Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivo tacrolimus perfusion.
Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation's definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095.


Construction and utility of 10-kb libraries for efficient clone-gap closure for rice genome sequencing.
Rice is an important crop and a model system for monocot genomics, and is a target for whole genome sequencing by the International Rice Genome Sequencing Project (IRGSP). The IRGSP is using a clone by clone approach to sequence rice based on minimum tiles of BAC or PAC clones. For chromosomes 10 and 3 we are using an integrated physical map based on two fingerprinted and end-sequenced BAC libraries to identifying a minimum tiling path of clones. In this study we constructed and tested two rice genomic libraries with an average insert size of 10 kb (10-kb library) to support the gap closure and finishing phases of the rice genome sequencing project. The HaeIII library contains 166,752 clones covering approximately 4.6x rice genome equivalents with an average insert size of 10.5 kb. The Sau3AI library contains 138,960 clones covering 4.2x genome equivalents with an average insert size of 11.6 kb. Both libraries were gridded in duplicate onto 11 high-density filters in a 5 x 5 pattern to facilitate screening by hybridization. The libraries contain an unbiased coverage of the rice genome with less than 5% contamination by clones containing organelle DNA or no insert. An efficient method was developed, consisting of pooled overgo hybridization, the selection of 10-kb gap spanning clones using end sequences, transposon sequencing and utilization of in silico draft sequence, to close relatively small gaps between sequenced BAC clones. Using this method we were able to close a majority of the gaps (up to approximately 50 kb) identified during the finishing phase of chromosome-10 sequencing. This method represents a useful way to close clone gaps and thus to complete the entire rice genome.


Leveraging epidemiology and clinical studies of cancer outcomes: recommendations and opportunities for translational research.
As the number of cancer survivors continues to grow, research investigating the factors that affect cancer outcomes, such as disease recurrence, risk of second malignant neoplasms, and the late effects of cancer treatments, becomes ever more important. Numerous epidemiologic studies have investigated factors that affect cancer risk, but far fewer have addressed the extent to which demographic, lifestyle, genomic, clinical, and psychosocial factors influence cancer outcomes. To identify research priorities as well as resources and infrastructure needed to advance the field of cancer outcomes and survivorship research, the National Cancer Institute sponsored a workshop titled "Utilizing Data from Cancer Survivor Cohorts: Understanding the Current State of Knowledge and Developing Future Research Priorities" on November 3, 2011, in Washington, DC. This commentary highlights recent findings presented at the workshop, opportunities to leverage existing data, and recommendations for future research, data, and infrastructure needed to address high priority clinical and research questions. Multidisciplinary teams that include epidemiologists, clinicians, biostatisticians, and bioinformaticists will be essential to facilitate future cancer outcome studies focused on improving clinical care of cancer patients, identifying those at high risk of poor outcomes, and implementing effective interventions to ultimately improve the quality and duration of survival.


Plasma Exosome Profiling of Cancer Patients by a Next Generation Systems Biology Approach.
Technologies capable of characterizing the full breadth of cellular systems need to be able to measure millions of proteins, isoforms, and complexes simultaneously. We describe an approach that fulfils this criterion: Adaptive Dynamic Artificial Poly-ligand Targeting (ADAPT). ADAPT employs an enriched library of single-stranded oligodeoxynucleotides (ssODNs) to profile complex biological samples, thus achieving an unprecedented coverage of system-wide, native biomolecules. We used ADAPT as a highly specific profiling tool that distinguishes women with or without breast cancer based on circulating exosomes in their blood. To develop ADAPT, we enriched a library of ~1011 ssODNs for those associating with exosomes from breast cancer patients or controls. The resulting 106 enriched ssODNs were then profiled against plasma from independent groups of healthy and breast cancer-positive women. ssODN-mediated affinity purification and mass spectrometry identified low-abundance exosome-associated proteins and protein complexes, some with known significance in both normal homeostasis and disease. Sequencing of the recovered ssODNs provided quantitative measures that were used to build highly accurate multi-analyte signatures for patient classification. Probing plasma from 500 subjects with a smaller subset of 2000 resynthesized ssODNs stratified healthy, breast biopsy-negative, and -positive women. An AUC of 0.73 was obtained when comparing healthy donors with biopsy-positive patients.


Public support for graphic health warning labels in the U.S.
In 2009, the U.S. Food and Drug Administration was required to mandate that graphic health warning labels be placed on cigarette packages and advertisements. To assess public support in the U.S. for graphic health warning labels from 2007 to 2012. Data from 17,498 respondents from 13 waves of the National Adult Tobacco Survey, a list-assisted random-digit-dial survey, were used. Overall support for graphic health warning labels, as well as support by smoking status, and by sociodemographics and smoker characteristics are estimated. Analyses were conducted in 2014. Since 2007, a majority of the public overall has been in favor of labels. Support increased significantly among the public overall and among non-smokers from 2007 through 2009 (p<0.001), after which it remained flat. Among smokers, support levels increased from 2007 through 2011 (p<0.001), but decreased significantly from 2011 through 2012 (p<0.001). Support was high regardless of smoking status, although among smokers, support varied by level of smoking, interest in quitting, and whether labels were seen as an important reason to quit. Support varied by sociodemographic characteristics, particularly among smokers. Younger, less-affluent, and less-educated smokers supported labels at higher levels than their counterparts. A majority of U.S. residents support graphic health warning labels for cigarette packs, though support among smokers declined after 2011.


A three-state model for the regulation of telomerase by TERRA and hnRNPA1.
Telomeres, the physical ends of eukaryotic chromosomes, are transcribed into telomeric repeat-containing RNA (TERRA), a large non-coding RNA, which forms an integral part of telomeric heterochromatin. In vitro, naked TERRA molecules are efficient inhibitors of human telomerase, base-pairing via their 5'-UUAGGG-3' repeats with the template sequence of telomerase RNA, in addition to contacting the telomerase reverse transcriptase protein subunit. In vivo, however, TERRA-mediated inhibition of telomerase can be prevented by unknown mechanisms. Also, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has been implicated in telomere length control. In vivo, TERRA is partially associated with hnRNPA1, and hnRNPA1 is also detected at telomeres. We demonstrate that on binding of TERRA, hnRNPA1 can alleviate the TERRA-mediated inhibition of telomerase. However, when in excess over TERRA, hnRNPA1 becomes itself an inhibitor of telomere extension, on binding of the telomeric DNA substrate. Yet, hnRNPA1 has no notable direct effects on the telomerase catalysis. Our in vitro results suggest that TERRA-mediated telomerase inhibition may be prevented by hnRNPA1 in vivo. Telomere extension by telomerase may require balanced levels of TERRA and hnRNPA1 at telomeres. Thus, TERRA and hnRNPA1 can function as a bimolecular regulator to turn telomerase and the telomere on and off.


Is There a Nonadditive Interaction Between Spontaneous and Evoked Activity? Phase-Dependence and Its Relation to the Temporal Structure of Scale-Free Brain Activity.
The aim of our study was to use functional magnetic resonance imaging to investigate how spontaneous activity interacts with evoked activity, as well as how the temporal structure of spontaneous activity, that is, long-range temporal correlations, relate to this interaction. Using an extremely sparse event-related design (intertrial intervals: 52-60 s), a novel blood oxygen level-dependent signal correction approach (accounting for spontaneous fluctuations using pseudotrials) and phase analysis, we provided direct evidence for a nonadditive interaction between spontaneous and evoked activity. We demonstrated the discrepancy between the present and previous observations on why a linear superposition between spontaneous and evoked activity can be seen by using co-occurring signals from homologous brain regions. Importantly, we further demonstrated that the nonadditive interaction can be characterized by phase-dependent effects of spontaneous activity, which is closely related to the degree of long-range temporal correlations in spontaneous activity as indexed by both power-law exponent and phase-amplitude coupling. Our findings not only contribute to the understanding of spontaneous brain activity and its scale-free properties, but also bear important implications for our understanding of neural activity in general.


Abrogation of the Circadian Nuclear Receptor REV-ERBα Exacerbates 6-Hydroxydopamine-Induced Dopaminergic Neurodegeneration.
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive degeneration of dopaminergic (DAergic) neurons, particularly in the substantia nigra (SN). Although circadian dysfunction has been suggested as one of the pathophysiological risk factors for PD, the exact molecular link between the circadian clock and PD remains largely unclear. We have recently demonstrated that REV-ERBα, a circadian nuclear receptor, serves as a key molecular link between the circadian and DAergic systems. It competitively cooperates with NURR1, another nuclear receptor required for the optimal development and function of DA neurons, to control DAergic gene transcription. Considering our previous findings, we hypothesize that REV-ERBα may have a role in the onset and/or progression of PD. In the present study, we therefore aimed to elucidate whether genetic abrogation of REV-ERBα affects PD-related phenotypes in a mouse model of PD produced by a unilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. REV-ERBα deficiency significantly exacerbated 6-OHDA-induced motor deficits as well as DAergic neuronal loss in the vertebral midbrain including the SN and the ventral tegmental area. The exacerbated DAergic degeneration likely involves neuroinflammation-mediated neurotoxicity. The Rev-erbα knockout mice showed prolonged microglial activation in the SN along with the overproduction of interleukin 1β, a pro-inflammatory cytokine, in response to 6-OHDA. In conclusion, the present study demonstrates for the first time that genetic abrogation of REV-ERBα can increase vulnerability of DAergic neurons to neurotoxic insults, such as 6-OHDA, thereby implying that its normal function may be beneficial for maintaining DAergic neuron populations during PD progression.


