Remotely-sensed detection of effects of extreme droughts on gross primary production.
Severe droughts strongly impact photosynthesis (GPP), and satellite imagery has yet to demonstrate its ability to detect drought effects. Especially changes in vegetation functioning when vegetation state remains unaltered (no browning or defoliation) pose a challenge to satellite-derived indicators. We evaluated the performance of different satellite indicators to detect strong drought effects on GPP in a beech forest in France (Hesse), where vegetation state remained largely unaffected while GPP decreased substantially. We compared the results with three additional sites: a Mediterranean holm oak forest (Puéchabon), a temperate beech forest (Hainich), and a semi-arid grassland (Bugacpuszta). In Hesse, a three-year reduction in GPP following drought was detected only by the Enhanced Vegetation Index (EVI). The Photochemical Reflectance Index (PRI) also detected this drought effect, but only after normalization for absorbed light. In Puéchabon normalized PRI outperformed the other indicators, while the short-term drought effect in Hainich was not detected by any tested indicator. In contrast, most indicators, but not PRI, captured the drought effects in Bugacpuszta. Hence, PRI improved detection of drought effects on GPP in forests and we propose that PRI normalized for absorbed light is considered in future algorithms to estimate GPP from space.


Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus.
Store-operated calcium entry (SOCE) is the mechanism by which extracellular signals elicit prolonged intracellular calcium elevation to drive changes in fundamental cellular processes. Here, we investigated the role of SOCE in the regulation of renal water reabsorption, using the inbred rat strain SHR-A3 as an animal model with disrupted SOCE. We found that SHR-A3, but not SHR-B2, have a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), the endoplasmic reticulum calcium (Ca(2+)) sensor that triggers SOCE. Balance studies revealed increased urine volume, hypertonic plasma, polydipsia, and impaired urinary concentrating ability accompanied by elevated circulating arginine vasopressin (AVP) levels in SHR-A3 compared with SHR-B2. Isolated, split-open collecting ducts (CD) from SHR-A3 displayed decreased basal intracellular Ca(2+) levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca(2+) mobilization that requires SOCE in CD cells from SHR-A3. This effect decreased the abundance of aquaporin 2 and enhanced its intracellular retention, suggesting impaired sensitivity of the CD to AVP in SHR-A3. Stim1 knockdown in cultured mpkCCDc14 cells reduced SOCE and basal intracellular Ca(2+) levels and prevented AVP-induced translocation of aquaporin 2, further suggesting the effects in SHR-A3 result from the expression of truncated STIM1. Overall, these results identify a novel mechanism of nephrogenic diabetes insipidus and uncover a role of SOCE in renal water handling.


Tapering of the cervical spinal canal in patients with scoliosis with and without the Chiari I malformation.
Cervical spinal canal tapering may increase CSF velocities and pressures. One report suggests that the cervical spinal canal tapers more steeply in patients with Chiari I than in healthy subjects. The goal of this study was to test the conclusion by measuring spinal canal tapering in another cohort of patients. Consecutive patients with scoliosis and MR imaging were selected. The MR images were evaluated for tonsillar herniation and syringomyelia. On a midline T2-weighted MR image, the anteroposterior diameter of the spinal canal was measured at each cervical level, and a linear trend line was fit by least-squares regression. The slope of this line was recorded as the taper ratio in millimeters/level. Patients with >5 mm of tonsillar herniation (with or without syrinx) were compared with those without tonsillar herniation (with or without syrinx). Differences in taper ratios for the 2 groups were tested for significance by the Kruskal-Willis test with significance set at .05. Fifty-four patients with scoliosis were identified; 22 had a Chiari malformation and 32 did not. Syringomyelia was identified in 20 of the patients with Chiari and in 8 of the others. The taper ratios averaged -0.9 mm/level for the patients with a Chiari malformation (with or without a syrinx) and -0.4 mm/level for those without it, significant at P = .035. Syringomyelia did not substantially alter the taper ratio in either group. Patients with scoliosis with a Chiari malformation have more steeply tapering cervical spinal canals than those without it.


Hibernation in the pygmy slow loris (Nycticebus pygmaeus): multiday torpor in primates is not restricted to Madagascar.
Hibernation and short daily torpor are states of energy conservation with reduced metabolism and body temperature. Both hibernation, also called multiday torpor, and daily torpor are common among mammals and occur in at least 11 orders. Within the primates, there is a peculiar situation, because to date torpor has been almost exclusively reported for Malagasy lemurs. The single exception is the African lesser bushbaby, which is capable of daily torpor, but uses it only under extremely adverse conditions. For true hibernation, the geographical restriction was absolute. No primate outside of Madagascar was previously known to hibernate. Since hibernation is commonly viewed as an ancient, plesiomorphic trait, theoretically this could mean that hibernation as an overwintering strategy was lost in all other primates in mainland Africa, Asia, and the Americas. However, we hypothesized that a good candidate species for the use of hibernation, outside of Madagascar should be the pygmy slow loris (Nycticebus pygmaeus), a small primate inhabiting tropical forests. Here, we show that pygmy slow lorises exposed to natural climatic conditions in northern Vietnam during winter indeed undergo torpor lasting up to 63 h, that is, hibernation. Thus, hibernation has been retained in at least one primate outside of Madagascar.


Prepartum, postpartum, and chronic depression effects on newborns.
In order to assess the effects of the onset and chronicity of maternal depression on neonatal physiology, eighty pregnant women were assessed for depression during mid-pregnancy (M gestational age = 25.9 weeks) and shortly after delivery. The women were classified as reporting depressive symptoms 1) only during the prepartum assessment; 2) only during the postpartum assessment; 3) during both the prepartum and postpartum assessments; or 4) reporting no depressive symptoms at either the prepartum or the postpartum assessment. Maternal mood and biochemistry were assessed during pregnancy, and the EEG and biochemical characteristics of their 1-week-old infants were assessed shortly after birth. As predicted, the newborns of the mothers with prepartum and postpartum depressive symptoms had elevated cortisol and norepinephrine levels, lower dopamine levels, and greater relative right frontal EEG asymmetry. The infants in the prepartum group also showed greater relative right frontal EEG asymmetry and higher norepinephrine levels. These data suggest that effects on newborn physiology depend more on prepartum than postpartum maternal depression but may also depend on the duration of the depressive symptoms.


Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic reticulum Ca2+ ATPase), tctp, mdr1, and cg10.
Resistance of Plasmodium falciparum to drugs such as chloroquine and sulfadoxine-pyrimethamine is a major problem in malaria control. Artemisinin (ART) derivatives, particularly in combination with other drugs, are thus increasingly used to treat malaria, reducing the probability that parasites resistant to the components will emerge. Although stable resistance to artemisinin has yet to be reported from laboratory or field studies, its emergence would be disastrous because of the lack of alternative treatments. Here, we report for the first time, to our knowledge, genetically stable and transmissible ART and artesunate (ATN)-resistant malaria parasites. Each of two lines of the rodent malaria parasite Plosmodium chabaudi chabaudi, grown in the presence of increasing concentrations of ART or ATN, showed 15-fold and 6-fold increased resistance to ART and ATN, respectively. Resistance remained stable after cloning, freeze-thawing, after passage in the absence of drug, and transmission through mosquitoes. The nucleotide sequences of the possible genetic modulators of ART resistance (mdr1, cg10, tctp, and atp6) of sensitive and resistant parasites were compared. No mutations in these genes were identified. In addition we investigated whether changes in the copy number of these genes could account for resistance but found that resistant parasites retained the same number of copies as their sensitive progenitors. We believe that this is the first report of a malaria parasite with genetically stable and transmissible resistance to artemisinin or its derivatives.


Brucella papionis sp. nov., isolated from baboons (Papio spp.).
Two Gram-negative, non-motile, non-spore-forming coccoid bacteria (strains F8/08-60(T) and F8/08-61) isolated from clinical specimens obtained from baboons (Papio spp.) that had delivered stillborn offspring were subjected to a polyphasic taxonomic study. On the basis of 16S rRNA gene sequence similarities, both strains, which possessed identical sequences, were assigned to the genus Brucella. This placement was confirmed by extended multilocus sequence analysis (MLSA), where both strains possessed identical sequences, and whole-genome sequencing of a representative isolate. All of the above analyses suggested that the two strains represent a novel lineage within the genus Brucella. The strains also possessed a unique profile when subjected to the phenotyping approach classically used to separate species of the genus Brucella, reacting only with Brucella A monospecific antiserum, being sensitive to the dyes thionin and fuchsin, being lysed by bacteriophage Wb, Bk2 and Fi phage at routine test dilution (RTD) but only partially sensitive to bacteriophage Tb, and with no requirement for CO2 and no production of H2S but strong urease activity. Biochemical profiling revealed a pattern of enzyme activity and metabolic capabilities distinct from existing species of the genus Brucella. Molecular analysis of the omp2 locus genes showed that both strains had a novel combination of two highly similar omp2b gene copies. The two strains shared a unique fingerprint profile of the multiple-copy Brucella-specific element IS711. Like MLSA, a multilocus variable number of tandem repeat analysis (MLVA) showed that the isolates clustered together very closely, but represent a distinct group within the genus Brucella. Isolates F8/08-60(T) and F8/08-61 could be distinguished clearly from all known species of the genus Brucella and their biovars by both phenotypic and molecular properties. Therefore, by applying the species concept for the genus Brucella suggested by the ICSP Subcommittee on the Taxonomy of Brucella, they represent a novel species within the genus Brucella, for which the name Brucella papionis sp. nov. is proposed, with the type strain F8/08-60(T) ( = NCTC 13660(T) = CIRMBP 0958(T)).


