A common variant in myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults.
The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities (P(comb) = 7.71 × 10(-10), n = 699), with an effect size of 4.87%. This association was also found in a sample from the general population (P = 0.048, n = 1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.


Syncoilin is an intermediate filament protein in activated hepatic stellate cells.
Hepatic stellate cells (HSCs) play an important role in several (patho)physiologic conditions in the liver. In response to chronic injury, HSCs are activated and change from quiescent to myofibroblast-like cells with contractile properties. This shift in phenotype is accompanied by a change in expression of intermediate filament (IF) proteins. HSCs express a broad, but variable spectrum of IF proteins. In muscle, syncoilin was identified as an alpha-dystrobrevin binding protein with sequence homology to IF proteins. We investigated the expression of syncoilin in mouse and human HSCs. Syncoilin expression in isolated and cultured HSCs was studied by qPCR, Western blotting, and fluorescence immunocytochemistry. Syncoilin expression was also evaluated in other primary liver cell types and in in vivo-activated HSCs as well as total liver samples from fibrotic mice and cirrhotic patients. Syncoilin mRNA was present in human and mouse HSCs and was highly expressed in in vitro- and in vivo-activated HSCs. Syncoilin protein was strongly upregulated during in vitro activation of HSCs and undetectable in hepatocytes and liver sinusoidal endothelial cells. Syncoilin mRNA levels were elevated in both CCl4- and common bile duct ligation-treated mice. Syncoilin immunocytochemistry revealed filamentous staining in activated mouse HSCs that partially colocalized with α-smooth muscle actin, β-actin, desmin, and α-tubulin. We show that in the liver, syncoilin is predominantly expressed by activated HSCs and displays very low-expression levels in other liver cell types, making it a good marker of activated HSCs. During in vitro activation of mouse HSCs, syncoilin is able to form filamentous structures or at least to closely interact with existing cellular filaments.


Body size and risk of differentiated thyroid carcinomas: findings from the EPIC study.
Results from case-control and prospective studies suggest a moderate positive association between obesity and height and differentiated thyroid carcinoma (TC). Little is known on the relationship between other measures of adiposity and differentiated TC risk. Here, we present the results of a study on body size and risk of differentiated TC based on a large European prospective study (EPIC). During follow-up, 508 incident cases of differentiated TC were identified in women, and 58 in men. 78% of cases were papillary TC. Cox proportional hazard models were used to estimate hazard ratios (HRs). In women, differentiated TC risk was significantly associated with body mass index (BMI, kg/m(2)) (HR highest vs lowest quintile = 1.41, 95% CI: 1.03-1.94); height (HR = 1.61; 95% CI: 1.18-2.20); HR highest vs lowest tertile waist (HR = 1.34, 95% CI: 1.00-1.79) and waist-to-hip ratio (HR = 1.42, 95% CI: 1.05-1.91). The association with BMI was somewhat stronger in women below age 50. Corresponding associations for papillary TC were similar to those for all differentiated TC. In men the only body size factors significantly associated with differentiated TC were height (non linear), and leg length (HR highest vs. lowest tertile = 3.03, 95% CI: 1.30-7.07). Our study lends further support to the presence of a moderate positive association between differentiated TC risk and overweight and obesity in women. The risk increase among taller individuals of both sexes suggests that some genetic characteristics or early environmental exposures may also be implicated in the etiology of differentiated TC.


Vivid visual mental imagery in the absence of the primary visual cortex.
The role of the primary visual cortex in visual mental imagery has provided significant debate in the imagery literature. Functional neuroimaging studies show considerable variation depending on task and technique. Patient studies can be difficult to interpret due to the diverse nature of cortical damage. The type of cortical damage in patient SBR is exceedingly rare as it is restricted to the gray matter of the calcarine sulcus. In this study, we show that in spite of his near-complete cortical blindness, SBR exhibits vivid visual mental imagery both behaviorally and when measured with functional magnetic resonance imaging. The pattern of cortical activation to visual mental imagery in SBR is indistinguishable from individual sighted subjects, in contrast to the visual perceptual responses, which are greatly attenuated.


Links between maternal postpartum depressive symptoms, maternal distress, infant gender and sensitivity in a high-risk population.
Maternal postpartum depression has an impact on mother-infant interaction. Mothers with depression display less positive affect and sensitivity in interaction with their infants compared to non-depressed mothers. Depressed women also show more signs of distress and difficulties adjusting to their role as mothers than non-depressed women. In addition, depressive mothers are reported to be affectively more negative with their sons than with daughters. A non-clinical sample of 106 mother-infant dyads at psychosocial risk (poverty, alcohol or drug abuse, lack of social support, teenage mothers and maternal psychic disorder) was investigated with EPDS (maternal postpartum depressive symptoms), the CARE-Index (maternal sensitivity in a dyadic context) and PSI-SF (maternal distress). The baseline data were collected when the babies had reached 19 weeks of age. A hierarchical regression analysis yielded a highly significant relation between the PSI-SF subscale "parental distress" and the EPDS total score, accounting for 55% of the variance in the EPDS. The other variables did not significantly predict the severity of depressive symptoms. A two-way ANOVA with "infant gender" and "maternal postpartum depressive symptoms" showed no interaction effect on maternal sensitivity. Depressive symptoms and maternal sensitivity were not linked. It is likely that we could not find any relation between both variables due to different measuring methods (self-reporting and observation). Maternal distress was strongly related to maternal depressive symptoms, probably due to the generally increased burden in the sample, and contributed to 55% of the variance of postpartum depressive symptoms.


The T-cell oncogenic protein HOX11 activates Aldh1 expression in NIH 3T3 cells but represses its expression in mouse spleen development.
Hox11 is a homeobox gene essential for spleen formation in mice, since atrophy of the anlage of a developing spleen occurs in early embryonic development in Hox11 null mice. HOX11 is also expressed in a subset of T-cell acute leukemias after specific chromosomal translocations. Since the protein has a homeodomain and can activate transcription, it probably exerts at least some of its effects in vivo by regulation of target genes. Representational difference analysis has been used to isolate cDNA clones corresponding to mRNA species activated following stable expression of HOX11 in NIH 3T3 cells. The gene encoding the retinoic acid-synthesizing enzyme aldehyde dehydrogenase 1 (Aldh1), initially called Hdg-1, was found to be ectopically activated by HOX11 in this system. Study of Aldh1 gene expression during spleen development showed that the presence of Aldh1 mRNA inversely correlated with Hox11. Hox11 null mouse embryos have elevated Aldh1 mRNA in spleen primordia prior to atrophy, while Aldh1 seems to be repressed by Hox11 during organogenesis of the spleens of wild-type mice. This result suggests that expression of Aldh1 protein is negatively regulated by Hox11 and that abnormal expression of Aldh1 in Hox11 null mice may cause loss of splenic precursor cells by aberrant retinoic acid metabolism.


Mobility of health professionals pre and post 2004 and 2007 EU enlargements: evidence from the EU project PROMeTHEUS.
EU enlargement has facilitated the mobility of EU citizens, including health professionals, from the 2004 and 2007 EU accession states. Fears have been raised about a mass exodus of health professionals and the consequences for the operation of health systems. However, to date a systematic analysis of the EU enlargement's effects on the mobility of health professionals has been lacking. The aim of this article is to shed light on the changes in the scale of movement, trends and directions of flows pre and post 2004 and 2007 EU enlargements. The study follows a pan-European secondary data analysis to (i) quantitatively and (ii) qualitatively analyse mobility before and after the EU enlargement. (i) The secondary data analysis covers 34 countries (including all EU Member States). (ii) Data were triangulated with the findings of 17 country case studies to qualitatively assess the effects of enlargement on health workforce mobility. The stock of health professionals from the new (EU-12) into the old EU Member States (EU-15) have increased following EU accession. The stock of medical doctors from the EU-12 in the EU-15 countries has more than doubled between 2003 and 2007. The available data suggest the same trend for dentists. The extremely limited data for nurses show that the stock of nurses has, in contrast, only slightly increased. However, while no reliable data is available evidence suggests that the number of undocumented or self-employed migrant nurses in the home-care sector has significantly increased. Health professionals trained in the EU-12 are becoming increasingly important in providing sufficient health care in some destination countries and regions facing staff shortages. A mass exodus of health professionals has not taken place after the 2004 and 2007 EU enlargements. The estimated annual outflows from the EU-12 countries have rarely exceeded 3% of the domestic workforce. This is partly due to labour market restrictions in the destination countries, but also to improvements in salaries and working conditions in some source countries. The overall mobility of health professionals is hence relatively moderate and in line with the overall movement of citizens within the EU. However, for some countries even losing small numbers of health professionals can have impacts in underserved regions.


