GIPR expression is induced by thiazolidinediones in a PPARγ-independent manner and repressed by obesogenic stimuli.
Adipose tissue (AT) dysfunctions are associated with the onset of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Targeting glucose-dependent insulinotropic peptide receptor (GIPR) is a valid option to increase the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists in T2DM treatment. Nevertheless, the therapeutic potential of targeting the GIP/GIPR axis and its effect on the AT are controversial. In this work, we explored the expression and regulation of GIPR in precursor cells and mature adipocytes, investigating if and how obesogenic stimuli and thiazolidinediones perturb GIPR expression. Using publicly available gene expression datasets, we assessed that, among white adipose tissue (WAT) cells, adipocytes express lower levels of GIPR compared to cells of mesothelial origin, pericytes, dendritic and NK/T cells. However, we report that GIPR levels markedly increase during the in vitro differentiation of both murine and human adipocytes, from 3T3-L1 and human mesenchymal precursor cells (MSCs), respectively. Notably, we demonstrated that thiazolidinediones - ie. synthetic PPARγ agonists widely used as anti-diabetic drugs and contained in the adipogenic mix - markedly induce GIPR expression. Moreover, using multiple in vitro systems, we assessed that thiazolidinediones induce GIPR in a PPARγ-independent manner. Our results support the hypothesis that PPARγ synthetic agonists may be used to increase GIPR levels in AT, potentially affecting in turn the targeting of GIP system in patients with metabolic dysfunctions. Furthermore, we demonstrate in vitro and in vivo that proinflammatory stimuli, and especially the TNFα, represses GIPR both in human and murine adipocytes, even though discordant results were obtained between human and murine cellular systems for other cytokines. Finally, we demonstrated that GIPR is negatively affected also by the excessive lipid engulfment. Overall, we report that obesogenic stimuli - ie. pro-inflammatory cytokines and the increased lipid accumulation - and PPARγ synthetic ligands oppositely modulate GIPR expression, possibly influencing the effectiveness of GIP agonists.


Anxious and egocentric: how specific emotions influence perspective taking.
People frequently feel anxious. Although prior research has extensively studied how feeling anxious shapes intrapsychic aspects of cognition, much less is known about how anxiety affects interpersonal aspects of cognition. Here, we examine the influence of incidental experiences of anxiety on perceptual and conceptual forms of perspective taking. Compared with participants experiencing other negative, high-arousal emotions (i.e., anger or disgust) or neutral feelings, anxious participants displayed greater egocentrism in their mental-state reasoning: They were more likely to describe an object using their own spatial perspective, had more difficulty resisting egocentric interference when identifying an object from others' spatial perspectives, and relied more heavily on privileged knowledge when inferring others' beliefs. Using both experimental-causal-chain and measurement-of-mediation approaches, we found that these effects were explained, in part, by uncertainty appraisal tendencies. Further supporting the role of uncertainty, a positive emotion associated with uncertainty (i.e., surprise) produced increases in egocentrism that were similar to anxiety. Collectively, the results suggest that incidentally experiencing emotions associated with uncertainty increase reliance on one's own egocentric perspective when reasoning about the mental states of others.


Thrombophilia Associated with Anti-DFS70 Autoantibodies.
Anti-DFS70 antibodies are the most frequent antinuclear antibodies (ANA) found in healthy individuals. We assessed the clinical significance of the presence of anti-DFS70 antibodies. We defined a group of patients (n = 421) with anti-DFS70 antibodies and a group of patients (n = 63) with a history of idiopathic arterial and/or venous thrombotic disease and/or obstetric complication (i.e. ≥ 3 miscarriages, fetal death or premature birth with eclampsia). Anti-DFS70 antibodies prevalence was also assessed in a cohort of 300 healthy blood donors. The prevalence of thrombotic disease and/or obstetric complication in the 421 patients with anti-DFS70 antibodies was 13.1% (n = 55) and the prevalence of connective tissue disease was 19% (n = 80). Among the 63 patients with a history of thrombosis and/or obstetric complications, 7 (11.1%) had anti-DFS70 antibodies and among the latter, 5 had no common thrombophilic factor. In contrast, the prevalence of anti-DFS70 antibodies was of 3.0% (9 out of 300) in healthy donors. Finally, the Activated Partial Thromboplastin Time (aPTT) ratio of patients with a history of thrombosis and anti-DFS70 antibodies was lower than the aPTT ratio of other patients, suggesting that thrombotic patients with anti-DFS70 antibodies may have a hypercoagulable state. We described here for the first time an immune procoagulant state involving anti-DFS70 antibodies.


The economics of obesity: dietary energy density and energy cost.
Highest rates of obesity and diabetes in the United States are found among the lower-income groups. The observed links between obesity and socioeconomic position may be related to dietary energy density and energy cost. Refined grains, added sugars, and added fats are among the lowest-cost sources of dietary energy. They are inexpensive, good tasting, and convenient. In contrast, the more nutrient-dense lean meats, fish, fresh vegetables, and fruit generally cost more. An inverse relationship between energy density of foods (kilojoules per gram) and their energy cost (dollars per megajoule) means that the more energy-dense diets are associated with lower daily food consumption costs and may be an effective way to save money. However, economic decisions affecting food choice may have physiologic consequences. Laboratory studies suggest that energy-dense foods and energy-dense diets have a lower satiating power and may result in passive overeating and therefore weight gain. Epidemiologic analyses suggest that the low-cost energy-dense diets also tend to be nutrient poor. If the rise in obesity rates is related to the growing price disparity between healthy and unhealthy foods, then the current strategies for obesity prevention may need to be revised. Encouraging low-income families to consume healthier but more costly foods to prevent future disease can be construed as an elitist approach to public health. Limiting access to inexpensive foods through taxes on frowned upon fats and sweets is a regressive measure. The broader problem may lie with growing disparities in incomes and wealth, declining value of the minimum wage, food imports, tariffs, and trade. Evidence is emerging that obesity in America is a largely economic issue.


Tracking intermediate performance of vigilant attention using multiple eye metrics.
Vigilance deficits account for a substantial number of accidents and errors. Current techniques to detect vigilance impairment measure only the most severe level evident in eyelid closure and falling asleep, which is often too late to avoid an accident or error. The present study sought to identify ocular biometrics of intermediate impairment of vigilance and develop a new technique that could detect a range of deficits in vigilant attention (VA). Sixteen healthy adults performed well-validated Psychomotor Vigilance Test (PVT) for tracking vigilance attention while undergoing simultaneous recording of eye metrics every 2 hours during 38 hours of continuous wakefulness. A novel marker was found that measured VA when the eyes were open-the prevalence of microsaccades. Notably, the prevalence of microsaccades decreased in response to sleep deprivation and time-on-task. In addition, a novel algorithm for detecting multilevel VA was developed, which estimated performance on the PVT by integrating the novel marker with other eye-related indices. The novel algorithm also tracked changes in intermediate level of VA (specific reaction times in the PVT, i.e. 300-500 ms) during prolonged time-on-task and sleep deprivation, which had not been tracked previously by conventional techniques. The implication of the findings is that this novel algorithm, named "eye-metrical estimation version of the PVT: PVT-E," can be used to reduce human-error-related accidents caused by vigilance impairment even when its level is intermediate.


Training in microvascular anastomosis - A randomized comparative study between chicken thigh specimen and live rat.
Training in microsurgical techniques on live rats is the gold standard, but raises ethical issues related to animal welfare and cost. The aim of this study was to compare acquisition of microsurgical techniques with primary training on chicken thigh specimens. Seventy six students were randomly assigned: 23 to exclusive rat training and 53 to primary chicken-leg training. Both groups were then evaluated on aortic suture and jugular aortic bypass surgery in live rats. The primary criterion for successful anastomosis was the patency test. The survival of the rat, the number of severe vascular wounds and the quality of the dissection were also assessed. Aortic anastomoses were of significantly better quality in the chicken group (p = 0.041). There was no significant difference in the number of serious injuries, rat mortality, or quality of dissection (p > 0.05). For jugular aortic bypass surgery, dissection quality (p = 0.02) and patency test (p = 0.05) were better in the chicken-leg group. There was no significant difference in number of severe wounds or rat mortality (p > 0.05). Students who started their microsurgical training on a chicken leg did not perform worse than those with exclusive live rat training. Initial training on chicken thigh specimens seems to be a reliable alternative to training on live models. LEVEL OF EVIDENCE: Level II - Randomized controlled trial.


Amphimerus bragai n. sp. (Digenea: Opisthorchiidae), a parasite of the rodent Nectomys squamipes (Cricetidae) from Minas Gerais, Brazil.
Amphimerus bragai n.sp. (Digenea, Opisthorchiidae) from the bile ducts of a rodent from the State of Minas Gerais, Brazil, Nectomys squamipes (Cricetidae), is described. The new species as studied by both light and scanning electron microscopy. A table is presented comparing the measurements of the new species with those of A. lancea (Diesing, 1850) and A. vallecaucensis Thatcher; 1970, parasites of dolphins and marsupials, respectively. The new species is similar in size and body form to A. vallecaucensis from which it differs in having a vitellarium that extends to the acetabulum while that of the former species are limited to the posterior one-third of the body. Additionally, the new species is from a rodent.


Generalized common fate: grouping by common luminance changes.
A critical step toward object recognition is the segmentation of a scene into relevant regions. One of the most important cues for segmentation is that of common fate: Elements that move together are grouped together Here we describe a new instantiation of common fate, in which elements move together not through physical space, but through luminance space. Experiment I shows that when elements of a scene become brighter together or darker together, observers group those elements together Experiments 2 and 3 show that this effect is not due to the availability of fixed luminance differences between target and background regions, but requires common changes within each region in the direction of luminance over time. The effect is differentiated from the recently discovered grouping cue of temporal synchrony, and is considered instead to be an extension of Wertheimer's original grouping factor of common fate. Common fate for luminance, or generalized common fate, is an extremely strong cue for the segmentation of a scene, yielding a tremendous advantage over grouping by fixed luminance cues.