Colicin FY inhibits pathogenic Yersinia enterocolitica in mice.
Yersiniosis belongs to the common foodborne diseases around the world, and frequently manifests as diarrhea that can be treated with probiotics. Colicin FY is an antibacterial agent produced by bacteria and it is capable of specific growth inhibition of Yersinia enterocolitica, the causative agent of gastrointestinal yersiniosis. In this study, recombinant E. coli producing colicin FY were constructed, using both known probiotic strains EcH22 and EcColinfant, and the newly isolated murine strains Ec1127 and Ec1145. All E. coli strains producing colicin FY inhibited growth of pathogenic Y. enterocolitica during co-cultivation in vitro. In dysbiotic mice treated with streptomycin, E. coli strains producing colicin FY inhibited progression of Y. enterocolitica infections. This growth inhibition was not observed in mice with normal gut microflora, likely due to insufficient colonization capacity of E. coli strains and/or due to spatial differences in intestinal niches. Isogenic Y. enterocolitica producing colicin FY was constructed and shown to inhibit pathogenic Y. enterocolitica in mice with normal microflora. Evidence of in vivo antimicrobial activity of colicin FY may have utility in the treatment of Y. enterocolitica infections.


Group contribution method for thermodynamic analysis of complex metabolic networks.
A new, to our knowledge, group contribution method based on the group contribution method of Mavrovouniotis is introduced for estimating the standard Gibbs free energy of formation (Delta(f)G'(o)) and reaction (Delta(r)G'(o)) in biochemical systems. Gibbs free energy contribution values were estimated for 74 distinct molecular substructures and 11 interaction factors using multiple linear regression against a training set of 645 reactions and 224 compounds. The standard error for the fitted values was 1.90 kcal/mol. Cross-validation analysis was utilized to determine the accuracy of the methodology in estimating Delta(r)G'(o) and Delta(f)G'(o) for reactions and compounds not included in the training set, and based on the results of the cross-validation, the standard error involved in these estimations is 2.22 kcal/mol. This group contribution method is demonstrated to be capable of estimating Delta(r)G'(o) and Delta(f)G'(o) for the majority of the biochemical compounds and reactions found in the iJR904 and iAF1260 genome-scale metabolic models of Escherichia coli and in the Kyoto Encyclopedia of Genes and Genomes and University of Minnesota Biocatalysis and Biodegradation Database. A web-based implementation of this new group contribution method is available free at http://sparta.chem-eng.northwestern.edu/cgi-bin/GCM/WebGCM.cgi.


1-methylnicotinamide and its structural analog 1,4-dimethylpyridine for the prevention of cancer metastasis.
1-methylnicotinamide (1-MNA), an endogenous metabolite of nicotinamide, has recently gained interest due to its anti-inflammatory and anti-thrombotic activities linked to the COX-2/PGI2 pathway. Given the previously reported anti-metastatic activity of prostacyclin (PGI2), we aimed to assess the effects of 1-MNA and its structurally related analog, 1,4-dimethylpyridine (1,4-DMP), in the prevention of cancer metastasis. All the studies on the anti-tumor and anti-metastatic activity of 1-MNA and 1,4-DMP were conducted using the model of murine mammary gland cancer (4T1) transplanted either orthotopically or intravenously into female BALB/c mouse. Additionally, the effect of the investigated molecules on cancer cell-induced angiogenesis was estimated using the matrigel plug assay utilizing 4T1 cells as a source of pro-angiogenic factors. Neither 1-MNA nor 1,4-DMP, when given in a monotherapy of metastatic cancer, influenced the growth of 4T1 primary tumors transplanted orthotopically; however, both compounds tended to inhibit 4T1 metastases formation in lungs of mice that were orthotopically or intravenously inoculated with 4T1 or 4T1-luc2-tdTomato cells, respectively. Additionally, while 1-MNA enhanced tumor vasculature formation and markedly increased PGI2 generation, 1,4-DMP did not have such an effect. The anti-metastatic activity of 1-MNA and 1,4-DMP was further confirmed when both agents were applied with a cytostatic drug in a combined treatment of 4T1 murine mammary gland cancer what resulted in up to 80 % diminution of lung metastases formation. The results of the studies presented below indicate that 1-MNA and its structural analog 1,4-DMP prevent metastasis and might be beneficially implemented into the treatment of metastatic breast cancer to ensure a comprehensive strategy of metastasis control.


Genetic Influences on Hippocampal Subfields: An Emerging Area of Neuroscience Research.
There is clear evidence that hippocampal subfield volumes have partly distinct genetic determinants associated with specific biological processes. The identification of genetic correlates of hippocampal subfield volumes may help to elucidate the mechanisms of neurologic diseases, as well as aging and neurodegenerative processes. However, despite the emerging interest in this area of research, the current knowledge of the genetic architecture of hippocampal subfields has not yet been consolidated. We aimed to provide a review of the current evidence from genetic studies of hippocampal subfields, highlighting current priorities and upcoming challenges. The limited number of studies investigating the influential genetic effects on hippocampal subfields, a lack of replicated results and longitudinal designs, and modest sample sizes combined with insufficient standardization of protocols are identified as the most pressing challenges in this emerging area of research.


Biomechanical Rigidity and Quantitative Proteomics Analysis of Segmental Regions of the Trabecular Meshwork at Physiologic and Elevated Pressures.
The extracellular matrix (ECM) of the trabecular meshwork (TM) modulates resistance to aqueous humor outflow, thereby regulating IOP. Glaucoma, a leading cause of irreversible blindness worldwide, is associated with changes in the ECM of the TM. The elastic modulus of glaucomatous TM is larger than age-matched normal TM; however, the biomechanical properties of segmental low (LF) and high flow (HF) TM regions and their response to elevated pressure, are unknown. We perfused human anterior segments at two pressures using an ex vivo organ culture system. After extraction, we measured the elastic modulus of HF and LF TM regions by atomic force microscopy and quantitated protein differences by proteomics analyses. The elastic modulus of LF regions was 2.3-fold larger than HF regions at physiological (1×) pressure, and 7.4-fold or 3.5-fold larger than HF regions at elevated (2×) pressure after 24 or 72 hours, respectively. Using quantitative proteomics, comparisons were made between HF and LF regions at 1× or 2× pressure. Significant ECM protein differences were observed between LF and HF regions perfused at 2×, and between HF regions at 1× compared to 2× pressures. Decorin, TGF-β-induced protein, keratocan, lumican, dermatopontin, and thrombospondin 4 were common differential candidates in both comparisons. These data show changes in biomechanical properties of segmental regions within the TM in response to elevated pressure, and levels of specific ECM proteins. Further studies are needed to determine whether these ECM proteins are specifically involved in outflow resistance and IOP homeostasis.


Solution-Processed Sensing Textiles with Adjustable Sensitivity and Linear Detection Range Enabled by Twisting Structure.
Wearable strain sensors are emerging rapidly for their promising applications in human motion detection for diagnosis, healthcare, training instruction, and rehabilitation exercise assessment. However, it remains a bottleneck in gaining comfortable and breathable devices with the features of high sensitivity, linear response, and tunable detection range. Textiles possess fascinating advantages of good breathability, aesthetic property, tailorability, and excellent mechanical compliance to conformably attach to human body. As the meandering loops in a textile can be extended in different directions, it provides plenty of room for exploring ideal sensors by tuning a twisting structure with rationally selected yarn materials. Herein, textile sensors with twisting architecture are designed via a solution-based process by using a stable water-based conductive ink that is composed of polypyrrole/polyvinyl alcohol nanoparticles with a mean diameter of 50 nm. Depending on the predesigned twisting models, the thus-fabricated textile sensors show adjustable performances, exhibiting a high sensitivity of 38.9 with good linearity and a broad detection range of 200%. Such sensors can be integrated into fabrics and conformably attached to skin for monitoring subtle (facial expressions, breathing, and speaking) and large (stretching, jumping, running and jogging, and sign language) human motions. As a proof-of-concept application, by integrating with a wireless transmitter, the signals detected by our sensors during exercise (e.g., running) can be remotely received and displayed on a smartphone. It is believed that the integration of our textile sensors with selected twisting models into a cloth promises full-range motion detection for wearable electronics and human-machine interfaces.


Antibiotic treatment in patients with sepsis: a narrative review.
Sepsis is a medical emergency and life-threatening condition due to a dysregulated host response to infection, with unacceptably high morbidity and mortality. Similar to acute myocardial infarction or cerebral vascular accident, sepsis is a severe and continuous time-dependent condition. Thus, in the case of sepsis, early and adequate administration of antimicrobials must be a priority, ideally within the first hour of diagnosis, simultaneously with organ support.As a consequence of the emergence of multidrug-resistant pathogens, the choice of antimicrobials should be performed according to the local pathogen patterns of resistance. Individual antimicrobial optimization is essential to achieve adequate concentrations of antimicrobials, to reduce adverse effects, and to ensure successful outcomes, as well as preventing the emergence of multidrug-resistant pathogens. The loading dose is the administration of an initial higher dose of antimicrobials, regardless of the presence of organ dysfunction. Further doses should be implemented according to pharmacokinetics/pharmacodynamics of antimicrobials and should be adjusted according to the presence of renal or liver dysfunction. Extended or continuous infusion of beta-lactams and therapeutic drug monitoring can help to achieve therapeutic levels of antimicrobials. Duration and adequacy of treatment must be reviewed at regular intervals to allow effective de-escalation and administration of short courses of antimicrobials for most patients. Antimicrobial stewardship frameworks, leadership, focus on the optimal duration of treatments, de-escalation, and novel diagnostic stewardship approaches will help us to improve patients the process of care and overall quality of care.


