Question:
Neuronal plasticity in form of long-term potentiation (LTP) is considered to be the underlying neurophysiological mechanism of learning and memory and plays a pivotal role in development ...and developmental disorders. Transcranial magnetic stimulation is a noninvasive and widespread method to induce and evaluate neuronal plasticity in humans. Biphasic transcranial quadri-pulse stimulation (QPS) consisting of one full-sine cycle for each stimulus demonstrated to be effective in induction of neuronal plasticity in human primary motor cortex. Two full-sine cycles demonstrated to be effective in evaluation of local excitability. Here, we aimed to study the effectiveness of QPS with two full-sine cycles (quadro-burst stimulation, QBS) in comparison to biphasic QPS with one full-sine cycle in induction of neuronal plasticity.
Methods:
We investigated 10 healthy volunteers (females:
n
= 6; males:
n
= 4; mean age, 24.7 years; range, 23-36 years) with QPS consisting of one and two full-sine cycles (duration, 160 µs) separated by an interstimulus interval of four stimuli of 5 ms and an interburst interval of 200 ms with a total amount of 1,440 pulses (total duration approximately 2 minutes). Resting motor threshold (rMT), and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1 mv (SI
1mV
) were measured before (Pre) intervention, directly after (Post 1), after 15 minutes (Post 2), after 30 minutes (Post 3), and after 60 minutes (Post 4).
Results:
We found a significant increase of MEPs after QPS with one and two full-sine cycles at interstimulus intervals of 5 ms and interburst intervals of 200 ms. While the MEP increase was immediately present after QPS with two full-sine cycles lasting for 1 hour (Post 1-4), QPS with one full-sine cycle resulted in a delayed MEP increase which became significant after 15 minutes (Post 2). No significant changes in rMT and no adverse events were observed.
Conclusion:
QPS with one and two full-sine cycles of the human primary motor cortex demonstrated to induce a lasting increase in corticospinal excitability. Considerable differences in time course may be suggestive of different underlying neurophysiological mechanisms. Varying the pulse configuration in very short protocols of QPS may provide new and safe opportunities in investigations of neuronal plasticity in development and developmental disorders.
An Imperial Path to Modernity examines the role of liberal intellectuals in reshaping transnational ideas and internationalist aspirations into national values and imperial ambitions in early ...twentieth-century Japan. Perceiving the relationship between liberalism and the international world order, a cohort of Japanese thinkers conformed to liberal ideas and institutions to direct Japan’s transformation into a liberal empire in Asia. To sustain and rationalize the imperial enterprise, these Japanese liberals sought to make the domestic political stage less hostile to liberalism. Facilitating the creation of print-mediated public opinion, liberal intellectuals attempted to enlist the new middle class as a social ally in circulating liberal ideas and practices within Japan and throughout the empire. In tracing the interconnections between liberalism and the imperial project, Jung-Sun N. Han focuses on the ideas and activities of Yoshino Sakuzo (1878–1933), who was and is remembered as a champion of prewar Japanese liberalism and Taisho democracy. Drawing insights from intellectual history, cultural studies, and international relations, this study argues that prewar Japanese liberalism grew out of the efforts of intellectuals such as Yoshino who worked to devise a transnational institution to govern the Japanese empire.
Small Heterodimer Partner (SHP) interacts with diverse transcription factors such as Runx2 and regulates many cellular events including differentiation, proliferation, and energy metabolism. SHP is ...reported to be a positive regulator of BMP2-induced bone formation. This study aimed to clarify the role of SHP in odontoblast differentiation and matrix mineralization. Rat tooth germs were isolated, and gene expression was determined by RT-PCR and real-time PCR. Localization of SHP protein expression was identified by immunofluorescent analysis. Primary human dental pulp cells (HDPCs) were cultured with BMP2 and/or Ad-siSHP. Matrix mineralization was evaluated by Alizarin red staining. Transient transfection experiment was performed with the SHP or Dlx5 expressional plasmids and the DSPP gene. In tooth germs from post-natal days 3 to 9, BMP-2 and SHP expression increased with DSPP and DMP1 mRNA expression. In an immunostaining study, SHP was expressed in odontoblasts and surrounding osteoblasts. When HDPCs were cultured with BMP2 in mineralization-inducing medium, SHP expression also increased with an increase in DSPP expression. Down-regulation of SHP by Ad-siSHP inhibited matrix mineralization. In transient transfection experiments, overexpression of SHP was shown to enhance DSPP promoter activity through interactions between SHP and Dlx5. These results suggest that SHP may mediate BMP2 signaling to promote mineralization of the dentin matrix.
Objectives
PEPDar compared the tolerability and safety of ritonavir‐boosted darunavir (DRV/r)‐based post‐exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The ...primary endpoint was the early discontinuation rate among the per‐protocol population.
Methods
PEPDar was an open‐label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty‐two private or university HIV clinics in Germany participated. Subjects were ≥ 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative.
Results
A total of 324 subjects were screened, the per‐protocol population was 305, and 273 subjects completed the study. One hundred and fifty‐five subjects received DRV/r‐based PEP and 150 subjects received ritonavir‐boosted lopinavir (LPV/r)‐based PEP for 28–30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow‐up.
