[10 years' experience with heart surgery in Jehovah's witnesses].
As a result of their interpretation of the Bible, members of Jehovah's Witnesses do not accept blood transfusions under any circumstances. Consequently, they present moral and ethical problems to surgeons and anesthetists, especially in cardiac surgery. PATIENTS and METHODS. From November 1978 to November 1988, 66 members Jehovah's Witnesses were scheduled for cardiac surgery; 57 patients were operated upon (mean age 33.3 years, 14 days to 70.4 years; mean body weight 51 kg, 0.7 to 95.5 kg); 21 were younger than 14 years. Patients with hematocrit (Hct) less than 35%, expected high intra- and postoperative blood loss, compromised left ventricular function, ST-segment alterations, critical aortic stenosis, severe unstable angina pectoris, complex heart defects, especially in children, extreme body weight, severe diabetes, renal insufficiency, coagulopathies, severe pulmonary disease, and heavy smokers were excluded from operation. Whereas in nonbypass patients no special blood-saving techniques were used, in bypass patients a modified version of isovolemic hemodilution, with a hypothermic, bloodless priming technique of extracorporeal circulation (ECC) was performed after induction of anesthesia. At the end of the ECC all blood collected in the pericardial and pleural cavities was returned to the oxygenator and the entire content of the extracorporeal circuit was infused into the patient through the aortic cannula. All patients receiving ECC were ventilated for 24 h postoperatively and received dopamine (2-5 micrograms/kg) and antibiotics routinely. Due to the above mentioned contraindications, 9 patients were not accepted for surgery, 10 were operated upon without cardiopulmonary bypass or blood-saving techniques. In 47 patients open heart surgery with ECC and moderate or deep hypothermia was performed. In the adult patients (n = 36) Hct values decreased from 44.4% (35-70%) preoperatively to 32.1% (21-46%) after hemodilution, reached their lowest levels during cardiopulmonary bypass at 17.9% (9.9-43%), and increased to 33.7% (22%-43%) at the end of the operation. Hct averaged 28.2% (20%-39%) on the 3rd and 33.2% (23%-46%) on the 12th postoperative day. In children (n = 11) Hct decreased from 47.2% (36.9%-70%) to 33.6% (27.2%-49.1%) after hemodilution, during bypass to 16.1% (10.5%-25.5%) and increased to 32.1% (24.4%-37.4%) at the end of the operation. On the 3rd postoperative day Hct was 25% (21.4%-39%) and increased to 29.4% (25.1%-40%) on the 12th postoperative day. No statistical differences in Hct values were found between both groups. (ABSTRACT TRUNCATED AT 400 WORDS)


Strategies for understanding and reducing the Plasmodium vivax and Plasmodium ovale hypnozoite reservoir in Papua New Guinean children: a randomised placebo-controlled trial and mathematical model.
The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children. From 17 August 2009 to 20 May 2010, 524 children aged 5-10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], 3 d; and primaquine [PQ], 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo [PL], 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow-up (P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 [95% CI 0.13, 0.77], p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 [95% CI 0.11, 0.61], p = 0.002). PQ also reduced the molecular force of P. vivax blood-stage infection in the first 3 mo of follow-up (PQ arm 1.90/y versus PL arm 7.75/y, incidence rate ratio [IRR] = 0.21 [95% CI 0.15, 0.28], p < 0.001). Children who received PQ were less likely to carry P. vivax gametocytes (IRR = 0.27 [95% CI 0.19, 0.38], p < 0.001). PQ had a comparable effect irrespective of the presence of P. vivax blood-stage infection at the time of treatment (p = 0.14). Modelling revealed that mass screening and treatment with highly sensitive quantitative real-time PCR, or MDA with blood-stage treatment alone, would have only a transient effect on P. vivax transmission levels, while MDA that includes liver-stage treatment is predicted to be a highly effective strategy for P. vivax elimination. The inclusion of a directly observed 20-d treatment regime maximises the efficiency of hypnozoite clearance but limits the generalisability of results to real-world MDA programmes. These results suggest that relapses cause approximately four of every five P. vivax infections and at least three of every five P. ovale infections in PNG children and are important in sustaining transmission. MDA campaigns combining blood- and liver-stage treatment are predicted to be a highly efficacious intervention for reducing P. vivax and P. ovale transmission. ClinicalTrials.gov NCT02143934.


Is there a potential application of a fermented nutraceutical in acute respiratory illnesses? An in-vivo placebo-controlled, cross-over clinical study in different age groups of healthy subjects.
The role of oxidants in viral diseases is fairly complex because it includes metabolic regulation both of host metabolism and viral replication. However, a role for reactive oxygen species (ROS) and reactive nitrogen species (RNS) as mediators of virus-induced lung damage is supported by studies and antioxidants can thus be expected to act at many different levels. The aim of the present pilot study was to test an antioxidant nutraceutical approach on some relevant immunological parameters known to be affected in common seasonal respiratory tract infection. The study population consisted of 90 sedentary healthy patients, previously selected as being GSTM1-positive, divided into three groups: A) 20-40 years; B) 41-65 years; B) over 65 years. Each patients was administered a life style and dietary questionnaire. Subjects were supplemented for 6 weeks with either 9g/day (4.5g twice a day sublingually) of a fermented papaya preparation (Osato Research Institute, Gifu, Japan) or placebo. After a further month period of wash out, subjects were treated again in a crossover manner. Parameters checked were as follows: routine blood tests with WBC formula, saliva flow rate and secretary IgA and lysozyme production and redox gene expression of Phase II enzyme and SOD from upper airways cells (from nasal lavage). Salivary secretion rate showed an age-related decline and was significantly increased by FPP supplementation only in the youngest age-group (p less than 0.05). Subjects treated with FPP showed a significantly higher lever of IgA and lisozyme production., irrespective of age group while their baseline production was significantly lower in the oldest age-group as compared to the youngest one (C vs A, p less than 0.05). FPP treatment brought about a significant upregulation of all phase II enzyme and SOD gene expression tested in nasal lavage cells. In conclusion, FPP supplementation during 1 month resulted in higher salivary IgA and increase in phase II and SOD enzyme expression, i.e the most important antioxidant in the respiratory tract. The biological significance of these effects i.e., whether it will help reducing the whole respiratory oxidative stress in the human airway and, hopefully, the incidence and/or severity of URTI remains to be demonstrated in longer clinical trials.


The Role of Retinal Dopamine in C57BL/6 Mouse Refractive Development as Revealed by Intravitreal Administration of 6-Hydroxydopamine.
Although retinal dopamine (DA) has been long implicated in myopia development, current studies demonstrate that retinal DA levels are unaltered in C57BL/6 mice with form-deprivation myopia. This work was undertaken to explore whether and how refractive development is perturbed in this mouse strain when retinal DA levels are reduced by 6-hydroxydopamine (6-OHDA) administration. On two successive days, 6-OHDA was injected into the vitreous of P18 mice. Retinal DA levels were measured by HPLC and TH levels analyzed by quantitative Western blotting. To choose appropriate 6-OHDA doses that significantly reduce retinal DA levels, but cause minimal disturbance of overall retinal physiology, ERG analysis was performed. Refractive errors were measured using a photorefractor, and ocular biometry performed with optical coherence tomography and photokeratometry. Administration of 6-OHDA of 6.25 μg and 12.5 μg significantly reduced retinal levels of DA and TH, but without affecting ERG a- and b-wave amplitudes. With normal visual experience, 6-OHDA induced myopic refractive shifts in a dose-dependent fashion. Form deprivation induced further myopic shifts in 6-OHDA-injected eyes, but did not cause further decline in retinal DA. Furthermore, 6-OHDA administration resulted in a shorter axial length and a steeper cornea, whereas form deprivation led to a longer axial length, without changing the corneal radius of curvature. Reducing retinal DA levels led to myopic refractive shifts in C57BL/6 mice, which mainly resulted from a steeper cornea. In addition to the DA-independent mechanism for form-deprivation myopia, there is a DA-dependent mechanism in parallel that underlies myopic refractive shifts under normal laboratory conditions in this mouse strain.


Fractional-order information in the visual control of lateral locomotor interception.
Previous work on locomotor interception of a target moving in the transverse plane has suggested that interception is achieved by maintaining the target's bearing angle (often inadvertently confused and/or confounded with the target heading angle) at a constant value. However, dynamics-based model simulations testing the veracity of the underlying control strategy of nulling the rate of change in the bearing angle have been restricted to limited conditions of target motion, and only a few alternatives have been considered. Exploring a wide range of target motion characteristics with straight and curving ball trajectories in a virtual reality setting, we examined how soccer goalkeepers moved along the goal line to intercept long-range shots on goal, a situation in which interception is naturally constrained to movement along a single dimension. Analyses of the movement patterns suggested reliance on combinations of optical position and velocity for straight trajectories and optical velocity and acceleration for curving trajectories. As an alternative to combining such standard integer-order derivatives, we demonstrate with a simple dynamical model that nulling a single informational variable of a self-tuned fractional (rather than integer) order efficiently captures the timing and patterning of the observed interception behaviors. This new perspective could fundamentally change the conception of what perceptual systems may actually provide, both in humans and in other animals. (PsycINFO Database Record


Phloroglucinols from anti-microbial deposit-resins of Australian stingless bees (Tetragonula carbonaria).
Stingless bees accumulate deposits of plant resins that are mixed with beeswax to produce propolis. Previous studies have reported anti-microbial constituents of stingless bee (Tetragonula carbonaria) propolis from East Australia, but several components remained to be characterized. In the search of natural products yet unreported for Australian propolis, four bee deposit-resins of T. carbonaria bees were analysed by gas and liquid chromatography mass spectrometry with accurate mass measurements. Ethanolic extracts of the deposit-resins were tested in vitro against Staphylococcus aureus ATCC 25983 and Pseudomonas aeruginosa ATCC 27853 by the agar diffusion method. Phloroglucinols, flavonoids and isoprenoids were identified in samples. The crude extracts showed strong anti-staphylococcal effects but were less active against the Gram-negative bacterium. The diagnostic data enabled the identification of markers that can be used for profiling other Australian propolis sources and to target the isolation of bioactive phloroglucinols in future studies against antibiotic resistant S. aureus strains.


