Performance-based risk-sharing arrangements-good practices for design, implementation, and evaluation: report of the ISPOR good practices for performance-based risk-sharing arrangements task force.
There is a significant and growing interest among both payers and producers of medical products for agreements that involve a "pay-for-performance" or "risk-sharing" element. These payment schemes-called "performance-based risk-sharing arrangements" (PBRSAs)-involve a plan by which the performance of the product is tracked in a defined patient population over a specified period of time and the amount or level of reimbursement is based on the health and cost outcomes achieved. There has always been considerable uncertainty at product launch about the ultimate real-world clinical and economic performance of new products, but this appears to have increased in recent years. PBRSAs represent one mechanism for reducing this uncertainty through greater investment in evidence collection while a technology is used within a health care system. The objective of this Task Force report was to set out the standards that should be applied to "good practices"-both research and operational-in the use of a PBRSA, encompassing questions around the desirability, design, implementation, and evaluation of such an arrangement. This report provides practical recommendations for the development and application of state-of-the-art methods to be used when considering, using, or reviewing PBRSAs. Key findings and recommendations include the following. Additional evidence collection is costly, and there are numerous barriers to establishing viable and cost-effective PBRSAs: negotiation, monitoring, and evaluation costs can be substantial. For good research practice in PBRSAs, it is critical to match the appropriate study and research design to the uncertainties being addressed. Good governance processes are also essential. The information generated as part of PBRSAs has public good aspects, bringing ethical and professional obligations, which need to be considered from a policy perspective. The societal desirability of a particular PBRSA is fundamentally an issue as to whether the cost of additional data collection is justified by the benefits of improved resource allocation decisions afforded by the additional evidence generated and the accompanying reduction in uncertainty. The ex post evaluation of a PBRSA should, however, be a multidimensional exercise that assesses many aspects, including not only the impact on long-term cost-effectiveness and whether appropriate evidence was generated but also process indicators, such as whether and how the evidence was used in coverage or reimbursement decisions, whether budget and time were appropriate, and whether the governance arrangements worked well. There is an important gap in the literature of structured ex post evaluation of PBRSAs. As an innovation in and of themselves, PBRSAs should also be evaluated from a long-run societal perspective in terms of their impact on dynamic efficiency (eliciting the optimal amount of innovation).


Hemodynamic Effects of Mechanical Circulatory Support Devices in Ventricular Septal Defect.
Ventricular septal defect (VSD) is a lethal complication of acute myocardial infarction (AMI) and is often associated with cardiogenic shock. The optimal form of percutaneous mechanical circulatory support (MCS) for AMI-VSD is unknown. We used a previously validated cardiovascular model to simulate AMI-VSD with parameters adjusted to replicate average hemodynamics reported in the literature, including a pulmonary-to-systemic blood flow ratio of 3.0. We then predicted effects of different types of percutaneous MCS (including intra-aortic balloon pumping, Impella, TandemHeart, and extracorporeal membrane oxygenation) on pressures and flows throughout the cardiovascular system. The simulation replicated all major hemodynamic parameters reported in the literature with AMI-VSD. Inotropes and vasopressors worsened left-to-right shunting, whereas vasodilators decreased shunting at the expense of worsening hypotension. All MCS devices increased forward blood flow and arterial pressure but other effects varied among devices. Impella 5.0 provided the greatest degree of pulmonary capillary wedge pressure reductions and decreased left-to-right shunting. Extracorporeal membrane oxygenation worsened pulmonary capillary wedge pressure and shunting, which could be improved by adding Impella or passive left ventricular vent. Pulmonary-to-systemic blood flow ratio could not be reduced below 2.0, and pulmonary flows remained high with all forms of MCS. Although no form of percutaneous MCS normalized hemodynamics in AMI-VSD, pulmonary capillary wedge pressure and shunting were worsened by extracorporeal membrane oxygenation and improved by Impella. Accordingly, based on hemodynamics alone, Impella provides the optimal form of support in AMI-VSD. However, other factors, including team experience, device availability, potential for tissue ingestion, and clinical characteristics, need to be considered when choosing a percutaneous MCS device for AMI-VSD.


