Non-Invasive Vagus Nerve Stimulation Improves Brain Lesion Volume and Neurobehavioral Outcomes in a Rat Model of Traumatic Brain Injury.

Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. This study assessed the effectiveness of non-invasive vagus nerve stimulation (nVNS) in reducing brain lesion volume and improving neurobehavioral performance in a rat model of TBI. Animals were randomized into three experimental groups: (1) TBI with sham stimulation treatment (Control), (2) TBI treated with five lower doses (2-min) nVNS, and (3) TBI treated with five higher doses (2 × 2-min) nVNS. We used the gammaCore nVNS device to deliver stimulations. Magnetic resonance imaging studies were performed 1 and 7 days post-injury to confirm lesion volume. We observed smaller brain lesion volume in the lower dose nVNS group compared with the control group on days 1 and 7. The lesion volume for the higher dose nVNS group was significantly smaller than either the lower dose nVNS or the control groups on days 1 and 7 post-injury. The apparent diffusion coefficient differences between the ipsilateral and contralateral hemispheres on day 1 were significantly smaller for the higher dose (2 × 2 min) nVNS group than for the control group. Voxel-based morphometry analysis revealed an increase in the ipsilateral cortical volume in the control group caused by tissue deformation and swelling. On day 1, these abnormal volume changes were 13% and 55% smaller in the lower dose and higher dose nVNS groups, respectively, compared with the control group. By day 7, nVNS dampened cortical volume loss by 35% and 89% in the lower dose and higher dose nVNS groups, respectively, compared with the control group. Rotarod, beam walking, and anxiety performances were significantly improved in the higher-dose nVNS group on day 1 compared with the control group. The anxiety indices were also improved on day 7 post-injury compared with the control and the lower-dose nVNS groups. In conclusion, the higher dose nVNS (five 2 × 2-min stimulations) reduced brain lesion volume to a level that further refined the role of nVNS therapy for the acute treatment of TBI. Should nVNS prove effective in additional pre-clinical TBI models and later in clinical settings, it would have an enormous impact on the clinical practice of TBI in both civilian and military settings, as it can easily be adopted into routine clinical practice.

Chromatin Accessibility of Human Mitral Valves and Functional Assessment of MVP Risk Loci.

RATIONALE: Mitral valve prolapse (MVP) is a common valvopathy that leads to mitral insufficiency, heart failure, and sudden death. Functional genomic studies in mitral valves are needed to better characterize MVP-associated variants and target genes. OBJECTIVE: To establish the chromatin accessibility profiles and assess functionality of variants and narrow down target genes at MVP loci. METHODS AND RESULTS: We mapped the open chromatin regions in nuclei from 11 human pathogenic and 7 nonpathogenic mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing. Open chromatin peaks were globally similar between pathogenic and nonpathogenic valves. Compared with the heart tissue and cardiac fibroblasts, we found that MV-specific assay for transposase-accessible chromatin with high-throughput sequencing peaks are enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. One of the most enriched motifs in MV-specific open chromatin peaks was for the nuclear factor of activated T cells family of TFs (transcription factors) involved in valve endocardial and interstitial cell formation. We also found that MVP-associated variants were significantly enriched (P<0.05) in mitral valve open chromatin peaks. Integration of the assay for transposase-accessible chromatin with high-throughput sequencing data with risk loci, extensive functional annotation, and gene reporter assay suggest plausible causal variants for rs2641440 at the SMG6/SRR locus and rs6723013 at the IGFBP2/IGFBP5/TNS1 locus. CRISPR-Cas9 deletion of the sequence including rs6723013 in human fibroblasts correlated with increased expression only for TNS1. Circular chromatin conformation capture followed by high-throughput sequencing experiments provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on chromosome 2. CONCLUSIONS: Here, we describe unprecedented genome-wide open chromatin profiles from human pathogenic and nonpathogenic MVs and report specific gene regulation profiles, compared with the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms. Graphic Abstract: A graphic abstract is available for this article.

Corrigendum: A Severe Lack of Evidence Limits Effective Conservation of the World's Primates.

[This corrects the article DOI: 10.1093/biosci/biaa082.].

A Severe Lack of Evidence Limits Effective Conservation of the World's Primates.

