Axonal degeneration as a therapeutic target in the CNS

Degeneration of the axon is an important step in the pathomechanism of traumatic, inflammatory and degenerative neurological diseases. Increasing evidence suggests that axonal degeneration occurs early in the course of these diseases and therefore represents a promising target for future therapeutic strategies. We review the evidence for axonal destruction from pathological findings and animal models with particular emphasis on neurodegenerative and neurotraumatic disorders. We discuss the basic morphological and temporal modalities of axonal degeneration (acute, chronic and focal axonal degeneration and Wallerian degeneration). Based on the mechanistic concepts, we then delineate in detail the major molecular mechanisms that underlie the degenerative cascade, such as calcium influx, axonal transport, protein aggregation and autophagy. We finally concentrate on putative therapeutic targets based on the mechanistic prerequisites

Using Terahertz Time-Domain Spectroscopy to Discriminate Among Water Contamination Levels in Diesel Engine Oil

Terahertz time-domain spectroscopy (THz-TDS) in the range of 0.5 to 2.0 THz was evaluated for discriminating among water contamination levels (0%, 0.1%, and 0.2%) in diesel engine oil (SAE 15W-40). The absorption coefficient demonstrated potential to discriminate among the three water contamination levels with significant differences among all three levels across the 1.111 to 1.332 THz and 1.669 to 1.934 THz ranges. At each of these frequency ranges, each water contamination level was significantly different from the other two. The 0% water contamination level had the lowest absorption coefficient, while 0.2% water had the highest absorption coefficient. The refractive index demonstrated greater potential to discriminate among water contamination levels with significant differences among all three water levels across the 0.5 to 1.5 THz range. The refractive index of 0% water was the lowest and 0.2% water was the highest across the THz range. Linear regression analysis of the refractive index as a predictor of water contamination level yielded a highly significant equation (p \u3c 0.0001, R2 = 0.99, RMSE = 0.01) when using the refractive indices at 0.5 THz. The refractive indices of these oil samples were promising for discrimination of water contamination. THz spectroscopy should be evaluated for discriminating other engine oil contaminants

Leaving home: An institutional perspective on intermediary HQ relocations

We investigate the effect of changing national institutions on relocations of intermediary HQs. Using a dataset of 154 cross-border relocations between the period from 2000 to 2015, we draw on the intermediary HQ's middle position within the MNC and investigate how a decrease in institutional quality in the HQ's host country and a change in institutional distance between different MNC units affect the relocation decision. Our findings advance the emergent literature on HQ relocations as well as our knowledge of intermediary HQs and the effect of changing institutions on organizational location choices. Beyond our theoretical contributions, we offer policy and managerial implications

Performance of international medical students in psychosocial medicine

Background: Particularly at the beginning of their studies, international medical students face a number of language-related, social and intercultural challenges. Thus, they perform poorer than their local counterparts in written and oral examinations as well as in Objective Structured Clinical Examinations (OSCEs) in the fields of internal medicine and surgery. It is still unknown how international students perform in an OSCE in the field of psychosocial medicine compared to their local fellow students. Methods: All students (N = 1033) taking the OSCE in the field of psychosocial medicine and an accompanying written examination in their eighth or ninth semester between 2012 and 2015 were included in the analysis. The OSCE consisted of four different stations, in which students had to perform and manage a patient encounter with simulated patients suffering from 1) post-traumatic stress disorder, 2) schizophrenia, 3) borderline personality disorder and 4) either suicidal tendency or dementia. Students were evaluated by trained lecturers using global checklists assessing specific professional domains, namely building a relationship with the patient, conversational skills, anamnesis, as well as psychopathological findings and decision-making. Results: International medical students scored significantly poorer than their local peers (p < .001; η2 = .042). Within the specific professional domains assessed, they showed poorer scores, with differences in conversational skills showing the highest effect (p < .001; η2 = .053). No differences emerged within the multiple-choice examination (p = .127). Conclusion: International students showed poorer results in clinical-practical exams in the field of psychosocial medicine, with conversational skills yielding the poorest scores. However, regarding factual and practical knowledge examined via a multiple-choice test, no differences emerged between international and local students. These findings have decisive implications for relationship building in the doctor-patient relationship

Науково-інформаційні ресурси порталу бібліотеки: формування, використання

Визначено шляхи вдосконалення процесів формування та використання електронних ресурсів порталу національної бібліотеки як базової компоненти єдиного науково-інформаційного простору держави.Определены пути усовершенствования процессов формирования и использования электронных ресурсов портала национальной библиотеки как базовой компоненты единого научно-информационного пространства государства.The ways of improvement of formation and usage processes of the electronic resources of the national library portal as a base component of unified scientific information space of the state are determined

Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration

Axonal degeneration is a key initiating event in many neurological diseases. Focal lesions to axons result in a rapid disintegration of the perilesional axon by acute axonal degeneration (AAD) within several hours. However, the underlying molecular mechanisms of AAD are only incompletely understood. Here, we studied AAD in vivo through live-imaging of the rat optic nerve and in vitro in primary rat cortical neurons in microfluidic chambers. We found that calpain is activated early during AAD of the optic nerve and that calpain inhibition completely inhibits axonal fragmentation on the proximal side of the crush while it attenuates AAD on the distal side. A screening of calpain targets revealed that collapsin response mediator protein-2 (CRMP2) is a main downstream target of calpain activation in AAD. CRMP2-overexpression delayed bulb formation and rescued impairment of axonal mitochondrial transport after axotomy in vitro. In vivo, CRMP2-overexpression effectively protected the proximal axon from fragmentation within 6 hours after crush. Finally, a proteomic analysis of the optic nerve was performed at 6 hours after crush, which identified further proteins regulated during AAD, including several interactors of CRMP2. These findings reveal CRMP2 as an important mediator of AAD and define it as a putative therapeutic target

From Therapeutic Drug Monitoring to Model-Informed Precision Dosing for Antibiotic

Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended

Dislocations and the critical endpoint of the melting line of vortex line lattices

We develop a theory for dislocation-mediated structural transitions in the vortex lattice which allows for a unified description of phase transitions between the three phases, the elastic vortex glass, the amorphous vortex glass, and the vortex liquid, in terms of a free energy functional for the dislocation density. The origin of a critical endpoint of the melting line at high magnetic fields, which has been recently observed experimentally, is explained.Comment: 4 pages, 1 figur

Intravenous digoxin as a bioavailability standard

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116960/1/cpt1975171117.pd