Is risk stratification ever the same as 'profiling'?
Physicians engage in risk stratification as a normative part of their professional duties. Risk stratification has the potential to be beneficial in many ways, and implicit recognition of this potential benefit underlies its acceptance as a cornerstone of the medical profession. However, risk stratification also has the potential to be harmful. We argue that 'profiling' is a term that corresponds to risk stratification strategies in which there is concern that ethical harms exceed likely or proven benefits. In the case of risk stratification for health goals, this would occur most frequently if benefits were obtained by threats to justice, autonomy or privacy. We discuss implications of the potential overlap between risk stratification and profiling for researchers and for clinicians, and we consider whether there are salient characteristics that make a particular risk stratification algorithm more or less likely to overlap with profiling, such as whether the risk stratification algorithm is based on voluntary versus non-voluntary characteristics, based on causal versus non-causal characteristics, or based on signifiers of historical disadvantage. We also discuss the ethical challenges created when a risk stratification scheme helps all subgroups but some more than others, or when risk stratification harms some subgroups but benefits the aggregate group.


First Report of Colletotrichum fructicola Causing Bitter Rot of Pear (Pyrus bretschneideri) in China.
Pyrus bretschneideri cv. Dangshansuli is the most important commercial Asiatic pear cultivar worldwide. In recent years, a fruit rot disease of unknown etiology have caused considerable fresh market losses in the 'Dangshansuli' production operations in Dangshan county, Anhui Province, China. Fresh market losses typically range from 60 to 90% and in 2008 were estimated at US$150 million. Symptomatic mature 'Dangshansuli' pears were collected from an orchard in Dangshan County in February 2008. A thin section (about 1 mm3) of symptomatic tissue was sterilized in a bleach and placed on potato dextrose agar (PDA) medium for isolation. From all fruit, a single fungus was recovered displaying gray-white dense aerial mycelium. Identical fungi were isolated from six additional symptomatic 'Dangshansuli' pears collected from other orchards in the county. Pathogenicity tests using one isolate (DS-0) were conducted in triplicate by placing 4 mm diameter discs from 7-day-old PDA plates onto the mature 'Dangshansuli' pear fruit that were incubated in an incubator at 25°C with a 12-h photoperiod for 30 days. An equal number of noncolonized PDA inoculations were included as a control. Isolate DS-0 caused symptoms similar to those in the field within 7 days and complete collapse of cortical tissues within 30 days. No symptoms were observed on control fruit. Round brownish lesions with a diameter of about 3 cm on inoculated fruit was populated by sunken, rotiform acervuli on which numerous, colorless, oblong single cell shape conidia with width/length of 6 × 20 μm were produced. A comparison of morphology and sequence analysis of the ribosomal internal transcribed spacer (ITS) regions in pre- and post-inoculation cultures from inoculated fruit confirmed the presence DS-0. To further characterize DS-0, aliquots of extracted genomic DNA from the fungus were subjected to PCR amplification and sequencing of seven gene regions from the ITS, actin (ACT), β-tubulin 2 (TUB2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), manganese-superoxide dismutase (SOD2), chitin synthase (CHS-1), and calmodulin (CAL), using the primers listed by Weir et al (4), except for the primer pair of ITS1 (5'-TCCGTAGGTGAACCTGCGG-3') and ITS4 (5'-TCCTCCGCTTATTGATATGC-3') for ITS amplification, and SODglo2-R (5'-TAGTACGCGTGCTCGGACAT-3') and SODglo2-R (5'-TAGTACGCGTGCTCGGACAT-3') for TBU2 amplification. Two or three clones of PCR products of each gene were sequenced and compared (GenBank Accession Nos. KC410780 to KC410786) to published data at http://www.cbs.knaw.nl/colletotrichum . The result indicated that DS-0 shared the highest similarity of 99.91% with Colletotrichum fructicola, corroborating numerous reports of Colletotrichum spp. causing bitter rot of pear on P. pyrifolia (1,2,3,4). C. fructicola was only recently reported as causing bitter rot of P. pyrifolia (4) and to our knowledge, this is the first report of C. fructicola causing bitter rot of P. bretschneideri, which will help producers select the best management practices for this devastating disease. References: (1) P. F. Cannon et al. Stud. Mycol. 73:181, 2012. (2) N. Tashiro et al. J. Gen. Plant Pathol. 78:221, 2012. (3) G. K. Wan et al. Mycobiology 35:238, 2007. (4) B. S. Weir et al. Stud. Mycol. 73:115, 2012.


National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the diagnosis and management of atrial fibrillation 2018.
Atrial fibrillation (AF) is increasing in prevalence and is associated with significant morbidity and mortality. The optimal diagnostic and treatment strategies for AF are continually evolving and care for patients requires confidence in integrating these new developments into practice. These clinical practice guidelines will assist Australian practitioners in the diagnosis and management of adult patients with AF. Main recommendations: These guidelines provide advice on the standardised assessment and management of patients with atrial fibrillation regarding: screening, prevention and diagnostic work-up; acute and chronic arrhythmia management with antiarrhythmic therapy and percutaneous and surgical ablative therapies; stroke prevention and optimal use of anticoagulants; and integrated multidisciplinary care. Changes in management as a result of the guideline: Opportunistic screening in the clinic or community is recommended for patients over 65 years of age. The importance of deciding between a rate and rhythm control strategy at the time of diagnosis and periodically thereafter is highlighted. β-Blockers or non-dihydropyridine calcium channel antagonists remain the first line choice for acute and chronic rate control. Cardioversion remains first line choice for acute rhythm control when clinically indicated. Flecainide is preferable to amiodarone for acute and chronic rhythm control. Failure of rate or rhythm control should prompt consideration of percutaneous or surgical ablation. The sexless CHA2DS2-VA score is recommended to assess stroke risk, which standardises thresholds across men and women; anticoagulation is not recommended for a score of 0, and is recommended for a score of ≥ 2. If anticoagulation is indicated, non-vitamin K oral anticoagulants are recommended in preference to warfarin. An integrated care approach should be adopted, delivered by multidisciplinary teams, including patient education and the use of eHealth tools and resources where available. Regular monitoring and feedback of risk factor control, treatment adherence and persistence should occur.


The evolution of genes encoding for green fluorescent proteins: insights from cephalochordates (amphioxus).
Green Fluorescent Protein (GFP) was originally found in cnidarians, and later in copepods and cephalochordates (amphioxus) (Branchiostoma spp). Here, we looked for GFP-encoding genes in Asymmetron, an early-diverged cephalochordate lineage, and found two such genes closely related to some of the Branchiostoma GFPs. Dim fluorescence was found throughout the body in adults of Asymmetron lucayanum, and, as in Branchiostoma floridae, was especially intense in the ripe ovaries. Spectra of the fluorescence were similar between Asymmetron and Branchiostoma. Lineage-specific expansion of GFP-encoding genes in the genus Branchiostoma was observed, largely driven by tandem duplications. Despite such expansion, purifying selection has strongly shaped the evolution of GFP-encoding genes in cephalochordates, with apparent relaxation for highly duplicated clades. All cephalochordate GFP-encoding genes are quite different from those of copepods and cnidarians. Thus, the ancestral cephalochordates probably had GFP, but since GFP appears to be lacking in more early-diverged deuterostomes (echinoderms, hemichordates), it is uncertain whether the ancestral cephalochordates (i.e. the common ancestor of Asymmetron and Branchiostoma) acquired GFP by horizontal gene transfer (HGT) from copepods or cnidarians or inherited it from the common ancestor of copepods and deuterostomes, i.e. the ancestral bilaterians.


Validity and Reliability of the Insole3 Instrumented Shoe Insole for Ground Reaction Force Measurement during Walking and Running.
Pressure-detecting insoles such as the Insole3 have potential as a portable alternative for assessing vertical ground reaction force (vGRF) outside of specialized laboratories. This study evaluated whether the Insole3 is a valid and reliable alternative to force plates for measuring vGRF. Eleven healthy participants walked overground at slow and moderately paced speeds and ran at a moderate pace while collecting vGRF simultaneously from a force plate (3000 Hz) and Insole3 (100 Hz). Intraclass correlation coefficients (ICC) demonstrated excellent vGRF agreement between systems during both walking speeds for Peak 1, Peak 2, the valley between peaks, and the vGRF impulse (ICC > 0.941). There was excellent agreement during running for the single vGRF peak (ICC = 0.942) and impulse (ICC = 0.940). The insoles slightly underestimated vGRF peaks (−3.7% to 0.9% bias) and valleys (−2.2% to −1.8% bias), and slightly overestimated impulses (4.2% to 5.6% bias). Reliability between visits for all three activities was excellent (ICC > 0.970). The Insole3 is a valid and reliable alternative to traditional force plates for assessing vGRF during walking and running in healthy adults. The excellent ICC values during slow walking suggests that the Insole3 may be particularly suitable for older adults in clinical and home settings.