Emergency and urgent care systems in Australia, Denmark, England, France, Germany and the Netherlands - Analyzing organization, payment and reforms.
Increasing numbers of hospital emergency department (ED) visits pose a challenge to health systems in many countries. This paper aims to examine emergency and urgent care systems, in six countries and to identify reform trends in response to current challenges. Based on a literature review, six countries - Australia, Denmark, England, France, Germany and the Netherlands - were selected for analysis. Information was collected using a standardized questionnaire that was completed by national experts. These experts reviewed relevant policy documents and provided information on (1) the organization and planning of emergency and urgent care, (2) payment systems for EDs and urgent primary care providers, and (3) reform initiatives. In the six countries four main reform approaches could be identified: (a) extending the availability of urgent primary care, (b) concentrating and centralizing the provision of urgent primary care, (c) improving coordination between urgent primary care and emergency care, and (d) concentrating emergency care provision at fewer institutions. The design of payment systems for urgent primary care and for emergency care is often aligned to support these reforms. Better guidance of patients and a reconfiguration of emergency and urgent care are the most important measures taken to address the current challenges. Nationwide planning of all emergency care providers, closely coordinated reforms and informing patients can support future reforms.


Orienting attention to semantic categories.
We investigated the ability to orient attention to a complex, non-perceptual attribute of stimuli-semantic category. Behavioral consequences and neural correlates of semantic orienting were revealed and compared with those of spatial orienting, using event-related functional magnetic-resonance imaging. Semantic orienting significantly shortened response times to identify word stimuli, showing that it is possible to focus attention on non-perceptual attributes of stimuli to enhance behavioral performance. Semantic-orienting cues engaged parietal and frontal areas that were also involved in spatial orienting, but in addition engaged brain areas associated with semantic analysis of words, such as the left anterior inferior frontal cortex. These findings show that attentional orienting selectively engages brain areas with functional specialization for the predicted attributes. They also support the existence of a core frontoparietal network, which controls attentional orienting in speeded response tasks independently of the type of expectations, interacting with task-relevant functionally specialized areas to optimize perception and action.


Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.
Synchronized oscillations and inhibitory interneurons have important and interconnected roles within cortical microcircuits. In particular, interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin have been suggested to be involved in gamma (30-80 Hz) oscillations, which are hypothesized to enhance information processing. However, because parvalbumin interneurons cannot be selectively controlled, definitive tests of their functional significance in gamma oscillations, and quantitative assessment of the impact of parvalbumin interneurons and gamma oscillations on cortical circuits, have been lacking despite potentially enormous significance (for example, abnormalities in parvalbumin interneurons may underlie altered gamma-frequency synchronization and cognition in schizophrenia and autism). Here we use a panel of optogenetic technologies in mice to selectively modulate multiple distinct circuit elements in neocortex, alone or in combination. We find that inhibiting parvalbumin interneurons suppresses gamma oscillations in vivo, whereas driving these interneurons (even by means of non-rhythmic principal cell activity) is sufficient to generate emergent gamma-frequency rhythmicity. Moreover, gamma-frequency modulation of excitatory input in turn was found to enhance signal transmission in neocortex by reducing circuit noise and amplifying circuit signals, including inputs to parvalbumin interneurons. As demonstrated here, optogenetics opens the door to a new kind of informational analysis of brain function, permitting quantitative delineation of the functional significance of individual elements in the emergent operation and function of intact neural circuitry.


Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.
Several Cre reporter strains of mice have been described, in which a lacZ gene is turned on in cells expressing Cre recombinase, as well as their daughter cells, following Cre-mediated excision of a loxP-flanked transcriptional "stop" sequence. These mice are useful for cell lineage tracing experiments as well as for monitoring the expression of Cre transgenes. The green fluorescent protein (GFP) and variants such as EYFP and ECFP offer an advantage over lacZ as a reporter, in that they can be easily visualized without recourse to the vital substrates required to visualize beta-gal in living tissue. In view of the general utility of targeting the ubiquitously expressed ROSA26 locus, we constructed a generic ROSA26 targeting vector. We then generated two reporter lines of mice by inserting EYFP or ECFP cDNAs into the ROSA26 locus, preceded by a loxP-flanked stop sequence. These strains were tested by crossing them with transgenic strains expressing Cre in a ubiquitous (beta-actin-Cre) or a cell-specific (Isl1-Cre and En1-Cre) pattern. The resulting EYFP or ECFP expression patterns indicated that the reporter strains function as faithful monitors of Cre activity. In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs. The non-overlapping emission spectra of EYFP and ECFP make them ideal for double labeling studies in living tissues.


In Silico Designed Axl Receptor Blocking Drug Candidates Against Zika Virus Infection.
After a large outbreak in Brazil, novel drugs against Zika virus became extremely necessary. Evaluation of virus-based pharmacological strategies concerning essential host factors brought us to the idea that targeting the Axl receptor by blocking its dimerization function could be critical for virus entry. Starting from experimentally validated compounds, such as RU-301, RU-302, warfarin, and R428, we identified a novel compound 2' (R428 derivative) to be the most potent for this task amongst a number of alternative compounds and leads. The improved affinity of compound 2' was confirmed by molecular docking as well as molecular dynamics simulation techniques using implicit solvation models. The current study summarizes a new possibility for inhibition of the Axl function as a potential target for future antiviral therapies.


Two-thirds of methodological research remained unpublished after presentation at Cochrane Colloquia: an empirical analysis.
To determine the extent to which abstracts of methodology research, initially presented at annual meetings of The Cochrane Collaboration, have been published as full reports and over what period of time. A secondary aim was to explore whether full publication varied in different methodological subject areas. The Cochrane Methodology Register (CMR) was searched for all abstracts reporting methodology research, presented at the 11 Cochrane Colloquia from 1997 to 2007. EMBASE, PubMed, and CMR were searched for full publications of the same research. We identified 908 eligible conference abstracts and found full publications for 312 (34.4%) of these, almost half of which (47.1%) had appeared by the end of the first year after the relevant Colloquium. The proportion of abstracts that had not been published by 3 years was 69.7%, falling to 66.2% at 5 years. Publication varied considerably between different methodological areas. Approximately two-thirds of methodological research studies presented at Cochrane Colloquia remain unpublished as full papers at least 5 years later. This highlights the importance of searching conference abstracts if one wishes to find as comprehensive and complete a sample of methodological research as possible.


Case management for people with severe mental disorders.
Since the 1960s, in many parts of the world, large psychiatric were closed down and people were treated in outpatient clinics, day centres or community mental health centres. Rising readmission rates suggested that this type of community care may be less effective than anticipated. In the 1970s case management arose as a means of co-ordinating the care of severely mentally ill people in the community. To determine the effects of case management as an approach to caring for severely mentally ill people in the community. Case management was compared against standard care on four main indices: (i) numbers remaining in contact with the psychiatric services; (ii) extent of psychiatric hospital admissions; (iii) clinical and social outcome; and (iv) costs. Electronic searches of CINAHL (1997), the Cochrane Schizophrenia Group's Register of trials (1997), EMBASE (1980-1995), MEDLINE (1966-1995), PsycLIT (1974-1995) and SCISEARCH (1997) were undertaken. References of all identified studies were searched for further trial citations. The inclusion criteria were that studies should be randomised controlled trials that (i) had compared case management to standard community care; and (ii) had involved people with severe mental disorder mainly between the ages of 18-65. Studies of case management were defined as those in which the investigators described the intervention as 'case' or 'care' management rather than 'Assertive Community Treatment' or 'ACT'. A study was carried out to test the reliability of the inclusion criteria. Categorical data were extracted twice and then cross-checked, any disagreements being resolved by discussion. Odds ratios and the number needed to treat were estimated. Continuous data collected by a measuring instrument was only included if the instrument (i) had been described in a peer-reviewed journal; (ii) was a self-report or had been completed by an independent rater; and (iii) provided a summary score for a broad area of functioning. Normally distributed continuous data were included if means and standard deviations were available. Non-normal data were included if analysed either after transformation or using non-parametric methods. Tests for heterogeneity were conducted. Case management increased the numbers remaining in contact with services (for case management odds ratio = 0.70; 99%CI 0.50-0. 98; n=1210). Case management approximately doubled the numbers admitted to psychiatric hospital (OR 1.84; 99% CI 1.33-2.57; n=1300). Except for a positive finding on compliance, from one study, case management showed no significant advantages over standard care on any psychiatric or social variable. Cost data did not favour case management but insufficient information was available to permit definitive conclusions. Case management ensures that more people remain in contact with psychiatric services (one extra person remains in contact for every 15 people who receive case management), but it also increases hospital admission rates. Present evidence suggests that case management also increases duration of hospital admissions, but this is not certain. Whilst there is some evidence that case management improves compliance, it does not produce clinically significant improvement in mental state, social functioning, or quality of life. There is no evidence that case management improves outcome on any other clinical or social variables. Present evidence suggests that case management increases health care costs, perhaps substantially, although this is not certain. In summary, therefore, case management is an intervention of questionable value, to the extent that it is doubtful whether it should be offered by community psychiatric services. It is hard to see how policy makers who subscribe to an evidence-based approach can justify retaining case management as 'the cornerstone' of community mental hea


Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module.
The molecular determinants of spleen organogenesis and the etiology of isolated congenital asplenia (ICA), a life-threatening human condition, are unknown. We previously reported that Pbx1 deficiency causes organ growth defects including asplenia. Here, we show that mice with splenic mesenchyme-specific Pbx1 inactivation exhibit hyposplenia. Moreover, the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors, perturbing the cell cycle. Removal of p15Ink4b in Pbx1 spleen-specific mutants partially rescues spleen growth. By whole-exome sequencing of a multiplex kindred with ICA, we identify a heterozygous missense mutation (P236H) in NKX2-5 showing reduced transactivation in vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.