Survival of naphthalene-degrading Pseudomonas putida NCIB 9816-4 in naphthalene-amended soils: toxicity of naphthalene and its metabolites.
Survival of naphthalene-degrading Pseudomonas putida NCIB 9816-4 was measured in nonsterile soil samples (coal tar-contaminated and pristine) with and without added crystalline naphthalene over a period of 21 days. A 2-3 log decrease in cfu occurred in the presence, but not absence, of added naphthalene. We used aqueous suspensions of crystalline naphthalene to explore potential mechanisms of its toxicity on the test bacterium under aerobic conditions. Measurements of dissolved naphthalene in medium indicated that uptake by P. putida NCIB 9816-4 maintained naphthalene at concentrations well below saturation. Accumulation of catechol was documented by high-performance liquid chromatography and gas chromatography/mass spectrometry in the presence of 0.5% (w/v) naphthalene crystals. Transient catechol accumulation was highest when cells entered stationary phase. A decrease in catechol concentration correlated with the development of brown color in the medium. Brown pigment accumulation correlated with a decrease in viable cell counts. These results suggested that catechol, related compounds, and their condensation products can accumulate to toxic levels in stationary phase P. putida NCIB 9816-4 cells. We hypothesize that the same mechanism of toxicity may occur under the nutrient-limited conditions expected in soil.


High prevalence of treponemes in bovine digital dermatitis-a molecular epidemiology.
To validate the epidemiology of Treponema spp. associated with digital dermatitis (DD) a large number of DD samples (n=56) were examined by DNA-DNA dot blot analyses using oligonucleotide probes specific for phylogenetic group I-VII of oral treponemes and DD-associated phylotypes DDKL-4, DDKL-12 and DDKL-20 as well as for T. brennaborense and T. socranskii. Positive hybridisation results were obtained for phylogenetic groups I, II and IV and phylotypes DDKL-4 and DDKL-12. While phylotype DDKL-4 was detected in 100% of the samples treponemes belonging to phylogenetic group TRE I, TRE II and TRE IV were prevalent in nearly 80% of the samples and phylotype DDKL-12 was detected in 66.1% of the samples. Analysis of Treponema groups present concurrently in the same sample revealed that a combination of TRE I-TRE II-TRE IV-DDKL-4 was most prevalent and could be detected in up to 71% of the samples. These data indicate that this combination of different Treponema spp. seems to be the most important one in the pathogenesis of DD. In contrast, T. brennaborense originally isolated from DD material this treponeme was not detected in any of the samples clearly indicating that this species is not absolutely associated with DD and therefore may represent only an incidental treponeme. Fluorescence in situ hybridisation (FISH) obviously highlights the invasive character of DD-associated treponemes. Mainly treponemes belonging to phylogenetic group TRE I and phylotype DDKL-4 were detected in high numbers compared to the total number of bacteria and also in deeper layers of the epithelium at the transition of unaffected and affected tissue. Our results confirm a high prevalence and diversity of Treponema spp. in DD lesions. In addition, our data indicate that certain combinations of Treponema spp. are detected much more frequently than others. Furthermore, Treponema spp. appears at the interface between healthy and diseased tissue underlining their importance for the pathogenesis of DD.


