Is there a role for carbohydrate restriction in the treatment and prevention of cancer?
Over the last years, evidence has accumulated suggesting that by systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress, or at least delay, the emergence of cancer, and that proliferation of already existing tumor cells could be slowed down. This hypothesis is supported by the association between modern chronic diseases like the metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to which more complex carbohydrates are ultimately digested, can have direct and indirect effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown anti-tumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose metabolism characterized by insulin resistance and may profit from an increased protein and fat intake.In this review, we address the possible beneficial effects of low CHO diets on cancer prevention and treatment. Emphasis will be placed on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.


Mixed vector immunization with recombinant adenovirus and MVA can improve vaccine efficacy while decreasing antivector immunity.
Substantial protection can be provided against the pre-erythrocytic stages of malaria by vaccination first with an adenoviral and then with an modified vaccinia virus Ankara (MVA) poxviral vector encoding the same ME.TRAP transgene. We investigated whether the two vaccine components adenovirus (Ad) and MVA could be coinjected as a mixture to enhance protection against malaria. A single-shot mixture at specific ratios of Ad and MVA (Ad+MVA) enhanced CD8(+) T cell-dependant protection of mice against challenge with Plasmodium berghei. Moreover, the degree of protection could be enhanced after homologous boosting with the same Ad+MVA mixture to levels comparable with classic heterologous Ad prime-MVA boost regimes. The mixture increased transgene-specific responses while decreasing the CD8(+) T cell antivector immunity compared to each vector used alone, particularly against the MVA backbone. Mixed vector immunization led to increased early circulating interferon-γ (IFN-γ) response levels and altered transcriptional microarray profiles. Furthermore, we found that sequential immunizations with the Ad+MVA mixture led to consistent boosting of the transgene-specific CD8(+) response for up to three mixture immunizations, whereas each vector used alone elicited progressively lower responses. Our findings offer the possibility of simplifying the deployment of viral vectors as a single mixture product rather than in heterologous prime-boost regimens.


Rising rural body-mass index is the main driver of the global obesity epidemic in adults.
Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities1,2. This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity3-6. Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.


Traditional Chinese medicine patterns and recommended acupuncture points in infertile and fertile women.
Acupuncture is rooted in traditional Chinese medicine (TCM) and emphasises individualised treatment according to TCM patterns. Eight TCM patterns are regarded as typical for female infertility. There are no empirical data comparing these patterns in fertile and infertile women. To identify and compare the TCM patterns and recommended acupuncture points in infertile and fertile women. The hypothesis that infertile and fertile women should differ in occurrence of TCM patterns described as typical for infertility was examined. A cross-sectional study examined the distribution of TCM patterns and acupuncture points among 24 infertile and 24 fertile women. TCM patterns and points proposed by two acupuncturists were analysed. The odds ratio was used as the effect measure. Three patterns were found in more than 92% of the women. Five patterns occurred more frequently among infertile (p≤0.03), and four among fertile (p≤0.02) women. Only three of the eight patterns assumed typical for infertile women were more common among infertile women. Two of the eight patterns were more common among fertile women. Acupuncture points KI3, LI3 and SP6 were chosen for almost all women, whereas CV4, CV3 and ST29 were chosen more often for infertile women (p<0.03), and SP3 more often for fertile women (p<0.001). The data indicate that the presence of some, and the absence of other, TCM patterns are associated with infertility. These results are not consistent with the assumed associations between eight specific patterns and infertility, as maintained by TCM textbooks.


From bedside back to bench? A commentary on: "The future of cognitive behavioral therapy for insomnia: what important research remains to be done?".
In this month's issue of the Journal of Clinical Psychology, Vitiello and colleagues articulate an important research agenda that will help advance cognitive-behavioral therapy for insomnia (CBT-I) research and clinical practice. In addition to this ambitious agenda, we also propose that pursuing a parallel research program, focusing on treatment mechanisms and process will help move the CBT-I field forward and optimize therapeutic dissemination and uptake.


Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS.
The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.


Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence.
B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.


LIN9, a subunit of the DREAM complex, regulates mitotic gene expression and proliferation of embryonic stem cells.
The DREAM complex plays an important role in regulation of gene expression during the cell cycle. We have previously shown that the DREAM subunit LIN9 is required for early embryonic development and for the maintenance of the inner cell mass in vitro. In this study we examined the effect of knocking down LIN9 on ESCs. We demonstrate that depletion of LIN9 alters the cell cycle distribution of ESCs and results in an accumulation of cells in G2 and M and in an increase of polyploid cells. Genome-wide expression studies showed that the depletion of LIN9 results in downregulation of mitotic genes and in upregulation of differentiation-specific genes. ChIP-on chip experiments showed that mitotic genes are direct targets of LIN9 while lineage specific markers are regulated indirectly. Importantly, depletion of LIN9 does not alter the expression of pluripotency markers SOX2, OCT4 and Nanog and LIN9 depleted ESCs retain alkaline phosphatase activity. We conclude that LIN9 is essential for proliferation and genome stability of ESCs by activating genes with important functions in mitosis and cytokinesis.


Phylogenetic classification of the world's tropical forests.
Knowledge about the biogeographic affinities of the world's tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world's tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.


Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial.
Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required. Medical Research Council (MR/L00528X/1).


Transcriptional profiling of human cord blood CD133+ and cultured bone marrow mesenchymal stem cells in response to hypoxia.
Umbilical cord blood (UCB) and bone marrow (BM)-derived stem and progenitor cells possess two characteristics required for successful tissue regeneration: extensive proliferative capacity and the ability to differentiate into multiple cell lineages. Within the normal BM and in pathological conditions, areas of hypoxia may have a role in maintaining stem cell fate or determining the fine equilibrium between their proliferation and differentiation. In this study, the transcriptional profiles and proliferation and differentiation potential of UCB CD133(+) cells and BM mesenchymal cells (BMMC) exposed to normoxia and hypoxia were analyzed and compared. Both progenitor cell populations responded to hypoxic stimuli by stabilizing the hypoxia inducible factor (HIF)-1alpha protein. Short exposures to hypoxia increased the clonogenic myeloid capacity of UCB CD133(+) cells and promoted a significant increase in BMMC number. The differentiation potential of UCB CD133(+) clonogenic myeloid cells was unaltered by short exposures to hypoxia. In contrast, the chondrogenic differentiation potential of BMMCs was enhanced by hypoxia, whereas adipogenesis and osteogenesis were unaltered. When their transcriptional profiles were compared, 183 genes in UCB CD133(+) cells and 45 genes in BMMC were differentially regulated by hypoxia. These genes included known hypoxia-responsive targets such as BNIP3, PGK1, ENO2, and VEGFA, and other genes not previously described to be regulated by hypoxia. Several of these genes, namely CDTSPL, CCL20, LSP1, NEDD9, TMEM45A, EDG-1, and EPHA3 were confirmed to be regulated by hypoxia using quantitative reverse transcriptase polymerase chain reaction. These results, therefore, provide a global view of the signaling and regulatory network that controls oxygen sensing in human adult stem/progenitor cells derived from hematopoietic tissues.


Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes.
It is well known that patients with type 2 diabetes have increased risk of cardiovascular disease, but it is not known whether they have underlying abnormalities in cardiac or skeletal muscle high-energy phosphate metabolism. We studied 21 patients with type 2 diabetes with no evidence of coronary artery disease or impaired cardiac function, as determined by echocardiography, and 15 age-, sex-, and body mass index-matched control subjects. Cardiac high-energy phosphate metabolites were measured at rest using 31P nuclear magnetic resonance spectroscopy (MRS). Skeletal muscle high-energy phosphate metabolites, intracellular pH, and oxygenation were measured using 31P MRS and near infrared spectrophotometry, respectively, before, during, and after exercise. Although their cardiac morphology, mass, and function appeared to be normal, the patients with diabetes had significantly lower phosphocreatine (PCr)/ATP ratios, at 1.50+/-0.11, than the healthy volunteers, at 2.30+/-0.12. The cardiac PCr/ATP ratios correlated negatively with the fasting plasma free fatty acid concentrations. Although skeletal muscle energetics and pH were normal at rest, PCr loss and pH decrease were significantly faster during exercise in the patients with diabetes, who had lower exercise tolerance. After exercise, PCr recovery was slower in the patients with diabetes and correlated with tissue reoxygenation times. The exercise times correlated negatively with the deoxygenation rates and the hemoglobin (Hb)A1c levels and the reoxygenation times correlated positively with the HbA1c levels. Type 2 diabetic patients with apparently normal cardiac function have impaired myocardial and skeletal muscle energy metabolism related to changes in circulating metabolic substrates.


