The effects of resveratrol on aging vessels.
Aging is a major risk factor for the development of cardiovascular disease. Despite a significant reduction in the mortality and morbidity rates over the last decade, the socio-economic burden of cardiovascular disease is still substantial. Consequently, there is a considerable need for alternative strategies, such as nutraceutical supplementation, that delay the functional vascular decline present in the elderly. Compromised autophagy and oxidative stress (OS) are considered major causes of the age-related endothelial dysfunction. OS reduces the bioavailability of nitric oxide (NO), which has been associated with hypertension, arteriosclerosis, and a reduced vasodilatory response. High levels of free radicals and the low bioavailability of NO lead to a positive feedback loop of further OS, organelle damage, poor repair, and endothelial dysfunction. Here we draw attention to the relationship between OS and autophagy in the aged vasculature. We have reviewed the published literature and provided arguments that support that treatment with resveratrol stimulates autophagy and thereby has the potential to restore oxidative balance in the endothelium, which indicates that treatment with resveratrol might have therapeutic potential to restore endothelial function in the elderly.


Like Wings of a Bird: Functional Divergence and Complementarity between HLA-A and HLA-B Molecules.
Human leukocyte antigen (HLA) genes are among the most polymorphic of our genome, as a likely consequence of balancing selection related to their central role in adaptive immunity. HLA-A and HLA-B genes were recently suggested to evolve through a model of joint divergent asymmetric selection conferring all human populations, including those with severe loss of diversity, an equivalent immune potential. However, the mechanisms by which these two genes might undergo joint evolution while displaying very distinct allelic profiles in populations are still unknown. To address this issue, we carried out extensive data analyses (among which factorial correspondence analysis and linear modeling) on 2,909 common and rare HLA-A, HLA-B, and HLA-C alleles and 200,000 simulated pathogenic peptides by taking into account sequence variation, predicted peptide-binding affinity and HLA allele frequencies in 123 populations worldwide. Our results show that HLA-A and HLA-B (but not HLA-C) molecules maintain considerable functional divergence in almost all populations, which likely plays an instrumental role in their immune defense. We also provide robust evidence of functional complementarity between HLA-A and HLA-B molecules, which display asymmetric relationships in terms of amino acid diversity at both inter- and intraprotein levels and in terms of promiscuous or fastidious peptide-binding specificities. Like two wings of a flying bird, the functional complementarity of HLA-A and HLA-B is a perfect example, in our genome, of duplicated genes sharing their capacity of assuming common vital functions while being submitted to complex and sometimes distinct environmental pressures.


Experience-dependent plasticity in S1 caused by noncoincident inputs.
Prior work has shown that coincident inputs became co-represented in somatic sensory cortex. In this study, the hypothesis that the co-representation of digits required synchronous inputs was tested, and the daily development of two-digit receptive fields was observed with cortical implants. Two adult primates detected temporal differences in tap pairs delivered to two adjacent digits. With stimulus onset asynchronies of > or = 100 ms, representations changed to include two-digit receptive fields across the first 4 wk of training. In addition, receptive fields at sites responsive to the taps enlarged more than twofold, and receptive fields at sites not responsive to the taps had no significant areal change. Further training did not increase the expression of two-digit receptive fields. Cortical responses to the taps were not dependent on the interval length. Stimuli preceding a hit, miss, false positives, and true negatives differed in the ongoing cortical rate from 50 to 100 ms after the stimulus but did not differ in the initial, principal, response to the taps. Response latencies to the emergent responses averaged 4.3 ms longer than old responses, which occurs if plasticity is cortical in origin. New response correlations developed in parallel with the new receptive fields. These data show co-representation can be caused by presentation of stimuli across a longer time window than predicted by spike-timing-dependent plasticity and suggest that increased cortical excitability accompanies new task learning.


The Multilayer Connectome of Caenorhabditis elegans.
Connectomics has focused primarily on the mapping of synaptic links in the brain; yet it is well established that extrasynaptic volume transmission, especially via monoamines and neuropeptides, is also critical to brain function and occurs primarily outside the synaptic connectome. We have mapped the putative monoamine connections, as well as a subset of neuropeptide connections, in C. elegans based on new and published gene expression data. The monoamine and neuropeptide networks exhibit distinct topological properties, with the monoamine network displaying a highly disassortative star-like structure with a rich-club of interconnected broadcasting hubs, and the neuropeptide network showing a more recurrent, highly clustered topology. Despite the low degree of overlap between the extrasynaptic (or wireless) and synaptic (or wired) connectomes, we find highly significant multilink motifs of interaction, pinpointing locations in the network where aminergic and neuropeptide signalling modulate synaptic activity. Thus, the C. elegans connectome can be mapped as a multiplex network with synaptic, gap junction, and neuromodulator layers representing alternative modes of interaction between neurons. This provides a new topological plan for understanding how aminergic and peptidergic modulation of behaviour is achieved by specific motifs and loci of integration between hard-wired synaptic or junctional circuits and extrasynaptic signals wirelessly broadcast from a small number of modulatory neurons.


The reproducibility of subjective appetite scores.
Although subjective appetite scores are widely used, studies on the reproducibility of this method are scarce. In the present study nine healthy, normal weight, young men recorded their subjective appetite sensations before and during 5 h after two different test meals A and B. The subjects tested each meal twice and in randomized order. Visual analogue scale (VAS) scores, 10 cm in length, were used to assess hunger, satiety, fullness, prospective food consumption and palatability of the meals. Plasma glucose and lactate concentrations were determined concomitantly. The repeatability was investigated for fasting values, delta-mean 5 h and mean 5 h values, delta-peak/nadir and peak/nadir values. Although the profiles of the postprandial responses were similar, the coefficients of repeatability (CR = 2SD) on the mean differences were large, ranging from 2.86 to 5.24 cm for fasting scores, 1.36 to 1.88 cm for mean scores, 2.98 to 5.42 cm for delta-mean scores, and 3.16 to 6.44 cm for peak and delta-peak scores. For palatability ratings the CR values varied more, ranging from 2.38 (taste) to 8.70 cm (aftertaste). Part of the difference in satiety ratings could be explained by the differences in palatability ratings. However, the low reproducibility may also be caused by a conditioned satiation or hunger due to the subjects' prior experience of the meals and therefore not just be a reflection of random noise. It is likely, however, that the variation in appetite ratings is due both to methodological day-to-day variation and to biological day-to-day variation in subjective appetite sensations.


Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide.
An immunological basis has been postulated for the strong association between at least five subtypes of the HLA-B27 allele (B27.01, .02, .04, .05, and .06) and ankylosing spondylitis, namely that cytotoxic T lymphocyte (CTL) responses are induced against an "arthritogenic" peptide that these different subtypes can all present. This requires a degree of overlap between the peptide binding repertoires of different B27 molecules. The present work, using CTL responses to Epstein-Barr virus (EBV) as a model system in which to identify B27-restricted epitopes, provides the first direct evidence that different disease-related alleles can present the same immunodominant peptide. We first noted that EBV-specific CTL clones, whether from B27.05-, B27.02-, or B27.04-positive donors, were largely subtype-specific in their restriction, recognizing only EBV-transformed B cell lines of the relevant B27 subtype. However, when tested against targets expressing individual EBV proteins from recombinant vaccinia virus vectors, all B27.05-restricted, all B27.02-restricted, and a proportion of B27.04-restricted clones were reactive to the same viral nuclear antigen, Epstein-Barr nuclear antigen (EBNA)3C. In subsequent peptide sensitization assays, all the EBNA3C-specific clones tested and also the EBNA3C-specific component within polyclonal CTL preparations from B27.05-, B27.02-, or B27.04-positive donors recognized the same immunodominant viral peptide RRIYDLIEL (EBNA3C residues 258-266). This sequence accords well with the proposed B27.05 peptide motif and clearly must be accommodated within the different peptide binding grooves of B27.05, B27.02, and B27.04 molecules. Clonal analysis revealed a second component of the B27.04-restricted response that was not shared with other subtypes. This was directed against an EBV latent membrane protein LMP2 epitope whose sequence RRRWRRLTV satisfies some but not all requirements of the B27.05 peptide motif. We conclude that there is indeed a degree of functional overlap between different B27 subtypes in their selection and presentation of CTL epitopes.


Effectiveness and cost-effectiveness of Self-Help Plus (SH+) for preventing mental disorders in refugees and asylum seekers in Europe and Turkey: study protocols for two randomised controlled trials.
This article describes two randomised controlled trials that will evaluate the effectiveness and cost-effectiveness of Self-Help Plus (SH+), a group self-help intervention developed by the WHO to reduce distress. In these trials SH+ is being tested as a preventative intervention to lower the incidence of mental disorders in asylum seekers and refugees with psychological distress resettled in Europe and Turkey. Two prospective, multicentre, randomised, rater-blinded, parallel-group studies will follow participants over a period of 12 months. One trial will be conducted in Europe and one in Turkey. In each trial, 600 asylum seekers and refugees screening positive on the General Health Questionnaire (≥3), but without a formal diagnosis of any mental disorders according to the Mini International Neuropsychiatric Interview, will be randomly allocated to SH+or to enhanced treatment-as-usual. The primary outcome will be a lower incidence of mental disorders at 6 month follow-up. Secondary outcomes will include the evaluation of psychological symptoms, functioning, well-being, treatment acceptability and indicators of intervention cost-effectiveness. The two trials received ethical clearance from the local Ethics Committees of the participating sites (seven sites), as well as from the WHO Ethics Committee. All participants will provide informed consent before screening and before study inclusion (a two-step procedure). The results of the trials will be disseminated in agreement with a dissemination plan that includes publication(s) in peer-reviewed journals and presentations at relevant national and international conferences and meetings. NCT03571347, NCT03587896.


