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The presubiculum is preserved from neurodegenerative changes in Alzheimer’s disease
2018; 6(1): Art. 62Abstract In the majority of affected brain regions the pathological hallmarks of Alzheimer’s disease (AD) are β-amyloid (Aβ) deposits in the form of diffuse and neuritic plaques, tau pathology in the form of neurofibrillary tangles, neuropil threads and plaque-associated abnormal neurites in combination with an inflammatory response. However, the anatomical area of the presubiculum, is characterised by the presence of a single large evenly distributed ‘lake-like’ Aβ deposit with minimal tau deposition or accumulation of inflammatory markers. Post-mortem brain samples from sporadic AD (SAD) and familial AD (FAD) and two hereditary cerebral amyloid diseases, familial British dementia (FBD) and familial Danish dementia (FDD) were used to compare the morphology of the extracellular proteins deposited in the presubiculum compared to the entorhinal cortex. The level of tau pathology and the extent of microglial activation were quantitated in the two brain regions in SAD and FAD. Frozen tissue was used to investigate the Aβ species and proteomic differences between the two regions. Consistent with our previous investigations of FBD and FDD cases we were able to establish that the ‘lake-like’ pre-amyloid deposits of the presubiculum were not a unique feature of AD but they also found two non-Aβ amyloidosis. Comparing the presubiculum to the entorhinal cortex the number of neurofibrillary tangles and tau load were significantly reduced; there was a reduction in microglial activation; there were differences in the Aβ profiles and the investigation of the whole proteome showed significant changes in different protein pathways. In summary, understanding why the presubiculum has a different morphological appearance, biochemical and proteomic makeup compared to surrounding brain regions severely affected by neurodegeneration could lead us to understanding protective mechanisms in neurodegenerative diseases. -
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Can the health related quality of life measure QOLIBRI- overall scale (OS) be of use after stroke? A validation study
2018; 18(1): Art. 98Abstract Background Brief measures of health-related quality of life (HRQOL) that assess both patient-reported functioning and well-being after stroke are scarce. The objective of this study was to examine reliability and validity of one of these measures, the patient-reported Quality of Life after Brain Injury–Overall Scale (QOLIBRI-OS), in patients after stroke. Methods Stroke survivors were examined prospectively using survey methods. Core survey data (n = 125) and retest data (n = 36) were obtained at 3 and 12 months, respectively. Item properties (distribution, floor and ceiling effects), psychometric properties (reliability and model fit), and validity (correlations with established measures of anxiety, depression and HRQOL) of the QOLIBRI-OS were examined. Results Missing responses on the questionnaire were low (0.5%). All items were positively skewed. No floor effects were present, whereas five out of six items showed ceiling effects. The summary QOLIBRI-OS score exhibited no floor or ceiling effects, and had excellent internal consistency (Cronbach’s α =0.93). All item-total correlations were high (0.73–0.88). The test-retest reliability of single items varied from 0.74 to 0.91 and was 0.93 for the overall score. The confirmatory factor analysis yielded an excellent fit for a five-item version and provided tentative support for the original six-item version. The convergent validity correlations were in the hypothesized directions, thus supporting the construct validity. Conclusions The brief QOLIBRI-OS is a valid and reliable brief health-related outcome measure that is appropriate for screening HRQOL in patients after stroke. -
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“Some fuzzy math”: relational information on debt value adjustments by managers and the financial press
Abstract This study provides comprehensive descriptive evidence on the occurrence, size, and reporting by managers and the financial press of debt value adjustments due to a change in own credit risk (DVAs). The study is motivated by a public debate about DVAs in which critics describe them as “counterintuitive” and claim that managers disclose DVA information strategically to make firms “look good”. Analyzing a sample of 405 firm-quarters of 19 US financial firms that report DVAs between 2007 and 2014, I found that positive and negative DVAs appear similarly often and with similar magnitude. I further found that managers provide more information on large negative DVAs compared to positive DVAs. Managers also provide more DVA information when they have strategic incentives to do so. Examining newspaper articles on 202 firm-quarters, I found that the financial press is more likely to cover large positive DVAs and DVAs about which managers provided more information. Analyzing the articles’ content, I found that the press is more likely to provide new DVA information if managers’ press releases contain little information. The findings are in line with popular claims of asymmetric DVA reporting by managers. They are further consistent with the financial press acting as a counterweight to such asymmetric reporting. -
