Miracle-dz/UniFAR-FTUs huggingface dataset:
Perspective on neuromuscular factors in poststroke fatigue

Purpose: To summarize the potential origins of fatigue poststroke from a neuromuscular perspective, including stroke-induced alterations at the cortical, spinal and muscle levels. Method: Perspective based on narrative literature review. Results: Fatigue is a highly prevalent, but poorly understood symptom poststroke. Neuromuscular fatigue has central and peripheral origins. Individuals with stroke experienced greater central fatigue and less peripheral fatigue during voluntary contractions of the paretic leg in comparison to healthy participants. Neuromuscular adaptations to stroke create an increased susceptibility to central fatigue, which may be a contributing factor to the increased perception of tiredness during performance of activities of daily living. Future studies should investigate whether intervention-induced cortical plasticity, gains in muscle strength and endurance will attenuate self-reported fatigability. Conclusions: Fatigue is a common and debilitating consequence of stroke. Neuromuscular fatigue of central origin may contribute to self-reported fatigue. Continued focused and properly designed research studies should provide substantial insight into the therapeutic interventions that will improve the management of fatigue poststroke. Implications for Rehabilitation Fatigue is a common and debilitating consequence of stroke, which has received little attention in clinical rehabilitation. Insufficient understanding of the pathophysiology of poststroke fatigue limits advances in its treatment. Neuromuscular fatigue of central origin may contribute to the self-reported fatigue poststroke. Although speculative, rehabilitation interventions that foster neuroplasticity, muscle strength and endurance may have a role in the management of fatigue poststroke.
Transcutaneous ultrasound augments lysis of arterial thrombi in vivo.

BACKGROUND External ultrasound has a synergistic effect on thrombus disruption with thrombolytic agents in vitro. We hypothesized that transcutaneous ultrasound could augment thrombolysis in vivo. METHOD AND RESULTS Thrombus formation was induced electrically in 48 pairs of iliofemoral arteries of 24 rabbits; arterial occlusions were documented angiographically. In 17 of 24 rabbits, 25000 units/kg streptokinase was then administered intravenously. The pairs of iliofemoral arteries were randomized to receive ultrasound treatment or no ultrasound treatment. Low-frequency (26 kHz) ultrasound (continuous wave, 18 W/cm2) was applied transcutaneously over the area of occlusion. In 7 of 24 rabbits, 14 thrombotically occluded iliofemoral arteries were exposed to ultrasound alone without streptokinase. The results were evaluated through the use of angiography (TIMI grade flow) and histopathology. After 30 +/- 10 minutes of activated sonication combined with intravenous streptokinase, 10 of 17 iliofemoral arteries (59%) treated with transcutaneous ultrasound were widely patent angiographically, with TIMI grade 3 flow. Histologically, the patent arteries had only minimal focal moral thrombus. The angiographic patency rate was significantly lower in the control groups: 1 of 17 arteries (6%) treated with streptokinase alone (P = .0012) and 1 of 14 arteries (7%) treated with ultrasound alone (P = .0036). CONCLUSIONS In vivo transcutaneous ultrasound significantly augments lysis of thrombi with streptokinase in rabbit iliofemoral arteries.
Transcriptional regulation of the rat tissue type plasminogen activator gene: localization of DNA elements and nuclear factors mediating constitutive and cyclic AMP-induced expression