The non-additive effects of body size on nest architecture in a polymorphic ant.
Like traditional organisms, eusocial insect societies express traits that are the target of natural selection. Variation at the colony level emerges from the combined attributes of thousands of workers and may yield characteristics not predicted from individual phenotypes. By manipulating the ratios of worker types, the basis of complex, colony-level traits can be reduced to the additive and non-additive interactions of their component parts. In this study, we investigated the independent and synergistic effects of body size on nest architecture in a seasonally polymorphic harvester ant, Veromessor pergandei Using network analysis, we compared wax casts of nests, and found that mixed-size groups built longer nests, excavated more sand and produced greater architectural complexity than single-sized worker groups. The nests built by polymorphic groups were not only larger in absolute terms, but larger than expected based on the combined contributions of both size classes in isolation. In effect, the interactions of different worker types yielded a colony-level trait that was not predicted from the sum of its parts. In nature, V. pergandei colonies with fewer fathers produce smaller workers each summer, and produce more workers annually. Because body size is linked to multiple colony-level traits, our findings demonstrate how selection acting on one characteristic, like mating frequency, could also shape unrelated characteristics, like nest architecture.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'.


An instrumental variable approach confirms that the duration of pretransplant dialysis has a negative impact on the survival of kidney transplant recipients and quantifies the risk.
Dialysis prior to kidney transplantation may have a detrimental effect on post-transplant outcomes. However, prior studies have not fully characterized the nature of this relationship and may have been subject to residual confounding. Here we investigated the association between pre-transplant dialysis duration and two post-transplant outcomes: all-cause death and death with functioning graft. This was a retrospective, population-based, cohort study in all deceased donor kidney transplants performed in Ontario, Canada, from April 1, 2002 to March 31, 2013. Patient blood type was chosen as an instrumental variable and a two-stage modeling procedure that included a threshold-adjusted Cox proportional hazards model was used to assess the association between dialysis time and the two post-transplant outcomes. Among 4,440 transplant recipients, the relative risk of all-cause death associated with each dialysis year prior to three years was 42% and fell to 5% per additional dialysis year thereafter. For death with functioning graft, each dialysis year before and after 2.8 years increased the relative risk by 31% and 4%, respectively. Peak panel reactive antibody of more than 50% was independently associated with an elevated risk of death with functioning graft but not with the risk of all-cause death. Thus, our findings highlight the urgency to develop strategies to ensure timely transplant listing and to shorten the total dialysis time before transplantation, with the goal of enhancing kidney transplant outcomes.


Urate oxidase knockdown decreases oxidative stress in a murine hepatic cell line.
Humans, birds, and some primates do not express the uric acid degrading enzyme urate oxidase (UOX) and, as a result, have plasma uric acid concentrations higher than UOX expressing animals. Although high uric acid concentrations are suggested to increase the antioxidant defense system and provide a health advantage to animals without UOX, knockout mice lacking UOX develop pathological complications including gout and kidney failure. As an alternative to the knockout model, RNA interference was used to decrease UOX expression using stable transfection in a mouse hepatic cell line (ATCC, FL83B). Urate oxidase mRNA was reduced 66% (p < 0.05) compared to wild type, as measured by real time RT-PCR. To determine if UOX knockdown resulted in enhanced protection against oxidative stress, cells were challenged with hexavalent chromium (Cr(VI)) or 3-morpholinosydnonimine hydrochloride (SIN-1). Compared to wild type, cells with UOX knockdown exhibited a 37.2 +/- 3.5% reduction (p < 0.05) in the electron spin resonance (ESR) signal after being exposed to Cr(VI) and displayed less DNA fragmentation (p < 0.05) following SIN-1 treatment. Cell viability decreased in wild type cells (p < 0.05), but not cells with UOX knockdown, after treatment with SIN-1. These results are consistent with an increased intracellular uric acid concentration and an increased defense against oxidative stress.


Immunoglobulin-E-mediated reactivity to self antigens: a controversial issue.
Immunoglobulin E (IgE) reactivity to self antigens is well established in vitro by ELISA, inhibition ELISA, Western blot analyses and T cell proliferation experiments. In vivo, IgE-binding self antigens are able to elicit strong type I reactions in sensitized individuals and, in the case of human manganese superoxide dismutase, to elicit eczematous reactions on healthy skin areas of patients suffering from atopic eczema. The reactions against self antigens sharing structural homology with environmental allergens can be plausibly explained by molecular mimicry between common B cell epitopes. For the second class of IgE-binding self antigens without sequence homology to known allergens, it is still unclear if the structures are able to induce a B cell switch to IgE production, or if the reactivity is due to sequence similarity shared with not yet detected environmental allergens. However, in all cases, cross-reactivity is never complete, indicating either a lower affinity of IgE antibodies to self allergens than to the homologous environmental allergens or the presence of additional B cell epitopes on the surface of the environmental allergens, or both. Increasing evidence shows that self allergens could play a decisive role in the exacerbation of long-lasting atopic diseases. However, the only observation supporting a clinical role of IgE-mediated autoreactivity is confined to the fact that IgE levels against self antigens correlate with disease severity.


The Role of Ovotransferrin in Egg-White Antimicrobial Activity: A Review.
Eggs are a whole food which affordably support human nutritional requirements worldwide. Eggs strongly resist bacterial infection due to an arsenal of defensive systems, many of which reside in the egg white. However, despite improved control of egg production and distribution, eggs remain a vehicle for foodborne transmission of Salmonella enterica serovar Enteritidis, which continues to represent a major public health challenge. It is generally accepted that iron deficiency, mediated by the iron-chelating properties of the egg-white protein ovotransferrin, has a key role in inhibiting infection of eggs by Salmonella. Ovotransferrin has an additional antibacterial activity beyond iron-chelation, which appears to depend on direct interaction with the bacterial cell surface, resulting in membrane perturbation. Current understanding of the antibacterial role of ovotransferrin is limited by a failure to fully consider its activity within the natural context of the egg white, where a series relevant environmental factors (such as alkalinity, high viscosity, ionic composition, and egg white protein interactions) may exert significant influence on ovotransferrin activity. This review provides an overview of what is known and what remains to be determined regarding the antimicrobial activity of ovotransferrin in egg white, and thus enhances understanding of egg safety through improved insight of this key antimicrobial component of eggs.


Wendy Johnson: Award for Distinguished Scientific Early Career Contributions to Psychology.
Presents Wendy Johnson, the 2011 winner of the American Psychological Association Award for Distinguished Scientific Early Career Contributions to Psychology. "For innovative research explicating the nature, origin, and consequences of individual differences in intelligence and personality. With methodological rigor and theoretical incisiveness, Wendy Johnson has addressed some of the most vexing questions in the psychology of individual differences. She has shown how genetic and environmental factors jointly influence many important life outcomes, explicated the structure of cognitive abilities, and demonstrated how cognitive ability and personality contribute to gender differences in academic achievement. Her consummate mastery of research methodology, genetics, personality theory, and human abilities has enabled her to advance an integrative program of research that is having a fundamental impact on the field." (PsycINFO Database Record (c) 2011 APA, all rights reserved).


Optimizing the Synthesis of Monodisperse Colloidal Spheres Using Holographic Particle Characterization.
Holographic particle characterization measures the sizes and compositions of individual colloidal particles dispersed in fluid media and rapidly amasses statistics on the distributions of these properties, even for complex heterogeneous dispersions. This information is useful for analyzing and optimizing protocols for synthesizing colloidal particles. We illustrate how holographic characterization can guide process design through a case study on a particularly versatile model system composed of an aqueous dispersion of micrometer-scale spheres synthesized from the organosilane monomer 3-(trimethoxysilyl)propyl methacrylate.


ANIMA: Association network integration for multiscale analysis.
Contextual functional interpretation of -omics data derived from clinical samples is a classical and difficult problem in computational systems biology. The measurement of thousands of data points on single samples has become routine but relating 'big data' datasets to the complexities of human pathobiology is an area of ongoing research. Complicating this is the fact that many publically available datasets use bulk transcriptomics data from complex tissues like blood. The most prevalent analytic approaches derive molecular 'signatures' of disease states or apply modular analysis frameworks to the data. Here we describe ANIMA (association network integration for multiscale analysis), a network-based data integration method using clinical phenotype and microarray data as inputs. ANIMA is implemented in R and Neo4j and runs in Docker containers. In short, the build algorithm iterates over one or more transcriptomics datasets to generate a large, multipartite association network by executing multiple independent analytic steps (differential expression, deconvolution, modular analysis based on co-expression, pathway analysis) and integrating the results. Once the network is built, it can be queried directly using Cypher, or via custom functions that communicate with the graph database via language-specific APIs. We developed a web application using Shiny, which provides fully interactive, multiscale views of the data. Using our approach, we show that we can reconstruct multiple features of disease states at various scales of organization, from transcript abundance patterns of individual genes through co-expression patterns of groups of genes to patterns of cellular behaviour in whole blood samples, both in single experiments as well as in a meta-analysis of multiple datasets.