Amputation rates of the lower limb by amputation level - observational study using German national hospital discharge data from 2005 to 2015.
In international comparisons, rates of amputations of the lower limb are relatively high in Germany. This study aims to analyze trends in lower limb amputations over time, as well as outcomes of care concerning in-hospital mortality and reamputation rates during the same hospital stay which might indicate the quality of surgical and perioperative health care processes. This work is an observational population-based study using complete national hospital discharge data (Diagnosis-Related Group Statistics (DRG Statistics)) from 2005 to 2015. All inpatient cases with lower limb amputation were identified and stratified by eight amputation levels. Time trends of case numbers and in-hospital mortality were studied age-sex standardized. For inpatient cases with reamputation during the same hospital stay, first and last amputation levels were cross tabulated. A total of 55,595 amputations of the lower limb in 2015 (52,096 in 2005) were identified. After age-sex standardization to the demographic structure of 2005, a relative decrease of - 11.1% was revealed (men - 2.6%, women - 25.0%). The stratified analysis by amputation levels showed that the decreases were induced by higher amputation levels, whereas the amputation levels of toe/foot ray after standardization still showed a relative increase of + 12.8%. In-hospital mortality of all cases with lower limb amputation fell from 11.2% in 2005 to 7.7% in 2015 (SMR 0.89 [95% CI 0.86; 0.92]). The percentage of reamputations during the same hospital stay declined from 13.2 to 10.2%. The number of lower limb amputations declined in Germany, however distinctly stronger in women than in men. The observed decreases of in-hospital mortality as well as of reamputation rates point to improvements in perioperative health care. Despite these indications of improvements, the distinct increase in case numbers at the level of toe/foot ray calls for additional targeted prevention efforts, especially for patients with diabetes.


Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice.
Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.


The relationship between household income and childhood respiratory health in the United Kingdom.
Growing empirical evidence on the association between household income and adverse child health outcomes has generated mixed results with some North-American studies showing a significant inverse relationship and some British studies identifying a much weaker association. We use data from the rich UK Millennium Cohort Study (MCS) dataset and check the robustness of these recent findings by focusing on the impact of household income on adverse childhood respiratory outcomes (i.e. asthma and wheezing). We also identify pathways, such as mother's child-health-related behaviours, parental health and grandparental socioeconomic status, through which income might influence child health. Our econometric strategy is to use, both in a cross-sectional and in a panel data context, detailed information in the MCS dataset to directly account for as many potential confounding factors as possible that might bias the income-child health nexus. Overall our results show that household income has a weak direct effect on child health after we control for potential mechanisms that mediate the income-child health association. We argue that our evidence should inform government health and broader fiscal policies aimed at reducing health inequalities in childhood.


Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.


The intellectual challenges and emotional consequences of equipoise contributed to the fragility of recruitment in six randomized controlled trials.
The aim of the study was to investigate how doctors considered and experienced the concept of equipoise while recruiting patients to randomized controlled trials (RCTs). In-depth interviews with 32 doctors in six publicly funded pragmatic RCTs explored their perceptions of equipoise as they undertook RCT recruitment. The RCTs varied in size, duration, type of complex intervention, and clinical specialties. Interview data were analyzed using qualitative content and thematic analytical methods derived from grounded theory and synthesized across six RCTs. All six RCTs suffered from poor recruitment. Doctors wanted to gather robust evidence but experienced considerable discomfort and emotion in relation to their clinical instincts and concerns about patient eligibility and safety. Although they relied on a sense of community equipoise to justify participation, most acknowledged having "hunches" about particular treatments and patients, some of which undermined recruitment. Surgeons experienced these issues most intensely. Training and support promoted greater confidence in equipoise and improved engagement and recruitment. Recruitment to RCTs is a fragile process and difficult for doctors intellectually and emotionally. Training and support can enable most doctors to become comfortable with key RCT concepts including equipoise, uncertainty, patient eligibility, and randomization, promoting a more resilient recruitment process in partnership with patients.


Measurement of relative cerebral blood volume using BOLD contrast and mild hypoxic hypoxia.
Relative cerebral blood volume (CBV) was estimated using a mild hypoxic challenge in humans, combined with BOLD contrast gradient-echo imaging at 3 T. Subjects breathed 16% inspired oxygen, eliciting mild arterial desaturation. The fractional BOLD signal change induced by mild hypoxia is expected to be proportional to CBV under conditions in which there are negligible changes in cerebral perfusion. By comparing the regional BOLD signal changes arising with the transition between normoxia and mild hypoxia, we calculated CBV ratios of 1.5 ± 0.2 (mean ± S.D.) for cortical gray matter to white matter and 1.0 ± 0.3 for cortical gray matter to deep gray matter.


A subpopulation of CD103(pos) ICOS(pos) Treg cells occurs at high frequency in lymphopenic mice and represents a lymph node specific differentiation stage.
Regulatory T (Treg) cells are pivotal for the maintenance of peripheral tolerance by controlling self-reactive, chronic, and homeostatic T-cell responses. Here, we report that the increase in Treg-cell suppressive function observed in lymphopenic mice correlates with the degree of lymphopenia and is caused by a higher frequency of a novel subpopulation of CD103(pos) ICOS(pos) Treg cells. Though present in the thymus, CD103(pos) ICOS(pos) Treg cells are not generated there but recirculate from the periphery to that site. The acquisition and maintenance of this distinctive phenotype requires the LN microenvironment and the in situ availability of antigen. Contrary to conventional effector and other Treg cells, the cellularity of CD103(pos) ICOS(pos) Treg cells is not affected by the absence of IL-7 and thymic stroma lymphopoetin. Given their increased frequency in lymphopenia, the absolute number of CD103(pos) ICOS(pos) Treg cells remains unchanged in the periphery irrespective of a paucity of total Treg cells. We furthermore demonstrate, with cell transfers in mice, that the CD103(pos) ICOS(pos) phenotype represents a LN-specific differentiation stage arrived at by several other Treg-cell subsets. Thus, tissue-specific cues determine the overall potency of the peripheral Treg-cell pool by shaping its subset composition.


Fission-fusion and the evolution of hominin social systems.
The course of hominin evolution has involved successive migrations towards higher absolute latitudes over the past three million years. Poorer habitat quality further from the equator has led to the necessity for groups occupying higher latitudes to live at lower population densities. Coupled with a trend towards increasing group size over this time period, this tendency towards expansion has led to exponential increases in the area requirements of hominin groups, and a concomitant need to adjust foraging patterns. The current analyses suggest that the development of increasingly complex, multi-level fission-fusion social systems could have freed hominins of the foraging constraints imposed by large group sizes and low population densities. Analyses of the fossil record suggest latitudinally-driven differences in area requirements of the australopithecines from East and South Africa, and African and Asian Homo erectus. In contrast, chronologically-driven differences appear between H. erectus as a whole and Homo heidelbergensis, and between H. heidelbergensis and the Neanderthals. These results are discussed in relation to studies of the foraging patterns of primates and hunter-gatherers.


Transcriptional control of microglia phenotypes in health and disease.
Microglia are the main resident macrophage population of the CNS and perform numerous functions required for CNS development, homeostasis, immunity, and repair. Many lines of evidence also indicate that dysregulation of microglia contributes to the pathogenesis of neurodegenerative and behavioral diseases. These observations provide a compelling argument to more clearly define the mechanisms that control microglia identity and function in health and disease. In this Review, we present a conceptual framework for how different classes of transcription factors interact to select and activate regulatory elements that control microglia development and their responses to internal and external signals. We then describe functions of specific transcription factors in normal and pathological contexts and conclude with a consideration of open questions to be addressed in the future.