We have characterized tissue type plasminogen activator (tPA) promoter elements and nuclear factors required for follicle-stimulating hormone (FSH)-induced transcription of the rat tPA gene in granulosa cells and constitutive expression of the gene in the rat neuroblastoma cell line B103. Run-on transcription analysis of isolated nuclei revealed that B103 cells transcribe the tPA gene at a high and constitutive level, while FSH was found to induce tPA gene transcription in a rapid and transient manner in granulosa cells. The maximal FSH-induced transcription rate was obtained after 20 min and was similar in the absence or presence of the protein synthesis inhibitor cycloheximide. However, in the presence of cycloheximide, tPA transcription was not turned off but continued at a high rate for several hours. This phenomenon may at least partly explain the earlier finding that tPA mRNA is superinduced by FSH in the presence of cycloheximide. DNase I footprinting analysis of the first 621 bp of the tPA promoter revealed a total of six regions that interact with nuclear factors from B103 and granulosa cells. Deletion of the promoter region from positions -269 to -621, a region that includes the two most-upstream footprints, had no effect on constitutive or FSH-induced transcription in transient expression experiments. Nuclear extracts from both granulosa cells and B103 cells showed strong binding to a consensus cyclic AMP-responsive element (CRE) at positions -178 to -185 and a neighboring binding site for nuclear factor 1 (NF1) at positions -145 to -158. The factors binding to these two regions were identified as members of the CRE-binding protein and NF1 families of transcription factors, respectively. Footprints were also obtained over two GC boxes at positions -64 to -71 and -41 to -49. These footprints were more pronounced with nuclear extracts from B103 cells than with extracts from untreated or FSH-treated granulosa cells, but gel shift assays indicate that similar amounts of two distinct factors bind to the two GC boxes in both cell types. Transfection experiments using promoter constructs with inactivated promoter elements indicate that both the CRE and NF1 sites contribute to the FSH responsiveness of the rat tPA gene in granulosa cells, while only the NF1 site is important for constitutive expression in B103 cells. The two GC boxes were found to be necessary both for constitutive expression in B103 cells and for FSH-induced expression in granulosa cells, and inactivation of both GC boxes essentially eliminated the tPA promoter activity in both cell types.
Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3

Mice lacking suppressor of cytokine signaling 3 (SOCS3) exhibited embryonic lethality with death occurring between days 11 and 13 of gestation. At this stage, SOCS3−/− embryos were slightly smaller than wild type but appeared otherwise normal, and histological analysis failed to detect any anatomical abnormalities responsible for the lethal phenotype. Rather, in all SOCS3−/− embryos examined, defects were evident in placental development that would account for their developmental arrest and death. The placental spongiotrophoblast layer was significantly reduced and accompanied by increased numbers of giant trophoblast cells. Delayed branching of the chorioallantois was evident, and, although embryonic blood vessels were present in the labyrinthine layer of SOCS3−/− placentas, the network of embryonic vessels and maternal sinuses was poorly developed. Yolk sac erythropoiesis was normal, and, although the SOCS3−/− fetal liver was small at day 12.5 of gestation (E12.5), normal frequencies of erythroblasts and hematopoietic progenitor cells, including blast forming unit-erythroid (BFU-E) and, colony forming unit-erythroid (CFU-E) were present at both E11.5 and E12.5. Colony formation for both BFU-E and CFU-E from SOCS3−/− mice displayed wild-type quantitative responsiveness to erythropoietin (EPO), in the presence or absence of IL-3 or stem cell factor (SCF). These data suggest that SOCS3 is required for placental development but dispensable for normal hematopoiesis in the mouse embryo.
Perinatal risk factors for major intraventricular haemorrhage in the Australian and New Zealand Neonatal Network, 1995–97

Background: In 1995, large differences were identified in rates of grade 3–4 intraventricular/periventricular haemorrhage (major IVH) among neonatal intensive care units (NICUs) in the Australian and New Zealand Neonatal Network. Aims: To develop a predictive model for major IVH in order to allow risk adjustment for the variation in rates of major IVH among NICUs. Methods: Rates of IVH were determined in 5712 infants of 24–30 weeks gestation born from 1995 to 1997. Significant antenatal and perinatal variables for major IVH in 1995 and 1996 were identified by univariate and multivariate analysis. A predictive model was developed and then validated on 1997 data. Results: Rates of all grades of IVH fell from 1995 to 1997 (30.4 to 24.3%) but wide interunit variation remained. Seven antenatal and perinatal characteristics had significant association with major IVH: fetal distress, intrauterine growth restriction (protective), antenatal corticosteroids (protective), gestational age, 1 minute Apgar <4, male gender, and transfer after birth. A predictive model based on the last five of these variables was developed using data from 1995 and 1996 which gave an area under the receiver operator characteristic (ROC) curve of 0.76. This model was then validated on the 1997 dataset where an identical ROC curve resulted. Conclusions: Antenatal and perinatal factors are important in the pathogenesis of major IVH. The predictive model developed from these factors can be used to adjust for confounders in interunit outcome comparison.
Synthesis of enzymatically resistant nociceptin‐related peptides containing a carbamic acid residue