Increasing power of genome-wide association studies by collecting additional single-nucleotide polymorphisms.
Genome-wide association studies (GWASs) have been effectively identifying the genomic regions associated with a disease trait. In a typical GWAS, an informative subset of the single-nucleotide polymorphisms (SNPs), called tag SNPs, is genotyped in case/control individuals. Once the tag SNP statistics are computed, the genomic regions that are in linkage disequilibrium (LD) with the most significantly associated tag SNPs are believed to contain the causal polymorphisms. However, such LD regions are often large and contain many additional polymorphisms. Following up all the SNPs included in these regions is costly and infeasible for biological validation. In this article we address how to characterize these regions cost effectively with the goal of providing investigators a clear direction for biological validation. We introduce a follow-up study approach for identifying all untyped associated SNPs by selecting additional SNPs, called follow-up SNPs, from the associated regions and genotyping them in the original case/control individuals. We introduce a novel SNP selection method with the goal of maximizing the number of associated SNPs among the chosen follow-up SNPs. We show how the observed statistics of the original tag SNPs and human genetic variation reference data such as the HapMap Project can be utilized to identify the follow-up SNPs. We use simulated and real association studies based on the HapMap data and the Wellcome Trust Case Control Consortium to demonstrate that our method shows superior performance to the correlation- and distance-based traditional follow-up SNP selection approaches. Our method is publicly available at http://genetics.cs.ucla.edu/followupSNPs.


Explanation and elaboration of the SQUIRE (Standards for Quality Improvement Reporting Excellence) Guidelines, V.2.0: examples of SQUIRE elements in the healthcare improvement literature.
Since its publication in 2008, SQUIRE (Standards for Quality Improvement Reporting Excellence) has contributed to the completeness and transparency of reporting of quality improvement work, providing guidance to authors and reviewers of reports on healthcare improvement work. In the interim, enormous growth has occurred in understanding factors that influence the success, and failure, of healthcare improvement efforts. Progress has been particularly strong in three areas: the understanding of the theoretical basis for improvement work; the impact of contextual factors on outcomes; and the development of methodologies for studying improvement work. Consequently, there is now a need to revise the original publication guidelines. To reflect the breadth of knowledge and experience in the field, we solicited input from a wide variety of authors, editors and improvement professionals during the guideline revision process. This Explanation and Elaboration document (E&E) is a companion to the revised SQUIRE guidelines, SQUIRE 2.0. The product of collaboration by an international and interprofessional group of authors, this document provides examples from the published literature, and an explanation of how each reflects the intent of a specific item in SQUIRE. The purpose of the guidelines is to assist authors in writing clearly, precisely and completely about systematic efforts to improve the quality, safety and value of healthcare services. Authors can explore the SQUIRE statement, this E&E and related documents in detail at http://www.squire-statement.org.


Data sharing among data monitoring committees and responsibilities to patients and science.
Over the past three decades it has become increasingly recognized that systematic assessment of as high a proportion as possible of relevant research evidence is needed to protect the best interests of patients and the public. For example, this principle is manifested in clinical guidelines and, increasingly, in the design and monitoring of new research. For scientific and ethical reasons, those responsible for monitoring the progress of ongoing clinical trials may need to seek unpublished and interim data to protect the interests of actual or potential participants in research. The challenge facing data monitoring committees has received relatively little attention, however. In this paper we review some of the commentaries on the issue and the few accounts of actual data monitoring committee experiences. We then present details of our own recent experience as members of the data monitoring committee for the BOOST-II UK trial (ISRCTN:0084226), one of five concurrent trials assessing the level of arterial oxygen which should be targeted in the care of very premature neonates. We conclude that efficient protection both of the interests of actual or potential participants in research and of science requires that data monitoring committees have access to all relevant research, including unpublished and interim data.


Pineal hyperactivity in spontaneously hypertensive rats: muscarinic regulation of indole metabolism.
1. Choline acetyltransferase activity and [3H]quinuclidinyl benzylate-binding sites were detected in the pineal gland of normotensive Wistar-Kyoto rats and of spontaneously hypertensive rats. 2. In vitro, muscarinic activation by pilocarpine increased the pineal metabolic production of hydroxyindole derivatives up to 5-hydroxytryptamine and produced a less marked stimulation of melatonin biosynthesis. 3. Electrical field stimulation of pineal gland slices caused similar metabolic effects. 4. Muscarinic blockade with atropine inhibited the effects on hydroxyindole metabolism. 5. [3H]Quinuclidinyl benzylate-binding sites, indicative of muscarinic receptors, were more numerous, and basal 5-hydroxytryptamine and melatonin levels were higher, in the pineal gland of spontaneously hypertensive rats compared with Wistar-Kyoto rats. 6. The atropine-sensitive metabolic effects of pilocarpine and electrical field stimulation on the pineal gland were increased in spontaneously hypertensive rats compared with Wistar-Kyoto rats.


Ectopic assembly of heterochromatin in Drosophila melanogaster triggered by transposable elements.
A persistent question in biology is how cis-acting sequence elements influence trans-acting factors and the local chromatin environment to modulate gene expression. We reported previously that the DNA transposon 1360 can enhance silencing of a reporter in a heterochromatic domain of Drosophila melanogaster. We have now generated a collection of variegating phiC31 landing-pad insertion lines containing 1360 and a heat-shock protein 70 (hsp70)-driven white reporter to explore the mechanism of 1360-sensitive silencing. Many 1360-sensitive sites were identified, some in apparently euchromatic domains, although all are close to heterochromatic masses. One such site (line 1198; insertion near the base of chromosome arm 2L) has been investigated in detail. ChIP analysis shows 1360-dependent Heterochromatin Protein 1a (HP1a) accumulation at this otherwise euchromatic site. The phiC31 landing pad system allows different 1360 constructs to be swapped with the full-length element at the same genomic site to identify the sequences that mediate 1360-sensitive silencing. Short deletions over sites with homology to PIWI-interacting RNAs (piRNAs) are sufficient to compromise 1360-sensitive silencing. Similar results were obtained on replacing 1360 with Invader4 (a retrotransposon), suggesting that this phenomenon likely applies to a broader set of transposable elements. Our results suggest a model in which piRNA sequence elements behave as cis-acting targets for heterochromatin assembly, likely in the early embryo, where piRNA pathway components are abundant, with the heterochromatic state subsequently propagated by chromatin modifiers present in somatic tissue.


Topography of the casein micelle surface by surface plasmon resonance (SPR) using a selection of specific monoclonal antibodies.
Several theoretical models of the casein micelle structure have been proposed in the past, but the exact organization of the four individual caseins (α(s1), α(s2), β, and κ) within this supramolecular structure remains unknown. The present study aims at determining the topography of the casein micelle surface by following the interaction between 44 monoclonal antibodies specific for different epitopes of α(s1)-, α(s2)-, β-, and κ-casein and the casein micelle in real time and no labeling using a surface plasmon resonance (SPR)-based biosensor. Although the four individual caseins were found to be accessible for antibody binding, data confirmed that the C-terminal extremity of κ-casein was highly accessible and located at the periphery of the structure. When casein micelles were submitted to proteolysis, the C-terminal extremity of κ-casein was rapidly hydrolyzed. Disintegration of the micellar structure resulted in an increased access for antibodies to hydrophobic areas of α(s1)- and α(s2)-casein.


Opportunities and challenges in Improving Access to Psychological Therapies for people with Severe Mental Illness (IAPT-SMI): evaluating the first operational year of the South London and Maudsley (SLaM) demonstration site for psychosis.
Despite its demonstrated clinical and economic effectiveness, access to Cognitive Behavioural Therapy for psychosis (CBTp) in routine practice remains low. The UK National Health Service (NHS England) Improving Access to Psychological Therapies for people with Severe Mental Illness (IAPT-SMI) initiative aims to address this problem. We report 14-month outcomes for our psychosis demonstration site. Primary and secondary care and self-referrals were screened to check the suitability of the service for the person. Psychotic symptoms, distress, service use, functioning and satisfaction were measured before and after therapy, by trained assessors. User-defined wellbeing and goal-attainment were rated sessionally. Access to CBTp increased almost threefold (2011/12 accepted referrals/year n = 106; 2012/13, n = 300). The IAPT-SMI assessment protocol proved feasible and acceptable to service users, with paired primary outcomes for 97% of closed cases. Therapy completion (≥5 sessions) was high (83%) irrespective of ethnicity, age and gender. Preliminary pre-post outcomes showed clinical improvement and reduced service use, with medium/high effect sizes. User-rated satisfaction was high. We conclude that individual psychological interventions for people with psychosis can be successfully delivered in routine services using an IAPT approach. High completion rates for paired outcomes demonstrate good user experience, clinical improvement, and potential future cost savings.


Differences in onset and abuse/dependence episodes between prescription opioids and heroin: results from the National Epidemiologic Survey on Alcohol and Related Conditions.
OBJECTIVES: To examine patterns of onset and abuse/dependence episodes of prescription opioid (PO) and heroin use disorders in a national sample of adults, and to explore differences by gender and substance abuse treatment status. METHODS: Analyses of data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). RESULTS: Of all respondents, 5% (n = 1815) reported a history of nonmedical PO use (NMPOU) and 0.3% (n = 150) a history of heroin use. Abuse was more prevalent than dependence among NMPOUs (PO abuse, 29%; dependence, 7%) and heroin users (heroin abuse, 63%; dependence, 28%). Heroin users reported a short mean interval from first use to onset of abuse (1.5 years) or dependence (2.0 years), and a lengthy mean duration for the longest episode of abuse (66 months) or dependence (59 months); the corresponding mean estimates for PO abuse and dependence among NMPOUs were 2.6 and 2.9 years, respectively, and 31 and 49 months, respectively. The mean number of years from first use to remission from the most recent episode was 6.9 years for PO abuse and 8.1 years for dependence; the mean number of years from first heroin use to remission from the most recent episode was 8.5 years for heroin abuse and 9.7 years for dependence. Most individuals with PO or heroin use disorders were remitted from the most recent episode. Treated individuals, whether their problem was heroin or POs, tended to have a longer mean duration of an episode than untreated individuals. CONCLUSION: Periodic remissions from opioid or heroin abuse or dependence episodes occur commonly but take a long time. Timely and effective use of treatment services are needed to mitigate the many adverse consequences from opioid/heroin abuse and dependence.