Comparison of geometric uncertainties using electronic portal imaging device in focal three-dimensional conformal radiation therapy using different head supports.
To study the geometric uncertainties in the treatment and evaluate the adequacy of the margins employed for planning target volume (PTV) generation in the treatment of focal conformal radiotherapy (CRT) for patients with brain tumors treated with different head support systems. The study population included 11 patients with brain tumors who were to be treated with CRT. Contrast-enhanced planning CT scan (5-mm spacing and reconstructed to 2 mm) of brain were performed. Five patients were immobilized using neck support only (NR-only) and six patients had neck support with flexion (NRF), the form of immobilization being decided by the likely beam arrangements to be employed for that particular patient. The data was transferred to the planning system (CadPlan) where three-dimensional conformal radiation therapy was planned. Digitally reconstructed radiographs (DRRs) were created for the orthogonal portals with the fixed field sizes of 10 x 10 taken at the isocenter. Treatment verification was done using an amorphous silicon detector portal imaging device for using orthogonal portals and the DRR was used as a reference image. An image matching software was used to match the anatomical landmarks in the DRR and the portal imaging and the displacement of the portals in x, y axis and rotation were noted in the anteroposterior (AP) and lateral images. Electronic portal imaging was repeated twice weekly and an average of 8-14 images per patient was recorded. The mean deviation in all the directions was calculated for the each patient. Comparison of setup errors between the two head support systems was done. A total 224 images were studied in anterior and lateral portals. The patient group with NR-only had 100 images, while the NRF group had 124 images. The mean total error in all patients, NR-only group, and NRF group was 0.33 mm, 0.24 mm, and 0.79 mm in the mediolateral (ML) direction; 1.16 mm, 0.14 mm, and 2.22 mm in the AP direction; and 0.67 mm, 0.31 mm, and 0.96 mm in the superoinferior (SI) direction, respectively. The systematic error (S) in all patients, NR-only group, and NRF group in the ML direction was 0.31 mm, 0.28 mm, and 0.78 mm; 1.29 mm, 0.1 mm, and 2.24 mm in the AP direction; and 0.75 mm, 0.52 mm, and 0.94 mm in the SI direction, respectively. Random error (s) in all patients, NR-only group, and NRF group in the ML direction was 1.25 mm, 1.04 mm, and 1.41 mm; 1.31 mm, 1.36 mm, and 1.28 mm in the AP direction; 1.38 mm, 1.37 mm, and 1.39 mm in the SI direction, respectively. In all patients, the PTV margin with Stroom's formula in the NR-only and NRF group was 1.29 mm and 2.55 mm in the ML, 1.15 mm and 5.38 mm in the AP, and 2.0 mm and 2.85 mm in the SI directions, respectively. A PTV margin of 5 mm appears to be adequate; further reduction to 3 mm may be considered based on our results. Errors were significantly higher in the AP direction with NRF when compared to NR-only. Differential PTV margin may therefore be considered, with more margin in the AP and less in other directions, especially with the use of flexion devices.


Adhesion of Neisseria meningitidis to dermal vessels leads to local vascular damage and purpura in a humanized mouse model.
Septic shock caused by Neisseria meningitidis is typically rapidly evolving and often fatal despite antibiotic therapy. Further understanding of the mechanisms underlying the disease is necessary to reduce fatality rates. Postmortem samples from the characteristic purpuric rashes of the infection show bacterial aggregates in close association with microvessel endothelium but the species specificity of N. meningitidis has previously hindered the development of an in vivo model to study the role of adhesion on disease progression. Here we introduced human dermal microvessels into SCID/Beige mice by xenografting human skin. Bacteria injected intravenously exclusively associated with the human vessel endothelium in the skin graft. Infection was accompanied by a potent inflammatory response with the secretion of human inflammatory cytokines and recruitment of inflammatory cells. Importantly, infection also led to local vascular damage with hemostasis, thrombosis, vascular leakage and finally purpura in the grafted skin, replicating the clinical presentation for the first time in an animal model. The adhesive properties of the type IV pili of N. meningitidis were found to be the main mediator of association with the dermal microvessels in vivo. Bacterial mutants with altered type IV pili function also did not trigger inflammation or lead to vascular damage. This work demonstrates that local type IV pili mediated adhesion of N. meningitidis to the vascular wall, as opposed to circulating bacteria, determines vascular dysfunction in meningococcemia.


Polycystic ovary syndrome: clinical perspectives and management.
The polycystic ovary syndrome (PCOS) is a common hyperandrogenic disorder and is characterized by a constellation of signs and symptoms often in association with a family history of hyperandrogenism and/or PCOS. It is often associated with hyperinsulinism and insulin resistance, which puts patients at risk for possible potential complications including type 2 diabetes mellitus and cardiovascular disease. Clinical signs may be subtle, and biochemical markers most often include an elevation of free testosterone (T) and possibly dehydroepiandrosterone sulfate (DHEAS). The diagnosis should be sought in any woman with hyperandrogenic features so that appropriate treatment may be used. There is often a good therapeutic response of the hirsutism, acne, or oligomenorrhea associated with PCOS. The new modalities that increase insulin sensitivity as well as weight reduction in the obese woman with PCOS may potentially be useful in modifying the potential later complications of this common endocrinopathy of young adult women.


