Vogesella alkaliphila sp. nov., isolated from an alkaline soil, and emended description of the genus Vogesella.
Strain JC141(T) was isolated from an alkaline soil (pH 8.8) at Mau, Uttar Pradesh, India. Colonies were blue with a metallic sheen; cells stained Gram-negative, and were oxidase- and catalase-positive, but chitinase-negative. Major fatty acids were C16:1ω7c/C16:1ω6c, C16:0 and C18:0 with minor amounts of C10:0, C10:0 3-OH, C12:0, C14:0 and C18:1ω7c. Strain JC141(T) contained phosphatidylethanolamine and phosphatidylglycerol as major polar lipids, with minor amounts of diphosphatidylglycerol, unidentified aminolipids (AL1-3) and unidentified lipids (L1-4). A bacterial hopane derivative (BHD1) was the major hopanoid. Genomic DNA G+C content was 62.5 mol%. 16S rRNA gene sequence comparisons indicated that strain JC141(T) represents a member of the genus Vogesella within the family Neisseriaceae of the class Betaproteobacteria. Strain JC141(T) had a 16S rRNA gene sequence similarity of 98% with Vogesella indigofera ATCC 19706(T) and <96.5% with other members of the genus Vogesella. However, strain JC141(T) showed 45.8% relatedness (based on DNA-DNA hybridization) with V. indigofera LMG 6867(T) (=ATCC 19706(T)). Distinct morphological, physiological and genotypic differences from previously described taxa support the classification of strain JC141(T) as a representative of a novel species in the genus Vogesella, for which the name Vogesella alkaliphila sp. nov. is proposed. The type strain is JC141(T) (=KCTC 32041(T)=LMG 27066(T)). An emended description of the genus Vogesella is also proposed.


The Pseudomonas secondary metabolite 2,4-diacetylphloroglucinol is a signal inducing rhizoplane expression of Azospirillum genes involved in plant-growth promotion.
During evolution, plants have become associated with guilds of plant-growth-promoting rhizobacteria (PGPR), which raises the possibility that individual PGPR populations may have developed mechanisms to cointeract with one another on plant roots. We hypothesize that this has resulted in signaling phenomena between different types of PGPR colonizing the same roots. Here, the objective was to determine whether the Pseudomonas secondary metabolite 2,4-diacetylphloroglucinol (DAPG) can act as a signal on Azospirillum PGPR and enhance the phytostimulation effects of the latter. On roots, the DAPG-producing Pseudomonas fluorescens F113 strain but not its phl-negative mutant enhanced the phytostimulatory effect of Azospirillum brasilense Sp245-Rif on wheat. Accordingly, DAPG enhanced Sp245-Rif traits involved in root colonization (cell motility, biofilm formation, and poly-β-hydroxybutyrate production) and phytostimulation (auxin production). A differential fluorescence induction promoter-trapping approach based on flow cytometry was then used to identify Sp245-Rif genes upregulated by DAPG. DAPG enhanced expression of a wide range of Sp245-Rif genes, including genes involved in phytostimulation. Four of them (i.e., ppdC, flgE, nirK, and nifX-nifB) tended to be upregulated on roots in the presence of P. fluorescens F113 compared with its phl-negative mutant. Our results indicate that DAPG can act as a signal by which some beneficial pseudomonads may stimulate plant-beneficial activities of Azospirillum PGPR.


Assessing intracortical myelin in the living human brain using myelinated cortical thickness.
Alterations in the myelination of the cerebral cortex may underlie abnormal cortical function in a variety of brain diseases. Here, we describe a technique for investigating changes in intracortical myelin in clinical populations on the basis of cortical thickness measurements with magnetic resonance imaging (MRI) at 3 Tesla. For this, we separately compute the thickness of the shallower, lightly myelinated portion of the cortex and its deeper, heavily myelinated portion (referred to herein as unmyelinated and myelinated cortex, respectively). Our expectation is that the thickness of the myelinated cortex will be a specific biomarker for disruptions in myeloarchitecture. We show representative atlases of total cortical thickness, T, unmyelinated cortical thickness, G, and myelinated cortical thickness, M, for a healthy group of 20 female subjects. We further demonstrate myelinated cortical thickness measurements in a preliminary clinical study of 10 bipolar disorder type-I subjects and 10 healthy controls, and report significant decreases in the middle frontal gyrus in T, G, and M in the disorder, with the largest percentage change occurring in M. This study highlights the potential of myelinated cortical thickness measurements for investigating intracortical myelin involvement in brain disease at clinically relevant field strengths and resolutions.


Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor.
Endothelin-1 (ET-1) is a potent vasoconstrictor that also stimulates cells in the osteoblast lineage by binding to the endothelin A receptor (ETAR). ET-1 ligand is widely secreted, particularly by the vasculature. However, the contributions of ETAR signaling to adult bone homeostasis have not been defined. ETAR was inactivated in osteoblasts by crossing ETAR-floxed and osteocalcin-Cre mice. Histomorphometric analyses were performed on 4-, 8-, and 12-week-old osteoblast-targeted ETAR knockout (KO) and wild-type (WT) male and female mice. Tibial trabecular bone volume was significantly lower from 12 weeks in KO versus WT mice in both males and females. Bone-formation rate, osteoblast density, and in vitro osteoblast differentiation were reduced by targeted inactivation of ETAR. A separate longitudinal analysis was performed between 8 and 64 weeks to examine the effect of aging and castration on bone metabolism in ETAR KO mice. Hypogonadism did not change the rate of bone accrual in WT or KO females. However, eugonadal KO males had a significantly larger increase in tibial and femoral bone acquisition than WT mice. Male mice castrated at 8 weeks of age showed the reverse: KO mice had reduced rates of tibial and femoral BMD acquisition compared with WT mice. In vitro, ET-1 increased osteoblast proliferation, survival, and differentiation. Dihydrotestosterone also increased osteoblast differentiation using a mechanism distinct from the actions of ET-1. These results demonstrate that endothelin signaling in osteoblasts is an important regulator of postnatal trabecular bone remodeling and a modulator of androgen effects on bone.


Anti-adipogenic effects of sesamol on human mesenchymal stem cells.
Human mesenchymal stem cells (hMSCs) from adult bone marrow are able to differentiate into adipocytes, osteoblasts, chondrocytes and neuronal cells. Adipocytes in bone marrow are primarily responsible for the maintenance of bone structure by maintaining cell number balance with other stromal cells. However, the number of adipocytes in the bone marrow increases with age, leading to an imbalance of the bone marrow microenvironment, which results in a disruption of bone structure. In addition, the excessive number of adipocytes in bone marrow can cause diseases, such as osteoporosis or anemia. In this study, we investigated the effect of sesamol, a major natural phenolic compound of sesame oil, on the adipogenic differentiation of hMSCs. Numerous studies have reported the anti-oxidant property of sesamol, but its effect on cell differentiation has not yet been shown. We first found that sesamol treatment during adipogenic differentiation of hMSCs reduced intracellular lipid accumulation, which was unrelated to lipolysis. Interestingly, sesamol diminished the expression of genes responsible for adipogenesis, but increased the expression of osteogenic genes. In addition, sesamol decreased the expression of genes necessary for adipocyte maturation without affecting the expression of hMSC-specific genes. Studies concerning intracellular signaling in hMSCs showed that the extracellular signal-regulated kinase 1/2 (ERK1/2) was decreased by sesamol, which was similar with the effect of an ERK1/2 inhibitor. Overall, this study demonstrates that sesamol can attenuate the adipogenic differentiation of hMSCs without affecting its characteristics through the inhibition of ERK1/2 pathway. Herein, this study reports for the first time the effect of sesamol on hMSC differentiation and suggests the possibility of using sesamol as a therapeutic agent to treat intraosseous disruption triggered by the excessive adipogenesis of hMSCs.


Early prediction of revascularisation by angiomotin-targeting positron emission tomography.
This study aimed to develop a PET imaging agent of angiomotin (AMOT) expression, a potential biomarker of functional tissue regeneration in post-ischaemic conditions. Methods: Hindlimb ischaemia was induced by ligature and resection of the right femoral artery in mice, and clinical score and limb perfusion were evaluated up to 30 days after surgery. AMOT expression was evaluated by histology and Western blot analysis. NODAGA-conjugates of AMOT ligand, sCD146, were designed, synthesised and radiolabelled with gallium-68. 68Ga-sCD146 microPET/CT imaging was performed from day 1 to day 30 after ischaemia. 68Ga-sCD146 specificity for AMOT was evaluated by autoradiography. Results: Immunohistochemistry showed a significant endothelial overexpression of AMOT from day 5 up to day 10 in the ischaemic hindlimb. 68Ga-sCD146 PET signal intensity correlated significantly with AMOT immunohistochemistry evaluation. 68Ga-sCD146 PET imaging showed a significant uptake in the ischaemic hindlimb from day 2 to day 15, peaking on day 5 (ipsi/contralateral ratio = 2.4 ± 1.3, P = 0.0005) and significantly decreased after pharmacological blocking (62.57 ± 11% decrease in PET signal P = 0.032). Finally, we observed a significant correlation between day 5 68Ga-sCD146 PET signal intensity and clinical recovery (day 28) or hindlimb perfusion recovery (day 30). Conclusions: This work reports for the first time an early and sustained increase in AMOT expression after hindlimb ischaemia in mice. We therefore developed an AMOT-targeting imaging agent, 68Ga-sCD146, and showed its specific uptake up to 21 days after ischaemic hindlimb using microPET imaging. Correlation of early post-ischaemic PET signal with both delayed perfusion recovery and clinical outcome allows us to postulate that 68Ga-sCD146 represents a promising radiotracer for tissue angiogenesis assessment.