European Respiratory Society guidelines for the management of adult bronchiectasis.
Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes.


Salmonella septic arthritis in systemic lupus erythematosus and other systemic diseases.
Salmonella infection is an important problem in immunocompromised patients. The synovium is a particular metastatic focus of Salmonella infection and can result in many disabilities of life. Systemic lupus erythematosus (SLE) patients were highly susceptible to Salmonella infection. In the past 6 years, 41 patients with Salmonella septic arthritis have been treated in our hospital. Eleven patients had an underlying systemic disease of SLE which presented with a distinctive clinical course. Alcoholic liver disease (six cases) was another common underlying systemic disease. The most frequent predisposing articular factor was avascular necrosis (16 cases). The hip joint was the most commonly involved site. Salmonella group B was the most common serotype (30/41). Seventy-three per cent (8/11) of the SLE group had involvement of two or more joints compared with only three out of 30 patients in the non-SLE group. The sex differentiation shows a predominance of young females (10/11) in the SLE group and middle-aged males in the non-SLE group. Moreover, in the SLE group, all 11 patients shared the risk of lupus nephritis and steroid use. Ten patients had Salmonella group B bacteraemia and five had urinary tract infections simultaneously. In the non-SLE group, there were 10 patients with a history of steroid use, three with antecedent enteritis, 12 with bacteraemia, and three with necrotising fasciitis. Seven patients in each of the groups had a recurrent course. However, three patients in the non-SLE group had died during the episode of septic arthritis.


An overview of techniques for dealing with large numbers of independent variables in epidemiologic studies.
Many studies of health and production problems in livestock involve the simultaneous evaluation of large numbers of risk factors. These analyses may be complicated by a number of problems including: multicollinearity (which arises because many of the risk factors may be related (correlated) to each other), confounding, interaction, problems related to sample size (and hence the power of the study), and the fact that many associations are evaluated from a single dataset. This paper focuses primarily on the problem of multicollinearity and discusses a number of techniques for dealing with this problem. However, some of the techniques discussed may also help to deal with the other problems identified above. The first general approach to dealing with multicollinearity involves reducing the number of independent variables prior to investigating associations with the disease. Techniques to accomplish this include: (1) excluding variables after screening for associations among independent variables; (2) creating indices or scores which combine data from multiple factors into a single variable; (3) creating a smaller set of independent variables through the use of multivariable techniques such as principal components analysis or factor analysis. The second general approach is to use appropriate steps and statistical techniques to investigate associations between the independent variables and the dependent variable. A preliminary screening of these associations may be performed using simple statistical tests. Subsequently, multivariable techniques such as linear or logistic regression or correspondence analysis can be used to identify important associations. The strengths and limitations of these techniques are discussed and the techniques are demonstrated using a dataset from a recent study of risk factors for pneumonia in swine. Emphasis is placed on comparing correspondence analysis with other techniques as it has been used less in the epidemiology literature.


Heart Failure Is Common and Under-Recognized in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia.
Heart failure (HF) prevalence in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) varies depending on study cohort and is not well characterized. This study sought to determine prevalence and predictors of HF in ARVC/D. Clinical HF, defined as at least 1 HF sign or symptom, was retrospectively adjudicated for 289 patients meeting ARVC/D Task Force Criteria. HF was present in 142 patients (49%): 113 had isolated RV involvement and 29 had evidence of LV dysfunction. Average age of HF onset was 40±14 years. Most commonly reported symptoms were exertional dyspnea (78%) and fatigue (73%). Only 40% (n=57/142) had signs of volume overload. Left-sided HF signs were rare. Patients with clinical HF before ARVC/D diagnosis (n=31) were older (P=0.005) and met fewer Task Force Criteria (P=0.013) than those who developed HF after ARVC/D presentation. Female sex (odds ratio, 2.2; 95% confidence interval, 1.21-4.01; P=0.01) and lateral precordial T-wave inversions (odds ratio, 9.87; 95% confidence interval, 1.07-91.1; P=0.043) were associated with increased odds of HF. Additionally, patients with symptomatic LV dysfunction had higher odds of lateral precordial T-wave inversions (odds ratio, 18.4; 95% confidence interval, 2.92-116.18; P=0.002). Patients with HF were more likely to undergo heart transplantation (15/142 versus 1/147; P<0.001) or die during study follow-up period (7 versus 0; P=0.007). HF symptoms, especially exertional dyspnea, are common in ARVC/D; yet, classic left-sided signs are typically absent and less than half have evidence of volume overload. Given the unique predominately right-sided phenotype, a large portion of patients with HF may be under-recognized.


Molecular Imaging of Neuroinflammation in Neurodegenerative Dementias: The Role of In Vivo PET Imaging.
Neurodegeneration elicits neuroinflammatory responses to kill pathogens, clear debris and support tissue repair. Neuroinflammation is a dynamic biological response characterized by the recruitment of innate and adaptive immune system cells in the site of tissue damage. Resident microglia and infiltrating immune cells partake in the restoration of central nervous system homeostasis. Nevertheless, their activation may shift to chronic and aggressive responses, which jeopardize neuron survival and may contribute to the disease process itself. Positron Emission Tomography (PET) molecular imaging represents a unique tool contributing to in vivo investigating of neuroinflammatory processes in patients. In the present review, we first provide an overview on the molecular basis of neuroinflammation in neurodegenerative diseases with emphasis on microglia activation, astrocytosis and the molecular targets for PET imaging. Then, we review the state-of-the-art of in vivo PET imaging for neuroinflammation in dementia conditions associated with different proteinopathies, such as Alzheimer's disease, frontotemporal lobar degeneration and Parkinsonian spectrum.


Driving working memory with frequency-tuned noninvasive brain stimulation.
Frequency-tuned noninvasive brain stimulation is a recent approach in cognitive neuroscience that involves matching the frequency of transcranially applied electromagnetic fields to that of specific oscillatory components of the underlying neurophysiology. The objective of this method is to modulate ongoing/intrinsic brain oscillations, which correspond to rhythmic fluctuations of neural excitability, to causally change behavior. We review the impact of frequency-tuned noninvasive brain stimulation on the research field of human working memory. We argue that this is a powerful method to probe and understand the mechanisms of memory functions, targeting specifically task-related oscillatory dynamics, neuronal representations, and brain networks. We report the main behavioral and neurophysiological outcomes published to date, in particular, how functionally relevant oscillatory signatures in signal power and interregional connectivity yield causal changes of working memory abilities. We also present recent developments of the technique that aim to modulate cross-frequency coupling in polyrhythmic neural activity. Overall, the method has led to significant advances in our understanding of the mechanisms of systems neuroscience, and the role of brain oscillations in cognition and behavior. We also emphasize the translational impact of noninvasive brain stimulation techniques in the development of therapeutic approaches.


Enhancement of late successional plants on ex-arable land by soil inoculations.
Restoration of species-rich grasslands on ex-arable land can help the conservation of biodiversity but faces three big challenges: absence of target plant propagules, high residual soil fertility and restoration of soil communities. Seed additions and top soil removal can solve some of these constraints, but restoring beneficial biotic soil conditions remains a challenge. Here we test the hypotheses that inoculation of soil from late secondary succession grasslands in arable receptor soil enhances performance of late successional plants, especially after top soil removal but pending on the added dose. To test this we grew mixtures of late successional plants in arable top (organic) soil or in underlying mineral soil mixed with donor soil in small or large proportions. Donor soils were collected from different grasslands that had been under restoration for 5 to 41 years, or from semi-natural grassland that has not been used intensively. Donor soil addition, especially when collected from older restoration sites, increased plant community biomass without altering its evenness. In contrast, addition of soil from semi-natural grassland promoted plant community evenness, and hence its diversity, but reduced community biomass. Effects of donor soil additions were stronger in mineral than in organic soil and larger with bigger proportions added. The variation in plant community composition was explained best by the abundances of nematodes, ergosterol concentration and soil pH. We show that in controlled conditions inoculation of soil from secondary succession grassland into ex-arable land can strongly promote target plant species, and that the role of soil biota in promoting target plant species is greatest when added after top soil removal. Together our results point out that transplantation of later secondary succession soil can promote grassland restoration on ex-arable land.