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Population genetic structure and evolutionary history of Bale monkeys (Chlorocebus djamdjamensis) in the southern Ethiopian Highlands
2018; 18(1): Art. 106Abstract Background Species with a restricted geographic distribution, and highly specialized habitat and dietary requirements, are particularly vulnerable to extinction. The Bale monkey (Chlorocebus djamdjamensis) is a little-known arboreal, bamboo-specialist primate endemic to the southern Ethiopian Highlands. While most Bale monkeys inhabit montane forests dominated by bamboo, some occupy forest fragments where bamboo is much less abundant. We used mitochondrial DNA (mtDNA) sequences to analyse the genetic structure and evolutionary history of Bale monkeys covering the majority of their remaining distribution range. We analysed 119 faecal samples from their two main habitats, continuous forest (CF) and fragmented forests (FF), and sequenced 735 bp of the hypervariable region I (HVI) of the control region. We added 12 orthologous sequences from congeneric vervets (C. pygerythrus) and grivets (C. aethiops) as well as animals identified as hybrids, previously collected in southern Ethiopia. Results We found strong genetic differentiation (with no shared mtDNA haplotypes) between Bale monkey populations from CF and FF. Phylogenetic analyses revealed two distinct and highly diverged clades: a Bale monkey clade containing only Bale monkeys from CF and a green monkey clade where Bale monkeys from FF cluster with grivets and vervets. Analyses of demographic history revealed that Bale monkey populations (CF and FF) have had stable population sizes over an extended period, but have all recently experienced population declines. Conclusions The pronounced genetic structure and deep mtDNA divergence between Bale monkey populations inhabiting CF and FF are likely to be the results of hybridization and introgression of the FF population with parapatric Chlorocebus species, in contrast to the CF population, which was most likely not impacted by hybridization. Hybridization in the FF population was probably enhanced by an alteration of the bamboo forest habitat towards a more open woodland habitat, which enabled the parapatric Chlorocebus species to invade the Bale monkey's range and introgress the FF population. We therefore propose that the CF and FF Bale monkey populations should be managed as separate units when developing conservation strategies for this threatened species. - Dokument ansehen
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How can we teach medical students to choose wisely? A randomised controlled cross-over study of video- versus text-based case scenarios
2018; 16(1): Art. 107Abstract Background The Choosing Wisely campaign highlights the importance of clinical reasoning abilities for competent and reflective physicians. The principles of this campaign should be addressed in undergraduate medical education. Recent research suggests that answering questions on important steps in patient management promotes knowledge retention. It is less clear whether increasing the authenticity of educational material by the inclusion of videos further enhances learning outcome. Methods In a prospective randomised controlled cross-over study, we assessed whether repeated video-based testing is more effective than repeated text-based testing in training students to choose appropriate diagnostic tests, arrive at correct diagnoses and identify advisable therapies. Following an entry exam, fourth-year undergraduate medical students attended 10 weekly computer-based seminars during which they studied patient case histories. Each case contained five key feature questions (items) on the diagnosis and treatment of the presented patient. Students were randomly allocated to read text cases (control condition) or watch videos (intervention), and assignment to either text or video was switched between groups every week. Using a within-subjects design, student performance on video-based and text-based items was assessed 13 weeks (exit exam) and 9 months (retention test) after the first day of term. The primary outcome was the within-subject difference in performance on video-based and text-based items in the exit exam. Results Of 125 eligible students, 93 provided data for all three exams (response rate 74.4%). Percent scores were significantly higher for video-based than for text-based items in the exit exam (76.2 ± 19.4% vs. 72.4 ± 19.1%, p = 0.026) but not the retention test (69.2 ± 20.2% vs. 66.4 ± 20.3%, p = 0.108). An additional Bayesian analysis of this retention test suggested that video-based training is marginally more effective than text-based training in the long term (Bayes factor 2.36). Regardless of presentation format, student responses revealed a high prevalence of erroneous beliefs that, if applied to the clinical context, could place patients at risk. Conclusion Repeated video-based key feature testing produces superior short-term learning outcome compared to text-based testing. Given the high prevalence of misconceptions, efforts to improve clinical reasoning training in medical education are warranted. The Choosing Wisely campaign lends itself to being part of this process. -