External validation of binary machine learning models for pain intensity perception classification from EEG in healthy individuals.
Discrimination of pain intensity using machine learning (ML) and electroencephalography (EEG) has significant potential for clinical applications, especially in scenarios where self-report is unsuitable. However, existing research is limited due to a lack of external validation (assessing performance using novel data). We aimed for the first external validation study for pain intensity classification with EEG. Pneumatic pressure stimuli were delivered to the fingernail bed at high and low pain intensities during two independent EEG experiments with healthy participants. Study one (n = 25) was utilised for training and cross-validation. Study two (n = 15) was used for external validation one (identical stimulation parameters to study one) and external validation two (new stimulation parameters). Time-frequency features of peri-stimulus EEG were computed on a single-trial basis for all electrodes. ML training and analysis were performed on a subset of features, identified through feature selection, which were distributed across scalp electrodes and included frontal, central, and parietal regions. Results demonstrated that ML models outperformed chance. The Random Forest (RF) achieved the greatest accuracies of 73.18, 68.32 and 60.42% for cross-validation, external validation one and two, respectively. Importantly, this research is the first to externally validate ML and EEG for the classification of intensity during experimental pain, demonstrating promising performance which generalises to novel samples and paradigms. These findings offer the most rigorous estimates of ML's clinical potential for pain classification.


Clinical stem cell therapies for severe autoimmune diseases.
Severe autoimmune diseases (ADs) are a major source of disability and reduced quality of life and may result in shortened life expectancy, particularly in treatment-resistant patients. For several decades, allogeneic and autologous haematopoietic stem cell transplantation (HSCT) has been the focus of scientific investigation as a potential means of delivering 'one-off' intensive treatment in severe ADs. Improvements in the clinical safety of HCST were followed by its increasing use in recent years as an experimental treatment for severe and resistant ADs. European and North American registries have accumulated between one and two thousand procedures. Retrospective analyses and prospective studies have demonstrated the feasibility, safety and initial efficacy data in various ADs. Profound cell biological changes induced by HSCT leading to stabilization or reversal of organ damage have been characterized. These have also shed light on basic disease mechanisms and support investigation of more specific cellular therapy in ADs. There is clear potential for harnessing a profound immunological effect through HSCT. However, there is a need for an ongoing balance against evolving non-transplant treatments for ADs. Ideally, these issues should be resolved in phase III studies, in which HSCT approaches are compared with the best comparator.


Risk factors for transmission of tuberculosis among United States-born African Americans and Whites.
Tuberculosis (TB) patients and their contacts enrolled in nine states and the District of Columbia from 16 December 2009 to 31 March 2011. To evaluate characteristics of TB patients that are predictive of tuberculous infection in their close contacts. The study population was enrolled from a list of eligible African-American and White TB patients from the TB registry at each site. Information about close contacts was abstracted from the standard reports of each site. Close contacts of African-American TB patients had twice the risk of infection of contacts of White patients (adjusted risk ratio [aRR] 2.1, 95%CI 1.3-3.4). Close contacts of patients whose sputum was positive for acid-fast bacilli on sputum smear microscopy had 1.6 times the risk of tuberculous infection compared to contacts of smear-negative patients (95%CI 1.1-2.3). TB patients with longer (>3 months) estimated times to diagnosis did not have higher proportions of infected contacts (aRR 1.2, 95%CI 0.9-1.6). African-American race and sputum smear positivity were predictive of tuberculous infection in close contacts. This study did not support previous findings that longer estimated time to diagnosis predicted tuberculous infection in contacts.