Mapping your competitive position.
A price-benefit positioning map helps you see, through your customers' eyes, how your product compares with all its competitors in a market. You can draw such a map quickly and objectively, without having to resort to costly, time-consuming consumer surveys or subjective estimates of the excellence of your product and the shortcomings of all the others. Creating a positioning map involves three steps: First, define your market to include everything your customers might consider to be your product's competitors or substitutes. Second, track the price your customers actually pay (wholesale or retail? bundled or unbundled?) and identify what your customers see as your offering's primary benefit. This is done through regression analysis, determining which of the product's attributes (as described objectively by rating services, government agencies, R&D departments, and the like) explains most of the variance in its price. Third, draw the map by plotting on a graph the position of every product in the market you've selected according to its price and its level of primary benefit, and draw a line that runs through the middle of the points. What you get is a picture of the competitive landscape of your market, where all the products above the line command a price premium owing to some secondary benefit customers value, and all those below the line are positioned to earn market share through lower prices and reduced secondary benefits. Using examples as varied as Harley-Davidson motorcycles, Motorola cell phones, and the New York restaurant market, Tuck professor D'Aveni demonstrates some of the many ways the maps can be used: to locate unoccupied or less-crowded spaces in highly competitive markets, for instance, or to identify opportunities created through changes in the relationship between the primary benefit and prices. The maps even allow companies to anticipate--and counter-- rivals' strategies. R eprint RO711G


MicroRNA regulation of cell lineages in mouse and human embryonic stem cells.
Cell fate decisions of pluripotent embryonic stem (ES) cells are dictated by activation and repression of lineage-specific genes. Numerous signaling and transcriptional networks progressively narrow and specify the potential of ES cells. Whether specific microRNAs help refine and limit gene expression and, thereby, could be used to manipulate ES cell differentiation has largely been unexplored. Here, we show that two serum response factor (SRF)-dependent muscle-specific microRNAs, miR-1 and miR-133, promote mesoderm formation from ES cells but have opposing functions during further differentiation into cardiac muscle progenitors. Furthermore, miR-1 and miR-133 were potent repressors of nonmuscle gene expression and cell fate during mouse and human ES cell differentiation. miR-1's effects were in part mediated by translational repression of the Notch ligand Delta-like 1 (Dll-1). Our findings indicate that muscle-specific miRNAs reinforce the silencing of nonmuscle genes during cell lineage commitment and suggest that miRNAs may have general utility in regulating cell-fate decisions from pluripotent ES cells.


1H magnetic resonance spectroscopy reveals neuronal injury in a simian immunodeficiency virus macaque model.
Infection with human immunodeficiency virus (HIV) commonly results in neurologic disease called the AIDS dementia complex. Neuronal loss and injury have been found in the HIV brain, but the underlying mechanisms are not understood. The simian immunodeficiency virus (SIV)-infected macaque is an excellent animal model for HIV infection, but neuronal loss has not been demonstrated. To determine whether neuronal damage occurs in the SIV brain, we quantified the neuronal marker N-acetylaspartate (NAA) using proton magnetic resonance spectroscopy (1H-MRS) in brain extracts of control and SIV-infected macaques and correlated these findings with histologic analyses. We found reduced NAA in the SIV-infected animals compared with controls (2.94 +/- 1.37 versus 6.21 +/- 1.73 micromol/g of wet weight; p = 0.004). A significant decrease in NAA was also found in SIV-infected animals sacrificed in the acute stages of infection 9 or 10 days after inoculation with SIVmacYnef. We conclude that SIV infection of rhesus macaques results in neuronal damage that is demonstrable shortly after infection and that 1H-MRS may be used to measure such injury. The results further support the SIV macaque as a useful model to study the mechanisms of neuropathogenesis by HIV.


The evidence base of sleep restriction therapy for treating insomnia disorder.
Sleep restriction therapy is routinely used within cognitive behavioral therapy to treat chronic insomnia. However, the efficacy for sleep restriction therapy as a standalone intervention has yet to be comprehensively reviewed. This review evaluates the evidence for the use of sleep restriction therapy in the treatment of chronic insomnia. The literature was searched using web-based databases, finding 1344 studies. Twenty-one were accessed in full (1323 were deemed irrelevant to this review). Nine were considered relevant and evaluated in relation to study design using a standardized study checklist and levels of evidence. Four trials met adequate methodological strength to examine the efficacy of therapy for chronic insomnia. Weighted effect sizes for self-reported sleep diary measures of sleep onset latency, wake time after sleep onset, and sleep efficiency were moderate-to-large after therapy. Total sleep time indicated a small improvement. Standalone sleep restriction therapy is efficacious for the treatment of chronic insomnia for sleep diary continuity variables. Studies are insufficient to evaluate the full impact on objective sleep variables. Measures of daytime functioning in response to therapy are lacking. Variability in the sleep restriction therapy implementation methods precludes any strong conclusions regarding the true impact of therapy. A future research agenda is outlined.


N-terminus of hMLH1 confers interaction of hMutLalpha and hMutLbeta with hMutSalpha.
Mismatch repair is a highly conserved system that ensures replication fidelity by repairing mispairs after DNA synthesis. In humans, the two protein heterodimers hMutSalpha (hMSH2-hMSH6) and hMutLalpha (hMLH1-hPMS2) constitute the centre of the repair reaction. After recognising a DNA replication error, hMutSalpha recruits hMutLalpha, which then is thought to transduce the repair signal to the excision machinery. We have expressed an ATPase mutant of hMutLalpha as well as its individual subunits hMLH1 and hPMS2 and fragments of hMLH1, followed by examination of their interaction properties with hMutSalpha using a novel interaction assay. We show that, although the interaction requires ATP, hMutLalpha does not need to hydrolyse this nucleotide to join hMutSalpha on DNA, suggesting that ATP hydrolysis by hMutLalpha happens downstream of complex formation. The analysis of the individual subunits of hMutLalpha demonstrated that the hMutSalpha-hMutLalpha interaction is predominantly conferred by hMLH1. Further experiments revealed that only the N-terminus of hMLH1 confers this interaction. In contrast, only the C-terminus stabilised and co-immunoprecipitated hPMS2 when both proteins were co-expressed in 293T cells, indicating that dimerisation and stabilisation are mediated by the C-terminal part of hMLH1. We also examined another human homologue of bacterial MutL, hMutLbeta (hMLH1-hPMS1). We show that hMutLbeta interacts as efficiently with hMutSalpha as hMutLalpha, and that it predominantly binds to hMutSalpha via hMLH1 as well.


The role of magnesium deficiency in cardiovascular and intestinal inflammation.
Hypomagnesemia continues to cause difficult clinical problems, such as significant cardiac arrhythmias where intravenous magnesium therapy can be lifesaving. Nutritional deficiency of magnesium may present with some subtle symptoms such as leg cramps and occasional palpitation. We have investigated dietary-induced magnesium deficiency in rodent models to assess the pathobiology associated with prolonged hypomagnesemia. We found that neuronal sources of the neuropeptide, substance P (SP), contributed to very early prooxidant/proinflammatory changes during Mg deficiency. This neurogenic inflammation is systemic in nature, affecting blood cells, cardiovascular, intestinal, and other tissues, leading to impaired cardiac contractility similar to that seen in patients with heart failure. We have used drugs that block the release of SP from neurons and SP-receptor blockers to prevent some of these pathobiological changes; whereas, blocking SP catabolism enhances inflammation. Our findings emphasize the essential role of this cation in preventing cardiomyopathic changes and intestinal inflammation in a well-studied animal model, and also implicate the need for more appreciation of the potential clinical relevance of optimal magnesium nutrition and therapy.


What aligns liquid crystals on solid substrates? The role of surface roughness anisotropy.
The mechanism responsible for liquid crystal (LC) alignment on mechanically buffed or UV exposed polymer films is poorly understood. A comprehensive study of LC alignment on variously prepared substrates unequivocally shows that the anisotropy in the surface roughness of the substrate completely determines the direction of LC alignment. In all the cases studied, including those where an anchoring transition occurs with temperature, the LC director (re)aligns in the directions of low roughness.