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The inflammatory response and neuronal injury in Streptococcus suis meningitis
2018; 18(1): Art. 297Abstract Background Many of the currently used models of bacterial meningitis have limitations due to direct inoculation of pathogens into the cerebrospinal fluid or brain and a relatively insensitive assessment of long-term sequelae. The present study evaluates the utility of a Streptococcus (S.) suis intranasal infection model for the investigation of experimental therapies in meningitis. Methods We examined the brains of 10 piglets with S. suis meningitis as well as 14 control piglets by histology, immunohistochemistry and in-situ tailing for morphological alterations in the hippocampal dentate gyrus and microglial activation in the neocortex. Results In piglets with meningitis, the density of apoptotic neurons was significantly higher than in control piglets. Moreover, scoring of microglial morphology revealed a significant activation of these cells during meningitis. The slight increase in the density of dividing cells, young neurons and microglia observed in piglets suffering from meningitis was not statistically significant, probably because of the short time frame between onset of clinical signs and organ sampling. Conclusions The morphological changes found during S. suis meningitis are in accordance with abnormalities in other animal models and human autopsy cases. Therefore, the pig should be considered as a model for evaluating effects of experimental therapeutic approaches on neurological function in bacterial meningitis. -
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Reducing antibiotic use for uncomplicated urinary tract infection in general practice by treatment with uva-ursi (REGATTA) – a double-blind, randomized, controlled comparative effectiveness trial
2018; 18(1): Art. 203Abstract Background Uncomplicated urinary tract infections (UTI) are common in general practice and usually treated with antibiotics. This contributes to increasing resistance rates of uropathogenic bacteria. A previous trial showed a reduction of antibiotic use in women with UTI by initial symptomatic treatment with ibuprofen. However, this treatment strategy is not suitable for all women equally. Arctostaphylos uva-ursi (UU, bearberry extract arbutin) is a potential alternative treatment. This study aims at investigating whether an initial treatment with UU in women with UTI can reduce antibiotic use without significantly increasing the symptom burden or rate of complications. Methods This is a double-blind, randomized, and controlled comparative effectiveness trial. Women between 18 and 75 years with suspected UTI and at least two of the symptoms dysuria, urgency, frequency or lower abdominal pain will be assessed for eligibility in general practice and enrolled into the trial. Participants will receive either a defined daily dose of 3 × 2 arbutin 105 mg for 5 days (intervention) or fosfomycin 3 g once (control). Antibiotic therapy will be provided in the intervention group only if needed, i.e. for women with worsening or persistent symptoms. Two co-primary outcomes are the number of all antibiotic courses regardless of the medical indication from day 0–28, and the symptom burden, defined as a weighted sum of the daily total symptom scores from day 0–7. The trial result is considered positive if superiority of initial treatment with UU is demonstrated with reference to the co-primary outcome number of antibiotic courses and non-inferiority of initial treatment with UU with reference to the co-primary outcome symptom burden. Discussion The trial’s aim is to investigate whether initial treatment with UU is a safe and effective alternative treatment strategy in women with UTI. In that case, the results might change the existing treatment strategy in general practice by promoting delayed prescription of antibiotics and a reduction of antibiotic use in primary care. Trial registration EudraCT: 2016–000477-21 . Clinical trials.gov: NCT03151603 (registered: 10 May 2017). -
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Enhancing oil production and harvest by combining the marine alga Nannochloropsis oceanica and the oleaginous fungus Mortierella elongata