Nociceptin, a 17‐amino acid peptide (FGGFTGARKSARKLANQ, N/OFQ), is the endogenous ligand of the nociceptin/orphanin FQ (NOP) receptor. This receptor–ligand system is involved in various physiological as well as pathophysiological mechanisms, but owing to the peptidic structure, it is rapidly degraded by enzymes. The enzymatic digestion of nociceptin involves mainly aminopeptidases and yields Noc(2‐17)‐OH and other smaller fragments. We aimed at increasing the enzymatic stability against aminopeptidases in the case of peptide Noc(1‐13)‐NH2, which possesses the minimum sequence capable of interacting with the NOP receptor. Therefore we developed a new procedure for the synthesis of peptides with the carbamic acid residue [·‐NH‐CH(R)‐CO‐NH‐CO‐NH‐CH(Q)‐CO‐·]. A set of four carbamic acid‐nociceptin derivatives were produced. The carbamic acid residue was incorporated into the inner part of the peptides, building on solid phase, by using a suitable dipeptide fragment with carbamic acid residue produced by a simple and efficient three‐step solution phase procedure. Enzymatic stability of carbamic acid peptides was studied in the presence of aminopeptidase M (AP‐M) and in rat brain membrane homogenate. The receptor‐binding properties were also studied by radioligand binding assay on crude rat brain membranes and the activity of the ligands were analyzed on isolated mouse vas deferens (MVD) tissues. We found that incorporation of the carbamic acid residue into the N‐terminal part of nociceptin significantly increases the resistance against AP‐M. We observed the decrease of binding affinities to the NOP receptor in case of the peptides modified in the N‐terminal portion. Consequently, the incorporation of the carbamic acid residue into peptides can be proposed as a promising and reasonable tool for increasing enzymatic stability, where the native molecule is less sensitive for carbamic acid residue–related structural change. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.
Activity of Linezolid in an In Vitro Pharmacokinetic-Pharmacodynamic Model Using Different Dosages and Staphylococcus aureus and Enterococcus faecalis Strains with and without a Hypermutator Phenotype

ABSTRACT The influence of antibiotic dosages and bacterial mutator phenotypes on the emergence of linezolid-resistant mutants was evaluated in an in vitro pharmacokinetic-pharmacodynamic model. A twice-daily 0.5-h infusion of a 200-, 600-, or 800-mg dose for 48 h was simulated against four strains (MIC, 2 μg/ml): Staphylococcus aureus RN4220 and its mutator derivative MutS2, Enterococcus faecalis ATCC 29212, and a mutator clinical strain of E. faecalis, Ef1497. The peak concentrations (4.38 to 4.79, 13.4 to 14.6, and 19.2 to 19.5 μg/ml) and half-lives at β-phase (5.01 to 6.72 h) fit human plasma linezolid pharmacokinetics. Due to its bacteriostatic property, the cumulative percentages of the dosing interval during which the drug concentration exceeded the MIC (T > MIC), 66.6 and 69.1% of the dosing interval, were not significant, except for Ef1497, with an 800-mg dose and a T > MIC of 80.9%. At the standard 600-mg dosage, resistant mutants (2- to 8-fold MIC increases) were selected only with Ef1497. A lower, 200-mg dosage did not select resistant mutants of E. faecalis ATCC 29212, but a higher, 800-mg dosage against Ef1497 did not prevent their emergence. For the most resistant mutant (MIC, 16 μg/ml), characterization of 23S rRNA genes revealed the substitution A2453G in two of the four operons, which was previously described only in in vitro mutants of archaebacteria. Nevertheless, this mutant did not yield further mutants under 600- or 200-mg treatment. In conclusion, linezolid was consistently efficient against S. aureus strains. The emergence of resistant E. faecalis mutants was probably favored by the rapid decline of linezolid concentrations against a strong mutator, a phenotype less exceptional in E. faecalis than in S. aureus.
Digital Learning Environments - Constructing Augmented and Virtual Reality in Fire Safety