Safe zone for the placement of medial malleolar screws.
Hardware placement for fracture fixation can put soft-tissue structures at risk for injury or abutment. The prominence of the hardware is a frequent cause of pain after the fixation of ankle fractures. This study was designed to assess the risk of injury or abutment of the posterior tibial tendon with the placement of medial malleolar screws. Ten unmatched cadaveric limbs that had been disarticulated at the knee were used, and the medial malleolus was exposed by dissection of the skin. With use of fluoroscopy and direct visualization of the deep fascia, three Kirschner wires were placed through the tip of the medial malleolus and directed parallel to the medial articular surface. The first wire was placed in the center of the anterior colliculus. Two additional wires were placed parallel and posterior to the initial wire at 5-mm intervals. The wires were overdrilled, and 4.0-mm screws were inserted over the Kirschner wires. The specimens were dissected to inspect for trauma and the proximity of the screws to the posterior tibial tendon. The medial malleolus was divided into three zones on the basis of anatomic landmarks. Zone 1 is the anterior colliculus; Zone 2, the intercollicular groove; and Zone 3, the posterior colliculus. Screws placed in Zone 1 (the anterior colliculus) did not contact the posterior tibial tendon in any specimens. Screws placed in Zone 2 (the intercollicular groove) were, on the average, 2 mm from the posterior tibial tendon. Screws placed in Zone 3 (the posterior colliculus) resulted in tendon abutment in all ten specimens and in tendon injury in five of the ten specimens. Screws inserted posterior to the anterior colliculus place the posterior tibial tendon at significant risk for injury or abutment.


A simple way to measure ethanol sensitivity in flies.
Low doses of ethanol cause flies to become hyperactive, while high doses are sedating. The sensitivity to ethanol-induced sedation of a given fly strain is correlated with that strain s ethanol preference, and therefore sedation is a highly relevant measure to study the genetics of alcohol responses and drinking. We demonstrate a simple way to expose flies to ethanol and measure its intoxicating effects. The assay we describe can determine acute sensitivity, as well as ethanol tolerance induced by repeat exposure. It does not require a technically involved setup, and can therefore be applied in any laboratory with basic fly culture tools.


Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor: An integrated study.
Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a single study to evaluate potency, selectivity, and effect on the human gastrointestinal tract. Twenty four healthy subjects (aged 18-45 years, 12 female) received high dose lumiracoxib (800 mg every day), standard dose naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized crossover study. At the start and end of each dosing period, COX-2 selectivity was assessed by ex vivo serum thromboxane B(2) (COX-1) and lipopolysaccharide stimulated prostaglandin (PG) E(2) (COX-2), mucosal injury by endoscopy, and small and large bowel permeability by 0- to 5-hour and 5- to 24-hour (51)Cr-EDTA absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and vortex-stimulated ex vivo gastric mucosal PGE(2) synthesis at the end of each treatment period by enzyme immunoassay. Lumiracoxib was well absorbed and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66% inhibition, respectively, vs. placebo), but it differed in being more selective (24% and 97% inhibition of thromboxane B(2) vs. placebo). Gastric PGE(2) was reduced by 69% by naproxen (P < 0.001 vs. placebo) and 29% by lumiracoxib (P < 0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). (51)Cr-EDTA absorption increased significantly with naproxen but not lumiracoxib. Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no endoscopically detected stomach or duodenal injury or changes in bowel permeability.


Early transduction produces highly functional chimeric antigen receptor-modified virus-specific T-cells with central memory markers: a Production Assistant for Cell Therapy (PACT) translational application.
Virus-specific T-cells (VSTs) proliferate exponentially after adoptive transfer into hematopoietic stem cell transplant (HSCT) recipients, eliminate virus infections, then persist and provide long-term protection from viral disease. If VSTs behaved similarly when modified with tumor-specific chimeric antigen receptors (CARs), they should have potent anti-tumor activity. This theory was evaluated by Cruz et al. in a previous clinical trial with CD19.CAR-modified VSTs, but there was little apparent expansion of these cells in patients. In that study, VSTs were gene-modified on day 19 of culture and we hypothesized that by this time, sufficient T-cell differentiation may have occurred to limit the subsequent proliferative capacity of the transduced T-cells. To facilitate the clinical testing of this hypothesis in a project supported by the NHLBI-PACT mechanism, we developed and optimized a good manufacturing practices (GMP) compliant method for the early transduction of VSTs directed to Epstein-Barr virus (EBV), Adenovirus (AdV) and cytomegalovirus (CMV) using a CAR directed to the tumor-associated antigen disialoganglioside (GD2). Ad-CMVpp65-transduced EBV-LCLs effectively stimulated VSTs directed to all three viruses (triVSTs). Transduction efficiency on day three was increased in the presence of cytokines and high-speed centrifugation of retroviral supernatant onto retronectin-coated plates, so that under optimal conditions up to 88% of tetramer-positive VSTs expressed the GD2.CAR. The average transduction efficiency of early-and late transduced VSTs was 55 ± 4% and 22 ± 5% respectively, and early-transduced VSTs maintained higher frequencies of T cells with central memory or intermediate memory phenotypes. Early-transduced VSTs also had higher proliferative capacity and produced higher levels of TH1 cytokines IL-2, TNF-α, IFN-γ, MIP-1α, MIP-1β and other cytokines in vitro. We developed a rapid and GMP compliant method for the early transduction of multivirus-specific T-cells that allowed stable expression of high levels of a tumor directed CAR. Since a proportion of early-transduced CAR-VSTs had a central memory phenotype, they should expand and persist in vivo, simultaneously protecting against infection and targeting residual malignancy. This manufacturing strategy is currently under clinical investigation in patients receiving allogeneic HSCT for relapsed neuroblastoma and B-cell malignancies (NCT01460901 using a GD2.CAR and NCT00840853 using a CD19.CAR).


Psychosocial distress among young breast cancer survivors: implications for healthcare providers.
Breast cancer (BC) experiences foster serious psychosocial problems among young survivors. Previous studies have repeatedly discussed younger age as a factor that puts women with BC at higher risk of psychosocial distress. Although most BC survivors receive the necessary information from healthcare providers on treatment options and procedures at diagnosis, they often fail to receive support and guidance after acute treatment has completed in dealing with the possible physical, emotional, social, and psychological effects of cancer. This article discusses common psychosocial problems experienced by young BC survivors, such as issues related to interpersonal relationships, sexuality, fertility, and employment. In particular, it examines influences of the Japanese sociocultural background on young survivors' distress and considers the clinical implications for Japanese healthcare. The importance of integrating psychosocial care with routine oncology care cannot be overemphasized.


Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein.
Alpha-synuclein (aSyn) is a central player in Parkinson's disease (PD) but the precise molecular mechanisms underlying its pathogenicity remain unclear. It has recently been suggested that nuclear aSyn may modulate gene expression, possibly via interactions with DNA. However, the biological behavior of aSyn in the nucleus and the factors affecting its transcriptional role are not known. Here, we investigated the mechanisms underlying aSyn-mediated transcription deregulation by assessing its effects in the nucleus and the impact of phosphorylation in these dynamics. We found that aSyn induced severe transcriptional deregulation, including the downregulation of important cell cycle-related genes. Importantly, transcriptional deregulation was concomitant with reduced binding of aSyn to DNA. By forcing the nuclear presence of aSyn in the nucleus (aSyn-NLS), we found the accumulation of high molecular weight aSyn species altered gene expression and reduced toxicity when compared with the wild-type or exclusively cytosolic protein. Interestingly, nuclear localization of aSyn, and the effect on gene expression and cytotoxicity, was also modulated by phosphorylation on serine 129. Thus, we hypothesize that the role of aSyn on gene expression and, ultimately, toxicity, may be modulated by the phosphorylation status and nuclear presence of different aSyn species. Our findings shed new light onto the subcellular dynamics of aSyn and unveil an intricate interplay between subcellular location, phosphorylation and toxicity, opening novel avenues for the design of future strategies for therapeutic intervention in PD and other synucleinopathies.


Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study.
Australia introduced a human papillomavirus (HPV) vaccination programme with the quadrivalent HPV vaccine for all women aged 12-26 years between 2007 and 2009. We analysed trends in cervical abnormalities in women in Victoria, Australia, before and after introduction of the vaccination programme. With data from the Victorian Cervical Cytology Registry between 2003 and 2009, we compared the incidence of histopathologically defined high-grade cervical abnormalities (HGAs, lesions coded as cervical intraepithelial neoplasia of grade 2 or worse or adenocarcinoma in situ; primary outcome) and low-grade cytological abnormalities (LGAs) in five age groups before (Jan 1, 2003, to March 31, 2007) and after (April 1, 2007, to Dec 31, 2009) the vaccination programme began. Binary comparisons between the two periods were done with Fisher's exact test. Poisson piecewise regression analysis was used to compare incident rate trends. After the introduction of the vaccination programme, we recorded a decrease in the incidence of HGAs by 0·38% (95% CI 0·61-0·16) in girls younger than 18 years. This decrease was progressive and significantly different to the linear trend in incidence before introduction of the vaccination (incident rate ratio 1·14, 1·00-1·30, p=0·05). No similar temporal decline was recorded for LGAs or in older age groups. This is the first report of a decrease in incidence of HGAs within 3 years after the implementation of a population-wide HPV vaccination programme. Linkage between vaccination and screening registers is needed to confirm that this ecological observation is attributable to vaccination and to monitor participation in screening among vaccinated women. None.


