Dynamic changes in hippocampal diffusion and kurtosis metrics following experimental mTBI correlate with glial reactivity

Diffusion magnetic resonance imaging biomarkers can provide quantifiable information of the brain tissue after a mild traumatic brain injury (mTBI). However, the commonly applied diffusion tensor imaging (DTI) model is not very specific to changes in the underlying cellular structures. To overcome these limitations, other diffusion models have recently emerged to provide a more complete view on the damage profile following TBI. In this study, we investigated longitudinal changes in advanced diffusion metrics following experimental mTBI, utilising three different diffusion models in a rat model of mTBI, including DTI, diffusion kurtosis imaging and a white matter model. Moreover, we investigated the association between the diffusion metrics with histological markers, including glial fibrillary acidic protein (GFAP), neurofilaments and synaptophysin in order to investigate specificity. Our results revealed significant decreases in mean diffusivity in the hippocampus and radial diffusivity and radial extra axonal diffusivity (RadEAD) in the cingulum one week post injury. Furthermore, correlation analysis showed that increased values of fractional anisotropy one day post injury in the hippocampus was highly correlated with GFAP reactivity three months post injury. Additionally, we observed a positive correlation between GFAP on one hand and the kurtosis parameters in the hippocampus on the other hand three months post injury. This result indicated that prolonged glial activation three months post injury is related to higher kurtosis values at later time points. In conclusion, our findings point out to the possible role of kurtosis metrics as well as metrics from the white matter model as prognostic biomarker to monitor prolonged glial reactivity and inflammatory responses after a mTBI not only at early timepoints but also several months after injury. Keywords: Mild traumatic brain injury, Diffusion magnetic resonance imaging, DTI, DKI, White matter mode

How common are motor problems in children with a developmental disorder: rule or exception?

Background Few co-morbidity studies have been conducted since the Leeds Consensus Statement on developmental co-ordination disorder (DCD) in 2006. In this Statement, international cut-offs and inclusion criteria were agreed and consequently, the status of DCD changed. Furthermore, most existing co-morbidity studies are small clinical studies, rather than epidemiological studies, resulting in a broad range of co-morbidity rates. DCD has a higher incidence for boys in comparison with girls; questions arise if this preponderance remains the same in combination with other developmental disorders. Therefore, in this study we aimed to determine co-morbidity and gender differences of motor problems in children with a pervasive developmental disorder, a hyperkinetic disorder and/or a speech, language or learning disability. Methods Profiles of 3608 children (mean age: 9 years 1 month) referred to rehabilitation centres for behavioural, developmental and sensorineural disorders were studied. Results Motor problems were reported in one-fifth of the total sample. Co-morbidity of motor problems in specific disorders varied from almost one-fourth to more than one-third. The male/female ratio was significantly higher in children with motor problems and two or more other disorders, compared with children with motor problems and less than two other disorders. Conclusions This study indicates that co-morbidity of motor problems with other clinical disorders is not exceptional and developmental deviance is seldom specific to one domain. However, current co-morbidity studies tend to overestimate the number of children with motor problems. In addition, there may be different patterns of symptoms between the genders. These findings stress the importance of assessing motor skills in children with various developmental disorders

The impact of protocol assignment for older adolescents with Hodgkin lymphoma

Background and Purpose: Hodgkin lymphoma (HL) treatment has evolved to reduce or avoid radiotherapy (RT) dose and volume and minimize the potential for late effects. Some older adolescents are treated on adult protocols. The purpose of this study is to examine the protocol assignment of older adolescents and its impact on radiation dose to relevant thoracic structures. Materials and Methods: Cooperative group data were reviewed and 12 adolescents were randomly selected from a pediatric HL protocol. Treatment plans were generated per one pediatric and two adult protocols. Dose volume histograms for heart, lung, and breast allowed comparison of radiation dose to these sites across these three protocols. Results: A total of 15.2% of adolescents were treated on adult HL protocols and received significantly higher radiation dosage to heart and lung compared to pediatric HL protocols. Adolescents treated on either pediatric or adult protocols received similar RT dose to breast. Conclusion: Older adolescents treated on adult HL protocols received higher RT dose to thoracic structures except breast. Level of nodal involvement may impact overall RT dose to breast. The impact of varying field design and RT dose on survival, local, and late effects needs further study for this vulnerable age group

Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting

The therapeutic scope of antibody and nonantibody protein scaffolds is still prohibitively limited against intracellular drug targets. Here, we demonstrate that the Alphabody scaffold can be engineered into a cell-penetrating protein antagonist against induced myeloid leukemia cell differentiation protein MCL-1, an intracellular target in cancer, by grafting the critical B-cell lymphoma 2 homology 3 helix of MCL-1 onto the Alphabody and tagging the scaffold’s termini with designed cell-penetration polypeptides. Introduction of an albumin-binding moiety extended the serum half-life of the engineered Alphabody to therapeutically relevant levels, and administration thereof in mouse tumor xenografts based on myeloma cell lines reduced tumor burden. Crystal structures of such a designed Alphabody in complex with MCL-1 and serum albumin provided the structural blueprint of the applied design principles. Collectively, we provide proof of concept for the use of Alphabodies against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics

Salivary concentrations of secretory leukocyte protease inhibitor and matrix metallopeptidase-9 following a single bout of exercise are associated with intensity and hydration status

AIM: To investigate the effects of exercise on salivary concentrations of inflammatory markers by analyzing a panel of 25 inflammatory markers in subjects who had participated in bicycle ergometer tests varying in workload and hydration status. METHODS: Fifteen healthy young men (20-35 years) had performed 4 different exercise protocols of 1 hour duration in a randomly assigned cross-over design, preceded by a rest protocol. Individual workloads depended on participant's pre-assessed individual maximum workload (Wmax): rest (protocol 1), 70% Wmax in hydrated (protocol 2) and dehydrated (protocol 3) state, 50% Wmax (protocol 4) and intermittent 85%/55% Wmax in 2 min blocks (protocol 5). Saliva samples were collected before (T0) and immediately after exercise (T1), and at several time points after exercise (2 hours (T3), 3 hours (T4), 6 hours (T5) and 24 hours (T6)). Secretory Leukocyte Protease Inhibitor (SLPI), Matrix Metallopeptidase-9 (MMP-9) and lactoferrin was analyzed using a commercial ELISA kit, a panel of 22 cytokines and chemokines were analyzed using a commercial multiplex immunoassay. Data was analyzed using a multilevel mixed linear model, with multiple test correction. RESULTS: Among a panel of 25 inflammatory markers, SLPI concentrations were significantly elevated immediately after exercise in all protocols compared to rest and higher concentrations reflected the intensity of exercise and hydration status. MMP-9 showed a significant increase in the 70% Wmax dehydrated, 50% Wmax and intermittent protocols. CONCLUSIONS: Salivary concentrations of SLPI and MMP-9 seem associated with exercise intensity and hydration status and may offer non-invasive biomarkers to study (local) inflammatory responses to different exercise intensities in human studies

Examining sustainability in a hospital setting: Case of smoking cessation

<p>Abstract</p> <p>Background</p> <p>The Ottawa Model of Smoking Cessation (OMSC) is a hospital-based smoking cessation program that is expanding across Canada. While the short-term effectiveness of hospital cessation programs has been documented, less is known about long-term sustainability. The purpose of this exploratory study was to understand how hospitals using the OMSC were addressing sustainability and determine if there were critical factors or issues that should be addressed as the program expanded.</p> <p>Methods</p> <p>Six hospitals that differed on OMSC program activities (identify and document smokers, advise quitting, provide medication, and offer follow-up) were intentionally selected, and two key informants per hospital were interviewed using a semi-structured interview guide. Key informants were asked to reflect on the initial decision to implement the OMSC, the current implementation process, and perceived sustainability of the program. Qualitative analysis of the interview transcripts was conducted and themes related to problem definition, stakeholder influence, and program features emerged.</p> <p>Results</p> <p>Sustainability was operationalized as higher performance of OMSC activities than at baseline. Factors identified in the literature as important for sustainability, such as program design, differences in implementation, organizational characteristics, and the community environment did not explain differences in program sustainability. Instead, key informants identified factors that reflected the interaction between how the health problem was defined by stakeholders, how priorities and concerns were addressed, features of the program itself, and fit within the hospital context and resources as being influential to the sustainability of the program.</p> <p>Conclusions</p> <p>Applying a sustainability model to a hospital smoking cessation program allowed for an examination of how decisions made during implementation may impact sustainability. Examining these factors during implementation may provide insight into issues affecting program sustainability, and foster development of a sustainability plan. Based on this study, we suggest that sustainability plans should focus on enhancing interactions between the health problem, program features, and stakeholder influence.</p

