Cognitive control of attention in the human brain: insights from orienting attention to mental representations.
In this review, we summarize a new line of experimentation showing that attentional orienting can bias information processing in the working memory domain as well as in the perceptual domain to optimize goal-directed behavior. A new experimental paradigm was developed, which revealed that spatial orienting cues that appear after perceptual events (retro-cues), when these have been internalized into working memory representations, can retrospectively enhance performance to a similar degree as spatial precues appearing before perceptual events. As part of their facilitatory action, retro-cues diminish the costs of retrieving items from increasing loads within working memory. Hemodynamic and electrophysiological brain imaging experiments show a high degree of overlap between brain areas and dynamics involved in spatial orienting in the working memory domain compared to the perceptual domain. In addition, functional magnetic resonance imaging points to the selective involvement of frontal areas during spatial orienting in the working memory domain. The roles of different frontal areas remain to be clarified but may include both early roles in guiding spatial shifts occurring within a mnemonic context as well as selection of memorized targets amidst distracting stimuli. Experiments have also begun to reveal the ability to orient attention selectively to object-based representations in working memory and suggest that the neural representations of objects in working memory can be directly modulated by this process. The findings bolster contemporary notions of a strong theoretical relationship between attentional orienting and working memory, suggesting that these two cognitive functions interact in more ways and directions than previously considered.


Correlating In Vitro Splice Switching Activity With Systemic In Vivo Delivery Using Novel ZEN-modified Oligonucleotides.
Splice switching oligonucleotides (SSOs) induce alternative splicing of pre-mRNA and typically employ chemical modifications to increase nuclease resistance and binding affinity to target pre-mRNA. Here we describe a new SSO non-base modifier (a naphthyl-azo group, "ZEN™") to direct exon exclusion in mutant dystrophin pre-mRNA to generate functional dystrophin protein. The ZEN modifier is placed near the ends of a 2'-O-methyl (2'OMe) oligonucleotide, increasing melting temperature and potency over unmodified 2'OMe oligonucleotides. In cultured H2K cells, a ZEN-modified 2'OMe phosphorothioate (PS) oligonucleotide delivered by lipid transfection greatly enhanced dystrophin exon skipping over the same 2'OMePS SSO lacking ZEN. However, when tested using free gymnotic uptake in vitro and following systemic delivery in vivo in dystrophin deficient mdx mice, the same ZEN-modified SSO failed to enhance potency. Importantly, we show for the first time that in vivo activity of anionic SSOs is modelled in vitro only when using gymnotic delivery. ZEN is thus a novel modifier that enhances activity of SSOs in vitro but will require improved delivery methods before its in vivo clinical potential can be realized.


Labeling stem cells with fluorescent dyes for non-invasive detection with optical imaging.
Optical imaging (OI) is an easy, fast and inexpensive tool for in vivo monitoring of new stem cell based therapies. The technique is based on ex vivo labeling of stem cells with a fluorescent dye, subsequent intravenous injection of the labeled cells and visualization of their accumulation in specific target organs or pathologies. The presented technique demonstrates how we label human mesenchymal stem cells (hMSC) by simple incubation with the lipophilic fluorescent dye DiD (C67H103CIN2O3S) and how we label human embryonic stem cells (hESC) with the FDA approved fluorescent dye Indocyanine Green (ICG). The uptake mechanism is via adherence and diffusion of the lypophilic dye across the phospholipid cell membrane bilayer. The labeling efficiency is usually improved if the cells are incubated with the dye in serum-free media as opposed to incubation in serum-containing media. Furthermore, the addition of the transfection agent Protamine Sulfate significantly improves contrast agent uptake.


Phytanic acid: measurement of plasma concentrations by gas-liquid chromatography-mass spectrometry analysis and associations with diet and other plasma fatty acids.
Epidemiological data suggest that a diet rich in animal foods may be associated with an increased risk of several cancers, including cancers of the prostate, colorectum and breast, but the possible mechanism is unclear. It is hypothesised that phytanic acid, a C20 branched-chain fatty acid found predominantly in foods from ruminant animals, may be involved in early cancer development because it has been shown to up regulate activity of alpha-methylacyl-coenzyme A racemase, an enzyme commonly found to be over-expressed in tumour cells compared with normal tissue. However, little is known about the distribution of plasma phytanic acid concentrations or its dietary determinants in the general population. The primary aim of the present cross-sectional study was to determine circulating phytanic acid concentrations among ninety-six meat-eating, lacto-ovo-vegetarian and vegan women, aged 20-69 years, recruited into the Oxford component of the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). Meat-eaters had, on average, a 6.7-fold higher geometric mean plasma phytanic acid concentration than the vegans (5.77 v. 0.86 micromol/l; P < 0.0001) and a 47 % higher mean concentration than the vegetarians (5.77 v. 3.93 micromol/l; P = 0.016). The strongest determinant of plasma phytanic acid concentration appeared to be dairy fat intake (r 0.68; P < 0.0001); phytanic acid levels were not associated with age or other lifestyle factors. These data show that a diet high in fat from dairy products is associated with increased plasma phytanic acid concentration, which may play a role in cancer development.


Differential glucocorticoid metabolism in patients with persistent versus resolving inflammatory arthritis.
Impairment in the ability of the inflamed synovium to generate cortisol has been proposed to be a factor in the persistence and severity of inflammatory arthritis. In the inflamed synovium, cortisol is generated from cortisone by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. The objective of this study was to determine the role of endogenous glucocorticoid metabolism in the development of persistent inflammatory arthritis. Urine samples were collected from patients with early arthritis (symptoms ≤12 weeks duration) whose final diagnostic outcomes were established after clinical follow-up and from patients with established rheumatoid arthritis (RA). All patients were free of disease-modifying anti-rheumatic drugs at the time of sample collection. Systemic measures of glucocorticoid metabolism were assessed in the urine samples by gas chromatography/mass spectrometry. Clinical data including CRP and ESR were also collected at baseline. Systemic measures of 11β-HSD1 activity were significantly higher in patients with early arthritis whose disease went on to persist, and also in the subgroup of patients with persistent disease who developed RA, when compared with patients whose synovitis resolved over time. We observed a significant positive correlation between systemic 11β-HSD1 activity and ESR/CRP in patients with established RA but not in any of the early arthritis patients group. The present study demonstrates that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11β-HSD1 activity when compared with patients whose synovitis developed into RA or other forms of persistent arthritis. Low absolute levels of 11β-HSD1 activity do not therefore appear to be a major contributor to the development of RA and it is possible that a high total body 11β-HSD1 activity during early arthritis may reduce the probability of disease resolution.


Common reef-building coral in the Northern Red Sea resistant to elevated temperature and acidification.
Coral reefs are currently experiencing substantial ecological impoverishment as a result of anthropogenic stressors, and the majority of reefs are facing immediate risk. Increasing ocean surface temperatures induce frequent coral mass bleaching events-the breakdown of the nutritional photo-symbiosis with intracellular algae (genus: Symbiodinium). Here, we report that Stylophora pistillata from a highly diverse reef in the Gulf of Aqaba showed no signs of bleaching despite spending 1.5 months at 1-2°C above their long-term summer maximum (amounting to 11 degree heating weeks) and a seawater pH of 7.8. Instead, their symbiotic dinoflagellates exhibited improved photochemistry, higher pigmentation and a doubling in net oxygen production, leading to a 51% increase in primary productivity. Nanoscale secondary ion mass spectrometry imaging revealed subtle cellular-level shifts in carbon and nitrogen metabolism under elevated temperatures, but overall host and symbiont biomass proxies were not significantly affected. Now living well below their thermal threshold in the Gulf of Aqaba, these corals have been evolutionarily selected for heat tolerance during their migration through the warm Southern Red Sea after the last ice age. This may allow them to withstand future warming for a longer period of time, provided that successful environmental conservation measures are enacted across national boundaries in the region.


The Neural Dynamics of Fronto-Parietal Networks in Childhood Revealed using Magnetoencephalography.
Our ability to hold information in mind is limited, requires a high degree of cognitive control, and is necessary for many subsequent cognitive processes. Children, in particular, are highly variable in how, trial-by-trial, they manage to recruit cognitive control in service of memory. Fronto-parietal networks, typically recruited under conditions where this cognitive control is needed, undergo protracted development. We explored, for the first time, whether dynamic changes in fronto-parietal activity could account for children's variability in tests of visual short-term memory (VSTM). We recorded oscillatory brain activity using magnetoencephalography (MEG) as 9- to 12-year-old children and adults performed a VSTM task. We combined temporal independent component analysis (ICA) with general linear modeling to test whether the strength of fronto-parietal activity correlated with VSTM performance on a trial-by-trial basis. In children, but not adults, slow frequency theta (4-7 Hz) activity within a right lateralized fronto-parietal network in anticipation of the memoranda predicted the accuracy with which those memory items were subsequently retrieved. These findings suggest that inconsistent use of anticipatory control mechanism contributes significantly to trial-to-trial variability in VSTM maintenance performance.