White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy.
The purpose of this study was to determine the time course for development of white matter changes induced by high-dose chemotherapy. Eight patients with advanced breast cancer were entered into a prospective, longitudinal trial that included examination by MR imaging and proton MR spectroscopy before chemotherapy and through 12 months after treatment with carmustine, cyclophosphamide, and cisplatin, combined with autologous hematopoietic progenitor cell support (AHPCS). Six patients completed induction chemotherapy, at which time all MR imaging studies appeared normal. At 3 months after the conclusion of high-dose chemotherapy and beyond, three of the four patients remaining in the study showed an increasing volume of white matter changes, which appeared to stabilize during the period from 6 months to 1 year. Maximal volumes of abnormal white matter ranged from 73 to 166 cm3. MR spectroscopy showed little or no change in metabolic ratios through the period of observation, although there was a suggestion of small transient treatment-related decreases in the ratio of N-acetyl aspartate (NAA) to creatine. White matter changes are common sequelae of treatment with high-dose chemotherapy combined with AHPCS, occurring early in the period following high-dose chemotherapy, with a rapid and progressive accumulation to about 6 months, but not accompanied by persistent neurologic symptoms. The MR spectroscopic analyses suggest a minimal disturbance of the neuronal marker NAA, a finding that may in part explain the good neurologic outcome.


Infinite space Green's function of the time-dependent radiative transfer equation.
This study contains the derivation of an infinite space Green's function of the time-dependent radiative transfer equation in an anisotropically scattering medium based on analytical approaches. The final solutions are analytical regarding the time variable and given by a superposition of real and complex exponential functions. The obtained expressions were successfully validated with Monte Carlo simulations.


Wealth status and risky sexual behaviour in Ghana and Kenya.
Emerging evidence seems to suggest that there is some association between individual socioeconomic status and sexual risk-taking behaviour in sub-Saharan Africa. A number of broad associations have emerged, among them, positive, neutral and negative relationships between wealth status and sexual risk-taking behaviour. Reduction in the number of sex partners as a behavioural change has been advocated as an important tool in HIV prevention, and affecting such a change requires an understanding of some of the factors that can influence social behaviour, interactions and activities of subpopulations. To further explore the determinants of sexual risk-taking behaviour (individuals having multiple sex partners), especially the effects that variations in household wealth status, gender and different subpopulation groups have on this behaviour. The relationship between wealth status and sexual risk-taking behaviour in the context of HIV/AIDS infection in Ghana and Kenya was assessed using raw data from the 2003 Demographic and Health Surveys of each country. Wealth quintiles were used as a proxy for economic status, while non-marital and non-cohabiting sexual partnerships were considered indicators for risky sexual behaviour. For females, there appears to be an increasing probability of sexual risk taking by wealth status in Kenya, while, in Ghana, an inverted J-shaped relationship is shown between wealth status and sexual risk taking. When controlled for other variables, the relationship between wealth status and sexual risk-taking behaviour disappears for females in the two countries. For males, there is no clearly discernable pattern between wealth status and sexual risk-taking behaviour in Ghana, while there is a general trend towards increasing sexual risk-taking behaviour by wealth status in Kenya. For Ghana, the highest probabilities are among the highest and the middle wealth quintiles; in Kenya, high probabilities were found for the two highest wealth quintiles. Controlling for the effects of other factors, the pattern for Ghana is further blurred (not statistically significant), but the relationship continues to show in the case of Kenya, and is significant for the highest quintile. In general, for both Ghana and Kenya, men in the highest wealth quintile were found to be more likely to have multiple sexual partners than the other groups. The changing phases of HIV infection indicate that it is no longer poverty that drives the epidemic. Rather, it is wealth and a number of other sociodemographic factors that explain sexual risk-taking behaviour that puts people at risk. Understanding local specific factors that predispose individuals towards sexual risk taking could help to expand the range of information and services needed to combat the HIV pandemic.


Time-Varying Association Between Severe Respiratory Syncytial Virus Infections and Subsequent Severe Asthma and Wheeze and Influences of Age at the Infection.
Early-life severe respiratory syncytial virus (RSV) infection has been associated with subsequent risk of asthma and recurrent wheeze. However, changes in the association over time and the interaction effect of the age at first RSV infection are less well understood. We aimed to assess the time-varying association between RSV and subsequent asthma and wheeze admission and explore how the association was affected by the age at RSV infection. We retrospectively followed up a cohort of 23 365 children for a median of 6.9 years using Scottish health databases. Children who were born between 2001 and 2013 and had RSV-associated respiratory tract infection (RTI) admissions under 2 years were in the exposed group; those with unintentional accident admissions under 2 years comprised the control group. The Cox proportional-hazards model was used to report adjusted hazard ratios (HRs) of RSV admissions on subsequent asthma and wheeze admissions. We did subgroup analyses by follow-up years. We also explored how this association was affected by the age at first RSV admission. The association was strongest in the first 2 years of follow-up and decreased over time. The association persisted for 6 years in children whose first RSV-RTI admission occurred at 6-23 months of age, with an adjusted HR of 3.9 (95% confidence interval [CI], 3.1-4.9) for the first 2 years, 2.3 (95% CI, 1.6-3.2) for 2 to <4 years, and 1.9 (95% CI, 1.2-2.9) for 4 to <6 years of follow-up. In contrast, the association was only significant for the first 2 years after first RSV-RTI admissions occurring at 0-5 months. We found a more persistent association for subsequent asthma and wheeze in children whose first severe RSV infection occurred at 6-23 months compared to those whose first severe RSV infection occurred at 0-6 months. This provides new evidence for further assessment of the association and RSV intervention programs.


Using Photocatalyst Metal Oxides as Antimicrobial Surface Coatings to Ensure Food Safety-Opportunities and Challenges.
Cross-contamination of foods with pathogenic microorganisms such as bacteria, viruses, and parasites may occur at any point in the farm to fork continuum. Food contact and nonfood contact surfaces are the most frequent source of microbial cross-contamination. In the wake of new and emerging food safety challenges, including antibiotic-resistant human pathogens, conventional sanitation and disinfection practices may not be sufficient to ensure safe food processing, proper preparation, and also not be environmentally friendly. Nanotechnology-enabled novel food safety interventions have a great potential to mitigate the risk of microbial cross-contamination in the food chain. Especially engineered nanoparticles (ENPs) are increasingly finding novel applications as antimicrobial agents. Among various ENPs, photocatalyst metal oxides have shown great promise as effective nontargeted disinfectants over a wide range of microorganisms. The present review provides an overview of antimicrobial properties of various photocatalyst metal oxides and their potential applications as surface coatings. Further, this review discusses the most common approaches to developing antimicrobial coatings, methods to characterize, test, and evaluate antimicrobial efficacy as well as the physical stability of the coatings. Finally, regulations and challenges concerning the use of these novel photocatalytic antimicrobial coatings are also discussed.


The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease.
Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.


Isotope-specific detection of low-density materials with laser-based monoenergetic gamma-rays.
What we believe to be the first demonstration of isotope-specific detection of a low-Z and low density object shielded by a high-Z and high-density material using monoenergetic gamma rays is reported. The isotope-specific detection of LiH shielded by Pb and Al is accomplished using the nuclear resonance fluorescence line of L7i at 478 keV. Resonant photons are produced via laser-based Compton scattering. The detection techniques are general, and the confidence level obtained is shown to be superior to that yielded by conventional x-ray and gamma-ray techniques in these situations.


Automatic screening and classification of diabetic retinopathy and maculopathy using fuzzy image processing.
Digital retinal imaging is a challenging screening method for which effective, robust and cost-effective approaches are still to be developed. Regular screening for diabetic retinopathy and diabetic maculopathy diseases is necessary in order to identify the group at risk of visual impairment. This paper presents a novel automatic detection of diabetic retinopathy and maculopathy in eye fundus images by employing fuzzy image processing techniques. The paper first introduces the existing systems for diabetic retinopathy screening, with an emphasis on the maculopathy detection methods. The proposed medical decision support system consists of four parts, namely: image acquisition, image preprocessing including four retinal structures localisation, feature extraction and the classification of diabetic retinopathy and maculopathy. A combination of fuzzy image processing techniques, the Circular Hough Transform and several feature extraction methods are implemented in the proposed system. The paper also presents a novel technique for the macula region localisation in order to detect the maculopathy. In addition to the proposed detection system, the paper highlights a novel online dataset and it presents the dataset collection, the expert diagnosis process and the advantages of our online database compared to other public eye fundus image databases for diabetic retinopathy purposes.


Can we predict patients that will not benefit from invasive mechanical ventilation? A novel scoring system in intensive care: the IMV Mortality Prediction Score (IMPRES)
The present study aimed to define the clinical and laboratory criteria for predicting patients that will not benefit from invasive mechanical ventilation (IMV) treatment and determine the prediction of mortality and prognosis of these critical ill patients. The study was designed as an observational, multicenter, prospective, and cross-sectional clinical study. It was conducted by 75 researchers at 41 centers in intensive care units (ICUs) located in various geographical areas of Turkey. It included a total of 1463 ICU patients who were receiving invasive mechanical ventilation (IMV) treatment. A total of 158 parameters were examined via logistic regression analysis to identify independent risk factors for mortality; using these data, the IMV Mortality Prediction Score (IMPRES) scoring system was developed. The following cut-off scores were used to indicate mortality risk: <2, low risk; 2–5, moderate risk; 5.1–8, high risk; >8, very high risk. There was a 26.8% mortality rate among the 254 patients who had a total IMPRES score of lower than 2. The mortality rate was 93.3% for patients with total IMPRES scores of greater than 8 (P < 0.001). The present study included a large number of patients from various geographical areas of the country who were admitted to various types of ICUs, had diverse diagnoses and comorbidities, were intubated with various indications in either urgent or elective settings, and were followed by physicians from various specialties. Therefore, our data are more general and can be applied to a broader population. This study devised a new scoring system for decision-making for critically ill patients as to whether they need to be intubated or not and presents a rapid and accurate prediction of mortality and prognosis prior to ICU admission using simple clinical data.