Threats to biodiversity are well documented. However, to effectively conserve species and their habitats, we need to know which conservation interventions do (or do not) work. Evidence-based conservation evaluates interventions within a scientific framework. The Conservation Evidence project has summarized thousands of studies testing conservation interventions and compiled these as synopses for various habitats and taxa. In the present article, we analyzed the interventions assessed in the primate synopsis and compared these with other taxa. We found that despite intensive efforts to study primates and the extensive threats they face, less than 1% of primate studies evaluated conservation effectiveness. The studies often lacked quantitative data, failed to undertake postimplementation monitoring of populations or individuals, or implemented several interventions at once. Furthermore, the studies were biased toward specific taxa, geographic regions, and interventions. We describe barriers for testing primate conservation interventions and propose actions to improve the conservation evidence base to protect this endangered and globally important taxon.

Single-stage bilateral distal femur replacement for traumatic distal femur fractures.

Treatment of periprosthetic distal femur fractures and comminuted intraarticular distal femur fractures with previous arthritis remains a difficult challenge for orthopedic surgeons. Previous case series have shown that distal femur replacement (DFR) can effectively compensate for bone loss, relieve knee pain, and allow for early ambulation in both of these fracture patterns. Owing to the typical low-energy mechanism of these injuries, a bilateral injury treated with DFR is rarely encountered. We present a patient with traumatic open left Rorabeck III/Su III periprosthetic distal femur fracture and closed right intraarticular distal femur fracture (AO fcation 33-C2) with end-stage arthrosis treated with single-stage bilateral DFR. We suggest that in patients with similar injuries, single-stage bilateral DFR can provide the benefits of early mobilization and accelerated recovery.

Bioimpedance Method for Human Body Hydration Assessment.

A high-precision wearable bioimpedance sensor developed at Imec was extensively tested. Unlike known bioimpedance sensors on the market, the new device enables hydration shift measurement in a single person, with no need for averaging over a population. For reaching this target, a method for hydration monitoring in case of altered hydration is tested. An assessment of fluid shift with sensitivity of about 700 ml has been demonstrated, which is comparable with the capabilities of known methods because of the device accuracy, immunity to electrode-skin impedance variation, and due to establishing the impedance baseline prior to fluid shift.

Examining the temporal behavior of the hydrocarbonaceous overlayer on an iron based Fischer-Tropsch catalyst.

In order to examine fundamental processes connected with the use of an unpromoted iron based Fischer-Tropsch synthesis (FTS) catalyst, model studies examining the temporal formation of hydrocarbonaceous species that form over the catalyst are undertaken using a combination of temperature-programmed oxidation, powder X-ray diffraction, Raman scattering, transmission electron microscopy and inelastic neutron scattering (INS). Catalyst samples were exposed to ambient pressure CO hydrogenation at 623 K for defined periods of time-on-stream (3, 6, 12 and 24 h) prior to analysis. INS reveals a progressive retention of hydrogenous species that is associated with the evolution of a hydrocarbonaceous overlayer, as evidenced by the presence of sp2 and sp3 hybridized C-H vibrational modes. Correlations between the formation of aliphatic and olefinic/aromatic moieties with post-reaction characterization leads to the proposal of a number of chemical transformations that, collectively, define the conditioning phase of the catalyst under the specified set of reaction conditions. A comparison between the inelastic neutron scattering spectra of the 24 h sample with that of an iron catalyst extracted from a commercial grade Fischer-Tropsch reactor validates the relevance of the experimental approach adopted.

Intestinal and non-intestinal nasal cavity adenocarcinoma: Impact of wood dust exposure.

The aim of the present study was to investigate the role of wood dust exposure in intestinal (ITAC) and non-intestinal type (non-ITAC) nasal adenocarcinoma, so as to improve understanding of the oncogenic mechanisms in the light of the recent literature and of evo-devo concepts. MATERIALS AND METHODS: All consecutive patients operated in our institution for nasal adenocarcinoma diagnosed on anatomopathology between May 2004 and February 2014 were included. Surgical specimens were examined twice by independent pathologists, blind to wood dust exposure status. Clinical and demographic data, including wood dust exposure, were collected for the two groups (ITAC and non-IATC). RESULTS: 90 patients (84 ITAC, 6 non-ITAC) were included. No non-ITAC patients had history of wood dust exposure, versus 83/84 cases (99%) in ITAC (mean exposure duration: 30±16 years; range 2-65 years). Only 12 ITAC patients (18%) were still exposed at diagnosis. ITAC may develop long after the end of wood dust exposure (up to 60 years). Eight patients (12%) had exposure durations of less than 5 years. Latency between onset of exposure and onset of disease did not decrease with exposure duration. CONCLUSION: Exposure to wood dust, even for short periods of time, incurs a risk of developing ITAC, usually after a long latency period. Any exposure requires lifetime follow-up, to ensure prompt treatment. Factors leading to the development of nasal ITAC and non-ITAC are probably different. The analogy with Barret's esophagus and esophageal adenocarcinoma may shed light on the oncogenesis of nasal ITAC.