In vitro recellularization of decellularized bovine carotid arteries using human endothelial colony forming cells.
Many patients suffering from peripheral arterial disease (PAD) are dependent on bypass surgery. However, in some patients no suitable replacements (i.e. autologous or prosthetic bypass grafts) are available. Advances have been made to develop autologous tissue engineered vascular grafts (TEVG) using endothelial colony forming cells (ECFC) obtained by peripheral blood draw in large animal trials. Clinical translation of this technique, however, still requires additional data for usability of isolated ECFC from high cardiovascular risk patients. Bovine carotid arteries (BCA) were decellularized using a combined SDS (sodium dodecyl sulfate) -free mechanical-osmotic-enzymatic-detergent approach to show the feasibility of xenogenous vessel decellularization. Decellularized BCA chips were seeded with human ECFC, isolated from a high cardiovascular risk patient group, suffering from diabetes, hypertension and/or chronic renal failure. ECFC were cultured alone or in coculture with rat or human mesenchymal stromal cells (rMSC/hMSC). Decellularized BCA chips were evaluated for biochemical, histological and mechanical properties. Successful isolation of ECFC and recellularization capabilities were analyzed by histology. Decellularized BCA showed retained extracellular matrix (ECM) composition and mechanical properties upon cell removal. Isolation of ECFC from the intended target group was successfully performed (80% isolation efficiency). Isolated cells showed a typical ECFC-phenotype. Upon recellularization, co-seeding of patient-isolated ECFC with rMSC/hMSC and further incubation was successful for 14 (n = 9) and 23 (n = 5) days. Reendothelialization (rMSC) and partial reendothelialization (hMSC) was achieved. Seeded cells were CD31 and vWF positive, however, human cells were detectable for up to 14 days in xenogenic cell-culture only. Seeding of ECFC without rMSC was not successful. Using our refined decellularization process we generated easily obtainable TEVG with retained ECM- and mechanical quality, serving as a platform to develop small-diameter (< 6 mm) TEVG. ECFC isolation from the cardiovascular risk target group is possible and sufficient. Survival of diabetic ECFC appears to be highly dependent on perivascular support by rMSC/hMSC under static conditions. ECFC survival was limited to 14 days post seeding.


Defining the dimensions of circulating tumor cells in a large series of breast, prostate, colon, and bladder cancer patients.
Circulating tumor cells (CTCs) in the blood of cancer patients are of high clinical relevance. Since detection and isolation of CTCs often rely on cell dimensions, knowledge of their size is key. We analyzed the median CTC size in a large cohort of breast (BC), prostate (PC), colorectal (CRC), and bladder (BLC) cancer patients. Images of patient-derived CTCs acquired on cartridges of the FDA-cleared CellSearch® method were retrospectively collected and automatically re-analyzed using the accept software package. The median CTC diameter (μm) was computed per tumor type. The size differences between the different tumor types and references (tumor cell lines and leukocytes) were nonparametrically tested. A total of 1962 CellSearch® cartridges containing 71 612 CTCs were included. In BC, the median computed diameter (CD) of patient-derived CTCs was 12.4 μm vs 18.4 μm for cultured cell line cells. For PC, CDs were 10.3 μm for CTCs vs 20.7 μm for cultured cell line cells. CDs for CTCs of CRC and BLC were 7.5 μm and 8.6 μm, respectively. Finally, leukocytes were 9.4 μm. CTC size differed statistically significantly between the four tumor types and between CTCs and the reference data. CTC size differences between tumor types are striking and CTCs are smaller than cell line tumor cells, whose size is often used as reference when developing CTC analysis methods. Based on our data, we suggest that the size of CTCs matters and should be kept in mind when designing and optimizing size-based isolation methods.


Review of toxicological effects caused by episodic stressor exposure.
Water quality monitoring tools that rely on data from stress-response tests with continuous exposure at constant concentrations are not always appropriately protective when stressor exposure in the field is episodic in nature. The present study identifies various approaches that have attempted to account for episodic stressor exposure, describes the development of a toxicological effects database of episodic stressor exposure collated from published scientific literature, and discusses whether any discernible trends are evident when these data are reviewed. The episodic stressor exposure literature indicated that few generalizations can be made regarding associated biological responses. Instead, when attempting to characterize the hazard of a certain episodic pollution event, the following situation-specific information is required: the specific species affected and its age, the specific stressor and its concentration, the number of exposures to the stressor, the duration of exposure to the stressor, and the recovery time after each exposure. The present study identifies four main challenges to the inclusion of episodic toxicity data in environmental water quality management: varying stressor concentration profiles, defining episodic stressor concentration levels, variation resulting from routes of exposure and modes of action, and species-specific responses to episodic stressor exposure. The database, available at http://iwr.ru.ac.za/iwr/download, could be particularly useful for site-specific risk assessments related to episodic exposures.


First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors.
AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population. Standard 3+3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies. Sixty-two patients were treated with doses ranging from 10 to 120 mg/m(2) twice weekly and 150 to 310 mg/m(2) once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m(2), which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m(2) as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients. AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.


Review of exercise intervention studies in cancer patients.
To present an overview of exercise interventions in cancer patients during and after treatment and evaluate dose-training response considering type, frequency, volume, and intensity of training along with expected physiological outcomes. The review is divided into studies that incorporated cardiovascular training, combination of cardiovascular, resistance, and flexibility training, and resistance training alone during and after cancer management. Criteria for inclusion were based on studies sourced from electronic and nonelectronic databases and that incorporated preintervention and postintervention assessment with statistical analysis of data. Twenty-six published studies were summarized. The majority of the studies demonstrate physiological and psychological benefits. However, most of these studies suffer limitations because they are not randomized controlled trials and/or use small sample sizes. Predominantly, studies have been conducted with breast cancer patients using cardiovascular training rather than resistance exercise as the exercise modality. Recent evidence supports use of resistance exercise or "anabolic exercise" during cancer management as an exercise mode to counteract side effects of the disease and treatment. Evidence underlines the preliminary positive physiological and psychological benefits from exercise when undertaken during or after traditional cancer treatment. As such, other cancer groups, in addition to those with breast cancer, should also be included in clinical trials to address more specifically dose-response training for this population. Contemporary resistance training designs that provide strong anabolic effects for muscle and bone may have an impact on counteracting some of the side effects of cancer management assisting patients to improve physical function and quality of life.


Retardation-induced plasmonic blinking in coupled nanoparticles.
We study how retardation leads to interference effects in radiatively coupled plasmonic nanoparticles. We show that inclined illumination through a glass substrate on two plasmonic particles results in either an enhanced field or an attenuated field localized at the position of the first particle. Periodic intensity blinking of the first particle is observed as a function of the particle separation. This phenomenon is nonsymmetric, and almost no blinking is observed on the second particle. The effect is strongest when the illumination angle is chosen such that the optical retardation path in the substrate coincides with the particle distance. Implications of this plasmonic blinking for near-field measurements are discussed.


Motion artifacts in capacitive ECG measurements: reducing the combined effect of DC voltages and capacitance changes using an injection signal.
Capacitive electrodes are a promising alternative to the conventional adhesive electrodes for ECG measurements. They provide more comfort to the patient when integrated in everyday objects (e.g., beds or seats) for long-term monitoring. However, the application of capacitive sensors is limited by their high sensitivity to motion artifacts. For example, motion at the body-electrode interface causes variations of the coupling capacitance which, in the presence of a dc voltage across the coupling capacitor, create strong artifacts in the measurements. The origin, relevance, and reduction of this specific and important type of artifacts are studied here. An injection signal is exploited to track the variations of the coupling capacitance in real time. This information is then used by an identification scheme to estimate the artifacts and subtract them from the measurements. The method was evaluated in simulations, lab environments, and in a real-life recording on an adult's chest. For the type of artifact under study, a strong artifact reduction ranging from 40 dB for simulated data to 9 dB for a given real-life recording was achieved. The proposed method is automated, does not require any knowledge about the measurement system parameters, and provides an online estimate for the dc voltage across the coupling capacitor.


Nicotinamide decreases MHC class II but not MHC class I expression and increases intercellular adhesion molecule-1 structures in non-obese diabetic mouse pancreas.
Pancreases of untreated and nicotinamide (NIC)-treated pre-diabetic (10-week-old) and overtly diabetic (25-week-old) female NOD (non-obese diabetic) mice and of NON (non-obese non-diabetic) control mice were studied, with the following results. (1) Islets and ducts of overtly diabetic untreated NOD mice (25-week-old) were found to express low levels of MHC class I and II molecules, like NON controls, and high levels of adhesive molecules. (2) NIC was able to slightly affect glycaemia and insulitis, slowing down diabetes progression. Moreover it significantly decreased MHC class II expression (but not class I) in vivo by week 10, and significantly enhanced intercellular adhesion molecule-1 (ICAM-1) expression, mainly by week 25, within the pancreas, where 5-bromo-2'-deoxyuridine positive nuclei and insulin positive cells were present, demonstrating that a stimulation of endocrine cell proliferation occurs. (3) In addition, NIC partly counteracted the fall of superoxide dismutase levels, observed in untreated diabetic NOD animals. (4) In vitro studies demonstrated that NIC: (i) was able to significantly reduce nitrite accumulation and to increase NAD+NADH content significantly, and (ii) was able to increase the levels of interleukin-4, a T helper 2 lymphocyte (Th2) protective cytokine, and of interferon-alpha (IFN-alpha), which is known to be able to induce MHC class I and ICAM-1 but not MHC class II expression, as well as IFN-gamma, which is also known to be able to induce MHC class I and ICAM-1 expression. The latter, although known to be a proinflammatory Th1 cytokine, has also recently been found to exert an anti-diabetogenic role. This study therefore clearly shows that adhesive mechanisms are ongoing during the later periods of diabetes in pancreatic ducts of NOD mice, and suggests they may be involved in a persistence of the immune mechanisms of recognition, adhesion and cytolysis and/or endocrine regeneration or differentiation processes, as both NIC-increased ICAM-1 expression and 5-bromo-2'-deoxyuridine positivity imply. The effects of NIC on MHC class II (i.e. a reduction) but not class I, and, mainly, on ICAM-1 expression (i.e. an increase), together with the increase in Th2 protective cytokine levels are very interesting, and could help to explain its mechanism of action and the reasons for alternate success or failure in protecting against type 1 diabetes development.