Conserved and distinct aspects of the avian Toll-like receptor (TLR) system: implications for transmission and control of bird-borne zoonoses.
This mini-review focuses on recent research with avian TLRs (Toll-like receptors), highlighting shared and distinct features compared with the more intensively studied mammalian TLR. These include the avian TLR repertoire and the response to various agonists. Studies with avian TLR can be applied to development of new approaches to control diseases of birds and is especially relevant to bird-borne zoonoses including avian influenza, Salmonella and Campylobacter.


Emotions are social.
In this paper, I question the assumption that emotions are first and foremost individual reactions, and suggest instead that they are often best viewed as social phenomena. I show that many of the causes of emotions are interpersonally, institutionally or culturally defined; that emotions usually have consequences for other people; and that they serve interpersonal as well as cultural functions in everyday life. Furthermore, many cases of emotion are essentially communicative rather than internal and reactive phenomena. Previous research has often underestimated the importance of social factors in the causation and constitution of emotion. In conclusion, I recommend that existing cognitive and physiological approaches to emotional phenomena be supplemented or supplanted by social psychological analysis.


Malaria elimination transmission and costing in the Asia-Pacific: Developing an investment case.
Background: The Asia-Pacific region has made significant progress against malaria, reducing cases and deaths by over 50% between 2010 and 2015. These gains have been facilitated in part, by strong political and financial commitment of governments and donors. However, funding gaps and persistent health system challenges threaten further progress. Achieving the regional goal of malaria elimination by 2030 will require an intensification of efforts and a plan for sustainable financing. This article presents an investment case for malaria elimination to facilitate these efforts. Methods: A transmission model was developed to project rates of decline of Plasmodium falciparum and Plasmodium vivax malaria and the output was used to determine the cost of the interventions that would be needed for elimination by 2030. In total, 80 scenarios were modelled under various assumptions of resistance and intervention coverage. The mortality and morbidity averted were estimated and health benefits were monetized by calculating the averted cost to the health system, individual households, and society. The full-income approach was used to estimate the economic impact of lost productivity due to premature death and illness, and a return on investment was computed. Results: The study estimated that malaria elimination in the region by 2030 could be achieved at a cost of USD 29.02 billion (range: USD 23.65-36.23 billion) between 2017 and 2030. Elimination would save over 400,000 lives and avert 123 million malaria cases, translating to almost USD 90 billion in economic benefits. Discontinuing vector control interventions and reducing treatment coverage rates to 50% will result in an additional 845 million cases, 3.5 million deaths, and excess costs of USD 7 billion. Malaria elimination provides a 6:1 return on investment. Conclusion: This investment case provides compelling evidence for the benefits of continued prioritization of funding for malaria and can be used to develop an advocacy strategy.


Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study.
To report trends in event and case fatality rates for acute myocardial infarction and examine the relative contributions of changes in these rates to changes in total mortality from acute myocardial infarction by sex, age, and geographical region between 2002 and 2010. Population based study using person linked routine hospital and mortality data. England. 840,175 people of all ages who were admitted to hospital for acute myocardial infarction or died suddenly from acute myocardial infarction. Acute myocardial infarction event, 30 day case fatality, and total mortality rates. From 2002 to 2010 in England, the age standardised total mortality rate fell by about half, whereas the age standardised event and case fatality rates both declined by about one third. In men, the acute myocardial infarction event, case fatality, and total mortality rates declined at an average annual rate of, respectively, 4.8% (95% confidence interval 3.0% to 6.5%), 3.6% (3.4% to 3.7%), and 8.6% (5.4% to 11.6%). In women, the corresponding figures were 4.5% (1.7% to 7.1%), 4.2% (4.0% to 4.3%), and 9.1% (4.5% to 13.6%). Overall, the relative contributions of the reductions in event and case fatality rates to the decline in acute myocardial infarction mortality rate were, respectively, 57% and 43% in men and 52% and 48% in women; however, the relative contributions differed by age, sex, and geographical region. Just over half of the decline in deaths from acute myocardial infarction during the 2000s in England can be attributed to a decline in event rate and just less than half to improved survival at 30 days. Both prevention of acute myocardial infarction and acute medical treatment have contributed to the decline in deaths from acute myocardial infarction over the past decade.


Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies.


Molecular and cellular approaches for diversifying and extending optogenetics.
Optogenetic technologies employ light to control biological processes within targeted cells in vivo with high temporal precision. Here, we show that application of molecular trafficking principles can expand the optogenetic repertoire along several long-sought dimensions. Subcellular and transcellular trafficking strategies now permit (1) optical regulation at the far-red/infrared border and extension of optogenetic control across the entire visible spectrum, (2) increased potency of optical inhibition without increased light power requirement (nanoampere-scale chloride-mediated photocurrents that maintain the light sensitivity and reversible, step-like kinetic stability of earlier tools), and (3) generalizable strategies for targeting cells based not only on genetic identity, but also on morphology and tissue topology, to allow versatile targeting when promoters are not known or in genetically intractable organisms. Together, these results illustrate use of cell-biological principles to enable expansion of the versatile fast optogenetic technologies suitable for intact-systems biology and behavior.


The current and potential impact of genetics and genomics on neuropsychopharmacology.
One justification for the major scientific and financial investments in genetic and genomic studies in medicine is their therapeutic potential, both for revealing novel targets for drugs which treat the disease process, as well as allowing for more effective and safe use of existing medications. This review considers the extent to which this promise has yet been realised within psychopharmacology, how things are likely to develop in the foreseeable future, and the key issues involved. It draws primarily on examples from schizophrenia and its treatments. One observation is that there is evidence for a range of genetic influences on different aspects of psychopharmacology in terms of discovery science, but far less evidence that meets the standards required before such discoveries impact upon clinical practice. One reason is that results reveal complex genetic influences that are hard to replicate and usually of very small effect. Similarly, the slow progress being made in revealing the genes that underlie the major psychiatric syndromes hampers attempts to apply the findings to identify novel drug targets. Nevertheless, there are some intriguing positive findings of various kinds, and clear potential for genetics and genomics to play an increasing and major role in psychiatric drug discovery.


Genetic evidence supports linguistic affinity of Mlabri--a hunter-gatherer group in Thailand.
The Mlabri are a group of nomadic hunter-gatherers inhabiting the rural highlands of Thailand. Little is known about the origins of the Mlabri and linguistic evidence suggests that the present-day Mlabri language most likely arose from Tin, a Khmuic language in the Austro-Asiatic language family. This study aims to examine whether the genetic affinity of the Mlabri is consistent with this linguistic relationship, and to further explore the origins of this enigmatic population. We conducted a genome-wide analysis of genetic variation using more than fifty thousand single nucleotide polymorphisms (SNPs) typed in thirteen population samples from Thailand, including the Mlabri, Htin and neighboring populations of the Northern Highlands, speaking Austro-Asiatic, Tai-Kadai and Hmong-Mien languages. The Mlabri population showed higher LD and lower haplotype diversity when compared with its neighboring populations. Both model-free and Bayesian model-based clustering analyses indicated a close genetic relationship between the Mlabri and the Htin, a group speaking a Tin language. Our results strongly suggested that the Mlabri share more recent common ancestry with the Htin. We thus provided, to our knowledge, the first genetic evidence that supports the linguistic affinity of Mlabri, and this association between linguistic and genetic classifications could reflect the same past population processes.


Comparison of Salmonella enterica serotype Infantis isolates from a veterinary teaching hospital.
To compare Salmonella enterica serotype Infantis isolates obtained from patients or the environment of a veterinary teaching hospital over a period of 9 years following a nosocomial outbreak to determine whether isolates were epidemiologically related or represented unrelated introductions into the hospital environment. Fifty-six S. Infantis isolates were compared based on their phenotypic (antimicrobial drug [AMD] susceptibility pattern) and genotypic (pulsed-field gel electrophoresis [PFGE] pattern and presence of integrons) characteristics. Epidemiologically unrelated S. Infantis isolates clustered separately from all but two of the hospital isolates, and several isolates from different years and various sources were indistinguishable from each other in cluster analysis of two-enzyme PFGE results. A high percentage of isolates (80.3%) were resistant to at least one AMD, with 67.8% showing resistance to >5 AMD. The majority (74.1%) of isolates tested contained type 1 integrons. Results strongly suggest that there was nosocomial transmission of S. Infantis during the initial outbreak, and that contamination arising from this outbreak persisted across years despite rigorous hygiene and biosecurity precautions and may have led to subsequent nosocomial infections. Evidence of persistence and transmission of Salmonella clones across years, even in the face of rigorous preventive measures, has important implications for other facilities that have experienced outbreaks of Salmonella infections.