Successful percutaneous coronary intervention in a centenarian patient with acute myocardial infarction.
Despite an increasing prevalence and burden of disease in the elderly, little is known about the management and outcomes of acute coronary syndromes in this group. We report the case of a 101-year-old female patient with a non-ST segment elevation myocardial infarction. Coronary angiography showed a total occlusion of the proximal right coronary artery (RCA), and a significant stenosis in the proximal to mid left anterior descending artery (LAD). Despite a very poor initial clinical status, a percutaneous coronary intervention was successfully performed for the total occlusion in the RCA. The LAD lesion was treated with medical therapy only, on account of the age and general condition of the patient. She was discharged after recovering to a good health status, free of chest pain or dyspnea.


Clonality analysis of multifocal ipsilateral breast carcinomas using X-chromosome inactivation patterns.
The definition of multifocal breast cancer is ambiguous, and its incidence varies depending on the definition and detection methods. Multifocal breast cancers either have the same clonal origin or arise from completely distinct progenitor cells. The current American Joint Committee on Cancer Staging system and College of American Pathologists breast tumor guidelines state that only the largest tumor needs to be staged and studied immunohistochemically, on the assumption that they are of the same origin. However, some multifocal tumors have been proved to have arisen from different clones. In the present study, 71 cases of surgically resected multifocal breast cancers were selected. To detect and characterize the tumors of each clonal origin, a human androgen receptor gene (HUMARA) assay to compare the X-chromosome inactivation patterns of multiple tumors was conducted. Twenty-nine of 71 (40.8%) patients were revealed to be heterozygous for HUMARA. Sixty-four (90.1%) patients had the same X chromosome inactivated in different tumors. Seven (9.9%) cases had different inactivated X chromosomes between multifocal tumors, indicating that those tumors were from separate progenitor cells. Five (7.0%) cases showed identical histologic features but had different inactivated HUMARA alleles. According to these results, 2 separate tumors might be synchronous primary tumors, although their histopathologic characteristics are similar. Furthermore, multifocal tumors can be of different origins despite being closely located to each other. These findings suggest that separate grouping of multiple breast tumors based on their clonal origin is needed for future studies.


Behavioral Variant Frontotemporal Dementia as a Serious Complication of Spontaneous Intracranial Hypotension.
Behavioral variant frontotemporal dementia (bvFTD) is a devastating early onset dementia. Symptoms of bvFTD may be caused by spontaneous intracranial hypotension (SIH), a treatable disorder, but no comprehensive study of such patients has been reported. To describe detailed characteristics of a large cohort of patients with SIH and symptoms of bvFTD. We identified patients with SIH who met clinical criteria for bvFTD. Patients were compared to a cohort of SIH patients without bvFTD. The mean age for the 21 men and 8 women was 52.9 yr (range, 37-65 yr). All 29 patients with bvFTD symptoms had hypersomnolence. Magnetic resonance imaging showed brain sagging in all patients, cerebrospinal fluid (CSF) opening pressure low in about half of patients, but a spinal CSF leak could not be detected in any patient. All patients underwent epidural blood patching, but 26 patients eventually underwent 1 or more surgical procedures. Overall, a good outcome was obtained in 21 patients (72%); 20 (91%) of 22 patients who had not undergone prior Chiari surgery compared to 1 (14%) of 7 patients who did undergo Chiari surgery (P < .003). Compared to SIH patients without symptoms of bvFTD (n = 547), those with bvFTD symptoms were older, more often male, less often demonstrated CSF leak on spinal imaging, and more often underwent surgery (P < .02). bvFTD in SIH is rare and associated with brain sagging and hypersomnolence. Spinal CSF leaks are rarely detected. bvFTD symptoms are often refractory to the usual percutaneous procedures but most patients can be cured.


Exploring community perceptions, attitudes and practices regarding the COVID-19 pandemic in Karachi, Pakistan.
The Government of Pakistan is facing difficulty to contain the surge of COVID-19 due to the country's social, political, economical and cultural context. Experiences from the previous epidemic suggest that community perceptions, social norms and cultural practices can impede COVID-19 containment. To understand social responses towards COVID-19, the study aims to explore the understanding of COVID-19 and the acceptance of control measures among community members. We conducted an exploratory qualitative study using a purposive sampling approach, at two communities of Karachi, Pakistan. In-depth interviews were conducted with community members including, young, middle-aged and older adults of both genders. Study data were analysed manually using the conventional content analysis technique. A total of 27 in-depth virtual interviews were conducted, between May and June 2020. Six overarching themes were identified: (1) community knowledge and perceptions around COVID-19; (2) trusted and preferred sources of health information; (3) initial thoughts and feeling towards COVID-19 pandemic; (4) community practices to prevent exposure from COVID-19; (5) perceived risks associated with poor adherence to infection control practices; and (6) future preparedness of community to avoid the second wave of the outbreak. Generally, community members had good knowledge about COVID-19, and positive behaviour and attitude towards using standard precautions. The knowledge is mainly acquired through electronic, print and social media platforms, which have pros and cons. However, some community members including younger individuals had poor adherence to safety measures. This may necessitate concentrated efforts to raise awareness through community mobilisation and sensitisation activities. This study provides an initial evidence base of communities' perceptions, and attitudes towards COVID-19 in an early stage of pandemic. The study emphasises that sufficient knowledge and awareness about COVID-19, adequate training and drills, and adherence to safety measures, are necessary to better prepare for the second wave of COVID-19.


Accurate Inference of Tree Topologies from Multiple Sequence Alignments Using Deep Learning.
Reconstructing the phylogenetic relationships between species is one of the most formidable tasks in evolutionary biology. Multiple methods exist to reconstruct phylogenetic trees, each with their own strengths and weaknesses. Both simulation and empirical studies have identified several "zones" of parameter space where accuracy of some methods can plummet, even for four-taxon trees. Further, some methods can have undesirable statistical properties such as statistical inconsistency and/or the tendency to be positively misleading (i.e. assert strong support for the incorrect tree topology). Recently, deep learning techniques have made inroads on a number of both new and longstanding problems in biological research. In this study, we designed a deep convolutional neural network (CNN) to infer quartet topologies from multiple sequence alignments. This CNN can readily be trained to make inferences using both gapped and ungapped data. We show that our approach is highly accurate on simulated data, often outperforming traditional methods, and is remarkably robust to bias-inducing regions of parameter space such as the Felsenstein zone and the Farris zone. We also demonstrate that the confidence scores produced by our CNN can more accurately assess support for the chosen topology than bootstrap and posterior probability scores from traditional methods. Although numerous practical challenges remain, these findings suggest that the deep learning approaches such as ours have the potential to produce more accurate phylogenetic inferences.


MALDI Mass Spectrometry Imaging of Early- and Late-Stage Serous Ovarian Cancer Tissue Reveals Stage-Specific N-Glycans.
Epithelial ovarian cancer is one of the most fatal gynecological malignancies in adult women. As studies on protein N-glycosylation have extensively reported aberrant patterns in the ovarian cancer tumor microenvironment, obtaining spatial information will uncover tumor-specific N-glycan alterations in ovarian cancer development and progression. matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is employed to investigate N-glycan distribution on formalin-fixed paraffin-embedded ovarian cancer tissue sections from early- and late-stage patients. Tumor-specific N-glycans are identified and structurally characterized by porous graphitized carbon-liquid chromatography-electrospray ionization-tandem mass spectrometry (PGC-LC-ESI-MS/MS), and then assigned to high-resolution images obtained from MALDI-MSI. Spatial distribution of 14 N-glycans is obtained by MALDI-MSI and 42 N-glycans (including structural and compositional isomers) identified and structurally characterized by LC-MS. The spatial distribution of oligomannose, complex neutral, bisecting, and sialylated N-glycan families are localized to the tumor regions of late-stage ovarian cancer patients relative to early-stage patients. Potential N-glycan diagnostic markers that emerge include the oligomannose structure, (Hex)6 + (Man)3 (GlcNAc)2 , and the complex neutral structure, (Hex)2 (HexNAc)2 (Deoxyhexose)1 + (Man)3 (GlcNAc)2 . The distribution of these markers is evaluated using a tissue microarray of early- and late-stage patients.


The influence of pre-motivational factors on behavior via motivational factors: a test of the I-Change model.
The I-Change Model for explaining motivational and behavioral change postulates that an awareness phase precedes the motivation phase of a person, and that effects of pre-motivational factors on behavior are partially mediated by motivational factors. This study tests this assumption with regard to physical activity. Observational longitudinal survey study (baseline, three months, six months) amongst Dutch adults (N = 2434). Structural equation modelling was used to investigate whether the influence of (1) knowledge, (2) cognizance, (3) cues, and (4) risk perception separately on intention and physical activity were mediated by motivational factors (i.e. attitudes, self-efficacy and social influence). Subsequently, a comprehensive model including all pre-motivational factors was estimated to test the same assumption for all pre-motivational factors simultaneously. The results indicate that the associations of cognizance, risk perception and cues with behavior were fully mediated by motivational factors when tested separately. When tested simultaneously only the effect of cognizance remained. Cognizance was most strongly associated with positive attitudes β = .13, p < .01, self-efficacy β = .13, p < .01, and intention β = .14, p < .01. No direct link with behavior was found. The results suggest that pre-motivational factors are important to form a motivation; however, they do not directly influence behavior. The inclusion of factors such as risk perception and cognizance would help to get a better understanding of motivation formation and behavior.