Vinyl chloride dysregulates metabolic homeostasis and enhances diet-induced liver injury in mice.

Vinyl chloride (VC), a common industrial organochlorine and environmental pollutant, has been shown to directly cause hepatic angiosarcoma and toxicant-associated steatohepatitis at high exposure levels. However, the impact of lower concentrations of VC on the progression of underlying liver diseases (e.g., nonalcoholic fatty liver disease [NAFLD]) is unclear. Given the high prevalence of NAFLD in the United States (and worldwide) population, this is an important concern. Recent studies by our group with VC metabolites suggest a potential interaction between VC exposure and underlying liver disease to cause enhanced damage. Here, a novel mouse model determined the effects of VC inhalation at levels below the current Occupational Safety and Health Administration limit (<1 ppm) in the context of NAFLD to better mimic human exposure and identify potential mechanisms of VC-induced liver injury. VC exposure caused no overt liver injury in mice fed a low-fat diet. However, in mice fed a high-fat diet (HFD), VC significantly increased liver damage, steatosis, and increased neutrophil infiltration. Moreover, VC further enhanced HFD-induced oxidative and endoplasmic reticulum stress. Importantly, VC exposure dysregulated energy homeostasis and impaired mitochondrial function, even in mice fed a low-fat diet. In toto, the results indicate that VC exposure causes metabolic stress that sensitizes the liver to steatohepatitis caused by HFD. Conclusion: The hypothesis that low-level (below the Occupational Safety and Health Administration limit) chronic exposure to VC by inhalation enhances liver injury caused by an HFD is supported. Importantly, our data raise concerns about the potential for overlap between fatty diets (i.e., Western diet) and exposure to VC and the health implications of this co-exposure for humans. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity. (Hepatology Communications 2018;2:270-284).

Endoscopic surgery of the olfactory cleft.

The olfactory cleft is the specific site of development of many tumours (respiratory epithelial adenomatoid hamartoma, intestinal-type adenocarcinoma, neuroblastoma, inverted papilloma, glomangiopericytoma, etc.) and is also the site of CSF rhinorrhoea via the cribriform plate (cribri-rhinorrhoea). Olfactory cleft surgery must therefore be considered to be a specific type of surgery, complementary to ethmoidal labyrinth surgery and anterior skull base surgery. Olfactory cleft tumours can be resected according to five different surgical procedures: olfactory cleft mucosal resection, partial resection of the olfactory cleft, total resection of the olfactory cleft, unilateral endoscopic anterior skull base resection, and bilateral endoscopic anterior skull base resection. The diagnosis and closure of cribri-rhinorrhoea (i.e. documented CSF rhinorrhoea, demonstrated to arise from the cribriform plate during endoscopic examination of the olfactory cleft under general anaesthesia in a patient with no localizing signs on imaging) completes this range of treatment options.

Chronic nasal dysfunction.

Chronic nasal dysfunction is a clinical concept in the diagnostic and therapeutic management of sinonasal diseases, based on the evo-devo theory of formation of the nose according to which the nose is not a single organ but rather an association of three organs: olfactory nose, respiratory nose and paranasal sinuses. In chronic nasal dysfunction theory, etiological diagnosis takes account of the possible pathophysiological independence of nasal symptoms, in accordance with the different origins and physiology of the three organs constituting the nose. The diagnostic approach of the chronic nasal dysfunction concept breaks down the pathology so as to propose treatment(s) adapted to the diseased organ(s) and to the capacity for physiological resolution of dysfunction induced in one organ by pathology in a neighboring nasal organ. The ethmoid is not a sinus according to evo-devo, and therefore functional endoscopic endonasal surgery (FEES) cannot be restricted to functional endoscopic sinus surgery (FESS). Evo-devo theory and the chronic nasal dysfunction concept offer an alternative to the concept of chronic rhinosinusitis with or without polyps for the management of sinonasal diseases.