Spatial and temporal acuity of visual perception can be enhanced selectively by attentional set.
The aim of this research was to study the relationship between perceptual judgments about space and time. If spatial and temporal judgments were dissociable, they should be modulated selectively by attention. We compared the effect of the attentional set upon fine-grained spatial versus temporal discrimination of visual perception in two experiments. Using identical sensory stimulation, we measured perceptual judgments on either the size of a small spatial gap or the duration of a brief temporal gap. The attentional set was manipulated by cuing the task that was most likely to be performed. In one experiment, a neutral cue was also used, to measure relative benefits and costs of spatial and temporal task sets. If the attentional set could be directed selectively to spatial and temporal task-relevant dimensions, performance on both spatial and temporal acuity tasks should be specifically modulated by task cuing. The results showed that the attentional set enhanced the speed and accuracy of perceptual judgments similarly on both spatial and temporal tasks. Moreover, accuracy in one task was selectively enhanced by attending to that task while remaining unaffected by attending to the alternative task. This finding suggests multiple mechanisms, by which visual processing of spatial and temporal features can be selectively prepared without interfering with one another.


"He loves me, he loves me not . . . ": uncertainty can increase romantic attraction.
This research qualifies a social psychological truism: that people like others who like them (the reciprocity principle). College women viewed the Facebook profiles of four male students who had previously seen their profiles. They were told that the men (a) liked them a lot, (b) liked them only an average amount, or (c) liked them either a lot or an average amount (uncertain condition). Comparison of the first two conditions yielded results consistent with the reciprocity principle. Participants were more attracted to men who liked them a lot than to men who liked them an average amount. Results for the uncertain condition, however, were consistent with research on the pleasures of uncertainty. Participants in the uncertain condition were most attracted to the men-even more attracted than were participants who were told that the men liked them a lot. Uncertain participants reported thinking about the men the most, and this increased their attraction toward the men.


Selected Plant Metabolites Involved in Oxidation-Reduction Processes during Bud Dormancy and Ontogenetic Development in Sweet Cherry Buds (Prunus avium L.).
Many biochemical processes are involved in regulating the consecutive transition of different phases of dormancy in sweet cherry buds. An evaluation based on a metabolic approach has, as yet, only been partly addressed. The aim of this work, therefore, was to determine which plant metabolites could serve as biomarkers for the different transitions in sweet cherry buds. The focus here was on those metabolites involved in oxidation-reduction processes during bud dormancy, as determined by targeted and untargeted mass spectrometry-based methods. The metabolites addressed included phenolic compounds, ascorbate/dehydroascorbate, reducing sugars, carotenoids and chlorophylls. The results demonstrate that the content of phenolic compounds decrease until the end of endodormancy. After a long period of constancy until the end of ecodormancy, a final phase of further decrease followed up to the phenophase open cluster. The main phenolic compounds were caffeoylquinic acids, coumaroylquinic acids and catechins, as well as quercetin and kaempferol derivatives. The data also support the protective role of ascorbate and glutathione in the para- and endodormancy phases. Consistent trends in the content of reducing sugars can be elucidated for the different phenophases of dormancy, too. The untargeted approach with principle component analysis (PCA) clearly differentiates the different timings of dormancy giving further valuable information.


Increased resting state functional connectivity in the default mode network in recovered anorexia nervosa.
Functional brain imaging studies have shown abnormal neural activity in individuals recovered from anorexia nervosa (AN) during both cognitive and emotional task paradigms. It has been suggested that this abnormal activity which persists into recovery might underpin the neurobiology of the disorder and constitute a neural biomarker for AN. However, no study to date has assessed functional changes in neural networks in the absence of task-induced activity in those recovered from AN. Therefore, the aim of this study was to investigate whole brain resting state functional connectivity in nonmedicated women recovered from anorexia nervosa. Functional magnetic resonance imaging scans were obtained from 16 nonmedicated participants recovered from anorexia nervosa and 15 healthy control participants. Independent component analysis revealed functionally relevant resting state networks. Dual regression analysis revealed increased temporal correlation (coherence) in the default mode network (DMN) which is thought to be involved in self-referential processing. Specifically, compared to healthy control participants the recovered anorexia nervosa participants showed increased temporal coherence between the DMN and the precuneus and the dorsolateral prefrontal cortex/inferior frontal gyrus. The findings support the view that dysfunction in resting state functional connectivity in regions involved in self-referential processing and cognitive control might be a vulnerability marker for the development of anorexia nervosa.


Trypanosome motion represents an adaptation to the crowded environment of the vertebrate bloodstream.
Blood is a remarkable habitat: it is highly viscous, contains a dense packaging of cells and perpetually flows at velocities varying over three orders of magnitude. Only few pathogens endure the harsh physical conditions within the vertebrate bloodstream and prosper despite being constantly attacked by host antibodies. African trypanosomes are strictly extracellular blood parasites, which evade the immune response through a system of antigenic variation and incessant motility. How the flagellates actually swim in blood remains to be elucidated. Here, we show that the mode and dynamics of trypanosome locomotion are a trait of life within a crowded environment. Using high-speed fluorescence microscopy and ordered micro-pillar arrays we show that the parasites mode of motility is adapted to the density of cells in blood. Trypanosomes are pulled forward by the planar beat of the single flagellum. Hydrodynamic flow across the asymmetrically shaped cell body translates into its rotational movement. Importantly, the presence of particles with the shape, size and spacing of blood cells is required and sufficient for trypanosomes to reach maximum forward velocity. If the density of obstacles, however, is further increased to resemble collagen networks or tissue spaces, the parasites reverse their flagellar beat and consequently swim backwards, in this way avoiding getting trapped. In the absence of obstacles, this flagellar beat reversal occurs randomly resulting in irregular waveforms and apparent cell tumbling. Thus, the swimming behavior of trypanosomes is a surprising example of micro-adaptation to life at low Reynolds numbers. For a precise physical interpretation, we compare our high-resolution microscopic data to results from a simulation technique that combines the method of multi-particle collision dynamics with a triangulated surface model. The simulation produces a rotating cell body and a helical swimming path, providing a functioning simulation method for a microorganism with a complex swimming strategy.


Optical deconstruction of parkinsonian neural circuitry.
Deep brain stimulation (DBS) is a therapeutic option for intractable neurological and psychiatric disorders, including Parkinson's disease and major depression. Because of the heterogeneity of brain tissues where electrodes are placed, it has been challenging to elucidate the relevant target cell types or underlying mechanisms of DBS. We used optogenetics and solid-state optics to systematically drive or inhibit an array of distinct circuit elements in freely moving parkinsonian rodents and found that therapeutic effects within the subthalamic nucleus can be accounted for by direct selective stimulation of afferent axons projecting to this region. In addition to providing insight into DBS mechanisms, these results demonstrate an optical approach for dissection of disease circuitry and define the technological toolbox needed for systematic deconstruction of disease circuits by selectively controlling individual components.