[A psychopathological study on three-dimensional computer graphics (3DCGs): special reference to pictures made by a schizophrenic patient before and after the onset].
A patient with catatonic type schizophrenia drawing 3-dimensional computer graphics (3DCGs) before and after the onset is reported. His 3DCGs are discussed from the view of psychopathology. A 21-year-old male was admitted to our hospital. He was an art student. For three months before admission, he had been absorbed in drawing 3DCGs. When he was asked to draw handmade pictures by his teacher, he experienced a bizarre mood and took an overdose of aspirin. At the time of admission, he was in a stupor state, and was diagnosed with catatonic type schizophrenia. After admission, he exhibited excitement and disorganized speech. These symptoms disappeared after administration of neuroleptics, and he was discharged. The 3DCGs he drew before and after the onset revealed several special characteristics. First, the compositions of his pictures were too geometric and too precise. Secondly, the themes of his pictures changed from romantic before the onset to symbolic after it, and the styles changed from realistic to abstractive after the onset. Finally, histograms of the 3DCGs revealed many colors before onset, which converged to simple colors after. Therefore, it was suggested that the latent pathological process at the beginning of schizophrenia might be reflected in his 3DCGs. 3DCGs are a new type of fine art. They can express beautiful and cool images more simply than handmade pictures. Due to these features, artists can create images of their innerworld, with less effort and talent than picture drawings, by computer assistance. This case suggests that the geometric working space, change-free viewpoints, and computer assistance, which are characteristics of the methods in making 3DCGs may be suitable for schizophrenic artists to create images of their innerworld. However, being absorbed in making 3DCGs could also promote the latent schizophrenic process to the onset.


Improving ruthenium-based ECL through nonionic surfactants and tertiary amines.
The influence of surfactants and coreactants on Ru(bpy)32+ electrogenerated chemiluminescence (ECL) was investigated comparatively. Specifically, the influence that the two tertiary amines, N-butyldiethanolamine (NBEA) and 2-(dibutylamino)ethanol (DBAE) have on the ECL reaction, alone and in the presence of the two surfactants Triton™ X-100 and Zonyl® FSN, was investigated, in comparison with that of the well-studied and established coreactant tripropylamine (TPA). Experiments were conducted on poly(methyl methacrylate) substrates coated with plasma-evaporated gold as used in many miniaturized systems. Upon optimization and study of the various combinations, the combination of NBEA/Zonyl FSN provided superior ECL signal characteristics. A limit of detection (LOD) of 2.2 nM Ru(bpy)32+ was obtained. Compared with the LOD of 0.59 μM for the commonly used TPA/Triton™ X-100 system, the resulting LOD is enhanced by a factor of 250. In addition, significantly more stable signals lead to an increase in sensitivity by a factor of 50. This makes the NBEA/Zonyl® FSN system an attractive ECL strategy, especially for miniaturized analytical systems. Furthermore, it became clear that previously postulated effects of surfactants on the enhancement of coreactant-based ECL do not translate to other surfactants and coreactants. We could demonstrate that more complicated mechanisms are at play as the ECL intensity for Ru(bpy)32+/NBEA was the highest in the presence of Zonyl® FSN, whereas the ECL signal decreased significantly upon introduction of the surfactant with DBAE as coreactant.


CD30/CD30 ligand (CD153) interaction regulates CD4+ T cell-mediated graft-versus-host disease.
CD30, a TNFR family member, is expressed on activated CD4(+) and CD8(+) T cells and B cells and is a marker of Hodgkin's lymphoma; its ligand, CD30L (CD153) is expressed by activated CD4(+) and CD8(+) T cells, B cells, and macrophages. Signaling via CD30 can lead to proliferation or cell death. CD30-deficient (-/-) mice have impaired thymic negative selection and increased autoreactivity. Although human alloreactive T cells preferentially reside within the CD30(+) T cell subset, implicating CD30 as a regulator of T cell immune responses, the role of CD30/CD153 in regulating graft-vs-host disease (GVHD) has not been reported. We used a neutralizing anti-CD153 mAb, CD30(-/-) donor mice, and generated CD153(-/-) recipient mice to analyze the effect of CD30/CD153 interaction on GVHD induction. Our data indicate that the CD30/CD153 pathway is a potent regulator of CD4(+), but not CD8(+), T cell-mediated GVHD. Although blocking CD30/CD153 interactions in vivo did not affect alloreactive CD4(+) T cell proliferation or apoptosis, a substantial reduction in donor CD4(+) T cell migration into the gastrointestinal tract was readily observed with lesser effects in other GVHD target organs. Blockade of the CD30/CD153 pathway represents a new approach for preventing CD4(+) T cell-mediated GVHD.


Optimization and comparison of knockdown efficacy between polymerase II expressed shRNA and artificial miRNA targeting luciferase and Apolipoprotein B100.
Controlling and limiting the expression of short hairpin RNA (shRNA) by using constitutive or tissue-specific polymerase II (pol II) expression can be a promising strategy to avoid RNAi toxicity. However, to date detailed studies on requirements for effective pol II shRNA expression and processing are not available. We investigated the optimal structural configuration of shRNA molecules, namely: hairpin location, stem length and termination signal required for effective pol II expression and compared it with an alternative strategy of avoiding toxicity by using artificial microRNA (miRNA) scaffolds. Highly effective shRNAs targeting luciferase (shLuc) or Apolipoprotein B100 (shApoB1 and shApoB2) were placed under the control of the pol II CMV promoter and expressed at +5 or +6 nucleotides (nt) with reference to the transcription start site (TSS). Different transcription termination signals (TTS), namely minimal polyadenylation (pA), poly T (T5) and U1 were also used. All pol II- expressed shRNA variants induced mild inhibition of Luciferase reporters carrying specific targets and none of them showed comparable efficacy to their polymerase III-expressed H1-shRNA controls, regardless of hairpin position and termination signal used. Extending hairpin stem length from 20 basepairs (bp) to 21, 25 or 29 bp yielded only slight improvement in the overall efficacy. When shLuc, shApoB1 and shApoB2 were placed in an artificial miRNA scaffold, two out of three were as potent as the H1-shRNA controls. Quantification of small interfering RNA (siRNA) molecules showed that the artificial miRNA constructs expressed less molecules than H1-shRNAs and that CMV-shRNA expressed the lowest amount of siRNA molecules suggesting that RNAi processing in this case is least effective. Furthermore, CMV-miApoB1 and CMV-miApoB2 were as effective as the corresponding H1-shApoB1 and H1-shApoB2 in inhibiting endogenous ApoB mRNA. Our results demonstrate that artificial miRNA have a better efficacy profile than shRNA expressed either from H1 or CMV promoter and will be used in the future for RNAi therapeutic development.


In vitro comparison of support capabilities of intra-aortic balloon pump and Impella 2.5 left percutaneous.
The Impella 2.5 left percutaneous (LP), a relatively new transvalvular assist device, challenges the position of the intra-aortic balloon pump (IABP), which has a long record in supporting patients after myocardial infarction and cardiac surgery. However, while more costly and more demanding in management, the advantages of the Impella 2.5 LP are yet to be established. The aim of this study was to evaluate the benefits of the 40 cc IABP and the Impella 2.5 LP operating at 47,000 rpm in vitro, and compare their circulatory support capabilities in terms of cardiac output, coronary flow, cardiac stroke work, and arterial blood pressure. Clinical scenarios of cardiogenic preshock and cardiogenic shock (CS), with blood pressure depression, lowered cardiac output, and constant heart rate of 80 bpm, were modeled in a model-controlled mock circulation, featuring a systemic, pulmonary, and coronary vascular bed. The ventricles, represented by servomotor-operated piston pumps, included the Frank-Starling mechanism. The systemic circulation was modeled with a flexible tube having close-to-human aortic dimensions and compliance properties. Proximally, it featured a branch mimicking the brachiocephalic arteries and a physiological correct coronary flow model. The rest of the systemic and pulmonary impedance was modeled by four-element Windkessel models. In this system, the enhancement of coronary flow and blood pressure was tested with both support systems under healthy and pathological conditions. Hemodynamic differences between the IABP and the Impella 2.5 LP were small. In our laboratory model, both systems approximately yielded a 10% cardiac output increase and a 10% coronary flow increase. However, since the Impella 2.5 LP provided significantly better left ventricular unloading, the circulatory support capabilities were slightly in favor of the Impella 2.5 LP. On the other hand, pulsatility was enhanced with the IABP and lowered with the Impella 2.5 LP. The support capabilities of both the IABP and the Impella 2.5 LP strongly depended on the simulated hemodynamic conditions. Maximum hemodynamic benefits were achieved when mechanical circulatory support was applied on a simulated scenario of deep CS.


Effective elements of cognitive behaviour therapy for psychosis: results of a novel type of subgroup analysis based on principal stratification.
Meta-analyses show that cognitive behaviour therapy for psychosis (CBT-P) improves distressing positive symptoms. However, it is a complex intervention involving a range of techniques. No previous study has assessed the delivery of the different elements of treatment and their effect on outcome. Our aim was to assess the differential effect of type of treatment delivered on the effectiveness of CBT-P, using novel statistical methodology. The Psychological Prevention of Relapse in Psychosis (PRP) trial was a multi-centre randomized controlled trial (RCT) that compared CBT-P with treatment as usual (TAU). Therapy was manualized, and detailed evaluations of therapy delivery and client engagement were made. Follow-up assessments were made at 12 and 24 months. In a planned analysis, we applied principal stratification (involving structural equation modelling with finite mixtures) to estimate intention-to-treat (ITT) effects for subgroups of participants, defined by qualitative and quantitative differences in receipt of therapy, while maintaining the constraints of randomization. Consistent delivery of full therapy, including specific cognitive and behavioural techniques, was associated with clinically and statistically significant increases in months in remission, and decreases in psychotic and affective symptoms. Delivery of partial therapy involving engagement and assessment was not effective. Our analyses suggest that CBT-P is of significant benefit on multiple outcomes to patients able to engage in the full range of therapy procedures. The novel statistical methods illustrated in this report have general application to the evaluation of heterogeneity in the effects of treatment.


Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.
Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.