B Cell Receptor Activation Predominantly Regulates AKT-mTORC1/2 Substrates Functionally Related to RNA Processing.
Protein kinase B (AKT) phosphorylates numerous substrates on the consensus motif RXRXXpS/T, a docking site for 14-3-3 interactions. To identify novel AKT-induced phosphorylation events following B cell receptor (BCR) activation, we performed proteomics, biochemical and bioinformatics analyses. Phosphorylated consensus motif-specific antibody enrichment, followed by tandem mass spectrometry, identified 446 proteins, containing 186 novel phosphorylation events. Moreover, we found 85 proteins with up regulated phosphorylation, while in 277 it was down regulated following stimulation. Up regulation was mainly in proteins involved in ribosomal and translational regulation, DNA binding and transcription regulation. Conversely, down regulation was preferentially in RNA binding, mRNA splicing and mRNP export proteins. Immunoblotting of two identified RNA regulatory proteins, RBM25 and MEF-2D, confirmed the proteomics data. Consistent with these findings, the AKT-inhibitor (MK-2206) dramatically reduced, while the mTORC-inhibitor PP242 totally blocked phosphorylation on the RXRXXpS/T motif. This demonstrates that this motif, previously suggested as an AKT target sequence, also is a substrate for mTORC1/2. Proteins with PDZ, PH and/or SH3 domains contained the consensus motif, whereas in those with an HMG-box, H15 domains and/or NF-X1-zinc-fingers, the motif was absent. Proteins carrying the consensus motif were found in all eukaryotic clades indicating that they regulate a phylogenetically conserved set of proteins.


P-Type Low-Molecular-Weight Hydrogelators.
As the use of low-molecular-weight gelators (LMWGs) as components in single and multicomponent systems for optoelectronic and solar cell applications increases, so does the need for more functional gelators. There are relatively few examples of p-type gelators that can be used in such systems. Here, the synthesis and characterization of three amino-acid-functionalized p-type gelators based on terthiophene, tetrathiafulvalene, and oligo(phenylenevinylene) are described. The cores of these molecules are already used as electron donors in optoelectronic applications. These newly designed molecules can gel water to form highly organized structures, which can be dried into thin films that show p-type behavior.


[Accelerated rubella control and the prevention of congenital rubella syndrome].
Congenital rubella syndrome (CRS) is associated with substantial morbidity and mortality and with high costs. Today, as a result of improved vaccination and epidemiological surveillance efforts directed at eradicating measles from the Western Hemisphere, there has been a notable increase in the ability to detect, prevent, and control rubella and CRS. The importance of these measures is undeniable, and this piece examines the components that are essential in moving ahead to reduce these major public health problems in Latin America and the Caribbean. One step in that direction would be to integrate the surveillance of measles with that of rubella and CRS.


CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.
Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.


Lung function and bronchial reactivity in aluminum potroom workers.
Lung function and bronchial reactivity were measured in 38 aluminum potroom workers with no airway symptoms and in 20 healthy referents (office workers). All of the participants were non-smokers. The magnitude of exposure to airborne dust (alumina) and fluorides was determined. The aluminum potroom workers had obstructive lung function impairment with a significant decrease in expiratory flow and an increase in residual volume. Diffusing capacity was found to be lower than in the referents. No bronchial hyperreactivity was found in the aluminum potroom workers. The exposure to inhaled alumina and particulate and gaseous fluorides in the plant was low, 15-20% of the Swedish exposure limits. The finding of only modest lung function alterations with no bronchial hyperreactivity in the aluminum potroom workers is not consistent with the results of other authors. This discrepancy can probably be explained by the fact that the exposure to inhaled contaminants in the investigated aluminum plant was low.


Longitudinal structural and metabolic changes in frontotemporal dementia.
To compare the sensitivity of structural MRI and 18F-fludeoxyglucose PET (18FDG-PET) to detect longitudinal changes in frontotemporal dementia (FTD). Thirty patients with behavioral variant FTD (bvFTD), 7 with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA), 16 with semantic variant primary progressive aphasia (svPPA), and 43 cognitively normal controls underwent 2-4 MRI and 18FDG-PET scans (total scans/visit = 270) as part of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study. Linear mixed-effects models were carried out voxel-wise and in regions of interest to identify areas showing decreased volume or metabolism over time in patients as compared to controls. At baseline, patients with bvFTD showed bilateral temporal, dorsolateral, and medial prefrontal atrophy/hypometabolism that extended with time into adjacent structures and parietal lobe. In nfvPPA, baseline atrophy/hypometabolism in supplementary motor cortex extended with time into left greater than right precentral, dorsolateral, and dorsomedial prefrontal cortex. In svPPA, baseline atrophy/hypometabolism encompassed the anterior temporal and medial prefrontal cortex and longitudinal changes were found in temporal, orbitofrontal, and lateral parietal cortex. Across syndromes, there was substantial overlap in the brain regions showing volume and metabolism loss. Even though the pattern of metabolic decline was more extensive, metabolic changes were also more variable and sample size estimates were similar or higher for 18FDG-PET compared to MRI. Our findings demonstrated the sensitivity of 18FDG-PET and structural MRI for tracking disease progression in FTD. Both modalities showed highly overlapping patterns of longitudinal change and comparable sample size estimates to detect longitudinal changes in future clinical trials.


Lactobacillus johnsonii N6.2 and Blueberry Phytophenols Affect Lipidome and Gut Microbiota Composition of Rats Under High-Fat Diet.
Obesity is considered a primary contributing factor in the development of many diseases, including cancer, diabetes, and cardiovascular illnesses. Phytochemical-rich foods, associated to healthy gastrointestinal microbiota, have been shown to reduce obesity and associated comorbidities. In the present article, we describe the effects of the probiotic Lactobacillus johnsonii N6.2 and blueberry extracts (BB) on the gut microbiota and lipid profile of rats under a high-fat (HF) or low-calorie (LC) diet. L. johnsonii was found to increase the levels of long chain fatty acids (LCFA) in the serum of all animals under HF diet, while reduced LCFA concentrations were observed in the adipose tissue of animals under HF diet supplemented with BB extracts. All animals under HF diet also showed lower protein levels of SREBP1 and SCAP when treated with L. johnsonii. The gut microbiota diversity, β-diversity was significantly changed by L. johnsonii in the presence of BB. A significant reduction in α-diversity was observed in the ileum of animals under HF diet supplemented with L. johnsonii and BB, while increased α-diversity was observed in the ilium of animals under LC diet supplemented with L. johnsonii or BB. In summary, L. johnsonii and BB supplementation induced significant changes in gut microbiota diversity and lipid metabolism. The phospholipids pool was the lipidome component directly affected by the interventions. The ileum and colon microbiota showed clear differences depending on the diet and the treatments examined.


Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes.
To analyse clinicoepidemiological features of neuromyelitis optica in a large cohort and to compare the differences between onset age, gender and clinical phenotypes. Antiaquaporin-4 antibody (AQP4-ab) levels were tested in 2366 serum samples of patients diagnosed as having central nervous system inflammatory demyelinating disorders by their referring physicians. AQP4-ab was measured by indirect immunofluorescence staining using human AQP4-transfected HEK 293 cells. A blinded analysis was performed and was combined with clinical information. A total of 583 patients (91.4% women) were AQP4-ab-positive. The average onset age was 42.9±15.9 years. According to MRI studies, spinal-cord lesions were detected in 85.3% of the patients, longitudinally extensive transverse myelitis in 72.7% and cerebral lesions in 51.1%. Unilateral or bilateral blindness was observed in 16.2% of patients, 19.8% were associated with Sjögren syndrome, and 13.6% were associated with thyroid diseases. Myelin basic protein was detected in the cerebrospinal fluid of 57.5% patients. In addition, men presented with an older onset age, a greater number of brainstem MRI lesions and positive myelin basic protein in the cerebrospinal fluid. All child-onset patients (<15 years, n=9) presented with optic neuritis as the first symptom, while older-onset patients presented with myelitis. Twenty patients initially developed limited brain lesions, and seven of these patients did not develop optic or spinal lesions during the 1-5-year follow-up period. The clinical characteristics of AQP4-ab-positive patients were similar. However, optic neuritis was more common in paediatric patients, while myelitis was more common in older patients. A small number of patients exhibited only cerebral, brainstem, or cerebellar lesions during the initial several years and lower Extended Disability Status Scale scores.


Invasion biology meets parasitology: a case study of parasite spill-back with Egyptian Fasciola gigantica in the invasive snail Pseudosuccinea columella.
The liver fluke Fasciola gigantica is a trematode parasite of ruminants and humans that occurs naturally in Africa and Asia. Cases of human fascioliasis, attributable at least in part to F. gigantica, are significantly increasing in the last decades. The introduced snail species Galba truncatula was already identified to be an important intermediate host for this parasite and the efficient invader Pseudosuccinea columella is another suspect in this case. Therefore, we investigated snails collected in irrigation canals in Fayoum governorate in Egypt for prevalence of trematodes with focus on P. columella and its role for the transmission of F. gigantica. Species were identified morphologically and by partial sequencing of the cytochrome oxidase subunit I gene (COI). Among all 689 snails found at the 21 sampling sites, P. columella was the most abundant snail with 296 individuals (42.96%) and it was also the most dominant species at 10 sites. It was not found at 8 sites. Molecular detection by PCR and sequencing of the ITS1-5.8S-ITS2 region of the ribosomal DNA (rDNA) revealed infections with F. gigantica (3.38%), Echinostoma caproni (2.36%) and another echinostome (7.09%) that could not be identified further according to its sequence. No dependency of snail size and trematode infection was found. Both high abundance of P. columella in the Fayoum irrigation system and common infection with F. gigantica might be a case of parasite spill-back (increased prevalence in local final hosts due to highly susceptible introduced intermediate host species) from the introduced P. columella to the human population, explaining at least partly the observed increase of reported fascioliasis-cases in Egypt. Eichhornia crassipes, the invasive water hyacinth, which covers huge areas of the irrigation canals, offers safe refuges for the amphibious P. columella during molluscicide application. As a consequence, this snail dominates snail communities and efficiently transmits F. gigantica.