Science in the cloud (SIC): A use case in MRI connectomics.

Modern technologies are enabling scientists to collect extraordinary amounts of complex and sophisticated data across a huge range of scales like never before. With this onslaught of data, we can allow the focal point to shift from data collection to data analysis. Unfortunately, lack of standardized sharing mechanisms and practices often make reproducing or extending scientific results very difficult. With the creation of data organization structures and tools that drastically improve code portability, we now have the opportunity to design such a framework for communicating extensible scientific discoveries. Our proposed solution leverages these existing technologies and standards, and provides an accessible and extensible model for reproducible research, called 'science in the cloud' (SIC). Exploiting scientific containers, cloud computing, and cloud data services, we show the capability to compute in the cloud and run a web service that enables intimate interaction with the tools and data presented. We hope this model will inspire the community to produce reproducible and, importantly, extensible results that will enable us to collectively accelerate the rate at which scientific breakthroughs are discovered, replicated, and extended.

Metabolic Profiling and Identification of Shikonins in Root Periderm of Two Invasive Echium spp. Weeds in Australia.

Metabolic profiling can be successfully implemented to analyse a living system's response to environmental conditions by providing critical information on an organism's physiological state at a particular point in time and allowing for both quantitative and qualitative assessment of a specific subset(s) of key metabolites. Shikonins are highly reactive chemicals that affect various cell signalling pathways and possess antifungal, antibacterial and allelopathic activity. Based on previous bioassay results, bioactive shikonins, are likely to play important roles in the regulation of rhizosphere interactions with neighbouring plants, microbes and herbivores. An effective platform allowing for rapid identification and accurate profiling of numerous structurally similar, difficult-to-separate bioactive isohexenylnaphthazarins (shikonins) was developed using UHPLC Q-TOF MS. Root periderm tissues of the invasive Australian weeds Echium plantagineum and its congener E. vulgare were extracted overnight in ethanol for shikonin profiling. Shikonin production was evaluated at seedling, rosette and flowering stages. Five populations of each species were compared for qualitative and quantitative differences in shikonin formation. Each species showed little populational variation in qualitative shikonin production; however, shikonin was considerably low in one population of E. plantagineum from Western New South Wales. Seedlings of all populations produced the bioactive metabolite acetylshikonin and production was upregulated over time. Mature plants of both species produced significantly higher total levels of shikonins and isovalerylshikonin > dimethylacrylshikonin > shikonin > acetylshikonin in mature E. plantagineum. Although qualitative metabolic profiles in both Echium spp. were nearly identical, shikonin abundance in mature plant periderm was approximately 2.5 times higher in perennial E. vulgare extracts in comparison to those of the annual E. plantagineum. These findings contribute to our understanding of the biosynthesis of shikonins in roots of two related invasive plants and their expression in relation to plant phenological stage.

Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is effective in the treatment of monocrotaline-induced PH in the rodent.

Human immunodeficiency virus type 1 derivative with 7% simian immunodeficiency virus genetic content is able to establish infections in pig-tailed macaques.

A human immunodeficiency virus type 1 (HIV-1) derivative (HIV(NL-DT5R)) containing sequences encoding a 7-amino-acid segment of CA and the entire vif gene from simian immunodeficiency virus (SIV) was previously shown to establish spreading infections in cultured macaque peripheral blood mononuclear cells. To assess its replicative and disease-inducing properties in vivo, HIV(NL-DT5R) was inoculated into pig-tailed macaques. HIV(NL-DT5R) generated plasma viremia in all five of the monkeys and elicited humoral responses against all of the HIV-1 structural proteins but did not cause CD4(+) T-lymphocyte depletion or clinical disease. Additional adaptation will be required to optimize infectivity in vivo.

Normal distribution of melanocytes in the mouse heart.