Down-regulation of Myelin Gene Expression in Human Oligodendrocytes by Nitric Oxide: Implications for Demyelination in Multiple Sclerosis.
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) with unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators and nitric oxide (NO), which is released by perivascular infiltrates and/or activated glial cells. Both endogenous NO released by microglia and astrocytes; and NO generated from exogenous NO donors are known to induce oligodendrocytes death. However, the molecular mechanism of oligodendroglial death is poorly understood. Here we explore the role of NO in modulating the expression of myelin-specific genes that leads to oligodendroglial death. We investigated the effect of NO on the expression of myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) in human primary oligodendrocytes. Combination of IFN-γ and bacterial lipopolysaccharide (LPS) or double stranded RNA in the form of polyIC induced the production of NO and decreased the expression of myelin gene in human fetal mixed glial cultures. Either a scavenger of NO (PTIO) or an inhibitor of inducible nitric oxide synthase (L-NIL) abrogated (LPS+IFN-γ)- and polyIC-mediated suppression of myelin genes in human mixed glial cells. The role of NO was further corroborated by the inhibition of myelin gene expression in purified human oligodendroglia by several NO donors including SNP, NOC-7, SIN-1, and SNAP. This study illustrates a novel biological role of NO in down-regulating the expression of myelin genes preceding the death of oligodendrocytes.


Inhibition of translation by a short element in the 5' leader of the herpes simplex virus 1 DNA polymerase transcript.
Many viruses regulate gene expression, both globally and specifically, to achieve maximal rates of replication. During herpes simplex virus 1 infection, translation of the DNA polymerase (Pol) catalytic subunit is inefficient relative to other proteins of the same temporal class (D. R. Yager, A. I. Marcy, and D. M. Coen., J. Virol. 64:2217-2225, 1990). To investigate the mechanisms involved in the inefficient translation of Pol and to determine whether this inefficient translation could affect viral replication, we performed a mutagenic analysis of the 5' end of the pol transcript. We found that a short sequence ( approximately 55 bases) in the 5' leader of the transcript is both necessary and sufficient to inhibit translation in rabbit reticulocyte lysates and sufficient to inhibit reporter gene translation in transfected cells. RNase structure mapping experiments indicated that the inhibitory element adopts a structure that contains regions of a double-stranded nature, which may interfere with ribosomal loading and/or scanning. Pol accumulated to approximately 2- to 3-fold-higher levels per mRNA in cells infected with a mutant virus containing a deletion of the approximately 55-base inhibitory element than in cells infected with a control virus containing this element. Additionally, the mutant virus replicated less efficiently than the control virus. These results suggest that the inhibitory element regulates Pol translation during infection and that its inhibition of Pol translation is beneficial for viral replication.


Delayed diagnosis and elevated mortality in an urban population with HIV and lung cancer: implications for patient care.
Lung cancer is more common in HIV-infected patients than in the general population. We examined how effectively lung cancer was being diagnosed in our HIV-infected patients. Retrospective study assessing clinical diagnosis of lung cancer in HIV-infected patients at Johns Hopkins Hospital between 1986 and 2004. Ninety-two patients were identified. Compared to HIV-indeterminate patients (n=4973), HIV-infected individuals were younger with more advanced cancer. CD4 counts and HIV-1 RNA levels indicated preserved immune function. Mortality was higher in HIV-infected patients, with 92% dying of lung cancer (hazard ratio, 1.57; 95% confidence interval, 1.25-1.96), compared to HIV-uninfected patients. Advanced stage and black race were associated with worse survival. After adjustment for these factors, HIV infection was not associated with increased mortality (hazard ratio, 1.04; 95% confidence interval, 0.83-1.32). Of 32 patients followed in our HIV clinic, 60% of chest radiographs had no evidence of neoplasm within 1 year of diagnosis compared to only 1 (4%) of 28 chest computed tomography scans. Nonspecific infiltrates were observed in 9 patients in the same area that cancer was subsequently diagnosed. HIV-infected lung cancer patients have shortened survival mainly due to advanced stage. Low clinical suspicion and overreliance on chest radiographs hindered earlier detection. Aggressive follow-up of nonspecific pulmonary infiltrates in these patients is warranted.


Paroxysmal axial spasms of spinal origin.
A 55-year-old man with a 4 1/2-year history of paroxysmal bouts of involuntary large-amplitude flexion jerks of the trunk and a 1-year history of persistent rhythmic small-amplitude movements of the anterior abdominal wall is described. Clinical and electrophysiological evidence suggested that the paroxysmal myoclonus arose in propriospinal systems intrinsic to the spinal cord.


A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2.
Zinc finger-containing Gli proteins mediate responsiveness to Hedgehog (Hh) signaling, with Gli2 acting as the major transcriptional activator in this pathway in mice. The discovery of disease-associated mutations points to a critical role for GLI2 in human Hh signaling as well. Here, we show that human GLI2 contains previously undescribed 5' sequence, extending the amino-terminus an additional 328 amino acids. In vitro, transcriptional activity of full-length GLI2 is up to 30 times lower than that of GLI2DeltaN (previously thought to represent the entire GLI2 protein), revealing the presence of an amino-terminal repressor domain in the full-length protein. GLI2DeltaN also exhibits potent transcriptional activity in vivo: overexpression in mouse skin leads to the formation of Hh-independent epithelial downgrowths resembling basal cell carcinomas, which in humans are associated with constitutive Hh signaling. The discovery of this additional, functionally relevant GLI2 sequence led us to re-examine several pathogenic human GLI2 mutants, now containing the entire amino-terminal domain. On the basis of the functional domains affected by the mutations, mutant GLI2 proteins exhibited either loss-of-function or dominant-negative activity. Moreover, deletion of the amino-terminus abrogated dominant-negative activity of mutant GLI2, revealing that this domain is required for transcriptional repressor activity of pathogenic GLI2. Our results establish the presence of an amino-terminal transcriptional repressor domain that plays a critical role in modulating the function of wild-type GLI2 and is essential for dominant-negative activity of a GLI2 mutant associated with human disease.


Nonequilibrium dynamics of a confined colloidal bilayer in a planar shear flow.
Using Brownian dynamics (BD) simulations we investigate the impact of shear flow on structural and dynamical properties of a system of charged colloids confined to a narrow slit pore. Our model consists of spherical microions interacting through a Derjaguin-Landau-Verwey-Overbeek (DLVO) and a soft-sphere potential. The DLVO parameters were chosen according to a system of moderately charged silica particles (with valence Z~35) in a solvent of low ionic strength. At the confinement conditions considered, the colloids form two well-pronounced layers. In the present study we investigate shear-induced transitions of the translational order and dynamics in the layers, including a discussion of the translational diffusion. In particular, we show that diffusion in the shear-melted state can be described by an analytical model involving a single shear-driven particle in a harmonic trap. We also explore the emergence of zigzag motion characterized by spatiotemporal oscillations of the particles in the layers in the vorticity direction. Similar behavior has been recently observed in experiments of much thicker colloidal films.


Voxel-wise and spatial modelling of binary lesion masks: Comparison of methods with a realistic simulation framework.
White matter lesions are a very common finding on MRI in older adults and their presence increases the risk of stroke and dementia. Accurate and computationally efficient modelling methods are necessary to map the association of lesion incidence with risk factors, such as hypertension. However, there is no consensus in the brain mapping literature whether a voxel-wise modelling approach is better for binary lesion data than a more computationally intensive spatial modelling approach that accounts for voxel dependence. We review three regression approaches for modelling binary lesion masks including mass-univariate probit regression modelling with either maximum likelihood estimates, or mean bias-reduced estimates, and spatial Bayesian modelling, where the regression coefficients have a conditional autoregressive model prior to account for local spatial dependence. We design a novel simulation framework of artificial lesion maps to compare the three alternative lesion mapping methods. The age effect on lesion probability estimated from a reference data set (13,680 individuals from the UK Biobank) is used to simulate a realistic voxel-wise distribution of lesions across age. To mimic the real features of lesion masks, we propose matching brain lesion summaries (total lesion volume, average lesion size and lesion count) across the reference data set and the simulated data sets. Thus, we allow for a fair comparison between the modelling approaches, under a realistic simulation setting. Our findings suggest that bias-reduced estimates for voxel-wise binary-response generalized linear models (GLMs) overcome the drawbacks of infinite and biased maximum likelihood estimates and scale well for large data sets because voxel-wise estimation can be performed in parallel across voxels. Contrary to the assumption of spatial dependence being key in lesion mapping, our results show that voxel-wise bias-reduction and spatial modelling result in largely similar estimates. Bias-reduced estimates for voxel-wise GLMs are not only accurate but also computationally efficient, which will become increasingly important as more biobank-scale neuroimaging data sets become available.