Prognostic value of immune cell infiltration, tertiary lymphoid structures and PD-L1 expression in Merkel cell carcinomas.
Merkel cell carcinoma (MCC) is an aggressive, virus-associated, neuroendocrine tumor of the skin mainly affecting immunocompromised patients. Higher intratumoral infiltration with CD3 and CD8 positive T-cells is associated with a better prognosis, highlighting the relevance of the immune system for MCC development and progression. In this study 21 primary MCCs were stained with immune cell markers including CD3, CD4, CD8, CD68, CD20, and S100. Furthermore, tumor-infiltrating neutrophils, tertiary lymphoid structures and PD-L1 expression were analyzed and correlated with overall and recurrence free survival. All MCCs were Merkel Cell Polyomavirus positive. Overall and recurrence-free survival did not correlate with intra- and peritumoral CD3 and CD8 T-cell infiltration. In addition, no significant association regarding prognosis was found for tumor-associated neutrophils, tumor-associated macrophages or PD-L1 positivity in MCCs. Interestingly, the presence of tertiary lymphoid structures (TLS) in the tumor microenvironment significantly correlated with recurrence-free survival (P=0.025). In addition, TLS were significantly associated with a higher CD8/CD4 ratio in the tumor periphery (P=0.032), but not in the center of the tumor (P > 0.999). These results demonstrate for the first time that TLS, easily assessed in paraffin-embedded tissue in the tumor periphery of MCCs, may be a valuable prognostic factor indicating prolonged recurrence free survival.


Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging.
A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial. We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism. NCT0061015.


Automated video-based assessment of surgical skills for training and evaluation in medical schools.
Routine evaluation of basic surgical skills in medical schools requires considerable time and effort from supervising faculty. For each surgical trainee, a supervisor has to observe the trainees in person. Alternatively, supervisors may use training videos, which reduces some of the logistical overhead. All these approaches however are still incredibly time consuming and involve human bias. In this paper, we present an automated system for surgical skills assessment by analyzing video data of surgical activities. We compare different techniques for video-based surgical skill evaluation. We use techniques that capture the motion information at a coarser granularity using symbols or words, extract motion dynamics using textural patterns in a frame kernel matrix, and analyze fine-grained motion information using frequency analysis. We were successfully able to classify surgeons into different skill levels with high accuracy. Our results indicate that fine-grained analysis of motion dynamics via frequency analysis is most effective in capturing the skill relevant information in surgical videos. Our evaluations show that frequency features perform better than motion texture features, which in-turn perform better than symbol-/word-based features. Put succinctly, skill classification accuracy is positively correlated with motion granularity as demonstrated by our results on two challenging video datasets.


Gastroschisis: one year outcomes from national cohort study.
To describe one year outcomes for a national cohort of infants with gastroschisis. Population based cohort study of all liveborn infants with gastroschisis born in the United Kingdom and Ireland from October 2006 to March 2008. All 28 paediatric surgical centres in the UK and Ireland. 301 infants (77%) from an original cohort of 393. Duration of parenteral nutrition and stay in hospital; time to establish full enteral feeding; rates of intestinal failure, liver disease associated with intestinal failure, unplanned reoperation; case fatality. Compared with infants with simple gastroschisis (intact, uncompromised, continuous bowel), those with complex gastroschisis (bowel perforation, necrosis, or atresia) took longer to reach full enteral feeding (median difference 21 days, 95% confidence interval 9 to 39 days); required a longer duration of parenteral nutrition (median difference 25 days, 9 to 46 days) and a longer stay in hospital (median difference 57 days, 29 to 95 days); were more likely to develop intestinal failure (81% (25 infants) v 41% (102); relative risk 1.96, 1.56 to 2.46) and liver disease associated with intestinal failure (23% (7) v 4% (11); 5.13, 2.15 to 12.3); and were more likely to require unplanned reoperation (42% (13) v 10% (24); 4.39, 2.50 to 7.70). Compared with infants managed with primary fascial closure, those managed with preformed silos took longer to reach full enteral feeding (median difference 5 days, 1 to 9) and had an increased risk of intestinal failure (52% (50) v 32% (38); 1.61, 1.17 to 2.24). Event rates for the other outcomes were low, and there were no other significant differences between these management groups. Twelve infants died (4%). This nationally representative study provides a benchmark against which individual centres can measure outcome and performance. Stratifying neonates with gastroschisis into simple and complex groups reliably predicts outcome at one year. There is sufficient clinical equipoise concerning the initial management strategy to embark on a multicentre randomised controlled trial comparing primary fascial closure with preformed silos in infants suitable at presentation for either treatment to determine the optimal initial management strategy and define algorithms of care.


Patient-derived malignant pleural mesothelioma cell cultures: a tool to advance biomarker-driven treatments.
Malignant pleural mesothelioma (MPM) is an aggressive cancer, associated with poor prognosis. We assessed the feasibility of patient-derived cell cultures to serve as an ex vivo model of MPM. Patient-derived MPM cell cultures (n=16) exhibited stemness features and reflected intratumour and interpatient heterogeneity. A subset of the cells were subjected to high-throughput drug screening and coculture assays with cancer-specific cytotoxic T cells and showed diverse responses. Some of the biphasic MPM cells were capable of processing and presenting the neoantigen SSX-2 endogenously. In conclusion, patient-derived MPM cell cultures are a promising and faithful ex vivo model of MPM.


Human stiff-person syndrome IgG induces anxious behavior in rats.
Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.


A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint.
DNA damage checkpoints arrest cell cycle progression to facilitate DNA repair. The ability to survive genotoxic insults depends not only on the initiation of cell cycle checkpoints but also on checkpoint maintenance. While activation of DNA damage checkpoints has been studied extensively, molecular mechanisms involved in sustaining and ultimately inactivating cell cycle checkpoints are largely unknown. Here, we explored feedback mechanisms that control the maintenance and termination of checkpoint function by computationally identifying an evolutionary conserved mitotic phosphorylation network within the DNA damage response. We demonstrate that the non-enzymatic checkpoint adaptor protein 53BP1 is an in vivo target of the cell cycle kinases Cyclin-dependent kinase-1 and Polo-like kinase-1 (Plk1). We show that Plk1 binds 53BP1 during mitosis and that this interaction is required for proper inactivation of the DNA damage checkpoint. 53BP1 mutants that are unable to bind Plk1 fail to restart the cell cycle after ionizing radiation-mediated cell cycle arrest. Importantly, we show that Plk1 also phosphorylates the 53BP1-binding checkpoint kinase Chk2 to inactivate its FHA domain and inhibit its kinase activity in mammalian cells. Thus, a mitotic kinase-mediated negative feedback loop regulates the ATM-Chk2 branch of the DNA damage signaling network by phosphorylating conserved sites in 53BP1 and Chk2 to inactivate checkpoint signaling and control checkpoint duration.


Maxillofacial injuries caused by terrorist bomb attack in Nairobi, Kenya.
Although military conflicts are common on the African continent, there is a paucity of data regarding bomb-blast injuries in this region and in Kenya in particular. This paper describes the pattern of maxillofacial injuries sustained after the August 1998 bomb blast that occurred in Nairobi, Kenya. A retrospective cross-sectional study was carried out using hospital-based records of 290 bomb-blast survivors admitted at the Kenyatta National Referral and Teaching Hospital in Nairobi. Using a self-designed form to record information about variables such as the sex and age of the survivors and type of location of soft- and hard-tissue injuries, it was found that of the 290 bomb-blast survivors, 78% had sustained one or more maxillofacial injuries. Soft-tissue injuries (cuts, lacerations or bruises) were the most common, constituting 61.3% of all injuries in the maxillofacial region; 27.6% had severe eye injuries, while 1.4% had fractures in the cranio-facial region. This paper concludes that the effective management of bomb-blast injuries as well as those caused by other types of disaster requires a multidisciplinary approach. The high percentage of maxillofacial injuries confirm that maxillofacial surgeons should form an integral part of this multidisciplinary team.


Neuroanatomical correlates of externally and internally generated human emotion.
Positron emission tomography was used to investigate the neural substrates of normal human emotional and their dependence on the types of emotional stimulus. Twelve healthy female subjects underwent 12 measurements of regional brain activity following the intravenous bolus administration of [15O]H2O as they alternated between emotion-generating and control film and recall tasks. Automated image analysis techniques were used to characterize and compare the increases in regional brain activity associated with the emotional response to complex visual (film) and cognitive (recall) stimuli. Film- and recall-generated emotion were each associated with significantly increased activity in the vicinity of the medial prefrontal cortex and thalamus, suggesting that these regions participate in aspects of emotion that do not depend on the nature of the emotional stimulus. Film-generated emotion was associated with significantly greater increases in activity bilaterally in the occipitotemporparietal cortex, lateral cerebellum, hypothalamus, and a region that includes the anterior temporal cortex, amygdala, and hippocampal formation, suggesting that these regions participate in the emotional response to certain exteroceptive sensory stimuli. Recall-generated sadness was associated with significantly greater increases in activity in the vicinity of the anterior insular cortex, suggesting that this region participates in the emotional response to potentially distressing cognitive or interoceptive sensory stimuli. While this study should be considered preliminary, it identified brain regions that participate in externally and internally generated human emotion.