On-chip monitoring of skeletal myoblast transplantation for the treatment of hypoxia-induced myocardial injury.
A comprehensive elucidation of the unexpected adverse events that occur in skeletal myoblast transplantation is fundamental for the optimization of myocardial therapeutic effects. However, a well-defined method to study the interactions between skeletal myoblasts and cardiomyocytes during the healing process is out of reach. Here, we describe a microfluidic method for monitoring the interactions between skeletal myoblasts and hypoxia-injured cardiomyocytes in a spatiotemporally-controlled manner, mimicking the in vivo cell transplantation process. A myocardial hypoxia environment was created using an oxygen consumption blocking reagent, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone. Meanwhile, the interactions between the skeletal L6 myoblasts and hypoxia-injured myocardium H9c2 cells were investigated, and the effects of a L6 conditional medium on H9c2 cells were comparatively analyzed by quantitatively measuring the morphological and pathophysiological dynamics of H9c2 cells. The results showed that skeletal myoblasts could repair hypoxia-injured H9c2 cells mainly through direct cell-to-cell interactions. This simple on-chip assay for investigating myocardial repair processes may provide avenues for the in vitro screening of drug-induced cardiotoxicity.


Metabolic instability of type 2 deiodinase is transferable to stable proteins independently of subcellular localization.
Thyroid hormone activation is catalyzed by two deiodinases, D1 and D2. Whereas D1 is a stable plasma membrane protein, D2 is resident in the endoplasmic reticulum (ER) and has a 20-min half-life due to selective ubiquitination and proteasomal degradation. Here we have shown that stable retention explains D2 residency in the ER, a mechanism that is nevertheless over-ridden by fusion to the long-lived plasma membrane protein, sodium-iodine symporter. Fusion to D2, but not D1, dramatically shortened sodium-iodine symporter half-life through a mechanism dependent on an 18-amino acid D2-specific instability loop. Similarly, the D2-specific loop-mediated protein destabilization was also observed after D2, but not D1, was fused to the stable ER resident protein SEC62. This indicates that the instability loop in D2, but not its subcellular localization, is the key determinant of D2 susceptibility to ubiquitination and rapid turnover rate. Our data also show that the 6 N-terminal amino acids, but not the 12 C-terminal ones, are the ones required for D2 recognition by WSB-1.


Vocal learning by greater spear-nosed bats.
Vocal learning is well known among passerine and psittacine birds, but most data on mammals are equivocal. Specific benefits of vocal learning are poorly understood for most species. One case where vocal learning should be favoured by selection is where calls indicate group membership and group mates are unrelated. Female greater spear-nosed bats, Phyllostomus hastatus, live in stable groups of unrelated bats and use loud, broadband calls to coordinate foraging movements of social group mates. Bats benefit from group foraging. Calls differ between female social groups and cave colonies, and playback experiments demonstrate that bats perceive these acoustic differences. Here I show that the group distinctive structure of calls arises through vocal learning. Females change call structure when group composition changes, resulting in increased similarity among new social group mates. Comparisons of transfers with age-matched half-sibs indicate that call changes are not simply due to maturation, the physical environment or heredity. These results suggest that studies testing vocal learning in mammals could profit by focusing on vocalizations that signify group membership.


Impact of type I Boston keratoprosthesis implantation on vision-related quality of life.
To determine the impact of type I Boston keratoprosthesis (KPro) implantation on vision-related quality of life (VRQoL). Prospective study in 33 patients (mean age 56±12 years, 67% male) with bilateral corneal blindness, who underwent a KPro implantation at a single tertiary eye hospital (June 2011-July 2015). VRQoL was evaluated using the Impact of Vision Impairment Questionnaire (IVI) at baseline and at 3-6 months postsurgery, after stabilisation of best-corrected visual acuity (BCVA). Rasch analysis was used to transform the IVI responses into interval-level measures comprising the 'reading', 'mobility' and 'emotional' subscales with effect sizes calculated for pre-post VRQoL scores. Mean preoperative BCVA was counting-fingers at 2 feet in the operated eye (20/240 fellow eye). Preoperative VRQoL scores: -2.27, -2.91 and -3.06 logits for the reading, mobility and emotional subscales, respectively. Device retention rate was 90% over the follow-up period (mean 26±12 months). We observed large gains for reading and mobility of 1.92 logits (effect size 0.88), and 2.64 logits (effect size 0.89) respectively, with a moderate gain in the emotional subscale of 2.11 logits (effect size 0.59). These improvements did not vary significantly with BCVA on multivariate analysis (all p>0.05). We observed a differential short-term improvement to VRQoL after KPro implantation with a significant impact on emotional well-being, which may not be fully explained by visual improvement alone. Further studies are required to confirm if these improvements in VRQoL are sustained in the long-term and are generalisable to other populations.


Enabling the implementation of evidence based practice: a conceptual framework.
The argument put forward in this paper is that successful implementation of research into practice is a function of the interplay of three core elements--the level and nature of the evidence, the context or environment into which the research is to be placed, and the method or way in which the process is facilitated. It also proposes that because current research is inconclusive as to which of these elements is most important in successful implementation they all should have equal standing. This is contrary to the often implicit assumptions currently being generated within the clinical effectiveness agenda where the level and rigour of the evidence seems to be the most important factor for consideration. The paper offers a conceptual framework that considers this imbalance, showing how it might work in clarifying some of the theoretical positions and as a checklist for staff to assess what they need to do to successfully implement research into practice.


Behavioural inbreeding avoidance in wild African elephants.
The costs of inbreeding depression, as well as the opportunity costs of inbreeding avoidance, determine whether and which mechanisms of inbreeding avoidance evolve. In African elephants, sex-biased dispersal does not lead to the complete separation of male and female relatives, and so individuals may experience selection to recognize kin and avoid inbreeding. However, because estrous females are rare and male-male competition for mates is intense, the opportunity costs of inbreeding avoidance may be high, particularly for males. Here we combine 28 years of behavioural and demographic data on wild elephants with genotypes from 545 adult females, adult males, and calves in Amboseli National Park, Kenya, to test the hypothesis that elephants engage in sexual behaviour and reproduction with relatives less often than expected by chance. We found support for this hypothesis: males engaged in proportionally fewer sexual behaviours and sired proportionally fewer offspring with females that were natal family members or close genetic relatives (both maternal and paternal) than they did with nonkin. We discuss the relevance of these results for understanding the evolution of inbreeding avoidance and for elephant conservation.


Who needs an orthopedic trauma surgeon? An analysis of US national injury patterns.
Many hospitals in the United States are seeking to obtain and maintain trauma credentialing. Assessment of trauma center success has traditionally focused on mortality without directed measure of surgical subspecialization. However, survival alone may not be a sufficient marker of success with modern health care. The purpose of this study was to determine the number of trauma patients nationally who would benefit from subspecialized care by an orthopedic traumatologist. A list of musculoskeletal DRG International Classification of Diseases-9th Rev. codes representing injuries warranting care by subspecialized orthopedic traumatologists was generated by survey to each of two cohorts: one consisting of 10 subspecialized orthopedic traumatologists and one consisting of 10 nontraumatologists. The 2006 National Inpatient Sample data set was used to estimate the national volume of patients sustaining an orthopedic injury and the number requiring subspecialty orthopedic trauma care, as defined by the DRG International Classification of Diseases-9th Rev. lists generated by our survey. Survey response rate was 100%. In 2006, 2,068,349 patients sustained a traumatic injury; 46.7% of these had an orthopedic injury. Our cohort of subspecialized orthopedic traumatologists identified 25.7% of all trauma patients as requiring an orthopedic traumatologist. Our cohort of general orthopedists identified 13.5% of all trauma patients as requiring an orthopedic traumatologist. Rates of polytrauma, injury severity, and treatment at trauma centers were similar between the two groups. Between 13.5% and 25.7% of all injured patients should, if resources permit, receive subspecialty orthopedic trauma care. The magnitude of this figure highlights the importance, from a public health perspective, of policy interventions aimed at better coordinating the field of orthopedic traumatology. Detailed outcome measures beyond mortality and triage guidelines suggesting which patients should receive subspecialty orthopedic trauma care should be developed. In addition, resources, including fellowship training, should be allocated in a methodical manner that matches supply to the national demand for this type of care. Economic/decision analysis, level IV.


Antigen presentation requires transport of MHC class I molecules from the endoplasmic reticulum.
The role of exocytosis of major histocompatibility complex (MHC) class I molecules in the presentation of antigens to mouse cytotoxic T lymphocytes (CTLs) was examined by use of a recombinant vaccinia virus that expresses the E19 glycoprotein from adenovirus. E19 blocked the presentation of vaccinia and influenza virus proteins to CTLs in a MHC class I allele-specific manner identical to its inhibition of MHC class I transport from the endoplasmic reticulum. This finding indicates that (i) the relevant parameter for antigen presentation is the rate of MHC class I molecule exocytosis, not the level of class I cell surface expression, and (ii) association of class I molecules with antigen is likely to occur within the endoplasmic reticulum.


A Systematic Review of Closed-Loop Feedback Techniques in Sleep Studies-Related Issues and Future Directions.
Advances in computer processing technology have enabled researchers to analyze real-time brain activity and build real-time closed-loop paradigms. In many fields, the effectiveness of these closed-loop protocols has proven to be better than that of the simple open-loop paradigms. Recently, sleep studies have attracted much attention as one possible application of closed-loop paradigms. To date, several studies that used closed-loop paradigms have been reported in the sleep-related literature and recommend a closed-loop feedback system to enhance specific brain activity during sleep, which leads to improvements in sleep's effects, such as memory consolidation. However, to the best of our knowledge, no report has reviewed and discussed the detailed technical issues that arise in designing sleep closed-loop paradigms. In this paper, we reviewed the most recent reports on sleep closed-loop paradigms and offered an in-depth discussion of some of their technical issues. We found 148 journal articles strongly related with 'sleep and stimulation' and reviewed 20 articles on closed-loop feedback sleep studies. We focused on human sleep studies conducting any modality of feedback stimulation. Then we introduced the main component of the closed-loop system and summarized several open-source libraries, which are widely used in closed-loop systems, with step-by-step guidelines for closed-loop system implementation for sleep. Further, we proposed future directions for sleep research with closed-loop feedback systems, which provide some insight into closed-loop feedback systems.