Construct validity of the Anxiety Sensitivity Index-3 in clinical samples.
Using two clinical samples of patients, the presented studies examined the construct validity of the recently revised Anxiety Sensitivity Index-3 (ASI-3). Confirmatory factor analyses established a clear three-factor structure that corresponds to the postulated subdivision of the construct into correlated somatic, social, and cognitive components. Participants with different primary clinical diagnoses differed from each other on the ASI-3 subscales in theoretically meaningful ways. Specifically, the ASI-3 successfully discriminated patients with anxiety disorders from patients with nonanxiety disorders. Moreover, patients with panic disorder or agoraphobia manifested more somatic concerns than patients with other anxiety disorders and patients with nonanxiety disorders. Finally, correlations of the ASI-3 scales with other measures of clinical symptoms and negative affect substantiated convergent and discriminant validity. Substantial positive correlations were found between the ASI-3 Somatic Concerns and body vigilance, between Social Concerns and fear of negative evaluation and socially inhibited behavior, and between Cognitive Concerns and depression symptoms, anxiety, fear of negative evaluation, and subjective complaints. Moreover, Social Concerns correlated negatively with dominant and intrusive behavior. Results are discussed with respect to the contribution of the ASI-3 to the assessment of anxiety-related disorders.


The IronChip evaluation package: a package of perl modules for robust analysis of custom microarrays.
Gene expression studies greatly contribute to our understanding of complex relationships in gene regulatory networks. However, the complexity of array design, production and manipulations are limiting factors, affecting data quality. The use of customized DNA microarrays improves overall data quality in many situations, however, only if for these specifically designed microarrays analysis tools are available. The IronChip Evaluation Package (ICEP) is a collection of Perl utilities and an easy to use data evaluation pipeline for the analysis of microarray data with a focus on data quality of custom-designed microarrays. The package has been developed for the statistical and bioinformatical analysis of the custom cDNA microarray IronChip but can be easily adapted for other cDNA or oligonucleotide-based designed microarray platforms. ICEP uses decision tree-based algorithms to assign quality flags and performs robust analysis based on chip design properties regarding multiple repetitions, ratio cut-off, background and negative controls. ICEP is a stand-alone Windows application to obtain optimal data quality from custom-designed microarrays and is freely available here (see "Additional Files" section) and at: http://www.alice-dsl.net/evgeniy.vainshtein/ICEP/


Does limited virucidal activity of biocides include duck hepatitis B virucidal action?
There is agreement that the infectivity assay with the duck hepatitis B virus (DHBV) is a suitable surrogate test to validate disinfectants for hepatitis B virucidal activity. However, since this test is not widely used, information is necessary whether disinfectants with limited virucidal activity also inactivate DHBV. In general, disinfectants with limited virucidal activity are used for skin and sensitive surfaces while agents with full activity are more aggressive. The present study compares the activity of five different biocides against DHBV and the classical test virus for limited virucidal activity, the vaccinia virus strain Lister Elstree (VACV) or the modified vaccinia Ankara strain (MVA). Virucidal assay was performed as suspension test according to the German DVV/RKI guideline. Duck hepatitis B virus obtained from congenitally infected Peking ducks was propagated in primary duck embryonic hepatocytes and was detected by indirect immunofluorescent antigen staining. The DHBV was inactivated by the use of 40% ethanol within 1-min and 30% isopropanol within 2-min exposure. In comparison, 40% ethanol within 2-min and 40% isopropanol within 1-min exposure were effective against VACV/MVA. These alcohols only have limited virucidal activity, while the following agents have full activity. 0.01% peracetic acid inactivated DHBV within 2 min and a concentration of 0.005% had virucidal efficacy against VACV/MVA within 1 min. After 2-min exposure, 0.05% glutardialdehyde showed a comparable activity against DHBV and VACV/MVA. This is also the case for 0.7% formaldehyde after a contact time of 30 min. Duck hepatitis B virus is at least as sensitive to limited virucidal activity as VACV/MVA. Peracetic acid is less effective against DHBV, while the alcohols are less effective against VACV/MVA. It can be expected that in absence of more direct tests the results may be extrapolated to HBV.


Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2.
Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells--specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells--influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2+ trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success.


Comparative Analysis of Zebrafish and Planarian Model Systems for Developmental Neurotoxicity Screens Using an 87-Compound Library.
There is a clear need to establish and validate new methodologies to more quickly and efficiently screen chemicals for potential toxic effects, particularly on development. The emergence of alternative animal systems for rapid toxicology screens presents valuable opportunities to evaluate how systems complement each other. In this article, we compare a chemical library of 87-compounds in 2 such systems, developing zebrafish and freshwater planarians, by screening for developmental neurotoxic effects. We show that the systems' toxicological profiles are complementary to each other, with zebrafish yielding more detailed morphological endpoints and planarians more behavioral endpoints. Overall, zebrafish was more sensitive to this chemical library, yielding 86/87 hits, compared with 50/87 hits in planarians. The difference in sensitivity could not be attributed to molecular weight, log Kow, or the bioconcentration factor. Of the 87 chemicals, 28 had previously been evaluated in mammalian developmental neuro- (DNT), neuro-, or developmental toxicity studies. Of the 28, 20 were hits in the planarian, and 27 were hits in zebrafish. Eighteen of the 28 had previously been identified as DNT hits in mammals and were highly associated with activity in zebrafish and planarian behavioral assays in this study. Only 1 chemical (of 28) was a false negative in both zebrafish and planarian systems. The differences in endpoint coverage and system sensitivity illustrate the value of a dual systems approach to rapidly query a large chemical-bioactivity space and provide weight-of-evidence for prioritization of chemicals for further testing.


Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.
Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.


Towards realtime multimodal fusion for image-guided interventions using self-similarities.
Image-guided interventions often rely on deformable multimodal registration to align pre-treatment and intra-operative scans. There are a number of requirements for automated image registration for this task, such as a robust similarity metric for scans of different modalities with different noise distributions and contrast, an efficient optimisation of the cost function to enable fast registration for this time-sensitive application, and an insensitive choice of registration parameters to avoid delays in practical clinical use. In this work, we build upon the concept of structural image representation for multi-modal similarity. Discriminative descriptors are densely extracted for the multi-modal scans based on the "self-similarity context". An efficient quantised representation is derived that enables very fast computation of point-wise distances between descriptors. A symmetric multi-scale discrete optimisation with diffusion reguIarisation is used to find smooth transformations. The method is evaluated for the registration of 3D ultrasound and MRI brain scans for neurosurgery and demonstrates a significantly reduced registration error (on average 2.1 mm) compared to commonly used similarity metrics and computation times of less than 30 seconds per 3D registration.


Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies.
Sex hormones in serum have been hypothesized to influence the risk of prostate cancer. We performed a collaborative analysis of the existing worldwide epidemiologic data to examine these associations in a uniform manner and to provide more precise estimates of risks. Data on serum concentrations of sex hormones from 18 prospective studies that included 3886 men with incident prostate cancer and 6438 control subjects were pooled by the Endogenous Hormones and Prostate Cancer Collaborative Group. Relative risks (RRs) of prostate cancer by fifths of serum hormone concentration were estimated by use of conditional logistic regression with stratification by study, age at recruitment, and year of recruitment. All statistical tests were two-sided. No associations were found between the risk of prostate cancer and serum concentrations of testosterone, calculated free testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, androstenedione, androstanediol glucuronide, estradiol, or calculated free estradiol. The serum concentration of sex hormone-binding globulin was modestly inversely associated with prostate cancer risk (RR in the highest vs lowest fifth = 0.86, 95% confidence interval = 0.75 to 0.98; P(trend) = .01). There was no statistical evidence of heterogeneity among studies, and adjustment for potential confounders made little difference to the risk estimates. In this collaborative analysis of the worldwide data on endogenous hormones and prostate cancer risk, serum concentrations of sex hormones were not associated with the risk of prostate cancer.


A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C.
To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D(3) (25[OH]D(3)) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061-2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D(3)<20 ng/mL) during all seasons, but 25(OH)D(3) serum levels were not associated with treatment outcome. Our study suggests a role of bioactive vitamin D (1,25[OH](2)D(3), calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D(3) is not a suitable predictor of treatment outcome.


Ten principles for a landscape approach to reconciling agriculture, conservation, and other competing land uses.
"Landscape approaches" seek to provide tools and concepts for allocating and managing land to achieve social, economic, and environmental objectives in areas where agriculture, mining, and other productive land uses compete with environmental and biodiversity goals. Here we synthesize the current consensus on landscape approaches. This is based on published literature and a consensus-building process to define good practice and is validated by a survey of practitioners. We find the landscape approach has been refined in response to increasing societal concerns about environment and development tradeoffs. Notably, there has been a shift from conservation-orientated perspectives toward increasing integration of poverty alleviation goals. We provide 10 summary principles to support implementation of a landscape approach as it is currently interpreted. These principles emphasize adaptive management, stakeholder involvement, and multiple objectives. Various constraints are recognized, with institutional and governance concerns identified as the most severe obstacles to implementation. We discuss how these principles differ from more traditional sectoral and project-based approaches. Although no panacea, we see few alternatives that are likely to address landscape challenges more effectively than an approach circumscribed by the principles outlined here.