Conclusions
Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.
We are interested in methods to solve mixed-integer nonlinear optimal control problems constrained by ordinary differential equations and combinatorial constraints on some of the control functions. ...To solve these problems we use a first discretize, then optimize approach to get a specially structured mixed-integer nonlinear program (MINLP). We decompose this MINLP into a nonlinear program (NLP) and a mixed-integer linear program (MILP), which is called the combinatorial integral approximation problem (CIAP). Previous results guarantee an integer gap for the MINLP depending on the objective function value of the CIAP. The focus of this study is the analysis of the CIAP and of a tailored branch-and-bound method. We link the huge computational gains compared to state-of-the-art MILP solvers to an analysis of subproblems on the branching tree. To this end we study properties of the Lagrangian relaxation of the CIAP. Special focus is given to special ordered set constraints that are present due to an outer convexification of the control problem. Also subproblems that arise by the application of branch-and-bound schemes are of interest. We prove polynomial runtime of the algorithm for special cases and give numerical evidence for efficiency by means of a numerical benchmark problem.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
Identifying factors that determine concentrations of antiretroviral drugs in CD4 cells are important for improving therapeutic efficacy. Experimental models indicate that the nucleoside ...reverse transcriptase inhibitor lamivudine is transported by the organic cation transporters 1 and 2 (OCT1 and OCT2, respectively). Here, we tested whether OCT1 and OCT2 contribute to the uptake of lamivudine into native CD4 cells of human immunodeficiency virus (HIV)-infected individuals.
Methods
CD4 cells obtained by non-activated cell sorting from 35 individuals with HIV-1 infection were incubated with lamivudine (10 μM, 30 min), and intracellular concentrations of lamivudine and its active metabolite lamivudine triphosphate were determined by liquid chromatography tandem mass spectrometry. The expression of OCT1 and OCT2 mRNA was measured by quantitative real-time polymerase chain reaction (PCR). A model of OCT2-transfected CD4 cells was established for mechanistic investigations.
Results
Intracellular concentrations of lamivudine and its active metabolite lamivudine triphosphate showed strong linear correlations with each other and with the CD4 mRNA expression of OCT1 and OCT2 (
r
> 0.80). Coincubation with protease inhibitors (ritonavir, nelfinavir) that inhibit OCT1 and OCT2 yielded decreased intracellular concentrations of lamivudine and lamivudine triphosphate. Incubation of CD4 cells from healthy donors transfected with an OCT2 expression vector yielded increased concentrations of lamivudine and lamivudine triphosphate.
Conclusion
Our studies indicate a role of OCT1 and OCT2 for the cellular accumulation of lamivudine in HIV-infected individuals.
Safety applications require fast, precise and highly reliable sensors at low costs. This paper presents signal processing methods for an active multispectral optical point sensor instrumentation for ...which a first technical implementation exists. Due to the very demanding requirements for safeguarding equipment, these processing methods are targeted to run on a small embedded system with a guaranteed reaction time T < 2 ms and a sufficiently low failure rate according to applicable safety standards, e.g., ISO-13849. The proposed data processing concept includes a novel technique for distance-aided fusion of multispectral data in order to compensate for displacement-related alteration of the measured signal. The distance measuring is based on triangulation with precise results even for low-resolution detectors, thus strengthening the practical applicability. Furthermore, standard components, such as support vector machines (SVMs), are used for reliable material classification. All methods have been evaluated for variants of the underlying sensor principle. Therefore, the results of the evaluation are independent of any specific hardware.
Question Noonan syndrome (NS; OMIM 163950 ) is a developmental disorder caused by activating mutations in various components of the RAS-MAPK pathway. Recent in vitro studies demonstrated impairment ...of synaptic plasticity caused by RAS-MAPK pathway hyperactivity. Induction of synaptic plasticity critically depends on the level of attention. We therefore studied the induction of synaptic plasticity in patients with NS and healthy volunteers under different conditions of attention using transcranial magnetic stimulation. Methods We investigated 10 patients with NS and healthy controls (HC) using paired associative stimulation (PAS) with different attention levels (unspecific, visual and electrical attention control). Changes in motor evoked potential (MEP) amplitudes were assessed immediately after as well as 30 and 60 min after PAS. Results We demonstrated before that MEP amplitudes of healthy controls significantly increased from 1.00 ± 0.17 to 1.74 ± 0.50 mV ( p = 0.001), which was not seen in patients with Noonan-Syndrome (0.88 ± 0.09 to 1.10 ± 0.48 mV, p = 0.148) and there was a significant difference between both groups ( p = 0.003) when using an unspecific attention control. Under specific electrical attention control, MEP amplitudes decreased significantly in patients with NS, whereas a visual attention focus diminished synaptic plasticity in healthy controls. Conclusion Our study provides evidence that synaptic plasticity is impaired in patients with NS, which is probably a consequence of constitutive activity of the RAS-MAPK pathway. The induction of synaptic plasticity in these patients critically depends on attention and results may have direct implications for learning and memory strategies in patients with a RAS-pathway disorder.
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