Impact of aging mechanism on model simulated carbonaceous aerosols.
Carbonaceous aerosols including organic carbon and black carbon have significant implications for both climate and air quality. In the current global climate or chemical transport models, a fixed hydrophobic-to-hydrophilic conversion lifetime for carbonaceous aerosol (τ) is generally assumed, which is usually around one day. We have implemented a new detailed aging scheme for carbonaceous aerosols in a chemical transport model (GEOS-Chem) to account for both the chemical oxidation and the physical condensation-coagulation effects, where τ is affected by local atmospheric environment including atmospheric concentrations of water vapor, ozone, hydroxyl radical and sulfuric acid. The updated τ exhibits large spatial and temporal variations with the global average (up to 11 km altitude) calculated to be 2.6 days. The chemical aging effects are found to be strongest over the tropical regions driven by the low ozone concentrations and high humidity there. The τ resulted from chemical aging generally decreases with altitude due to increases in ozone concentration and decreases in humidity. The condensation-coagulation effects are found to be most important for the high-latitude areas, in particular the polar regions, where the τ values are calculated to be up to 15 days. When both the chemical aging and condensation-coagulation effects are considered, the total atmospheric burdens and global average lifetimes of BC, black carbon, (OC, organic carbon) are calculated to increase by 9% (3%) compared to the control simulation, with considerable enhancements of BC and OC concentrations in the Southern Hemisphere. Model evaluations against data from multiple datasets show that the updated aging scheme improves model simulations of carbonaceous aerosols for some regions, especially for the remote areas in the Northern Hemisphere. The improvement helps explain the persistent low model bias for carbonaceous aerosols in the Northern Hemisphere reported in literature. Further model sensitivity simulations focusing on the continental outflow of carbonaceous aerosols demonstrate that previous studies using the old aging scheme could have significantly underestimated the intercontinental transport of carbonaceous aerosols.


Patterns of Y-chromosome diversity intersect with the Trans-New Guinea hypothesis.
The island of New Guinea received part of the first human expansion out of Africa (>40,000 years ago), but its human genetic history remains poorly understood. In this study, we examined Y-chromosome diversity in 162 samples from the Bird's Head region of northwest New Guinea (NWNG) and compared the results with previously obtained data from other parts of the island. NWNG harbors a high level of cultural and linguistic diversity and is inhabited by non-Austronesian (i.e., Papuan)-speaking groups as well as harboring most of West New Guinea's (WNG) Austronesian-speaking groups. However, 97.5% of its Y-chromosomes belong to 5 haplogroups that originated in Melanesia; hence, the Y-chromosome diversity of NWNG (and, according to available data, of New Guinea as a whole) essentially reflects a local history. The remaining 2.5% belong to 2 haplogroups (O-M119 and O-M122) of East Asian origin, which were brought to New Guinea by Austronesian-speaking migrants around 3,500 years ago. Thus, the Austronesian expansion had only a small impact on shaping Y-chromosome diversity in NWNG, although the linguistic impact of this expansion to this region was much higher. In contrast, the expansion of Trans-New Guinea (TNG) speakers (non-Austronesian) starting about 6,000-10,000 years ago from the central highlands of what is now Papua New Guinea, presumably in combination with the expansion of agriculture, played a more important role in determining the Y-chromosome diversity of New Guinea. In particular, we identified 2 haplogroups (M-P34 and K-M254) as suggestive markers for the TNG expansion, whereas 2 other haplogroups (C-M38 and K-M9) most likely reflect the earlier local Y-chromosome diversity. We propose that sex-biased differences in the social structure and cultural heritage of the people involved in the Austronesian and the TNG expansions played an important role (among other factors) in shaping the New Guinean Y-chromosome landscape.


Joint modelling of diffusion MRI and microscopy.
The combination of diffusion MRI (dMRI) with microscopy provides unique opportunities to study microstructural features of tissue, particularly when acquired in the same sample. Microscopy is frequently used to validate dMRI microstructure models, addressing the indirect nature of dMRI signals. Typically, these modalities are analysed separately, and microscopy is taken as a gold standard against which dMRI-derived parameters are validated. Here we propose an alternative approach in which we combine dMRI and microscopy data obtained from the same tissue sample to drive a single, joint model. This simultaneous analysis allows us to take advantage of the breadth of information provided by complementary data acquired from different modalities. By applying this framework to a spherical-deconvolution analysis, we are able to overcome a known degeneracy between fibre dispersion and radial diffusion. Spherical-deconvolution based approaches typically estimate a global fibre response function to determine the fibre orientation distribution in each voxel. However, the assumption of a 'brain-wide' fibre response function may be challenged if the diffusion characteristics of white matter vary across the brain. Using a generative joint dMRI-histology model, we demonstrate that the fibre response function is dependent on local anatomy, and that current spherical-deconvolution based models may be overestimating dispersion and underestimating the number of distinct fibre populations per voxel.


Immune-enhancing role of vitamin C and zinc and effect on clinical conditions.
Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress. Supplementation of vitamin C was found to improve components of the human immune system such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis, and delayed-type hypersensitivity. Vitamin C contributes to maintaining the redox integrity of cells and thereby protects them against reactive oxygen species generated during the respiratory burst and in the inflammatory response. Likewise, zinc undernutrition or deficiency was shown to impair cellular mediators of innate immunity such as phagocytosis, natural killer cell activity, and the generation of oxidative burst. Therefore, both nutrients play important roles in immune function and the modulation of host resistance to infectious agents, reducing the risk, severity, and duration of infectious diseases. This is of special importance in populations in which insufficient intake of these nutrients is prevalent. In the developing world, this is the case in low- and middle-income countries, but also in subpopulations in industrialized countries, e.g. in the elderly. A large number of randomized controlled intervention trials with intakes of up to 1 g of vitamin C and up to 30 mg of zinc are available. These trials document that adequate intakes of vitamin C and zinc ameliorate symptoms and shorten the duration of respiratory tract infections including the common cold. Furthermore, vitamin C and zinc reduce the incidence and improve the outcome of pneumonia, malaria, and diarrhea infections, especially in children in developing countries.


Population response to habitat fragmentation in a stream-dwelling brook trout population.
Fragmentation can strongly influence population persistence and expression of life-history strategies in spatially-structured populations. In this study, we directly estimated size-specific dispersal, growth, and survival of stream-dwelling brook trout in a stream network with connected and naturally-isolated tributaries. We used multiple-generation, individual-based data to develop and parameterize a size-class and location-based population projection model, allowing us to test effects of fragmentation on population dynamics at local (i.e., subpopulation) and system-wide (i.e., metapopulation) scales, and to identify demographic rates which influence the persistence of isolated and fragmented populations. In the naturally-isolated tributary, persistence was associated with higher early juvenile survival ( approximately 45% greater), shorter generation time (one-half) and strong selection against large body size compared to the open system, resulting in a stage-distribution skewed towards younger, smaller fish. Simulating barriers to upstream migration into two currently-connected tributary populations caused rapid (2-6 generations) local extinction. These local extinctions in turn increased the likelihood of system-wide extinction, as tributaries could no longer function as population sources. Extinction could be prevented in the open system if sufficient immigrants from downstream areas were available, but the influx of individuals necessary to counteract fragmentation effects was high (7-46% of the total population annually). In the absence of sufficient immigration, a demographic change (higher early survival characteristic of the isolated tributary) was also sufficient to rescue the population from fragmentation, suggesting that the observed differences in size distributions between the naturally-isolated and open system may reflect an evolutionary response to isolation. Combined with strong genetic divergence between the isolated tributary and open system, these results suggest that local adaptation can 'rescue' isolated populations, particularly in one-dimensional stream networks where both natural and anthropogenically-mediated isolation is common. However, whether rescue will occur before extinction depends critically on the race between adaptation and reduced survival in response to fragmentation.


Semi-blind spectral deconvolution with adaptive Tikhonov regularization.
Deconvolution has become one of the most used methods for improving spectral resolution. Deconvolution is an ill-posed problem, especially when the point spread function (PSF) is unknown. Non-blind deconvolution methods use a predefined PSF, but in practice the PSF is not known exactly. Blind deconvolution methods estimate the PSF and spectrum simultaneously from the observed spectra, which become even more difficult in the presence of strong noise. In this paper, we present a semi-blind deconvolution method to improve the spectral resolution that does not assume a known PSF but models it as a parametric function in combination with the a priori knowledge about the characteristics of the instrumental response. First, we construct the energy functional, including Tikhonov regularization terms for both the spectrum and the parametric PSF. Moreover, an adaptive weighting term is devised in terms of the magnitude of the first derivative of spectral data to adjust the Tikhonov regularization for the spectrum. Then we minimize the energy functional to obtain the spectrum and the parameters of the PSF. We also discuss how to select the regularization parameters. Comparative results with other deconvolution methods on simulated degraded spectra, as well as on experimental infrared spectra, are presented.


Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel.
Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.