A PET-CT study on the specificity of acupoints through acupuncture treatment in migraine patients.
In the field of acupuncture research, the topic of acupoint specificity has received increasing attention, but no unified conclusion has been reached on whether or not acupoint specificity exists. Furthermore, the majority of previous acupuncture neuroimaging studies have been performed using healthy subjects. In this study, patients with migraine were used to investigate acupoint specificity. Thirty patients with migraine were enrolled and randomized into three groups: Traditional Acupuncture Group (TAG), Control Acupuncture Group (CAG), and Migraine Group (MG). The TAG was treated by acupuncture stimulation at Waiguan (TE5), Yang Lingquan (GB34), and Fengchi (GB20). The CAG was treated at Touwei (ST8), Pianli (LI6), and Zusanli (ST36). The MG received no treatment. Positron emission tomography with computed tomography (PET-CT) was used to test for differences in brain activation between the TAG and CAG versus MG, respectively. Traditional acupuncture treatment was more effective for pain reduction than control acupuncture treatment. The TAG showed higher brain metabolism than the MG in the middle temporal cortex (MTC), orbital frontal cortex (OFC), insula, middle frontal gyrus, angular gyrus, post-cingulate cortex (PCC), the precuneus, and the middle cingulate cortex (MCC). Metabolism decreased in the parahippocampus, hippocampus, fusiform gyrus, postcentral gyrus, and cerebellum in the TAG compared with the MG. In the CAG, metabolism increased compared with the MG in the MTC, supratemporal gyrus, supramarginal gyrus, and MCC, whereas metabolism decreased in the cerebellum. Acupuncture stimulation of different points on similar body regions in migraine patients reduced pain and induced different levels of cerebral glucose metabolism in pain-related brain regions. These findings may support the functional specificity of migraine- treatment-related acupoint. The number of our clinical trial registration is: ChiCTR-TRC-11001813, and the protocol and inclusion criteria have already been registered as ChiCTR-TRC-11001813.


Fractal-based description of natural scenes.
This paper addresses the problems of 1) representing natural shapes such as mountains, trees, and clouds, and 2) computing their description from image data. To solve these problems, we must be able to relate natural surfaces to their images; this requires a good model of natural surface shapes. Fractal functions are a good choice for modeling 3-D natural surfaces because 1) many physical processes produce a fractal surface shape, 2) fractals are widely used as a graphics tool for generating natural-looking shapes, and 3) a survey of natural imagery has shown that the 3-D fractal surface model, transformed by the image formation process, furnishes an accurate description of both textured and shaded image regions. The 3-D fractal model provides a characterization of 3-D surfaces and their images for which the appropriateness of the model is verifiable. Furthermore, this characterization is stable over transformations of scale and linear transforms of intensity. The 3-D fractal model has been successfully applied to the problems of 1) texture segmentation and classification, 2) estimation of 3-D shape information, and 3) distinguishing between perceptually ``smooth'' and perceptually ``textured'' surfaces in the scene.


Transition from long-term nonprogression to HIV-1 disease associated with escape from cellular immune control.
Transition from long-term nonprogressive infection to progressive HIV-1 disease presents an opportunity to investigate pathogenesis in a defined immunogenetic background. We studied a male long-term nonprogressor (LTNP) who remained asymptomatic and viremic and had normal CD4 T-cell counts without antiretroviral therapy for >18 years and then experienced a transition to disease progression. We analyzed the complete HIV-1 genomic RNA sequence from plasma and cellular immune responses to predefined human leukocyte antigen-matched autologous viral peptides spanning the viral genome, before and after progression. Serial viral sequences did not seem attenuated and consistently utilized coreceptor CCR5. LTNP status was associated with elongated V2 domains and broad low-level T-cell immune responses targeting several regions of the viral genome. The transition to progressive disease was associated with the acquisition of viral mutations conferring escape from CD8 T-cell responses. Multiple changes in HIV-1 sequence and loss of immune response over time most likely contributed to the transition from LTNP status to progressive disease. These data are relevant to vaccine design and identification of the correlates of protection from disease progression.


A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae.
A series of yeast shuttle vectors and host strains has been created to allow more efficient manipulation of DNA in Saccharomyces cerevisiae. Transplacement vectors were constructed and used to derive yeast strains containing nonreverting his3, trp1, leu2 and ura3 mutations. A set of YCp and YIp vectors (pRS series) was then made based on the backbone of the multipurpose plasmid pBLUESCRIPT. These pRS vectors are all uniform in structure and differ only in the yeast selectable marker gene used (HIS3, TRP1, LEU2 and URA3). They possess all of the attributes of pBLUESCRIPT and several yeast-specific features as well. Using a pRS vector, one can perform most standard DNA manipulations in the same plasmid that is introduced into yeast.


Self-Management Support Using a Digital Health System Compared With Usual Care for Chronic Obstructive Pulmonary Disease: Randomized Controlled Trial.
We conducted a randomized controlled trial of a digital health system supporting clinical care through monitoring and self-management support in community-based patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The aim of this study was to determine the efficacy of a fully automated Internet-linked, tablet computer-based system of monitoring and self-management support (EDGE' sElf-management anD support proGrammE) in improving quality of life and clinical outcomes. We compared daily use of EDGE with usual care for 12 months. The primary outcome was COPD-specific health status measured with the St George's Respiratory Questionnaire for COPD (SGRQ-C). A total of 166 patients were randomized (110 EDGE, 56 usual care). All patients were included in an intention to treat analysis. The estimated difference in SGRQ-C at 12 months (EDGE-usual care) was -1.7 with a 95% CI of -6.6 to 3.2 (P=.49). The relative risk of hospital admission for EDGE was 0.83 (0.56-1.24, P=.37) compared with usual care. Generic health status (EQ-5D, EuroQol 5-Dimension Questionnaire) between the groups differed significantly with better health status for the EDGE group (0.076, 95% CI 0.008-0.14, P=.03). The median number of visits to general practitioners for EDGE versus usual care were 4 versus 5.5 (P=.06) and to practice nurses were 1.5 versus 2.5 (P=.03), respectively. The EDGE clinical trial does not provide evidence for an effect on COPD-specific health status in comparison with usual care, despite uptake of the intervention. However, there appears to be an overall benefit in generic health status; and the effect sizes for improved depression score, reductions in hospital admissions, and general practice visits warrants further evaluation and could make an important contribution to supporting people with COPD. International Standard Randomized Controlled Trial Number (ISRCTN): 40367841; http://www.isrctn.com/ISRCTN40367841 (Archived by WebCite at http://www.webcitation.org/6pmfIJ9KK).


Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations.
An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed.


Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a prevalence of 1 million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli and leads to death by asphyxiation. We previously discovered that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs) that serve as a cell of origin for disease-mediating myofibroblasts. In a prior genomewide transcriptional analysis, we found that IPF MPCs displayed increased expression of S100 calcium-binding A4 (S100A4), a protein linked to cancer cell proliferation and invasiveness. Here, we have examined whether S100A4 mediates MPC fibrogenicity. Ex vivo analysis revealed that IPF MPCs had increased levels of nuclear S100A4, which interacts with L-isoaspartyl methyltransferase to promote p53 degradation and MPC self-renewal. In vivo, injection of human IPF MPCs converted a self-limited bleomycin-induced mouse model of lung fibrosis to a model of persistent fibrosis in an S100A4-dependent manner. S100A4 gain of function was sufficient to confer fibrotic properties to non-IPF MPCs. In IPF tissue, fibroblastic foci contained cells expressing Ki67 and the MPC markers SSEA4 and S100A4. The expression colocalized in an interface region between myofibroblasts in the focus core and normal alveolar structures, defining this region as an active fibrotic front. Our findings indicate that IPF MPCs are intrinsically fibrogenic and that S100A4 confers MPCs with fibrogenicity.


Overview of mathematical approaches used to model bacterial chemotaxis I: the single cell.
Mathematical modeling of bacterial chemotaxis systems has been influential and insightful in helping to understand experimental observations. We provide here a comprehensive overview of the range of mathematical approaches used for modeling, within a single bacterium, chemotactic processes caused by changes to external gradients in its environment. Specific areas of the bacterial system which have been studied and modeled are discussed in detail, including the modeling of adaptation in response to attractant gradients, the intracellular phosphorylation cascade, membrane receptor clustering, and spatial modeling of intracellular protein signal transduction. The importance of producing robust models that address adaptation, gain, and sensitivity are also discussed. This review highlights that while mathematical modeling has aided in understanding bacterial chemotaxis on the individual cell scale and guiding experimental design, no single model succeeds in robustly describing all of the basic elements of the cell. We conclude by discussing the importance of this and the future of modeling in this area.