Work-family conflict, cardiometabolic risk, and sleep duration in nursing employees.
We investigated associations of work-family conflict and work and family conditions with objectively measured cardiometabolic risk and sleep. Multilevel analyses assessed cross-sectional associations between employee and job characteristics and health in analyses of 1,524 employees in 30 extended-care facilities in a single company. We examined work and family conditions in relation to: (a) validated, cardiometabolic risk score based on measured blood pressure, cholesterol, glycosylated hemoglobin, body mass index, and self-reported tobacco consumption and (b) wrist actigraphy-based sleep duration. In fully adjusted multilevel models, work-to-family conflict but not family-to-work conflict was positively associated with cardiometabolic risk. Having a lower level occupation (nursing assistant vs. nurse) was associated with increased cardiometabolic risk, whereas being married and having younger children at home was protective. A significant Age × Work-to-Family Conflict interaction revealed that higher work-to-family conflict was more strongly associated with increased cardiometabolic risk in younger employees. High family-to-work conflict was significantly associated with shorter sleep duration. Working long hours and having children at home were both independently associated with shorter sleep duration. High work-to-family conflict was associated with longer sleep duration. These results indicate that different dimensions of work-family conflict may pose threats to cardiometabolic health and sleep duration for employees. This study contributes to the research on work-family conflict, suggesting that work-to-family and family-to-work conflict are associated with specific health outcomes. Translating theory and findings to preventive interventions entails recognition of the dimensionality of work and family dynamics and the need to target specific work and family conditions.


Remembering to forget: the amnesic effect of daydreaming.
Daydreaming mentally transports people to another place or time. Many daydreams are similar in content to the thoughts that people generate when they intentionally try to forget. Thus, thoughts like those generated during daydreaming can cause forgetting of previously encoded events. We conducted two experiments to test the hypothesis that daydreams that are more different from the current moment (e.g., in distance, time, or circumstance) will result in more forgetting than daydreams that are less different from the current moment, because they result in a greater contextual shift. Daydreaming was simulated in the laboratory via instructions to engage in a diversionary thought. Participants learned a list of words, were asked to think about autobiographical memories, and then learned a second list of words. They tended to forget more words from the first list when they thought about their parents' home than when they thought about their current home (Experiment 1). They also tended to forget more when they thought about an international vacation than when they thought about a domestic vacation (Experiment 2). These results support a context-change account of the amnesic effects of daydreaming.


MEDEVAC Use of Ketamine for Postintubation Transport.
The use of traditional sedatives and analgesics in intubated patients can have undesired hemodynamic consequences with increases in sedation exacerbating hypotension and potentially avoidable morbidity and mortality. This project compared 50 intubated patients using traditional analgesics and sedatives to 20 intubated patients using ketamine with the hypothesis that there would be a significant difference in subsequent blood pressure drop between the two groups. Though the results did not prove to be statistically significant within this small study, the authors did observe a trend toward significance. Additionally, some hypotensive patients had traditional analgesics and sedatives withheld altogether, which did not occur within the ketamine group. Due to the reduced side-effect profile, deployed medical providers should have increased training with and use of ketamine in the pre-hospital setting.


Vibration arthrometry in assessment of knee disorders: the problem of angular velocity.
A knee joint that has sustained a painful injury will typically require skillful examination, by an orthopaedic surgeon, for signs of internal damage. These signs include characteristic sounds and vibrations, which are produced by the knee when it is stressed. The technique of vibration arthrometry is being developed to assist the clinical examiner in identifying these vibrations and to improve diagnostic accuracy. To detect and record the knee vibrations, small lightweight accelerometers are positioned on various bony prominences around the knee. These produce electronic signals which permit objective analysis of the vibration characteristics. It has been found that varying the investigative procedure can affect the magnitude of some parameters of the vibration signal. If these parameters are to be used in evidence of knee pathology, the effect of the investigative procedure must be normalized. The effect of speed of joint movement has been quantified in a pilot study involving 24 patients with internal knee damage. Custom-designed hardware was used to measure joint speed as the rate of change of joint angle, which was measured by an electrogoniometer. It was found that the energy content of the vibration, reflected by the peak amplitude and root mean square value was strongly affected by joint speed. However, the characteristic shape of the vibration, reflected by the peak frequency in the harmonic spectrum of the signal, remained similar for the range of joint speed in the investigation.


Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis.
Orotic acid (OA) is an intermediate of pyrimidine nucleotide biosynthesis. Hereditary deficiencies in some enzymes associated with pyrimidine synthesis or the urea cycle induce OA accumulation, resulting in orotic aciduria. A link between patients with orotic aciduria and hypertension has been reported; however, the molecular mechanisms remain elusive. In this study, to elucidate the role of OA in vascular insulin resistance, we investigated whether OA induced endothelial dysfunction and hypertension. OA inhibited insulin- or metformin-stimulated nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation in human umbilical vein endothelial cells. A decreased insulin response by OA was mediated by impairment of the insulin-stimulated phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway in cells overexpressing the p110-PI3K catalytic subunit. Impaired effects of metformin on eNOS phosphorylation and NO production were reversed in cells transfected with constitutively active AMP-activated protein kinase. Moreover, experimental induction of orotic aciduria in rats caused insulin resistance, measured as a 125% increase in the homeostasis model assessment, and hypertension, measured as a 25% increase in systolic blood pressure. OA increased the plasma concentration of endothelin-1 by 201% and significantly inhibited insulin- or metformin-induced vasodilation. A compromised insulin or metformin response on the Akt/eNOS and AMP-activated protein kinase/eNOS pathway was observed in aortic rings of OA-fed rats. Taken together, we showed that OA induces endothelial dysfunction by contributing to vascular and systemic insulin resistance that affects insulin- or metformin-induced NO production, leading to the development of hypertension.


Bacteriophages with the ability to degrade uropathogenic Escherichia coli biofilms.
Escherichia coli-associated urinary tract infections (UTIs) are among the most common bacterial infections in humans. UTIs are usually managed with antibiotic therapy, but over the years, antibiotic-resistant strains of uropathogenic E. coli (UPEC) have emerged. The formation of biofilms further complicates the treatment of these infections by making them resistant to killing by the host immune system as well as by antibiotics. This has encouraged research into therapy using bacteriophages (phages) as a supplement or substitute for antibiotics. In this study we characterized 253 UPEC in terms of their biofilm-forming capabilities, serotype, and antimicrobial resistance. Three phages were then isolated (vB_EcoP_ACG-C91, vB_EcoM_ACG-C40 and vB_EcoS_ACG-M12) which were able to lyse 80.5% of a subset (42) of the UPEC strains able to form biofilms. Correlation was established between phage sensitivity and specific serotypes of the UPEC strains. The phages' genome sequences were determined and resulted in classification of vB_EcoP_ACG-C91 as a SP6likevirus, vB_EcoM_ACG-C40 as a T4likevirus and vB_EcoS_ACG-M12 as T1likevirus. We assessed the ability of the three phages to eradicate the established biofilm of one of the UPEC strains used in the study. All phages significantly reduced the biofilm within 2-12 h of incubation.


Effect of lumican on the migration of human mesenchymal stem cells and endothelial progenitor cells: involvement of matrix metalloproteinase-14.
Increasing number of evidence shows that soluble factors and extracellular matrix (ECM) components provide an optimal microenvironment controlling human bone marrow mesenchymal stem cell (MSC) functions. Successful in vivo administration of stem cells lies in their ability to migrate through ECM barriers and to differentiate along tissue-specific lineages, including endothelium. Lumican, a protein of the small leucine-rich proteoglycan (SLRP) family, was shown to impede cell migration and angiogenesis. The aim of the present study was to analyze the role of lumican in the control of MSC migration and transition to functional endothelial progenitor cell (EPC). Lumican inhibited tube-like structures formation on Matrigel® by MSC, but not EPC. Since matrix metalloproteinases (MMPs), in particular MMP-14, play an important role in remodelling of ECM and enhancing cell migration, their expression and activity were investigated in the cells grown on different ECM substrata. Lumican down-regulated the MMP-14 expression and activity in MSC, but not in EPC. Lumican inhibited MSC, but not EPC migration and invasion. The inhibition of MSC migration and invasion by lumican was reversed by MMP-14 overexpression. Altogether, our results suggest that lumican inhibits MSC tube-like structure formation and migration via mechanisms that involve a decrease of MMP-14 expression and activity.


Stratification of antibody-positive subjects by antibody level reveals an impact of immunogenicity on pharmacokinetics.
The availability of highly sensitive immunoassays enables the detection of antidrug antibody (ADA) responses of various concentrations and affinities. The analysis of the impact of antibody status on drug pharmacokinetics (PK) is confounded by the presence of low-affinity or low-concentration antibody responses within the dataset. In a phase 2 clinical trial, a large proportion of subjects (45%) developed ADA following weekly dosing with AMG 317, a fully human monoclonal antibody therapeutic. The antibody responses displayed a wide range of relative concentrations (30 ng/mL to >13 μg/mL) and peaked at various times during the study. To evaluate the impact of immunogenicity on PK, AMG 317 concentration data were analyzed following stratification by dose group, time point, antibody status (positive or negative), and antibody level (relative concentration). With dose group as a stratifying variable, a moderate reduction in AMG 317 levels (<50%) was observed in antibody-positive subjects when compared to antibody-negative subjects, but the difference was not statistically significant in all dose groups. The most significant reduction in AMG 317 levels was revealed when antibody data was stratified by both time point and antibody level. In general, high ADA concentrations (>500 ng/mL) and later time points (week 12) were associated with significantly (up to 97%) lower trough AMG 317 concentrations. The use of quasi-quantitative antibody data and appropriate statistical methods was critical for the most comprehensive evaluation of the impact of immunogenicity on PK.