Trends in bio-behavioural risk factors of non-communicable diseases among adults in Sao Tome and Principe.
Understanding national trends in risk factors of noncommunicable diseases (NCDs) may have health policy implications. The aim of the study was to assess the prevalence and social and demographic factors associated with risk factors of NCDs in adults from 2008 to 2019 in Sao Tome and Principe. In repeat cross-sectional national STEPS surveys 2,457 adults (median age 37 years) in 2008 and 1,893 adults (median age 38 years) in 2019 in Sao Tome and Principe responded to structured interviews, physical and biochemical measures. Logistic regressions were applied to estimate predictors of NCD risk factors. Having three to seven NCD risk factors significantly decreased among men but not women from 36.6% in 2008 to 26.8% in 2019. The proportion of specific risk factors of NCD increased significantly for low physical activity from 17.4% in 2008 to 30.9% in 2019, and overweight/obesity from 37.3% in 2008 to 51.0% in 2019. Insufficient fruit/vegetable consumption decreased from 83.1% in 2008 to 53.3% in 2019, frequent alcohol use from 32.6% in 2008 to 24.8% in 2019, and diabetes from 3.1% in 2008 to 1.2% in 2019, while the proportion of current tobacco use and hypertension remained unchanged from 2008 to 2019. Men engaged more often than women in current tobacco use and frequent alcohol use, and women had higher rates of low physical activity and overweight/obesity than men. Higher educational levels were positively associated with overweight/obesity, and inversely associated with frequent alcohol use and inadequate fruit/vegetable intake. Between 2008 and 2019, the prevalence of seven risk factors for NCDs in Sao Tome and Principe declined among men, but not among women. Several associated variables have been identified for each individual risk factor of NCD that may help guide interventions.


Blended diets for gastrostomy fed children and young people: a scoping review.
The present review aimed to identify what is known about the use of blended diets in gastrostomy fed children and young people (i.e. children and young people refers to those who are aged up to 25 years with special educational needs or a disability in accordance with Part 3 of the Children and Family Act 2014; within the review, the word children is used for simplicity but encompasses young people too) and to identify gaps in the literature on this topic to inform future research and policy. A scoping review methodology was used searching the online databases PUBMED, PsychINFO, CINAHL, SCOPUS and AMED, EMBASE for articles that addressed issues pertaining to blended diets. The review identified a broad range of literature, regardless of study design, and described and evaluated the quality, range and nature of research activity related to the use of blenderised diets. Forty-three studies were included in the review. The studies focused on nutrition, equipment, the views of carers and patients, and the views of professionals. Several studies described the lack of evidence regarding pros and cons of blended diets and highlighted the need for further research into the field. There were gaps in the evidence base regarding the impact of blended diets on the health and well-being of the children who receive them and upon the carers who feed the children. The nutritional impact of blended diets is not fully understood and the knowledge and views of professionals involved in the care of those receiving blended diets varies.


[Genetic performance criteria for valproate in patients with epilepsy].
We found a clear correlation between the presence of the CC genotype and genotype combination CC and CT P-glycoproteins rs1045642 and rs1128503 with farmakorezystentnistyu data of patients with valproate (P < 0,01). Also, based on studies demonstrated that the presence of polymorphism TT P-glycoproteins rs1045642 is a positive criterion of forecast performance valproate in a particular patient with epilepsy. We use the definition of P-glycoproteins SNPs rs1045642 and rs1128503 to accelerate the selection of adequate antiepileptic that reduces the selection of adequate treatment tactics in a particular patient. This in turn will prevent the development epileptohenezu that increase the likelihood of full kurabelnosti patient.


Neuronal transmission through hippocampal pathways dependent on behavior.
1. In chronically prepared, freely moving rats, electrical stimulation was applied to the angular bundle, and responses were recorded extracellularly at a variety of sites in the ipsilateral hippocampal formation. At each recording site the stimulus-response relationship was tested during four different behavioral states. These were slow-wave sleep (SWS), REM sleep ( REM), and also two waking behaviors consisting of the still, alert condition (labeled SAL), and voluntary movement (AW theta). 2. Two varieties of evoked responses were recorded: those due to the synchronous firing of neuronal action potentials (EAPs) and those produced by excitatory synaptic activity (ESPs). The overall pattern of monosynaptic, di-, and trisynaptic responses found was similar in the rat to that found by Andersen et al. (3-5) in cat and rabbit. 3. When the trisynaptic EAP was recorded in CA1, the threshold was similar during all four behavioral states. However, suprathreshold stimuli evoked a greater response during SWS than during the other three states. The trisynaptic ESP was also greater during SWS. 4. Disynaptically, EAPs were recorded in CA3. These were greater in magnitude during SWS than during SAL, but were intermediate in mean amplitude during AWtheta and REM. Response variability was much greater during AWtheta and REM. 5. The monosynaptic EAP recorded in the upper blade of the dentate gyrus (DG) exhibited the same behaviorally correlated properties found disynaptically in CA3. 6. The monosynaptic ESP recorded in the DG, in contrast to the EAP, was greater in magnitude during SAL than during SWS. 7. The primary afferent volley was also recorded at high gain in the DG. The amplitude of this was found to be dependent solely on stimulus intensity and not on behavioral state. 8. The results are interpreted as suggesting that the granule cell membranes in the DG are relatively hyperpolarized during SAL compared with SWS as the result of either tonic excitatory bombardment occurring during SWS or tonic inhibitory bombardment during SAL.


A Hydrogel Drink With High Fructose Content Generates Higher Exogenous Carbohydrate Oxidation and Lower Dental Biofilm pH Compared to Two Other, Commercially Available, Carbohydrate Sports Drinks.
The purpose of this study was to evaluate the substrate oxidation of three commercially available, 14%-carbohydrate sports drinks with different compositions, osmolality, and pH for their impact on dental exposure to low pH. In a cross-over, randomized double-blinded design, 12 endurance athletes (age 31. 2 ± 7.7 years, V ˙ O2max 65.6 ± 5.0 mL·kg-1) completed 180 min of cycling at 55% Wmax. During the first 100 min of cycling, athletes consumed amylopectin starch (AP), maltodextrin+sucrose (MD+SUC), or maltodextrin+fructose hydrogel (MD+FRU) drinks providing 95 g carbohydrate·h-1, followed by water intake only at 120 and 160 min. Fuel use was determined using indirect calorimetry and stable-isotope techniques. Additionally, dental biofilm pH was measured using the microtouch method in a subsample of participants (n = 6) during resting conditions before, and at different time intervals up to 45 min following a single bolus of drink. Exogenous carbohydrate oxidation (CHOEXO) during the 2nd hour of exercise was significantly (P < 0.05) different between all three drinks: MD+FRU (1.17 ± 0.17 g·min-1), MD+SUC (1.01 ± 0.13 g·min-1), and AP (0.84 ± 0.11 g·min-1). At the end of exercise, CHOEXO and blood glucose concentrations (3.54 ± 0.50, 4.07 ± 0.67, and 4.28 ± 0.47 mmol·L-1, respectively) were significantly lower post MD+FRU consumption than post MD+SUC and AP consumption (P < 0.05). Biofilm acidogenicity at rest demonstrated a less pronounced pH fall for MD+FRU compared to the acidulant-containing MD+SUC and AP (P < 0.05). In conclusion, while total intake of MD+FRU showed signs of completed uptake before end of monitoring, this was less so for MD+SUC, and not at all the case for AP. Thus, this study showed that despite carbohydrates being encapsulated in a hydrogel, a higher CHOEXO was observed following MD+FRU drink ingestion compared to AP and MD+SUC consumption upon exposure to the acidic environment of the stomach. This finding may be related to the higher fructose content of the MD+FRU drink compared with the MD+SUC and AP drinks. Furthermore, a carbohydrate solution without added acidulants, which are commonly included in commercial sport drinks, may have less deleterious effects on oral health.


UPF2-Dependent Nonsense-Mediated mRNA Decay Pathway Is Essential for Spermatogenesis by Selectively Eliminating Longer 3'UTR Transcripts.
During transcription, most eukaryotic genes generate multiple alternative cleavage and polyadenylation (APA) sites, leading to the production of transcript isoforms with variable lengths in the 3' untranslated region (3'UTR). In contrast to somatic cells, male germ cells, especially pachytene spermatocytes and round spermatids, express a distinct reservoir of mRNAs with shorter 3'UTRs that are essential for spermatogenesis and male fertility. However, the mechanisms underlying the enrichment of shorter 3'UTR transcripts in the developing male germ cells remain unknown. Here, we report that UPF2-mediated nonsense-mediated mRNA decay (NMD) plays an essential role in male germ cells by eliminating ubiquitous genes-derived, longer 3'UTR transcripts, and that this role is independent of its canonical role in degrading "premature termination codon" (PTC)-containing transcripts in somatic cell lineages. This report provides physiological evidence supporting a noncanonical role of the NMD pathway in achieving global 3'UTR shortening in the male germ cells during spermatogenesis.


Pathogenesis of cervical artery dissections: association with connective tissue abnormalities.
The etiology of spontaneous cervical artery dissection (CAD) is largely unknown. An underlying connective tissue disorder has often been postulated. To further assess the association of CAD with ultrastructural abnormalities of the dermal connective tissue. In a multicenter study, skin biopsies of 65 patients with proven nontraumatic CAD and 10 control subjects were evaluated. The ultrastructural morphology of the dermal connective tissue components was assessed by transmission electron microscopy. Only three patients (5%) had clinical manifestations of skin, joint, or skeletal abnormalities. Ultrastructural aberrations were seen in 36 of 65 patients (55%), consisting of the regular occurrence of composite fibrils within collagen bundles that in some cases resembled the aberrations found in Ehlers-Danlos syndrome type II or III and elastic fiber abnormalities with minicalcifications and fragmentation. A grading scale according to the severity of the findings is introduced. Intraindividual variability over time was excluded by a second biopsy of the skin in eight patients with pronounced aberrations. Recurrent CAD correlated with connective tissue aberrations. In addition, similar connective tissue abnormalities were detected in four first-degree relatives with familial CAD. CAD is associated with ultrastructural connective tissue abnormalities, mostly without other clinical manifestations of a connective tissue disease. A structural defect in the extracellular matrix of the arterial wall leading to a genetic predisposition is suggested. The dermal connective tissue abnormalities detected can serve as a phenotypic marker for further genetic studies in patients with CAD and large families to possibly identify the underlying basic molecular defect(s).