2018; 11(1): Art. 174Abstract Background Although microalgal biofuels have potential advantages over conventional fossil fuels, high production costs limit their application in the market. We developed bio-flocculation and incubation methods for the marine alga, Nannochloropsis oceanica CCMP1779, and the oleaginous fungus, Mortierella elongata AG77, resulting in increased oil productivity. Results By growing separately and then combining the cells, the M. elongata mycelium could efficiently capture N. oceanica due to an intricate cellular interaction between the two species leading to bio-flocculation. Use of a high-salt culture medium induced accumulation of triacylglycerol (TAG) and enhanced the contents of polyunsaturated fatty acids (PUFAs) including arachidonic acid and docosahexaenoic acid in M. elongata. To increase TAG productivity in the alga, we developed an effective, reduced nitrogen-supply regime based on ammonium in environmental photobioreactors. Under optimized conditions, N. oceanica produced high levels of TAG that could be indirectly monitored by following chlorophyll content. Combining N. oceanica and M. elongata to initiate bio-flocculation yielded high levels of TAG and total fatty acids, with ~ 15 and 22% of total dry weight (DW), respectively, as well as high levels of PUFAs. Genetic engineering of N. oceanica for higher TAG content in nutrient-replete medium was accomplished by overexpressing DGTT5, a gene encoding the type II acyl-CoA:diacylglycerol acyltransferase 5. Combined with bio-flocculation, this approach led to increased production of TAG under nutrient-replete conditions (~ 10% of DW) compared to the wild type (~ 6% of DW). Conclusions The combined use of M. elongata and N. oceanica with available genomes and genetic engineering tools for both species opens up new avenues to improve biofuel productivity and allows for the engineering of polyunsaturated fatty acids. -
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In-depth proteomic analyses of Haliotis laevigata (greenlip abalone) nacre and prismatic organic shell matrix
2018; 16(1): Art. 11Abstract Background The shells of various Haliotis species have served as models of invertebrate biomineralization and physical shell properties for more than 20 years. A focus of this research has been the nacreous inner layer of the shell with its conspicuous arrangement of aragonite platelets, resembling in cross-section a brick-and-mortar wall. In comparison, the outer, less stable, calcitic prismatic layer has received much less attention. One of the first molluscan shell proteins to be characterized at the molecular level was Lustrin A, a component of the nacreous organic matrix of Haliotis rufescens. This was soon followed by the C-type lectin perlucin and the growth factor-binding perlustrin, both isolated from H. laevigata nacre, and the crystal growth-modulating AP7 and AP24, isolated from H. rufescens nacre. Mass spectrometry-based proteomics was subsequently applied to to Haliotis biomineralization research with the analysis of the H. asinina shell matrix and yielded 14 different shell-associated proteins. That study was the most comprehensive for a Haliotis species to date. Methods The shell proteomes of nacre and prismatic layer of the marine gastropod Haliotis laevigata were analyzed combining mass spectrometry-based proteomics and next generation sequencing. Results We identified 297 proteins from the nacreous shell layer and 350 proteins from the prismatic shell layer from the green lip abalone H. laevigata. Considering the overlap between the two sets we identified a total of 448 proteins. Fifty-one nacre proteins and 43 prismatic layer proteins were defined as major proteins based on their abundance at more than 0.2% of the total. The remaining proteins occurred at low abundance and may not play any significant role in shell fabrication. The overlap of major proteins between the two shell layers was 17, amounting to a total of 77 major proteins. Conclusions The H. laevigata shell proteome shares moderate sequence similarity at the protein level with other gastropod, bivalve and more distantly related invertebrate biomineralising proteomes. Features conserved in H. laevigata and other molluscan shell proteomes include short repetitive sequences of low complexity predicted to lack intrinsic three-dimensional structure, and domains such as tyrosinase, chitin-binding, and carbonic anhydrase. This catalogue of H. laevigata shell proteins represents the most comprehensive for a haliotid and should support future efforts to elucidate the molecular mechanisms of shell assembly. -
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Medicine, market and communication: ethical considerations in regard to persuasive communication in direct-to-consumer genetic testing services
