Miracle-dz/UniFAR-FTUs huggingface dataset:
The next step in translational research: lessons learned from the first preclinical randomized controlled trial

For years, low reproducibility of preclinical trials and poor translation of promising preclinical therapies to the clinic have posed major challenges to translational research in most biomedical fields. To overcome the limitations that stand between experimental and clinical research, international consortia have attempted to establish standardized guidelines for study design and for reporting the resulting data. In addition, multicenter preclinical randomized controlled trials (pRCTs) have been proposed as a suitable tool for ‘bridging the gap’ between experimental research and clinical trials. We recently reported the design and results of the first such pRCT in which we confirmed the feasibility of using a coordinated approach with standardized protocols in collaboration with independent multinational research centers. However, despite its successes, this first pRCT also had several difficulties, particularly with respect to following the protocols established in the study design and analyzing the data. Here, we review our experiences performing the study, and we analyze and discuss the lessons learned from performing the first pRCT. Moreover, we provide suggestions regarding how obstacles can be overcome to improve the performance and outcome of future pRCT studies.
Use of two grading systems in determining risks associated with timing of fracture fixation

BACKGROUND The early appropriate care (EAC) protocol and clinical grading system (CGS1) propose criteria that suggest timing of definitive fracture fixation by assessing risk for complications. This study applies these criteria to a cohort of patients with orthopedic injuries and determines clinical outcomes for groups stratified by risk and timing of fracture fixation. METHODS This retrospective work was performed at a Level I trauma center. Patients with operative femur, pelvis, acetabulum, and/or thoracolumbar spine injuries were included. Fractures were treated surgically, either early or delayed. Patients were retrospectively categorized into low- or high-risk groups using the EAC protocol and described as stable, borderline, unstable, or in extremis using a modified CGS (mCGS). RESULTS In the EAC analysis, low-risk patients treated early had fewer complications compared with delayed treatment. Among high-risk patients, no significant difference was noted. With the use of the mCGS, stable patients treated early had fewer complications compared with delayed patients. No difference in complications was detected for unstable and in extremis patients. Borderline patients treated early had fewer complications compared with delayed treatment, although results were not supported by sensitivity analysis. CONCLUSION The EAC protocol can effectively distinguish patients who are at high risk for complications if treated early. Early treatment in the low-risk group was associated with fewer complications. The mCGS differentiates stable patients who benefit from early definitive treatment of fractures as well as severely injured patients (unstable or in extremis) who may benefit from damage-control orthopedics. Borderline patients may also benefit from early definitive treatment, but criteria defining borderline patients require further study. LEVEL OF EVIDENCE Prognostic study, level III.
DNAzyme Delivery Systems: Getting Past First Base

DNAzyme technology has evolved into a discipline with the potential for presenting drug agents against cancer and atherosclerosis. However, current approaches still rely on sub-optimal drug delivery systems (DDSs) for DNAzymes. Certain DDSs have shown potential, such as chitosan and polyethylenimine (PEI), although more emphasis needs to be placed on actual efficacy and safety, in addition to establishing the pharmacokinetics of the molecule being tested. Unfortunately, the plethora of DDSs reported for antisense delivery – the trailblazer for target gene knockdown agents – have yet to yield even one entity capable of being used clinically, and clinicians have resorted to administering continuous systemic free oligonucleotides with promising, albeit lukewarm results. The challenge ahead for DNAzymes to be considered genuine drug candidates alongside siRNA and antisense simply lies in the better implementation of DDSs.
Reforming Social Work Education: Some Reflections on the Contribution of Practice Learning

Social work in the UK is currently undergoing a process of major reform and a wide range of recommendations have been made aimed at improving practice and education. This paper focuses on the Social Work Reform Board's proposals for improving practice learning in qualifying level social work education. It examines how recommendations for better partnership working between Higher Education Institutions and employers and developing critical reflection in agencies are likely to impact on student learning. Drawing on experience of social work education in Northern Ireland it considers the potential of the Reform Board's proposals for improving the quality of practice learning and enhancing students' preparedness for employment. The paper concludes that differences in educational aims and priorities, resistant practice cultures and cut-backs in resourcing could present major obstacles that must be overcome if this potential is to be realised.
BDNF isoforms: a round trip ticket between neurogenesis and serotonin?