Building on Margalef: Testing the links between landscape structure, energy and information flows driven by farming and biodiversity.
The aim of this paper is to test two methodologies, applicable to different spatial scales (from regional to local), to predict the capacity of agroecosystems to provide habitats for the species richness of butterflies and birds, based on the ways their socio-metabolic flows change the ecological functionality of bio-cultural landscapes. First, we use the more general Intermediate Disturbance-Complexity (IDC) model to assess how different levels of human appropriation of photosynthetic production affect the landscape functional structure that hosts biodiversity. Second, we apply a more detailed Energy-Landscape Integrated Analysis (ELIA) model that focusses on the energy storage carried out by the internal biomass loops, and the energy information held in the network of energy flows driven by farmers, in order to correlate both (the energy reinvested and redistributed) with the energy imprinted in the landscape patterns and processes that sustain biodiversity. The results obtained after applying both models in the province and the metropolitan region of Barcelona support the Margalef's energy-information-structure hypothesis by showing positive relations between butterflies' species richness, IDC and ELIA, and between birds' species richness and energy information. Our findings support the view that strong relationships between farming energy flows, agroecosystem functioning and biodiversity can be detected, and highlight the importance of farmers' knowledge and labour to maintain bio-cultural landscapes.


Prenatal exposure to lead and cognitive deficit in 7- and 14-year-old children in the presence of concomitant exposure to similar molar concentration of methylmercury.
Few studies have examined the effects of mixed metal exposures in humans. We have evaluated the effect of prenatal lead exposure in a Faroese birth cohort in the presence of similar molar-level exposure to methylmercury. A cohort of 1022 singleton births was assembled in the Faroe Islands during 1986-1987 from whom lead was measured in cord-blood. A total of 896 cohort subjects participated in a clinical examination at age 7 and 808 subjects in a second examination at age 14. We evaluated the association between cord-blood lead concentrations and cognitive deficits (attention/working memory, language, visuospatial, and memory) using multiple regression models. Overall, the lead concentration showed no clear pattern of association. However, in subjects with a low methylmercury exposure, after inclusion of statistical interaction terms, lead-associated adverse effects on cognitive functions were observed. In particular, higher cord-blood lead was associated with a lower digit span forward score on the Wechsler Intelligence Scale for Children-Revised (WISC-R) [beta=-1.70, 95% confidence interval (CI): -3.12 to -0.28] at age 7 and a lower digit span backward score on the WISC-R (beta=-2.73, 95%CI: -4.32 to -1.14) at age 14. Some interaction terms between lead and methylmercury suggested that the combined effect of the exposures was less than additive. The present study indicates that adverse effects of exposure may be overlooked if the effects of a co-pollutant are ignored. The present study supports the existence of adverse effects on cognitive functions at prenatal lead exposures corresponding to an average cord-blood concentration of 16 μg/L.


Insulin within islets is a physiologic glucagon release inhibitor.
To determine if glucagon secretion is under physiological control of intra-islet insulin, pancreata from normal rats were perfused at a 100 mg/dl glucose concentration with either guinea pig antiinsulin serum or normal guinea pig serum in a nonrecirculating system. Perfusion of antiserum was followed within 3 min by a significant rise in glucagon that reached peak levels three times the base-line values and assumed a hectic pattern that returned rapidly to base-line levels upon termination of the antiserum perfusion. Nonimmune guinea pig serum had no effect. To gain insight into the probable site of insulin neutralization, 125I-labeled human gamma-globulin was added to antiserum or nonimmune serum and perfused for 3 min. More than 83% of the radioactivity was recovered in the effluent within 3 min after termination of the infusion, and only 0.05 +/- 0.015% of the radioactivity injected was present in the pancreas 10 min after the perfusion. The maximal amount of insulin that could be completely bound to insulin antibody at a dilution and under conditions simulating those of the perfusion experiments was 20 mU/min. It is concluded that insulin maintains an ongoing restraint upon alpha cell secretion and in its absence causes hectic hypersecretion of glucagon. This restraint probably occurs largely in the intravascular compartment. Loss of this release-inhibiting action of insulin may account for initiation of hyperglucagonemia in insulin-deficient states.


Prevalence of needlestick injuries and other high risk exposures among healthcare workers in Jamaica.
To assess the prevalence of needlestick injuries (NSIs) and other high risk exposures among healthcare workers at two hospitals in Jamaica. Employing a cross-sectional study design, medical personnel (physicians, nurses) at two hospitals in Jamaica, were studied, utilizing a structured questionnaire consisting of 14 items to collect data on needle stick injuries and other injuries. There were 67 needlestick injuries in 47 persons. Of those sustaining an injury, 52% of physicians and 40% of nurses had NSIs. Re-capping needles accounted for 21% of injuries, various minor procedures, 21%, injury during surgery, 19.4% and taking blood, 12%. In those sustaining NSIs, 47% were reported and 26% of reported cases received counselling. Appropriate blood tests were performed on 34% and post-exposure prophylaxis (PEP) for HIV was administered to 30%. Hollow bore needles caused 47.8% of injuries, 25.4% occurred with suture needles and 19.4% with intravenous branulas. Other occupational exposure was reported by 31%, including blood on hands and other body parts 39%, blood to face and eyes, 18%, splashed with liquor, 18%, splashed with bloody fluid, 11% and contact with vomitus and urine in eye, 4%. Needlestick injuries and other high risk exposures were high; incident reporting and post exposure management were inadequate. A comprehensive programme to address factors that contribute to the occurrence of NSIs and other occupational exposures is urgently needed.


T3 levels in relation to prognostic factors in breast cancer: a population-based prospective cohort study.
The issue of a potential association between thyroid conditions/hormones and breast cancer has been studied extensively during the last decades but the results have been inconclusive and almost no studies have investigated breast cancer aggressiveness. We have previously found a positive association between prospectively measured levels of triiodothyronine (T3) and breast cancer incidence as well as breast cancer mortality. We now investigated prediagnostic T3 levels in relation to specific prognostic factors in breast cancer. The Malmö Preventive Project is a population-based prospective cohort including 2185 women in whom T3 levels were measured at baseline. That is, total T3 levels were measured before a potential diagnosis of breast cancer. Mean follow-up was 23.3 years and 149 women in the study population were diagnosed with invasive breast cancer. Tumours were classified according to selected prognostic factors of breast cancer; i.e. grade, tumour size, lymph node metastasis, and hormonal receptor status. T3 was handled both as tertiles and as a continuous variable. A Cox's proportional hazards analysis yielded hazard ratios with 95% confidence intervals. All analyses were also restricted to postmenopausal women. Overall there was a statistically significant association between T3 and "all" breast cancers. The adjusted Hazard Ratio (HR) in the third tertile, as compared to the first, was (1.61:1.07-2.43). There was a statistically significant positive association between the third T3 tertile and large tumours, i.e. > 20 mm, (3.17:1.20-8.36) and the occurrence of lymph node metastases, (4.53:1.60-12.83). Other prognostic factors positively associated with T3 were negative oestrogen receptor (ER) status, (3.52:1.32-9.41) and negative progesterone receptor (PGR) status, (3.52:1.42-8.75). The analyses of T3 as a continuous variable and analysis restricted to postmenopausal women, confirmed the results but also showed an association with smaller tumours and in postmenopausal women a contemporary association with negative lymph nodes. This prospective study of serum T3 levels in relation to breast cancer aggressiveness is the first of its kind. We found statistically significant positive associations between higher prediagnostic T3 levels and larger tumours, occurrence of lymph node metastases, and negative ER and PGR status.


Plasmid-encapsulated polyethylene glycol-grafted polyethylenimine nanoparticles for gene delivery into rat mesenchymal stem cells.
Mesenchymal stem cell transplantation is a promising method in regenerative medicine. Gene-modified mesenchymal stem cells possess superior characteristics of specific tissue differentiation, resistance to apoptosis, and directional migration. Viral vectors have the disadvantages of potential immunogenicity, carcinogenicity, and complicated synthetic procedures. Polyethylene glycol-grafted polyethylenimine (PEG-PEI) holds promise in gene delivery because of easy preparation and potentially targeting modification. A PEG8k-PEI25k graft copolymer was synthesized. Agarose gel retardation assay and dynamic light scattering were used to determine the properties of the nanoparticles. MTT reduction, wound and healing, and differentiation assays were used to test the cytobiological characteristics of rat mesenchymal stem cells, fluorescence microscopy and flow cytometry were used to determine transfection efficiency, and atomic force microscopy was used to evaluate the interaction between PEG-PEI/plasmid nanoparticles and mesenchymal stem cells. After incubation with the copolymer, the bionomics of mesenchymal stem cells showed no significant change. The mesenchymal stem cells still maintained high viability, resettled the wound area, and differentiated into adipocytes and osteoblasts. The PEG-PEI completely packed plasmid and condensed plasmid into stable nanoparticles of 100-150 nm diameter. After optimizing the N/P ratio, the PEG-PEI/plasmid microcapsules delivered plasmid into mesenchymal stem cells and obtained an optimum transfection efficiency of 15%-21%, which was higher than for cationic liposomes. These data indicate that PEG-PEI is a valid gene delivery agent and has better transfection efficiency than cationic liposomes in mesenchymal stem cells.


The compelling case for low-violence-risk preclusion in American prison policy.
This article recommends the development of broad policies of preclusion regarding the use of incarceration for offenders who are highly unlikely to commit a violent crime in the future. The proposal builds on the new Model Penal Code: Sentencing's provision on the limited utilitarian purposes of incarceration. Such low-violence-risk-preclusion strategies (LVRPs) would stand on the most powerful predictive capabilities of today's risk assessment technology. If implemented properly, there is reason to believe that substantial drops in prison rates could be realized in most states. The preclusion groups would include defendants who should not be sent to prison or jail by sentencing judges even though the law allows for such penalties; those serving prison sentences who should be released by parole boards or other releasing authorities at the earliest opportunity; and probation and parole violators who should not be revoked to prison or jail. The strongest objection to the LVRP proposal is the fear of racial or other unacceptable biases in its apportionment of reduced-incarceration benefits. Given current high levels of disproportionality in prison and jail populations, however, there is reason to think that the benefits of LVRP would be especially pronounced in disadvantaged communities.


Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.
The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.


Recent advances in organic thermally activated delayed fluorescence materials.
Organic materials that exhibit thermally activated delayed fluorescence (TADF) are an attractive class of functional materials that have witnessed a booming development in recent years. Since Adachi et al. reported high-performance TADF-OLED devices in 2012, there have been many reports regarding the design and synthesis of new TADF luminogens, which have various molecular structures and are used for different applications. In this review, we summarize and discuss the latest progress concerning this rapidly developing research field, in which the majority of the reported TADF systems are discussed, along with their derived structure-property relationships, TADF mechanisms and applications. We hope that such a review provides a clear outlook of these novel functional materials for a broad range of scientists within different disciplinary areas and attracts more researchers to devote themselves to this interesting research field.


A personal exposure study employing scripted activities and paths in conjunction with atmospheric releases of perfluorocarbon tracers in Manhattan, New York.
A personal exposure study was conducted in New York City as part of the Urban Dispersion Program (UDP). It examined the contact of individuals with four harmless perflourocarbon tracers (PFT) released in Midtown Manhattan with approval by city agencies at separate locations, during two types of experiments, completed during each release period. Two continuous 1 h release periods separated by a 1.5 h ventilation time were completed on 3 October 2005. Stationary site and personal exposure measurements were taken during each period, and the first half hour after the release ended. Two types of scripted exposure activities are reported: Outdoor Source Scale, and Outdoor Neighborhood Scale; requiring 1- and 10-min duration samples, respectively. The results showed that exposures were influenced by the surface winds, the urban terrain, and the movements of people and vehicles typical in urban centers. The source scale exposure data indicated that local conditions significantly affected the distribution of each tracer, and consequently the exposures. The highest PFT exposures resulted from interaction of the scripted activities with local surface conditions. The range measured for 1- min exposures were large with measured values exceeding 5000 ppqv (parts per quadrillion by volume). The neighborhood scale measurements quantified exposures at distances up to seven blocks away from the release points. Generally, but not always, the PFT levels returned quickly to zero indicating that after cessation of the emissions the concentrations decrease rapidly, and reduce the intensity of local exposures. The near source and neighborhood personal exposure route results provided information to establish a baseline for determining how a release could affect both the general public and emergency responders, and evaluate the adequacy of re-entry or exit strategies from a local area. Finally, the data also show that local characteristics can produce "hot spots".


Insulin-like growth factor-I (IGF-I) and IGF-II hormonal action in cultured rat granulosa cells: mediation via type I but not type II IGF receptors.
Both insulin-like growth factor-I (IGF-I) and IGF-II have been shown to promote granulosa cell differentiation and proliferation. While both type I and type II IGF receptors have been observed in rat granulosa cells, the identity of the IGF receptor type(s) mediating IGF hormonal action remains uncertain. Whereas the role of the rat type I IGF receptor cannot be completely evaluated at this time due to the lack of specific reagents, the availability of antibodies specific for the rat type II IGF receptor (R-II-PAB1) has made studies of this receptor type possible. To validate the utility of the R-II-PAB1 antiserum at the level of the rat granulosa cell, its ability to immunoneutralize the granulosa cell type II IGF receptor was examined. Significantly, R-II-PAB1 (10-100 micrograms/ml) proved a potent inhibitor of [125I]IGF-II (but not [125I]IGF-I) binding to granulosa cell membrane preparations. Substantial, albeit finite, R-II-PAB1-mediated inhibition of the cross-linking of [125I]IGF-II was also observed. Moreover, R-II-PAB1 proved highly potent in immunoprecipitating the rat granulosa cell type II IGF receptor. In light of these observations, we have proceeded to use R-II-PAB1 to assess the functional role of the rat granulosa cell type II IGF receptor in IGF-I and IGF-II hormonal action. To this end, FSH (20 ng/ml)-primed granulosa cells were cultured for 72 h in the absence or presence of IGF-I or IGF-II (50 ng/ml) with or without increasing (receptor-active) concentrations of R-II-PAB1 (10-100 micrograms/ml). Control incubations were carried out with an ammonium sulfate precipitate of nonimmune rabbit serum dialyzed against PBS. Significantly, both R-II-PAB1 and nonimmune rabbit serum were without effect on the cytodifferentiative action of either IGF-I or IGF-II. Subject to limitations inherent to the immunoneutralizing potency of R-II-PAB1, these findings are in keeping with the notion that (inasmuch as the conventional cytodifferentiative process is concerned) the granulosa cell type II IGF receptor does not appear to participate in transmembrane IGF signalling. By inference, these findings also suggest that IGF-I and IGF-II hormonal action at the level of the granulosa cell may be exerted largely, if not exclusively, via the type I IGF receptor. Thus, the potential relevance and the functional role(s), if any, of the granulosa cell type II IGF receptor remain to be determined.


¹H, ¹³C, and ¹⁵N backbone resonance assignments of the connexin43 carboxyl terminal domain attached to the 4th transmembrane domain in detergent micelles.
Gap junctions are specialized membrane channels that enable coordination of cellular functions and whole-organ responses by facilitating both molecular and electrical communication between neighboring cells. Connexin43 (Cx43) is the most widely expressed and well-studied gap junction protein. In the heart, Cx43 is essential for normal cardiac development and function. Studies using a soluble version of the Cx43 carboxyl-terminal domain (Cx43CT; S255-I382) have established the central role it plays in channel regulation. However, in purifying and characterizing a more 'native-like' construct (Cx43CT attached to the fourth transmembrane domain (TM4-Cx43CT; D196-I382)), we have identified that the TM4-Cx43CT is a better model than the soluble Cx43CT to further investigate the mechanisms governing Cx43 channel regulation. Here, we report the backbone (1)H, (15)N, and (13)C assignments and predicted secondary structure of the TM4-Cx43CT. Assignment of the TM4-Cx43CT is a key step towards a better understanding of the structural basis of Cx43 regulation, which will lead to improved strategies for modulation of junctional communication that has been altered due to disease or ischemic injury.


Protein Deimination and Extracellular Vesicle Profiles in Antarctic Seabirds.
Pelagic seabirds are amongst the most threatened of all avian groups. They face a range of immunological challenges which seem destined to increase due to environmental changes in their breeding and foraging habitats, affecting prey resources and exposure to pollution and pathogens. Therefore, the identification of biomarkers for the assessment of their health status is of considerable importance. Peptidylarginine deiminases (PADs) post-translationally convert arginine into citrulline in target proteins in an irreversible manner. PAD-mediated deimination can cause structural and functional changes in target proteins, allowing for protein moonlighting in physiological and pathophysiological processes. PADs furthermore contribute to the release of extracellular vesicles (EVs), which play important roles in cellular communication. In the present study, post-translationally deiminated protein and EV profiles of plasma were assessed in eight seabird species from the Antarctic, representing two avian orders: Procellariiformes (albatrosses and petrels) and Charadriiformes (waders, auks, gulls and skuas). We report some differences between the species assessed, with the narrowest EV profiles of 50-200 nm in the northern giant petrel Macronectes halli, and the highest abundance of larger 250-500 nm EVs in the brown skua Stercorarius antarcticus. The seabird EVs were positive for phylogenetically conserved EV markers and showed characteristic EV morphology. Post-translational deimination was identified in a range of key plasma proteins critical for immune response and metabolic pathways in three of the bird species under study; the wandering albatross Diomedea exulans, south polar skua Stercorarius maccormicki and northern giant petrel. Some differences in Gene Ontology (GO) biological and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for deiminated proteins were observed between these three species. This indicates that target proteins for deimination may differ, potentially contributing to a range of physiological functions relating to metabolism and immune response, as well as to key defence mechanisms. PAD protein homologues were identified in the seabird plasma by Western blotting via cross-reaction with human PAD antibodies, at an expected 75 kDa size. This is the first study to profile EVs and to identify deiminated proteins as putative novel plasma biomarkers in Antarctic seabirds. These biomarkers may be further refined to become useful indicators of physiological and immunological status in seabirds-many of which are globally threatened.


Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation.
Findings are inconsistent in a few studies of the effect of n-3 fatty acid supplementation on urinary calcium and oxalate excretion in stone formers. We evaluated the physiological effects of supplementation with eicosapentaenoic acid and docosahexaenoic acid on urinary risk factors for calcium oxalate stone formation under standardized conditions. We studied 15 healthy subjects initially while consuming a standardized diet for 5 days (control phase). During consecutive intervention phases 1-5-day standardized diet, 2-20-day free diet and 3-5-day standardized diet participants received 900 mg eicosapentaenoic acid and 600 mg docosahexaenoic acid daily. While ingesting the standardized diets, daily 24-hour urine samples were collected. After short-term supplementation with eicosapentaenoic acid and docosahexaenoic acid in phase 1 we noted no changes in urinary parameters compared to the control phase. After 30-day supplementation with eicosapentaenoic acid and docosahexaenoic acid in phase 3 relative supersaturation with calcium oxalate decreased significantly by 23% from a mean ± SD of 2.01 ± 1.26 to 1.55 ± 0.84 due to significantly decreased urinary oxalate excretion (p = 0.023). Other urinary variables were not affected by supplementation. Results show that 30-day n-3 fatty acid supplementation effectively decreases urinary oxalate excretion and the risk of calcium oxalate crystallization. The mechanism of the physiological effect may be decreased cellular oxalic acid exchange attributable to an altered fatty acid pattern of membrane phospholipids with concomitant changes in oxalate transporter activity. Calcium oxalate stone formers may benefit from long-term n-3 fatty acid supplementation.