The method of deriving human T-cell clones alters the proportion of IL-10-producing cells.
It is now well documented that the mode of primary stimulation in the mouse determines the ratio of Th1-, Th0- or Th2-type T cells obtained. In this paper we determine whether driving and cloning human peripheral blood mononuclear cells (PBMC) non-specifically with interleukin-2 (IL-2) and/or IL-4 and mitogen, will differentially select T cells for IL-10 production. The presence of IL-2 during culture (with or without IL-4) yielded predominantly Th1-type clones (81% of clones with IL-2 alone and 77% with IL-2 + IL-4) and a low frequency of Th0-type clones (19% of clones with IL-2 and 10% of clones with IL-2 + IL-4), whereas IL-4 alone increased the yield of the IL-4 producing Th0 (35%) clones. The proportions of IL-2-producing clones did not alter with treatment; however, the combination of IL-2 + IL-4 altered the proportions of IL-10-producing clones. 47% of IL-2-cultured cells and 51% of IL-4-cultured cells produced IL-10 respectively, whereas only 22% of clones driven with IL-2 + IL-4 produced detectable levels of IL-10. Thus in the preliminary experiments described here we have demonstrated that the cytokines used to initially drive out human T cells and maintain the T-cell growth can skew the Th1/Th2/Th0 cytokine profiles of the clones obtained from mitogen-stimulated cultures. Moreover and unexpectedly the proportion of IL-10-producing cells is altered. These results are important in interpreting analysis of the cytokine profiles of human T cells and raise questions concerning how we should derive T-cell clones for a cytokine analysis that truly reflects the in vivo situation.


Enhanced lysosomal function is critical for paclitaxel resistance in cancer cells: reversed by artesunate.
The mechanism underlying the resistance of cancer cells to chemotherapeutic drug varies with different cancer cells. Recent evidence shows that lysosomal function is associated with drug resistance of cancer cells. Artesunate, a derivative of artemisinin, displays broad antitumor activity and direct cytotoxicity on various tumor cells. Our previous study shows that artesunate increases autophagosome accumulation, while significantly decreases autolysosome number in cancer cells, suggesting that artesunate might impair the lysosomal function. In this study, we investigated the effects of artesunate on lysosomal function and its relationship with chemotherapeutic drug resistance in cancer cells. We found that the lysosomal function was significantly enhanced in two drug-resistant (A549/TAX and A549/DDP) cells. Furthermore, we showed that the enhanced lysosomal function by overexpression of transcription factor EB (TFEB) significantly increased MCF-7 cells resistance to doxorubicin (DOX), whereas the decreased lysosomal function by TFEB-knockdown or lysosome inhibitor chloroquine increased MCF-7 cells sensitivity to DOX. Treatment of A549/TAX cells with artesunate (2.5-50 μM) dose-dependently inhibited lysosomal function and the clearance of dysfunctional mitochondria, and induced cell apoptosis. Moreover, we demonstrated that artesunate exerted more potent inhibition on the resistant (A549/TAX and MCF-7/ADR) cells with higher activity of lysosomal function. Our results suggest that artesunate or other inhibitors of lysosomal function would be potential in the treatment of cancer cells with drug resistance caused by the enhanced lysosomal function.


Non-psychotropic medication and risk of suicide or attempted suicide: a systematic review.
To establish which non-psychotropic medications have been assessed in relation to risk of suicide or attempted suicide in observational studies, document reported associations and consider study strengths and limitations. Systematic review. Four databases (Embase, Medline, PsycINFO and International Pharmaceutical Abstracts) were searched from 1990 to June 2014, and reference lists of included articles were hand-searched. Case-control, cohort and case only studies which reported suicide or attempted suicide in association with any non-psychotropic medication were included. The outcomes eligible for inclusion were suicide and attempted suicide, as defined by the authors of the included study. Of 11,792 retrieved articles, 19 were eligible for inclusion. Five studies considered cardiovascular medication and antiepileptics; two considered leukotriene receptor antagonists, isotretinoin and corticosteroids; one assessed antibiotics and another assessed varenicline. An additional study compared multiple medications prescribed to suicide cases versus controls. There was marked heterogeneity in study design, outcome and exposure classification, and control for confounding factors; particularly comorbid mental and physical illness. No increased risk was associated with cardiovascular medications, but associations with other medications remained inconclusive and meta-analysis was inappropriate due to study heterogeneity. Whether non-psychotropic medications are associated with increased risk of suicide or attempted suicide remains largely unknown. Robust identification of suicide outcomes and control of comorbidities could improve quantification of risk associated with non-psychotropic medication, beyond that conferred by underlying physical and mental illnesses.


