of the MEPs with postoperative nerve function.

Caspases uncouple p27(Kip1) from cell cycle regulated degradation and abolish its ability to stimulate cell migration and invasion.

In addition to their role in programmed cell death, caspases exert non-lethal functions in diverse developmental processes including cell differentiation or tissue remodeling. Terminal cell cycle exit and differentiation can be promoted by increased level of the CDK inhibitor p27(Kip1). Activated caspases cause proteolytic processing of p27, and we identified a novel caspase cleavage site in human p27 that removes a C-terminal fragment of 22 amino acids from the CDK inhibitor, including a phosphodegron.

Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance.

Intracellular binding of cisplatin to non-DNA partners, such as proteins, has received increasing attention as an additional mode of action and as mechanism of resistance. We investigated two cisplatin-interacting isoforms of protein disulfide isomerase regarding their contribution to acquired cisplatin resistance using sensitive and resistant A2780/A2780cis ovarian cancer cells. Cisplatin cytotoxicity was assessed after knockdown of either protein disulfide isomerase family A member 1 (PDIA1) or protein disulfide isomerase family A member 3 (PDIA3).

Congenital left temporal large arachnoid cyst causing intraorbital optic nerve damage in the second decade of life.

Aim: Intracranial sylvian arachnoid cysts are often asymptomatic lesions. We present a 16-year-old female patient with progressive loss of vision together with an unusual visual field defect on the left eye accompanied by headache.

Method: A left frontotemporal sylvian arachnoid cyst was known since she was 9 months old, but observed ever since in the asymptomatic patient.

Combination of two-dimensional gel electrophoresis and a fluorescent carboxyfluorescein-diacetate-labeled cisplatin analogue allows the identification of intracellular cisplatin-protein adducts.

Cisplatin is one of the most widely used anticancer agents, but a major problem for successful chemotherapy is the development of drug resistance of tumor cells against cisplatin. Resistance to cisplatin is a multifactorial problem. A method to detect and identify intracellular cisplatin-protein adducts was developed using a fluorescent carboxyfluorescein-diacetate-labeled cisplatin analogue (CFDA-cisplatin), 2DE, and ESI-MS/MS.

Statin-induced depletion of geranylgeranyl pyrophosphate inhibits cell proliferation by a novel pathway of Skp2 degradation.

Statins, such as lovastatin, can induce a cell cycle arrest in the G1 phase. This robust antiproliferative activity remains intact in many cancer cells that are deficient in cell cycle checkpoints and leads to an increased expression of CDK inhibitor proteins p27Kip1 and p21Cip1. The molecular details of this statin-induced growth arrest remains unclear.