The brain‐derived neurotrophic factor, BDNF, was discovered more than 30 years ago and, like other members of the neurotrophin family, this neuropeptide is synthetized as a proneurotrophin, the pro‐BDNF, which is further cleaved to yield mature BDNF. The myriad of actions of these two BDNF isoforms in the central nervous system is constantly increasing and requires the development of sophisticated tools and animal models to refine our understanding. This review is focused on BDNF isoforms, their participation in the process of neurogenesis taking place in the hippocampus of adult mammals, and the modulation of their expression by serotonergic agents. Interestingly, around this triumvirate of BDNF, serotonin, and neurogenesis, a series of recent research has emerged with apparently counterintuitive results. This calls for an exhaustive analysis of the data published so far and encourages thorough work in the quest for new hypotheses in the field.
Tissue kallikrein protects SH‐SY5Y neuronal cells against oxygen and glucose deprivation‐induced injury through bradykinin B2 receptor‐dependent regulation of autophagy induction

Previous studies have demonstrated that tissue kallikrein (TK) protects against cerebral ischemia injury mainly through inhibition of apoptosis via bradykinin B2 receptor (B2R). In this study, we proposed that autophagy induction contributed to the neuroprotective mechanism of TK. To validate this hypothesis, we investigated TK‐induced autophagy and its signaling mechanisms in human SH‐SY5Y cells exposed to oxygen and glucose deprivation (OGD). We found that TK treatment enhanced autophagy induction, reflected by augmented LC3 conversion and Beclin1 expression, decreased p62 levels and increased monomeric red fluorescent protein‐LC3 puncta formation. Green fluorescent protein‐monomeric red fluorescent protein‐LC3 adenovirus assay indicated that TK maintained autophagic flux. Moreover, bafilomycin A1 (Baf.A1) caused obvious LC3‐II accumulation either in the presence or absence of TK. Autophagy inhibition by Beclin1 knockdown or Baf.A1 treatment abrogated the neuroprotective effects of TK. Mitogen‐activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal‐regulated kinase (ERK)1/2 and AMP‐activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR) signaling were induced by OGD stress and enhanced by TK. MEK/ERK inhibitor U0126 alone elevated autophagy in OGD conditions, but impaired TK‐induced autophagy. Blockade of AMPK/TSC2/mTOR signaling by AMPK inhibitor compound C and shRNA mediated the knockdown of AMPK α1 and TSC2 but abolished autophagy in SH‐SY5Y cells exposed to OGD treated either with or without TK. Moreover, B2R expression was up‐regulated by OGD exposure. B2R knockdown attenuated autophagy and suppressed MEK1/2/ERK1/2 and AMPK/TSC2/mTOR signaling in OGD conditions in either the presence or absence of TK. In sum, we revealed the significance of B2R‐mediated MEK/ERK and AMPK signaling in autophagy induction under OGD stress, and proposed novel mechanisms involved in the neuropotective function of TK through B2R‐dependent regulation of autophagy.
Proteolysis of α‐synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology

Progression of α‐synuclein inclusion pathology may occur through cycles of release and uptake of α‐synuclein aggregates, which induce additional intracellular α‐synuclein inclusion pathology. This process may explain (i) the presence of α‐synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human α‐synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread. We investigated the cellular mechanisms underlying intraneuronal α‐synuclein aggregation following exposure to exogenous preformed α‐synuclein amyloid fibrils. Exogenous α‐synuclein fibrils efficiently attached to cell membranes and were subsequently internalized and degraded within the endosomal/lysosomal system. However, internalized α‐synuclein amyloid fibrils can apparently overwhelm the endosomal/lysosomal machinery leading to the induction of intraneuronal α‐synuclein inclusions comprised of endogenous α‐synuclein. Furthermore, the efficiency of inclusion formation was relatively low in these studies compared to studies using primary neuronal‐glial cultures over‐expressing α‐synuclein. Our study indicates that under physiologic conditions, endosomal/lysosomal function acts as an endogenous barrier to the induction of α‐synuclein inclusion pathology, but when compromised, it may lower the threshold for pathology induction/transmission.
Neonatal seizures are associated with redistribution and loss of GABAA α‐subunits in the hypoxic‐ischaemic pig