Higher-Order Explanations of Graph Neural Networks via Relevant Walks.
Graph Neural Networks (GNNs) are a popular approach for predicting graph structured data. As GNNs tightly entangle the input graph into the neural network structure, common explainable AI approaches are not applicable. To a large extent, GNNs have remained black-boxes for the user so far. In this paper, we show that GNNs can in fact be naturally explained using higher-order expansions, i.e., by identifying groups of edges that jointly contribute to the prediction. Practically, we find that such explanations can be extracted using a nested attribution scheme, where existing techniques such as layer-wise relevance propagation (LRP) can be applied at each step. The output is a collection of walks into the input graph that are relevant for the prediction. Our novel explanation method, which we denote by GNN-LRP, is applicable to a broad range of graph neural networks and lets us extract practically relevant insights on sentiment analysis of text data, structure-property relationships in quantum chemistry, and image classification.


Efficacy of immobilization of the tarsal joint to alleviate strain on the common calcaneal tendon in dogs.
To measure strain in the common calcaneal tendon during trotting in dogs and to compare strain before and after immobilization of the tarsal joint. 6 dogs. A microminiature strain gauge was surgically implanted on the tendinous portion of the gastrocnemius muscle. Surface electromyography (EMG) values, percentage strain, and ground reaction forces were measured before and after immobilization. Peak vertical force; vertical impulse; initial, maximum, and final strain; and peak-to-peak EMG amplitude were recorded. Data were analyzed by use of a repeated-measures ANOVA and paired t tests. Timing of strain data correlated closely with foot strike of the hind limb and EMG activity in all dogs. Maximum tendon strain was simultaneous with peak vertical force. Continued muscle contraction was evident after immobilization. There was no significant difference in maximum strain after immobilization, compared with maximum strain during normal motion. Minimum strain, both at the beginning and end of the strain curve, was significantly decreased for the immobilized state, compared with results for nonimmobilized joints. Immobilization of the tarsal joint did not eliminate calcaneal tendon strain during weight bearing in dogs. Decreased isometric muscle contraction during the swing phase of the gait could account for smaller minimum strain in immobilized joints. Immobilization is frequently applied after Achilles tendon rupture to alleviate strain and force on the sutured repair, with possible complications because of the immobilization method. Consideration of these findings could be important in adjusting current treatment recommendations.


Collision-induced and complex-mediated roaming dynamics in the H + C2H4 → H2 + C2H3 reaction.
Roaming is a novel mechanism in reaction dynamics. It describes an unusual pathway, which can be quite different from the conventional minimum-energy path, leading to products. While roaming has been reported or suggested in a number of unimolecular reactions, it has been rarely reported for bimolecular reactions. Here, we report a high-level computational study of roaming dynamics in the important bimolecular combustion reaction H + C2H4 → H2 + C2H3, using a new, high-level machine learning-based potential energy surface. In addition to the complex-mediated roaming mechanism, a non-complex forming roaming mechanism is found. It can be described as a direct inelastic collision where the departing H atom roams and then abstracts an H atom. We denoted this as "collision-induced" roaming. These two roaming mechanisms have different angular distributions; however, both produce highly internally excited C2H3. The roaming pathway leads to remarkably different dynamics as compared with the direct abstraction pathway. A clear signature of the roaming mechanism is highly internally excited C2H3, which could be observed experimentally.


Differentiation of monocytic U937 cells under static magnetic field exposure.
We present here a morphological, cytochemical and biochemical study of the macrophagic differentiation of human pro-monocytic U937 cells exposed to moderate intensity (6 mT) static magnetic fields (MF). It was found that the following substances induced differentiation in U937 cells to a progressively lower degree: 50 ng/mL 12-0-tetradecanoyl-13-phorbol acetate (TPA), low concentration of glutamine (0,05 mM/L), 10% dimethyl sulfoxide (DMSO) and 100 mM/L Zn++. Differentiated U937 cells shift from a round shape to a macrophage-like morphology, from suspension to adhesion growth and acquire phagocytotic activity, the cytoskeleton adapting accordingly. Exposure to static MF at 6 mT of intensity decreases the degree of differentiation for all differentiating molecules with a consequent fall in cell adhesion and increased polarization of pseudopodia and cytoplasmic protrusions. Differentiation alone, or in combination with exposure to static MFs, affects the distribution and quantity of cell surface sugar residues, the surface expression of markers of macrophage differentiation, and phagocytotic capability. Our results indicate that moderate-intensity static MFs exert a considerable effect on the process of macrophage differentiation of pro-monocytic U937 cells and suggest the need for further studies to investigate the in vivo possible harmful consequences of this.


Integration of Mass Spectrometry Data for Structural Biology.
Mass spectrometry (MS) is increasingly being used to probe the structure and dynamics of proteins and the complexes they form with other macromolecules. There are now several specialized MS methods, each with unique sample preparation, data acquisition, and data processing protocols. Collectively, these methods are referred to as structural MS and include cross-linking, hydrogen-deuterium exchange, hydroxyl radical footprinting, native, ion mobility, and top-down MS. Each of these provides a unique type of structural information, ranging from composition and stoichiometry through to residue level proximity and solvent accessibility. Structural MS has proved particularly beneficial in studying protein classes for which analysis by classic structural biology techniques proves challenging such as glycosylated or intrinsically disordered proteins. To capture the structural details for a particular system, especially larger multiprotein complexes, more than one structural MS method with other structural and biophysical techniques is often required. Key to integrating these diverse data are computational strategies and software solutions to facilitate this process. We provide a background to the structural MS methods and briefly summarize other structural methods and how these are combined with MS. We then describe current state of the art approaches for the integration of structural MS data for structural biology. We quantify how often these methods are used together and provide examples where such combinations have been fruitful. To illustrate the power of integrative approaches, we discuss progress in solving the structures of the proteasome and the nuclear pore complex. We also discuss how information from structural MS, particularly pertaining to protein dynamics, is not currently utilized in integrative workflows and how such information can provide a more accurate picture of the systems studied. We conclude by discussing new developments in the MS and computational fields that will further enable in-cell structural studies.


[Experiences in realization of guidelines of the nursing care insurance regulation--outcome in home care service after expert assessment by medical service personnel].
The German Pflegeversicherung is a new kind of insurance system for dependence on nursing care (Nursing Care Insurance). Grading into groups according to the intensity of help required, effected by physicians and nurses of the Medical Service of the statutory insurance bodies, as well as the grading system itself have been subjected to severe criticism. However, the emotions in this regard have recently calmed down considerably. The questions are: Do the benefits of the Pflegeversicherung result in improving the financial situation at home? Does it signify increase professional nursing at home? The purpose of our study is to find an answer to these and other questions. We interviewed 150 nursing care dependent persons receiving benefits according to the new system. Senile dementia was the most frequent diagnosis in groups II and III of the official grading scale. Despite of the financial support, a change to more professional nursing care was rarely observed; on the contrary, at times the costly professional services were no longer requested. Deterioration of physical health was seen in every second patient since the first rating by the Medical Service 4 to 6 months ago. Notification of grading and payments to the families took place without delay except in cases of "Kombinationsleistung" (financial support plus financing ambulatory professional nursing-care). We observed major deficits in the counselling of patients or their relatives; there were mostly no courses in nursing care for relatives. Patients and their care-providing relatives usually were satisfied by the benefits provided; relatives felt the financial benefits as an acknowledgement of their engagement. In summary, most care-providing relatives were satisfied by the benefits, but the lack of nonfinancial services (counselling, courses in nursing care, payments for social security) showed up major deficiencies.


Potential danger of ocular compression in paroxysmal supraventricular tachycardia in patients with latent preexcitation.
The vagal maneuver is the first line of therapeutic available for patients with paroxysmal supraventricular tachycardia. It increases vagal tone and includes the traditional ocular compression, carotid sinus massage, and Valsalva maneuver. A 40-year-old man was admitted because of 180 beats/min regular narrow QRS-complex tachycardia. The physician in the emergency department had performed an ocular compression, and at its ending, the tachycardia degenerated into unstable hemodynamically high ventricular rate atrial fibrillation. It was reverted to sinus rhythm by electrical shock. The electrophysiologic study documented a latent posterolateral bypass tract, with an anterograde refractory period of 210 milliseconds, which was successfully ablated.


Harmonizing Labeling and Analytical Strategies to Obtain Protein Turnover Rates in Intact Adult Animals.
Changes in the abundance of individual proteins in the proteome can be elicited by modulation of protein synthesis (the rate of input of newly synthesized proteins into the protein pool) or degradation (the rate of removal of protein molecules from the pool). A full understanding of proteome changes therefore requires a definition of the roles of these two processes in proteostasis, collectively known as protein turnover. Because protein turnover occurs even in the absence of overt changes in pool abundance, turnover measurements necessitate monitoring the flux of stable isotope-labeled precursors through the protein pool such as labeled amino acids or metabolic precursors such as ammonium chloride or heavy water. In cells in culture, the ability to manipulate precursor pools by rapid medium changes is simple, but for more complex systems such as intact animals, the approach becomes more convoluted. Individual methods bring specific complications, and the suitability of different methods has not been comprehensively explored. In this study, we compare the turnover rates of proteins across four mouse tissues, obtained from the same inbred mouse strain maintained under identical husbandry conditions, measured using either [13C6]lysine or [2H2]O as the labeling precursor. We show that for long-lived proteins, the two approaches yield essentially identical measures of the first-order rate constant for degradation. For short-lived proteins, there is a need to compensate for the slower equilibration of lysine through the precursor pools. We evaluate different approaches to provide that compensation. We conclude that both labels are suitable, but careful determination of precursor enrichment kinetics in amino acid labeling is critical and has a considerable influence on the numerical values of the derived protein turnover rates.