Reporting of participant flow diagrams in published reports of randomized trials.
Reporting of the flow of participants through each stage of a randomized trial is essential to assess the generalisability and validity of its results. We assessed the type and completeness of information reported in CONSORT (Consolidated Standards of Reporting Trials) flow diagrams published in current reports of randomized trials. A cross sectional review of all primary reports of randomized trials which included a CONSORT flow diagram indexed in PubMed core clinical journals (2009). We assessed the proportion of parallel group trial publications reporting specific items recommended by CONSORT for inclusion in a flow diagram. Of 469 primary reports of randomized trials, 263 (56%) included a CONSORT flow diagram of which 89% (237/263) were published in a CONSORT endorsing journal. Reports published in CONSORT endorsing journals were more likely to include a flow diagram (62%; 237/380 versus 29%; 26/89). Ninety percent (236/263) of reports which included a flow diagram had a parallel group design, of which 49% (116/236) evaluated drug interventions, 58% (137/236) were multicentre, and 79% (187/236) compared two study groups, with a median sample size of 213 participants. Eighty-one percent (191/236) reported the overall number of participants assessed for eligibility, 71% (168/236) the number excluded prior to randomization and 98% (231/236) the overall number randomized. Reasons for exclusion prior to randomization were more poorly reported. Ninety-four percent (223/236) reported the number of participants allocated to each arm of the trial. However, only 40% (95/236) reported the number who actually received the allocated intervention, 67% (158/236) the number lost to follow up in each arm of the trial, 61% (145/236) whether participants discontinued the intervention during the trial and 54% (128/236) the number included in the main analysis. Over half of published reports of randomized trials included a diagram showing the flow of participants through the trial. However, information was often missing from published flow diagrams, even in articles published in CONSORT endorsing journals. If important information is not reported it can be difficult and sometimes impossible to know if the conclusions of that trial are justified by the data presented.


Systemic cytokine response after major surgery.
The systemic cytokine response to major surgical trauma was studied in 20 patients undergoing elective aortic surgery and five patients after inguinal hernia repair. Tumour necrosis factor alpha and interferon gamma were not detected in these patients. An early and short-lived interleukin 1 beta (IL-1 beta) response to major surgery was detected only by intensive sampling in the perioperative period. The IL-1 beta peak preceded a more marked interleukin 6 (IL-6) response that peaked 4-48 h after surgery. IL-6 levels had fallen sharply by 48-72 h in all patients who had an uneventful postoperative course. The IL-6 peaks were significantly lower after hernia surgery than after major aortic operations (P < 0.001); IL-1 beta was not detected in any samples. Three patients undergoing aortic surgery developed unexpected major postoperative complications. IL-6 levels in this group were significantly higher than those of the other patients undergoing aortic surgery within 6-8 h of skin incision, and remained elevated for longer. These rises in plasma IL-6 levels preceded the clinical onset of major complications by 12-48 h. The systemic IL-1 beta and IL-6 response to surgical trauma increased with the severity of the surgical insult. An early, exaggerated IL-6 response was associated with the subsequent clinical development of major complications.


Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy.
Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN. Focusing on DRG neurons expressing the sodium channel Nav1.8, we applied transgenic, electrophysiological, imaging, and chemogenetic techniques to test this hypothesis. In the high-fat diet mouse model of PDN, we were able to prevent and reverse mechanical allodynia and small-fiber degeneration by limiting CXCR4 signaling or neuronal excitability. This study reveals that excitatory CXCR4/CXCL12 signaling in Nav1.8-positive DRG neurons plays a critical role in the pathogenesis of mechanical allodynia and small-fiber degeneration in a mouse model of PDN. Hence, we propose that targeting CXCR4-mediated DRG nociceptor hyperexcitability is a promising therapeutic approach for disease-modifying treatments for this currently intractable and widespread affliction.


MIND: modality independent neighbourhood descriptor for multi-modal deformable registration.
Deformable registration of images obtained from different modalities remains a challenging task in medical image analysis. This paper addresses this important problem and proposes a modality independent neighbourhood descriptor (MIND) for both linear and deformable multi-modal registration. Based on the similarity of small image patches within one image, it aims to extract the distinctive structure in a local neighbourhood, which is preserved across modalities. The descriptor is based on the concept of image self-similarity, which has been introduced for non-local means filtering for image denoising. It is able to distinguish between different types of features such as corners, edges and homogeneously textured regions. MIND is robust to the most considerable differences between modalities: non-functional intensity relations, image noise and non-uniform bias fields. The multi-dimensional descriptor can be efficiently computed in a dense fashion across the whole image and provides point-wise local similarity across modalities based on the absolute or squared difference between descriptors, making it applicable for a wide range of transformation models and optimisation algorithms. We use the sum of squared differences of the MIND representations of the images as a similarity metric within a symmetric non-parametric Gauss-Newton registration framework. In principle, MIND would be applicable to the registration of arbitrary modalities. In this work, we apply and validate it for the registration of clinical 3D thoracic CT scans between inhale and exhale as well as the alignment of 3D CT and MRI scans. Experimental results show the advantages of MIND over state-of-the-art techniques such as conditional mutual information and entropy images, with respect to clinically annotated landmark locations.


Association between two polymorphisms in the SRD5A2 gene and serum androgen concentrations in British men.
Androgens are essential for the growth of the prostate gland and have been implicated in the development of prostate cancer. Little is known about the determinants of androgen levels in men, although observed ethnic differences suggest they may have a genetic basis. Several polymorphisms have been identified in the steroid 5 alpha-reductase type II gene (SRD5A2), which encodes an enzyme that catalyzes the conversion of testosterone to its more potent metabolite, dihydrotestosterone. Although some of these polymorphisms have been associated with increased prostate cancer risk, the association with circulating androgen levels remains unclear. The purpose of this study is to investigate the association between the (TA)(n) dinucleotide repeat polymorphism in the 3' untranslated region and the A49T polymorphism (which replaces the normal alanine with threonine at codon 49) in the SRD5A2 gene and serum androgen concentrations in 604 British men. In particular, we wanted to test the hypotheses that the variant alleles are associated with an increased serum concentration of androstanediol glucuronide, a direct metabolite of dihydrotestosterone and a serum marker of 5 alpha-reductase activity. Mean hormone concentrations were evaluated in each genotype, and adjusted for age and other relevant factors. We found no evidence that the SRD5A2 (TA)(n) repeat polymorphism was associated with androgen levels. Men who possessed one or two copies of the variant T allele in the A49T polymorphism had a significantly 24% lower androstanediol glucuronide concentration than men who were homozygous for the wild-type allele (P = 0.0003). Because of the rarity of this variant allele, larger studies are needed to additionally clarify the role of the A49T polymorphism in androgen metabolism.


Proximal and distal movement patterns during a graphomotor task in typically developing children and children with handwriting problems.
Therapists specializing in handwriting difficulties in children often address motor problems including both proximal and distal movements in the upper extremity. Kinematic measures can be used to investigate various aspects of handwriting. This study examined differences in movement patterns in proximal and distal joints of the upper extremity during graphomotor tasks between typically developing children with and without handwriting problems. Additionally, it explored relationships between movement patterns, speed, and legibility of writing. Forty-one children, aged 7-11 years, were assessed with the Aleph Aleph Ktav Yad Hebrew Handwriting assessment and the Beery Test of Visual Motor Integration and, based on their scores, were divided into a research group (with handwriting difficulties) and a control group (without handwriting difficulties). Upper extremity joint movement patterns were analyzed with a motion capture system. Differences in the quality of shapes traced and copied on a graphics tablet positioned horizontally and vertically were compared. Between-group differences and relationships with speed and legibility were analyzed. In both groups, there was greater movement in the distal compared to the proximal joints, greater movement when performing the task in a horizontal compared to a vertical plane, and greater movement when tracing than copying. Joint movements in the arm executed scaled-down versions of the shapes being drawn. While the amount of joint displacement was similar between groups, children in the research group showed greater dissimilarity between the drawn shape and the shape produced by the proximal joints. Finally, the drawing measure on the tablet was a significant predictor of legibility, speed of writing, visual motor integration and motor coordination, whereas the dissimilarity measure of joint movement was a significant predictor of speed of writing and motor coordination. This study provides support for the role of the distal upper extremity joints in the writing process and some guidance to assist clinicians in devising treatment strategies for movement-related handwriting problems. While we observed differences in proximal joint movements between the children with and without handwriting difficulties, the extent to which they are responsible for the differences in drawing quality remains to be determined. Further studies should use a similar methodology to examine additional tasks such as drawing shapes of varying sizes.


Cytoplasmic pH regulation and chloride/bicarbonate exchange in avian osteoclasts.
Osteoclasts resorb bone by first attaching to the bone surface and then secreting protons into an isolated extracellular compartment formed at the cell-bone attachment site. This secretion of protons (local acidification) is required to solubilize bone hydroxyapatite crystals and for activity of bone collagen-degrading acid proteases. However, the large quantity of protons required, 2 mol/mol of calcium, would result in an equal accumulation of cytosolic base equivalents. This alkaline load must be corrected to maintain cytosolic pH within physiologic limits. In this study, we have measured cytoplasmic pH with pH-sensitive fluorescent compounds, while varying the extracellular ionic composition of the medium, to determine the nature of the compensatory mechanism used by osteoclasts during bone resorption. Our data show that osteoclasts possess a chloride/bicarbonate exchanger that enables them to maintain normal intracellular pH in the face of a significant proton efflux. This conclusion follows from the demonstration of a dramatic cytoplasmic acidification when osteoclasts that have been incubated in bicarbonate-containing medium are transferred into bicarbonate-free medium. This acidification is absolutely dependent on and proportional to medium [Cl-]. Furthermore, acidification is inhibited by the classic inhibitor of red cell anion exchange, 4,4'-diisothiocyanatostilbene-2,2'-disulfonate, and by diphenylamine-2-carboxylate, an inhibitor of chloride specific channels. However, the acidification process is neither energy nor sodium dependent. The physiologic importance of chloride/bicarbonate exchange is demonstrated by the chloride dependence of recovery from an endogenous or exogenous alkaline load in osteoclasts. We conclude that chloride/bicarbonate exchange is in large part responsible for cytoplasmic pH homeostasis of active osteoclasts, showing that these cells are similar to renal tubular epithelial cells in their regulation of intracellular pH.