Seizures are a common manifestation of hypoxic‐ischaemic brain injury in the neonate. In status epilepticus models alterations to GABAAR subunit expression have been suggested to contribute to (i) abnormal development of the GABAergic system, (ii) why seizures become self‐sustaining and (iii) the development of pharmacoresistance. Detailed investigation of GABAAR subunit protein expression after neonatal hypoxia‐ischaemia (HI) is currently insufficient. Using our pig model of HI and subsequent spontaneous neonatal seizures, we investigated changes in protein expression of the three predominant α‐subunits of the GABAAR; α1, α2 and α3. Anaesthetized, ventilated newborn pigs (< 24 h old) were subjected to 30 min HI and subsequently recovered to 24 or 72 h. Amplitude‐integrated electroencephalography was used to monitor brain activity and identify seizure activity. Brain tissue was collected post‐mortem and GABAAR α‐subunit protein expression was analysed using western blot and immunohistochemistry. GABAAR α1 and α3 protein expression was significantly reduced in animals that developed seizures after HI; HI animals that did not develop seizures did not exhibit the same reductions. Immunohistochemistry revealed decreased α1 and α3 expression, and α1 redistribution from the cell membrane to the cytosol, in the hippocampus of seizure animals. Multivariate analyses, controlling for HI severity and neuronal injury, revealed that seizures were independently associated with significant GABAAR α3 reduction. This is the first study to show loss and redistribution of GABAAR α‐subunits in a neonatal brain experiencing seizures. Our findings are similar to those reported in models of SE and in chronic epilepsy.
Internal anatomy of Haliclystus antarcticus (Cnidaria, Staurozoa) with a discussion on histological features used in staurozoan taxonomy

Stauromedusae have relatively few macromorphological characters, making both their taxonomy and identification difficult. For this reason, histological characters are also employed in the taxonomy of the group. This study presents a detailed description of the histomorphology of Haliclystus antarcticus Pfeffer, 1889 (Cnidaria, Staurozoa). We make new observations for the species and for the class, and address functional, taxonomical, and evolutionary aspects of staurozoan histo‐anatomy. A complete reconstruction of H. antarcticus body plan is used to guide a more detailed observation, based on light microscopy, of structures rarely cited in the literature, such as the intertentacular lobules, the ostia between adjacent perradial pockets, and the male and female gonadal vesicles. Two possible regions of nematocyst formation are hypothesized and discussed. We also provide a review of the current use of histological characters in the taxonomy of the group. Understanding the body plan of stauromedusae is a challenge, because each single individual presents characters found in medusae and in polyps of other medusozoans. Comprehensive histological descriptions are important to establish relations of homology within Staurozoa and Cnidaria, providing crucial data on their evolution. J. Morphol. 274:1365–1383, 2013. © 2013 Wiley Periodicals, Inc.
Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling

Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long‐term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response‐outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene‐exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision‐making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug‐use.
Near real-time automated dose restoration in IMPT to compensate for daily tissue density variations in prostate cancer

Proton therapy is very sensitive to daily density changes along the pencil beam paths. The purpose of this study is to develop and evaluate an automated method for adaptation of IMPT plans to compensate for these daily tissue density variations. A two-step restoration method for ‘densities-of-the-day’ was created: (1) restoration of spot positions (Bragg peaks) by adapting the energy of each pencil beam to the new water equivalent path length; and (2) re-optimization of pencil beam weights by minimizing the dosimetric difference with the planned dose distribution, using a fast and exact quadratic solver. The method was developed and evaluated using 8–10 repeat CT scans of 10 prostate cancer patients. Experiments demonstrated that giving a high weight to the PTV in the re-optimization resulted in clinically acceptable restorations. For all scans we obtained V95% ⩾ 98% and V107% ⩽ 2%. For the bladder, the differences between the restored and the intended treatment plan were below +2 Gy and +2%-point. The rectum differences were below +2 Gy and +2%-point for 90% of the scans. In the remaining scans the rectum was filled with air, which partly overlapped with the PTV. The air cavity distorted the Bragg peak resulting in less favorable rectum doses.
Gill morphometrics of the thresher sharks (Genus Alopias): Correlation of gill dimensions with aerobic demand and environmental oxygen