CRM197-conjugated serogroup C meningococcal capsular polysaccharide, but not the native polysaccharide, induces persistent antigen-specific memory B cells.
Neisseria meningitidis is one of the leading causes of bacterial meningitis and septicemia in children. Vaccines containing the purified polysaccharide capsule from the organism, a T cell-independent antigen, have been available for decades but do not appear to provide protection in infancy or immunologic memory as measured by antibody responses. By contrast, T cell-dependent serogroup C protein-polysaccharide conjugate vaccines protect against serogroup C meningococcal disease from infancy onward and prime for immunologic memory. We compared the magnitude and kinetics of plasma cell and memory B-cell responses to a meningococcal plain polysaccharide vaccine and a serogroup C glycoconjugate vaccine in adolescents previously primed with the conjugate vaccine. Plasma cell kinetics were similar for both vaccines, though the magnitude of the response was greater for the glycoconjugate. In contrast to the glycoconjugate vaccine, the plain polysaccharide vaccine did not induce a persistent immunoglobulin G (IgG) memory B-cell response. This is the first study to directly show that serogroup C meningococcal glycoconjugate vaccines induce persistent production of memory B cells and that plain polysaccharide vaccines do not, supporting the use of the conjugate vaccine for sustained population protection. Detection of peripheral blood memory B-cell responses after vaccination may be a useful signature of successful induction of immunologic memory during novel vaccine evaluation.


Fluorescent protein-mediated colour polymorphism in reef corals: multicopy genes extend the adaptation/acclimatization potential to variable light environments.
The genomic framework that enables corals to adjust to unfavourable conditions is crucial for coral reef survival in a rapidly changing climate. We have explored the striking intraspecific variability in the expression of coral pigments from the green fluorescent protein (GFP) family to elucidate the genomic basis for the plasticity of stress responses among reef corals. We show that multicopy genes can greatly increase the dynamic range over which corals can modulate transcript levels in response to the light environment. Using the red fluorescent protein amilFP597 in the coral Acropora millepora as a model, we demonstrate that its expression increases with light intensity, but both the minimal and maximal gene transcript levels vary markedly among colour morphs. The pigment concentration in the tissue of different morphs is strongly correlated with the number of gene copies with a particular promoter type. These findings indicate that colour polymorphism in reef corals can be caused by the environmentally regulated expression of multicopy genes. High-level expression of amilFP597 is correlated with reduced photodamage of zooxanthellae under acute light stress, supporting a photoprotective function of this pigment. The cluster of light-regulated pigment genes can enable corals to invest either in expensive high-level pigmentation, offering benefits under light stress, or to rely on low tissue pigment concentrations and use the conserved resources for other purposes, which is preferable in less light-exposed environments. The genomic framework described here allows corals to pursue different strategies to succeed in habitats with highly variable light stress levels. In summary, our results suggest that the intraspecific plasticity of reef corals' stress responses is larger than previously thought.


Low shear stress induces M1 macrophage polarization in murine thin-cap atherosclerotic plaques.
Macrophages, a significant component of atherosclerotic plaques vulnerable to acute complications, can be pro-inflammatory (designated M1), regulatory (M2), lipid- (Mox) or Heme-induced (Mhem). We showed previously that low (LSS) and oscillatory (OSS) shear stress cause thin-cap fibroatheroma and stable smooth muscle cell-rich plaque formation respectively in ApoE-knockout (ApoE(-/-)) mice. Here we investigated whether different shear stress conditions relate to specific changes in macrophage polarization and plaque morphology by applying a shear stress-altering cast to the carotid arteries of high fat-fed ApoE(-/-) mice. The M1 markers iNOS and IRF5 were highly expressed in macrophage-rich areas of LSS lesions compared to OSS lesions 6weeks after cast placement, while the M2 marker Arginase-1, and Mox/Mhem markers HO-1 and CD163 were elevated in OSS lesions. Our data indicates shear stress could be an important determinant of macrophage polarization in atherosclerosis, with low shear promoting M1 programming.


Selection of a highly invasive neuroblastoma cell population through long-term human cytomegalovirus infection.
The human cytomegalovirus (HCMV) is suspected to increase tumour malignancy by infection of cancer and/or stroma cells (oncomodulation). So far, oncomodulatory mechanisms have been attributed to the presence of HCMV and direct action of its gene products on cancer cells. Here, we investigated whether the prolonged presence of HCMV can result in the irreversible selection of a cancer cell population with increased malignancy. The neuroblastoma cell line UKF-NB-4 was long-term (200 passages) infected with the HCMV strain Hi91 (UKF-NB-4(Hi)) before virus eradication using ganciclovir (UKF-NB-4(HiGCV)). Global gene expression profiling of UKF-NB-4, UKF-NB-4(Hi) and UKF-NB-4(HiGCV) cells and subsequent bioinformatic signal transduction pathway analysis revealed clear differences between UKF-NB-4 and UKF-NB-4(Hi), as well as between UKF-NB-4 and UKF-NB-4(HiGCV) cells, but only minor differences between UKF-NB-4(Hi) and UKF-NB-4(HiGCV) cells. Investigation of the expression of a subset of five genes in different chronically HCMV-infected cell lines before and after virus eradication suggested that long-term HCMV infection reproducibly causes specific changes. Array comparative genomic hybridisation showed virtually the same genomic differences for the comparisons UKF-NB-4(Hi)/UKF-NB-4 and UKF-NB-4(HiGCV)/UKF-NB-4. UKF-NB-4(Hi) cells are characterised by an increased invasive potential compared with UKF-NB-4 cells. This phenotype was completely retained in UKF-NB-4(HiGCV) cells. Moreover, there was a substantial overlap in the signal transduction pathways that differed significantly between UKF-NB-4(Hi)/UKF-NB-4(HiGCV) and UKF-NB-4 cells and those differentially regulated between tumour tissues from neuroblastoma patients with favourable or poor outcome. In conclusion, we present the first experimental evidence that long-term HCMV infection can result in the selection of tumour cell populations with enhanced malignancy.


Strengthening ethical community engagement in contemporary Malawi.
Although community engagement is increasingly promoted in global health research to improve ethical research practice, there is sometimes a disconnect between the broader moral ambitions for community engagement in the literature and guidelines on the one hand and its rather narrower practical application in health research on the other. In practice, less attention is paid to engaging communities for the 'intrinsic' value of showing respect and ensuring inclusive participation of community partners in research design. Rather, more attention is paid to the use of community engagement for 'instrumental' purposes to improve community understanding of research and ensure successful study implementation. Against this backdrop, we reviewed the literature and engaged various research stakeholders at a workshop to discuss ways of strengthening ethical engagement of communities and to develop context-relevant guidelines for community engagement in health research in Malawi.


A cross-sectional study assessing the association between online ratings and structural and quality of care measures: results from two German physician rating websites.
Even though physician rating websites (PRWs) have been gaining in importance in both practice and research, little evidence is available on the association of patients' online ratings with the quality of care of physicians. It thus remains unclear whether patients should rely on these ratings when selecting a physician. The objective of this study was to measure the association between online ratings and structural and quality of care measures for 65 physician practices from the German Integrated Health Care Network "Quality and Efficiency" (QuE). Online reviews from two German PRWs were included which covered a three-year period (2011 to 2013) and included 1179 and 991 ratings, respectively. Information for 65 QuE practices was obtained for the year 2012 and included 21 measures related to structural information (N = 6), process quality (N = 10), intermediate outcomes (N = 2), patient satisfaction (N = 1), and costs (N = 2). The Spearman rank coefficient of correlation was applied to measure the association between ratings and practice-related information. Patient satisfaction results from offline surveys and the patients per doctor ratio in a practice were shown to be significantly associated with online ratings on both PRWs. For one PRW, additional significant associations could be shown between online ratings and cost-related measures for medication, preventative examinations, and one diabetes type 2-related intermediate outcome measure. There again, results from the second PRW showed significant associations with the age of the physicians and the number of patients per practice, four process-related quality measures for diabetes type 2 and asthma, and one cost-related measure for medication. Several significant associations were found which varied between the PRWs. Patients interested in the satisfaction of other patients with a physician might select a physician on the basis of online ratings. Even though our results indicate associations with some diabetes and asthma measures, but not with coronary heart disease measures, there is still insufficient evidence to draw strong conclusions. The limited number of practices in our study may have weakened our findings.