Theory and simulations of adhesion receptor dimerization on membrane surfaces.
The equilibrium constants of trans and cis dimerization of membrane bound (2D) and freely moving (3D) adhesion receptors are expressed and compared using elementary statistical-thermodynamics. Both processes are mediated by the binding of extracellular subdomains whose range of motion in the 2D environment is reduced upon dimerization, defining a thin reaction shell where dimer formation and dissociation take place. We show that the ratio between the 2D and 3D equilibrium constants can be expressed as a product of individual factors describing, respectively, the spatial ranges of motions of the adhesive domains, and their rotational freedom within the reaction shell. The results predicted by the theory are compared to those obtained from a novel, to our knowledge, dynamical simulations methodology, whereby pairs of receptors perform realistic translational, internal, and rotational motions in 2D and 3D. We use cadherins as our model system. The theory and simulations explain how the strength of cis and trans interactions of adhesive receptors are affected both by their presence in the constrained intermembrane space and by the 2D environment of membrane surfaces. Our work provides fundamental insights as to the mechanism of lateral clustering of adhesion receptors after cell-cell contact and, more generally, to the formation of lateral microclusters of proteins on cell surfaces.


Treatment with 6-Gingerol Regulates Dendritic Cell Activity and Ameliorates the Severity of Experimental Autoimmune Encephalomyelitis.
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder, with increasing incidence worldwide but unknown etiology. 6-Gingerol (6-GIN), a major dietary compound found in ginger rhizome, has immunomodulatory activity. However, its role in autoimmune diseases, as well as the underlying mechanisms, are unclear. In this study, it is evaluated if 6-GIN can effectively ameliorate the clinical disease severity of experimental autoimmune encephalomyelitis, an animal model of MS. Clinical scores of experimental autoimmune encephalomyelitis (EAE) mice are recorded daily. Inflammation of periphery and neuroinflammation of EAE mice are determined by flow cytometry analysis, ELISA, and histopathological analysis, and results show that 6-GIN significantly inhibits inflammatory cell infiltration from the periphery into the central nervous system and reduces neuroinflammation and demyelination. Flow cytometry analysis, ELISA, and quantitative PCR show that 6-GIN could suppress lipolysaccharide-induced dendritic cell (DC) activation and induce the tolerogenic DCs. Immunoblot analysis reveals that the phosphorylation of nuclear factor-κB and mitogen-activated protein kinase, two critical regulators of inflammatory signaling, are significantly inhibited in 6-GIN-treated DCs. The results of this study demonstrate that 6-GIN has significant potential as a novel anti-inflammatory agent for the treatment of autoimmune diseases such as MS via direct modulatory effects on DCs.


Temporal Changes in Concentrations of Lead and Other Trace Metals in Free-Ranging Eurasian Eagle Owls Bubo bubo in Sweden.
Patterns of lead and other trace metals were examined in 122 Eurasian eagle owls Bubo bubo found dead in Sweden in the period 1978-2013. Environmental lead (Pb) has decreased over recent decades from reduced anthropogenic emissions but mortality by Pb poisoning is still frequently reported for avian raptors and scavengers exposed to Pb ammunition. One objective here was to determine if Pb concentrations in a nocturnal non-scavenging raptor follow the general decline observed in other biota. Pb concentration in owl liver was significantly correlated with body weight, sex, latitude, longitude and season. Pb showed a significant decreasing trend towards north and west. Starved birds had significantly higher concentrations. Total Pb concentrations in liver averaged 0.179 μg g-1 dry weight (median 0.103) and decreased by 5.6% per year 1978-2013, or 5.3% after adjustment for confounding factors, similar to trends in other species. Among 14 other trace elements only antimony and arsenic showed decreasing trends. Lead isotope ratios 206Pb/207Pb and 208Pb/207Pb increased from 1.138 and 2.408 in 1978-1985 to 1.170 and 2.435 in 2010-2013, respectively, demonstrating that the decreasing Pb concentration in eagle owl is related to the phase-out of leaded gasoline in Europe, where Pb additives had much lower isotope ratios than natural lead in Swedish soils. Only one incidence of suspected Pb poisoning (40.7 μg g-1 in liver) was observed indicating that poisoning from ingestion of metallic lead is rare (< 1%) in eagle owl in Sweden, in contrast to what has been reported for eagles.


Top-down fabrication of ordered arrays of GaN nanowires by selective area sublimation.
We demonstrate the top-down fabrication of ordered arrays of GaN nanowires by selective area sublimation of pre-patterned GaN(0001) layers grown by hydride vapor phase epitaxy on Al2O3. Arrays with nanowire diameters and spacings ranging from 50 to 90 nm and 0.1 to 0.7 μm, respectively, are simultaneously produced under identical conditions. The sublimation process, carried out under high vacuum conditions, is analyzed in situ by reflection high-energy electron diffraction and line-of-sight quadrupole mass spectrometry. During the sublimation process, the GaN(0001) surface vanishes, giving way to the formation of semi-polar {11̄03} facets which decompose congruently following an Arrhenius temperature dependence with an activation energy of (3.54 ± 0.07) eV and an exponential prefactor of 1.58 × 1031 atoms per cm2 per s. The analysis of the samples by low-temperature cathodoluminescence spectroscopy reveals that, in contrast to dry etching, the sublimation process does not introduce nonradiative recombination centers at the nanowire sidewalls. This technique is suitable for the top-down fabrication of a variety of ordered nanostructures, and could possibly be extended to other material systems with similar crystallographic properties such as ZnO.


Metabolic disorders during pregnancy and postpartum cardiometabolic risk.
Hormonal changes during pregnancy can trigger gestational diabetes (GDM), which is constantly increasing. Its main characteristic is pronounced insulin resistance, but it appears to be a multifactorial process involving several metabolic factors; taken together, the latter leads to silent or clinically evident cardiovascular (CV) events. Insulin resistance and central adiposity are of crucial importance in the development of metabolic syndrome, and they appear to correlate with CV risk factors, including hypertension and atherogenic dyslipidaemia. Hypertensive disease of pregnancy (HDP) is more likely to be an accompanying co-morbidity in pregnancies complicated with GDM. There is still inconsistent evidence as to whether or not co-existent GDM and HDP have a synergistic effects on postpartum risk of cardiometabolic disease; however, this synergism is becoming more accepted since both these conditions may promote endothelial inflammation and early atherosclerosis. Regardless of the presence or absence of the synergism between GDM and HDP, these conditions need to be dealt early enough, in order to reduce CV morbidity and to improve health outcomes for both women and their offspring.


Struma ovarii and the thyroid surgeon.
Struma ovarii is a rare, monodermal, ovarian teratoma. The common presentation is abdominal, with pelvic mass and pain, traditionally managed by gynaecologists. The malignant form is extremely rare and consists of differentiated thyroid cancer. It is rare for struma ovarii to present with features of hyperthyroidism. We present two unusual cases of struma ovarii and discuss the role of the thyroid surgeon in their management. The first case involved a 40-year-old woman with a two-month history of swelling in the lower abdomen. Investigations revealed a mass arising from the left ovary. Surgery revealed a follicular carcinoma arising in a struma ovarii. She underwent a total thyroidectomy prior to radio-iodine therapy. The second case involved a 60-year-old woman who underwent thyroidectomy for thyrotoxicosis. Three months post-operatively, she remained thyrotoxic despite stopping thyroxine. A whole body radio-iodine scan revealed high uptake in the left ovary. Histological analysis of the resected ovary showed benign struma ovarii. These two cases highlight the diagnostic and therapeutic role of thyroid surgeons in the management of benign and malignant forms of struma ovarii.


Erythrocyte membrane n-3 PUFA are inversely associated with breast cancer risk among Chinese women.
The relationship between erythrocyte membrane n-3 PUFA and breast cancer risk is controversial. We aimed to examine the associations of erythrocyte membrane n-3 PUFA with odds of breast cancer among Chinese women by using a relatively large sample size. A case-control study was conducted including 853 newly diagnosed, histologically confirmed breast cancer cases and 892 frequency-matched controls (5-year interval). Erythrocyte membrane n-3 PUFA were measured by GC. Logistic regression and restricted cubic spline were used to quantify the association between erythrocyte membrane n-3 PUFA and odds of breast cancer. Erythrocyte membrane α-linolenic acid (ALA), docosapentaenoic acid (DPA) and total n-3 PUFA were inversely and non-linearly associated with odds of breast cancer. The OR values (95 % CI), comparing the highest with the lowest quartile (Q), were 0·57 (0·43, 0·76), 0·43 (0·32, 0·58) and 0·36 (0·27, 0·49) for ALA, DPA and total n-3 PUFA, respectively. Erythrocyte membrane EPA and DHA were linearly and inversely associated with odds of breast cancer ((EPA: ORQ4 v. Q1 (95 % CI) = 0·59 (0·45, 0·79); DHA: ORQ4 v. Q1 (95 % CI) = 0·50 (0·37, 0·67)). The inverse associations were observed between ALA and odds of breast cancer in postmenopausal women, and between DHA and oestrogen receptor+ breast cancer. This study showed that erythrocyte membrane total and individual n-3 PUFA were inversely associated with odds of breast cancer. Other factors, such as menopause and hormone receptor status, may warrant further investigation when examining the association between n-3 PUFA and odds of breast cancer.