Overexpression of Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 (LGR5) Represents a Typical Wnt/β-Catenin Pathway-Activated Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common and most frequently lethal cancers worldwide. Although many advances have been made in the analysis of multistage hepatocarcinogenesis, we still lack information to guide adequate clinical management options for HCC. A large number of genetic alterations occur during hepatocarcinogenesis, and many genetic studies have indicated that one of the most frequently mutated oncogenes found in HCC is β-catenin. Molecular subclassification of HCC based on gene expression signatures has identified a typical hepatocyte-like subclass of HCC harboring β-catenin mutations; this subclass is characterized by better histological differentiation and a less aggressive nature. We previously identified overexpression of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), also known as GPR49, in HCC with β-catenin mutations. LGR5 has been indicated as one of the downstream target genes of the Wnt signaling pathway; however, the functional role of LGR5 in cancer is largely unknown. We demonstrated that HCC cells transfected with LGR5 exhibited higher colony forming activity and were more resistant to a cytotoxic drug than the control HCC cells were. Overexpression of LGR5 also retarded cell migration. LGR5-transfected HCC cells formed nodule-type tumors in the livers of immunodeficient mice, whereas control cells formed more invasive tumors. Results of our recent research suggest that aberrant expression of LGR5 could regulate the epithelial cell phenotype and promotes HCC cell survival. HCC cells overexpressing LGR5 seem to represent a typical phenotype of a less aggressive HCC. Recent efforts on the molecular classification of HCC have led us to new strategies for dealing with HCC. These specific signatures may predict the risk of recurrence or the patient survival rate, which affect the outlook and may suggest treatment strategies for HCC patients.


Cooperative Pho2-Pho4 interactions at the PHO5 promoter are critical for binding of Pho4 to UASp1 and for efficient transactivation by Pho4 at UASp2.
The activation of the PHO5 gene in Saccharomyces cerevisiae in response to phosphate starvation critically depends on two transcriptional activators, the basic helix-loop-helix protein Pho4 and the homeodomain protein Pho2. Pho4 acts through two essential binding sites corresponding to the regulatory elements UASp1 and UASp2. Mutation of either of them results in a 10-fold decrease in promoter activity, and mutation of both sites renders the promoter totally uninducible. The role of Pho4 appears relatively straightforward, but the mechanism of action of Pho2 had remained elusive. By in vitro footprinting, we have recently mapped multiple Pho2 binding sites adjacent to the Pho4 sites, and by mutating them individually or in combination, we now show that each of them contributes to PHO5 promoter activity. Their function is not only to recruit Pho2 to the promoter but to allow cooperative binding of Pho4 together with Pho2. Cooperativity requires DNA binding of Pho2 to its target sites and Pho2-Pho4 interactions. A Pho4 derivative lacking the Pho2 interaction domain is unable to activate the promoter, but testing of UASp1 and UASp2 individually in a minimal CYC1 promoter reveals a striking difference between the two UAS elements. UASp1 is fully inactive, presumably because the Pho4 derivative is not recruited to its binding site. In contrast, UASp2 activates strongly in a Pho2-independent manner. From in vivo footprinting experiments and activity measurements with a promoter variant containing two UASp2 elements, we conclude that at UASp2, Pho2 is mainly required for the ability of Pho4 to transactivate.


Nanomedicine based approaches for the delivery of siRNA in cancer.
Small interfering RNA (siRNA) technology holds great promise as a therapeutic intervention for targeted gene silencing in cancer and other diseases. However, in vivo systemic delivery of siRNA-based therapeutics to tumour tissues/cells remains a challenge. The major limitations against the use of siRNA as a therapeutic tool are its degradation by serum nucleases, poor cellular uptake and rapid renal clearance following systemic administration. Several siRNA-based loco-regional therapeutics are already in clinical trials. Further development of siRNAs for anti-cancer therapy depends on the development of safe and effective nanocarriers for systemic administration. To overcome these hurdles, nuclease-resistant chemically modified siRNAs and variety of synthetic and natural biodegradable lipids and polymers have been developed to systemically deliver siRNA with different efficacy and safety profiles. Cationic liposomes have emerged as one of the most attractive carriers because of their ability to form complexes with negatively charged siRNA and high in vitro transfection efficiency. However, their effectiveness as potential therapeutic carriers is limited by potential for pulmonary toxicity. Recently, our laboratories described the use of neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine based nanoliposomes in murine tumour models. We found this approach to be safe and 10- and 30-fold more effective than cationic liposomes and naked siRNA, respectively, for systemic delivery of siRNA into tumour tissues. Here, we review potential approaches for systemic delivery of siRNA for cancer therapy.


Spread of pathological human Tau from neurons to oligodendrocytes and loss of high-firing pyramidal neurons in aging mice.
Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of the THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing prosubicular pyramidal cells, but the firing population retains its coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity, but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms maintain cortical neuronal coordination, counteracting the widespread pTau aggregation, loss of high-firing cells, and neurodegeneration.


Comparison of INTAKE24 (an Online 24-h Dietary Recall Tool) with Interviewer-Led 24-h Recall in 11-24 Year-Old.
Online dietary assessment tools offer a convenient, low cost alternative to traditional dietary assessment methods such as weighed records and face-to-face interviewer-led 24-h recalls. INTAKE24 is an online multiple pass 24-h recall tool developed for use with 11-24 year-old. The aim of the study was to undertake a comparison of INTAKE24 (the test method) with interviewer-led multiple pass 24-h recalls (the comparison method) in 180 people aged 11-24 years. Each participant completed both an INTAKE24 24-h recall and an interviewer-led 24-h recall on the same day on four occasions over a one-month period. The daily energy and nutrient intakes reported in INTAKE24 were compared to those reported in the interviewer-led recall. Mean intakes reported using INTAKE24 were similar to the intakes reported in the interviewer-led recall for energy and macronutrients. INTAKE24 was found to underestimate energy intake by 1% on average compared to the interviewer-led recall with the limits of agreement ranging from minus 49% to plus 93%. Mean intakes of all macronutrients and micronutrients (except non-milk extrinsic sugars) were within 4% of the interviewer-led recall. Dietary assessment that utilises technology may offer a viable alternative and be more engaging than paper based methods, particularly for children and young adults.


Structural basis of light harvesting by carotenoids: peridinin-chlorophyll-protein from Amphidinium carterae.
Peridinin-chlorophyll-protein, a water-soluble light-harvesting complex that has a blue-green absorbing carotenoid as its main pigment, is present in most photosynthetic dinoflagellates. Its high-resolution (2.0 angstrom) x-ray structure reveals a noncrystallographic trimer in which each polypeptide contains an unusual jellyroll fold of the alpha-helical amino- and carboxyl-terminal domains. These domains constitute a scaffold with pseudo-twofold symmetry surrounding a hydrophobic cavity filled by two lipid, eight peridinin, and two chlorophyll a molecules. The structural basis for efficient excitonic energy transfer from peridinin to chlorophyll is found in the clustering of peridinins around the chlorophylls at van der Waals distances.


Identification of bladder cancer antigens recognized by IgG antibodies of a patient with metastatic bladder cancer.
To identify tumor antigens useful for the diagnosis and treatment of patients with bladder cancer, a lambda phage cDNA library constructed from a high-grade bladder cancer cell line was screened with autologous serum from a patient with metastatic bladder cancer. Forty-eight distinct antigens were isolated. By evaluating the immunogenicity and the tissue-specific expression, KU-BL-1 and KU-BL-2 were identified as immunogenic antigens with restricted tissue expression. KU-BL-1 was found to be a putative human lipoic acid synthetase with a metal-binding site, CXXXCXXC, that was expressed in bladder cancer cell lines and most bladder cancer tissues, as well as normal bladder mucosa and testis tissues. Immunoglobulin (Ig)G antibody to KU-BL-1 was detected in 2 of 28 patients with bladder cancer, but not in 30 healthy individuals. KU-BL-2 was found to be a putative human kelch-like protein that was homologous to Drosophila kelch, with a BTB/POZ domain and kelch repeats. KU-BL-2 was expressed in bladder cancer cell lines, most bladder cancer tissues, testis and heart, but not in normal bladder mucosa. IgG antibody to KU-BL-2 was detected in 8 of 28 patients with bladder cancer, but not in 16 healthy individuals. Tumor reactive T cells were induced from peripheral blood mononuclear cells (PBMC) by stimulation with one of the HLA-A24 binding KU-BL-2 peptides. Therefore, KU-BL-1 and KU-BL-2, which showed preferential expression in bladder cancer with restricted expression in normal tissues, as well as immunogenicity in multiple patients with bladder cancer, may be useful for the development of diagnostic and therapeutic methods for patients with bladder cancer.


A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards.
Drug attrition rates have increased in past years, resulting in growing costs for the pharmaceutical industry and consumers. The reasons for this include the lack of in vitro models that correlate with clinical results and poor preclinical toxicity screening assays. The in vitro production of human cardiac progenitor cells and cardiomyocytes from human pluripotent stem cells provides an amenable source of cells for applications in drug discovery, disease modeling, regenerative medicine, and cardiotoxicity screening. In addition, the ability to derive human-induced pluripotent stem cells from somatic tissues, combined with current high-throughput screening and pharmacogenomics, may help realize the use of these cells to fulfill the potential of personalized medicine. In this review, we discuss the use of pluripotent stem cell-derived cardiomyocytes for drug discovery and cardiotoxicity screening, as well as current hurdles that must be overcome for wider clinical applications of this promising approach.


Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with chloroquine derivatives.
The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and an ongoing severe pandemic. Curative drugs specific for COVID-19 are currently lacking. Chloroquine phosphate and its derivative hydroxychloroquine, which have been used in the treatment and prevention of malaria and autoimmune diseases for decades, were found to inhibit SARS-CoV-2 infection with high potency in vitro and have shown clinical and virologic benefits in COVID-19 patients. Therefore, chloroquine phosphate was first used in the treatment of COVID-19 in China. Later, under a limited emergency-use authorization from the FDA, hydroxychloroquine in combination with azithromycin was used to treat COVID-19 patients in the USA, although the mechanisms of the anti-COVID-19 effects remain unclear. Preliminary outcomes from clinical trials in several countries have generated controversial results. The desperation to control the pandemic overrode the concerns regarding the serious adverse effects of chloroquine derivatives and combination drugs, including lethal arrhythmias and cardiomyopathy. The risks of these treatments have become more complex as a result of findings that COVID-19 is actually a multisystem disease. While respiratory symptoms are the major clinical manifestations, cardiovascular abnormalities, including arrhythmias, myocarditis, heart failure, and ischemic stroke, have been reported in a significant number of COVID-19 patients. Patients with preexisting cardiovascular conditions (hypertension, arrhythmias, etc.) are at increased risk of severe COVID-19 and death. From pharmacological and cardiovascular perspectives, therefore, the treatment of COVID-19 with chloroquine and its derivatives should be systematically evaluated, and patients should be routinely monitored for cardiovascular conditions to prevent lethal adverse events.


Interleukin 2-induced lymphocyte proliferation is independent of increases in cytosolic-free calcium concentrations.
Activation of lymphocytes by mitogenic lectins initiates a sequence of events that culminates in DNA synthesis and cell proliferation. The mitogenic effects of lectins on T lymphocytes leads to the production of a group of lymphokines including the interleukins. The binding of interleukin 2 (IL 2) to its receptor results in activation of the cell leading to DNA synthesis. An increase in cytosolic-free Ca++ ([Ca++]i) is associated with activation of lymphocytes by mitogenic lectins and also appears to be a prerequisite for induction of DNA synthesis and cell proliferation. We have determined whether the proliferative response triggered by IL 2 binding to its receptor is associated with or requires an increase in [Ca++]i. Using human and murine IL 2-sensitive cell lines, we have demonstrated that the IL 2-induced proliferative response, in contrast to that induced by mitogens such as phytohemagglutinin or concanavalin A, is not accompanied by an increase in [Ca++]i as monitored by the fluorescent indicator quin-2. Furthermore, IL 2-dependent triggering of lymphoblasts occurs in the presence of extremely low extracellular calcium concentrations that prevent transmembrane calcium flux. Activation of IL 2 receptor-bearing T cells, therefore, does not appear to be associated with or to require an increase in [Ca++]i as part of the activation and signaling process. The critical step requiring calcium flux in cell signaling by mitogenic lectins must therefore occur elsewhere in the activation cascade.


Genome and sequence determinants governing the expression of horizontally acquired DNA in bacteria.
While horizontal gene transfer is prevalent across the biosphere, the regulatory features that enable expression and functionalization of foreign DNA remain poorly understood. Here, we combine high-throughput promoter activity measurements and large-scale genomic analysis of regulatory regions to investigate the cross-compatibility of regulatory elements (REs) in bacteria. Functional characterization of thousands of natural REs in three distinct bacterial species revealed distinct expression patterns according to RE and recipient phylogeny. Host capacity to activate foreign promoters was proportional to their genomic GC content, while many low GC regulatory elements were both broadly active and had more transcription start sites across hosts. The difference in expression capabilities could be explained by the influence of the host GC content on the stringency of the AT-rich canonical σ70 motif necessary for transcription initiation. We further confirm the generalizability of this model and find widespread GC content adaptation of the σ70 motif in a set of 1,545 genomes from all major bacterial phyla. Our analysis identifies a key mechanism by which the strength of the AT-rich σ70 motif relative to a host's genomic GC content governs the capacity for expression of acquired DNA. These findings shed light on regulatory adaptation in the context of evolving genomic composition.


One grammar or two? Sign Languages and the Nature of Human Language.
Linguistic research has identified abstract properties that seem to be shared by all languages-such properties may be considered defining characteristics. In recent decades, the recognition that human language is found not only in the spoken modality but also in the form of sign languages has led to a reconsideration of some of these potential linguistic universals. In large part, the linguistic analysis of sign languages has led to the conclusion that universal characteristics of language can be stated at an abstract enough level to include languages in both spoken and signed modalities. For example, languages in both modalities display hierarchical structure at sub-lexical and phrasal level, and recursive rule application. However, this does not mean that modality-based differences between signed and spoken languages are trivial. In this article, we consider several candidate domains for modality effects, in light of the overarching question: are signed and spoken languages subject to the same abstract grammatical constraints, or is a substantially different conception of grammar needed for the sign language case? We look at differences between language types based on the use of space, iconicity, and the possibility for simultaneity in linguistic expression. The inclusion of sign languages does support some broadening of the conception of human language-in ways that are applicable for spoken languages as well. Still, the overall conclusion is that one grammar applies for human language, no matter the modality of expression. WIREs Cogn Sci 2014, 5:387-401. doi: 10.1002/wcs.1297 This article is categorized under: Linguistics > Linguistic Theory.


Molecular population genetics of the gene encoding the human fertilization protein zonadhesin reveals rapid adaptive evolution.
A hallmark of positive selection (adaptive evolution) in protein-coding regions is a d(N)/d(S) ratio >1, where d(N) is the number of nonsynonymous substitutions/nonsynonymous sites and d(S) is the number of synonymous substitutions/synonymous sites. Zonadhesin is a male reproductive protein localized on the sperm head, comprising many domains known to be involved in cell-cell interaction or cell adhesion. Previous studies have shown that VWD domains (homologous to the D domains of the von Willebrand factor) are involved directly in binding to the female zona pellucida (ZP) in a species-specific manner. In this study, we sequenced 47 coding exons in 12 primate species and, by using maximum-likelihood methods to determine sites under positive selection, we show that VWD2, membrane/A5 antigen mu receptor, and mucin-like domains in zonadhesin are rapidly evolving and, thus, may be involved in binding to the ZP in a species-specific manner in primates. In addition, polymorphism data from 48 human individuals revealed significant polymorphism-to-divergence heterogeneity and a significant departure from equilibrium-neutral expectations in the frequency spectrum, suggesting balancing selection and positive selection occurring in zonadhesin (ZAN) within human populations. Finally, we observe adaptive evolution in haplotypes segregating for a frameshift mutation that was previously thought to indicate that ZAN was a potential pseudogene.


Establishing a professional profile of community health workers: results from a national study of roles, activities and training.
Community Health Workers (CHWs) have gained national recognition for their role in addressing health disparities and are increasingly integrated into the health care delivery system. There is a lack of consensus, however, regarding empirical evidence on the impact of CHW interventions on health outcomes. In this paper, we present results from the 2010 National Community Health Worker Advocacy Survey (NCHWAS) in an effort to strengthen a generalized understanding of the CHW profession that can be integrated into ongoing efforts to improve the health care delivery system. Results indicate that regardless of geographical location, work setting, and demographic characteristics, CHWs generally share similar professional characteristics, training preparation, and job activities. CHWs are likely to be female, representative of the community they serve, and to work in community health centers, clinics, community-based organizations, and health departments. The most common type of training is on-the-job and conference training. Most CHWs work with clients, groups, other CHWs and less frequently community leaders to address health issues, the most common of which are chronic disease, prevention and health care access. Descriptions of CHW activities documented in the survey demonstrate that CHWs apply core competencies in a synergistic manner in an effort to assure that their clients get the services they need. NCHWAS findings suggest that over the past 50 years, the CHW field has become standardized in response to the unmet needs of their communities. In research and practice, the field would benefit from being considered a health profession rather than an intervention.


Clinico-immunological profile and their correlation with severity of atopic dermatitis in Eastern Indian children.
To study the clinical features, absolute eosinophil count, and total immunoglobulin E (IgE) level and their association with severity of atopic dermatitis in Eastern Indian children (Bihar). Prospective hospital-based study. Pediatrics out-patient Department (OPD) and Dermatology OPD of a Tertiary Care Teaching Hospital located in Rohtas District of Bihar. The study was carried out over a period of 2 years during January 2010 to December 2011. One hundred and thirty two children aged 0 month to 15 years were diagnosed with atopic dermatitis. Demographic profile, common clinical features, absolute eosinophil count, and total IgE level and their correlation with severity of atopic dermatitis in Eastern Indian children. Out of a total 1829 pediatric patients aged 0 month to 15 years with some pediatric dermatoses, 132 (7.21%) had atopic dermatitis. Of 132 patients, 57 (43.2%) were boys and 75 (56.8%) were girls, with a male to female ratio 1:1.3. Of these 29 were infants and 103 were children. Two (62.1%) patients belonged to rural area whereas 50 (37.9%) belonged to urban area. Personal history, family history (up to third degree relatives), and both personal and family history of atopy were present in 43.18%, 33.34%, and 12.1% of the subjects respectively. Majority (89.4%) of patients had onset before 5 years of age. In infantile Atopic dermatitis (AD), mean age ± SD at onset was 5.2 months ± 3.01 months. In infantile group, 8 (27.6%) had mild, 14 (48.3%) moderate, and 7 (24.1%) had severe atopic dermatitis. Infantile AD had statistically significant higher SCORing Atopic Dermatitis (SCORAD) index score in all three grades of severity of the disease. One hundred and three patients had childhood AD, out of which 40 (38.8%) were boys and 63 (61.2%) were girls, with a male to female ratio 1:1.57. In childhood AD, mean age ± SD at onset of the disease was 3.47 years ± 3.02 years. Sixty three (61.1%) belonged to rural area whereas 40 (38.9%) were from urban area. One hundred and thirty (98%) patients presented with itching. Ninety two (69.7%) patients had high absolute eosinophils count (AEC) with mean ± SD of 1004.1 ± 596.2 (range 325-2510). Eighty seven (65.9%) patients had increased total serum immunoglobulin E (TsIgE) with mean ± SD value of 1127.11 IU/ml ± 731.69 IU/ml (range: 125-2680 IU/ml). Epidemiological data on atopic dermatitis in India are mainly hospital-based, true-point prevalence in community is still scanty. Although the prevalence of AD is considered to be increasing, it still remains low in comparison to developed countries. In Indian children, the disease is relatively milder than children of developed countries. This study identified that both AEC and TsIgE increased significantly in about 66% patient and directly correlated with the severity of the AD.