This article gives examples of how the use of Augmented Reality (AR) and Virtual Reality (VR) environments support the fire prevention training. We present the VR and AR games that we designed for fire safety training. Here, we see the VR environment as a digital learning environment while the AR environment is a mixed learning environment on-site. Combining VR and AR learning environments, physical, psychological, social and pedagogic dimensions are distinguished. We also describe the internal and external learning environment in the context of future technologies. The internal learning environment includes the virtual scenario, whereas the external learning environment is the situation in the room around the player - the authentic learning experience before, during and after the game play. These two layers need to be concerned and further developed when designing serious games. If not, the challenge is that the game, instead of being serious, remains on the level of entertainment.
The DNA Replication-related Element (DRE)/DRE-binding Factor System Is a Transcriptional Regulator of the Drosophila E2FGene*

Two mRNA species were observed for theDrosophila E2F (dE2F) gene, differing with regard to the first exons (exon 1-a and exon 1-b), which were expressed differently during development. A single transcription initiation site for mRNA containing exon 1-b was mapped by primer extension analysis and numbered +1. We found three tandemly aligned sequences, similar to the DNA replication-related element (DRE; 5′-TATCGATA), which is commonly required for transcription of genes related to DNA replication and cell proliferation, in the region upstream of this site. Band mobility shift analyses using oligonucleotides containing the DRE-related sequences with or without various base substitutions revealed that two out of three DRE-related sequences are especially important for binding to the DRE-binding factor (DREF). On footprinting analysis with Kc cell nuclear extracts and a glutathioneS-transferase fusion protein with the N-terminal fragment (1–125 amino acid residues) of DREF, all three DRE-related sequences were found to be protected. Transient luciferase expression assays in Kc cells demonstrated that the region containing the three DRE-related sequences is required for high promoter activity. We have established transgenic lines of Drosophila in which ectopic expression of DREF was targeted to the eye imaginal disc cells. Overexpression of DREF in eye imaginal disc cells enhanced the promoter activity ofdE2F. The obtained results indicate that the DRE/DREF system activates transcription of the dE2F gene.
Fine grained adaptive simulation with application to NoCs

We present a new adaptive simulation approach, where the simulation precision can be changed between RTL and gate level for individual submodules online during simulation. As gate level precision is rarely required for the total simulated duration, the low simulation performance that comes along with full gate level simulations calls for a methodology to simulate at highest precision only when actually needed. To fulfill this need, we introduce adaptive SystemC models encapsulating an RTL model and a synthesized gate level counterpart. Adaptive models multiplex between fixed abstraction models and efficiently perform the necessary state transfer, which is enabled in an automated way by giving limited access to the simulation kernel. Evaluations highlight the applicability of adaptive simulations whenever gate level simulations are only required part time, as speedups of 150 were achieved compared to full gate level simulation.
Toward routine detection of extracellular vesicles in clinical samples

The majority, if not all, of human cell types secrete extracellular vesicles (EVs) into their environment, at least partly as a means of intercellular communication. These secreted vesicles can be detected in most bodily fluids including blood, urine, and saliva. The number of secreted vesicles and their composition is altered in various pathological conditions, raising opportunities to exploit EVs as diagnostic and/or prognostic biomarkers. For this to become a reality, it is important to reach consensus regarding the standardization of protocols for sample collection, EV isolation, handling, and storage for valid comparison and interpretation of measurements. Depending on the information required, there are several detection options including EV number and size distribution, molecular surface markers, procoagulation activity, and RNA content. For these purposes, different techniques are currently utilized or under development. This review discusses the techniques that have the potential to become standard EV detection methods in a clinical diagnostic setting. In addition to the accuracy of the detection technique, other factors such as high‐throughput, cost‐effectiveness, time consumption, and required operator skill are important to consider. A combination of increasing fundamental knowledge, technological progress, standardization of sample collection, and processing protocols is required for EVs to become reliable predictors of altered physiology or development of disease suitable for routine clinical diagnostics. Cancer and (cardio)vascular disorders are examples of pathologies where EV detection may be applied in the near future for diagnosis and/or prognosis.
Effects of Isoflurane and Sevoflurane on Intracellular Calcium and Contractility in Pressure-overload Hypertrophy