Chest compression rates during cardiopulmonary resuscitation are suboptimal: a prospective study during in-hospital cardiac arrest.
Recent data highlight a vital link between well-performed cardiopulmonary resuscitation (CPR) and survival after cardiac arrest; however, the quality of CPR as actually performed by trained healthcare providers is largely unknown. We sought to measure in-hospital chest compression rates and to determine compliance with published international guidelines. We developed and validated a handheld recording device to measure chest compression rate as a surrogate for CPR quality. A prospective observational study of adult cardiac arrests was performed at 3 hospitals from April 2002 to October 2003. Resuscitations were witnessed by trained observers using a customized personal digital assistant programmed to store the exact time of each chest compression, allowing offline calculation of compression rates at serial time points. In 97 arrests, data from 813 minutes during which chest compressions were delivered were analyzed in 30-second time segments. In 36.9% of the total number of segments, compression rates were <80 compressions per minute (cpm), and 21.7% had rates <70 cpm. Higher chest compression rates were significantly correlated with initial return of spontaneous circulation (mean chest compression rates for initial survivors and nonsurvivors, 90+/-17 and 79+/-18 cpm, respectively; P=0.0033). In-hospital chest compression rates were below published resuscitation recommendations, and suboptimal compression rates in our study correlated with poor return of spontaneous circulation. CPR quality is likely a critical determinant of survival after cardiac arrest, suggesting the need for routine measurement, monitoring, and feedback systems during actual resuscitation.


Pleasure systems in the brain.
Pleasure is mediated by well-developed mesocorticolimbic circuitry and serves adaptive functions. In affective disorders, anhedonia (lack of pleasure) or dysphoria (negative affect) can result from breakdowns of that hedonic system. Human neuroimaging studies indicate that surprisingly similar circuitry is activated by quite diverse pleasures, suggesting a common neural currency shared by all. Wanting for reward is generated by a large and distributed brain system. Liking, or pleasure itself, is generated by a smaller set of hedonic hot spots within limbic circuitry. Those hot spots also can be embedded in broader anatomical patterns of valence organization, such as in a keyboard pattern of nucleus accumbens generators for desire versus dread. In contrast, some of the best known textbook candidates for pleasure generators, including classic pleasure electrodes and the mesolimbic dopamine system, may not generate pleasure after all. These emerging insights into brain pleasure mechanisms may eventually facilitate better treatments for affective disorders.


Audio-tactile cues from an object's fall change estimates of one's body height.
When we drop an object from our hands, we use internal models of both our body height and object-motion to predict when it will hit the floor. What happens if the sensory feedback finally received from the impact conflicts with this prediction? The present study shows that such conflict results in changes in the internal estimates of our body height: When the object people dropped takes longer than expected to hit the floor, they report feeling taller and behave as if their legs were longer. This provides the first evidence of cross-modal recalibration of body-height representations as a function of changes in the distant environment. Crucially, the recalibration results from a mismatch between the predicted and actual outcome of an action, the ball's release and impact, which are causally-related but separated in space and time. These results suggest that implicit models of object-motion can interact with implicit and explicit models of one's body height.


Chrna5 genotype determines the long-lasting effects of developmental in vivo nicotine exposure on prefrontal attention circuitry.
Maternal smoking during pregnancy repeatedly exposes the developing fetus to nicotine and is linked with attention deficits in offspring. Corticothalamic neurons within layer VI of the medial prefrontal cortex are potential targets in the disruption of attention circuitry by nicotine, a process termed teratogenesis. These prefrontal layer VI neurons would be likely targets because they are developmentally excited and morphologically sculpted by a population of nicotinic acetylcholine receptors (nAChRs) that are sensitive to activation and/or desensitization by nicotine. The maturational effects of these α4β2* nAChRs and their susceptibility to desensitization are both profoundly altered by the incorporation of an α5 subunit, encoded by the chrna5 gene. Here, we investigate nicotine teratogenesis in layer VI neurons of wildtype and α5(-/-) mice. In vivo chronic nicotine exposure during development significantly modified apical dendrite morphology and nAChR currents, compared with vehicle control. The direction of the changes was dependent on chrna5 genotype. Surprisingly, neurons from wildtype mice treated with in vivo nicotine resembled those from α5(-/-) mice treated with vehicle, maintaining into adulthood a morphological phenotype characteristic of immature mice together with reduced nAChR currents. In α5(-/-) mice, however, developmental in vivo nicotine tended to normalize both adult morphology and nAChR currents. These findings suggest that chrna5 genotype can determine the effect of developmental in vivo nicotine on the prefrontal cortex. In wildtype mice, the lasting alterations to the morphology and nAChR activation of prefrontal layer VI neurons are teratogenic changes consistent with the attention deficits observed following developmental nicotine exposure.


5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP-Ribose)Polymerases (PARPs).
5-Aminoisoquinolin-1-one (5-AIQ) is a water-soluble inhibitor of the poly(ADPribose) polymerases (PARPs), lacking isoform-selectivity. Although of only moderate potency in vitro against PARP-1, it is highly active in many assays in cells and in models in vivo, indicating excellent uptake. Optimisation of the several synthetic sequences to 5-AIQ has led to development of a short and efficient route from 1-chloroisoquinoline. It has been used widely as a biochemical and pharmacological tool to study the effects of inhibition of the PARPs. It ameliorates the damage to cells and tissues following reperfusion of ischaemic tissue, showing significant protective activity in a rodent model of haemorrhagic shock at the remarkably low dose of 30 µg Kg(-1). Protection is also seen in models of myocardial infarction, ischaemic kidney and liver disorders, stroke and organ transplantation. Inhibition of PARP-1 by 5-AIQ causes down-regulation of the activity of NF-κB, which then down-regulates the expression of several gene products. Thus 5-AIQ has anti-inflammatory activity in vivo, through modulating the expression of cytokines and adhesion molecules. This indirect inhibition of expression is relevant in the activity of 5-AIQ in models of arthritis, Parkinson's disease, multiple sclerosis, spinal cord injury, periodontitis and inflammatory conditions of the lung. Inhibition of expression of matrix metalloproteinases and other factors gives rise to anti-angiogenic activity and to remarkable anti-metastatic activity in a mouse model. Thus, although it has been overtaken by other PARP-inhibiting drugs in the oncological clinic, 5-AIQ remains a valuable tool to study the roles of PARPs in health and in diverse diseases.


In vitro effects of CpG oligodeoxynucleotides delivered by gelatin nanoparticles on canine peripheral blood mononuclear cells of atopic and healthy dogs - a pilot study.
Cytosine-phosphate-guanine (CpG) oligodeoxynucleotides offer a novel promising immunotherapeutic approach for atopic dermatitis (AD) both in humans and animals. Gelatin nanoparticles (GNP) enhance and prolong CpG-associated immunomodulatory effects and minimize adverse effects both in vitro and in vivo. Information about the effects of this combination in dogs is lacking. The aim of this study was to evaluate immunological effects of CpG coupled to GNP on canine peripheral blood mononuclear cells (PBMCs) in vitro. Eight dogs with AD, diagnosed by standard criteria and with a concurrent immediate hypersensitivity to house dust mites were included. Control samples were taken from eight healthy, age-matched control dogs without history or evidence of cutaneous or systemic illness. Peripheral blood mononuclear cells of healthy and allergic dogs were incubated with CpG-GNP and the uptake of CpG-GNP was demonstrated using confocal laser scanning microscopy. Cell culture supernatant concentrations of interferon gamma (IFN-γ), interleukin (IL)-4, IL-6 and IL-10 were measured by Canine Cytokine Milliplex. No significant changes in IFN-γ and IL-4 were found when comparing PBMCs incubated with CpG and CpG-GNP with the negative controls in atopic and healthy dogs. Interleukin-6 was not detected in any of the groups. However, a statistically significant increase in IL-10 concentration was found after 24 h stimulation with CpG-GNP compared with CpG alone both in atopic and healthy dogs. As IL-10 is considered an immunosuppressive cytokine playing a key role in peripheral tolerance; the reported CpG-GNP formulation could be a new approach in allergy treatment.


Apoptosis of the midline glia during Drosophila embryogenesis: a correlation with axon contact.
We have examined cell death within lineages in the midline of Drosophila embryos. Approximately 50% of cells within the anterior, middle and posterior midline glial (MGA, MGM and MGP) lineages died by apoptosis after separation of the commissural axon tracts. Glial apoptosis is blocked in embryos deficient for reaper, where greater than wild-type numbers of midline glia (MG) are present after stage 12. Quantitative studies revealed that MG death followed a consistent temporal pattern during embryogenesis. Apoptotic MG were expelled from the central nervous system and were subsequently engulfed by phagocytic haemocytes. MGA and MGM survival was apparently dependent upon proper axonal contact. In embryos mutant for the commissureless gene, a decrease in axon-glia contact correlated with a decrease in MGA and MGM survival and accelerated the time course of MG death. In embryos mutant for the slit gene, MGA and MGM maintained contact with longitudinally and contralaterally projecting axons and MG survival was comparable to that in wild-type embryos. The initial number of MG within individual ventral nerve cord segments was increased by ectopic expression of the rhomboid gene, without changing axon number. Extra MGA and MGM were eliminated from the ventral nerve cord by apoptosis to restore wild-type numbers of midline glia. Ectopic rhomboid expression also shifted MGA and MGM cell death to an earlier stage of embryogenesis. One possible explanation is that axon-glia contact or communication promotes survival of the MG and that MG death may result from a competition for available axon contact.