We report the consistent distribution of a population of pigmented trp-1-positive cells in several important septal and valvular structures of the normal mouse (C57BL/6) heart. The pigmented cell population was first apparent by E16.5 p.c. in the right atrial wall and extended into the atrium along the interatrial septum. By E17.5, these cells were found along the apical membranous interventricular septum near or below the surface of the endocardium. The most striking distribution of dark pigmented cells was found in the tricuspid and mitral valvular leaflets and chordae tendineae. The normal distribution of pigmented cells in the valvuloseptal apparatus of C57BL/6 adult heart suggests that a premelanocytic lineage may participate in the earlier morphogenesis of the valve leaflets and chordae tendineae. The origin of the premelanocyte lineage is currently unknown. The most likely candidate populations include the neural crest and the epicardially derived cells. The only cell type in the heart previously shown to form melanocytes is the neural crest. The presence of neural crest cells, but not melanocytes, in some of the regions we describe has been reported by others. However, previous reports have not shown a contribution of melanocytes or neural crest derivatives to the atrioventricular valve leaflets or chordae tendineae in mouse hearts. If these cells are of neural crest origin, it would suggest a possibly greater contribution and persistence of neural crest cells to the valvuloseptal apparatus than has been previously understood.

Effects of spaceflight on the attachment of tendons to bone in the hindlimb of the pregnant rat.

The objective of this study was to determine the effects of spaceflight on the structure of the tendon-bone junction (TBJ). Pregnant rats either flew in the space shuttle Atlantis (flight group; F) or were exposed to simulated launch and landing protocols (synchronous control group; SC) during days 9-19 of pregnancy. Following birth of their pups, maternal hindlimbs were studied using scanning electron and light microscopic histomophometric techniques. The tibial and calcaneal tuberosities, the fibular head, and the tibia-fibula junction were studied. Myofiber density and cross-sectional area of the quadratus femoris and soleus muscles and diameters of the calcaneal and patellar tendons were also evaluated. Cortical erosion was significantly greater at the tibial tuberosity and the fibular head in F animals compared to SC animals (P < 0.001). Sharpey fiber density was significantly less at the tibial tuberosity and fibular head in F animals compared to SC animals (P < 0.001). The myofiber area of both the soleus and quadratus femoris muscles and the diameters of both calcaneal and patellar tendons were significantly less in F compared to SC rats (P < 0.05). Our data illustrate that the TBJ morphology is affected by spaceflight at the attachment sites of the soleus and quadratus femoris muscles in pregnant animals, which could adversely affect their physical properties. These atrophic TBJ changes could have resulted from atrophy of the adjacent muscles and their tendons. Atrophic changes in the structure of the TBJ could predispose an animal to injury following spaceflight, when normal gravity conditions are reestablished.

Indices of environmental temperatures for primates in open habitats.

Studies of thermoregulation in primates are under-represented in the literature, although there is sufficient evidence to suggest that temperature represents an important ecological constraint. One of the problems in examining thermoregulation in primates, however, is the difficulty in quantifying the thermal environment, since shade temperatures, solar radiation, humidity and wind speed all serve to alter an animal's 'perceived' temperature. Since animals respond to their perceived temperature, we need methods to account for each of these factors, both individually and collectively, if we are to understand the integrated impact of the thermal environment on primates. Here, we present a review of some thermal indices currently available. Black bulb temperatures can account for the effect of solar radiation, with wind chill equivalent temperatures and the heat index providing quantifiable estimates of the relative impact of wind speed and humidity, respectively. We present three potential indices of the 'perceived environmental temperature' (PET) that account for the combined impact of solar radiation, humidity and wind speed on temperature, and perform a preliminary test of all of the climatic indices against behavioural data from a field study of chacma baboons ( Papio cynocephalus ursinus) at De Hoop Nature Reserve, South Africa. One measure of the perceived environmental temperature, PET2, is an effective thermal index, since it enters the models for feeding and resting behaviour, and also accounts for levels of allogrooming. Solar radiation intensity is an important factor underlying these relationships, although the wind chill equivalent temperature and humidity enter the models for other behaviours. Future studies should thus be mindful of the impact of each of these elements of the thermal environment. A detailed understanding of primate thermoregulation will only come with the development of biophysical models of the thermal characteristics of the species and its environment. Until such developments, however, the indices presented here should permit a more detailed examination of the thermal environment, allowing thermoregulation to be given greater precedence in future studies of primate behaviour.