Background: Depression of myocardial contractility as a result of isoflurane appears to be greater in myocardial hypertrophy, and the cellular basis for this difference in susceptibility is not clear. In this study we examined the effects of isoflurane and sevoflurane on contractility and intracellular calcium in an animal model of pressure-overload hypertrophy. Methods: Pressure-overload hypertrophy was established in young male ferrets by banding the main pulmonary artery for 1 month and the effects of isoflurane and sevoflurane on contractility and intracellular calcium ([Ca2+]i) were examined in isolated right ventricular papillary muscles, trabeculae, and myocytes. Intracellular calcium was measured with the bioluminescent photoprotein aequorin in isolated papillary muscles, and also with the fluorescent indicator fluo-3 in isolated ventricular myocytes. In addition, Ca2+ sensitivity was assessed in isolated trabeculae after disruption of the surface membrane with a nonionic detergent (skinned fibers). Results: In the presence of isoflurane and sevoflurane, papillary muscles from banded animals exhibited a greater depression of contractility and isolated ventricular myocytes showed a greater decrease in peak [Ca2+]i. Furthermore, baseline calcium sensitivity was decreased and the slope of the relationship between [Ca2+] and force was increased in skinned trabeculae from banded animals. Isoflurane decreased calcium sensitivity in trabeculae from both normal and banded animals. Conclusions: These results suggest that changes in [Ca2+]i and altered calcium sensitivity are both responsible for the exaggerated effects of some volatile anesthetics on contractility in pressure-overload hypertrophy.
Assessment of clinically significant changes in acute pain in children.

OBJECTIVE To quantify, using two pain assessment scales, the amount of change in pain severity required to achieve a clinically significant improvement in pain in children presenting to a pediatric emergency department (ED) with pain. METHODS Prospective, descriptive study involving all children presenting to a pediatric ED between 5 and 16 years of age inclusive with acute pain. Children were excluded if they 1) were intoxicated or had altered sensorium, 2) were clinically unstable, 3) were non-English-speaking, or 4) were developmentally delayed. Written informed consent was obtained. Children were asked to mark their current pain severity on the standardized Color Analogue Scale (CAS) and Faces Pain Scale (FPS). After each pain control intervention the child was asked to repeat these measurements and to describe whether his or her pain was "much less," "a little less," "about the same," "a little worse," or "much worse" compared with before. This process was repeated until the child was discharged from the ED or had a score of zero. The main outcome measure was the smallest change on the CAS or FPS necessary to cause the child to describe his or her pain as a "little less. " This was defined as the clinically significant change in pain. The "ideal" change in pain was defined as the amount of change necessary for the child to describe the pain as "much less" or at which point the child thought he or she no longer required any medicine to help the pain go away. RESULTS One hundred twenty-one children were enrolled with a mean age of 9.8 years (SD +/- 3.15). Males accounted for 56%. Pain was traumatic in 65% and nontraumatic in 35%. A total of 153 pain comparisons were made using the CAS and 154 using the FPS. Only three children complained that their pain got worse (two a little worse and one much worse). Pain was described as "the same" in 20. Of the 60 pain comparisons judged to be a "little less," the CAS score changed by a median of 2.0 cm [interquartile ratio (IQR) 1-3], and the FPS by 1.0 face (IQR 1-2). In the 71 children who judged their pain to be "much less," the CAS decreased by a median of 4.0 cm (IQR 2-5) and the FPS by 2.0 faces (IQR 2-3). CONCLUSIONS The assessment and treatment of pain in children are an important component of pediatric practice, especially in the ED. This study provides health care professionals and clinical investigators the information necessary to assess whether their method of pain control in children is clinically relevant.