Prevalence and progression of visual impairment in patients newly diagnosed with clinical type 2 diabetes: a 6-year follow up study.
Many diabetic patients fear visual loss as the worst consequence of diabetes. In most studies the main eye pathology is assigned as the cause of visual impairment. This study analysed a broad range of possible ocular and non-ocular predictors of visual impairment prospectively in patients newly diagnosed with clinical type 2 diabetes. Data were from a population-based cohort of 1,241 persons newly diagnosed with clinical, often symptomatic type 2 diabetes aged ≥ 40 years. After 6 years, 807 patients were followed up. Standard eye examinations were done by practising ophthalmologists. At diabetes diagnosis median age was 65.5 years. Over 6 years, the prevalence of blindness (visual acuity of best seeing eye ≤ 0.1) rose from 0.9% (11/1,241) to 2.4% (19/807) and the prevalence of moderate visual impairment (> 0.1; < 0.5) rose from 5.4% (67/1,241) to 6.7% (54/807). The incidence (95% confidence interval) of blindness was 40.2 (25.3-63.8) per 10,000 patient-years. Baseline predictors of level of visual acuity (age, age-related macular degeneration (AMD), cataract, living alone, low self-rated health, and sedentary life-style) and speed of continued visual loss (age, AMD, diabetic retinopathy (DR), cataract, living alone, and high fasting triglycerides) were identified. In a comprehensive assessment of predictors of visual impairment, even in a health care system allowing self-referral to free eye examinations, treatable eye pathologies such as DR and cataract emerge together with age as the most notable predictors of continued visual loss after diabetes diagnosis. Our results underline the importance of eliminating barriers to efficient eye care by increasing patients' and primary care practitioners' awareness of the necessity of regular eye examinations and timely surgical treatment.


Sparc-like protein 1 is a new marker of human glioma progression.
High-grade gliomas (glioblastomas) are the most common and deadly brain tumors in adults, currently with no satisfactory treatment available. Apart from de novo glioblastoma, it is currently accepted that these malignancies mainly progress from lower grade glial tumors. However, the molecular entities governing the progression of gliomas are poorly understood. Extracellular and membrane proteins are key biomolecules found at the cell-to-cell communication interface and hence are a promising proteome subpopulation that could help understand the development of glioma. Accordingly, the current study aims at identifying new protein markers of human glioma progression. For this purpose, we used glial tumors generated orthotopically with T98G and U373 human glioma cells in nude mice. This setup allowed also to discriminate the protein origin, namely, human (tumor) or mouse (host). Extracellular and membrane proteins were selectively purified using biotinylation followed by streptavidin affinity chromatography. Isolated proteins were digested and then identified and quantified employing 2D-nano-HPLC-MS/MS analysis. A total of 23 and 27 up-regulated extracellular and membrane proteins were identified in the T98G and U373 models, respectively. Approximately two-thirds of these were predominantly produced by the tumor, whereas the remaining proteins appeared to be mainly overexpressed by the host tissue. Following extensive validation, we have focused our attention on sparc-like protein 1. This protein was further investigated using immunohistochemistry in a large collection of human glioma samples of different grades. The results showed that sparc-like protein 1 expression correlates with glioma grade, suggesting the possible role for this protein in the progression of this malignancy.


Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial.
As part of the UK NCRI AML17 trial, adult patients with acute myeloid leukemia in remission could be randomized to receive the mammalian target of rapamycin inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse-free survival. At 5 years there was no difference in relapse-free survival [29% versus 40%; odds ratio 1.19 (0.9-1.59) P=0.2], cumulative incidence of relapse [60% versus 54%: odds ratio 1.12 (0.82-1.52): P=0.5] or overall survival [45% versus 58%: odds ratio 1.3 (0.94-1.81): P=0.11]. The independent Data Monitoring Committee advised study termination after randomization of 339 of the intended 600 patients because of excess mortality in the everolimus arm without any evidence of beneficial disease control. The delivery of the everolimus dose was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mammalian target of rapamycin inhibition to chemotherapy provides no benefit.


Using Out-of-Batch Reference Populations to Improve Untargeted Metabolomics for Screening Inborn Errors of Metabolism.
Untargeted metabolomics is an emerging technology in the laboratory diagnosis of inborn errors of metabolism (IEM). Analysis of a large number of reference samples is crucial for correcting variations in metabolite concentrations that result from factors, such as diet, age, and gender in order to judge whether metabolite levels are abnormal. However, a large number of reference samples requires the use of out-of-batch samples, which is hampered by the semi-quantitative nature of untargeted metabolomics data, i.e., technical variations between batches. Methods to merge and accurately normalize data from multiple batches are urgently needed. Based on six metrics, we compared the existing normalization methods on their ability to reduce the batch effects from nine independently processed batches. Many of those showed marginal performances, which motivated us to develop Metchalizer, a normalization method that uses 10 stable isotope-labeled internal standards and a mixed effect model. In addition, we propose a regression model with age and sex as covariates fitted on reference samples that were obtained from all nine batches. Metchalizer applied on log-transformed data showed the most promising performance on batch effect removal, as well as in the detection of 195 known biomarkers across 49 IEM patient samples and performed at least similar to an approach utilizing 15 within-batch reference samples. Furthermore, our regression model indicates that 6.5-37% of the considered features showed significant age-dependent variations. Our comprehensive comparison of normalization methods showed that our Log-Metchalizer approach enables the use out-of-batch reference samples to establish clinically-relevant reference values for metabolite concentrations. These findings open the possibilities to use large scale out-of-batch reference samples in a clinical setting, increasing the throughput and detection accuracy.


Mechanochemical synthesis of chitosan submicron particles from the gladius of Todarodes pacificus.
The present work focused on the synthesis of β-chitosan submicron particles (CSPs) from Todarodes pacificus using mechanochemical techniques. The gladius was submitted to a sequence of mechanical and chemical treatments to synthesize β-chitin (CT), which was further deacetylated to form spherical chitosan submicron particles with an average diameter of ⩽100 nm. The surface morphology of β-chitin and CSPs was observed using electron microscopy. The degree of deacetylation (DD%), evaluated from the absorbance peak of a Fourier Transform Infrared (FTIR) spectrum, was 80 ± 2.5%. Physicochemical characterization exhibited good crystallinity, positive zeta potential and low molecular weight, as well as reduced ash content and high water-binding capacity. CSPs exhibit significant antimicrobial properties toward all tested pathogenic bacterial and fungal microorganisms. Antioxidant analysis revealed high reducing power and excellent scavenging and chelating ability. Hence, CSPs synthesized from gladius of Todarodes pacificus using mechanochemical techniques are promising candidates for biomedical applications.


Utilization of agricultural waste corn cob for the preparation of carbon adsorbent.
In the present study, a series of activated carbons were prepared from agricultural waste corn cob by chemical and physical activations with potassium hydroxide (KOH)/potassium carbonate (K2CO3) and carbon dioxide (CO2). The effect of process variables such as impregnation ratio, impregnation time, activation temperature and soaking time of CO2 was studied in order to relate these preparation parameters with the physical properties of final carbon products. The resulting activated carbons were characterized by nitrogen adsorption-desorption isotherms at 77 K. The surface areas and pore volumes of carbons were estimated by the BET equation, the Langmuir equation and the t-plot method. Under the experimental conditions investigated, the main parameters in the activation of corn cob were found to be the impregnation ratio and activation temperature. The soaking time of CO2 is another important variable, which had a strong effect on the pore volume development. The BET surface area and total pore volume were as large as about 2000 m2/g and about 1.0 cm3/g, respectively. This study showed that the activation of agricultural waste corn cob with KOH/K2CO3 and CO2 was suitable for the preparation of large-surface-area activated carbons.


Efficient coherent combining of widely tunable fiber lasers.
We have experimentally demonstrated coherent combining of 2 and then 4 fiber lasers, with respectively 99% and 95% combining efficiency. The combining method investigated here is based on a multi-arm resonator of interferometric configuration. In spite of its interferometric nature, the multi-arm laser operates without significant power fluctuations, even in an unprotected environment. This occurs when the arm length difference is large enough to introduce spectral modulations of period smaller than the laser bandwidth. We have also experimentally shown that the combining method is compatible with wavelength tuning. A Mach- Zehnder Fiber Laser was tuned over a wide spectral range of 60nm. Theoretically then, we confirm that the combining method can be scaled to a large number of lasers without decreasing the combining efficiency.


Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial.
Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors-exemestane or anastrozole. We postulated that exemestane-a mildly androgenic steroid-might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of -2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than -2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than -2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of -2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than -2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than -2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (-0·92%, 95% CI -2·35 to 0·50 vs -2·39%, 95% CI -3·77 to -1·01; p=0·08). Respective mean loss in the hip was -1·93% (95% CI -2·93 to -0·93) versus -2·71% (95% CI -4·32 to -1·11; p=0·10). Likewise for those who started with T-scores of less than -2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI -0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI -1·45 to 5·63 vs 0·0%, 95% CI -3·67 to 3·66; p=0·28). Patients with baseline T-score of -2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than -2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than -2·0. Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.


Microsatellite genotyping reveals end-Pleistocene decline in mammoth autosomal genetic variation.
The last glaciation was a dynamic period with strong impact on the demography of many species and populations. In recent years, mitochondrial DNA sequences retrieved from radiocarbon-dated remains have provided novel insights into the history of Late Pleistocene populations. However, genotyping of loci from the nuclear genome may provide enhanced resolution of population-level changes. Here, we use four autosomal microsatellite DNA markers to investigate the demographic history of woolly mammoths (Mammuthus primigenius) in north-eastern Siberia from before 60 000 years ago up until the species' final disappearance c.4000 years ago. We identified two genetic groups, implying a marked temporal genetic differentiation between samples with radiocarbon ages older than 12 thousand radiocarbon years before present (ka) and those younger than 9ka. Simulation-based analysis indicates that this dramatic change in genetic composition, which included a decrease in individual heterozygosity of approximately 30%, was due to a multifold reduction in effective population size. A corresponding reduction in genetic variation was also detected in the mitochondrial DNA, where about 65% of the diversity was lost. We observed no further loss in genetic variation during the Holocene, which suggests a rapid final extinction event.