Sympathetic nerve activity in stress-induced cardiomyopathy.
To evaluate directly recorded efferent sympathetic nerve traffic in patients with stress-induced cardiomyopathy (SIC). SIC is a syndrome affecting mostly postmenopausal women following severe emotional stress. Though the precise pathophysiology is not well understood, a catecholamine overstimulation of the myocardium is thought to underlie the pathogenesis. Direct recordings of multiunit efferent postganglionic muscle sympathetic nerve activity (MSNA) were obtained from 12 female patients, 5 in the acute (24-48 h) and 7 in the recovery phase (1-6 months), with apical ballooning pattern and 12 healthy matched controls. MSNA was expressed as burst frequency (BF), burst incidence (BI) and relative median burst amplitude (RMBA %). One of the twelve patients in this study was on beta blockade treatment due to a different illness, at time of onset of SIC. All patients were investigated with ongoing medication. MSNA was lower in patients with SIC as compared to matched controls, but did not differ between the acute and recovery phase of SIC. RMBA %, blood pressure and heart rate did not differ between the groups. MSNA is shown to be lower in patients with SIC compared to healthy controls, suggesting that sympathetic neuronal outflow is rapidly reduced following the initial phase of SIC. A distension of the ventricular myocardium, due to excessive catecholamine release over the heart in the acute phase, may increase the firing rate of unmyelinated cardiac c-fibre afferents resulting in widespread sympathetic inhibition. Such a mechanism may underlie the lower MSNA reported in our patients.


Recording with microchannel electrodes in a noisy environment.
Microchannels containing electrodes have a number of favourable properties that make them potentially suitable as the basis of a peripheral nerve interface design. In this study we have evaluated microchannel recording in vitro in the presence of a realistic simulation of electrical interference from musculature adjacent to an implanted interface. Tripolar recording and high-pass filtration both help improve signal discrimination. At high noise levels designed to replicate the effects of intense muscular activity, a combination of both these techniques is required, and only signals in larger axons can be recovered.


Importance of protected areas for biodiversity conservation in central Côte D'ivoire: comparison of termite assemblages between two neighboring areas under differing levels of disturbance.
To highlight human impact on biodiversity in the Lamto region, termites were studied with regard to their use as bio-indicators of habitat change in the tropics. Using a standardized method, termites were sampled in the three most common habitat types, i.e., in semi-deciduous forest, savanna woodland, and annually burned savanna, all inside Lamto Reserve and its surrounding rural domain. Termite species richness fell from 25 species in the Lamto forest to 13 species in the rural area, involving strong modification in the species composition (species turnover = 59 %). In contrast, no significant change in diversity was found between the Lamto savannas and the rural ones. In addition, the relative abundance of termites showed a significantly greater decline in the rural domain, even in the species Ancistrotermes cavithorax (Sjöstedt) (Isoptera: Termitidae), which is known to be ecologically especially versatile. Overall, the findings of this study suggest further investigation around Lamto Reserve on the impact of human activities on biodiversity, focusing on forest conversion to land uses (e.g. agricultural and silvicultural systems).


What is 'best practice' in health care? State of the art and perspectives in improving the effectiveness and efficiency of the European health care systems.
A framework for the classification of information on maintaining or improving effectiveness and efficiency in health care systems is proposed. Activities, disciplines and methods that are available to identify, implement and monitor the available evidence in health care are called 'best practice'. We reviewed the literature in order to (1) establish a definition for 'best practice' in the health sector, (2) develop a framework to classify relevant information, and (3) synthesise the literature on activities, disciplines and methods pertinent to the concept. Health care, public health activities and health policy should be advised by the best available evidence. Currently, the concept can be broken down into three activities (Health Technology Assessment (HTA), Evidence-Based Medicine (EBM), Clinical Practice Guidelines (CPGs)) by which evidence is synthesised either as an evidence base (EBM and most HTA) or in the form of recommendations (CPGs and some HTA) for different decision purposes in health care. These activities gain input mainly through four disciplines: clinical research, clinical epidemiology, health economics and health services research. The different disciplines are related to each other in three 'domains': (a) input, (b) dissemination/implementation and (c) monitoring/outcome. These provide evidence on (a) the (potential) effects of health care interventions and policies; (b) on ways to implement them; and (c) on ways to monitor their actual outcome. None of these separate approaches and activities exclusively forms a successful and all-embracing strategy to ascertain 'best practice'. A collective approach in the management of information is expected to add value to individual efforts. Resources should be devoted to increase quality and quantity of both primary and secondary research as well as the establishment of networks to synthesise, disseminate, implement and monitor 'best practice'.


From a conservative to a liberal welfare state: decomposing changes in income-related health inequalities in Germany, 1994-2011.
Individual socio-economic status and the respective socio-economic and political contexts are both important determinants of health. Welfare regimes may be linked with health and health inequalities through two potential pathways: first, they may influence the associations between socio-economic status and health. Second, they may influence the income-related distributions of socio-economic determinants of health within a society. Using the Socio-Economic Panel (SOEP) for the years 1994-2011, we analyze how income-related health inequalities evolved in the context of the transformation from a conservative to a liberal welfare system in Germany. We use the concentration index to measure health inequalities, and the annual concentration indices are decomposed to reveal how the contributions of the explanatory variables age, sex, income, education, and occupation changed over time. The changes in the contributions are further decomposed to distinguish whether changes in health inequalities stem from redistributions of the explanatory variables, from changes in their associations with health, or from changes in their means. Income-related health inequalities to the disadvantage of the economically deprived roughly doubled over time, which can largely be explained by changes in the contributions of individual characteristics representing weaker labor market positions, particularly income and unemployment. The social and labor market reforms coincide with the observed changes in the distributions of these characteristics and, to a lesser extent, with changes of their associations with health.


The first report of Gyrodactylus salaris Malmberg, 1957 (Platyhelminthes, Monogenea) on Italian cultured stocks of rainbow trout (Oncorhynchus mykiss Walbaum).
The monogenean Gyrodactylus salaris Malmberg, 1957 is considered one of the most important parasites of wild salmonids in the European Community due to the heavy ecological and economical damage it has inflicted on Atlantic salmon (Salmo salar) parr populations. Rainbow trout (Oncorhynchus mykiss) is susceptible to G. salaris and can act as a suitable carrier host and, consequently, its trade in EU territory is restricted in relation to the status of "recognized free" zones. Despite the economic importance of rainbow trout farming in Italy, information on the Italian gyrodactylid fauna is lacking and prior to this study, G. salaris had not been officially reported. During a routine health examination of farmed rainbow trout stock throughout Central and Northern Italy in 2004-2005, five fish farms were found to be infected with G. salaris alongside three other gyrodactylids. Morphological and molecular characterisation confirmed the presence of G. salaris, Gyrodactylus teuchis Lautraite, Blanc, Thiery, Daniel et Vigneulle, 1999 and Gyrodactylus derjavinoides Malmberg, Collins, Cunningham et Jalali, 2007, while Gyrodactylus truttae Gläser, 1974 was identified by morphological analysis only. The findings from this study extend the distribution of G. salaris within Europe and highlight the importance of the rainbow trout trade in its dissemination.


Structure of the regulatory domain of the LysR family regulator NMB2055 (MetR-like protein) from Neisseria meningitidis.
The crystal structure of the regulatory domain of NMB2055, a putative MetR regulator from Neisseria meningitidis, is reported at 2.5 Å resolution. The structure revealed that there is a disulfide bond inside the predicted effector-binding pocket of the regulatory domain. Mutation of the cysteines (Cys103 and Cys106) that form the disulfide bond to serines resulted in significant changes to the structure of the effector pocket. Taken together with the high degree of conservation of these cysteine residues within MetR-related transcription factors, it is suggested that the Cys103 and Cys106 residues play an important role in the function of MetR regulators.