Suppression of HLA expression by lentivirus-mediated gene transfer of siRNA cassettes and in vivo chemoselection to enhance hematopoietic stem cell transplantation.
Current approaches for hematopoietic stem cell (HSC) and organ transplantation are limited by donor and host-mediated immune responses to allo-antigens. Application of these therapies is limited by the toxicity of preparative and post-transplant immunosuppressive regimens and a shortage of appropriate HLA-matched donors. We have been exploring two complementary approaches for genetically modifying donor cells that achieve long-term suppression of cellular proteins that elicit host immune responses to mismatched donor antigens, and provide a selective advantage to genetically engineered donor cells after transplantation. The first approach is based on recent advances that make feasible targeted down-regulation of HLA expression. Suppression of HLA expression could help to overcome limitations imposed by extensive HLA polymorphisms that restrict the availability of suitable donors. Accordingly, we have recently investigated whether knockdown of HLA by RNA interference (RNAi) enables allogeneic cells to evade immune recognition. For efficient and stable delivery of short hairpin-type RNAi constructs (shRNA), we employed lentivirus-based gene transfer vectors that integrate into genomic DNA, thereby permanently modifying transduced donor cells. Lentivirus-mediated delivery of shRNA targeting pan-Class I and allele-specific HLA achieved efficient and dose-dependent reduction in surface expression of HLA in human cells, and enhanced resistance to allo-reactive T lymphocyte-mediated cytotoxicity, while avoiding non-MHC restricted killing. Complementary strategies for genetic engineering of HSC that would provide a selective advantage for transplanted donor cells and enable successful engraftment with less toxic preparative and immunosuppressive regimens would increase the numbers of individuals to whom HLA suppression therapy could be offered. Our second strategy is to provide a mechanism for in vivo selection of genetically modified HSC and other donor cells. We have uniquely combined transplantation during the neonatal period, when tolerance may be more readily achieved, with a positive selection strategy for in vivo amplification of drug-resistant donor HSC. This model system enables the evaluation of mechanisms of tolerance induction to neo-antigens, and allogeneic stem cells during immune ontogeny. HSC are transduced ex vivo by lentivirus-mediated gene transfer of P140K-O(6)-methylguanine-methyltransferase (MGMT(P140K)). The MGMT(P140K) DNA repair enzyme confers resistance to benzylguanine, an inhibitor of endogenous MGMT, and to chloroethylating agents such as BCNU. In vivo chemoselection enables enrichment of donor cells at the stem cell level. Using complementary approaches of in vivo chemoselection and RNAi-induced silencing of HLA expression may enable the generation of histocompatibility-enhanced, and eventually, perhaps "universally" compatible cellular grafts.


Role of the human medial frontal cortex in task switching: a combined fMRI and TMS study.
We used event-related functional magnetic resonance imaging (fMRI) to measure brain activity when subjects were performing identical tasks in the context of either a task-set switch or a continuation of earlier performance. The context, i.e., switching or staying with the current task, influenced medial frontal cortical activation; the medial frontal cortex is transiently activated at the time that subjects switch from one way of performing a task to another. Two types of task-set-switching paradigms were investigated. In the response-switching (RS) paradigm, subjects switched between different rules for response selection and had to choose between competing responses. In the visual-switching (VS) paradigm, subjects switched between different rules for stimulus selection and had to choose between competing visual stimuli. The type of conflict, sensory (VS) or motor (RS), involved in switching was critical in determining medial frontal activation. Switching in the RS paradigm was associated with clear blood-oxygenation-level-dependent signal increases ("activations") in three medial frontal areas: the rostral cingulate zone, the caudal cingulate zone, and the presupplementary motor area (pre-SMA). Switching in the VS task was associated with definite activation in just one medial frontal area, a region on the border between the pre-SMA and the SMA. Subsequent to the fMRI session, we used MRI-guided frameless stereotaxic procedures and repetitive transcranial magnetic stimulation (rTMS) to test the importance of the medial frontal activations for task switching. Applying rTMS over the pre-SMA disrupted subsequent RS performance but only when it was applied in the context of a switch. This result shows, first, that the pre-SMA is essential for task switching and second that its essential role is transient and limited to just the time of behavioral switching. The results are consistent with a role for the pre-SMA in selecting between response sets at a superordinate level rather than in selecting individual responses. The effect of the rTMS was not simply due to the tactile and auditory artifacts associated with each pulse; rTMS over several control regions did not selectively disrupt switching. Applying rTMS over the SMA/pre-SMA area activated in the VS paradigm did not disrupt switching. This result, first, confirms the limited importance of the medial frontal cortex for sensory attentional switching. Second, the VS rTMS results suggest that just because an area is activated in two paradigms does not mean that it plays the same essential role in both cases.


GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement.
γ-Aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter in the brain and is important in motor learning. We aimed to measure GABA content in primary motor cortex poststroke (using GABA-edited magnetic resonance spectroscopy [MRS]) and in relation to motor recovery during 2 weeks of constraint-induced movement therapy (CIMT). Twenty-one patients (3-12 months poststroke) and 20 healthy subjects were recruited. Magnetic resonance imaging structural T1 and GABA-edited MRS were performed at baseline and after CIMT, and once in healthy subjects. GABA:creatine (GABA:Cr) ratio was measured by GABA-edited MRS. Motor function was measured using Wolf Motor Function Test (WMFT). Baseline comparison between stroke patients (n = 19) and healthy subjects showed a significantly lower GABA:Cr ratio in stroke patients (P < .001) even after correcting for gray matter content in the voxel (P < .01) and when expressing GABA relative to N-acetylaspartic acid (NAA; P = .03). After 2 weeks of CIMT patients improved significantly on WMFT, but no consistent change across the group was observed for the GABA:Cr ratio (n = 17). However, the extent of improvement on WMFT correlated significantly with the magnitude of GABA:Cr changes (P < .01), with decreases in GABA:Cr ratio being associated with better improvements in motor function. In patients 3 to 12 months poststroke, GABA levels are lower in the primary motor cortex than in healthy subjects. The observed association between GABA and recovery warrants further studies on the potential use of GABA MRS as a biomarker in poststroke recovery.


Characterizing estuarine plume discharge into the coastal ocean using fatty acid biomarkers and pigment analysis.
The transformation of estuaries by human activities continues to alter the biogeochemical balance of the coastal ocean. The disruption of this balance can negatively impact the provision of goods and services, including fisheries, commerce and transportation, recreation and esthetic enjoyment. Here we examine a link, between the Elkhorn Slough and the coastal ocean in Monterey Bay, California (USA) using a novel application of fatty acid and pigment analysis. Fatty acid analysis of filtered water samples showed biologically distinct water types between the Elkhorn Slough plume and the receiving waters of the coastal ocean. A remarkable feature of the biological content of the plume entering the coastal ocean was the abundance of bacteria-specific fatty acids, which correlated well with concentrations of colored dissolved organic matter (CDOM). Pigment analysis showed that plume waters contained higher concentrations of diatoms and cryptophytes, while the coastal ocean waters showed higher relative concentrations of dinoflagellates. Bacteria and cryptophytes can provide a source of labile, energy-rich organic matter that may be locally important as a source of food for pelagic and benthic communities. Surface and depth surveys of the plume show that the biogeochemical constituents of the slough waters are injected into the coastal waters and become entrained in the northward flowing, nearshore current of Monterey Bay. Transport of these materials to the northern portion of the bay can fuel a bloom incubator, which exists in this region. This study shows that fatty acid markers can reveal the biogeochemical interactions between estuaries and the coastal ocean and highlights how man-made changes have the potential to influence coastal ecological change.


Can pain and function be distinguished in the Oxford Hip Score in a meaningful way? : an exploratory and confirmatory factor analysis.
The objective of this study was to explore dimensionality of the Oxford Hip Score (OHS) and examine whether self-reported pain and functioning can be distinguished in the form of subscales. This was a secondary data analysis of the UK NHS hospital episode statistics/patient-reported outcome measures dataset containing pre-operative OHS scores on 97 487 patients who were undergoing hip replacement surgery. The proposed number of factors to extract depended on the method of extraction employed. Velicer's Minimum Average Partial test and the Parallel Analysis suggested one factor, the Cattell's scree test and Kaiser-over-1 rule suggested two factors. Exploratory factor analysis demonstrated that the two-factor OHS had most of the items saliently loading either of the two factors. These factors were named 'Pain' and 'Function' and their respective subscales were created. There was some cross-loading of items: 8 (pain on standing up from a chair) and 11 (pain during work). These items were assigned to the 'Pain' subscale. The final 'Pain' subscale consisted of items 1, 8, 9, 10, 11 and 12. The 'Function' subscale consisted of items 2, 3, 4, 5, 6 and 7, with the recommended scoring of the subscales being from 0 (worst) to 100 (best). Cronbach's alpha was 0.855 for the 'Pain' subscale and 0.861 for the 'Function' subscale. A confirmatory factor analysis demonstrated that the two-factor model of the OHS had a better fit. However, none of the one-factor or two-factor models was rejected. Factor analyses demonstrated that, in addition to current usage as a single summary scale, separate information on pain and self-reported function can be extracted from the OHS in a meaningful way in the form of subscales. Cite this article: Bone Joint Res 2014;3:305-9.