Randomized clinical trial to evaluate the immunogenicity of quadrivalent meningococcal conjugate and polysaccharide vaccines in adults in the United kingdom.
Meningococcal conjugate vaccines are today successfully deployed in universal programs for children and adolescents in different geographic regions to control meningitis and septicemia. However, in adults, the advantages of these conjugates over the older polysaccharide vaccines are less clear. In this randomized clinical trial, we demonstrated that both conjugate and polysaccharide quadrivalent meningococcal vaccines elicit protective antibody responses in adults aged 18 to 70. (This study has been registered at www.clinicaltrials.gov under registration no. NCT00901940.).


Creating the living brand.
It's easy to conclude from the literature and the lore that top-notch customer service is the province of a few luxury companies and that any retailer outside that rarefied atmosphere is condemned to offer mediocre service at best. But even companies that position themselves for the mass market can provide outstanding customer-employee interactions and profit from them, if they train employees to reflect the brand's core values. The authors studied the convenience store industry in depth and focused on two that have developed a devoted following: QuikTrip (QT) and Wawa. Turnover rates at QT and Wawa are 14% and 22% respectively, much lower than the typical rate in retail. The authors found six principles that both firms embrace to create a strong culture of customer service. Know what you're looking for: A focus on candidates' intrinsic traits allows the companies to hire people who will naturally bring the right qualities to the job. Make the most of talent: In mass-market retail, talent is generally viewed as a commodity, but that outlook becomes a self-fulfilling prophesy. Create pride in the brand: Service quality depends directly on employees' attachment to the brand. Build community: Wawa and QT have made concerted efforts to build customer loyalty through a sense of community. Share the business context: Employees need a clear understanding of how their company operates and how it defines success. Satisfy the soul: To win an employee's passionate engagement, a company must meet his or her needs for security, esteem, and justice.


Heterogeneity of colorectal cancer risk by tumour characteristics: Large prospective study of UK women.
Associations between behavioural and other personal factors and colorectal cancer risk have been reported to vary by tumour characteristics, but evidence is inconsistent. In a large UK-based prospective study we examined associations of 14 postulated risk factors with colorectal cancer risk overall, and across three anatomical sites and four morphological subtypes. Among 1.3 million women, 18,518 incident colorectal cancers were identified during 13.8 (SD 3.4) years follow-up via record linkage to national cancer registry data. Cox regression yielded adjusted relative risks. Statistical significance was assessed using correction for multiple testing. Overall, colorectal cancer risk was significantly associated with height, body mass index (BMI), smoking, alcohol intake, physical activity, parity and menopausal hormone therapy use. For smoking there was substantial heterogeneity across morphological types; relative risks around two or greater were seen in current smokers both for signet ring cell and for neuroendocrine tumours. Obese women were also at higher risk for signet ring cell tumours. For adenocarcinomas, the large majority of colorectal cancers in the cohort, all risk factor associations were weak. There was little or no heterogeneity in risk between tumours of the right colon, left colon and rectum for any of the 14 factors examined. These epidemiological findings complement an emerging picture from molecular studies of possible different developmental pathways for different tumour types.


Infectious delivery and long-term persistence of transgene expression in the brain by a 135-kb iBAC-FXN genomic DNA expression vector.
Novel gene-based therapies for disease will depend in many cases on long-term persistent transgene expression. To develop gene therapy strategies for Friedreich's ataxia (FRDA), we have examined the persistence of transgene expression in the brain in vivo provided by the entire 135 kb FXN genomic DNA locus delivered as an infectious bacterial artificial chromosome (iBAC) herpes simplex virus type 1 (HSV-1)-based vector injected in the adult mouse cerebellum. We constructed genomic DNA-reporter fusion vectors carrying a complete 135 kb FXN genomic locus with an insertion of the Escherichia coli lacZ gene at the ATG start codon (iBAC-FXN-lacZ). SHSY5Y human neuroblastoma cells transduced by iBAC-FXN-lacZ showed high efficiency of vector delivery and LacZ expression. Direct intracranial injection of iBAC-FXN-lacZ into the adult mouse cerebellum resulted in a large number of easily detectable transduced cells, with LacZ expression driven by the FXN genomic locus, which persisted for at least 75 days. Green fluorescent protein expression driven from the same vector but by the strong HSV-1 IE4/5 promoter was transient. Our data demonstrate for the first time sustained transgene expression in vivo by infectious delivery of a genomic DNA locus >100 kb in size. Such an approach may be suitable for gene rescue strategies in neurological disease, such as FRDA.


Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.
To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD). Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560). People >50 years of age with untreated nAMD in the study eye who read ≥ 25 letters on the Early Treatment Diabetic Retinopathy Study chart. We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review. The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs. Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001). The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety. Proprietary or commercial disclosures may be found after the references.


Private predictive analysis on encrypted medical data.
Increasingly, confidential medical records are being stored in data centers hosted by hospitals or large companies. As sophisticated algorithms for predictive analysis on medical data continue to be developed, it is likely that, in the future, more and more computation will be done on private patient data. While encryption provides a tool for assuring the privacy of medical information, it limits the functionality for operating on such data. Conventional encryption methods used today provide only very restricted possibilities or none at all to operate on encrypted data without decrypting it first. Homomorphic encryption provides a tool for handling such computations on encrypted data, without decrypting the data, and without even needing the decryption key. In this paper, we discuss possible application scenarios for homomorphic encryption in order to ensure privacy of sensitive medical data. We describe how to privately conduct predictive analysis tasks on encrypted data using homomorphic encryption. As a proof of concept, we present a working implementation of a prediction service running in the cloud (hosted on Microsoft's Windows Azure), which takes as input private encrypted health data, and returns the probability for suffering cardiovascular disease in encrypted form. Since the cloud service uses homomorphic encryption, it makes this prediction while handling only encrypted data, learning nothing about the submitted confidential medical data.


Impaired regulation of neuronal nitric oxide synthase and heart rate during exercise in mice lacking one nNOS allele.
We tested the hypothesis that a single allele deletion of neuronal nitric oxide synthase (nNOS) would impair the neural control of heart rate following physical training, and that this phenotype could be restored following targeted gene transfer of nNOS. Voluntary wheel-running (+EX) in heterozygous nNOS knockout mice (nNOS(+/-), +EX; n= 52; peak performance 9.1 +/- 1.8 km day(-1)) was undertaken and compared to wild-type mice (n= 38; 9.5 +/- 0.8 km day(-1)). In anaesthetized wild-type mice, exercise increased phenylephrine-induced bradycardia by 67% (measured as heart rate change, in beats per minute, divided by the change in arterial blood pressure, in mmHg) or pulse interval response to phenylephrine by 52% (measured as interbeat interval change, in milliseconds, divided by the change in blood pressure). Heart rate changes or interbeat interval changes in response to right vagal nerve stimulation were also enhanced by exercise in wild-type atria (P < 0.05), whereas both in vivo and in vitro responses to exercise were absent in nNOS(+/-) mice. nNOS inhibition attenuated heart rate responses to vagal nerve stimulation in all atria (P < 0.05) and normalized the responses in wild-type, +EX with respect to wild-type with no exercise (-EX) atria. Atrial nNOS mRNA and protein were increased in wild-type, +EX compared to wild-type, -EX (P < 0.05), although exercise failed to have any effect in nNOS(+/-) atria. In vivo nNOS gene transfer using adenoviruses targeted to atrial ganglia enhanced choline acetyltransferase-nNOS co-localization (P < 0.05) and increased phenylephrine-induced bradycardia in vivo and heart rate responses to vagal nerve stimulation in vitro compared to gene transfer of enhanced green fluorescent protein (eGFP, P < 0.01). This difference was abolished by nNOS inhibition (P < 0.05). In conclusion, genomic regulation of NO bioavailability from nNOS in cardiac autonomic ganglia in response to training is dependent on both alleles of the gene. Although basal expression of nNOS is normal, polymorphisms of nNOS may interfere with neural regulation of heart rate following training. Targeted gene transfer of nNOS can restore this impairment.


Biocompatibility of implantable materials: An oxidative stress viewpoint.
Oxidative stress occurs when the production of oxidants surpasses the antioxidant capacity in living cells. Oxidative stress is implicated in a number of pathological conditions such as cardiovascular and neurodegenerative diseases but it also has crucial roles in the regulation of cellular activities. Over the last few decades, many studies have identified significant connections between oxidative stress, inflammation and healing. In particular, increasing evidence indicates that the production of oxidants and the cellular response to oxidative stress are intricately connected to the fate of implanted biomaterials. This review article provides an overview of the major mechanisms underlying the link between oxidative stress and the biocompatibility of biomaterials. ROS, RNS and lipid peroxidation products act as chemo-attractants, signalling molecules and agents of degradation during the inflammation and healing phases. As chemo-attractants and signalling molecules, they contribute to the recruitment and activation of inflammatory and healing cells, which in turn produce more oxidants. As agents of degradation, they contribute to the maturation of the extracellular matrix at the healing site and to the degradation of the implanted material. Oxidative stress is itself influenced by the material properties, such as by their composition, their surface properties and their degradation products. Because both cells and materials produce and react with oxidants, oxidative stress may be the most direct route mediating the communication between cells and materials. Improved understanding of the oxidative stress mechanisms following biomaterial implantation may therefore help the development of new biomaterials with enhanced biocompatibility.