Macro-to-micro structural proteomics: native source proteins for high-throughput crystallization.
Structural biology and structural genomics projects routinely rely on recombinantly expressed proteins, but many proteins and complexes are difficult to obtain by this approach. We investigated native source proteins for high-throughput protein crystallography applications. The Escherichia coli proteome was fractionated, purified, crystallized, and structurally characterized. Macro-scale fermentation and fractionation were used to subdivide the soluble proteome into 408 unique fractions of which 295 fractions yielded crystals in microfluidic crystallization chips. Of the 295 crystals, 152 were selected for optimization, diffraction screening, and data collection. Twenty-three structures were determined, four of which were novel. This study demonstrates the utility of native source proteins for high-throughput crystallography.


AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells.
Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17 β-hydroxysteroid dehydrogenase, is responsible for intratumoral androgen biosynthesis, contributing to the development of castration-resistant prostate cancer (CRPC) and eventual chemotherapeutic failure. Significant upregulation of AKR1C3 is observed in CRPC patient samples and derived CRPC cell lines. As AKR1C3 is a downstream steroidogenic enzyme synthesizing intratumoral testosterone (T) and 5α-dihydrotestosterone (DHT), the enzyme represents a promising therapeutic target to manage CRPC and combat the emergence of resistance to clinically employed androgen deprivation therapy. Herein, we demonstrate the antineoplastic activity of a potent, isoform-selective and hydrolytically stable AKR1C3 inhibitor (E)-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl)acrylic acid (KV-37), which reduces prostate cancer cell growth in vitro and in vivo and sensitizes CRPC cell lines (22Rv1 and LNCaP1C3) toward the antitumor effects of enzalutamide. Crucially, KV-37 does not induce toxicity in nonmalignant WPMY-1 prostate cells nor does it induce weight loss in mouse xenografts. Moreover, KV-37 reduces androgen receptor (AR) transactivation and prostate-specific antigen expression levels in CRPC cell lines indicative of a therapeutic effect in prostate cancer. Combination studies of KV-37 with enzalutamide reveal a very high degree of synergistic drug interaction that induces significant reduction in prostate cancer cell viability via apoptosis, resulting in >200-fold potentiation of enzalutamide action in drug-resistant 22Rv1 cells. These results demonstrate a promising therapeutic strategy for the treatment of drug-resistant CRPC that invariably develops in prostate cancer patients following initial treatment with AR antagonists such as enzalutamide. Mol Cancer Ther; 17(9); 1833-45. ©2018 AACR.


Bioconversion of Organic Pollutants in Fish-Canning Wastewater into Volatile Fatty Acids and Polyhydroxyalkanoate.
The wastewater from the cookers of a tuna-canning plant was used as feedstock for the process. It was acidified in a continuous stirred tank reactor (CSTR) of 1.5 L to produce a mixture of volatile fatty acids (VFAs). The effluent contained 28.3 ± 8.7 g CODS/L and 25.0 ± 4.6 g CODVFA/L, 4.4 ± 1.6 g NH4+/L, and 10.9 ± 4.0 g Na+/L, which corresponds to about 28 g NaCl/L approximately. This was used to feed a PHA production system. The enriched MMC presented a capacity to accumulate PHAs from the fermented tuna wastewater. The maximum PHA content of the biomass in the fed-batch (8.35 wt% PHA) seemed very low, possibly due to the variable salinity (from 2.2 up to 12.3 g NaCl/L) and the presence of ammonium (which promoted the biomass growth). The batch assay showed a PHA accumulation of 5.70 wt% PHA, but this is a much better result if the productivity of the reactor is taken into account. The fed-batch reactor had a productivity of 10.3 mg PHA/(L h), while the batch value was about five times higher (55.4 mg PHA/(L h)). At the sight of the results, it can be seen that the acidification of fish-canning wastewater is possible even at high saline concentrations (27.7 g NaCl/L). On the other hand, the enrichment and accumulation results show us promising news and which direction has to be followed: PHAs can be obtained from challenging substrates, and the feeding mode during the accumulation stage has an important role to play when it comes to inhibition.


Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19-A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium.
The COVID-19 pandemic continues to affect millions of people globally, with increasing reports of neurological manifestations but limited data on their incidence and associations with outcome. To determine the neurological phenotypes, incidence, and outcomes among adults hospitalized with COVID-19. This cohort study included patients with clinically diagnosed or laboratory-confirmed COVID-19 at 28 centers, representing 13 countries and 4 continents. The study was performed by the Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID) from March 1 to September 30, 2020, and the European Academy of Neurology (EAN) Neuro-COVID Registry (ENERGY) from March to October 2020. Three cohorts were included: (1) the GCS-NeuroCOVID all COVID-19 cohort (n = 3055), which included consecutive hospitalized patients with COVID-19 with and without neurological manifestations; (2) the GCS-NeuroCOVID COVID-19 neurological cohort (n = 475), which comprised consecutive patients hospitalized with COVID-19 who had confirmed neurological manifestations; and (3) the ENERGY cohort (n = 214), which included patients with COVID-19 who received formal neurological consultation. Clinically diagnosed or laboratory-confirmed COVID-19. Neurological phenotypes were classified as self-reported symptoms or neurological signs and/or syndromes assessed by clinical evaluation. Composite incidence was reported for groups with at least 1 neurological manifestation. The main outcome measure was in-hospital mortality. Of the 3055 patients in the all COVID-19 cohort, 1742 (57%) were men, and the mean age was 59.9 years (95% CI, 59.3-60.6 years). Of the 475 patients in the COVID-19 neurological cohort, 262 (55%) were men, and the mean age was 62.6 years (95% CI, 61.1-64.1 years). Of the 214 patients in the ENERGY cohort, 133 (62%) were men, and the mean age was 67 years (95% CI, 52-78 years). A total of 3083 of 3743 patients (82%) across cohorts had any neurological manifestation (self-reported neurological symptoms and/or clinically captured neurological sign and/or syndrome). The most common self-reported symptoms included headache (1385 of 3732 patients [37%]) and anosmia or ageusia (977 of 3700 patients [26%]). The most prevalent neurological signs and/or syndromes were acute encephalopathy (1845 of 3740 patients [49%]), coma (649 of 3737 patients [17%]), and stroke (222 of 3737 patients [6%]), while meningitis and/or encephalitis were rare (19 of 3741 patients [0.5%]). Presence of clinically captured neurologic signs and/or syndromes was associated with increased risk of in-hospital death (adjusted odds ratio [aOR], 5.99; 95% CI, 4.33-8.28) after adjusting for study site, age, sex, race, and ethnicity. Presence of preexisting neurological disorders (aOR, 2.23; 95% CI, 1.80-2.75) was associated with increased risk of developing neurological signs and/or syndromes with COVID-19. In this multicohort study, neurological manifestations were prevalent among patients hospitalized with COVID-19 and were associated with higher in-hospital mortality. Preexisting neurological disorders were associated with increased risk of developing neurological signs and/or syndromes in COVID-19.


Understanding the relation between research and clinical policy: a study of clinicians' views.
To describe the relation between research evidence and local obstetric unit policy for specific areas of care and to explore clinicians' views about the reasons for any discrepancies identified. An independent evaluation of a project undertaken by a district maternity services liaison committee (MSLC) to promote evidence based maternity care in specific areas of care. The evaluation involved a combination of qualitative methodologies including documentary analysis, non-participant observation, semi-structured interviews, and self completed open ended questionnaires. One English health district with three obstetric units. Congruence between unit policies and research evidence in specific areas of care. Views expressed by unit staff concerning the reasons for any discrepancies identified. Consistency between staff views within and between units. Unit attitudes to modification of discrepant policies and details of any subsequent changes made. Of the 12 unit policies considered, seven were consistent with the research evidence. In all cases in which unit policy did not reflect the evidence, provider unit staff thought that the differences were justified. In several cases there were substantive differences of view between staff in different units. No differences of view were expressed between staff in the same unit. There were three different types of concern about the research evidence and the problems of using it as a basis for deciding unit policy. These were: concerns about the adequacy or completeness of the evidence; concerns about the applicability of the evidence in the local setting; and concerns about local capacity to act on the evidence. At the time of the project, none of the units expressed any intention of modifying the policies under discussion. Subsequently, two of them did make changes of this sort. The results suggest the need for further research to ascertain what factors may produce such varying assessments of the validity and adequacy of particular sets of research findings as were found between clinicians in this study and to understand what considerations other than views about evidence may affect decisions to alter clinical policy. When clinicians have clear reasons for not following research evidence, two contrasting responses are possible. One is to take the view that the clinicians are mistaken, and seek to change their attitudes or persuade them to change their behaviour regardless of their views. An alternative response is to accept that the concerns they express may be legitimate and consider how their doubts may be addressed. The challenge is to recognise which response is preferable in any particular situation.


Complex epigenetic patterns in cerebellum generated after developmental exposure to trichloroethylene and/or high fat diet in autoimmune-prone mice.
Trichloroethylene (TCE) is an environmental contaminant associated with immune-mediated inflammatory disorders and neurotoxicity. Based on known negative effects of developmental overnutrition on neurodevelopment, we hypothesized that developmental exposure to high fat diet (HFD) consisting of 40% kcal fat would enhance neurotoxicity of low-level (6 μg per kg per day) TCE exposure in offspring over either stressor alone. Male offspring were evaluated at ∼6 weeks of age after exposure beginning 4 weeks preconception in the dams until weaning. TCE, whether used as a single exposure or together with HFD, appeared to be more robust than HFD alone in altering one-carbon metabolites involved in glutathione redox homeostasis and methylation capacity. In contrast, opposing effects of expression of key enzymes related to DNA methylation related to HFD and TCE exposure were observed. The mice generated unique patterns of anti-brain antibodies detected by western blotting attributable to both TCE and HFD. Taken together, developmental exposure to TCE and/or HFD appear to act in complex ways to alter brain biomarkers in offspring.