Mutation and abnormal expression of the p53 gene in the viral skin carcinogenesis of epidermodysplasia verruciformis.
Patients suffering from epidermodysplasia verruciformis are prone to nonmelanoma skin cancers, due to an inherited abnormal susceptibility to the oncogenic human papillomavirus type 5. Genotoxic sunlight ultraviolet B radiations are likely to be a cofactor. Lesions of two human-papillomavirus-type-5-infected epidermodysplasia verruciformis patients collected during an 8 y period were retrospectively studied for p53 mutations in exons 5 through 8 by a polymerase chain reaction single-strand conformation polymorphism technique and/or by DNA sequencing of amplified exons. Mutations were detected in 11 of 26 (42.3%) specimens, including five (62.5%) squamous cell carcinomas, three (33.3%) Bowen's carcinomas in situ, two (40%) actinic keratoses, and one (33%) benign lesion. The nine mutations characterized by sequencing were shown to be missense and to affect mutational hotspots in human cancers. Five were C-->T transitions at dicytidine sites considered as ultraviolet signature mutations. Two were transversions (C-->G and C-->A) at dicytidine sites and two were C-->T transitions at nondipyrimidine sites. A marked p53 immunoreactivity was disclosed in 72.7% of 11 invasive carcinomas, 55.6% of nine carcinomas in situ, 37.5% of eight actinic keratoses, and one of three benign lesions. This includes 81.8% of 11 specimens with a p53 mutation but also 50% of 14 specimens with no mutation detected. A dysfunction of the p53 gene is thus likely to play a part in epidermodysplasia verruciformis carcinogenesis, either due to ultraviolet-B-induced p53 mutations, as in nonmelanoma skin cancers in the general population, or involving other mutagens or mechanisms. The part played by human papillomavirus type 5 proteins expressed in epidermodysplasia verruciformis keratinocytes remains to be determined.


Denitrification responses to increasing cadmium exposure in Baltic Sea sediments.
Benthic ecosystems have come under intense pressure, due to eutrophication-driven oxygen decline and industrial metal contamination. One of the most toxic metals is Cadmium (Cd), which is lethal to many aquatic organisms already at low concentrations. Denitrification by facultative anaerobic microorganisms is an essential process to transform, but also to remove, excess nitrate in eutrophied systems. Cd has been shown to decrease denitrification and sequester free sulfide, which is available when oxygen is scarce and generally inhibits complete denitrification (i.e. N2O to N2). In polluted sediments, an interaction between oxygen and Cd may influence denitrification and this relationship has not been studied. For example, in the Baltic Sea some sediments are double exposed to both Cd and hypoxia. In this study, we examined how the double exposure of Cd and fluctuations in oxygen affects denitrification in Baltic Sea sediment. Results show that oxygen largely regulated N2O and N2 production after 21 days of exposure to Cd (ranging from 0 to 500 μg/L, 5 different treatments, measured by the isotope pairing technique (IPT)). In the high Cd treatment (500 μg/L) the variation in N2 production increased compared to the other treatments. Increases in N2 production are suggested to be an effect of 1) enhanced nitrification that increases NO3- availability thus stimulating denitrification, and 2) Cd successfully sequestrating sulfide (yielding CdS), which allows for full denitrification to N2. The in situ field sediment contained initially high Cd concentrations in the pore water (∼10 μg/L) and microbial communities might already have been adapted to metal stress, making the effect of low Cd levels negligible. Here we show that high levels of cadmium pollution might increase N2 production and influence nitrogen cycling in marine sediments.


Brain volumes predict neurodevelopment in adolescents after surgery for congenital heart disease.
Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.


Aggressive resection is indicated for cecal diverticulitis.
Because of the difficulties in preoperative diagnosis and controversies in the management, cecal diverticulitis has received much discussion in the literature. There, however, are still many questions that remain unanswered. During a 5-year period, 112 patients with a clinical diagnosis of cecal diverticulitis were treated. Twenty-seven patients were excluded because of uncertainty in diagnosis or incomplete data collection, leaving 85 patients as the study group. The diagnosis of cecal diverticulitis was made by pathology, surgical findings, or image study. Nonoperative management was applied to 18 patients initially. Three patients had recurrent diverticulitis during follow up. These patients responded satisfactorily to another course of medical treatment. Laparotomy was performed in 67 patients. Acute appendicitis was the preoperative diagnosis in 47 patients (70%). Of the other 20 patients, 6 received operation because of repeated attack of diverticulitis, 7 had preoperative computed tomography (CT) diagnosis of cecal diverticulitis with perforation, 5 had preoperative diagnosis of cecal tumor, and 2 had medical treatment failure. All these 20 patients received right hemicolectomy. In the 47 patients with a preoperative diagnosis of acute appendicitis, 24 received appendectomy, 9 received diverticulectomy, and 14 received right hemicolectomy. Overall, 34 patients received right hemicolectomy, 9 received diverticulectomy, and 24 received appendectomy only. In the right hemicolectomy group, there were 2 deaths with underlying diseases and 5 complications. In the appendectomy group, there was no postoperative mortality, but in 7 patients recurrent diverticulitis developed. Three of them required right hemicolectomy. The natural history of cecal diverticulitis varies from benign and self-limiting to fulminant in the oriental population. Less than 40% (32 of 85) of patients were successfully treated with conservative methods initially and had no recurrence during the follow-up period. We recommend aggressive surgical resection for patients with a definite diagnosis. Adjuvant appendectomy without resection of the lesion should be considered only in uncomplicated patients whose diagnosis is in doubt.


SpaC and NisC, the cyclases involved in subtilin and nisin biosynthesis, are zinc proteins.
Lantibiotics are peptide-derived antimicrobial agents that are ribosomally synthesized and posttranslationally modified by a multienzyme complex to their biologically active forms. Nisin has attracted much attention recently due to its novel mechanism of action including specific binding to the bacterial cell wall precursor lipid II, followed by membrane permeabilization. Nisin has been commercially used as a food preservative, while other lantibiotics show promising activity against bacterial infections. The posttranslational modifications are believed to be carried out by a multienzyme complex. At present the enzymes catalyzing the formation of the lantibiotic signature structural motifs, dehydroalanine (Dha), dehydrobutyrine (Dhb), lanthionine (Ln), and methyllanthionine (MeLn), are poorly characterized. In an effort to gain insight into the mechanism by which lantibiotics are biosynthesized, the cyclase enzymes involved in the synthesis of nisin and subtilin (NisC and SpaC, respectively) have been cloned, expressed, and purified. Both proteins exist as monomers in solution and contain a stoichiometric zinc atom. EXAFS data on SpaC and a C349A mutant are in line with two cysteine ligands to the metal in the wild-type enzyme with possibly two additional histidines. The two cysteine ligands are likely Cys303 and Cys349 on the basis of sequence alignments and EXAFS data. The metal may function to activate the cysteine thiol of the peptide substrate toward intramolecular Michael addition to the dehydroalanine and dehydrobutyrine residues in the peptide.


Design and evaluation of a new mechatronic platform for assessment and prevention of fall risks.
Studying the responses in human behaviour to external perturbations during daily motor tasks is of key importance for understanding mechanisms of balance control and for investigating the functional response of targeted subjects. Experimental platforms as far developed entail a low number of perturbations and, only in few cases, have been designed to measure variables used at run time to trigger events during a certain motor task. This work introduces a new mechatronic device, named SENLY, that provides balance perturbations while subjects carry out daily motor tasks (e.g., walking, upright stance). SENLY mainly consists of two independently-controlled treadmills that destabilize balance by suddenly perturbing belts movements in the horizontal plane. It is also provided with force sensors, which can be used at run time to estimate the ground reaction forces and identify events along the gait cycle in order to trigger the platform perturbation. The paper also describes the customized procedures adopted to calibrate the platform and the first testing trials aimed at evaluating its performance. SENLY allows to measure both vertical ground reaction forces and their related location more precisely and more accurately than other platforms of the same size. Moreover, the platform kinematic and kinetic performance meets all required specifications, with a negligible influence of the instrumental noise. A new perturbing platform able to reproduce different slipping paradigms while measuring GRFs at run time in order to enable the asynchronous triggering during the gait cycle was designed and developed. Calibration procedures and pilot tests show that SENLY allows to suitably estimate dynamical features of the load and to standardize experimental sessions, improving the efficacy of functional analysis.


Hemoglobin encapsulation in vesicles retards NO and CO binding and O2 release when perfused through narrow gas-permeable tubes.
Intravenous administration of cell-free Hb induces vasoconstriction and circulatory disorders, presumably because of the intrinsic affinities to endogenous nitric oxide (NO) and carbon monoxide (CO) as vasorelaxation factors and because of the facilitated O(2) release that might induce autoregulatory vasoconstriction. We examined these gas reactions when Hb-containing solutions of four kinds were perfused through artificial narrow tubes at a practical Hb concentration (10 g/dl). Purified Hb solution, polymerized bovine Hb (Poly(B)Hb), encapsulated Hb [Hb-vesicles (HbV), 279 nm], and red blood cells (RBCs) were perfused through a gas-permeable narrow tube (25 microm inner diameter) at 1 mm/s centerline velocity. The level of reactions was determined microscopically based on the visible-light absorption spectrum of Hb. When the tube was immersed in NO and CO atmospheres, both NO binding and CO binding of deoxygenated Hb (deoxy-Hb) and Poly(B)Hb in the tube was faster than those of HbV and RBCs, and HbV and RBCs showed almost identical binding rates. When the tube was immersed in a N(2) atmosphere, oxygenated Hb and Poly(B)Hb showed much faster O(2) release than did HbV and RBCs. Poly(B)Hb showed a faster reaction than Hb because of the lower O(2) affinity of Poly(B)Hb than Hb. The diffusion process of the particles was simulated using Navier-Stokes and Maxwell-Stefan equations. Results clarified that small Hb (6 nm) diffuses laterally and mixes rapidly. However, the large-dimension HbV shows no such rapid diffusion. The purely physicochemical differences in diffusivity of the particles and the resulting reactivity with gas molecules are one factor inducing biological vasoconstriction of Hb-based oxygen carriers.