Lactobacillus plantarum AR501 Alleviates the Oxidative Stress of D-Galactose-Induced Aging Mice Liver by Upregulation of Nrf2-Mediated Antioxidant Enzyme Expression.
Lactic acid bacteria (LAB) have been used as ingredients of functional foods to promote health and prevent diseases because of their beneficial effects. This study aimed to investigate the antioxidative effects of LAB on the hepatotoxicity in D-galactose-induced aging mice. LAB were isolated from the traditional Chinese fermented foods and screened by the tolerance of hydrogen peroxide (H2 O2 ). Male ICR (Institute of Cancer Research) mice were subcutaneously injected with D-galactose for 5 weeks and then gastric gavage with LAB for 6 weeks. The results showed that Lactobacillus plantarum AR113 and AR501, and Pediococcu pentosaceus AR243 could tolerate up to 1.5 mM H2 O2 in vitro, and they could live through simulated gastrointestinal tract (GIT) to colonizing the GIT of host. In vivo, oral administration of L. plantarum AR113 and AR501 improved the antioxidant status of D-galactose-induced oxidative stress mice such as alleviated liver damages and reduced abnormal activities of superoxide dismutase, glutathione peroxidase, and catalase to normal levels. In addition, L. plantarum AR501 markedly elevated the gene expression of nuclear factor erythroid-2-related factor 2 and upregulated the expressions of several antioxidant genes such as glutathione reductase, glutathione S-transferase, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, and NAD(P)H quinone oxidoreductase 1 in the liver of an aging mice. Therefore, L. plantarum AR501 could be a good candidate for producing antiaging functional foods.


High prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections among HIV-1 negative men who have sex with men in coastal Kenya.
To assess the burden of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) in high-risk HIV-1 negative men who have sex with men (MSM) in Africa. Before the start of a pre-exposure prophylaxis trial, HIV-1 negative volunteers were screened for sexually transmitted infection (STI) including CT and NG, using a highly sensitive and specific nucleic acid amplification test. Samples positive for CT by Aptima testing, were evaluated for the presence of lymphogranuloma venereum (LGV) serovars using an in-house PCR assay. All men were asked to submit a urine specimen, and all had a rectal swab collected by a clinician. Men were asked if they had dysuria, urethral or rectal discharge, or rectal pain. 43 HIV-1 negative MSM were screened, of whom 13 reported sex with men only; the majority (27/43) reported sex work. One volunteer had dysuria and another, rectal pain. Eleven MSM (26%, 95% CI 14% to 41%) had infections with either or both pathogens. Homosexual men had a higher prevalence of any infection than bisexual men (46% vs 17%, p=0.04), and all cases of rectal infections, including one with CT, two with NG and two with CT/NG co-infection. All patients with CT were negative for LGV. One patient with a rectal NG infection reported rectal pain. A remarkably high burden of STI infection was found among HIV-1 negative MSM. Most (12/13) infections, including three of four rectal NG infections, were subclinical. These findings suggest that high-risk MSM will benefit from effective STI screening in Kenya.


Mental disorders as risk factors for substance use, abuse and dependence: results from the 10-year follow-up of the National Comorbidity Survey.
The comorbidity of mental disorders and substance dependence is well documented, but prospective investigations in community samples are rare. This investigation examines the role of primary mental disorders as risk factors for the later onset of nicotine, alcohol and illicit drug use, abuse and dependence with abuse. The National Comorbidity Survey (NCS) was a nationally representative survey of mental and substance disorders in the United States carried out in 1990-92. The NCS-2 re-interviewed a probability subsample of NCS respondents in 2001-03, a decade after the baseline survey. A total of 5001 NCS respondents were re-interviewed in the NCS-2 (87.6% of baseline sample). Aggregate analyses demonstrated significant prospective risks posed by baseline mental disorders for the onset of nicotine, alcohol and illicit drug dependence with abuse over the follow-up period. Particularly strong and consistent associations were observed for behavioral disorders and previous substance use conditions, as well as for certain mood and anxiety disorders. Conditional analyses demonstrated that many observed associations were limited to specific categories of use, abuse or dependence, including several mental disorders that were non-significant predictors in the aggregate analyses. Many mental disorders are associated with an increased risk of later substance use conditions, but important differences in these associations are observed across the categories of use, abuse and dependence with abuse. These prospective findings have implications for the precision of prevention and treatment strategies targeting substance use disorders.


Feasibility of Motivational Interviewing to Engage Older Inpatients in Fall Prevention: A Pilot Randomized Controlled Trial.
In the current 3-month, two arm, unblinded, single site, pilot randomized controlled trial, 120 high fall risk hospitalized older adults (age ≥65) were contacted, and 67 participants were enrolled. The intervention arm received a brief motivational interviewing (MI) intervention. Both arms received routine hospital fall prevention protocols. Measurements were conducted at baseline, 2 days, 1 week, 1 month, and 3 months. MI intervention took approximately 21 minutes and was provided at beginning proficiency level. Approximately 66% of participants completed 3-month data collection. The intervention group reported a greater decrease in fear of falling after the intervention than the control arm (β = -0.856 vs. β = -0.236) and maintained fall prevention behaviors at 3 months (β = 0.001 vs. β = -0.083) (p < 0.05). The current study found brief MI for fall prevention in acute settings feasible and provided preliminary evidence for a positive impact of MI [Journal of Gerontological Nursing, 45(9), 19-29.].


Genetic signatures of strong recent positive selection at the lactase gene.
In most human populations, the ability to digest lactose contained in milk usually disappears in childhood, but in European-derived populations, lactase activity frequently persists into adulthood (Scrimshaw and Murray 1988). It has been suggested (Cavalli-Sforza 1973; Hollox et al. 2001; Enattah et al. 2002; Poulter et al. 2003) that a selective advantage based on additional nutrition from dairy explains these genetically determined population differences (Simoons 1970; Kretchmer 1971; Scrimshaw and Murray 1988; Enattah et al. 2002), but formal population-genetics-based evidence of selection has not yet been provided. To assess the population-genetics evidence for selection, we typed 101 single-nucleotide polymorphisms covering 3.2 Mb around the lactase gene. In northern European-derived populations, two alleles that are tightly associated with lactase persistence (Enattah et al. 2002) uniquely mark a common (~77%) haplotype that extends largely undisrupted for >1 Mb. We provide two new lines of genetic evidence that this long, common haplotype arose rapidly due to recent selection: (1) by use of the traditional F(ST) measure and a novel test based on p(excess), we demonstrate large frequency differences among populations for the persistence-associated markers and for flanking markers throughout the haplotype, and (2) we show that the haplotype is unusually long, given its high frequency--a hallmark of recent selection. We estimate that strong selection occurred within the past 5,000-10,000 years, consistent with an advantage to lactase persistence in the setting of dairy farming; the signals of selection we observe are among the strongest yet seen for any gene in the genome.


miR-34a and miR-34b/c Suppress Intestinal Tumorigenesis.
The p53-inducible miR-34a and miR-34b/c genes are frequently silenced in colorectal cancer. To address the in vivo relevance of miR-34a/b/c function for suppression of intestinal tumor formation, we generated ApcMin/+ mice with deletions of the miR-34a and/or miR-34b/c genes separately or in combination. Combined deletion of miR-34a/b/c increased the number of intestinal stem cells as well as Paneth and Goblet cells, resulting in enlarged intestinal crypts. miR-34a/b/c-deficient ApcMin/+ mice displayed an increased tumor burden and grade and decreased survival. miR-34a/b/c-deficient adenomas showed elevated proliferation and decreased apoptosis and displayed pronounced bacterial infiltration, which may be due to an observed decrease in infiltrating immune cells and downregulation of barrier proteins. mRNA induction in miR-34a/b/c-deficient tumors was enriched for miR-34a/b/c seed-matching sites and for mRNAs encoding proteins related to epithelial-mesenchymal transition, stemness, and Wnt signaling. Accordingly, cells explanted from miR-34a/b/c-deficient adenomas formed tumor organoids at an increased rate. Several upregulated miR-34 targets displayed elevated expression in primary human colorectal cancers that was associated with lymph-node metastases (INHBB, AXL, FGFR1, and PDFGRB) and upregulation of INHBB and AXL in primary colorectal cancer was associated with poor patient survival. In conclusion, our results show that miR-34a/b/c suppress tumor formation caused by loss of Apc and control intestinal stem cell and secretory cell homeostasis by downregulation of multiple target mRNAs. Cancer Res; 77(10); 2746-58. ©2017 AACR.


Inhibition of direct and indirect TLR-mediated activation of human NK cells by low molecular weight dextran sulfate.
NK cells express toll-like receptors (TLR) that recognize conserved pathogen or damage associated molecular patterns and play a fundamental role in innate immunity. Low molecular weight dextran sulfate (DXS), known to inhibit the complement system, has recently been reported by us to inhibit TLR4-induced maturation of human monocyte-derived dendritic cells (MoDC). In this study, we investigated the capability of DXS to interfere with human NK cell activation triggered directly by TLR2 agonists or indirectly by supernatants of TLR4-activated MoDC. Both TLR2 agonists and supernatants of TLR4-activated MoDC activated NK cells phenotypically, as demonstrated by the analysis of NK cell activation markers (CD56, CD25, CD69, NKp30, NKp44, NKp46, DNAM-1 and NKG2D), and functionally as shown by increased NK cell degranulation (CD107a surface expression) and IFN-gamma secretion. DXS prevented the up-regulation of NK cell activation markers triggered by TLR2 ligands or supernatants of TLR4-activated MoDC and dose-dependently abrogated NK cell degranulation and IFN-gamma secretion. In summary our results suggest that DXS may be a useful reagent to inhibit the direct and indirect TLR-mediated activation of NK cells.