'My dreams are shuttered down and it hurts lots'-a qualitative study of palliative care needs and their management by HIV outpatient services in Kenya and Uganda.
Despite the huge burden of HIV in sub-Saharan Africa, there is little evidence of the multidimensional needs of patients with HIV infection to inform the person-centred care across physical, psychological, social and spiritual domains stipulated in policy guidance. We aimed to describe the problems experienced by people with HIV in Kenya and Uganda and the management of these problems by HIV outpatient services. Local researchers conducted in depth qualitative interviews with HIV patients, caregivers and service staff at 12 HIV outpatient facilities (6 in Kenya, 6 in Uganda). Interview data were analysed thematically. 189 people were interviewed (83 patients, 47 caregivers, 59 staff). The impact of pain and symptoms and their causes (HIV, comorbidities, treatment side-effects) were described. Staff reported that effective pain relief was not always available, particularly in Kenya. Psychosocial distress (isolation, loneliness, worry) was exacerbated by stigma and poverty, and detrimentally affected adherence. Illness led to despair and hopelessness. Provision of counselling was reported, but spiritual support appeared to be less common. Neither pain nor psychosocial problems were routinely reported to service staff. Collaboration with local hospices and income-generation activities for patients were highlighted as useful. The findings demonstrate the multiple and interrelated problems associated with living with HIV and how psychosocial and spiritual distress can contribute to 'total pain' in this population. In line with the palliative care approach, HIV care requires holistic care and assessment that take into account psychological, socioeconomic and spiritual distress alongside improved access to pain-relieving drugs, including opioids.


Electrophysiological correlates of word repetition spacing: ERP and induced band power old/new effects with massed and spaced repetitions.
The EEG was recorded in 21 participants who were required to make 'old' vs. 'new' decisions during a continuous recognition memory task with massed word repetitions (i.e., immediate repetitions) and spaced word repetitions (i.e., with six intervening words). After completion of the recognition task, they were given an unexpected free recall task. Behavioral measures revealed better recognition but worse free recall with massed repetitions, and worse recognition but better free recall with spaced repetitions. The ERP data revealed that for the 350- to 450-ms time window (representing the N400) the repetition effect was widely distributed across central and parietal scalp sites and was larger with massed than with spaced word repetitions. Peak latencies of the late positive complex (LPC) at Pz were shorter for massed than for spaced repetitions. Mean area around peak measures at Pz indicated that the LPC repetition effect was also larger with massed than with spaced repetitions. In the frequency domain, we found a theta (4-6 Hz) induced band power (IBP) repetition effect for massed repetitions, with theta power in the 250- to 625-ms time window being larger to repeated words than to new words. For spaced repetitions, we found an upper alpha (10-12 Hz) IBP repetition effect with the upper alpha power in the 625- to 1000-ms time window being smaller to repeated words than to new words. With spaced repetitions, we further found that larger LPC and theta IBP repetition effects were associated with smaller recall performance enhancements. The results mainly support a deficient processing account of the spacing effect.


Species distribution models have limited spatial transferability for invasive species.
The reliability of transferring species distribution models (SDMs) to new ranges and future climates has been widely debated. Biological invasions offer the unique opportunity to evaluate model transferability, as distribution data between species' native and introduced ranges are geographically independent of each other. Here, we performed the first global quantitative synthesis of the spatial transferability of SDMs for 235 invasive species and assessed the association of model transferability with the focal invader, model choice and parameterisation. We found that SDMs had limited spatial transferability overall. However, model transferability was higher for terrestrial endotherms, species introduced from or to the Southern Hemisphere, and species introduced more recently. Model transferability was also positively associated with the number of presences for model calibration and evaluation, respectively, but negatively with the number of predictors. These findings highlight the importance of considering the characteristics of the focal invader, environment and modelling in the application and assessment of SDMs.


Nutrient profiling for regulatory purposes.
In this paper, I first provide definitions of nutrient profiling and of a nutrient profile model. I set out the purposes of nutrient profiling: both general and specific. I give two examples of nutrient profile models that have been developed for regulatory purposes by the Food Standards Agency (FSA) in the UK and the WHO for its European Region - the UK FSA/Ofcom and the WHO-Euro models - and compare the way the models are constructed and function, how they have been developed, the extent to which they have been tested and validated and their use in regulation. Finally I draw some conclusions about the future use of nutrient profiling for regulatory purposes. I argue that its full potential has yet to be realised and give some reasons why. I pose some urgent research questions with respect to nutrient profiling.


The Antibacterial Activity of Metal Complexes Containing 1,10- phenanthroline: Potential as Alternative Therapeutics in the Era of Antibiotic Resistance.
The "antibiotic era", characterized by the overuse and misuse of antibiotics, over the last half-century has culminated in the present critical "era of resistance". The treatment of bacterial infections is challenging because of a decline in the current arsenal of useful antibiotics and the slow rate of new drug development. The discovery of a new gene (mcr-1) in 2015, which enables bacteria to be highly resistant to polymyxins (such as colistin), the last line of antibiotic defence left, heralds a new level of concern as this gene is susceptible to horizontal gene transfer, with alarming potential to be spread between different bacterial populations, suggesting that the progression from "extensive drug resistance" to "pan-drug resistance" may be inevitable. Clearly there is a need for the development of novel classes of anti-bacterial agents capable of killing bacteria through mechanisms that are different to those of the known classes of antibiotics. 1,10-phenanthroline (phen) is a heterocyclic organic compound which exerts in vitro antimicrobial activity against a broad-spectrum of bacteria. The antimicrobial activity of phen can be significantly modulated by modifying its structure. The development of metal-phen complexes offers the medicinal chemist an opportunity to expand such structural diversity by controlling the geometry and varying the oxidation states of the metal centre, with the inclusion of appropriate auxiliary ligands in the structure, offering the opportunity to target different biochemical pathways in bacteria. In this review, we summarize what is currently known about the antibacterial capability of metal-phen complexes and their mechanisms of action.


Retained differentiation capacity of human skeletal muscle satellite cells from spinal cord-injured individuals.
Despite the well-known role of satellite cells in skeletal muscle plasticity, the effect of spinal cord injury on their function in humans remains unknown. We determined whether spinal cord injury affects the intrinsic ability of satellite cells to differentiate and produce metabolically healthy myotubes. We obtained vastus lateralis biopsies from eight spinal cord-injured and six able-bodied individuals. Satellite cells were isolated, grown and differentiated in vitro. Gene expression was measured by quantitative PCR. Abundance of differentiation markers and regulatory proteins was determined by Western blotting. Protein synthesis and fatty acid oxidation were measured by radioactive tracer-based assays. Activated satellite cells (myoblasts) and differentiated myotubes derived from skeletal muscle of able-bodied and spinal cord-injured individuals expressed similar (P > 0.05) mRNA levels of myogenic regulatory factors. Myogenic differentiation factor 1 expression was higher in myoblasts from spinal cord-injured individuals. Desmin and myogenin protein content was increased upon differentiation in both groups, while myotubes from spinal cord-injured individuals contained more type I and II myosin heavy chain. Phosphorylated and total protein levels of Akt-mechanistic target of rapamycin and forkhead box protein O signalling axes and protein synthesis rate in myotubes were similar (P > 0.05) between groups. Additionally, fatty acid oxidation of myotubes from spinal cord-injured individuals was unchanged (P > 0.05) compared to able-bodied controls. Our results indicate that the intrinsic differentiation capacity of satellite cells and metabolic characteristics of myotubes are preserved following spinal cord injury. This may inform potential interventions targeting satellite cell activation to alleviate skeletal muscle atrophy.


Characterization of sodium dodecylsulphate and dodecylphosphocholine mixed micelles through NMR and dynamic light scattering.
The complexity of biological membranes leads to the use of extremely simplified models in biophysical investigations of membrane-bound proteins and peptides. Liposomes are probably the most widely used membrane models due, especially, to their versatility in terms of electric charge and size. However, liquid-state NMR suffers the lack of such a model, because even the smallest liposomes slowly tumble in solution, resulting in a dramatic signals broadening. Micelles are typically used as good substitutes, with sodium dodecylsulphate (SDS) and dodecylphosphocholine (DPC) being the most widely employed surfactants. However, they are always used separately to mimic prokaryotic and eukaryotic membranes, respectively, and accurate investigations as a function of surface charge cannot be performed. In this work, the critical micelle concentration (CMC) of binary mixtures with different SDS/DPC ratios has been determined by following the chemical shift variation of selected (1)H and (31)P NMR signals as a function of total surfactant concentration. The regular solution theory and the Motomura's formalism have been applied to characterize the micellization both in water and in phosphate buffer saline, and results were compared with those obtained directly from the experimental NMR chemical shift. The ζ-potential and size distribution of the mixed micelles have been estimated with dynamic light scattering measurements. Results showed that SDS and DPC are synergic and can be used together to prepare mixed micelles with different negative/zwitterionic surfactants molar ratio.