Interneuron activity leads to initiation of low-voltage fast-onset seizures.
Seizures in temporal lobe epilepsy can be classified as hypersynchronous and low-voltage fast according to their onset patterns. Experimental evidence suggests that low-voltage fast-onset seizures mainly result from the synchronous activity of γ-aminobutyric acid-releasing cells. In this study, we tested this hypothesis using the optogenetic control of parvalbumin-positive interneurons in the entorhinal cortex, in the in vitro 4-aminopyridine model. We found that both spontaneous and optogenetically induced seizures had similar low-voltage fast-onset patterns. In addition, both types of seizures presented with higher ripple than fast ripple rates. Our data demonstrate the involvement of interneuronal networks in the initiation of low-voltage fast-onset seizures.


iTRAQ-based proteomics profiling reveals increased metabolic activity and cellular cross-talk in angiogenic compared with invasive glioblastoma phenotype.
Malignant gliomas (glioblastoma multiforme) have a poor prognosis with an average patient survival under current treatment regimens ranging between 12 and 14 months. The tumors are characterized by rapid cell growth, extensive neovascularization, and diffuse cellular infiltration of normal brain structures. We have developed a human glioblastoma xenograft model in nude rats that is characterized by a highly infiltrative non-angiogenic phenotype. Upon serial transplantation this phenotype will develop into a highly angiogenic tumor. Thus, we have developed an animal model where we are able to establish two characteristic tumor phenotypes that define human glioblastoma (i.e. diffuse infiltration and high neovascularization). Here we aimed at identifying potential biomarkers expressed by the non-angiogenic and the angiogenic phenotypes and elucidating the molecular pathways involved in the switch from invasive to angiogenic growth. Focusing on membrane-associated proteins, we profiled protein expression during the progression from an invasive to an angiogenic phenotype by analyzing serially transplanted glioma xenografts in rats. Applying isobaric peptide tagging chemistry (iTRAQ) combined with two-dimensional LC and MALDI-TOF/TOF mass spectrometry, we were able to identify several thousand proteins in membrane-enriched fractions of which 1460 were extracted as quantifiable proteins (isoform- and species-specific and present in more than one sample). Known and novel candidate proteins were identified that characterize the switch from a non-angiogenic to a highly angiogenic phenotype. The robustness of the data was corroborated by extensive bioinformatics analysis and by validation of selected proteins on tissue microarrays from xenograft and clinical gliomas. The data point to enhanced intercellular cross-talk and metabolic activity adopted by tumor cells in the angiogenic compared with the non-angiogenic phenotype. In conclusion, we describe molecular profiles that reflect the change from an invasive to an angiogenic brain tumor phenotype. The identified proteins could be further exploited as biomarkers or therapeutic targets for malignant gliomas.


A rare complication after vestibular schwannoma surgery: Neurogenic pulmonary edema.
In our center, large vestibular schwannoma (VS) is typically managed by a planned partial resection through the translabyrinthine route. Here, we report on a rare complication of VS surgery and severe neurogenic pulmonary edema. A 33-year-old male was referred to our skull-base center with a large VS. A planned partial resection was performed. The surgery was without complications and the patient showed good recovery without facial nerve dysfunction. In the evening of the 2nd day after surgery, the patient showed rapid neurological deterioration, accompanied by cardiac arrest. After the patient was resuscitated, a computed tomography (CT) was made, which showed generalized (infra- and supratentorial) brain edema and hematoma in the resection cavity. Despite rapid removal of the hematoma, there was no change in the neurological situation. The next CT scan showed a further increase of brain edema and the patient died eventually. Autopsy revealed generalized lung edema, brain edema, and Hashimoto's thyroiditis. The pathologist diagnosed neurogenic lung edema. Neurogenic lung edema can occur on the 2nd day after surgery and induce rapid deterioration of the patient with massive brain edema.


Calmodulin-binding proteins and calmodulin-regulated enzymes in dog pancreas.
Calmodulin was isolated and purified to homogeneity from dog pancreas. Highly purified subcellular fractions were prepared from dog pancreas by zonal sucrose-density ultracentrifugation and assayed for their ability to bind 125I-calmodulin in vitro. Proteins contained in these fractions were also examined for binding of 125I-calmodulin after their separation by polyacrylamide-gel electrophoresis in SDS. Calmodulin-binding proteins were detected in all subcellular fractions except the zymogen granule and zymogen-granule membrane fractions. One calmodulin-binding protein (Mr 240,000), observed in a washed smooth-microsomal fraction, has properties similar to those of alpha-fodrin. The postribosomal-supernatant fraction contained three prominent calmodulin-binding proteins, with apparent Mr values of 62,000, 50,000 and 40,000. Calmodulin-binding proteins, prepared from a postmicrosomal-supernatant fraction by Ca2+-dependent affinity chromatography on immobilized calmodulin, exhibited calmodulin-dependent phosphodiesterase, protein phosphatase and protein kinase activities. In the presence of Ca2+ and calmodulin, phosphorylation of smooth-muscle myosin light chain and brain synapsin and autophosphorylation of a Mr-50,000 protein were observed. Analysis of the protein composition of the preparation by SDS/polyacrylamide-gel electrophoresis revealed a major protein of Mr 50,000 which bound 125I-calmodulin. This protein shares characteristics with the calmodulin-dependent multifunctional protein kinase (kinase II) recently observed to have a widespread distribution. The possible role of calmodulin-binding proteins and calmodulin-regulated enzymes in the regulation of exocrine pancreatic protein synthesis and secretion is discussed.


Autism spectrum disorder in a rural community in Bangladesh: A mid-childhood assessment.
Population-based studies employing standardized diagnostics are needed to determine the burden of autism spectrum disorder (ASD) in low-resource settings. A community-based study was conducted among 8-11 year old children in rural, northwestern Bangladesh to establish the prevalence of ASD. A standardized screening and diagnosis protocol was adapted and deployed comprising the social communication questionnaire (SCQ), and the autism diagnostic observation schedule 2, (ADOS-2), and the autism diagnostic interview, revised (ADI-R), respectively. A year-long research training was conducted for a clinical psychologist to be certified to administer ADOS-2 and ADI-R. Over 8000 children were visited at home and administered the SCQ leading to some, based on their score, being further evaluated using the ADOS-2 and ADI-R by the clinical psychologist. Based on ADOS-2 applying the diagnoses of autism or autism spectrum, the prevalence was 40 (95% CI: 27, 54) per 10,000. Autistic disorder using ADI-R was found at 12 (95% CI: 5, 20) per 10,000. Boys were at a higher risk than girls with the rates among boys being 46 (95% CI: 25, 67) using ADOS-2 and 19 (95% CI:6, 33) using ADI-R. Among girls the rates were 34 (95% CI:16, 52) and 5 (95% CI:0, 12) per 10,000, respectively. Challenges to undertaking ASD research in a rural South Asian context are discussed. There was a low-to-moderate prevalence of ASD in a rural, child population in Bangladesh. Future research is needed to estimate rates of ASD and its causes and socioeconomic consequences in rural and urban settings of South Asia. LAY SUMMARY: In a study of over 8000, 8-11 year old children in a rural area of Bangladesh, two to four out of 1000 had ASD. Boys more than girls had ASD. Conducting ASD assessment in this setting was difficult, but more such research is needed to understand what causes ASD and its consequences for the individual, families and the society in rural and urban areas of low-income countries.


MOF-Bacteriophage Biosensor for Highly Sensitive and Specific Detection of Staphylococcus aureus.
To produce a sensitive and specific biosensor for Staphylococcus aureus, bacteriophages have been interfaced with a water-dispersible and environmentally stable metal-organic framework (MOF), NH2-MIL-53(Fe). The conjugation of the MOF with bacteriophages has been achieved through the use of glutaraldehyde as cross-linker. Highly sensitive detection of S. aureus in both synthetic and real samples was realized by the proposed MOF-bacteriophage biosensor based on the photoluminescence quenching phenomena: limit of detection (31 CFU/mL) and range of detection (40 to 4 × 108 CFU/mL). This is the first report exploiting the use of an MOF-bacteriophage complex for the biosensing of S. aureus. The results of our study highlight that the proposed biosensor is more sensitive than most of the previous methods while exhibiting some advanced features like specificity, regenerability, extended range of linear detection, and stability for long-term storage (even at room temperature).


SorLA deficiency dissects amyloid pathology from tau and cholinergic neurodegeneration in a mouse model of Alzheimer's disease.
Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimer's disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-β protein precursor (AβPP) to amyloid-β. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AβPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve growth factor (NGF) mouse, in which amyloid-β accumulation derives from the altered processing of endogenous AβPP. In addition to alterations in AβPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AβPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD.


Longitudinal brainstem laceration associated with complex basilar skull fractures due to a fall: an autopsy case.
This report describes an autopsy case of a rare longitudinal brainstem laceration associated with complex basilar skull fractures. The victim was a 40-year-old male who died immediately after falling from a roof (9.2m in height) of a factory onto a concrete floor. The postmortem examination revealed an incomplete ring fracture of the base of the skull with longitudinal fractures of the sphenoid (clivus of the dorsum sellae turcicae) and occipital bones, cerebral contusions in the frontal and temporal poles, a longitudinal brainstem laceration at the posterior median sulcus of the pons accompanied with multiple contusional hemorrhages in the brainstem and corpus callosum. Related blunt-force injuries were observed in the parieto-occipital region of the head, shoulder and upper back involving the fractures of the cervical and thoracic vertebrae, and sternum and ribs, indicating a huge impact to the occiput and subsequent impression of the vertebral column into the base of the skull due to violent anteroflexion of the neck, which caused the complex basilar skull fractures, contusions and longitudinal laceration of the brainstem.


Incidence and predictors of radial artery injury following transradial procedures: Yet another benefit of renin-angiotensin system blockade?
Vasodilatory function of radial artery (RA) declines following the transradial catheterization. However, it is uncertain whether impaired vasodilatory function develops in every patient. The aim of this study was to investigate the incidence and predictive factors of impaired vasodilatory function following transradial procedures. Consecutive patients undergoing elective transradial procedures were prospectively enrolled. Ultrasound examination of RA was recorded just before and 1 week after the procedure. RA diameters and flow velocities were measured at baseline, after flow mediated vasodilation (FMD) and after nitrate mediated vasodilation (NMD). Fifty-one patients were included (62 ± 11 years, 55% male, 41% hypertensive, 20% diabetic, 65% with coronary artery disease). Overall FMD and NMD were significantly impaired after 1 week. However, deterioration of FMD and NMD was observed in 67% and 71% of patients, respectively. Absolute change in FMD was significantly different in patients using a renin- angiotensin system (RAS) inhibitor compared to those who were not (1.9 ± 12.9 vs. -7.7 ± ± 12.7%, respectively, p = 0.025). Additionally, there was a moderate but significant correlation between baseline RA diameter and absolute change in NMD (r = 0.419, p < 0.001). RAS blockade was independently associated with protection against FMD deterioration (OR 0.241, 95% CI 0.066-0.883, p = 0.032), whereas RA diameter (OR 0.079, 95% CI 0.009-0.720, p = 0.024) and procedure time (OR 1.156, 95% CI 0.989-1.350, p = 0.068) were associated with NMD deterioration, although the latter had borderline significance. Vasodilatory function of RA gets impaired in most patients following transradial procedures. RAS blockade seems to exert a protective role against deteriorating endothelium- dependent vasodilation, whereas smaller RA diameter and potentially longer procedure time are associated with impaired endothelium-independent vasodilation.