Non-lymphoma hematological malignancies in systemic lupus erythematosus.
To describe non-lymphoma hematological malignancies in systemic lupus erythematosus (SLE). A large SLE cohort was linked to cancer registries. We examined the types of non-lymphoma hematological cancers. In 16,409 patients, 115 hematological cancers [including myelodysplastic syndrome (MDS)] occurred. Among these, 33 were non-lymphoma. Of the 33 non-lymphoma cases, 13 were of lymphoid lineage: multiple myeloma (n = 5), plasmacytoma (n = 3), B cell chronic lymphocytic leukemia (B-CLL; n = 3), precursor cell lymphoblastic leukemia (n = 1) and unspecified lymphoid leukemia (n = 1). The remaining 20 cases were of myeloid lineage: MDS (n = 7), acute myeloid leukemia (AML; n = 7), chronic myeloid leukemia (CML; n = 2) and 4 unspecified leukemias. Most of these malignancies occurred in female Caucasians, except for plasma cell neoplasms (4/5 multiple myeloma and 1/3 plasmacytoma cases occurred in blacks). In this large SLE cohort, the most common non-lymphoma hematological malignancies were myeloid types (MDS and AML). This is in contrast to the general population, where lymphoid types are 1.7 times more common than myeloid non-lymphoma hematological malignancies. Most (80%) multiple myeloma cases occurred in blacks; this requires further investigation.


Microsatellite instability in Arabidopsis increases with plant development.
Plant development consists of the initial phase of intensive cell division followed by continuous genome endoreduplication, cell growth, and elongation. The maintenance of genome stability under these conditions is the main task performed by DNA repair and genome surveillance mechanisms. Our previous work showed that the rate of homologous recombination repair in older plants decreases. We hypothesized that this age-dependent decrease in the recombination rate is paralleled with other changes in DNA repair capacity. Here, we analyzed microsatellite stability using transgenic Arabidopsis (Arabidopsis thaliana) plants that carry the nonfunctional β-glucuronidase gene disrupted by microsatellite repeats. We found that microsatellite instability increased dramatically with plant age. We analyzed the contribution of various mechanisms to microsatellite instability, including replication errors and mistakes of DNA repair mechanisms such as mismatch repair, excision repair, and strand break repair. Analysis of total DNA polymerase activity using partially purified protein extracts showed an age-dependent decrease in activity and an increase in fidelity. Analysis of the steady-state RNA level of DNA replicative polymerases α, δ, Pol I-like A, and Pol I-like B and the expression of mutS homolog 2 (Msh2) and Msh6 showed an age-dependent decrease. An in vitro repair assay showed lower efficiency of nonhomologous end joining in older plants, paralleled by an increase in Ku70 gene expression. Thus, we assume that the more frequent involvement of nonhomologous end joining in strand break repair and the less efficient end-joining repair together with lower levels of mismatch repair activities may be the main contributors to the observed age-dependent increase in microsatellite instability.


Prevalence of diabetes mellitus and population attributable fractions for coronary heart disease and stroke mortality in the WHO South-East Asia and Western Pacific regions.
The aims of this study were to obtain the most recent representative data for the prevalence of diabetes in adult populations in the World Health Organisation's South-East Asia and Western Pacific regions and to quantify the contribution of diabetes to the burden of mortality from cardiovascular diseases in these regions. Previous reports indicate that there are 83 million individuals with diabetes in the Asia-Pacific region, but since many of the country-specific estimates were not from nationally representative studies, this figure may not accurately reflect the current burden of diabetes. Information on the prevalence of diabetes was obtained by searching Medline and government health websites. Data were available from 12 countries representing 78% of the total population of the Asia-Pacific region. Six of 10 countries with complete data reported a prevalence of diabetes exceeding those estimates currently cited by the World Health Organization; three of which have also already exceeded the World Health Organization projections for 2030. In the 12 countries in the region with nationally representative data, the prevalence of diabetes ranged from 2.6% to 15.1%. Hazard ratios from the Asia Pacific Cohort Studies Collaboration were used to calculate population attributable fractions for diabetes for fatal cardiovascular diseases in the region. Population attributable fractions ranged from 2% to 12% for coronary heart disease, 1% to 6% for haemorrhagic stroke, and 2% to 11% for ischaemic stroke. Accurate estimates of the prevalence of diabetes are of great importance and standard methods are needed for periodic surveillance across the Asia-Pacific region and elsewhere.


First-principles investigation of intrinsic defects and self-diffusion in ordered phases of V2C.
The self-diffusion behavior of vanadium subcarbide (V2C) is investigated using density functional theory calculations, owing to its potential application as a diffusion barrier in nuclear applications. Three ordered V2C structures, two of which correspond to experimentally observed phases, are characterized in terms of their equilibrium structural, electronic and elastic properties. Our model for self-diffusion in V2C considers diffusion of carbon and vanadium to occur separately on each sublattice. Two sets of self-diffusion coefficients are calculated for each structure: one for vacancy-mediated diffusion of vanadium and the other for interstitial diffusion of carbon. Calculated activation energies and diffusion prefactors are compared to experimental data for the cubic transition metal carbides as there is no experimental self-diffusion data for any of the hexagonal subcarbides.


Juvenile hormone titer versus juvenile hormone synthesis in female nymphs and adults of the German cockroach, Blattella germanica.
Abstract Patterns of juvenile hormone have been intensively studied in the cockroach Blattella germanica under different physiological situations. However, data have been mainly obtained in vitro, and refer to hormone synthesized by isolated corpora allata, whereas information available on hormone concentration in the hemolymph is restricted to adult females. In order to complement our studies in vitro, we have measured juvenile hormone titer in the hemolymph of B. germanica females in four characteristic physiological situations: penultimate and last instar nymphs, adults during the first vitellogenic cycle, and adults transporting egg cases (ootheca). In general, a significant positive correlation between rates of hormone synthesis and concentration in the hemolymph is observed. The main disparities appear in the penultimate day of the period of ootheca transport, where titer is high whereas synthesis is low, and on day 6 of the first vitellogenic cycle, where synthesis increases whereas titer decreases. At these stages, the observed disparities between synthesis and titer might be explained by differential action of degradation enzymes.


The axonemal axis and Ca2+-induced asymmetry of active microtubule sliding in sea urchin sperm tails.
Structural studies of stationary principal bends and of definitive patterns of spontaneous microtubule sliding disruption permitted description of the bending axis in sea urchin sperm tail axonemes. Lytechinus pictus sperm were demembranated in a buffer containing Triton X-100 and EGTA. Subsequent resuspension in a reactivation buffer containing 0.4 mM CaCl2 and 1.0 mM MgATP2- resulted in quiescent, rather than motile, cells and each sperm tail axoneme took on an extreme, basal principal bend of 5.2 rad. Thereafter, such flagellar axonemes began to disrupt spontaneously into two subsets of microtubules by active sliding requiring ATP. Darkfield light microscopy demonstrated that subset "1" is composed of microtubules from the inside edge of the principal bend. Subset "2" is composed of microtubules from the outside edge of the principal bend and always scatters less light in darkfield than subset 1. Subset 2, which always slides in the proximal direction, relative to subset 1, results in a basal loop of microtubules, and the subset 2 loop is restricted to the bend plane during sliding disruption. Electron microscopy revealed that doublets 8, 9, 1, 2, 3 and the central pair comprise subset 1, and doublets 4, 5, the bridge, 6, and 7 comprise subset 2. The microtubules of isolated subset 2 are maintained in a circular arc in the absence of spoke-central pair interaction. Longitudinal sections show that the bending plane bisects the central pair. We therefore conclude that the bend plane passes through doublet 1 and the 5-6 bridge and that doublet 1 is at the inside edge of the principal bend. Experimental definition of the axis permits explicit discussion of the location of active axonemal components which result in Ca2+-induced stationary basal bends and explicit description of components responsible for alternating basal principal and reverse bends.


Antipolysaccharide antibodies in 450 children with otitis media.
We have measured antibodies to pneumococcal and Haemophilus polysaccharides in a prospective study of 450 children aged 2-16 years with otitis media requiring grommets (ear tubes). Pneumococcal antibody levels were significantly higher in the 2-6 year (P < 0.004) and 7-10 year (P < 0.04) study groups in comparison with age-matched controls. There was no difference in Haemophilus antibody levels between the study and control group children for the age groups 2-6 years and 11-16 years. Haemophilus antibody levels were significantly lower in the 7-10 year (P < 0.003) group in comparison with age-matched controls. Eighty-eight out of 450 (19.6%) children had pneumococcal antibody levels below the 25th percentile. Nineteen out of 88 (21.6%) children with pneumococcal antibody levels below the 25th centile were test immunized with 23 valent Pneumococcal polysaccharide and unconjugated Haemophilus type b capsular polysaccharide. Of these 19 children (aged 4-11 years), five mounted suboptimal responses to both polysaccharide antigens, whilst one child failed to respond to Haemophilus polysaccharide alone. There was no significant difference in the prevalence of IgG subclass deficiency between the normal responders and poor responders to immunization (P = 0.12). We found no evidence of specific polysaccharide antibody deficiency in the vast majority of the 450 children studied. However, the significance of poor antibody responses to test immunization in a small minority of children with otitis media is unclear. Long-term follow up of these children is required to determine whether poor immunization responses herald the development of frank antibody deficiency.