Relations between drawing cubes and copying line diagrams of cubes in 7- to 10-year-old children.
Previous research has suggested both links and differences between children's copying of line diagrams and their drawings of solid objects. If the diagram represents a familiar object, children make more errors than when copying a diagram of a nonobject or unfamiliar object, as if they are drawing from their representation of the object rather than copying the surface features of the diagram. However, copying a diagram yields fewer and different types of errors than drawing the equivalent solid, which suggests a different process. In Experiment 1 (n = 72), possible relations between copying and drawing are investigated by asking children to draw a solid cube, then to copy or trace a line diagram of the cube in oblique projection, and finally to draw the solid again. Copying was better than drawing, and there was positive transfer to a subsequent drawing. Tracing was very accurate, but transfer to drawing did not occur, possibly because of the automatic nature of tracing. In Experiment 2 (n = 120) different groups received versions of the copying task that differed in the extent to which temporal order of line copying was structured. Asking children to copy the lines in a systematic order led to improved copies, but this performance did not carry over to a subsequent drawing of the solid. In contrast, when temporal ordering of line copying was not manipulated, there was positive transfer from copying to the subsequent drawing. In Experiment 3 (n = 80), provision of structure that emphasized faces by color-groupings of lines or coloring faces led to improved copies and did not hinder transfer to drawing the solid. Experiment 4 (n = 90) showed that in a solid drawing task emphasis on faces but not edges produced a positive effect, both on the immediate drawing and on a subsequent drawing of a plain cube. We conclude that emphasis on order of line copying improves performance in a copying task because in that case line-to-line matching is an important element of the skill, whereas this does not aid drawing of the solid object, in which the focus is primarily on representation of faces and their interrelations.


From market access to patient access: overview of evidence-based approaches for the reimbursement and pricing of pharmaceuticals in 36 European countries.
Coverage decisions determining the benefit baskets of health systems have been increasingly relying on evidence regarding patient benefit and costs. Relevant structures, methodologies, and processes have especially been established for pharmaceuticals but approaches differ. The objective of this work was thus to identify institutions in a broad range of European countries (n = 36) in charge of determining the value of pharmaceuticals for pricing and reimbursement purposes and to map their decision-making process; to examine the different approaches and consider national and supranational possibilities for best practice. Institutions were identified through websites of international networks, ministries, and published literature. Details on institutional practices were supplemented with information from institution websites and linked online sources. The type and extent of information available varied considerably across countries. Different types of public regulatory bodies are involved in pharmaceutical coverage decisions, assuming a range of responsibilities. As a rule, the assessment of scientific evidence is kept structurally separate from its appraisal. Recommendations on value are uniformly issued by specific committees within or commissioned by responsible institutions; these institutions often also act as decision-makers on reimbursement status and level or market price. While effectiveness and costs are important criteria in all countries, the latter are often considered on a case-by-case basis. In all countries, manufacturer applications, including relevant evidence, are used as one of the main sources of information for the assessment. Transparency of evidence-based coverage decisions should be enhanced. International collaboration can facilitate knowledge exchange, improve efficiency of information production, and strengthen new or developing systems.


Virotherapy of canine tumors with oncolytic vaccinia virus GLV-1h109 expressing an anti-VEGF single-chain antibody.
Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for cancer therapy. We have previously reported that oncolytic vaccinia virus strains expressing an anti-VEGF (Vascular Endothelial Growth Factor) single-chain antibody (scAb) GLAF-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. Here, we describe the use of oncolytic vaccinia virus GLV-1h109 encoding GLAF-1 for canine cancer therapy. In this study we analyzed the virus-mediated delivery and production of scAb GLAF-1 and the oncolytic and immunological effects of the GLV-1h109 vaccinia virus strain against canine soft tissue sarcoma and canine prostate carcinoma in xenograft models. Cell culture data demonstrated that the GLV-1h109 virus efficiently infect, replicate in and destroy both tested canine cancer cell lines. In addition, successful expression of GLAF-1 was demonstrated in virus-infected canine cancer cells and the antibody specifically recognized canine VEGF. In two different xenograft models, the systemic administration of the GLV-1h109 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. Furthermore, tumor-specific virus infection led to a continued production of functional scAb GLAF-1, resulting in inhibition of angiogenesis. Overall, the GLV-1h109-mediated cancer therapy and production of immunotherapeutic anti-VEGF scAb may open the way for combination therapy concept i.e. vaccinia virus mediated oncolysis and intratumoral production of therapeutic drugs in canine cancer patients.


Haemoglobin and flow-mediated vasodilation.
A low [Hb] (Hb concentration) is out-balanced by peripheral vasodilation via mechanisms that are incompletely understood. Peripheral vasodilation is influenced by NO (nitric oxide) released from vascular endothelium in response to increased vessel wall shear stress, and absorption by Hb is the main mechanism by which the bioactivity of NO is disarmed. Thus we propose that graded NO absorption is the mechanism through which a low [Hb] is related to peripheral vasodilation. In the present study, we examined the relationship between [Hb] and FMD (flow-mediated vasodilation; 5 min of cuff ischaemia) of the radial and brachial arteries in 33 normal subjects and in 13 patients with Type II diabetes, known to have impaired NO-mediated vasodilation. The smaller radial artery provided the more sensitive test, as it had a 2-fold larger FMD than the brachial artery (22+/-18% compared with 9+/-18% respectively, in normal subjects; means+/-S.D., P<0.05). FMD of the radial artery had a negative correlation with [Hb] (r(2)=-0.66, P<0.05; n=27). In subjects with [Hb] below and above the median of 14.1 g/dl, the radial artery FMD was 30+/-22% compared with 13+/-12% respectively (P<0.05). In diabetic patients, FMD was lower and a co-variation with [Hb] could not be established. Thus, in normal subjects, NO-mediated endothelium-related vasodilation at least partly out-balanced the 'added burden' of a low [Hb] during post-ischaemic reperfusion.


The effects of life stress and neural learning signals on fluid intelligence.
Fluid intelligence (fluid IQ), defined as the capacity for rapid problem solving and behavioral adaptation, is known to be modulated by learning and experience. Both stressful life events (SLES) and neural correlates of learning [specifically, a key mediator of adaptive learning in the brain, namely the ventral striatal representation of prediction errors (PE)] have been shown to be associated with individual differences in fluid IQ. Here, we examine the interaction between adaptive learning signals (using a well-characterized probabilistic reversal learning task in combination with fMRI) and SLES on fluid IQ measures. We find that the correlation between ventral striatal BOLD PE and fluid IQ, which we have previously reported, is quantitatively modulated by the amount of reported SLES. Thus, after experiencing adversity, basic neuronal learning signatures appear to align more closely with a general measure of flexible learning (fluid IQ), a finding complementing studies on the effects of acute stress on learning. The results suggest that an understanding of the neurobiological correlates of trait variables like fluid IQ needs to take socioemotional influences such as chronic stress into account.


Modelling physiological deterioration in post-operative patient vital-sign data.
Patients who undergo upper-gastrointestinal surgery have a high incidence of post-operative complications, often requiring admission to the intensive care unit several days after surgery. A dataset comprising observational vital-sign data from 171 post-operative patients taking part in a two-phase clinical trial at the Oxford Cancer Centre, was used to explore the trajectory of patients' vital-sign changes during their stay in the post-operative ward using both univariate and multivariate analyses. A model of normality based vital-sign data from patients who had a "normal" recovery was constructed using a kernel density estimate, and tested with "abnormal" data from patients who deteriorated sufficiently to be re-admitted to the intensive care unit. The vital-sign distributions from "normal" patients were found to vary over time from admission to the post-operative ward to their discharge home, but no significant changes in their distributions were observed from halfway through their stay on the ward to the time of discharge. The model of normality identified patient deterioration when tested with unseen "abnormal" data, suggesting that such techniques may be used to provide early warning of adverse physiological events.


Engineering cell-material interfaces for long-term expansion of human pluripotent stem cells.
Cost-effective and scalable synthetic matrices that support long-term expansion of human pluripotent stem cells (hPSCs) have many applications, ranging from drug screening platforms to regenerative medicine. Here, we report the development of a hydrogel-based matrix containing synthetic heparin-mimicking moieties that supports the long-term expansion of hPSCs (≥20 passages) in a chemically defined medium. HPSCs expanded on this synthetic matrix maintained their characteristic morphology, colony forming ability, karyotypic stability, and differentiation potential. We also used the synthetic matrix as a platform to investigate the effects of various physicochemical properties of the extracellular environment on the adhesion, growth, and self-renewal of hPSCs. The observed cellular responses can be explained in terms of matrix interface-mediated binding of extracellular matrix proteins, growth factors, and other cell-secreted factors, which create an instructive microenvironment to support self-renewal of hPSCs. These synthetic matrices, which comprise of "off-the-shelf" components and are easy to synthesize, provide an ideal tool to elucidate the molecular mechanisms that control stem cell fate.


Long-term behavioural, molecular and morphological effects of neonatal NMDA receptor antagonism.
Brief N-methyl-D-aspartate (NMDA) receptor blockade in neonatal rats has been reported to increase neuronal apoptosis. We replicated this finding using MK-801 (0.5 mg/kg) administered twice on postnatal day 7, and then studied the long-term consequences. In adulthood, treated rats showed reduced volume and neuronal number within the hippocampus, and altered hippocampal NMDA receptor (NR1 subunit) expression. Synaptophysin mRNA was decreased in the thalamus (laterodorsal nucleus). Adult MK-801-treated females had prepulse inhibition deficits and increased locomotor activity. The data show that a transient and limited glutamatergic intervention during development can have chronic behavioural, structural and molecular effects. The effects are reminiscent of alterations reported in schizophrenia and, as such, are consistent with hypotheses advocating a role for NMDA receptor hypofunction, and aberrant apoptosis, in the neurodevelopmental pathogenesis of the disorder.