Pharmacological experiments on the binding and internalization of the 50,000 dalton carboxyterminus of tetanus toxin at the cholinergic neuromuscular junction.
Experiments were done to compare the binding and subsequent internalization of the intact tetanus toxin molecule and of the isolated binding component from the molecule (i.e., 50,000 dalton carboxyterminus). In all respects, the isolated component behaved like the intact molecule. Both the holotoxin and the isolated carboxyterminus bind to neuromuscular preparations in a way that is only poorly dissociable. At low temperature (4 degrees C), the holotoxin remains at or near the cell surface and thus remains accessible to the neutralizing effects of polyclonal antibody. At the same temperature, the isolated binding component remains associated with receptors and thus antagonizes binding of the intact toxin. Warming tissues (35 degrees C) slowly promotes internalization of the toxin and of the isolated binding component, and nerve stimulation more rapidly promotes internalization. Ammonium chloride and methylamine hydrochloride antagonize the process by which nerve stimulation promotes internalization of bound protein. Data from chase experiments suggest that the receptor for tetanus toxin either has a relatively rapid turnover rate or exists in relative excess. Data from monoclonal antibody experiments show that, even when the toxin is bound to nerve endings, antibodies directed against epitopes in the carboxyterminus can cause appreciable neutralization. The most important implication of the data is that the isolated carboxyterminus of tetanus toxin can be used as a pharmacological tool to target drugs of interest to nerve endings.


Taste discrimination in conditioned taste aversion of the pond snail Lymnaea stagnalis.
Conditioned taste aversion (CTA) in the pond snail Lymnaea stagnalis has been widely used as a model for gaining an understanding of the molecular and behavioral mechanisms underlying learning and memory. At the behavioral level, however, it is still unclear how taste discrimination and CTA interact. We thus examined how CTA to one taste affected the feeding response induced by another appetitive food stimulus. We first demonstrated that snails have the capacity to recognize sucrose and carrot juice as distinct appetitive stimuli. We then found that snails can become conditioned (i.e. CTA) to avoid one of the stimuli and not the other. These results show that snails can distinguish between appetitive stimuli during CTA, suggesting that taste discrimination is processed upstream of the site where memory consolidation in the snail brain occurs. Moreover, we examined second-order conditioning with two appetitive stimuli and one aversive stimulus. Snails acquired second-order conditioning and were still able to distinguish between the different stimuli. Finally, we repeatedly presented the conditional stimulus alone to the conditioned snails, but this procedure did not extinguish the long-term memory of CTA in the snails. Taken together, our data suggest that CTA causes specific, irreversible and rigid changes from appetitive stimuli to aversive ones in the conditioning procedure.


Interictal burden attributable to episodic headache: findings from the Eurolight project.
Most primary headaches are episodic, and most estimates of the heavy disability burden attributed to headache derive from epidemiological data focused on the episodic subtypes of migraine and tension-type headache (TTH). These disorders give rise directly but intermittently to symptom burden. Nevertheless, people with these disorders may not be symptom-free between attacks. We analysed the Eurolight dataset for interictal burden. Eurolight was a cross-sectional survey using modified cluster sampling from the adult population (18-65 years) in 10 countries of the European Union. We used data from nine. The questionnaire included headache-diagnostic questions based on ICHD-II and several question sets addressing impact, including interictal and cumulative burdens. There were 6455 participants with headache (male 2444 [37.9 %]). Interictal symptoms were reported by 26.0 % of those with migraine and 18.9 % with TTH: interictal anxiety by 10.6 % with migraine and avoidance (lifestyle compromise) by 14.8 %, both much more common than in TTH (3.1 % [OR 3.8] and 4.7 % [OR 3.5] respectively). Mean time spent in the interictal state was 317 days/year for migraine, 331 days/year for TTH. Those who were "rarely" or "never" in control of their headaches (migraine 15.2 %, TTH 9.6 %) had significantly raised odds of interictal anxiety, avoidance and other interictal symptoms. Among those with migraine, interictal anxiety increased markedly with headache intensity and frequency, avoidance less so but still significantly. Lost productive time was associated with high ORs (up to 5.3) of anxiety and avoidance. A third (32.9 %) with migraine and a quarter (26.7 %) with TTH (difference: p < 0.0001) were reluctant to tell others of their headaches. About 10 % with each disorder felt families and friends did not understand their headaches. Nearly 12 % with migraine reported their employers and colleagues did not. Regarding cumulative burden, 11.8 % reported they had done less well in education because of headache, 5.9 % reported reduced earnings and 7.4 % that their careers had suffered. Interictal burden in those with episodic headache is common, more so in migraine than TTH. Some elements have the potential to be profoundly consequential. New methodology is needed to measure interictal burden if descriptions of headache burden are to be complete.