Hypophysitis and other autoimmune complications related to immune checkpoints inhibitors´ treatment: Spectrum of imaging appearances.
Immune checkpoints inhibitors (ICI) represent a new therapy option for the treatment of several advanced tumors. However, this therapy has been linked to a spectrum of ICI related autoimmune (AI) adverse events. Some may be life threatening and their diagnosis is tricky. The aim of our study was to describe various imaging appearances of ICI related secondary hypophysitis and other coincidental AI diseases. We included 28 patients (19 females, 9 men, mean aged 58±13 years), who were consecutively treated mostly for advanced stage melanoma by different ICI. All their CT/MRI records and clinical data were reviewed. We found 5 (18%) cases of endocrinology proven secondary hypophysitis; 2 cases of panhypopituitarism and 3 cases of central hypocortisolism. Four cases were MRI positive, 1 case was MRI negative. Three cases were accompanied by other AI diseases: 1 by hemorrhagic colitis and mesenterial lymphadenitis, 1 by AI pancreatitis and 1 by pneumonitis. On MRI pituitary gland was swollen in 3 cases, twice enhanced non-homogenously, once homogenously; infundibular enlargement was present in 2 cases. Those 3 cases reacted to glucocorticoid therapy by hypophyseal shrinkage. In 1 case of MRI positive hypophysitis, the pituitary gland was not enlarged, slightly nonhomogeneous with peripheral contour enhancement; no reaction to glucocorticoids was mentioned. Secondary hypophysitis is probably more common ICI related adverse event than reported in the literature. Its MRI appearance is variable. Most of our cases were in coincidence with other AI ICI related events that affected their clinical manifestations.


Malaria heat shock proteins: drug targets that chaperone other drug targets.
Ongoing research into the chaperone systems of malaria parasites, and particularly of Plasmodium falciparum, suggests that heat shock proteins (Hsps) could potentially be an excellent class of drug targets. The P. falciparum genome encodes a vast range and large number of chaperones, including 43 Hsp40, six Hsp70, and three Hsp90 proteins (PfHsp40s, PfHsp70s and PfHsp90s), which are involved in a number of fundamental cellular processes including protein folding and assembly, protein translocation, signal transduction and the cellular stress response. Despite the fact that Hsps are relatively conserved across different species, PfHsps do exhibit a considerable number of unique structural and functional features. One PfHsp90 is thought to be sufficiently different to human Hsp90 to allow for selective targeting. PfHsp70s could potentially be used as drug targets in two ways: either by the specific inhibition of Hsp70s by small molecule modulators, as well as disruption of the interactions between Hsp70s and co-chaperones such as the Hsp70/Hsp90 organising protein (Hop) and Hsp40s. Of the many PfHsp40s present on the parasite, there are certain unique or essential members which are considered to have good potential as drug targets. This review critically evaluates the potential of Hsps as malaria drug targets, as well as the use of chaperones as aids in the heterologous expression of other potential malarial drug targets.


Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future.
The calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) are associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish their overall benefits for long-term graft survival. Nephrotoxicity is difficult to distinguish from chronic allograft rejection and is a particular problem in the setting of renal transplantation. Minimizing immunosuppressant-induced nephrotoxicity could improve long-term renal allograft survival. However, to obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on calcineurin inhibitors. Recipients of other transplanted organs, as well as patients with autoimmune diseases who require immunosuppressant therapy, could also benefit from this change in immunosuppressive drug strategy because their healthy, native kidneys are particularly susceptible to the nephrotoxic effects of CsA and FK506. CsA- and FK506-sparing regimens, which use reduced doses of CsA and FK506 in combination with other nonnephrotoxic immunosuppressants, may be the best current option for reducing nephrotoxicity. The chemical immunosuppressant mycophenolate mofetil (MMF) has been used as part of CsA- and FK506-sparing regimens that provide improved renal function while maintaining adequate immunosuppression. Such regimens should reduce patient morbidity and mortality. Also, because immunosuppressant-induced nephrotoxicity has been associated with significant financial costs, CsA- and FK506-sparing regimens should result in substantial savings in health care costs.


Collective dynamics of stock market efficiency.
Summarized by the efficient market hypothesis, the idea that stock prices fully reflect all available information is always confronted with the behavior of real-world markets. While there is plenty of evidence indicating and quantifying the efficiency of stock markets, most studies assume this efficiency to be constant over time so that its dynamical and collective aspects remain poorly understood. Here we define the time-varying efficiency of stock markets by calculating the permutation entropy within sliding time-windows of log-returns of stock market indices. We show that major world stock markets can be hierarchically classified into several groups that display similar long-term efficiency profiles. However, we also show that efficiency ranks and clusters of markets with similar trends are only stable for a few months at a time. We thus propose a network representation of stock markets that aggregates their short-term efficiency patterns into a global and coherent picture. We find this financial network to be strongly entangled while also having a modular structure that consists of two distinct groups of stock markets. Our results suggest that stock market efficiency is a collective phenomenon that can drive its operation at a high level of informational efficiency, but also places the entire system under risk of failure.


Neurophysiological changes associated with vibroacoustically-augmented breath-focused mindfulness for dissociation: targeting interoception and attention.
Dissociative symptoms can emerge after trauma and interfere with attentional control and interoception; disruptions to these processes are barriers to mind-body interventions such as breath-focused mindfulness (BFM). To overcome these barriers, we tested the use of an exteroceptive augmentation to BFM, using vibrations equivalent to the amplitude of the auditory waveform of the actual breath, delivered via a wearable subwoofer in real time (VBFM). We tested whether this device enhanced interoceptive processes, attentional control and autonomic regulation in trauma-exposed women with dissociative symptoms. 65 women, majority (82%) Black American, aged 18-65 completed self-report measures of interoception and 6 BFM sessions, during which electrocardiographic recordings were taken to derive high-frequency heart rate variability (HRV) estimates. A subset (n = 31) of participants completed functional MRI at pre- and post-intervention, during which they were administered an affective attentional control task. Compared to those who received BFM only, women who received VBFM demonstrated greater increases in interoception, particularly their ability to trust body signals, increased sustained attention, as well as increased connectivity between nodes of emotion processing and interoceptive networks. Intervention condition moderated the relationship between interoception change and dissociation change, as well as the relationship between dissociation and HRV change. Vibration feedback during breath focus yielded greater improvements in interoception, sustained attention and increased connectivity of emotion processing and interoceptive networks. Augmenting BFM with vibration appears to have considerable effects on interoception, attention and autonomic regulation; it could be used as a monotherapy or to address trauma treatment barriers.


Bayesian spatiotemporal analysis of socio-ecologic drivers of Ross River virus transmission in Queensland, Australia.
This study aims to examine the impact of socio-ecologic factors on the transmission of Ross River virus (RRV) infection and to identify areas prone to social and ecologic-driven epidemics in Queensland, Australia. We used a Bayesian spatiotemporal conditional autoregressive model to quantify the relationship between monthly variation of RRV incidence and socio-ecologic factors and to determine spatiotemporal patterns. Our results show that the average increase in monthly RRV incidence was 2.4% (95% credible interval (CrI): 0.1-4.5%) and 2.0% (95% CrI: 1.6-2.3%) for a 1 degrees C increase in monthly average maximum temperature and a 10 mm increase in monthly average rainfall, respectively. A significant spatiotemporal variation and interactive effect between temperature and rainfall on RRV incidence were found. No association between Socio-economic Index for Areas (SEIFA) and RRV was observed. The transmission of RRV in Queensland, Australia appeared to be primarily driven by ecologic variables rather than social factors.


Pediatric liver transplantation. A single center experience spanning 20 years.
Survival after liver transplantation has improved significantly over the last decade with pediatric recipients faring better than adults. The 20-year experience of pediatric liver transplantation at Children's Hospital of Pittsburgh is reported in terms of patient survival; graft survival in relation to age, gender, and immunosuppressive protocols; causes of death; and indications for retransplantation. From March 1981 to April 1998, 808 children received liver transplants at Children's Hospital of Pittsburgh. All patients were followed until March 2001, with a mean follow-up of 12.2+/-3.9 years (median=12.6; range=2.9-20). There were 405 female (50.2%) and 403 male (49.8%) pediatric recipients. Mean age at transplant was 5.3+/-4.9 years (mean=3.3; range 0.04-17.95), with 285 children (25.3%) being less than 2 years of age at transplant. Cyclosporine (CsA)-based immunosuppression was used before November 1989 in 482 children (50.7%), and the subsequent 326 recipients (40.3%) were treated with tacrolimus-based immunosuppression. Actuarial survival was calculated using the Kaplan-Meier statistical method. Differences in survival were calculated by log-rank analysis. Overall patient survival at 1, 5, 10, 15, and 20 years was 77.1%, 72.6%, 69.4%, 65.8%, and 64.4%, respectively. There was no difference in survival for male or female patients at any time point. At up to 10 years posttransplant, the survival for children greater than 2 years of age (79.5%, 75.7%, and 71.6% at 1, 5, and 10 years, respectively) was slightly higher than those at less than 2 years of age (72.6%, 66.9%, and 65.3% at 1, 5, and 10 years, respectively). However, at 15 and 20 years posttransplant, survival rates were similar (>2 years=67.3% and 65.8%; <2 years=64.1% and 64.1%). A significant difference in survival was seen in CsA-based immunosuppression (71.2%, 68.1%, 65.4%, and 61%) versus tacrolimus-based immunosuppression (85.8%, 84.7%, 83.3%, and 82.9%) at 1, 3, 5, and 10 years, respectively (P=0.0001). The maximum difference in survival was noted in the first 3 months between CsA and tacrolimus; thus, indicating there may have been other factors (nonimmunological factors) involved in terms of donor and recipient selection and technical issues. The mean annual death rate beyond 2 years posttransplant was 0.47%, with the mean annual death rate for patients who received tacrolimus-based immunosuppression being significantly lower than those who received CsA-based immunosuppression (0.14% vs. 0.8%; P=0.001). The most common etiologies of graft loss were hepatic artery thrombosis (33.4%), acute or chronic rejection (26.6%), and primary nonfunction (16.7%). Of note, retransplantation for graft loss because of acute or chronic rejection occurred only in those patients who received CsA-based immuno-suppression. The overall 20-year actuarial survival for pediatric liver transplantation is 64%. Survival has increased by 20% in the last 12 years with tacrolimus-based immunosuppression. Although this improvement may be the result of several factors, retransplantation as a result of acute or chronic rejection has been completely eliminated in patients treated with tacrolimus.