The relationship between trough concentration of vancomycin and effect on methicillin-resistant Staphylococcus aureus in critically ill patients.
The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections in intensive care units in Malaysia is significant. Invasive MRSA infections are commonly treated with vancomycin. In clinical practice, the serum vancomycin trough concentration is used as a surrogate marker of vancomycin efficacy. A low concentration of vancomycin may result in less effective therapy and increase the risk of bacterial resistance. We evaluated the relationship between the resolution of MRSA infections and trough concentrations of vancomycin. A total of 76 patients admitted between January 2005 and February 2011 were included in the study. Serum vancomycin trough concentration data were collected from the microbiology records. The clinical response was evaluated on the basis of clinical notes and culture test results. A total of 262 appropriate trough concentration data were included, with a median of 3 trough concentrations per patient. Fifty-four patients responded to vancomycin therapy. The initial trough concentration did not differ between responders and non-responders (p=0.135) but the corrected trough concentration was higher among responders than among non-responders (11.64±1.50 mg/l and 9.25±1.59 mg/l, respectively; p=0.036). The average total daily dose of vancomycin was significantly higher among the responders (p=0.008). In this critically ill population, a vancomycin dose of 15 mg/kg/day was found sufficient to produce optimal trough concentrations to eradicate the MRSA infection. This study demonstrated the significant relationship between response to treatment of MRSA infection and serum vancomycin trough concentrations.


Temporal analysis of the honey bee microbiome reveals four novel viruses and seasonal prevalence of known viruses, Nosema, and Crithidia.
Honey bees (Apis mellifera) play a critical role in global food production as pollinators of numerous crops. Recently, honey bee populations in the United States, Canada, and Europe have suffered an unexplained increase in annual losses due to a phenomenon known as Colony Collapse Disorder (CCD). Epidemiological analysis of CCD is confounded by a relative dearth of bee pathogen field studies. To identify what constitutes an abnormal pathophysiological condition in a honey bee colony, it is critical to have characterized the spectrum of exogenous infectious agents in healthy hives over time. We conducted a prospective study of a large scale migratory bee keeping operation using high-frequency sampling paired with comprehensive molecular detection methods, including a custom microarray, qPCR, and ultra deep sequencing. We established seasonal incidence and abundance of known viruses, Nosema sp., Crithidia mellificae, and bacteria. Ultra deep sequence analysis further identified four novel RNA viruses, two of which were the most abundant observed components of the honey bee microbiome (∼10(11) viruses per honey bee). Our results demonstrate episodic viral incidence and distinct pathogen patterns between summer and winter time-points. Peak infection of common honey bee viruses and Nosema occurred in the summer, whereas levels of the trypanosomatid Crithidia mellificae and Lake Sinai virus 2, a novel virus, peaked in January.


Oxidising agents in sub-arc mantle melts link slab devolatilisation and arc magmas.
Subduction zone magmas are more oxidised on eruption than those at mid-ocean ridges. This is attributed either to oxidising components, derived from subducted lithosphere (slab) and added to the mantle wedge, or to oxidation processes occurring during magma ascent via differentiation. Here we provide direct evidence for contributions of oxidising slab agents to melts trapped in the sub-arc mantle. Measurements of sulfur (S) valence state in sub-arc mantle peridotites identify sulfate, both as crystalline anhydrite (CaSO4) and dissolved SO42- in spinel-hosted glass (formerly melt) inclusions. Copper-rich sulfide precipitates in the inclusions and increased Fe3+/∑Fe in spinel record a S6+-Fe2+ redox coupling during melt percolation through the sub-arc mantle. Sulfate-rich glass inclusions exhibit high U/Th, Pb/Ce, Sr/Nd and δ34S (+ 7 to + 11‰), indicating the involvement of dehydration products of serpentinised slab rocks in their parental melt sources. These observations provide a link between liberated slab components and oxidised arc magmas.


Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects.
The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.


Usage patterns, health, and nutritional status of long-term multiple dietary supplement users: a cross-sectional study.
Dietary supplement use in the United States is prevalent and represents an important source of nutrition. However, little is known about individuals who routinely consume multiple dietary supplements. This study describes the dietary supplement usage patterns, health, and nutritional status of long-term multiple dietary supplement users, and where possible makes comparisons to non-users and multivitamin/mineral supplement users. Using a cross-sectional study design, information was obtained by online questionnaires and physical examination (fasting blood, blood pressure, body weight) from a convenience sample of long-term users of multiple dietary supplements manufactured by Shaklee Corporation (Multiple Supp users, n = 278). Data for non-users (No Supp users, n = 602) and multivitamin/mineral supplement users (Single Supp users, n = 176) were obtained from the National Health and Nutrition Examination Survey (NHANES) 2001-2002 and NHANES III 1988-1994. Logistic regression methods were used to estimate odds ratios with 95% confidence intervals. Dietary supplements consumed on a daily basis by more than 50% of Multiple Supp users included a multivitamin/mineral, B-complex, vitamin C, carotenoids, vitamin E, calcium with vitamin D, omega-3 fatty acids, flavonoids, lecithin, alfalfa, coenzyme Q10 with resveratrol, glucosamine, and a herbal immune supplement. The majority of women also consumed gamma linolenic acid and a probiotic supplement, whereas men also consumed zinc, garlic, saw palmetto, and a soy protein supplement. Serum nutrient concentrations generally increased with increasing dietary supplement use. After adjustment for age, gender, income, education and body mass index, greater degree of supplement use was associated with more favorable concentrations of serum homocysteine, C-reactive protein, high-density lipoprotein cholesterol, and triglycerides, as well as lower risk of prevalent elevated blood pressure and diabetes. This group of long-term multiple dietary supplement users consumed a broad array of vitamin/mineral, herbal, and condition-specific dietary supplements on a daily basis. They were more likely to have optimal concentrations of chronic disease-related biomarkers, and less likely to have suboptimal blood nutrient concentrations, elevated blood pressure, and diabetes compared to non-users and multivitamin/mineral users. These findings should be confirmed by studying the dietary supplement usage patterns, health, and nutritional status of other groups of heavy users of dietary supplements.


Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene.
Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia.


Affective neural circuitry and mind-body influences in asthma.
Individuals with asthma have twice the risk of developing mood and anxiety disorders as individuals without asthma and these psychological factors are associated with worse outcomes and greater need for medical intervention. Similarly, asthma symptom onset and exacerbation often occur during times of increased psychological stress. Remission from depression, on the other hand, is associated with improvement in asthma symptoms and decreased usage of asthma medication. Yet research aimed at understanding the biological underpinnings of asthma has focused almost exclusively on the periphery. An extensive literature documents the relationship between emotion and asthma, but little work has explored the function of affective neural circuitry in asthma symptom expression. Therefore, the following review integrates neuroimaging research related to factors that may impact symptom expression in asthma, such as individual differences in sensitivity to visceral signals, the influence of expectation and emotion on symptom perception, and changes related to disease chronicity, such as conditioning and plasticity. The synthesis of these literatures suggests that the insular and anterior cingulate cortices, in addition to other brain regions previously implicated in the regulation of emotion, may be both responsive to asthma-related bodily changes and important in influencing the appearance and persistence of symptom expression in asthma.