Reconstructing the history of marriage strategies in Indo-European-speaking societies: monogamy and polygyny.
Explanations for the emergence of monogamous marriage have focused on the cross-cultural distribution of marriage strategies, thus failing to account for their history. In this paper I reconstruct the pattern of change in marriage strategies in the history of societies speaking Indo-European languages, using cross-cultural data in the systematic and explicitly historical framework afforded by the phylogenetic comparative approach. The analysis provides evidence in support of Proto-Indo-European monogamy, and that this pattern may have extended back to Proto-Indo-Hittite. These reconstructions push the origin of monogamous marriage into prehistory, well beyond the earliest instances documented in the historical record; this, in turn, challenges notions that the cross-cultural distribution of monogamous marriage reflects features of social organization typically associated with Eurasian societies, and with "societal complexity" and "modernization" more generally. I discuss implications of these findings in the context of the archaeological and genetic evidence on prehistoric social organization.


Group B Streptococcal Disease in England (1998 - 2017): A Population-based Observational Study.
Group B Streptococcus (GBS) is the leading cause of sepsis and meningitis in infants <90 days. In this study, the burden of GBS disease and mortality in young infants in England was assessed. Using linked hospitalization records from every National Health Service (NHS) hospital from April 1, 1998 to March 31, 2017, we calculated annual GBS incidence in infants aged <90 days and, using regression models, compared their perinatal factors, rates of hospital-recorded disease outcomes, and all-cause infant mortality rates with those of the general infant population. 15 429 infants aged <90 days had a hospital-recorded diagnosis of GBS, giving an average annual incidence of 1.28 per 1000 live births (95% CI 1.26-1.30) with no significant trend over time. GBS-attributable mortality declined significantly from 0.044 (95% CI .029-.065) per 1000 live births in 2001 to 0.014 (95% CI .010-.026) in 2017 (annual percentage change -6.6, 95% CI -9.1 to -4.0). Infants with GBS had higher relative rates of visual impairment (HR 7.0 95% CI 4.1-12.1), cerebral palsy (HR 9.3 95% CI 6.6-13.3), hydrocephalus (HR 17.3 95% CI 13.8-21.6), and necrotizing enterocolitis (HR 18.8 95% CI 16.7-21.2) compared with those without GBS. Annual rates of GBS disease in infants have not changed over 19 years. The reduction in mortality is likely multifactorial and due to widespread implementation of antibiotics in at-risk mothers and babies, as well as advances in managing acutely unwell infants. New methods for prevention, such as maternal vaccination, must be prioritized.


Population-based study of acute- and long-term care costs after stroke in patients with AF.
New treatments for atrial fibrillation patients have been shown to be effective at reducing subsequent vascular event recurrence. However, there are few data on stroke costs in atrial fibrillation patients to allow the cost-effectiveness of these treatments to be assessed. Using data from a population-based study, we assessed the acute and long-term costs of stroke in atrial fibrillation patients. Health-care costs one-year before and five-years after stroke were obtained from a large population-based study (Oxford Vascular study). Costs were assessed for the three-months poststroke (acute period) and annually thereafter (postacute period). Annual postacute costs were compared with annual baseline costs. Based on patients' living arrangements, costs of institutionalization after the event were included. A total of 191 strokes occurred in 153 patients with known prior atrial fibrillation. Mean health-care costs after stroke were £10 413 (standard deviation 15 105) in the acute phase, with annual postacute health-care costs nonsignificantly smaller than those incurred before the event (£2400 vs. £3356, respectively; P = 0·198). However, for the 136 strokes surviving past the 90-day acute period, costs were nonsignificantly higher than those incurred in the year before the event (£3370 vs. £2566, respectively; P = 0·333). After stroke, 25 (13%) patients were newly admitted into long-term warden, nursing, or residential care, resulting in annual costs of £6880 (standard deviation 15 600) averaged across the 136 stroke cases surviving past the acute period. Although annual post acute phase hospital and primary health-care costs in stroke patients with prior atrial fibrillation were not significantly different to those incurred before the stroke, long-term nursing/residential care costs were substantial.


Metabolically healthy obesity: facts and fantasies.
Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered "metabolically healthy." However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO - specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.


Challenges of a hidden epidemic: HIV prevention among women in the United States.
HIV/AIDS trends in the United States depict a concentrated epidemic with hot spots that vary by location, poverty, race/ethnicity, and transmission mode. HIV/AIDS is a leading cause of death among US women of color; two-thirds of new infections among women occur in black women, despite the fact that black women account for just 14% of the US female population. The gravity of the HIV epidemic among US women is often not appreciated by those at risk and by the broader scientific community. We summarize the current epidemiology of HIV/AIDS among US women and discuss clinical, research, and public health intervention components that must be brought together in a cohesive plan to reduce new HIV infections in US women. Only by accelerating research and programmatic efforts will the hidden epidemic of HIV among US women emerge into the light and come under control.


Defining long-term maintenance conditions of human embryonic stem cells with arrayed cellular microenvironment technology.
The optimization of defined growth conditions is necessary for the development of clinical application of human embryonic stem cells (hESCs). Current research has focused on developing defined media formulations for long-term culture of hESCs with little attention on the establishment of defined substrates for hESC proliferation and self-renewal. Presently available technologies are insufficient to address the full complement of factors that may regulate hESC proliferation and maintenance of pluripotency. Here, we report the application of a multifactorial array technology to identify fully defined and optimized culture conditions for the proliferation of hESCs. Through the systematic screening of extracellular matrix proteins (ECMPs) and other signaling molecules, we developed and characterized a completely defined culture system for the long-term self-renewal of three independent hESC lines. In the future, the novel array platform and analysis procedure presented here will be applied toward the directed differentiation of hESCs and maintenance of other stem and progenitor cell populations.


The regulatory function of self-conscious emotion: insights from patients with orbitofrontal damage.
Although once considered disruptive, self-conscious emotions are now theorized to be fundamentally involved in the regulation of social behavior. The present study examined the social regulation function of self-conscious emotions by comparing healthy participants with a neuropsychological population--patients with orbitofrontal lesions--characterized by selective regulatory deficits. Orbitofrontal patients and healthy controls participated in a series of tasks designed to assess their social regulation and self-conscious emotions. Another task assessed the ability to infer others' emotional states, an appraisal process involved in self-conscious emotion. Consistent with the theory that self-conscious emotions are important for regulating social behavior, the findings show that deficient behavioral regulation is associated with inappropriate self-conscious emotions that reinforce maladaptive behavior. Additionally, deficient behavioral regulation is associated with impairments in interpreting the self-conscious emotions of others.


Ultra-soft PDMS-based magnetoactive elastomers as dynamic cell culture substrata.
Mechanical cues such as extracellular matrix stiffness and movement have a major impact on cell differentiation and function. To replicate these biological features in vitro, soft substrata with tunable elasticity and the possibility for controlled surface translocation are desirable. Here we report on the use of ultra-soft (Young's modulus <100 kPa) PDMS-based magnetoactive elastomers (MAE) as suitable cell culture substrata. Soft non-viscous PDMS (<18 kPa) is produced using a modified extended crosslinker. MAEs are generated by embedding magnetic microparticles into a soft PDMS matrix. Both substrata yield an elasticity-dependent (14 vs. 100 kPa) modulation of α-smooth muscle actin expression in primary human fibroblasts. To allow for static or dynamic control of MAE material properties, we devise low magnetic field (≈40 mT) stimulation systems compatible with cell-culture environments. Magnetic field-instigated stiffening (14 to 200 kPa) of soft MAE enhances the spreading of primary human fibroblasts and decreases PAX-7 transcription in human mesenchymal stem cells. Pulsatile MAE movements are generated using oscillating magnetic fields and are well tolerated by adherent human fibroblasts. This MAE system provides spatial and temporal control of substratum material characteristics and permits novel designs when used as dynamic cell culture substrata or cell culture-coated actuator in tissue engineering applications or biomedical devices.


Long-term remission of diabetes in NOD mice is induced by nondepleting anti-CD4 and anti-CD8 antibodies.
Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell-specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell-specific T-cell tolerance at the onset of clinical diabetes.