Nasal anatomy of the non-mammaliaform cynodont Brasilitherium riograndensis (Eucynodontia, Therapsida) reveals new insight into mammalian evolution.
The mammalian nasal cavity is characterized by a unique anatomy with complex internal features. The evolution of turbinals was correlated with endothermic and macrosmatic adaptations in therapsids and in early mammals, which is still apparent in their twofold function (warming and moistening of air, olfaction). Fossil evidence for the transformation from the nonmammalian to the mammalian nasal cavity pattern has been poor and inadequate. Ossification of the cartilaginous nasal capsule and turbinals seems to be a feature that occurred only very late in synapsid evolution but delicate ethmoidal bones are rarely preserved. Here we provide the first µCT investigation of the nasal cavity of the advanced non-mammaliaform cynodont Brasilitherium riograndensis from the Late Triassic of Southern Brazil, a member of the sister-group of mammaliaforms, in order to elucidate a critical anatomical transition in early mammalian evolution. Brasilitherium riograndensis already had at least partially ossified turbinals as remnants of the nasoturbinal and the first ethmoturbinal are preserved. The posterior nasal septum is partly ossified and contributes to a mesethmoid. The nasal cavity is posteriorly expanded and forms a distinctive pars posterior (ethmoidal recess) that is ventrally separated from the nasopharyngeal duct by a distinct lamina terminalis. Thus, our observations clearly demonstrate that principal features of the mammalian nasal cavity were already present in the sister-group of mammaliaforms.


Protein-protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics.
Antibiotics are potent pharmacological weapons against bacterial infections; however, the growing antibiotic resistance of microorganisms is compromising the efficacy of the currently available pharmacotherapies. Even though antimicrobial resistance is not a new problem, antibiotic development has failed to match the growth of resistant pathogens and hence, it is highly critical to discover new anti-infective drugs with novel mechanisms of action which will help reducing the burden of multidrug-resistant microorganisms. Protein-protein interactions (PPIs) are involved in a myriad of vital cellular processes and have become an attractive target to treat diseases. Therefore, targeting PPI networks in bacteria may offer a new and unconventional point of intervention to develop novel anti-infective drugs which can combat the ever-increasing rate of multidrug-resistant bacteria. This review describes the progress achieved towards the discovery of molecules that disrupt PPI systems in bacteria for which inhibitors have been identified and whose targets could represent an alternative lead discovery strategy to obtain new anti-infective molecules.


Implications of stunting on morphology of freshwater fishes.
The purpose of this study was to assess morphological differences between stunted and non-stunted white perch Morone americana and green sunfish Lepomis cyanellus. Few female M. americana were captured; thus, morphological differences between adult males and juveniles were assessed for M. americana. Similarly, few immature (juvenile) L. cyanellus were captured for the stunted morphotype; thus, male and female morphological differences were assessed for L. cyanellus. Features of the head tended to be relatively larger in stunted fish of both species, whereas the mid-body tended to be relatively larger in non-stunted M. americana, but not in non-stunted L. cyanellus. Adult and juvenile morphology overlapped considerably in non-stunted M. americana, but there was a clear distinction between adult and juvenile morphology of stunted M. americana. There was little sexual dimorphism in shape in stunted L. cyanellus, whereas sexual dimorphism was evident in non-stunted L. cyanellus. It appears that selective forces imposed by predation and food limitation may contribute to morphological diversification between stunted and non-stunted fishes.


Theranostic Copolymers Neutralize Reactive Oxygen Species and Lipid Peroxidation Products for the Combined Treatment of Traumatic Brain Injury.
Traumatic brain injury (TBI) results in the generation of reactive oxygen species (ROS) and lipid peroxidation product (LPOx), including acrolein and 4-hydroxynonenal (4HNE). The presence of these biochemical derangements results in neurodegeneration during the secondary phase of the injury. The ability to rapidly neutralize multiple species could significantly improve outcomes for TBI patients. However, the difficulty in creating therapies that target multiple biochemical derangements simultaneously has greatly limited therapeutic efficacy. Therefore, our goal was to design a material that could rapidly bind and neutralize both ROS and LPOx following TBI. To do this, a series of thiol-functionalized biocompatible copolymers based on lipoic acid methacrylate and polyethylene glycol monomethyl ether methacrylate (FW ∼ 950 Da) (O950) were prepared. A polymerizable gadolinium-DOTA methacrylate monomer (Gd-MA) was also synthesized starting from cyclen to facilitate direct magnetic resonance imaging and in vivo tracking of accumulation. These neuroprotective copolymers (NPCs) were shown to rapidly and effectively neutralize both ROS and LPOx. Horseradish peroxidase absorbance assays showed that the NPCs efficiently neutralized H2O2, while R-phycoerythrin protection assays demonstrated their ability to protect the fluorescent protein from oxidative damage. 1H NMR studies indicated that the thiol-functional NPCs rapidly form covalent bonds with acrolein, efficiently removing it from solution. In vitro cell studies with SH-SY5Y-differentiated neurons showed that NPCs provide unique protection against toxic concentrations of both H2O2 and acrolein. NPCs rapidly accumulate and are retained in the injured brain in controlled cortical impact mice and reduce post-traumatic oxidative stress. Therefore, these materials show promise for improved target engagement of multiple biochemical derangements in hopes of improving TBI therapeutic outcomes.


Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial.
Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients. This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation. This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps. This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254.


Intrinsic signal imaging in macaque retina reveals different types of flash-induced light reflectance changes of different origins.
Intrinsic signal imaging is a newly developed technique that can map the neural activity of tissues noninvasively. It has been used to map the functional organization of the retina by recording flash-induced light reflectance changes in the cone and rod photoreceptors. The purpose of this study was to investigate the properties of the intrinsic signals in the monkey's retina. To accomplish this, the intrinsic signals and the electroretinograms (ERGs) evoked by the same stimuli were measured under different recording conditions. The fundus of macaque monkeys was observed with infrared light and recorded with a charge-coupled device (CCD) camera. The intrinsic signals were measured as retinal light reflectance changes induced by diffuse or focal flash stimuli. ERGs were recorded under the same stimulating conditions. The reflectance changes induced by different flash intensities, flash intervals, and background luminance were compared. The intrinsic signals were categorized into different groups based on the location in the fundus. Fast signals (peak: approximately 100 ms) were recorded from the posterior retina including the fovea, and slow signals (peak: 5.0-6.0 seconds) were recorded from the optic disc and nonfoveal posterior retina. The threshold of the slow signal changes was comparable to that of the ERG b-wave, and the thresholds of the fast signals were higher than that of the ERG a- and b-waves. The retinal intrinsic signals are composed of several components with different response properties and different sources. This recording technique may be useful for mapping the retinal function in eyes with various disorders.


Comparison of complications associated with peripherally inserted central catheters and Hickman™ catheters in patients with intestinal failure receiving home parenteral nutrition. Six-year follow up study.
Patients with intestinal failure (IF) are dependent on parenteral nutrition delivered through central access such as Hickman™ catheters. The peripherally inserted central catheter (PICC) is becoming increasingly popular for the purpose. The aim of the present study was to compare complication rates between the two types of catheters. Over a six-year period (2008-2014), we included 136 patients with IF receiving home parenteral nutrition (HPN). These patients had a total of 295 catheters (169 Hickman™ catheters and 126 PICCs). Data were collected by reviewing their medical records. Incidences are given per 1000 catheter days. Data are given as means ± standard deviation (SD) and compared using independent student's t-tests, Mann-Whitney-Wilcoxon, and X(2)-tests. A survival analysis for time to the first infection was conducted using Cox regression. The total number of catheter days was 54,912 days for Hickman™ catheters (mean dwell time 325 ± 402) and 15,974 days for PICCs (mean dwell time 127 ± 121), respectively. The incidence of catheter-related blood stream infection (CRBSI) per 1000 catheter days was significantly lower for Hickman™ catheters compared to PICCs (0.56 vs. 1.63, p < 0.05). The mean time to first CRBSI was significantly shorter for PICCs compared to Hickman™ catheters (84 ± 94 days vs. 297 ± 387 days, p < 0.05), which was confirmed with a cox analysis corrected for age and gender. A total of 75 catheters were removed due to CRBSI, 49 Hickman™ catheters and 26 PICCs respectively. In addition, PICCs were more often removed due to local infection/phlebitis and mechanical causes (p < 0.001). We found a higher risk and shorter time to first CRBSI in PICCs compared to Hickman catheters supporting that PICCs should mainly be chosen for planned HPN up to 3-6 months. We therefore conclude that the choice of catheter must still be determined on an individual basis.


Advantages of aberration correction for HRTEM investigation of complex layer compounds.
Aberration-corrected high-resolution transmission electron microscopy (HRTEM) has been applied to resolve the atomic structure of a complex layered crystal, (PbS)(1.14)NbS(2), which comprises a high density of incommensurate interfaces. The strong suppression of image delocalization and the favourable contrast transfer under negative C(s) imaging (NCSI) conditions have been exploited for obtaining HRTEM images which directly reveal the projected crystal structure and allow to study lattice imperfections, like stacking disorder and layer undulations, with atomic scale resolution. The advantages of aberration-corrected HRTEM over conventional HRTEM are demonstrated by direct comparison of experimental images and computer simulations.


Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS.
The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.