The long-term effects of repetitive mild head injuries in sports.
At least 300 000 sports-related concussions occur in the United States annually. With millions of American athletes, the long-term effects of repeated concussion or mild traumatic brain injury are an important topic. Unfortunately, there is a lack of strong data on the causality or prevalence of long-term effects among athletes. Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative tauopathy, with associated clinical, behavioral, and neuropathological findings, is an important clinical entity in need of further study. Diffusion tensor imaging can elucidate trauma-induced white matter damage, but the diagnosis of CTE cannot be proven until postmortem neuropathology shows characteristic neurofibrillary and astrocytic tangles. Concern exists that athletes subject to repeated concussive and even subconcussive blows may be at risk of CTE, but no definitive data exist due to the difficulty in diagnosis. Animal models suggest that mild traumatic brain injuries lead to primarily a metabolic derangement with increased excitotoxic neurotransmitter release, extracellular potassium, and intracellular calcium. Further understanding of the underlying pathophysiology may eventually lead to better therapeutic and diagnostic options for the treating clinician.


Homogeneous catalysis in supercritical fluids.
Supercritical fluids (SCFs), compounds heated and pressurized beyond the critical point, have many unusual properties. Homogeneous molecular catalysts, which have far greater control over selectivity than heterogeneous solid catalysts, are now being tested in SCFs, and early results show that high rates, improved selectivity, and elimination of masstransfer problems can be achieved. As industry moves away from toxic or environmentally damaging solvents, supercritical carbon dioxide may be an ideal replacement medium for nonpolar or weakly polar chemical processes. More than simply substitutes for nonpolar solvents, SCFs can radically change the observed chemistry. Supercritical carbon dioxide is also an excellent medium for its own fixation, as demonstrated by studies of its hydrogenation.


Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients.
Extranodal marginal zone B-cell lymphoma is the most common orbital tumour. We conducted a retrospective analysis to examine: (i) the impact of initial presentation and staging on outcome and (ii) response to various treatment modalities and the effect of the latter on recurrence. Ninety patients with primary ocular adnexal marginal zone lymphoma (POAML) diagnosed at our institution between 1984 and 2009 were studied. POAML was associated with monoclonal gammopathy (13%) at presentation. Most POAML patients (86%) presented with Ann-Arbor stage I disease. Radiotherapy led to excellent local control, but relapses occurred in 18% of Ann-Arbor stage I patients during a median follow-up of 5 years. Local relapses, including secondary central nervous system (CNS) involvement, were observed in patients receiving radiation doses <30·6 Gy. No differences in relapse rate and survival were observed between patients who did or did not undergo staging bone marrow biopsy. Ann-Arbor stage II-IV disease and high lactate dehydrogenase levels were associated with shorter freedom from progression. In conclusion, POAML is an indolent lymphoma with continuous risk for relapse. Radiation doses of at least 30·6 Gy should be given in Ann-Arbor stage I disease, since lower doses may be more frequently associated with relapses, including CNS relapses.


A Paleolithic-type diet results in iodine deficiency: a 2-year randomized trial in postmenopausal obese women.
Different diets are used for weight loss. A Paleolithic-type diet (PD) has beneficial metabolic effects, but two of the largest iodine sources, table salt and dairy products, are excluded. The objectives of this study were to compare 24-h urinary iodine concentration (24-UIC) in subjects on PD with 24-UIC in subjects on a diet according to the Nordic Nutrition Recommendations (NNR) and to study if PD results in a higher risk of developing iodine deficiency (ID), than NNR diet. A 2-year prospective randomized trial in a tertiary referral center where healthy postmenopausal overweight or obese women were randomized to either PD (n=35) or NNR diet (n=35). Dietary iodine intake, 24-UIC, 24-h urinary iodine excretion (24-UIE), free thyroxin (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) were measured at baseline, 6 and 24 months. Completeness of urine sampling was monitored by para-aminobenzoic acid and salt intake by urinary sodium. At baseline, median 24-UIC (71.0 μg/l) and 24-UIE (134.0 μg/d) were similar in the PD and NNR groups. After 6 months, 24-UIC had decreased to 36.0 μg/l (P=0.001) and 24-UIE to 77.0 μg/d (P=0.001) in the PD group; in the NNR group, levels were unaltered. FT4, TSH and FT3 were similar in both groups, except for FT3 at 6 months being lower in PD than in NNR group. A PD results in a higher risk of developing ID, than a diet according to the NNR. Therefore, we suggest iodine supplementation should be considered when on a PD.


Abatement vs. treatment for efficient diffuse source water pollution management in terrestrial-marine systems.
Marine ecosystems are affected by water pollution originating from coastal catchments. The delivery of water pollutants can be reduced through water pollution abatement as well as water pollution treatment. Hence, sustainable economic development of coastal regions requires balancing of the marginal costs from water pollution abatement and/or treatment and the associated marginal benefits from marine resource appreciation. Water pollution delivery reduction costs are, however, not equal across abatement and treatment options. In this paper, an optimal control approach is developed and applied to explore welfare maximizing rates of water pollution abatement and/or treatment for efficient diffuse source water pollution management in terrestrial-marine systems. For the case of diffuse source dissolved inorganic nitrogen water pollution in the Tully-Murray region, Queensland, Australia, (agricultural) water pollution abatement cost, (wetland) water pollution treatment cost and marine benefit functions are determined to explore welfare maximizing rates of water pollution abatement and/or treatment. Considering partial (wetland) treatment costs and positive water quality improvement benefits, results show that welfare gains can be obtained, primarily, through diffuse source water pollution abatement (improved agricultural management practices) and, to a minor extent, through diffuse source water pollution treatment (wetland restoration).


Polyanionic candidate microbicides accelerate the formation of semen-derived amyloid fibrils to enhance HIV-1 infection.
Polyanionic candidate microbicides, including cellulose sulfate, carrageenan, PRO 2000, were proven ineffective in preventing HIV-1 transmission and even cellulose sulfate showed increased risk of HIV acquisition in the Phase III efficacy trials. Semen plays critical roles in HIV-1 sexual transmission. Specifically, amyloid fibrils formed by fragments of prostatic acidic phosphatase (PAP) in semen termed semen-derived enhancer of virus infection (SEVI) could drastically enhance HIV-1 infection. Here we investigated the interaction between polyanions and PAP248-286, a prototype peptide of SEVI, to understand the possible cause of polyanionic candidate microbicides to fail in clinical trials. We found anionic polymers could efficiently promote SEVI fibril formation, most likely mediated by the natural electrostatic interaction between polyanions and PAP248-286, as revealed by acid native PAGE and Western blot. The overall anti-HIV-1 activity of polyanions in the presence or absence of PAP248-286 or semen was evaluated. In the viral infection assay, the supernatants of polyanions/PAP248-286 or polyanions/semen mixtures containing the free, unbound polyanionic molecules showed a general reduction in antiviral efficacy, while the pellets containing amyloid fibrils formed by the polyanion-bound PAP248-286 showed aggravated enhancement of viral infection. Collectively, from the point of drug-host protein interaction, our study revealed that polyanions facilitate SEVI fibril formation to promote HIV-1 infection, thus highlighting a molecular mechanism underlying the failure of polyanions in clinical trials and the importance of drug-semen interaction in evaluating the anti-HIV-1 efficacy of candidate microbicides.


The effects of caregiver depression on childhood asthma: Pathways and mechanisms.
To review the literature regarding the effects of caregiver depression on childhood asthma and integrate the findings into a multilevel model of pathways by which these effects occur to further the understanding of the complex biopsychosocial nature of childhood asthma and the key role that is played by caregiver depression. PubMed was searched for articles published from 2007 to the present (10-year search), and Google Scholar was searched for articles published in 2017 and 2018 to identify the most recent publications. Studies selected were recent, empirical, or meta-analytic, conducted in humans, and had specific relevance to one or more of the identified pathways. Articles published before 2007 were included if deemed essential because they addressed key pathways, for which there were no more recent articles. Review of the literature substantiates that caregiver depression plays a key role in the socioeconomic, familial, psychological, and biological cascade of effects on childhood asthma. Childhood asthma outcomes are affected indirectly by socioeconomic status and family stress mediated by caregiver depression, which affects disease management, and/or stress and depression in the child, which, in turn, affect asthma through alterations in immune modulation and autonomic regulation. Findings indicate that future research should concentrate on mediators and moderators to further clarify the complex interplay of these factors that affect childhood asthma. The findings also have substantial translational implications. Given that child stress and depression contribute to asthma disease activity and that treating caregiver depression improves child stress and depression, there is strong rationale for treating depressed caregivers of children with asthma as a component means of improving childhood asthma control.


Usefulness of caudomedial-craniolateral oblique radiographic views for the diagnosis of injury to the origin of the cranial cruciate ligament in two horses.
CASE DESCRIPTION A 12-year-old mixed-breed mare (horse 1) and 6-year-old Friesian gelding (horse 2) were examined for chronic lameness associated with the stifle joint. CLINICAL FINDINGS Lameness examination revealed effusion of the right (horse 1) or left (horse 2) femoropatellar and medial femorotibial joints and grade 3/5 (horse 1) or 4/5 (horse 2) lameness. A diagnosis of cranial cruciate ligament (CCL) injury with associated mineralization and avulsion (horse 1) or mineralization alone (horse 2) was facilitated in both horses with a caudomedial-craniolateral oblique radiographic view obtained 45° medial to the caudocranial line, which highlighted the origin of the ligament on the caudoaxial aspect of the lateral femoral condyle within the intercondylar fossa. These lesions were subsequently confirmed via CT. TREATMENT AND OUTCOME Arthroscopy of the medial and lateral femorotibial joints was performed for horse 1 and revealed the osseous fragment associated with the CCL, but the fragment could not be removed. Horse 2 was euthanized while anesthetized following CT owing to the poor prognosis. CONCLUSIONS AND CLINICAL RELEVANCE Radiography is typically the first imaging modality attempted for horses with CCL injury, particularly outside the hospital setting. A 45° caudomedial-craniolateral oblique radiographic view may aid in diagnosis of CCL injury when avulsion or mineralization is present. Although this view is not commonly included in the typical radiographic series for imaging of the stifle joint in horses, it should be considered when CCL injury is suspected.