Structural and energetic characterization of nucleic acid-binding to the fingers domain of Moloney murine leukemia virus reverse transcriptase.
Reverse transcriptase is an essential retroviral enzyme that replicates the single-stranded RNA genome of the retrovirus producing a double-stranded DNA copy, which is subsequently integrated into the host's genome. We have previously reported that processive DNA synthesis of Moloney murine leukemia virus reverse transcriptase (MMLV RT) is severely compromised by substitution of an Ala for the fingers domain residue Arg 116. In order to further investigate the role of Arg 116 in interactions of MMLV RT with nucleic acids, we have determined the crystal structure of the R116A N-terminal fragment and characterized the binding of two self-complementary DNA duplexes [d(CATGCATG)2 and d(CGCGCGCG)2] to both the wild-type and R116A fragments by isothermal titration calorimetry. The resultant thermodynamic profiles extrapolated to 25 degrees C reveal that binding of the wild-type N-terminal fragment to both DNA duplexes is enthalpy-driven and characterized by an unfavorable entropy. Although the temperature dependence of the respective protein-DNA binding enthalpies is markedly different reflecting distinct heat capacity changes, the binding free energies are nearly identical and relatively invariant to temperature (DeltaG approximately -6.0 kcal x mol(-1)). In contrast to the wild-type fragment, the R116A fragment exhibits no measurable affinity for either DNA duplex, yet its crystal structure reveals no significant changes when compared to the wild-type structures. We suggest that hydrogen-bonding interactions involving the fingers domain residue Arg 116 are critical for DNA binding as well as processive DNA synthesis by MMLV RT.


Surgeon and hospital characteristics as predictors of major adverse outcomes following colon cancer surgery: understanding the volume-outcome relationship.
Although numerous studies have demonstrated an association between surgical volume and improved outcome in cancer surgery, the specific structures and mechanisms of care that are associated with volume and lead to improved outcomes remain poorly defined. We hypothesize that there are modifiable surgeon and hospital characteristics that explain observed volume-outcome relationships. Retrospective cohort study. Surveillance, Epidemiology, and End Results cancer registry areas. Patients aged 66 years and older, diagnosed and surgically treated for stage I, II, or III colon cancer between 1992 and 1996 (n = 22 672). Thirty-day postoperative mortality and 30-day postoperative procedural interventions, including reoperation and image-guided percutaneous procedures. Surgeon volume, but not hospital volume, is a significant predictor of postoperative procedural intervention (adjusted odds ratio for very high-volume surgeons vs low-volume surgeons, 0.79; 95% confidence interval, 0.64-0.98). In the unadjusted analyses, high hospital volume (odds ratio, 0.67; 95% confidence interval, 0.56-0.81) and very high hospital volume (odds ratio, 0.65; 95% confidence interval, 0.54-0.79) is associated with lower postoperative mortality. Postoperative procedural intervention is not a significant mediator of the relationship between hospital volume and mortality. A single variable-the presence of sophisticated clinical services-was the most important explanatory variable underlying the relationship between hospital volume and mortality. Very high surgeon volume is associated with a reduction in surgical complications. However, the association between increasing hospital volume and postoperative mortality appears to derive mainly from a full spectrum of clinical services that may facilitate the prompt recognition and treatment of complications.


Methods of measurement of image quality in teleultrasound.
In recent years, teleultrasound has emerged as a potentially effective method of provision of ultrasound services to remote areas of the community. Transmission of teleultrasound, however, requires a high degree of compression when utilizing the relatively low bandwidth ISDN connections available within the UK. The actual amount of compression occurring varies both with the connection and the image content, often on a frame to frame basis. For this reason, traditional measurements of image quality using test tools are ineffective. Most studies to date have assessed equipment performance by testing diagnostic performance. Although this is the most important method of assessing the results of image degradation, few studies have attempted to perform physical measurements of degradation. The aims of this study were to measure the amount of degradation within a teleultrasound system and, using a number of methods, to ascertain the most useful indicators of loss of image quality. Groups of successive abdominal ultrasound images were captured and digitized both before and after degradation via an ISDN6 teleultrasound system. Normalized mean squared error (NMSE), pixel histograms, line and surface plots, Fourier spectra and contrast measurements were carried out on regions of interest in both sets of images. The NMSE was most sensitive to degradation, with alterations in the NMSE value depending on image content and degree of degradation. Fourier analysis was also indicative, showing consistent changes in high frequency content again varying with image content.


Public finance of rotavirus vaccination in India and Ethiopia: an extended cost-effectiveness analysis.
An estimated 4% of global child deaths (approximately 300,000 deaths) were attributed to rotavirus in 2010. About a third of these deaths occurred in India and Ethiopia. Public finance of rotavirus vaccination in these two countries could substantially decrease child mortality and also reduce rotavirus-related hospitalizations, prevent health-related impoverishment and bring significant cost savings to households. We use a methodology of 'extended cost-effectiveness analysis' (ECEA) to evaluate a hypothetical publicly financed program for rotavirus vaccination in India and Ethiopia. We measure program impact along four dimensions: 1) rotavirus deaths averted; 2) household expenditures averted; 3) financial risk protection afforded; 4) distributional consequences across the wealth strata of the country populations. In India and Ethiopia, the program would lead to a substantial decrease in rotavirus deaths, mainly among the poorer; it would reduce household expenditures across all income groups and it would effectively provide financial risk protection, mostly concentrated among the poorest. Potential indirect benefits of vaccination (herd immunity) would increase program benefits among all income groups, whereas potentially decreased vaccine efficacy among poorer households would reduce the equity benefits of the program. Our approach incorporates financial risk protection and distributional consequences into the systematic economic evaluation of vaccine policy, illustrated here with the case study of public finance for rotavirus vaccination. This enables selection of vaccine packages based on the quantitative inclusion of information on equity and on how much financial risk protection is being bought per dollar expenditure on vaccine policy, in addition to how much health is being bought.


Salmonella Typhi, Paratyphi A, Enteritidis and Typhimurium core proteomes reveal differentially expressed proteins linked to the cell surface and pathogenicity.
Salmonella enterica subsp. enterica contains more than 2,600 serovars of which four are of major medical relevance for humans. While the typhoidal serovars (Typhi and Paratyphi A) are human-restricted and cause enteric fever, non-typhoidal Salmonella serovars (Typhimurium and Enteritidis) have a broad host range and predominantly cause gastroenteritis. We compared the core proteomes of Salmonella Typhi, Paratyphi A, Typhimurium and Enteritidis using contemporary proteomics. For each serovar, five clinical isolates (covering different geographical origins) and one reference strain were grown in vitro to the exponential phase. Levels of orthologous proteins quantified in all four serovars and within the typhoidal and non-typhoidal groups were compared and subjected to gene ontology term enrichment and inferred regulatory interactions. Differential expression of the core proteomes of the typhoidal serovars appears mainly related to cell surface components and, for the non-typhoidal serovars, to pathogenicity. Our comparative proteome analysis indicated differences in the expression of surface proteins between Salmonella Typhi and Paratyphi A, and in pathogenesis-related proteins between Salmonella Typhimurium and Enteritidis. Our findings may guide future development of novel diagnostics and vaccines, as well as understanding of disease progression.


Downregulation of lncRNA PVT1 inhibits proliferation and migration of mesothelioma cells by targeting FOXM1.
Malignant mesothelioma is a highly aggressive tumor, and an effective strategy for its treatment is not yet available. Long non‑coding RNAs (lncRNAs) have been reported to be associated with various biological processes, including the regulation of gene expression of cancer‑related pathways. Among various lncRNAs, plasmacytoma variant translocation 1 (PVT1) acts as a tumor promoter in several human cancers, but its mechanism of action has not yet been elucidated. Increased PVT1 expression was identified in ACC‑MESO‑1, ACC‑MESO‑4, CRL‑5915, and CRL‑5946 mesothelioma cell lines. PVT1 expression was investigated in mesothelioma cell lines by reverse transcription‑quantitative polymerase chain reaction and its functional analysis by cell proliferation, cell cycle, cell migration, and cell invasion assays, as well as western blot analysis of downstream target genes. Knockdown of PVT1 expression in these cell lines by small interfering RNA transfection resulted in decreased cell proliferation and migration and increased the proportion of cells in the G2/M phase. The results of reverse transcription‑quantitative polymerase chain reaction analysis revealed that PVT1 knockdown in mesothelioma cell lines caused the downregulation of Forkhead box M1 (FOXM1) expression, while the results of western blot analysis revealed that this knockdown reduced FOXM1 expression at the protein level. In addition, combined knockdown of PVT1 and FOXM1 decreased the proliferation of mesothelioma cell lines. In conclusion, PVT1 and FOXM1 were involved in the proliferation of cancer cells. Therefore, PVT1‑FOXM1 pathways may be considered as candidate targets for the treatment of malignant mesothelioma.


Use of Social Networking Sites and Adherence to Physical Activity and Screen Time Recommendations in Adolescents.
Adolescents are recommended to achieve ≥ 60 min/day of moderate-to-vigorous physical activity (PA) and ≤2 h/day of screen time (ST). This study examined the relationships between the use of social networking sites (SNSs) and adherence to PA and ST recommendations in a large sample of Canadian adolescents. This cross-sectional school-based survey included a representative sample of 9388 students in grades 7 to 12 across Ontario, Canada. After adjustment for several confounding variables, results showed that male adolescents who use SNSs for fewer hours (≤ 1 h/day) had greater odds of adherence to PA and to both PA and ST recommendations concurrently, while those who use it for more hours (≥ 3 h/day) had lower odds of adherence to the ST recommendation. Female adolescents who use SNSs for more hours had lower odds of adherence to the ST recommendation (use of SNSs ≥ 2 h/day) and to both PA and ST recommendations concurrently (use of SNSs ≥ 5 h/day). Heavy use of SNSs has a negative influence on the adherence to the ST recommendation in both males and females; however, infrequent use of SNSs was related to the adherence to the PA recommendation and concurrent adherence to both recommendations in males only.