Stresses inside critical nuclei.
The usual derivation of classical nucleation theory is inappropriate for crystal nucleation. In particular, it leads to a seriously flawed estimate of the pressure inside a critical nucleus. This has consequences for the prediction of possible metastable phases during the nucleation process. In this paper, we reanalyze the theory for crystal nucleation based on the thermodynamics of small crystals suspended in a liquid, due to Mullins (J. Chem. Phys. 1984, 81, 1436). As an illustration of the difference between the classical picture and the present approach, we consider a numerical study of crystal nucleation in binary mixtures of hard spherical colloids with a size ratio of 1:10. The stable crystal phase of this system can be either dense or expanded. We find that, in the vicinity of the solid-solid critical point where the crystallites are highly compressible, small crystal nuclei are less dense than large nuclei. This phenomenon cannot be accounted for by either classical nucleation theory or by the Gibbsian droplet model.


QTL mapping identifies a major locus for resistance in wheat to Sunn pest (Eurygaster integriceps) feeding at the vegetative growth stage.
This research provides the first report of a major locus controlling wheat resistance to Sunn pest. It developed and validated SNP markers that will be useful for marker-assisted selection. Sunn pest (Eurygaster integriceps Puton) is the most destructive insect pest of bread wheat and durum wheat in West and Central Asia and East Europe. Breeding for resistance at the vegetative stage of growth is vital in reducing the damage caused by overwintered adult populations that feed on shoot and leaves of seedlings, and in reducing the next generation of pest populations (nymphs and adults), which can cause damage to grain quality by feeding on spikes. In the present study, two doubled haploid (DH) populations involving resistant landraces from Afghanistan were genotyped with the 90k SNP iSelect assay and candidate gene-based KASP markers. The DH lines and parents were phenotyped for resistance to Sunn pest feeding, using artificial infestation cages at Terbol station, in Lebanon, over three years. Quantitative trait locus (QTL) analysis identified a single major locus on chromosome 4BS in the two populations, with the resistance allele derived from the landrace accessions, IG139431 and IG139883. The QTL explained a maximum of 42 % of the phenotypic variation in the Cham6 × IG139431 and 56 % in the Cham6 × IG139883 populations. SNP markers closest to the QTL showed high similarity to rice genes that putatively encode proteins for defense response to herbivory and wounding. The markers were validated in a large, unrelated population of parental wheat genotypes. All wheat lines carrying the 'C-G' haplotype at the identified SNPs were resistant, suggesting that selection based on a haplotype of favourable alleles would be effective in predicting resistance status of unknown genotypes.


Model-based tracking by classification in a tiny discrete pose space.
A method is presented for tracking 3D objects as they transform rigidly in space within a sparse range image sequence. The method operates in discrete space and exploits the coherence across image frames that results from the relationship between known bounds on the object's velocity and the sensor frame rate. These motion bounds allow the interframe transformation space to be reduced to a reasonable and indeed tiny size, comprising only tens or hundreds of possible states. The tracking problem is in this way cast into a classification framework, effectively trading off localization precision for runtime efficiency and robustness. The method has been implemented and tested extensively on a variety of freeform objects within a sparse range data stream comprising only a few hundred points per image. It has been shown to compare favorably against continuous domain Iterative Closest Point (ICP) tracking methods, performing both more efficiently and more robustly. A hybrid method has also been implemented that executes a small number of ICP iterations following the initial discrete classification phase. This hybrid method is both more efficient than the ICP alone and more robust than either the discrete classification method or the ICP separately.


Characterization of AMD, the AMP deaminase gene in yeast. Production of amd strain, cloning, nucleotide sequence, and properties of the protein.
The structural gene for AMP deaminase (AMD) from Saccharomyces cerevisiae has been cloned and characterized. A yeast strain deficient in AMP deaminase activity was produced and shown to be deficient in AMP deaminase protein by Western blot analysis. The gene for AMP deaminase was located in a lambda gt11 library of yeast genomic DNA, and a DNA fragment from the lambda gt11 clone was used to locate homologous DNA in a yeast genomic library in the centromeric plasmid YCp50, a yeast-Escherichia coli shuttle vector. One plasmid was selected for its ability to restore AMP catalytic activity to the deficient strain. Yeast deficient in AMP deaminase or those overproducing the enzyme grow at near normal rates. The open reading frame corresponding to AMD codes for a protein of 810 amino acids, molecular weight 93,286. The yeast AMD transcript is 3.0 +/- 0.2 kb, and the transcriptional initiation sites have been identified. Western blot analysis of extracts prepared from actively growing yeast indicates a major band at approximately 96,000 molecular weight with several bands at lower molecular weight, including 83,000. When the AMD gene is expressed in E. coli, the large Mr form of AMP deaminase is produced. These results show that the purified enzyme (Mr = 83,000) is a truncated form of the full-length translation product. No adenine nucleotide binding sites were located based on the consensus sequence from other nucleotide binding proteins. No overall homology was found between yeast AMP deaminase and E. coli AMP nucleosidase. Although their metabolic roles and regulatory mechanisms are similar, these enzymes have arisen from separate ancestral proteins.


A bimodal map of space: somatosensory receptive fields in the macaque putamen with corresponding visual receptive fields.
The macaque putamen contains neurons that respond to somatosensory stimuli such as light touch, joint movement, or deep muscle pressure. Their receptive fields are arranged to form a map of the body. In the face and arm region of this somatotopic map we found neurons that responded to visual stimuli. Some neurons were bimodal, responding to both visual and somatosensory stimuli, while others were purely visual, or purely somatosensory. The bimodal neurons usually responded to light cutaneous stimulation, rather than to joint movement or deep muscle pressure. They responded to visual stimuli near their tactile receptive field and were not selective for the shape or the color of the stimuli. For cells with tactile receptive fields on the face, the visual receptive field subtended a solid angle extending from the tactile receptive field to about 10 cm. For cells with tactile receptive fields on the arm, the visual receptive field often extended further from the animal. These bimodal properties provide a map of the visual space that immediately surrounds the monkey. The map is organized somatotopically, that is, by body part, rather than retinotopically as in most visual areas. It could function to guide movements in the animal's immediate vicinity. Cortical areas 6, 7b, and VIP contain bimodal cells with very similar properties to those in the putamen. We suggest that the bimodal cells in area 6, 7b, VIP, and the putamen form part of an interconnected system that represents extra personal space in a somatotopic fashion.


Secondary prevention of coronary artery disease.
Coronary artery disease is the leading cause of mortality in the United States. In patients who have had a myocardial infarction or revascularization procedure, secondary prevention of coronary artery disease by comprehensive risk factor modification reduces mortality, decreases subsequent cardiac events, and improves quality of life. Options for secondary prevention include medical therapy and surgical revascularization in the form of coronary artery bypass grafting or percutaneous coronary intervention. Medical therapy focuses on comprehensive risk factor modification. Therapeutic lifestyle changes (including weight management, physical activity, tobacco cessation, and dietary modification) improve cardiac risk factors and are universally recommended by evidence-based guidelines. Treatment of hypertension and dyslipidemia reduces morbidity and mortality. Recommendations for persons with diabetes mellitus generally encourage glucose control, but current evidence has not shown reductions in mortality with intensive glucose management. Aspirin, angiotensin-converting enzyme inhibitors, and beta blockers reduce recurrent cardiac events in patients after myocardial infarction. Surgical revascularization by coronary artery bypass grafting is recommended for those with significant left main coronary artery stenosis, significant stenosis of the proximal left anterior descending artery, multivessel coronary disease, or disabling angina. Percutaneous coronary intervention may be considered in select patients with objective evidence of ischemia demonstrated by noninvasive testing.


The Cape Town Declaration on Vaccines 2012: Unlocking the full potential of vaccines in Africa.
Delegates at the first International African Vaccinology Conference noted, with dismay, that many African children have limited access to existing and new vaccines as a consequence of weak immunisation programmes, lack of political will, and high vaccine prices. This inequality is a denial of the African child her basic right to a healthy life, and jeopardises long term economic growth on the continent. In addition, there is insufficient emphasis in Africa on adolescent and adult immunisation. The delegates documented various concerns and made various commitments; contained in this Cape Town Declaration on Vaccines, adopted on 11 November 2012. Finally, delegates confirmed their agreement with the goals and strategic objectives of the Global Vaccine Action Plan, and committed to hold African leaders accountable for its implementation during the Decade of Vaccines. The full list of registered conference delegates is provided as supplementary data to this manuscript.


Vascular injuries of the extremities are a major challenge in a third world country.
Traumatic vascular injuries of the extremities are a major challenge especially in the third world countries. These injuries are mostly due to poor traffic laws, street crimes, firearms and blast associated injuries. We therefore would like to share our 10 years of experience in dealing with vascular injuries in Pakistan. This was a retrospective observational study conducted in the department of vascular surgery of Liaquat National Hospital, Karachi, Pakistan. Patients' records were retrieved from the department and were reviewed. Cases with vascular injuries of upper and lower limb that presented with signs of salvageable limb and presented within 12 hours of injury were included in the study. Patients with more than 12 hours of presentation and in whom primary amputation was done, were excluded from the study. There were 328 patients who presented with vascular injuries of the extremities that fell in the inclusion criteria. Limb salvage rate was 41 %, whereas 30-days perioperative mortality was 5.48 %. The major cause of limb loss was delay in presentation of more than 8 h of injury. Major vessels involved were popliteal artery (41.76 %), followed by femoral artery (27.43 %). Vascular injuries are becoming a major contributor of limb loss in third world countries due to violence, terrorism and unavailability of vascular facilities. This morbidity can be reduced by improving law and order situation, evolving an effective emergency ambulatory system and with better training and provision of vascular services in remote areas so that the delay factor can be reduced.