Diversity of rotavirus serotypes in Mexican infants with gastroenteritis.
One hundred thirty-two stool specimens from infants with rotavirus gastroenteritis hospitalized in two Mexican cities (Mexico City and Mérida) were examined by serotype- and subgroup-specific enzyme immunoassays. Among them, 38 (29%) were serotype 1, 15 (11%) were serotype 2, 13 (10%) were serotype 3, 22 (17%) were serotype 4, none was serotype 5 or 6, and 44 (33%) could not be serotyped. By subgrouping, 121 specimens were characterized as follows: 24 (18%) were subgroup 1, 97 (74%) were subgroup 2, and none had both subgroup specificities. While serotype 1 rotavirus predominated in the Mexico City area for 4 consecutive years (1984 to 1987), serotype 4 predominated in Mérida during the single epidemic season studied (1985). These data demonstrate that all four primary human rotavirus serotypes circulated in Mexico, with serotype 1 being the most prevalent. The seroneutralization responses of 14 of the 22 patients infected with serotype 4 strains had been previously studied. Of these 14 infants, 11 appeared to have primary infections, as indicated by absence of neutralizing antibodies in the acute-phase sera and their young age (8 months on average) at the time of illness. Seven patients seroresponded to serotypes 1 and 4; two seroresponded to serotypes 1, 3, and 4; three seroresponded to serotype 1; and two had low-level seroresponses to serotype 3 or 4. These data indicate that heterotypic neutralizing antibody responses occur frequently following infection with serotype 4 rotaviruses.


Causality of Drugs Involved in Acute Liver Failure Leading to Transplantation: Results from the Study of Acute Liver Transplant (SALT).
Several methods have been proposed to assess causality in drug-induced liver injury but none have been tested in the specific context of acute liver failure leading to transplantation (ALFT). We took advantage of the Study of Acute Liver Transplant (SALT), a European case-population study of ALFT, to test different causality scales. Causality was assessed by experts in SALT, a 7-country case-population study from 2005 to 2007 of adult otherwise unexplained ALFT, for all drugs found within 30 days prior to the date of initial symptoms of liver disease (index date), using information content, causality scales, and data circuit determined from a pilot study, Salome. The consensus points from Salome were to provide full data on drugs including international non-proprietary name (INN) and doses except for non-steroidal anti-inflammatory drugs (NSAIDs) and to use the World Health Organization (WHO) causality scale. In SALT, among the 9,479 identified patients, 600 (6.3%) were cases of ALFT, of which 187 had been exposed to drugs within 30 days, without overdose. In 130 (69.5%) of these the causality score was possible, probable, or highly probable. In ALFT cases, once other clinical causes have been excluded and drug exposure established within 30 days, the main discriminant characteristic for causality will be previous knowledge of possible hepatotoxicity.


Roles of mitochondria in health and disease.
Mitochondria play a central role in cell life and cell death. An increasing number of studies place mitochondrial dysfunction at the heart of disease, most notably in the heart and the central nervous system. In this article, I review some of the key features of mitochondrial biology and focus on the pathways of mitochondrial calcium accumulation. Substantial evidence now suggests that the accumulation of calcium into mitochondria may play a key role as a trigger to mitochondrial pathology, especially when that calcium uptake is accompanied by another stressor, in particular nitrosative or oxidative stress. The major process involved is the opening of the mitochondrial permeability transition pore, a large conductance pore that causes a collapse of the mitochondrial membrane potential, leading to ATP depletion and necrotic cell death or to cytochrome c release and apoptosis, depending on the rate of ATP consumption. I discuss two models in particular in which these processes have been characterized. The first is a model of oxidative stress in cardiomyocytes, in which reperfusion after ischemia causes mitochondrial calcium overload, and oxidative stress. Recent experiments suggest that cardioprotection by hypoxic preconditioning or exposure to the ATP-dependent K(+) channel opener diazoxide increases mitochondrial resistance to oxidative injury. In a second model, of calcium overload in neurons, the neurotoxicity of glutamate depends on mitochondrial calcium uptake, but the toxicity to mitochondria also requires the generation of nitric oxide. Glutamate toxicity after activation of N-methyl-D-aspartate (NMDA) receptors results from the colocalization of NMDA receptors with neuronal nitric oxide synthase (nNOS). The calcium increase mediated by NMDA receptor activation is thus associated with nitric oxide generation, and the combination leads to the collapse of mitochondrial membrane potential followed by cell death.


Anesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects.
Children with mitochondrial defects (MD) may have an increased risk for cardiorespiratory and neurological complications from anesthesia. The aim of this study was to determine the incidence of perioperative complications and adverse events in children with MD. We performed a retrospective review of the anesthesia, surgical and medical records of 155 children up to 10 years who underwent a diagnostic surgical muscle biopsy for suspected mitochondrial and muscle disorders between 1999 and 2003. The data of the 122 patients where a definite MD diagnosis was found were analyzed. Anesthesia was conducted according to the discretion of the attending staff. In children with MD the activity of the different complexes of the oxidative phosphorylation system was measured. From the preoperative assessment, signs of encephalopathy were most frequent (n = 93), followed by muscle weakness (n = 32), lactic acidosis (n = 15), cardiomyopathy and/or conduction defects (n = 10) and chronic respiratory problems (n = 7). The mean age of the children with MD was 32.4 months (SD = 26.9). The mean duration of anesthesia was 36.0 min (SD = 12.6) and the mean length of stay in the recovery room was 33.0 min (SD = 24.0). There were no major changes in heart rate or blood pressure which required pharmacological intervention during anesthesia or postanesthesia care unit (PACU) stay. A short episode of SpO2 <80% with airway obstruction occurred once in the PACU. Biochemical analysis in the children with a MD showed an isolated deficiency of one of the five protein complexes of oxidative phosphorylation in 42 children, a combination of complex deficiencies in 41 and no definite localization in 39 children. With standard preoperative assessment, monitoring and anesthesia management, there were no major peroperative and postoperative anesthesia-related complications in children undergoing surgical muscle biopsy with a MD diagnosis.


Are shoulders with a reverse shoulder prosthesis strong enough? A pilot study.
It has been suggested that limited active ROM of reverse shoulder prostheses relates to lack of strength. However, the postoperative strength has not been quantified. We therefore measured joint torques in patients with reverse shoulder prostheses and correlated torques with functional scores. We recruited 33 patients (age, 72 ± 8 years) with a reverse prosthesis (37 shoulders, 21 primary and 16 revisions). We obtained Constant-Murley, DASH, and Simple Shoulder Test ([D]SST) scores, and performed two isokinetic protocols (abduction/adduction and external/internal rotation) at 60° per second. Minimum followup was 4 months (average, 23 months; range, 4-63 months). Twenty-three patients (24 shoulders; 13 primaries, 11 revisions) were able to perform at least one of the defined tasks. Mean abduction and adduction torques were 15 Nm ± 7 Nm and 16 Nm ± 10 Nm (19%-78% of normal shoulders). External and internal rotation tasks could be performed by only 13 patients (14 shoulders; nine primary, five revisions) generating 9 Nm ± 4 Nm and 8 Nm ± 3 Nm, respectively (13%-71% of normal shoulders). We found moderate correlations between Constant-Murley, DASH and (D)SST (D = Dutch translation) scores and abduction and external rotation. Patients with a reverse prosthesis had reduced strength when compared with normal values reported in the literature (only 65% of patients could perform the protocol). This effect was greatest for external rotation and might explain clinical outcomes with which a moderately strong relationship was observed. Our observations suggest limited strength is a major factor in reduced ROM.


Mandatory labeling requirements and over-the-counter cough and cold medication use in early childhood.
Due to rare but severe adverse events, Health Canada in October 2009 required manufacturers to relabel over-the-counter (OTC) cough and cold medication (CCM) to state that the products should not be used in children <6 years of age. The main objective of this study was to determine whether this labeling standard decreased OTC CCM use among young children with a recent cough, cold or flu. An interrupted time series study was conducted using data from the TARGet Kids! practice-based research network. A total of 3,515 healthy children 1-5 years of age were recruited from 2008-2011; of these, 1,072 had a cough, cold or flu in the previous month. Parents completed a standardized survey instrument. For the primary analysis, use of OTC CCMs prior to and after October 1, 2009 was compared using time series analyses. For the secondary analysis, multivariable logistic regression was used to identify predictors of recent OTC CCM use. OTC CCM use was reported in 222 of 1,072 (20.7%) children with a cough, cold or flu within the previous month. OTC CCM use declined from 22.2% to 17.8% following the October 2009 Health Canada labeling standard (p = 0.014). Maternal age <35 years (OR 1.49; 95% CI: 1.05-2.13) and having older siblings (OR 1.65; 95% CI: 1.16-2.35) were independently associated with OTC CCM use. Labeling legislation against OTC CCM use for children <6 years resulted in a small decrease in OTC CCM use. Stronger measures may be needed to curtail OTC CCM use, particularly for younger parents and those with multiple children.


Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells.
Natural products represent a rich reservoir of potential small chemical molecules exhibiting anti-proliferative and chemopreventive properties. Here, we show that treatment of pancreatic ductal adenocarcinoma (PDAC) cells (PANC-1, MiaPaCa-2) with the isoquinoline alkaloid berberine (0.3-6 µM) inhibited DNA synthesis and proliferation of these cells and delay the progression of their cell cycle in G1. Berberine treatment also reduced (by 70%) the growth of MiaPaCa-2 cell growth when implanted into the flanks of nu/nu mice. Mechanistic studies revealed that berberine decreased mitochondrial membrane potential and intracellular ATP levels and induced potent AMPK activation, as shown by phosphorylation of AMPK α subunit at Thr-172 and acetyl-CoA carboxylase (ACC) at Ser79. Furthermore, berberine dose-dependently inhibited mTORC1 (phosphorylation of S6K at Thr389 and S6 at Ser240/244) and ERK activation in PDAC cells stimulated by insulin and neurotensin or fetal bovine serum. Knockdown of α1 and α2 catalytic subunit expression of AMPK reversed the inhibitory effect produced by treatment with low concentrations of berberine on mTORC1, ERK and DNA synthesis in PDAC cells. However, at higher concentrations, berberine inhibited mitogenic signaling (mTORC1 and ERK) and DNA synthesis through an AMPK-independent mechanism. Similar results were obtained with metformin used at doses that induced either modest or pronounced reductions in intracellular ATP levels, which were virtually identical to the decreases in ATP levels obtained in response to berberine. We propose that berberine and metformin inhibit mitogenic signaling in PDAC cells through dose-dependent AMPK-dependent and independent pathways.


Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations.
Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.


Fossil lemurs from Egypt and Kenya suggest an African origin for Madagascar's aye-aye.
In 1967 G.G. Simpson described three partial mandibles from early Miocene deposits in Kenya that he interpreted as belonging to a new strepsirrhine primate, Propotto. This interpretation was quickly challenged, with the assertion that Propotto was not a primate, but rather a pteropodid fruit bat. The latter interpretation has not been questioned for almost half a century. Here we re-evaluate the affinities of Propotto, drawing upon diverse lines of evidence to establish that this strange mammal is a strepsirrhine primate as originally suggested by Simpson. Moreover, our phylogenetic analyses support the recognition of Propotto, together with late Eocene Plesiopithecus from Egypt, as African stem chiromyiform lemurs that are exclusively related to the extant aye-aye (Daubentonia) from Madagascar. Our results challenge the long-held view that all lemurs are descended from a single ancient colonization of Madagascar, and present an intriguing alternative scenario in which two lemur lineages dispersed from Africa to Madagascar independently, possibly during the later Cenozoic.


An innovative ex-vivo porcine upper gastrointestinal model for submucosal tunnelling endoscopic resection (STER).
Background and study aims: Submucosal tunnelling endoscopic resection (STER) is a novel endoscopic technique to remove submucosal tumour (SMT). We propose a novel, low cost simulator for training of techniques for STER. Patients and methods: The model consisted of an ex-planted porcine oesophagus, stomach and duodenum with marbles embedded surgically in the submucosal plane. Two expert endoscopists with experience in submucosal tunnelling and 5 board-certified endoscopists with no experience in submucosal tunnelling were recruited. Participants were asked to perform a diagnostic endoscopy and 2 STER procedures, 1 in the oesophagus and 1 in the stomach. They also answered a structured questionnaire. Factors including operative time, mucosal and muscular injury rate, injection volume and accuracy of endoscopic closure were assessed. Results: The median time for localization of all SMTs was 40.1 seconds for experts and 38.5 seconds for novices (P = 1.000). For esophageal STER, the length of mucosal incisions and tunnelling distances were comparable between the 2 groups. The median volume injected by the novice group was significantly lower than the experts (15 mL vs 42.5 mL (P = 0.05). The median tunnelling time per length was 25.9 seconds/mm for the experts and 40.8 seconds/mm for the novice group (P = 0.38). There was a higher rate of mucosal injury and muscular perforation in the novice group (8 vs 0; P = 0.05). For gastric STER, the length of mucosal incisions and tunnel distances were comparable between the 2 groups. The median tunnelling time per length for the experts was 23.3 seconds/mm and 34.6 seconds/mm for the novice group (P = 0.38). One mucosal injury was incurred by a novice. The rate of dissection in the stomach and the oesophagus was not statistically different (P = 0.620). All participants voted that the model provides a realistic simulation and recommended it for training. Conclusions: STER is an advanced endoscopic technique where its indication is currently explored. Experienced and novice STER endoscopists have expressed the usefulness of this model as a training tool. This low-cost model can be used for future research in STER.


Appropriate Reliance on Artificial Intelligence in Radiology Education.
Users of artificial intelligence (AI) can become overreliant on AI, negatively affecting the performance of human-AI teams. For a future in which radiologists use interpretive AI tools routinely in clinical practice, radiology education will need to evolve to provide radiologists with the skills to use AI appropriately and wisely. In this work, we examine how overreliance on AI may develop in radiology trainees and explore how this problem can be mitigated, including through the use of AI-augmented education. Radiology trainees will still need to develop the perceptual skills and mastery of knowledge fundamental to radiology to use AI safely. We propose a framework for radiology trainees to use AI tools with appropriate reliance, drawing on lessons from human-AI interactions research.


Absence of toxic effects in silver reclamation workers.
Recent reports have alleged that silver presents a toxic hazard to exposed workers. To define the potential risks of long-term exposure to silver better, a cross-sectional investigation was conducted of 27 Caucasian males occupationally exposed to primarily insoluble silver compounds and 27 matched referents. Physical examination and electron microscopy of skin biopsies revealed no cases of generalized argyria. Measurements of facial discoloration, judged from color photographs by panels of laymen and physicians, showed no significant difference between the two groups. Although 29% of the silver workers and none of the referents exhibited ocular silver deposition, optometric and contrast sensitivity test results revealed no significant deficits in visual performance. The kidney and respiratory findings were essentially normal in both populations. Despite the increased presence of silver in the blood, feces, and hair of the recovery workers versus the referents, there was no evidence that chronic silver exposure adversely affected the health of these employees.


Construct validity of the Dining Environment Audit Protocol: a secondary data analysis of the Making Most of Mealtimes (M3) study.
Research has demonstrated the importance of physical environments at mealtimes for residents in long term care (LTC). However, a lack of a standardized measurement to assess physical dining environments has resulted in inconsistent research with potentially invalid and unreliable conclusions. The development of a standardized, construct valid instrument that assesses dining rooms is imperative to systematically examine physical environments in LTC. The purpose of this study was to determine the construct validity of the new Dining Environment Audit Protocol (DEAP) tool. Secondary data collected from the Making Most of Mealtimes (M3) study was used for this analysis. Data were collected in 32 long term care homes, which included 82 dining rooms and 639 residents. A variety of resident and dining room level constructs were compared to the summative scales found on the DEAP using Spearman correlations and Student t-tests. A regression analysis identified individual characteristics assessed with DEAP that were associated with the summative scales of homelikeness and functionality. Regression analysis (p < 0.05) identified that the DEAP homelikeness scale was positively associated with a view of the garden/green space, presence of a clock and a posted menu. The functionality scale was positively associated with number of chairs and lighting, while negatively associated with furniture with rounded edges and clutter. Additionally, the functionality scale was positively associated (p < 0.05) with the Mealtime Scan physical scale (ρ = 0.52), the dining room Mealtime-Relational Care Checklist (M-RCC) (ρ = 0.25), the DEAP total score (ρ = 0.56), and the Mini Nutritional Assessment- Short Form (ρ = 0.26). Homelikeness was positively associated (p < 0.05) with the DEAP total score (ρ = 0.53), staff Person Directed Care score (ρ = 0.49) and the resident Cognitive Performance Scale (t = 2.56), while negatively associated with energy (ρ = -0.26) and protein intake (ρ = -0.24). The homelikeness and functionality scales were also associated with one another (ρ = 0.26). The construct validity of the DEAP was supported through significant correlations with a variety of measures that are theoretically related to the homelikeness and functionality of LTC dining rooms. This secondary analysis supports the use of the DEAP in future research to quantify the physical environment of LTC dining rooms. Protocol registered with ClinicalTrials.gov ID: NCT02800291; Registered retrospectively June 7, 2016.


National Institutes of Health Extramural Associates Program:research opportunity.
This research opportunity for underrepresented minorities and women provides the right stuff to help you do the right thing in indicating and maintaining a steady, progressive path toward success in academic research. If this nation is to meet the predicted shortages of scientists in the next decade, more women and minorities must be recruited and retained in scientific careers (Diggs, 1990). Since its inception in July 1978, the Extramural Associates (EA) Program exemplifies the NIH effort to promote entry and participation of underrepresented minorities and women in biomedical and behavioral research. This competitive program is described as an opportunity for advancing the research careers of minorities and women in nursing science. Activities comprising a five month in-residence program are highlighted and substantive research-related outcomes are elaborated. Doctorally prepared nurse scientists from institutions with significant minority and/or women enrollments are encouraged to apply.


In Vivo 7T MR Quantitative Susceptibility Mapping Reveals Opposite Susceptibility Contrast between Cortical and White Matter Lesions in Multiple Sclerosis.
Magnetic susceptibility measured with quantitative susceptibility mapping has been proposed as a biomarker for demyelination and inflammation in patients with MS, but investigations have mostly been on white matter lesions. A detailed characterization of cortical lesions has not been performed. The purpose of this study was to evaluate magnetic susceptibility in both cortical and WM lesions in MS by using quantitative susceptibility mapping. Fourteen patients with MS were scanned on a 7T MR imaging scanner with T1-, T2-, and T2*-weighted sequences. The T2*-weighted sequence was used to perform quantitative susceptibility mapping and generate tissue susceptibility maps. The susceptibility contrast of a lesion was quantified as the relative susceptibility between the lesion and its adjacent normal-appearing parenchyma. The susceptibility difference between cortical and WM lesions was assessed by using a t test. The mean relative susceptibility was significantly negative for cortical lesions (P < 10-7) but positive for WM lesions (P < 10-22). A similar pattern was also observed in the cortical (P = .054) and WM portions (P = .043) of mixed lesions. The negative susceptibility in cortical lesions suggests that iron loss dominates the susceptibility contrast in cortical lesions. The opposite susceptibility contrast between cortical and WM lesions may reflect both their structural (degree of myelination) and pathologic (degree of inflammation) differences, in which the latter may lead to a faster release of iron in cortical lesions.