Gill morphometrics of the three thresher shark species (genus Alopias) were determined to examine how metabolism and habitat correlate with respiratory specialization for increased gas exchange. Thresher sharks have large gill surface areas, short water–blood barrier distances, and thin lamellae. Their large gill areas are derived from long total filament lengths and large lamellae, a morphometric configuration documented for other active elasmobranchs (i.e., lamnid sharks, Lamnidae) that augments respiratory surface area while limiting increases in branchial resistance to ventilatory flow. The bigeye thresher, Alopias superciliosus, which can experience prolonged exposure to hypoxia during diel vertical migrations, has the largest gill surface area documented for any elasmobranch species studied to date. The pelagic thresher shark, A. pelagicus, a warm‐water epi‐pelagic species, has a gill surface area comparable to that of the common thresher shark, A. vulpinus, despite the latter's expected higher aerobic requirements associated with regional endothermy. In addition, A. vulpinus has a significantly longer water–blood barrier distance than A. pelagicus and A. superciliosus, which likely reflects its cold, well‐oxygenated habitat relative to the two other Alopias species. In fast‐swimming fishes (such as A. vulpinus and A. pelagicus) cranial streamlining may impose morphological constraints on gill size. However, such constraints may be relaxed in hypoxia‐dwelling species (such as A. superciliosus) that are likely less dependent on streamlining and can therefore accommodate larger branchial chambers and gills. J. Morphol. 276:589–600, 2015. © 2015 Wiley Periodicals, Inc.
Assessment of dosimetric impact of system specific geometric distortion in an MRI only based radiotherapy workflow for prostate

Dosimetric errors in a magnetic resonance imaging (MRI) only radiotherapy workflow may be caused by system specific geometric distortion from MRI. The aim of this study was to evaluate the impact on planned dose distribution and delineated structures for prostate patients, originating from this distortion. A method was developed, in which computer tomography (CT) images were distorted using the MRI distortion field. The displacement map for an optimized MRI treatment planning sequence was measured using a dedicated phantom in a 3 T MRI system. To simulate the distortion aspects of a synthetic CT (electron density derived from MR images), the displacement map was applied to CT images, referred to as distorted CT images. A volumetric modulated arc prostate treatment plan was applied to the original CT and the distorted CT, creating a reference and a distorted CT dose distribution. By applying the inverse of the displacement map to the distorted CT dose distribution, a dose distribution in the same geometry as the original CT images was created. For 10 prostate cancer patients, the dose difference between the reference dose distribution and inverse distorted CT dose distribution was analyzed in isodose level bins. The mean magnitude of the geometric distortion was 1.97 mm for the radial distance of 200–250 mm from isocenter. The mean percentage dose differences for all isodose level bins, were ⩽0.02% and the radiotherapy structure mean volume deviations were <0.2%. The method developed can quantify the dosimetric effects of MRI system specific distortion in a prostate MRI only radiotherapy workflow, separated from dosimetric effects originating from synthetic CT generation. No clinically relevant dose difference or structure deformation was found when 3D distortion correction and high acquisition bandwidth was used. The method could be used for any MRI sequence together with any anatomy of interest.
Morphological specializations for fetal maintenance in viviparous vertebrates: An introduction and historical retrospective

In many viviparous vertebrates, pregnant females sustain their developing embryos and provide them with nutrients by means of placentas and a diversity of other types of specializations. With this article, we introduce a virtual (online) issue of the Journal of Morphology that presents 12 recent papers on fetal maintenance in viviparous vertebrates. We also outline the history of research in this area and document the central role of morphology in helping to explain the function and evolution of specializations for fetal nutrition. This virtual issue of the Journal of Morphology is an outgrowth of a symposium held under auspices of the International Congress of Vertebrate Morphology. The included papers reflect a diversity of taxa, research methods, and biological issues. To celebrate the publication of this virtual issue of the Journal of Morphology, the publisher is making freely available to readers a number of other relevant papers published in the journal over the past 128 years. J. Morphol. 276:1–16, 2015. © 2015 Wiley Periodicals, Inc.
Polyenergetic known-component CT reconstruction with unknown material compositions and unknown x-ray spectra

Metal artifacts can cause substantial image quality issues in computed tomography. This is particularly true in interventional imaging where surgical tools or metal implants are in the field-of-view. Moreover, the region-of-interest is often near such devices which is exactly where image quality degradations are largest. Previous work on known-component reconstruction (KCR) has shown the incorporation of a physical model (e.g. shape, material composition, etc) of the metal component into the reconstruction algorithm can significantly reduce artifacts even near the edge of a metal component. However, for such approaches to be effective, they must have an accurate model of the component that include energy-dependent properties of both the metal device and the CT scanner, placing a burden on system characterization and component material knowledge. In this work, we propose a modified KCR approach that adopts a mixed forward model with a polyenergetic model for the component and a monoenergetic model for the background anatomy. This new approach called Poly-KCR jointly estimates a spectral transfer function associated with known components in addition to the background attenuation values. Thus, this approach eliminates both the need to know component material composition a prior as well as the requirement for an energy-dependent characterization of the CT scanner. We demonstrate the efficacy of this novel approach and illustrate its improved performance over traditional and model-based iterative reconstruction methods in both simulation studies and in physical data including an implanted cadaver sample.