Seeing Your Foot Move Changes Muscle Proprioceptive Feedback.
Multisensory effects are found when the input from single senses combines, and this has been well researched in the brain. Presently, we examined in humans the potential impact of visuo-proprioceptive interactions at the peripheral level, using microneurography, and compared it with a similar behavioral task. We used a paradigm where participants had either proprioceptive information only (no vision) or combined visual and proprioceptive signals (vision). We moved the foot to measure changes in the sensitivity of single muscle afferents, which can be altered by the descending fusimotor drive. Visual information interacted with proprioceptive information, where we found that for the same passive movement, the response of muscle afferents increased when the proprioceptive channel was the only source of information, as compared with when visual cues were added, regardless of the attentional level. Behaviorally, when participants looked at their foot moving, they more accurately judged differences between movement amplitudes, than in the absence of visual cues. These results impact our understanding of multisensory interactions throughout the nervous system, where the information from different senses can modify the sensitivity of peripheral receptors. This has clinical implications, where future strategies may modulate such visual signals during sensorimotor rehabilitation.


Health issues for surfers.
Surfers are prone to acute injuries as well as conditions resulting from chronic environmental exposure. Sprains, lacerations, strains, and fractures are the most common types of trauma. Injury from the rider's own surfboard may be the prevailing mechanism. Minor wound infections can be treated on an outpatient basis with ciprofloxacin or trimethoprim-sulfamethoxazole. Jellyfish stings are common and may be treated with heat application. Other treatment regimens have had mixed results. Seabather's eruption is a pruritic skin reaction caused by exposure to nematocyst-containing coelenterate larvae. Additional surfing hazards include stingrays, coral reefs, and, occasionally, sharks. Otologic sequelae of surfing include auditory exostoses, tympanic membrane rupture, and otitis externa. Sun exposure and skin cancer risk are inherent dangers of this sport.


HIV vaccine research: the way forward.
The need to broaden research directed at answering fundamental questions in HIV vaccine discovery through laboratory, nonhuman primate (NHP), and clinical research has recently been emphasized. In addition, the importance of attracting and retaining young researchers, developing better NHP models, and more closely linking NHP and clinical research is being stressed. In an era of a level budget for biomedical research at the U.S. National Institutes of Health (NIH), HIV/AIDS vaccine research efforts will need to be carefully prioritized such that resources to energize HIV vaccine discovery can be identified. This article summarizes progress and challenges in HIV vaccine research, the priorities arising from a recent summit at NIAID, and the actions needed, some already under way, to address those priorities.


Zero-broadening SBS slow light propagation in an optical fiber using two broadband pump beams.
A new method of tailoring stimulated Brillouin scattering (SBS) gain spectrum for slow light propagation is proposed by use of two Gaussian-shaped broadband pump beams with different powers and spectral widths. The central frequency interval between the two pump beams are carefully set to be two inherent Brillouin frequency shift, ensuring that the gain spectrum of one pump has the same central frequency with the loss spectrum of the other one. Different gain profiles are obtained and analyzed. Among them a special gain profile is found that ensures a zero-broadening of the signal pulse independent of the Brillouin gain. This is owing to the compensation between the positive gain-dependent broadening and the negative GVD (group velocity dispersion) dependent broadening. The relationship of two pump beams is also found for constructing such a gain profile. It provides us a new idea of managing the broadening of SBS-based slow pulse by artificially constructing and optimizing the profile of gain spectrum.


Pilot study of a new rehabilitation tool: improved unilateral short-term adaptation of the human angular vestibulo-ocular reflex.
Unilateral vestibulo-ocular reflex (VOR) short-term adaptation training causes some increase toward the nonadapting side (~30% of increase on adapting side). We conducted a pilot study to determine if the increase could be reduced by providing a visual stimulus during rotations to the nonadapting side. Unilateral vestibular short-term adaptation is a technique that could increase the ipsilesional VOR response of vestibular patients with unilateral hypofunction. However, this technique results in the VOR response increasing for rotations toward the nonadapting (normal) side, which is undesirable because the VOR will be overcompensatory (causing nonstable vision) during head rotations toward the normal side. We built a portable helmet device that sensed horizontal angular head velocity to generate a visual target that required a preset VOR gain (eye velocity/head velocity) for optimal image stabilization that could be set differently for leftward and rightward head rotations. We tested 10 subjects (six controls and four patients with vestibular hypofunction). We measured the active and passive VOR gain during high-peak-acceleration, unilateral, transient head rotations (head impulses) before and after unilateral VOR adaptation training. In control subjects, for rotations toward the adapting side (target gain = 1.5), the VOR gain increased because of training by 26.1% ± 23.4% during active head impulses and by 14.6% ± 13.0% during passive head impulses. In contrast, for rotations toward the nonadapting side, there were no statistically significant increases. A visual stimulus driving the VOR gain to unity toward the nonadapting side aids unilateral adaptation more so than no visual stimulus.


Changing social norm compliance with noninvasive brain stimulation.
All known human societies have maintained social order by enforcing compliance with social norms. The biological mechanisms underlying norm compliance are, however, hardly understood. We show that the right lateral prefrontal cortex (rLPFC) is involved in both voluntary and sanction-induced norm compliance. Both types of compliance could be changed by varying the neural excitability of this brain region with transcranial direct current stimulation, but they were affected in opposite ways, suggesting that the stimulated region plays a fundamentally different role in voluntary and sanction-based compliance. Brain stimulation had a particularly strong effect on compliance in the context of socially constituted sanctions, whereas it left beliefs about what the norm prescribes and about subjectively expected sanctions unaffected. Our findings suggest that rLPFC activity is a key biological prerequisite for an evolutionarily and socially important aspect of human behavior.


Transcription of the T cell receptor beta-chain gene is controlled by multiple regulatory elements.
The cis-acting sequences regulating transcription of the beta-chain of the TCR have been analyzed and multiple elements identified. The minimum 5' upstream sequence displaying promoter activity is a fragment extending 85 bp upstream of the transcriptional start site. Deletion of an additional 43 bp from the 5' end of this fragment abolished promoter activity. The presence of the conserved TCR beta-chain decanucleotide motif, an AP-1 consensus sequence and an inverted repeat in the deleted region, suggests their role as targets for transacting factors regulating transcription of the beta chain gene. Sequences between -343 and -85 increase transcription from the -85 fragment in T cells. The promoter is active in both T cells and fibroblasts. The enhancer was capable of enhancing TCR V beta 2 promoter activity in both T cells and fibroblasts. Sequences further upstream of the V beta 2 promoter down regulate V beta 2 promoter activity in the absence of the enhancer but its repressive influence is overcome in the presence of the TCR beta-chain enhancer.


Adapting North American wheat production to climatic challenges, 1839-2009.
The Intergovernmental Panel on Climate Change projects that temperatures in the major grain-growing areas of North America will rise by 3-4 °C by 2100. Such abrupt changes will create major challenges, significantly altering the area suitable for wheat. The historical record offers insight into the capability of agriculture to adapt to climatic challenges. Using a new county-level dataset on wheat production and climate norms, we show that during the 19th and 20th centuries North American grain farmers pushed wheat production into environments once considered too arid, too variable, and too harsh to cultivate. As summary measures, the median annual precipitation norm of the 2007 distribution of North American wheat production was one-half that of the 1839 distribution, and the median annual temperature norm was 3.7 °C lower. This shift, which occurred mostly before 1929, required new biological technologies. The Green Revolution associated with the pioneering work of Norman Borlaug represented an important advance in this longer process of biological innovation. However, well before the Green Revolution, generations of North American farmers overcame significant climatic challenges.


Use of Leaf Wetness and Temperature to Time Fungicide Applications to Control Anthracnose Fruit Rot of Strawberry in Florida.
Anthracnose fruit rot (AFR), caused by Colletotrichum acutatum, is a major disease of strawberry in Florida and is generally controlled by weekly fungicide applications. More than 20 applications may be made during the growing season, most commonly using captan and the quinone-outside inhibitors. Field experiments were conducted for three seasons on a susceptible and a partially resistant cultivar to evaluate the effectiveness of timing fungicide applications for managing AFR based on a previously published model by Wilson and associates that uses leaf wetness duration and temperature to predict fruit infection by C. acutatum under controlled conditions. For most treatments, rules were established where captan was applied when the predicted proportion of fruit infected (INF) from the model exceeded 0.15 and pyraclostrobin was applied when INF exceeded 0.5. For one model-timed treatment where captan and pyraclostrobin were applied before symptoms first appeared in the field, disease control was as good as the treatment where calendar weekly applications were made and the model-timed treatment utilized 47% fewer sprays. In treatments where fungicide application began after symptom appearance, the number of applications was reduced further but disease control was 40% less effective. Model-timed fungicide treatments that included pyraclostrobin gave better control than the treatments using captan alone. The model relating leaf wetness and temperature to predict AFR infection can be used effectively in a disease-forecasting system to time fungicide treatments and greatly reduce the number of applications without loss of disease control or yield.