2018; 19(1): Art. 56Abstract Background Commercial genetic testing offered over the internet, known as direct-to-consumer genetic testing (DTC GT), currently is under ethical attack. A common critique aims at the limited validation of the tests as well as the risk of psycho-social stress or adaption of incorrect behavior by users triggered by misleading health information. Here, we examine in detail the specific role of advertising communication of DTC GT companies from a medical ethical perspective. Our argumentative analysis departs from the starting point that DTC GT operates at the intersection of two different contexts: medicine on the one hand and the market on the other. Both fields differ strongly with regard to their standards of communication practices and the underlying normative assumptions regarding autonomy and responsibility. Methods Following a short review of the ethical contexts of medical and commercial communication, we provide case examples for persuasive messages of DTC GT websites and briefly analyze their design with a multi-modal approach to illustrate some of their problematic implications. Results We observe three main aspects in DTC GT advertising communication: (1) the use of material suggesting medical professional legitimacy as a trust-establishing tool, (2) the suggestion of empowerment as a benefit of using DTC GT services and (3) the narrative of responsibility as a persuasive appeal to a moral self-conception. Conclusions While strengthening and respecting the autonomy of a patient is the focus in medical communication, specifically genetic counselling, persuasive communication is the normal mode in marketing of consumer goods, presuming an autonomous, rational, independent consumer. This creates tension in the context of DTC GT regarding the expectation and normative assessment of communication strategies. Our analysis can even the ground for a better understanding of ethical problems associated with intersections of medical and commercial communication and point to perspectives of analysis of DTC GT advertising. -
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Activin A increases phagocytosis of Escherichia coli K1 by primary murine microglial cells activated by toll-like receptor agonists
2018; 15(1): Art. 175Abstract Background Bacterial meningitis is associated with high mortality and long-term neurological sequelae. Increasing the phagocytic activity of microglia could improve the resistance of the CNS against infections. We studied the influence of activin A, a member of the TGF-β family with known immunoregulatory and neuroprotective effects, on the functions of microglial cells in vitro. Methods Primary murine microglial cells were treated with activin A (0.13 ng/ml–13 μg/ml) alone or in combination with agonists of TLR2, 4, and 9. Phagocytosis of Escherichia coli K1 as well as release of TNF-α, IL-6, CXCL1, and NO was assessed. Results Activin A dose-dependently enhanced the phagocytosis of Escherichia coli K1 by microglial cells activated by agonists of TLR2, 4, and 9 without further increasing NO and proinflammatory cytokine release. Cell viability of microglial cells was not affected by activin A. Conclusions Priming of microglial cells with activin A could increase the elimination of bacteria in bacterial CNS infections. This preventive strategy could improve the resistance of the brain to infections, particularly in elderly and immunocompromised patients. -
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The effect of a new lifetime-cardiovascular-risk display on patients’ motivation to participate in shared decision-making
2018; 19(1): Art. 84Abstract Background This study investigated the effects of three different risk displays used in a cardiovascular risk calculator on patients’ motivation for shared decision-making (SDM). We compared a newly developed time-to-event (TTE) display with two established absolute risk displays (i.e. emoticons and bar charts). The accessibility, that is, how understandable, helpful, and trustworthy patients found each display, was also investigated. Methods We analysed a sample of 353 patients recruited in general practices. After giving consent, patients were introduced to one of three fictional vignettes with low, medium or high cardiovascular risk. All three risk displays were shown in a randomized order. Patients were asked to rate each display with regard to motivation for SDM and accessibility. Two-factorial repeated measures analyses of variance were conducted to compare the displays and investigate possible interactions with age. Results Regarding motivation for SDM, the TTE elicited the highest motivation, followed by the emoticons and bar chart (p < .001). The displays had no differential influence on the age groups (p = .445). While the TTE was generally rated more accessible than the emoticons and bar chart (p < .001), the emoticons were only superior to the bar chart in the younger subsample. However, this was only to a small effect (interaction between display and age, p < .01, η 2 = 0.018). Conclusions Using fictional case vignettes, the novel TTE display was superior regarding motivation for SDM and accessibility when compared to established displays using emoticons and a bar chart. If future research can replicate these results in real-life consultations, the TTE display will be a valuable addition to current risk calculators and decision aids by improving patients’ participation. -
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Promoting reading attitudes of girls and boys: a new challenge for educational policy? Multi-group analyses across four European countries