On Teaching International Courses on Health Information Systems. Lessons Learned during 16 Years of Frank - van Swieten Lectures on Strategic Information Management in Health Information Systems.
Health information systems (HIS) are one of the most important areas for biomedical and health informatics. In order to professionally deal with HIS well-educated informaticians are needed. Because of these reasons, in 2001 an international course has been established: The Frank - van Swieten Lectures on Strategic Information Management of Health Information Systems. Reporting about the Frank - van Swieten Lectures and about our students' feedback on this course during the last 16 years. Summarizing our lessons learned and making recommendations for such international courses on HIS. The basic concept of the Frank - van Swieten lectures is to teach the theoretical background in local lectures, to organize practical exercises on modelling sub-information systems of the respective local HIS and finally to conduct Joint Three Days as an international meeting were the resulting models are introduced and compared. During the last 16 years, the Universities of Amsterdam, Braunschweig, Heidelberg/Heilbronn, Leipzig as well as UMIT were involved in running this course. Overall, 517 students from these universities participated. Our students' feedback was clearly positive. The Joint Three Days of the Frank - van Swieten Lectures, where at the end of the course all students can meet, turned out to be an important component of this course. Based on the last 16 years, we recommend common teaching materials, agreement on equivalent clinical areas for the exercises, support of group building of international student groups, motivation of using a collaboration platform, ensuring quality management of the course, addressing different levels of knowledge of the students, and ensuring sufficient funding for joint activities. Although associated with considerable additional efforts, we can clearly recommend establishing such international courses on HIS, such as the Frank - van Swieten Lectures.


A system for incubations at high gas partial pressure.
High-pressure is a key feature of deep subsurface environments. High partial pressure of dissolved gasses plays an important role in microbial metabolism, because thermodynamic feasibility of many reactions depends on the concentration of reactants. For gases, this is controlled by their partial pressure, which can exceed 1 MPa at in situ conditions. Therefore, high hydrostatic pressure alone is not sufficient to recreate true deep subsurface in situ conditions, but the partial pressure of dissolved gasses has to be controlled as well. We developed an incubation system that allows for incubations at hydrostatic pressure up to 60 MPa, temperatures up to 120°C, and at high gas partial pressure. The composition and partial pressure of gasses can be manipulated during the experiment. To keep costs low, the system is mainly made from off-the-shelf components with only very few custom-made parts. A flexible and inert PVDF (polyvinylidene fluoride) incubator sleeve, which is almost impermeable for gases, holds the sample and separates it from the pressure fluid. The flexibility of the incubator sleeve allows for sub-sampling of the medium without loss of pressure. Experiments can be run in both static and flow-through mode. The incubation system described here is usable for versatile purposes, not only the incubation of microorganisms and determination of growth rates, but also for chemical degradation or extraction experiments under high gas saturation, e.g., fluid-gas-rock-interactions in relation to carbon dioxide sequestration. As an application of the system we extracted organic compounds from sub-bituminous coal using H(2)O as well as a H(2)O-CO(2) mixture at elevated temperature (90°C) and pressure (5 MPa). Subsamples were taken at different time points during the incubation and analyzed by ion chromatography. Furthermore we demonstrated the applicability of the system for studies of microbial activity, using samples from the Isis mud volcano. We could detect an increase in sulfate reduction rate upon the addition of methane to the sample.


Specificity and responsiveness of patient-reported and clinician-rated outcome measures in the context of elbow surgery, comparing patients with and without rheumatoid arthritis.
To examine and contrast the ability of patient-reported and clinician-rated measures, reflecting different levels of specificity, to detect differences in outcomes between patients with and without rheumatoid arthritis (RA), at 6 months following elbow surgery. One hundred and four consecutive patients/elbows self-completed the Oxford Elbow Score (OES), Disabilities of the Arm, Shoulder and Hand (DASH) and SF-36 general health questionnaires prior to elbow surgery. A surgeon assessed the standard Mayo Elbow Performance Score (MEPS) and recorded patients' diagnoses. Assessments were repeated 6 months following surgery in an outpatient clinic. Patients also completed pain "transition" and global satisfaction items. Patients who did not attend completed their assessment by post. Twenty-three (22%) patients had RA. These patients were more likely than other patients to have bilateral elbow problems and to have total elbow replacement (85.7% versus 10.5% P<0.001). Patients with RA had more severe preoperative elbow-specific scores, and experienced a large and significantly greater amount of change in elbow function, as measured by the OES function (P=0.002) and pain scales (P=0.013). The surgeon-assessed elbow-specific MEPS score also detected a large and significant difference between the two groups (P<0.001). However, these differences were not detected by the upper limb specific DASH, by any SF-36 general health dimensions, or by transition or satisfaction items. The OES performed well in assessing surgical outcomes in patients with RA. Neither the upper limb specific DASH nor the SF-36 is specific or responsive enough to warrant its exclusive use as an outcome measure for elbow surgery. Level II (prospective non-randomised study).


An X-linked haplotype of Neandertal origin is present among all non-African populations.
Recent work on the Neandertal genome has raised the possibility of admixture between Neandertals and the expanding population of Homo sapiens who left Africa between 80 and 50 Kya (thousand years ago) to colonize the rest of the world. Here, we provide evidence of a notable presence (9% overall) of a Neandertal-derived X chromosome segment among all contemporary human populations outside Africa. Our analysis of 6,092 X-chromosomes from all inhabited continents supports earlier contentions that a mosaic of lineages of different time depths and different geographic provenance could have contributed to the genetic constitution of modern humans. It indicates a very early admixture between expanding African migrants and Neandertals prior to or very early on the route of the out-of-Africa expansion that led to the successful colonization of the planet.


The structure of paranoia in the general population.
Psychotic phenomena appear to form a continuum with normal experience and beliefs, and may build on common emotional interpersonal concerns. We tested predictions that paranoid ideation is exponentially distributed and hierarchically arranged in the general population, and that persecutory ideas build on more common cognitions of mistrust, interpersonal sensitivity and ideas of reference. Items were chosen from the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) questionnaire and the Psychosis Screening Questionnaire in the second British National Survey of Psychiatric Morbidity (n = 8580), to test a putative hierarchy of paranoid development using confirmatory factor analysis, latent class analysis and factor mixture modelling analysis. Different types of paranoid ideation ranged in frequency from less than 2% to nearly 30%. Total scores on these items followed an almost perfect exponential distribution (r = 0.99). Our four a priori first-order factors were corroborated (interpersonal sensitivity; mistrust; ideas of reference; ideas of persecution). These mapped onto four classes of individual respondents: a rare, severe, persecutory class with high endorsement of all item factors, including persecutory ideation; a quasi-normal class with infrequent endorsement of interpersonal sensitivity, mistrust and ideas of reference, and no ideas of persecution; and two intermediate classes, characterised respectively by relatively high endorsement of items relating to mistrust and to ideas of reference. The paranoia continuum has implications for the aetiology, mechanisms and treatment of psychotic disorders, while confirming the lack of a clear distinction from normal experiences and processes.


Use of incisional vacuum-assisted closure in the prevention of postoperative infection in high-risk patients who underwent spine surgery: a proof-of-concept study.
This proof-of-concept study was conducted to determine whether negative-pressure wound therapy, through the use of incisional vacuum-assisted closure (VAC), is associated with a reduction in surgical site infections (SSIs) when compared to standard wound dressings in patients undergoing open posterior spinal fusion who have a high risk of infection. A total of 64 patients were examined; 21 patients received incisional VAC application (VAC group) versus 43 diagnosis-matched patients who received standard wound dressings (control group). Patients in the VAC group were prospectively enrolled in a consecutive series between March 2013 and March 2014 if they met the following diagnostic criteria for high risk of infection: posterior open surgery across the cervicothoracic junction; thoracic kyphosis due to metastatic disease; high-energy trauma; or multilevel revision reconstructive surgery. Patients in the VAC group also met one or more comorbidity criteria, including body mass index ≥ 35 or < 18.5, diabetes, previous radiation at surgical site, chemotherapy, steroid use, bedridden state, large traumatic soft-tissue disruption, or immunocompromised state. Consecutive patients in the control group were retrospectively selected from the previous year by the same high-risk infection diagnostic criteria as the VAC group. All surgeries were conducted by the same surgeon at a single site. The primary outcome was SSI. All patients had 1 year of follow-up after their surgery. Baseline demographics, intraoperative parameters, and postoperative wound infection rates were compared between groups. Patient demographics including underlying comorbidities were similar, with the exception that VAC-treated patients were malnourished (p = 0.020). VAC-treated patients underwent longer surgeries (p < 0.001) and required more postoperative ICU admissions (p = 0.039). The median length of hospital stay was not different between groups. In total, 9 control patients (21%) developed an SSI, versus 2 VAC-treated patients (10%). Patients in this cohort were selected to have an increased risk of infection; accordingly, the rate of SSI was high. However, negative-pressure wound therapy through VAC application to the postoperative incision resulted in a 50% reduction in SSI. No adverse effects were noted secondary to VAC application. The preliminary data confirm the authors' proof of concept and strongly support the need for a prospective randomized trial.