Experimental jet velocity and edge tone investigations on a foot model of an organ pipe.
In order to investigate the physical processes involved in the build-up of the sound signal in a labial organ pipe a pipe foot model has been developed. The main important parameters, such as positions of the lower and upper lips, the wind pressure in the pipe foot, and the width of the flue, can be adjusted by means of this model. Moreover, different types of languids and pipe bodies (resonators) can be attached to the model. For the reason of corresponding to a real metal organ pipe these parts of the model are made of a typical alloy used in organ building. The reproducibility of measurements is provided by the micrometer screws applied for the adjustments. Flow and edge tone measurements are carried out with the help of this model. Velocity measurements with different flue widths show that the exit velocity of the jet corresponds to the Bernoulli-velocity and is asymmetrically contracted. At larger distances (>5 mm) the velocity distribution can be described by a Gauss-function having linearly increasing width. A mathematical relation of the centerline velocity as a function of the cut-up height L is found. The results of edge tone measurements show differences between previous studies and the present one. No frequency stages (and hysteresis phenomena) are found within the investigated pressure and cut-up range; the frequency modes of the edge tone coexist. The measured frequencies can be described by theoretical models.


The ascidian embryo: An experimental system for studying genetic circuitry for embryonic cell specification and morphogenesis.
Ascidians have served as an appropriate experimental system in developmental biology for more than a century. The fertilized egg develops quickly into a tadpole larva, which consists of a small number of tissues including the epidermis, central nervous system with two sensory organs, nerve cord, endoderm, mesenchyme, notochord and muscle. Lineage of these embryonic cells is completely described up to the gastrula stage. These features of the ascidian embryo provide an opportunity to study the mechanisms underlying the differentiation of tissues in development. To understand the molecular basis of ascidian embryogenesis, cloning of various genes has been performed, including those that exhibit a lineage-associated expression pattern and those encoding transcription factors, which are expected to be involved in differentiation of tissues, lineage specification, axis formation and regionalization in developmental fields. Here, we present recent advances in the isolation and characterization of these genes. We emphasize the advantages of the ascidian embryo as an experimental system to study genetic circuitries that are required for cellular differentiation and morphogenesis.


Depressive symptoms and mortality risk in a national sample: confounding effects of health status.
We examined the association between depressive symptoms and all-cause mortality in a population sample. Published findings on the relation between depressive symptoms and mortality risk point to an inconsistent association and one that is likely influenced by health status. Few studies have assessed this relation in randomly selected population samples. Participants were 3617 noninstitutionalized adults, age 25 years or older, from the Americans' Changing Lives Study, an ongoing longitudinal study of a nationally representative sample. Depressive symptoms were measured by the 11-item version of the Center for Epidemiological Studies Depression Scale (CES-D). Cox proportional hazards models estimated the relative risk of mortality as a function of the CES-D scores at baseline. In 7.5 years of follow-up, 542 deaths occurred. Each 1-standard unit increase on the CES-D predicted a 21% increased risk of all-cause mortality, adjusting for age, gender, and race (hazard ratio = 1.21, 95% confidence interval = 1.08 to 1.36, p = .001). This association was weakened somewhat following adjustment for education, income, body mass index, smoking and alcohol consumption (hazard ratio = 1.13, 95% confidence interval = 0.99 to 1.28, p = .06). However, control for self-reported functional limitations or chronic health conditions at baseline effectively eliminated the relationship. Analyses limited to participants with good to excellent health or no functional impairments at baseline showed no association between depressive symptoms and subsequent mortality risk. Secondary analyses showed no association between depressive symptoms and cardiovascular mortality. These findings from a randomly selected, nationally representative sample do not support the hypothesis that depressive symptoms are independently related to mortality in the general population, after adequate adjustment for the confounding effects of physical health status.


Use of D-STAT to prevent bleeding following percutaneous transhepatic intraportal islet transplantation.
An infrequent but nevertheless concerning complication associated with percutaneous transhepatic islet transplantation is bleeding. Historically in 61 procedures at this institution, we experienced four bleeding complications in three patients (6.6%), two requiring blood transfusion (3.3%) and two asymptomatic intraperitoneal bleeds detected sonographically at 24 h postprocedure (3.3%). It is suggested that the source of the majority of these bleeds is the liver parenchymal tract following removal of the infusion catheter combined with a significant dose of heparin administered to prevent portal vein thrombosis. Various techniques have been used to reduce the risk of tract bleeding, including gelfoam, intravascular coils, and cautery. In our experience gelfoam alone has been used to plug the catheter tract (n = 47); however, in the aforementioned three patients, this technique failed, either due to dislodgement of, or bleeding peripheral to, the plug. This article describes the use of D-Stat, a collagen/thrombin paste that is injected into the peripheral tract. In five consecutive cases performed using D-Stat, there has been no bleeding or thromboses detected. D-Stat combined with a single gelfoam plug offers a quick, easy, efficacious way of sealing the entire catheter tract without leaving any permanent hardware in the liver. This new method may simplify tract closure and reduce bleeding complications in islet transplantation.


Information transfer and criticality in the Ising model on the human connectome.
We implement the Ising model on a structural connectivity matrix describing the brain at two different resolutions. Tuning the model temperature to its critical value, i.e. at the susceptibility peak, we find a maximal amount of total information transfer between the spin variables. At this point the amount of information that can be redistributed by some nodes reaches a limit and the net dynamics exhibits signature of the law of diminishing marginal returns, a fundamental principle connected to saturated levels of production. Our results extend the recent analysis of dynamical oscillators models on the connectome structure, taking into account lagged and directional influences, focusing only on the nodes that are more prone to became bottlenecks of information. The ratio between the outgoing and the incoming information at each node is related to the the sum of the weights to that node and to the average time between consecutive time flips of spins. The results for the connectome of 66 nodes and for that of 998 nodes are similar, thus suggesting that these properties are scale-independent. Finally, we also find that the brain dynamics at criticality is organized maximally to a rich-club w.r.t. the network of information flows.


A copper-hydrogen peroxide redox system induces dityrosine cross-links and chemokine oligomerisation.
The activity of the chemoattractant cytokines, the chemokines, in vivo is enhanced by oligomerisation and aggregation on glycosaminoglycan (GAG), particularly heparan sulphate, side chains of proteoglycans. The chemokine RANTES (CCL5) is a T-lymphocyte and monocyte chemoattractant, which has a minimum tetrameric structure for in vivo activity and a propensity to form higher order oligomers. RANTES is unusual among the chemokines in having five tyrosine residues, an amino acid susceptible to oxidative cross-linking. Using fluorescence emission spectroscopy, Western blot analysis and LCMS-MS, we show that a copper/H2O2 redox system induces the formation of covalent dityrosine cross-links and RANTES oligomerisation with the formation of tetramers, as well as higher order oligomers. Amongst the transition metals tested, namely copper, nickel, mercury, iron and zinc, copper appeared unique in this respect. At high (400 μM) concentrations of H2O2, RANTES monomers, dimers and oligomers are destroyed, but heparan sulphate protects the chemokine from oxidative damage, promoting dityrosine cross-links and multimer formation under oxidative conditions. Low levels of dityrosine cross-links were detected in copper/H2O2-treated IL-8 (CXCL8), which has one tyrosine residue, and none were detected in ENA-78 (CXCL5), which has none. Redox-treated RANTES was fully functional in Boyden chamber assays of T-cell migration and receptor usage on activated T-cells following RANTES oligomerisation was not altered. Our results point to a protective, anti-oxidant, role for heparan sulphate and a previously unrecognised role for copper in chemokine oligomerisation that may offer an explanation for the known anti-inflammatory effect of copper-chelators such as penicillamine and tobramycin.


Guidance for the utility of linear models in meta-analysis of genetic association studies of binary phenotypes.
Linear mixed models are increasingly used for the analysis of genome-wide association studies (GWAS) of binary phenotypes because they can efficiently and robustly account for population stratification and relatedness through inclusion of random effects for a genetic relationship matrix. However, the utility of linear (mixed) models in the context of meta-analysis of GWAS of binary phenotypes has not been previously explored. In this investigation, we present simulations to compare the performance of linear and logistic regression models under alternative weighting schemes in a fixed-effects meta-analysis framework, considering designs that incorporate variable case-control imbalance, confounding factors and population stratification. Our results demonstrate that linear models can be used for meta-analysis of GWAS of binary phenotypes, without loss of power, even in the presence of extreme case-control imbalance, provided that one of the following schemes is used: (i) effective sample size weighting of Z-scores or (ii) inverse-variance weighting of allelic effect sizes after conversion onto the log-odds scale. Our conclusions thus provide essential recommendations for the development of robust protocols for meta-analysis of binary phenotypes with linear models.


Femoral preparation in cemented total hip arthroplasty: reaming or broaching?
Surgical techniques continue to be refined to improve the results of primary cemented total hip arthroplasty. Although there has been much research in the areas of cementation and implant design, little work has specifically addressed how bone preparation can be optimized on the femoral side. On the basis of available scientific data, it appears that the broach-only system has several potential advantages over the traditional ream-and-broach technique. Broaching is usually faster, leaves behind more bone stock, and may improve both microinterlock and macrointerlock. Additionally, the excess bone resulting from broaching without reaming does not seem to compromise fixation at the bone-cement interface. Such differences may become even more important as the indications for cemented hip arthroplasty broaden to include increasingly younger and more active patients, because revision in these individuals is likely. In most cases, reaming is probably counterproductive, although it may be advantageous when used to open the femoral canal, to prevent varus stem orientation, and to manage sclerosis or deformity of bone due to a preexisting hip disorder or the presence of internal fixation devices. Regardless of which method is chosen, good bone surface cleansing and cement penetration remain paramount. More studies comparing reamed and nonreamed preparation are necessary to resolve this controversial issue definitively.


Ectopic Thyroid in Stomach; a Case Report.
An ectopic thyroid is a form of thyroid dysgenesis in which an entire or parts of the thyroid gland may be located in another part of the body than what is the usual place. The most frequent location is the base of tongue. Although most cases are asymptomatic, symptoms related to tumor size and its relationship with surrounding tissues, hormonal dysfunction and seldom malignancy may also occur. Any disease affecting the thyroid gland may involve the ectopic thyroid, including malignancy.