2018; 6(1): Art. 5Abstract Background Numerous studies have investigated the relationships between various student, home and contextual factors and reading achievement. However, the relationship between such factors and reading attitudes has been investigated far less, despite the fact that theoretical frameworks of large-scale assessments and school effectiveness research emphasize the importance of non-cognitive outcomes. Methods Based on a series of multi-group analyses using a structural equation modeling approach, we elucidate the relationships between student attitudes toward reading and student-, home- and context-related factors. In order to shed light on the role of different educational systems, we make use of the representative data from four national PIRLS samples (France, Germany, Italy and the Netherlands) from 2011 (n = 16,622). As gender differences are apparent in reading achievement and reading choices, we apply a multi-group comparative approach in order to control for potential gender-biased estimates caused by measurement non-invariance of the PIRLS instrument Attitude toward Reading. Results Our results reveal the importance of individual student and home characteristics for promoting students’ reading attitudes, particularly the number of books at home and the amount of reading outside school. Our results also indicate that school- and classroom-related factors such as the time spent on reading and the availability of a classroom or school library show no or only little interrelation with students’ reading attitudes. These findings are relatively stable in the cross-country comparison. Conclusions As expected, our results also support previous findings on gender differences in reading attitudes, as girls show more positive attitudes toward reading than boys. The implications of these results for researchers, politicians and practitioners are discussed. -
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Health care service provision in Europe and regional diversity: a stochastic metafrontier approach
2018; 8(1): Art. 11Abstract ■■■ In the last decades, demographic change coupled with new and expensive medical innovations have put most health care systems in developed countries under financial pressure. Therefore, ensuring efficient service provision is essential for a sustainable health care system. This paper investigates the performance of regional health care services in six West European countries between 2005 and 2014. We apply a stochastic metafrontier model to capture the different conditions in the health care systems in the countries within the European Union. By means of this approach, it is possible to detect performance differences in the European health care systems subject to different conditions and technologies relative to the potential technology available. The results indicate that regional deprivation plays a key role for the efficiency of health care provision. Furthermore, a pooled model which assumes a similar technology for all countries cannot sufficiently account for differences between countries. Surprisingly, the Scandinavian regions lag behind other regions with respect to the metafrontier. JEL Classification C23, D61, I12, I18, R10 -
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Calcification of the acetabular labrum of the hip: prevalence in the general population and relation to hip articular cartilage and fibrocartilage degeneration
2018; 20(1): Art. 104Abstract Background Meniscal calcification is considered to play a relevant role in the pathogenesis of osteoarthritis of the knee. Little is known about the biology of acetabular labral disease and its importance in hip pathology. Here, we analyze for the first time the calcification of the acetabular labrum of the hip (ALH) and its relation to hip cartilage degeneration. Methods In this cross-sectional post-mortem study of an unselected sample of the general population, 170 ALH specimens and 170 femoral heads from 85 donors (38 female, 47 male; mean age 62.1 years) were analyzed by high-resolution digital contact radiography (DCR) and histological degeneration grade. The medial menisci (MM) from the same 85 donors served as an intra-individual reference for cartilage calcification (CC). Scanning electron microscopy (SEM), energy dispersive analysis (ED) and Raman spectroscopy were performed for characterization of ALH CC. Results The prevalence of CC in the ALH was 100% and that in the articular cartilage of the hip (ACH) was 96.5%. Quantitative analysis revealed that the amount of ALH CC was higher than that in the ACH (factor 3.0, p < 0.001) and in the MM (factor 1.3, p < 0.001). There was significant correlation between the amount of CC in the fibrocartilage of the left and right ALH (r = 0.70, p < 0.001). Independent of age, the amount of ALH CC correlated with histological degeneration of the ALH (Krenn score) (r = 0.55; p < 0.001) and the ACH (Osteoarthritis Research Society International (OARSI), r = 0.69; p < 0.001). Calcification of the ALH was characterized as calcium pyrophosphate dihydrate deposition. Conclusion The finding that ALH fibrocartilage is a strongly calcifying tissue is unexpected and novel. The fact that ALH calcification correlates with cartilage degeneration independent of age is suggestive of an important role of ALH calcification in osteoarthritis of the hip and renders it a potential target for the prevention and treatment of hip joint degeneration. -