Persistent suppression of subthalamic beta-band activity during rhythmic finger tapping in Parkinson's disease.
The function of synchronous oscillatory activity at beta band (15-30Hz) frequencies within the basal ganglia is unclear. Here we sought support for the hypothesis that beta activity has a global function within the basal ganglia and is not directly involved in the coding of specific biomechanical parameters of movement. We recorded local field potential activity from the subthalamic nuclei of 11 patients with Parkinson's disease during a synchronized tapping task at three different externally cued rates. Beta activity was suppressed during tapping, reaching a minimum that differed little across the different tapping rates despite an increase in velocity of finger movements. Thus beta power suppression was independent of specific motor parameters. Moreover, although beta oscillations remained suppressed during all tapping rates, periods of resynchronization between taps were markedly attenuated during high rate tapping. As such, a beta rebound above baseline between taps at the lower rates was absent at the high rate. Our results demonstrate that beta desynchronization in the region of the subthalamic nucleus is independent of motor parameters and that the beta resynchronization is differentially modulated by rate of finger tapping, These findings implicate consistent beta suppression in the facilitation of continuous movement sequences.


Requirement for deoxycytidine kinase in T and B lymphocyte development.
Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway that recycles products of DNA degradation. dCK phosphorylates and therefore activates nucleoside analog prodrugs frequently used in cancer, autoimmunity, and viral infections. In contrast to its well established therapeutic relevance, the biological function of dCK remains enigmatic. Highest levels of dCK expression are found in thymus and bone marrow, indicating a possible role in lymphopoiesis. To test this hypothesis we generated and analyzed dCK knockout (KO) mice. dCK inactivation selectively and profoundly affected T and B cell development. A 90-fold decrease in thymic cellularity was observed in the dCK KO mice relative to wild-type littermates. Lymphocyte numbers in the dCK KO mice were 5- to 13-fold below normal values. The severe impact of dCK inactivation on lymphopoiesis was unexpected given that nucleoside salvage has been thought to play a limited, "fine-tuning" role in regulating deoxyribonucleotide triphosphate pools produced by the de novo pathway. The dCK KO phenotype challenges this view and indicates that, in contrast to the great majority of other somatic cells, normal lymphocyte development critically requires the deoxyribonucleoside salvage pathway.


[Effect of electroacupuncture of "Taichong" (LR 3) on liver function in mild alcoholic liver injury rats].
To observe the effect of electroacupuncture (EA) of "Taichong" (LR 3) on liver function in rats with mild alcoholic liver injury (MALI) so as to explore the feasibility of acupuncture in improving mild alcoholic liver injury. Forty SD rats were randomly divided into control, model, EA-LR 3 and EA-non-acupoint groups (10 rats/group). MALI model was duplicated by intragastric administration of distillate spirit (14 mL/kg) for 12 hours. Rats of the control group were fed with the same volume of normal saline. EA (2 Hz, 6 V) was applied to bilateral "Taichong" (LR 3) and non-acupoint (the interspace between the 4th and 5th bones of toes in parallel with LR 3) for 30 min, respectively. At the end of experiments, rats were sacrificed for collecting liver tissues. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) of the liver supernatant were detected by using Lai's method. IIn comparison with the control group, liver ALT and AST activities in the model group were increased significantly (P < 0.05), while in comparison with the model group, liver ALT and AST levels in the EA-LR 3 group were down-regulated remarkably (P < 0.05). No significant changes were found in liver ALT and AST level in the EA-non-acupoint group (P > 0.05). There was no significant improvement in the pathological changes of liver in the EA-LR 3 and EA-non-acupoint groups. EA of "Taichong"(LR 3) may reduce distillate-spirit induced mild alcoholic liver injury in rats.


Is acupuncture beneficial in the treatment of Bell's palsy?: best evidence topic (BET).
A best evidence topic in facial nerve surgery was written according to a structured protocol. The question addressed was: in [patients with Bell's palsy], does [acupuncture] improve [facial nerve function and/or pain]? A total of 43 papers were identified using the reported search protocol, of which three articles represented the best available evidence to answer the clinical question. Two of these articles were review papers and together encompassed 13 primary articles. Publication details, type of study, patients studied, outcomes and results are tabulated. The two level 1 articles concluded that before firm conclusions can be drawn, better designed trials are required in order to establish whether acupuncture confers any benefit to patients with Bell's palsy. The level 2 randomised controlled trial (RCT) suggested that two methods of acupuncture were associated with significant improvements in pain in Bell's palsy, although the trial was poorly controlled and had risk of bias. Therefore, the clinical bottom line is that until well designed trials are able to clearly demonstrate a role for acupuncture in Bell's palsy, its efficacy should be considered to remain unproven.


Flow enhanced non-linear magnetophoretic separation of beads based on magnetic susceptibility.
Magnetic separation provides a rapid and efficient means of isolating biomaterials from complex mixtures based on their adsorption on superparamagnetic (SPM) beads. Flow enhanced non-linear magnetophoresis (FNLM) is a high-resolution mode of separation in which hydrodynamic and magnetic fields are controlled with micron resolution to isolate SPM beads with specific physical properties. In this article we demonstrate that a change in the critical frequency of FNLM can be used to identify beads with magnetic susceptibilities between 0.01 and 1.0 with a sensitivity of 0.01 Hz(-1). We derived an analytical expression for the critical frequency that explicitly incorporates the magnetic and non-magnetic composition of a complex to be separated. This expression was then applied to two cases involving the detection and separation of biological targets. This study defines the operating principles of FNLM and highlights the potential for using this technique for multiplexing diagnostic assays and isolating rare cell types.


Acupuncture for cerebral vasospasm after subarachnoid hemorrhage: a retrospective case-control study.
To examine the possibility of acupuncture as a new promising treatment to prevent delayed cerebral vasospasm, retrospective comparison was done of patient outcomes in patients with subarachnoid hemorrhage (SAH) treated with and without acupuncture. Twenty (20) patients with SAH were treated after their ruptured aneurysms had been secured. Acupuncture treatments were applied to the bilateral Zusanli (ST36) and Neiguan (PC6) once a day for 2 weeks, starting within 3 days of the aneurysm rupture. The incidence of angiographic vasospasm and delayed ischemic neurological deficit (DIND), the patient's functional status at discharge, and mortality rate were analyzed. Patient outcomes were compared with those of an age- and severity-matched comparison group composed of patients treated in the hospital without acupuncture. None of the patients who received acupuncture died. Angiographic vasospasms occurred in 5 patients (25.0%) and DIND in 2 (10%). In terms of functional impairment, the modified Rankin score at discharge was ≤2 in 7 patients (35%). In the control group, angiographic vasospasms occurred in 10 patients (55.6%) and DIND in 7 (38.9%), similar to the reported incidence in conventionally treated patients. Patients with SAH who received acupuncture had a significantly lower incidence of DIND and significantly improved function at discharge, suggesting that acupuncture is effective in preventing cerebral vasospasm. In light of these promising results, a randomized controlled trial is warranted to determine the efficacy of acupuncture in a clinical setting.


Oocyte glycoproteins regulate the form and function of the follicle basal lamina and theca cells.
Maintaining follicle integrity during development, whereby each follicle is a functional unit containing a single oocyte, is essential for the generation of healthy oocytes. However, the mechanisms that regulate this critical function have not been determined. In this paper we investigate the role of the oocyte in maintaining follicle development. To investigate this role, we use a mouse model with oocyte-specific deletion of C1galt1 which is required for the generation of core 1-derived O-glycans. The loss of oocyte-generated O-glycans results in the joining of follicles and the generation of Multiple-Oocyte Follicles (MOFs). The aim was to determine how Mutant follicle development is modified thus enabling follicles to join. Extracellular matrix and follicle permeability were studied using histology, immunohistochemistry and electron microscopy (EM). In ovaries containing Mutant Oocytes, the Follicle basal lamina (FBL) is altered both functionally and structurally from the primary stage onwards with Mutant follicles possessing unexpectedly thicker FBL. In Mutant ovaries, the theca cell layer is also modified with intermingling of theca between adjacent follicles. MOF function was analysed but despite increased numbers of preantral MOFs in Mutants, these do not reach the preovulatory stage after gonadotrophin stimulation. We propose a model describing how oocyte initiated changes in FBL and theca cells result in follicles joining. These data reveal new and important roles for the oocyte in follicle development and follicle integrity.


Global data for ecology and epidemiology: a novel algorithm for temporal Fourier processing MODIS data.
Remotely-sensed environmental data from earth-orbiting satellites are increasingly used to model the distribution and abundance of both plant and animal species, especially those of economic or conservation importance. Time series of data from the MODerate-resolution Imaging Spectroradiometer (MODIS) sensors on-board NASA's Terra and Aqua satellites offer the potential to capture environmental thermal and vegetation seasonality, through temporal Fourier analysis, more accurately than was previously possible using the NOAA Advanced Very High Resolution Radiometer (AVHRR) sensor data. MODIS data are composited over 8- or 16-day time intervals that pose unique problems for temporal Fourier analysis. Applying standard techniques to MODIS data can introduce errors of up to 30% in the estimation of the amplitudes and phases of the Fourier harmonics. We present a novel spline-based algorithm that overcomes the processing problems of composited MODIS data. The algorithm is tested on artificial data generated using randomly selected values of both amplitudes and phases, and provides an accurate estimate of the input variables under all conditions. The algorithm was then applied to produce layers that capture the seasonality in MODIS data for the period from 2001 to 2005. Global temporal Fourier processed images of 1 km MODIS data for Middle Infrared Reflectance, day- and night-time Land Surface Temperature (LST), Normalised Difference Vegetation Index (NDVI), and Enhanced Vegetation Index (EVI) are presented for ecological and epidemiological applications. The finer spatial and temporal resolution, combined with the greater geolocational and spectral accuracy of the MODIS instruments, compared with previous multi-temporal data sets, mean that these data may be used with greater confidence in species' distribution modelling.


Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain.
Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression.


Mechanism for aldose-ketose interconversion by D-xylose isomerase involving ring opening followed by a 1,2-hydride shift.
The active site and mechanism of D-xylose isomerase have been probed by determination of the crystal structures of the enzyme bound to various substrates, inhibitors and cations. Ring-opening is an obligatory first step of the reaction and is believed to be the rate-determining step for the aldose to ketose conversion. The structure of a complex with a cyclic thio-glucose has been determined and it is concluded that this is an analogue of the Michaelis complex. At -10 degrees C substrates in crystals are observed in the extended chain form. The absence of an appropriately situated base for either the cyclic or extended chain forms from the substrate binding site indicates that the isomerisation does not take place by an enediol or enediolate mechanism. Binding of a trivalent cation places an additional charge at the active site, producing a substrate complex that is analogous to a possible transition state. Of the two binding sites for divalent cations, [1] is permanently occupied under catalytic conditions and is co-ordinated to four carboxylate groups. In the absence of substrate it is exposed to solvent, and in the Michaelis complex analogue, site [1] is octahedrally coordinated, with ligands to O-3 and O-4 of the thiopyranose. In the complex with an open-chain substrate it remains octahedrally co-ordinated, with ligands to O-2 and O-4. Binding at a second cation site [2] is also necessary for catalysis and this site is believed to bind Co2+ more strongly than site [1]. This site is octahedrally co-ordinated to three carboxylate groups (bidentate co-ordination to one of them), an imidazole and a solvent molecule. It is proposed that during the hydride shift the C-O-1 and C-O-2 bonds of the substrate are polarized by the close approach of the site [2] cation. In the transition-state analogue this cation is observed at a site [2'], 1.0 A from site [2] and about 2.7 A from O-1 and O-2 of the substrate. It is likely that co-ordination of the cation to O-1 and O-2 would be concomitant with ionisation of the sugar hydroxyl group. The polarisation of C-O-1 and C-O-2 is assisted by the co-ordination of O-2 to cation [1] and O-1 to a lysine side-chain.(ABSTRACT TRUNCATED AT 400 WORDS)


Synthesis, crystal structure and catalytic behavior of homo- and heteronuclear coordination polymers [M(tdc)(bpy)] (M2+ = Fe2+, Co2+, Zn2+, Cd2+; tdc2- = 2,5-thiophenedicarboxylate).
A series of isostructural 3D coordination polymers (3)∞[M(tdc)(bpy)] (M(2+) = Zn(2+), Cd(2+), Co(2+), Fe(2+); tdc(2-) = 2,5-thiophenedicarboxylate; bpy = 4,4'-bipyridine) was synthesized and characterized by X-ray diffraction, thermal analysis, and gas adsorption measurements. The materials show high thermal stability up to approximately 400 °C and a solvent induced phase transition. Single crystal X-ray structure determination was successfully performed for all compounds after the phase transition. In the zinc-based coordination polymer, various amounts of a second type of metal ions such as Co(2+) or Fe(2+) could be incorporated. Furthermore, the catalytic behavior of the homo- and heteronuclear 3D coordination polymers in an oxidation model reaction was investigated.


Quantitative analysis of ipsilateral and contralateral supracerebellar infratentorial and occipital transtentorial approaches to the cisternal pulvinar: laboratory anatomical investigation.
The cisternal pulvinar is a challenging location for neurosurgery. Four approaches for reaching the pulvinar without cortical transgression are the ipsilateral supracerebellar infratentorial (iSCIT), contralateral supracerebellar infratentorial (cSCIT), ipsilateral occipital transtentorial (iOCTT), and contralateral occipital transtentorial/falcine (cOCTF) approaches. This study quantitatively compared these approaches in terms of surgical exposure and maneuverability. Each of the 4 approaches was performed in 4 cadaveric heads (8 specimens in total). A 6-sided anatomical polygonal region was configured over the cisternal pulvinar, defined by 6 reachable anatomical points in different vectors. Multiple polygons were subsequently formed to calculate the areas of exposure. The surgical freedom of each approach was calculated as the maximum allowable working area at the proximal end of a probe, with the distal end fixed at the posterior pole of the pulvinar. Areas of exposure, surgical freedom, and the working distance (surgical depth) of all approaches were compared. No significant difference was found among the 4 different approaches with regard to the surgical depth, surgical freedom, or medial exposure area of the pulvinar. In the pairwise comparison, the cSCIT approach provided a significantly larger lateral exposure (39 ± 9.8 mm2) than iSCIT (19 ± 10.3 mm2, p < 0.01), iOCTT (19 ± 8.2 mm2, p < 0.01), and cOCTF (28 ± 7.3 mm2, p = 0.02) approaches. The total exposure area with a cSCIT approach (75 ± 23.1 mm2) was significantly larger than with iOCTT (43 ± 16.4 mm2, p < 0.01) and iSCIT (40 ± 20.2 mm2, p = 0.01) approaches (pairwise, p ≤ 0.01). The cSCIT approach is preferable among the 4 compared approaches, demonstrating better exposure to the cisternal pulvinar than ipsilateral approaches and a larger lateral exposure than the cOCTF approach. Both contralateral approaches described (cSCIT and cOCTF) provided enhanced lateral exposure to the pulvinar, while the cOCTF provided a larger exposure to the lateral portion of the pulvinar than the iOCTT. Medial exposure and maneuverability did not differ among the approaches. A short tentorium may negatively impact an ipsilateral approach because the cingulate isthmus and parahippocampal gyrus tend to protrude, in which case they can obstruct access to the cisternal pulvinar ipsilaterally.


Gamma knife surgery for skull base meningiomas.
Skull base meningiomas are challenging tumors owing in part to their close proximity to important neurovascular structures. Complete microsurgical resection can be associated with significant morbidity, and recurrence rates are not inconsequential. In this study, the authors evaluate the outcomes of skull base meningiomas treated with Gamma Knife surgery (GKS) both as an adjunct to microsurgery and as a primary treatment modality. The authors performed a retrospective review of a prospectively compiled database detailing the outcomes in 255 patients with skull base meningiomas treated at the University of Virginia from 1989 to 2006. All patients had a minimum follow-up of 24 months. The group comprised 54 male and 201 female patients, with a median age of 55 years (range 19-85 years). One hundred nine patients were treated with upfront radiosurgery, and 146 patients were treated with GKS following resection. Patients were assessed clinically and radiographically at routine intervals following GKS. Factors predictive of new neurological deficit following GKS were assessed via univariate and multivariate analysis, and Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression. Meningiomas were centered over the cerebellopontine angle in 43 patients (17%), the clivus in 40 (16%), the petroclival region in 28 (11%), the petrous region in 6 (2%), and the parasellar region in 138 (54%). The median duration of follow-up was 6.5 years (range 2-18 years). The mean preradiosurgery tumor volume was 5.0 cm(3) (range 0.3-54.8 cm(3)). At most recent follow-up, 220 patients (86%) displayed either no change or a decrease in tumor volume, and 35 (14%) displayed an increase in volume. Actuarial progression-free survival at 3, 5, and 10 years was 99%, 96%, and 79%, respectively. In Cox multivariate analysis, pre-GKS covariates associated with tumor progression included age greater then 65 years (HR 3.41, 95% CI 1.63-7.13, p = 0.001) and decreasing dose to tumor margin (HR 0.90, 95% CI 0.80-1.00, p = 0.05). At most recent clinical follow-up, 230 patients (90%) demonstrated no change or improvement in their neurological condition and the condition of 25 patients had deteriorated (10%). In multivariate analysis, the factors predictive of new or worsening symptoms were increasing duration of follow-up (OR 1.01, 95% CI 1.00-1.02, p = 0.015), tumor progression (OR 2.91, 95% CI 1.60-5.31, p < 0.001), decreasing maximum dose (OR 0.90, 95% CI 0.84-0.97, p = 0.007), and petrous or clival location versus parasellar, petroclival, and cerebellopontine angle location (OR 3.47, 95% CI 1.23-9.74, p = 0.018). Stereotactic radiosurgery offers a high rate of tumor control and neurological preservation in patients with skull base meningiomas. After radiosurgery, better outcomes were observed for those receiving an optimal radiosurgery dose and harboring tumors located in a cerebellopontine angle, parasellar, or petroclival location.