Exploring Biological and Geological Age-related Changes through Variations in Intra- and Intertooth Proteomes of Ancient Dentine.
Proteomic analyses are becoming more widely used in archeology not only due to the greater preservation of proteins in ancient specimens than DNA but also because they can offer different information, particularly relating to compositional preservation and potentially a means to estimate biological and geological age. However, it remains unclear to what extent different burial environments impact these aspects of proteome decay. Teeth have to date been much less studied than bone but are ideal to explore how proteins decay with time due to the negligible turnover that occurs in dentine relative to bone. We investigated the proteome variability and deamidation levels of different sections of molar teeth from archeological bovine mandibles as well as their mandibular bone. We obtained a greater yield of proteins from the crown of the teeth but did not find differences between the different molars analyzed within each mandible. We also obtained the best variety of protein from a well-preserved mandible that was not the youngest one in terms of chronological age, showing the influence of the preservation conditions on the final proteomic outcome. Intriguingly, we also noticed an increase in abundance levels of fetuin-A in biologically younger mandibles as reported previously, but the opposite trend in tooth dentine. Interestingly, we observed higher glutamine deamidation levels in teeth from the geologically oldest mandible despite it being the biologically youngest specimen, showing that the archeological age strongly impacts on the level of deamidations observed, much more so than biological aging. This indicates that the glutamine deamidation ratio of selected peptides may act as a good predictor of the relative geochronological age of archeological specimens.


Yellow nail syndrome in a medical clinic.
Yellow nail syndrome is a very rare clinical entity usually diagnosed from a combination of yellow dystrophic nails, lymphoedema and respiratory diseases. The aetiology is not known though dysfunctional hypoplastic lymphatics is speculated. Most cases occur sporadically but few cases may be associated with systemic diseases or may be inherited. This report documents another case in a 56-year old Caribbean female who presented with a six-year history of recurrent respiratory symptoms and later yellow dystrophic nails and lymphoedema. She responded well to vitamin E and oral fluconazole. We also did a short literature review of yellow nail syndrome.


Civilian blast-related burn injuries.
There is limited English literature describing the experience of a civilian hospital managing blast-related burn injuries. As the largest regional burn unit, we reviewed our cases with the aim of identifying means to improve current management. A 6-year retrospective analysis of all patients coded as sustaining blast-related burns was conducted through the unit's burns database. Medical case notes were reviewed for information on burn demographics, management and outcomes. 42 patients were identified. Male to female ratio was 37:5. Age range was 12-84 years, (mean=33 years). Total body surface area (%TBSA) burn ranged from 0.25% to 60%, (median=1%). The most common burn injury was flame (31/42, 73.8%). Gas explosions were the most common mechanism of injury (19 cases; 45.2%). 7/42 cases (16.7%) had full ATLS management pre-transfer to the burns unit. The Injury Severity Score (ISS) ranged from 0-43 (median=2). 17/42 (40.4%) patients required admission. 37/36 (88.1%) patients were managed conservatively of which 1 patient later required surgery due to deeper burns. 5/42 (11.9%) patients required surgical management at presentation and these were noted to be burns with >15% TBSA requiring resuscitation. One case required emergency escharotomies and finger amputations. All patients survived their burn injuries. Blast-related burn injuries are generally uncommon in the civilian setting. Following proper assessment, most of these cases can be deemed as minor injuries and managed conservatively. Improvement in burns management education and training at local emergency departments would provide efficient patient care and avoid unnecessary referrals to a burns unit.


The journey of Malaysian NCVD-PCI (National Cardiovascular Disease Database-Percutaneous Coronary Intervention) Registry: a summary of three years report.
The Malaysian National Cardiovascular Disease Database (NCVD) team presents Percutaneous Coronary Intervention (PCI) Registry report for the year 2007 to 2009. It provides comprehensive information regarding practice and outcome of PCI in Malaysia. It was a voluntary, multi-centered, observational, cohort study and included patients of 18 years or above who underwent PCI at eleven participating centers in Malaysia from the year 2007 to 2009. Ten thousand six hundred and two patients underwent 11,498 PCI procedures with 18,116 stents for 15,538 lesions. Mean age of the patients was 57 years and more than 98% of patients had at least one cardiovascular risk factor. A significant number of our patients were diabetic (50%) and had renal impairment (44.7% had ≤ stage 3 chronic kidney disease) at the time of procedure. Fifty eight percent of the lesions were type B2 or type C lesion. Twenty eight percent of the lesions had high risk characteristics. Procedural success rate was about 97% and post-procedural complications were low. Overall in-hospital, all cause mortality was 1%, of which 85% were cardiac related deaths. The poor prognostic factors for in-hospital mortality were acute coronary syndrome cases, higher Killip class and increasing age. Compared to other registries, Malaysian patients undergoing PCI were much younger with high prevalence of risk factors. In spite of complex and high risk lesions, procedural success was high, with overall low mortality rate. NCVD-PCI Registry aims to improve over-all cardiac services in Malaysia through its ongoing journey.


Moles and Mole Control on British Farms, Amenities and Gardens after Strychnine Withdrawal.
Moles are considered pests in Britain, but this issue has been little studied. Lower welfare standards have been tolerated for moles than for most other managed wild mammal species, as use of both the controversial poison, strychnine, and unregulated traps have been permitted. Strychnine was withdrawn in 2006 and there were fears that mole populations would increase as a result. In 2007, we conducted a comprehensive, nationwide survey of land manager perceptions, opinions and behaviour regarding moles and mole control on farms, amenities and domestic gardens in Britain. We surveyed 2150 land managers (achieving a 59% response rate) and ground-truthed 29 responses. Moles were reported to be present on most farms and amenities, and 13% of gardens, and were more common in lighter soils. Where present, moles were usually considered pests, this being more likely in Wales, Scotland and northern England, on livestock and mixed farms, and on large, high-value amenities, e.g., racecourses and golf courses. Mole control followed similar patterns to mole presence. More control may occur than is economically, and therefore potentially ethically, justified. Control should be more carefully considered and, where necessary, more effectively targeted. Kill-trapping was the favoured recent and future method on farms and amenities, even if strychnine was to be reintroduced; however, because mole traps are currently unregulated, some might not meet current welfare standards if tested. We found no evidence for an increase in moles since a farm questionnaire survey conducted in 1992; this could have wider implications for future wildlife management policy changes.


Genetic exchange across a paracentric inversion of the mouse t complex.
Mouse t haplotypes are distinguished from wild-type forms of chromosome 17 by four nonoverlapping paracentric inversions which span a genetic distance of 20 cM. These inversion polymorphisms are responsible for a 100-200-fold suppression of recombination which maintains the integrity of complete t haplotypes and has led to their divergence from the wild-type chromosomes of four species of house mice within which t haplotypes reside. As evidence for the long period of recombinational isolation, alleles that distinguish all t haplotypes from all wild-type chromosomes have been established at a number of loci spread across the 20-cM variant region. However, a more complex picture emerges upon analysis of other t-associated loci. In particular, "mosaic haplotypes" have been identified that carry a mixture of wild-type and t-specific alleles. To investigate the genetic basis for mosaic chromosomes, we conducted a comprehensive analysis of eight t complex loci within 76 animals representing 10 taxa in the genus Mus, and including 23 previously characterized t haplotypes. Higher resolution restriction mapping and sequence analysis was also performed for alleles at the Hba-ps4 locus. The results indicate that a short tract of DNA was transferred relatively recently across an inversion from a t haplotype allele of Hba-ps4 to the corresponding locus on a wild-type homolog leading to the creation of a new hybrid allele. Several classes of wild-type Hba-ps4 alleles, including the most common form in inbred strains, appear to be derived from this hybrid allele. The accumulated data suggest that a common form of genetic exchange across one of the four t-associated inversions is gene conversion at isolated loci that do not play a role in the transmission ratio distortion phenotype required for t haplotype propagation. The implications of the results pose questions concerning the evolutionary stability of gene complexes within large paracentric inversions and suggest that recombinational isolation may be best established for loci residing within a short distance from inversion breakpoints.


Identification of replication-competent HSV-1 Cgal+ strain targets in a mouse model of human hepatocarcinoma xenograft.
Recent studies based on animal models have shown the advantages and potential of oncolytic viral therapy using HSV-1 -based replication-competent vectors in the treatment of liver tumors, but little is known about the cellular targets that are modulated during viral infection. In the present work, we have studied the effects of intratumoral injections of HSV-1 Cgal(+) strain in a murine model of human hepatoma xenografts. Viral replication was assessed for more than 1month, leading to a significant reduction of tumor growth rate mediated, in part, by a cyclin B dependent cell proliferation arrest. Early events resulting in this effect were analyzed using a proteomic approach. Protein extracts from xenografted human hepatomas treated with saline or HSV-1 Cgal(+) strain during 24h were compared by 2-D DIGE and differential spots were identified by nanoLC-ESI-MS/MS. Alterations on glutathione S transferase 1 Omega, and ERp29 suggest novel HSV-1 Cgal(+) targets in solid liver tumors. Additionally, ERp29 showed a complex differential isoform pattern upon HSV-1 Cgal(+) infection, suggesting regulatory mechanisms based on post-translational modification events.