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Correction to: Proteomic characterization of adrenal gland embryonic development reveals early initiation of steroid metabolism and reduction of the retinoic acid pathway
2018; 16(1): Art. 10Upon publication of the original article [1], Marwa Eltoweissy noticed that her affiliation: “3. Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt” was missing. This affiliation has now been added in this correction article. -
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Changes in the microstructure of compact and trabecular bone tissues of mice subchronically exposed to alcohol
2018; 25(1): Art. 8Abstract Background Alcohol is one of the most commonly consumed neurotoxins by humans. Its negative effect on bone health is known for a long time. However, its impact on qualitative and quantitative 2D characteristics of the compact bone is still unclear. Therefore, the aim of this study was to investigate in detail the effects of subchronic alcohol exposure on compact and trabecular bone tissues microstructure of laboratory mice using 2D and 3D imaging methods. Ten clinically healthy 12 weeks-old mice (males) were randomly divided into two groups. Animals from experimental group (group E; n = 5) drank a solution composed of 15% ethanol and water (1.7 g 100% ethanol kg−1 b.w. per day) for 8 weeks, while those from control group (group C; n = 5) drank only water. Results Subchronic exposure to alcohol leads to several changes in qualitative 2D characteristics of the compact bone such as the presence of primary vascular radial bone tissue in pars anterior of endosteal border and a higher number of resorption lacunae (five times more) in the middle part of substantia compacta. Morphometrical 2D evaluations of the compact bone showed significantly increased sizes of primary osteons’ vascular canals (p < 0.05) in mice from the experimental group (E group). Sizes of Haversian canals and secondary osteons were not affected by alcohol consumption. In mice from the E group, significantly lower values for relative bone volume and bone mineral density of the compact bone were observed. In the trabecular bone, decreased values for bone volume, trabecular number, trabecular thickness and bone surface (p < 0.05) were documented. Conclusions Alcohol decreased not only bone volume and density of the compact bone, but it also reduced trabecular bone volume and leads to trabecular thinning. It caused vasodilation of primary osteons’ vascular canals and increased porosity in the compact bone. -
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A checklist for clinical trials in rare disease: obstacles and anticipatory actions—lessons learned from the FOR-DMD trial
2018; 19(1): Art. 291Abstract Background Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate. -
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Cartilage calcification of the ankle joint is associated with osteoarthritis in the general population
2018; 19(1): Art. 169Abstract Background Cartilage calcification (CC) is associated with osteoarthritis (OA) in weight-bearing joints, such as the hip and the knee. However, little is known about the impact of CC and degeneration on other weight-bearing joints, especially as it relates to the occurrence of OA in the ankles. The goal of this study is to analyse the prevalence of ankle joint cartilage calcification (AJ CC) and to determine its correlation with factors such as histological OA grade, age and BMI in the general population. Methods CC of the distal tibia and talus in 160 ankle joints obtained from 80 donors (mean age 62.4 years, 34 females, 46 males) was qualitatively and quantitatively analysed using high-resolution digital contact radiography (DCR). Correlations with factors, such as the joint’s histological OA grade (OARSI score), donor’s age and BMI, were investigated. Results The prevalence of AJ CC was 51.3% (95% CI [0.40, 0.63]), independent of gender (p = 0.18) and/or the joint’s side (p = 0.82). CC of the distal tibia was detected in 35.0% (28/80) (95% CI [0.25, 0.47]) and talar CC in 47.5% (38/80) (95% CI [0.36, 0.59]) of all cases. Significant correlations were noted between the mean amount of tibial and talar CC (r = 0.59, p = 0.002), as well as between the mean amount of CC observed in one ankle joint with that of the contralateral side (r = 0.52, p = 0.02). Furthermore, although the amount of AJ CC observed in the distal tibia and talus correlated with the histological OA-grade of the joint (r = 0.70, p < 0.001 and r = 0.72, p < 0.001, respectively), no such correlation was seen in the general population with relation to age (p = 0.32 and p = 0.49) or BMI (p = 0.51 and p = 0.87). Conclusion The prevalence of AJ CC in the general population is much higher than expected. The relationship between the amount of AJ CC and OA, independent of the donors’ age and BMI, indicates that CC may play a causative role in the development of OA in ankles.