Age-related cellular copper dynamics in the fungal ageing model Podospora anserina and in ageing human fibroblasts.
In previous investigations an impact of cellular copper homeostasis on ageing of the ascomycete Podospora anserina has been demonstrated. Here we provide new data indicating that mitochondria play a major role in this process. Determination of copper in the cytosolic fraction using total reflection X-ray fluorescence spectroscopy analysis and eGfp reporter gene studies indicate an age-related increase of cytosolic copper levels. We show that components of the mitochondrial matrix (i.e. eGFP targeted to mitochondria) become released from the organelle during ageing. Decreasing the accessibility of mitochondrial copper in P. anserina via targeting a copper metallothionein to the mitochondrial matrix was found to result in a switch from a copper-dependent cytochrome-c oxidase to a copper-independent alternative oxidase type of respiration and results in lifespan extension. In addition, we demonstrate that increased copper concentrations in the culture medium lead to the appearance of senescence biomarkers in human diploid fibroblasts (HDFs). Significantly, expression of copper-regulated genes is induced during in vitro ageing in medium devoid of excess copper suggesting that cytosolic copper levels also increase during senescence of HDFs. These data suggest that the identified molecular pathway of age-dependent copper dynamics may not be restricted to P. anserina but may be conserved from lower eukaryotes to humans.


Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease.
Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered reno-protective. EETs are degraded by the enzyme soluble epoxide hydrolase (sEH) and sEH inhibitors are considered treatment for chronic renal failure (CRF). We determined whether sEH inhibition attenuates the progression of CRF in the 5/6-nephrectomy model (5/6-Nx) in mice. 5/6-Nx mice were treated with a placebo, an ACE-inhibitor (Ramipril, 40 mg/kg), the sEH-inhibitor cAUCB or the CYP-inhibitor fenbendazole for 8 weeks. 5/6-Nx induced hypertension, albuminuria, glomerulosclerosis and tubulo-interstitial damage and these effects were attenuated by Ramipril. In contrast, cAUCB failed to lower the blood pressure and albuminuria was more severe as compared to placebo. Plasma EET-levels were doubled in 5/6 Nx-mice as compared to sham mice receiving placebo. Renal sEH expression was attenuated in 5/6-Nx mice but cAUCB in these animals still further increased the EET-level. cAUCB also increased 5-HETE and 15-HETE, which derive from peroxidation or lipoxygenases. Similar to cAUCB, CYP450 inhibition increased HETEs and promoted albuminuria. Thus, sEH-inhibition failed to elicit protective effects in the 5/6-Nx model and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway.


Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele.
The APOE epsilon4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE epsilon4-carriers and 18 matched noncarriers (age range: 20-35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased "default mode network" (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in epsilon4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in epsilon4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE epsilon4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.


Imaging angiogenesis, inflammation, and metastasis in the tumor microenvironment with magnetic resonance imaging.
With the development of new imaging techniques, the potential for probing the molecular, cellular, and structural components of the tumor microenvironment in situ has increased dramatically. A multitude of imaging modalities have been successfully employed to probe different aspects of the tumor microenvironment, including expression of molecules, cell motion, cellularity, vessel permeability, vascular perfusion, metabolic and physiological changes, apoptosis, and inflammation. This chapter focuses on the most recent advances in magnetic resonance imaging methods, which offer a number of advantages over other methodologies, including high spatial resolution and the use of nonionizing radiation, as well as the use of such methods in the context of primary and secondary brain tumors. It also highlights how they can be used to assess the molecular and cellular changes in the tumor microenvironment in response to therapy.


Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China.
Obstacles to developing an HIV-1 vaccine include extensive viral diversity and lack of correlates of protective immunity. High mutation rates allow HIV-1 to adapt rapidly to selective forces such as antiretroviral therapy and immune pressure, including HIV-1-specific CTLs that select viral variants which escape T-cell recognition. Multiple factors contribute to HIV-1 diversity, making it difficult to disentangle the contribution of CTL selection without using complex analytical approaches. We describe an HIV-1 outbreak in 231 former plasma donors in China, where a narrow-source virus that had contaminated the donation system was apparently transmitted to many persons contemporaneously. The genetic divergence now evident in these subjects should uniquely reveal how much viral diversity at the population level is solely attributable to host factors. We found significant correlations between pair-wise divergence of viral sequences and HLA class I genotypes across epitope-length windows in HIV-1 Gag, reverse transcriptase, integrase, and Nef, corresponding to sites of 140 HLA class I allele-associated viral polymorphisms. Of all polymorphic sites across these 4 proteins, 24%-56% were sites of HLA-associated selection. These data confirm that CTL pressure has a major effect on inter-host HIV-1 viral diversity and probably represents a key element of viral control.


A comparison of visual and quantitative assessment of left ventricular ejection fraction by cardiac magnetic resonance.
To determine the accuracy of visual analysis of left ventricular (LV) function in comparison with the accepted quantitative gold standard method, cardiac magnetic resonance (CMR). Cine CMR imaging was performed at 1.5 T on 44 patients with a range of ejection fractions (EF, 5-80%). Clinicians (n = 18) were asked to visually assess EF after sequentially being shown cine images of a four chamber (horizontal long axis; HLA), two chamber (vertical long axis; VLA) and a short axis stack (SAS) and results were compared to a commercially available analysis package. There were strong correlations between visual and quantitative assessment. However, the EF was underestimated in all categories (by 8.4% for HLA, 8.4% for HLA + VLA and 7.9% for HLA + VLA + SAS, P all < 0.01) and particularly underestimated in mild LV impairment (17.4%, P < 0.01), less so for moderate (4.9%) and not for severe impairment (1%). Assessing more than one view of the heart improved visual assessment of LV, EF, however, clinicians underestimated EF by 8.4% on average, with particular inaccuracy in those with mild dysfunction. Given the important clinical information provided by LV assessment, quantitative analysis is recommended for accurate assessment.


Investigating the potential for ethnic group harm in collaborative genomics research in Africa: is ethnic stigmatisation likely?
A common assumption in genomics research is that the use of ethnic categories has the potential to lead to ethnic stigmatisation - particularly when the research is done on minority populations. Yet few empirical studies have sought to investigate the relation between genomics and stigma, and fewer still with a focus on Africa. In this paper, we investigate the potential for genomics research to lead to harms to ethnic groups. We carried out 49 semi-structured, open-ended interviews with stakeholders in a current medical genomics research project in Africa, MalariaGEN. Interviews were conducted with MalariaGEN researchers, fieldworkers, members of three ethics committees who reviewed MalariaGEN project proposals, and with members of the two funding bodies providing support to the MalariaGEN project. Interviews were conducted in Kenya, The Gambia and the UK between June 2008 and October 2009. They covered a range of aspects relating to the use of ethnicity in the genomics project, including views on adverse effects of the inclusion of ethnicity in such research. Drawing on the empirical data, we argue that the risk of harm to ethnic groups is likely to be more acute in specific types of genomics research. We develop a typology of research questions and projects that carry a greater risk of harm to the populations included in genomics research. We conclude that the potential of generating harm to ethnic groups in genomics research is present if research includes populations that are already stigmatised or discriminated against, or where the research investigates questions with particular normative implications. We identify a clear need for genomics researchers to take account of the social context of the work they are proposing to do, including understanding the local realities and relations between ethnic groups, and whether diseases are already stigmatised.