Predictors of patient self-ratings of quality of life in Alzheimer disease: cross-sectional results from the Canadian Alzheimer's Disease Quality of Life Study.
To assess whether the core symptoms of Alzheimer disease (AD) consistently predict patient self-rated quality of life (QOL) as assessed by a variety of QOL measures in a large national sample of AD patients. Cross-sectional. Fifteen dementia and geriatric clinics across Canada. Community-living patients with AD (n = 370) with Mini-Mental State Exam (MMSE) scores greater than 10. Patients rated their QOL by using two utility indexes, the European QOL-5 Dimensions and the Quality of Well-Being Scale, a global QOL Visual Analog Scale, and the disease-specific QOL-AD instrument. Cognition was assessed with the AD Assessment Scale-Cognitive subscale and MMSE, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory and the Geriatric Depression Scale (GDS). One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between core dementia symptoms and QOL ratings. The QOL measures had only small-to-moderate correlations with each other. For all QOL measures, patient ratings were significantly lower among patients with more depressive symptoms. In multivariable analyses, the GDS score was the only significant independent predictor of patient self-ratings for all four QOL measures. Self-rated symptoms of depression were a consistent independent predictor of patient-rated QOL across diverse QOL measures, while performance-based measures of cognition and informant-based functional status were not. These findings confirm the importance of identifying and treating depression in patients with AD and endorse the use of measures of self-rated depressive symptoms and QOL as outcomes in AD clinical trials.


Student peer mentoring: Feasibility and acceptability of mHealth-based tool for alcohol and substance abuse prevention by peer mentors at a university in Kenya.
The use of mobile health (mHealth)-based interventions for the prevention of alcohol and other psychoactive substances use is an emerging practice for which new evidence is required. This study evaluated the feasibility and acceptability of a mHealth-based peer mentoring tool for early screening, brief intervention, and referral of students who abuse alcohol and other psychoactive substances. It compared the implementation of a mHealth-delivered intervention to the paper-based practice that is the standard at the University of Nairobi. A quasi-experimental study using purposive sampling was used to select a cohort of n = 100 (51 experimental, 49 control) first-year student peer mentors on two campuses of the University of Nairobi in Kenya. Data were collected on the mentors' sociodemographic characteristics as well as the feasibility and acceptability of the interventions by way of, the magnitude of reach, feedback to investigators, referral of cases, and perceived ease of use. The mHealth-based peer mentoring tool scored high with 100% of users rating it as feasible and acceptable. Among the two study cohorts, there were no differences in the acceptability of the peer mentoring intervention. When comparing the feasibility of the peer mentoring practice, actual use of the interventions, and intervention reach, the mHealth-based cohort mentored four mentees for every one mentored by the standard practice cohort. The mHealth-based peer mentoring tool had high feasibility and acceptability among student peer mentors. The intervention provided evidence for the need to expand the availability of screening services for alcohol and other psychoactive substances use among students in the university and promote the appropriate management practices within and outside the university.


Physiological Exploration of the Long Term Evolutionary Selection against Expression of N-Glycolylneuraminic Acid in the Brain.
All vertebrate cell surfaces display a dense glycan layer often terminated with sialic acids, which have multiple functions due to their location and diverse modifications. The major sialic acids in most mammalian tissues are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter being derived from Neu5Ac via addition of one oxygen atom at the sugar nucleotide level by CMP-Neu5Ac hydroxylase (Cmah). Contrasting with other organs that express various ratios of Neu5Ac and Neu5Gc depending on the variable expression of Cmah, Neu5Gc expression in the brain is extremely low in all vertebrates studied to date, suggesting that neural expression is detrimental to animals. However, physiological exploration of the reasons for this long term evolutionary selection has been lacking. To explore the consequences of forced expression of Neu5Gc in the brain, we have established brain-specific Cmah transgenic mice. Such Neu5Gc overexpression in the brain resulted in abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination. Brain-specific Cmah transgenic mice were also lethally sensitive to a Neu5Gc-preferring bacterial toxin, even though Neu5Gc was overexpressed only in the brain and other organs maintained endogenous Neu5Gc expression, as in wild-type mice. Therefore, the unusually strict evolutionary suppression of Neu5Gc expression in the vertebrate brain may be explained by evasion of negative effects on neural functions and by selection against pathogens.


Is visceral obesity associated with colorectal cancer? The first volumetric study using all CT slices.
We aimed to examine the possible relationship between abdominal adiposity parameters and the presence of colorectal cancer (CRC) and between these adiposity parameters and various histopathologic findings of the tumor. A total of 60 control subjects and 111 CRC patients, 63 with early-stage and 48 with advanced-stage disease, were enrolled. Medical data and abdominopelvic computed tomography (CT) examinations of each study group were retrospectively reviewed. Abdominal adiposity parameters, including visceral adipose tissue (VAT) volume, subcutaneous adipose tissue (SAT) volume, and total adipose tissue (TAT) volume, were calculated on all slices of the CT examinations with specialized software, and results for each study group were compared. Adiposity parameters were also compared with tumor histopathologic findings. We found lower VAT and higher SAT volumes in advanced-stage CRC patients, compared with the early-stage group. However, this relationship was not statistically significant (P = 0.721 for VAT and P = 0.432 for SAT volumes). We detected significantly lower VAT and SAT volumes in the early-stage CRC group compared with the control group (P = 0.014 for both). There was no significant relationship between TAT volumes and the study groups (P = 0.06). No statistically significant relationship was detected between adipose tissue parameters and histopathologic features of the CRC group (P > 0.05). We found statistically significant lower VAT and SAT volumes in patients with early-stage CRC compared with the control group. Volumetric adipose tissue measurements may be more accurate than area measurements and can easily be performed on abdominopelvic CT examination, which is the routine imaging modality for CRC patients.


Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients.
Primary pulmonary hypertension (PPH) is characterized by intimal fibrosis and cell proliferation (including fibroblasts, smooth muscle and endothelial cells) in the distal pulmonary arterial tree. Considerable interest has been generated by recent reports of PPH in human immunodeficiency virus (HIV)-1-infected individuals. Although the lack of evidence for a pulmonary artery infection has suggested that in such cases HIV may act through mediator release rather than by direct endothelial infection, the mechanisms underlying HIV-associated PPH remain poorly defined. Platelet-derived growth factor (PDGF) has the ability to induce smooth muscle cell and fibroblast proliferation and migration. Given these considerations, we have attempted to document a possible role for PDGF in PPH occurring in HIV seropositive and seronegative patients. Using semiquantitative polymerase chain reaction (PCR), PDGF A-chain messenger ribonucleic acid (mRNA) expression was analysed in surgical lung biopsies from 13 HIV seronegative patients and one HIV seropositive patient, all displaying severe PPH. In parallel, lung samples from two patients with HIV-1-associated PPH were studied by immunohistochemistry and in situ hybridization. Results were compared to those obtained in three HIV-1-infected individuals with no pulmonary complication (as demonstrated by clinical, radiological, bacteriological, and necropsy findings) and five control lung biopsies. As compared to controls, PDGF A-chain mRNA expression is elevated in lung biopsies from patients displaying PPH (p=0.029). In HIV-1-associated PPH, interstitial perivascular cells expressing PDGF A-chain mRNA and protein could be detected by in situ hybridization and immunohistochemistry, respectively. Platelet-derived growth factor expression is elevated in lung biopsies of patients displaying primary pulmonary hypertension. Growth factors such as platelet-derived growth factor may play a part in the initiation and/or progression of primary pulmonary hypertension.


Differences in Mobility and Dispersal Capacity Determine Body Size Clines in Two Common Alpine-Tundra Arthropods.
The Arctic is projected to be severely impacted by changes in temperature and precipitation. Species react to these changes by shifts in ranges, phenology, and body size. In ectotherms, the patterns of body size clines and their underlying mechanisms are often hard to untangle. Mountains provide a space-for-time substitute to study these shifts along multiple spatial gradients. As such, mobility and dispersal capacity might conceal reactions with elevation. We test this influence on body size clines by comparing two common arthropods of the alpine tundra. We find that high mobility in the lycosid spider Pardosa palustris blurs elevational effects. Partially low mobility at least during development makes the carabid beetle Amara alpina more susceptible to elevational effects. Specific life-history mechanisms, such as brood care in lycosid spiders and holometabolic development in carabid beetles, are the possible cause.


Exploring Protein-Protein Interactions and Oligomerization State of Pulmonary Surfactant Protein C (SP-C) through FRET and Fluorescence Self-Quenching.
Pulmonary surfactant (PS) is a lipid-protein complex that forms films reducing surface tension at the alveolar air-liquid interface. Surfactant Protein C (SP-C) plays a key role in rearranging the lipids at the PS surface layers during breathing. The N-terminal segment of SP-C, a lipopeptide of 35 amino acids, contains two palmitoylated cysteines, which affect the stability and structure of the molecule. The C-terminal region comprises a transmembrane α-helix that contains a ALLMG motif, supposedly analogous to a well-studied dimerization motif in glycophorin A. Previous studies have demonstrated the potential interaction between SP-C molecules using approaches such as Bimolecular Complementation assays or computational simulations. In this work, the oligomerization state of SP-C in membrane systems has been studied using fluorescence spectroscopy techniques. We have performed self-quenching and FRET assays to analyze dimerization of native palmitoylated SP-C and of a non-palmitoylated recombinant version of SP-C (rSP-C) using fluorescently labeled versions of either protein reconstituted in different lipid systems mimicking pulmonary surfactant environments. Our results reveal that doubly palmitoylated native SP-C remains primarily monomeric. In contrast, non-palmitoylated recombinant SP-C exhibits dimerization, potentiated at high concentrations, especially in membranes with lipid phase separation. Therefore, palmitoylation could play a crucial role in stabilizing the monomeric α-helical conformation of SP-C. Depalmitoylation, high protein densities as a consequence of membrane compartmentalization, and other factors may all lead to the formation of protein dimers and higher-order oligomers, which could have functional implications under certain pathological conditions and contribute to membrane transformations associated with surfactant metabolism and alveolar homeostasis. This article is protected by copyright. All rights reserved.


Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease.
Mitochondria produce reactive oxygen species that may contribute to vascular dysfunction. alpha-Lipoic acid and acetyl-L-carnitine reduce oxidative stress and improve mitochondrial function. In a double-blind crossover study, the authors examined the effects of combined alpha-lipoic acid/acetyl-L-carnitine treatment and placebo (8 weeks per treatment) on vasodilator function and blood pressure in 36 subjects with coronary artery disease. Active treatment increased brachial artery diameter by 2.3% (P=.008), consistent with reduced arterial tone. Active treatment tended to decrease systolic blood pressure for the whole group (P=.07) and had a significant effect in the subgroup with blood pressure above the median (151+/-20 to 142+/-18 mm Hg; P=.03) and in the subgroup with the metabolic syndrome (139+/-21 to 130+/-18 mm Hg; P=.03). Thus, mitochondrial dysfunction may contribute to the regulation of blood pressure and vascular tone. Further studies are needed to confirm these findings and determine the clinical utility of alpha-lipoic acid/acetyl-L-carnitine as antihypertensive therapy.


Balance and walking involvement in facioscapulohumeral dystrophy: a pilot study on the effects of custom lower limb orthoses.
Autosomal dominant facioscapulohumeral dystrophy (FSHD), the third most common muscular dystrophy, is characterised by asymmetric and highly variable muscle weakness. In FSHD patients, the coupling of the ankle muscles impairment with the knee, hip and abdominal muscles impairment, causes complex alterations of balance and walking with deterioration of quality of life (QoL). The aim of this pilot study is to evaluate the effects of custom orthoses (foot orthosis-FO and ankle foot orthosis-AFO) on balance, walking and QoL of FSHD patients through a multidimensional approach. Pilot study. Outpatient Rehabilitation Department of Don Gnocchi Foundation. Fifteen patients with facioscapulohumeral muscular dystrophy were studied. On 15 FSHD patients clinical evaluation (Manual Muscle Test-MMT, Clinical Severity Score), performance tests (10 meter Walking test-10mWT and 2 minute Walking Test-2minWT), instrumental assessment (stabilometric evaluation), disability (Rivermead Mobility Index- RMI, Berg Balance Scale-BBS) and patient-oriented (Medical Outcome Study 36-item Short Form-SF-36, North American Spine Society-NASS and Visual Analogue Scale-VAS) measures were performed. Patients were evaluated first, wearing their shoes and then wearing their shoes plus orthoses. This evaluation was performed 1 month after wearing the orthoses. The shoes plus orthoses evaluation, performed after one month in which the patients daily wore the custom lower limb orthoses, showed a significant improvement of walking performance (10-mWT p<0.01), balance (Romberg Index p<0.05; Medio-Lateral Velocity p<0.05) and QoL (PCS p<0.01). This pilot study shows that in FSHD patients' custom lower limb orthoses (foot-orthoses and ankle-foot-orthoses); evaluated by using a multidimensional approach, improve walking, balance and QoL. These preliminary results suggest that custom lower limb orthoses could reduce the risk of falling with a positive effect on our patients' safety. Our results should encourage the scientific community to do efficacy study on this hot topic.


Chronic fatigue syndrome and mitochondrial dysfunction.
This study aims to improve the health of patients suffering from chronic fatigue syndrome (CFS) by interventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP (adenosine triphosphate), the energy currency for all body functions, and recycling ADP (adenosine diphosphate) to replenish the ATP supply as needed. Patients attending a private medical practice specializing in CFS were diagnosed using the Centers for Disease Control criteria. In consultation with each patient, an integer on the Bell Ability Scale was assigned, and a blood sample was taken for the "ATP profile" test, designed for CFS and other fatigue conditions. Each test produced 5 numerical factors which describe the availability of ATP in neutrophils, the fraction complexed with magnesium, the efficiency of oxidative phosphorylation, and the transfer efficiencies of ADP into the mitochondria and ATP into the cytosol where the energy is used. With the consent of each of 71 patients and 53 normal, healthy controls the 5 factors have been collated and compared with the Bell Ability Scale. The individual numerical factors show that patients have different combinations of biochemical lesions. When the factors are combined, a remarkable correlation is observed between the degree of mitochondrial dysfunction and the severity of illness (P<0.001). Only 1 of the 71 patients overlaps the normal region. The "ATP profile" test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction. The individual factors indicate which remedial actions, in the form of dietary supplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carried out.


Clinical and radiographic outcomes following traumatic Grade 3 and 4 carotid artery injuries: a 10-year retrospective analysis from a Level 1 trauma center. The Parkland Carotid and Vertebral Artery Injury Survey.
Screening, management, and follow-up of Grade 3 and 4 blunt carotid artery injuries (BCAIs) remain controversial. These high-grade BCAIs were analyzed to define their natural history and establish a rational management plan based on lesion progression and cerebral infarction. A retrospective review of a prospectively maintained database of all blunt traumatic carotid and vertebral artery injuries from August 2003 to April 2013 was performed, and Grade 3 and 4 BCAIs were identified. The authors define Grade 3 injuries as stenosis of the vessel greater than 50%, or the development of a pseudoaneurysm, and Grade 4 injuries as complete vessel occlusion. Demographic information, imaging findings, number of images obtained per individual, length of radiographic follow-up examination, radiographic outcome at end of follow-up period, treatment(s), and documentation of ischemic stroke or transient ischemic attack (TIA) were recorded. Fifty-three Grade 3 BCAIs in 44 patients and 5 Grade 4 BCAIs in 5 patients were identified and had available follow-up information. The mean follow-up duration for Grade 3 BCAIs was 113 days, and the mean follow-up for Grade 4 BCAIs was 78 days. Final imaging of Grade 3 BCAIs showed that 53% of cases were radiographically stable, 11% had resolved, and 11% were improved, whereas 25% had radiographically worsened. In terms of treatment, 75% of patients received aspirin (ASA) alone, 5% received various medications, and 2% received no treatment. Eighteen percent of the patients in the Grade 3 BCAI group underwent endovascular intervention, and in all of these cases, treatment with ASA was continued after the procedure. Final imaging of the Grade 4 BCAIs showed that 60% remained stable (with persistent occlusion), whereas the remaining arteries improved (with recanalization of the vessel). All patients in the Grade 4 BCAI follow-up group were treated with ASA, although in 1 patient treatment was transitioned to Coumadin. There were 3 cases of cerebral infarction that appeared to be related to Grade 3 BCAIs (7% of 44 patients in the Grade 3 group), and 1 case of stroke that appeared to be related to a Grade 4 BCAI. All identified cases of stroke developed soon after hospital admission. Although the posttraumatic cerebral infarction rate may be overestimated, the results of this study suggest that the Grade 3 and 4 BCAIs carry the highest stroke risk of the blunt cerebrovascular injuries, and those infarctions were identified on or shortly after hospital admission. Despite a 40% recanalization rate in the Grade 4 BCAI group and an 89% rate of persistent pseudoaneurysm in the Grade 3 BCAI group, follow-up imaging showed progressive worsening without radiographic improvement in only a small number of patients, and these findings alone did not correlate with adverse clinical outcome. Follow-up protocols may require amending; however, further prospective studies are needed to make conclusive changes as they relate to management.


Insight into the peopling of Mainland Southeast Asia from Thai population genetic structure.
There is considerable ethno-linguistic and genetic variation among human populations in Asia, although tracing the origins of this diversity is complicated by migration events. Thailand is at the center of Mainland Southeast Asia (MSEA), a region within Asia that has not been extensively studied. Genetic substructure may exist in the Thai population, since waves of migration from southern China throughout its recent history may have contributed to substantial gene flow. Autosomal SNP data were collated for 438,503 markers from 992 Thai individuals. Using the available self-reported regional origin, four Thai subpopulations genetically distinct from each other and from other Asian populations were resolved by Neighbor-Joining analysis using a 41,569 marker subset. Using an independent Principal Components-based unsupervised clustering approach, four major MSEA subpopulations were resolved in which regional bias was apparent. A major ancestry component was common to these MSEA subpopulations and distinguishes them from other Asian subpopulations. On the other hand, these MSEA subpopulations were admixed with other ancestries, in particular one shared with Chinese. Subpopulation clustering using only Thai individuals and the complete marker set resolved four subpopulations, which are distributed differently across Thailand. A Sino-Thai subpopulation was concentrated in the Central region of Thailand, although this constituted a minority in an otherwise diverse region. Among the most highly differentiated markers which distinguish the Thai subpopulations, several map to regions known to affect phenotypic traits such as skin pigmentation and susceptibility to common diseases. The subpopulation patterns elucidated have important implications for evolutionary and medical genetics. The subpopulation structure within Thailand may reflect the contributions of different migrants throughout the history of MSEA. The information will also be important for genetic association studies to account for population-structure confounding effects.


Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study.
Deteriorating sleep quality and physical or mental fatigue in older adults leads to decreased quality of life and increased mortality rates. This study investigated the effects of the time-dependent intake of nicotinamide mononucleotide (NMN) on sleep quality, fatigue, and physical performance in older adults. This randomized, double-blind placebo-controlled study evaluated 108 participants divided into four groups (NMN_AM; antemeridian, NMN_PM; post meridian, Placebo_AM, Placebo_PM). NMN (250 mg) or placebo was administered once a day for 12 weeks. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Fatigue was evaluated using the "Jikaku-sho shirabe" questionnaire. Grip strength, 5-times sit-to-stand (5-STS), timed up and go, and 5-m habitual walk were evaluated to assess the physical performance. Significant interactions were observed between 5-STS and drowsiness. 5-STS of all groups on post-intervention and drowsiness of the NMN_PM and Placebo_PM groups on mid- and post-intervention showed significant improvement compared with those in pre-intervention. The NMN_PM group demonstrated the largest effect size for 5-STS (d = 0.72) and drowsiness (d = 0.64). Overall, NMN intake in the afternoon effectively improved lower limb function and reduced drowsiness in older adults. These findings suggest the potential of NMN in preventing loss of physical performance and improving fatigue in older adults.