Replacement of nitrite in meat products by natural bioactive compounds results in reduced exposure to N‐Nitroso compounds: the PHYTOME project

Scope: It has been proposed that endogenously form N‐nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as critical factor in the formation of NOCs, the impact of replacing the additive sodium nitrite (E250) by botanical extracts in the PHYTOME project is evaluated. Method and Results: A human dietary intervention study is conducted in which healthy subjects consume 300 g of meat for 2 weeks, in subsequent order: conventional processed red meat, white meat, and processed red meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of red meat products enriched with phytochemicals leads to a significant reduction in the faecal excretion of NOCs, as compared to traditionally processed red meat products. Gene expression changes identify cell proliferation as main affects molecular mechanism. High nitrate levels in drinking water in combination with processed red meat intake further stimulates NOC formation, an effect that could be mitigated by replacement of E250 by natural plant extracts. Conclusion: These findings suggest that addition of natural extracts to conventionally processed red meat products may help to reduce CRC risk, which is mechanistically support by gene expression analyses

A Phylogeny and Timescale for the Evolution of Pseudocheiridae (Marsupialia: Diprotodontia) in Australia and New Guinea

Pseudocheiridae (Marsupialia: Diprotodontia) is a family of endemic Australasian arboreal folivores, more commonly known as ringtail possums. Seventeen extant species are grouped into six genera (Pseudocheirus, Pseudochirulus, Hemibelideus, Petauroides, Pseudochirops, Petropseudes). Pseudochirops and Pseudochirulus are the only genera with representatives on New Guinea and surrounding western islands. Here, we examine phylogenetic relationships among 13 of the 17 extant pseudocheirid species based on protein-coding portions of the ApoB, BRCA1, ENAM, IRBP, Rag1, and vWF genes. Maximum parsimony, maximum likelihood, and Bayesian methods were used to estimate phylogenetic relationships. Two different relaxed molecular clock methods were used to estimate divergence times. Bayesian and maximum parsimony methods were used to reconstruct ancestral character states for geographic provenance and maximum elevation occupied. We find robust support for the monophyly of Pseudocheirinae (Pseudochirulus + Pseudocheirus), Hemibelidinae (Hemibelideus + Petauroides), and Pseudochiropsinae (Pseudochirops + Petropseudes), respectively, and for an association of Pseudocheirinae and Hemibelidinae to the exclusion of Pseudochiropsinae. Within Pseudochiropsinae, Petropseudes grouped more closely with the New Guinean Pseudochirops spp. than with the Australian Pseudochirops archeri, rendering Pseudochirops paraphyletic. New Guinean species belonging to Pseudochirops are monophyletic, as are New Guinean species belonging to Pseudochirulus. Molecular dates and ancestral reconstructions of geographic provenance combine to suggest that the ancestors of extant New Guinean Pseudochirops spp. and Pseudochirulus spp. dispersed from Australia to New Guinea ∼12.1–6.5 Ma (Pseudochirops) and ∼6.0–2.4 Ma (Pseudochirulus). Ancestral state reconstructions support the hypothesis that occupation of high elevations (>3000 m) is a derived feature that evolved on the terminal branch leading to Pseudochirops cupreus, and either evolved in the ancestor of Pseudochirulus forbesi, Pseudochirulus mayeri, and Pseudochirulus caroli, with subsequent loss in P. caroli, or evolved independently in P. mayeri and P. forbesi. Divergence times within the New Guinean Pseudochirops clade are generally coincident with the uplift of the central cordillera and other highlands. Diversification within New Guinean Pseudochirulus occurred in the Plio-Pleistocene after the establishment of the Central Range and other highlands

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points