The DrosDel collection: a set of P-element insertions for generating custom chromosomal aberrations in Drosophila melanogaster.
We describe a collection of P-element insertions that have considerable utility for generating custom chromosomal aberrations in Drosophila melanogaster. We have mobilized a pair of engineered P elements, p[RS3] and p[RS5], to collect 3243 lines unambiguously mapped to the Drosophila genome sequence. The collection contains, on average, an element every 35 kb. We demonstrate the utility of the collection for generating custom chromosomal deletions that have their end points mapped, with base-pair resolution, to the genome sequence. The collection was generated in an isogenic strain, thus affording a uniform background for screens where sensitivity to genetic background is high. The entire collection, along with a computational and genetic toolbox for designing and generating custom deletions, is publicly available. Using the collection it is theoretically possible to generate >12,000 deletions between 1 bp and 1 Mb in size by simple eye color selection. In addition, a further 37,000 deletions, selectable by molecular screening, may be generated. We are now using the collection to generate a second-generation deficiency kit that is precisely mapped to the genome sequence.


Head cooling during sleep improves sleep quality in the luteal phase in female university students: A randomized crossover-controlled pilot study.
Although selective head-cooling has been reported to decrease scalp and tympanic temperature and improve sleep quality, whether head-cooling during sleep can improve sleep quality in women during the luteal phase has not been elucidated. This randomized, controlled crossover open trial aimed to investigate the effect of head cooling during sleep on sleep quality in women during the luteal phase. Female university students aged 19-25 years with increased daytime sleepiness during the luteal phase were recruited by poster advertisement at their university from May to June 2016 and from May to June 2017. Fourteen women aged 19-22 years participated in this study. The temperature-controllable cooling sheet containing tubes filled with circulating water was used for head-cooling, and the head-cooling and the controlled temperature were set at 25°C and 35°C, respectively. Electroencephalogram data were obtained using a single-channel portable electroencephalogram device. The difference in sleep-related variables and tympanic temperature between head-cooling and control were analyzed using a linear mixed model. The proportion of arousal was lower with head cooling than with the control. In contrast, the proportion of non-REM3 and the delta power were higher with head cooling than with the control. The proportion of non-REM2 and non-REM3 among sleep EEG stages were positively and negatively correlated with the mean tympanic temperature during sleep, respectively. However, arousal and REM were not correlated with tympanic temperature. We considered the reduction of arousal time by head-cooling might be related to scalp temperature rather than tympanic temperature. Further, our results suggested that head-cooling also improved subjective sleep comfort. In conclusion, head-cooling during sleep could improve sleep quality in young women during the luteal phase.


Impact of lunch provision on anthropometry, hemoglobin, and micronutrient status of female Cambodian garment workers: exploratory randomized controlled trial.
Lunch provision is expected to improve the nutritional status of Cambodian garment workers. The objective of this study is to evaluate the effects of a model lunch provision through a canteen on anthropometry, hemoglobin, and micronutrient status in female garment workers in Cambodia. This exploratory randomized controlled trial was implemented at a garment factory in Phnom Penh, Cambodia. Female workers (nulliparous, non-pregnant) were recruited and randomly allocated into an intervention arm (workday's lunch provision) and a control arm. Served lunch sets (~ 700 kcal on average) included diverse local dishes. Anthropometry (body mass index, weight, triceps skinfold thickness, and mid-upper arm muscle circumference), as well as hemoglobin, serum ferritin and soluble transferrin receptor, serum retinol binding protein, and serum folate concentrations were assessed at baseline and after 5 months of lunch provision. A general linear model with adjustments for baseline values was used to estimate intervention effects for each outcome variable. Two hundred twenty-three women were recruited (n = 112 control and n = 111 intervention). 172 (n = 86 in each arm) completed the study. Baseline prevalence of underweight, anemia, depleted iron stores, and marginal iron stores, were 31, 24, 21, and 50%, respectively. Subjects were not affected by frank vitamin A or folate deficiency, whereas 30% showed a marginal folate status. Overall, mean changes in anthropometric variables, hemoglobin, and retinol binding protein were marginal and not significant among intervention subjects. Mean folate concentration increased insignificantly by + 1.1 ng/mL (- 0.02, 2.2) (p = 0.054). On the other hand, mean ferritin decreased by - 6.6 μg/L (- 11.9, - 1.3) (p = 0.015). Subgroup analysis prompts that effects are differently pronounced according to the baseline status of workers. Findings indicate that model lunch sets provided a beneficial amount of dietary folate, but need to be revisited for iron content and/or iron bioavailability. It is believed that distinct positive effects on anthropometry, hemoglobin, and micronutrient status can solely be expected in malnourished individuals. The authors suggest that similar larger trials, which include sets adapted to the concrete needs of workers affected by underweight, anemia and/or definite micronutrient deficiencies, should be performed. The trial was registered at the German Clinical Trials Register (9 January 2015, Identifier: DRKS00007666).


Metabolism of 15N-labelled urea in the functioning and defunctioned human colon.
1. The luminal metabolism of urea was studied using double-labelled urea ([15N2]urea) which was placed in the lumen of the colon through a colostomy. The recovery of label was measured as [15N2]urea or [14N, 15N]urea in urine and as 15N in stool. 2. Five patients with a loop colostomy allowed a comparison of the right functioning colon with the left defunctioned colon in the same individual. Five subjects with a left end-colostomy enabled a comparison of the right with the left functioning colon. 3. A significantly greater proportion of labelled urea was recovered as [15N2]urea in the urine when the dose was placed in the left defunctioned colon (29%) compared with either the left or the right functioning colon (9 and 4%, respectively). This is interpreted as being a result of a decrease in the bacterial activity and concomitant urea hydrolysis in the defunctioned colon. 4. On average more than half of the label was retained in the body, regardless of whether the urea was placed in the functioning or the defunctioned colon, on the left or on the right. 5. The data confirm that the colon is permeable to the intact urea molecule. Intraluminal urea is readily hydrolysed in the functioning colon. A large proportion of the nitrogen released by urea hydrolysis may be retained within the metabolic nitrogen pool of the host. There are significant differences in the handling of urea nitrogen in the defunctioned colon relative to the functioning colon.


Constraints on polyploid evolution: a test of the minority cytotype exclusion principle.
Polyploid evolution is often considered a mechanism of instant speciation; yet the establishment of rare tetraploids within diploid populations may be constrained by a frequency-dependent mating disadvantage (minority cytotype exclusion principle). I tested this hypothesis using experimental populations of Chamerion angustifolium (Onagraceae) that contained different proportions of tetraploids and diploids. Fitness, measured as total seed production over the entire flowering season, was calculated from a census of flower number and estimates of ovule number per flower and proportion of seed set per fruit. The fitness of tetraploids relative to diploids was frequency dependent, increasing from 0.4, when tetraploids were rare, to 0.7 when at 50% and 1.15 when they were in the majority (67%). This pattern exists because of a negative relationship between tetraploid frequency and seed set per fruit in diploids. Seed set in tetraploids was independent of cytotype frequency. The frequency-independent effect in tetraploids reflects higher assortative mating, partly because of non-random patterns of bee visitation. Bees visited a disproportionately high number of diploid inflorescences; however, the proportion of successive flights between tetraploids increased above random expectations as the frequency of tetraploids decreased. These results provide the first experimental test of frequency-dependent fitness in diploid-polyploid mixtures and suggest an important role for more gradual, population processes governing the evolution of polyploidy in natural populations.


When seeing outweighs feeling: a role for prefrontal cortex in passive control of negative affect in blindsight.
Affective neuroscience has been strongly influenced by the view that a 'feeling' is the perception of somatic changes and has consequently often neglected the neural mechanisms that underlie the integration of somatic and other information in affective experience. Here, we investigate affective processing by means of functional magnetic resonance imaging in nine cortically blind patients. In these patients, unilateral postgeniculate lesions prevent primary cortical visual processing in part of the visual field which, as a result, becomes subjectively blind. Residual subcortical processing of visual information, however, is assumed to occur in the entire visual field. As we have reported earlier, these patients show significant startle reflex potentiation when a threat-related visual stimulus is shown in their blind visual field. Critically, this was associated with an increase of brain activity in somatosensory-related areas, and an increase in experienced negative affect. Here, we investigated the patients' response when the visual stimulus was shown in the sighted visual field, that is, when it was visible and cortically processed. Despite the fact that startle reflex potentiation was similar in the blind and sighted visual field, patients reported significantly less negative affect during stimulation of the sighted visual field. In other words, when the visual stimulus was visible and received full cortical processing, the patients' phenomenal experience of affect did not closely reflect somatic changes. This decoupling of phenomenal affective experience and somatic changes was associated with an increase of activity in the left ventrolateral prefrontal cortex and a decrease of affect-related somatosensory activity. Moreover, patients who showed stronger left ventrolateral prefrontal cortex activity tended to show a stronger decrease of affect-related somatosensory activity. Our findings show that similar affective somatic changes can be associated with different phenomenal experiences of affect, depending on the depth of cortical processing. They are in line with a model in which the left ventrolateral prefrontal cortex is a relay station that integrates information about subcortically triggered somatic responses and information resulting from in-depth cortical stimulus processing. Tentatively, we suggest that the observed decoupling of somatic responses and experienced affect, and the reduction of negative phenomenal experience, can be explained by a left ventrolateral prefrontal cortex-mediated inhibition of affect-related somatosensory activity.