Cuing consumerism: situational materialism undermines personal and social well-being.
Correlational evidence indicates that materialistic individuals experience relatively low levels of well-being. Across four experiments, we found that situational cuing can also trigger materialistic mind-sets, with similarly negative personal and social consequences. Merely viewing desirable consumer goods resulted in increases in materialistic concerns and led to heightened negative affect and reduced social involvement (Experiment 1). Framing a computer task as a "Consumer Reaction Study" led to a stronger automatic bias toward values reflecting self-enhancement, compared with framing the same task as a "Citizen Reaction Study" (Experiment 2). Consumer cues also increased competitiveness (Experiment 3) and selfishness in a water-conservation dilemma (Experiment 4). Thus, the costs of materialism are not localized only in particularly materialistic people, but can also be found in individuals who happen to be exposed to environmental cues that activate consumerism-cues that are commonplace in contemporary society.


Feasibility of Lithium Storage on Graphene and Its Derivatives.
Nanomaterials are anticipated to be promising storage media, owing to their high surface-to-mass ratio. The high hydrogen capacity achieved by using graphene has reinforced this opinion and motivated investigations of the possibility to use it to store another important energy carrier - lithium (Li). While the first-principles computations show that the Li capacity of pristine graphene, limited by Li clustering and phase separation, is lower than that offered by Li intercalation in graphite, we explore the feasibility of modifying graphene for better Li storage. It is found that certain structural defects in graphene can bind Li stably, yet a more efficacious approach is through substitution doping with boron (B). In particular, the layered C3B compound stands out as a promising Li storage medium. The monolayer C3B has a capacity of 714 mAh/g (as Li1.25C3B), and the capacity of stacked C3B is 857 mAh/g (as Li1.5C3B), which is about twice as large as graphite's 372 mAh/g (as LiC6). Our results help clarify the mechanism of Li storage in low-dimensional materials, and shed light on the rational design of nanoarchitectures for energy storage.


Efficacy and safety of mesalazine (Salofalk) in an open study of 20 patients with ankylosing spondylitis.
Mesalazine (Salofalk) was found to be effective and showed low toxicity in patients with inflammatory bowel disease. The association of gut lesions and spondyloarthropathy (SpA) is well known and we studied the efficacy and safety of a relatively high dose of mesalazine in patients with ankylosing spondylitis (AS). In an open study, mesalazine (3-4 g/day) was prescribed for 24 weeks to 20 patients (aged 18-70 yrs) with active AS, defined as the presence of at least one clinical criterion (morning stiffness > 30 min, peripheral synovitis, enthesopathy, or pain score > 2 on a visual analog scale of 10 cm) and one laboratory criterion [erythrocyte sedimentation rate (ESR) > 20 mm/h or C-reactive protein (CRP) > 20 mg/l]. Data on toxicity and disease activity variables (ESR, CRP, BASDAI, BASFI, BASMI, global assessment, and joint count) were obtained at baseline and after 4, 12, and 24 weeks, and analyzed on an intention-to-treat basis. Study patients had a mean age of 41 years, with mean disease duration of 7.9 years and a mean ESR at baseline of 29 mm/h. After a mean of 9.3 weeks (range 2-22), 8 of the 20 patients prematurely stopped the medication because of adverse effects, mainly gastrointestinal complaints. Twelve patients completed the 24 weeks of the study using a mean dose of 3.2 g/day (range 1-4) mesalazine. Analysis of the data showed improvement in ESR, CRP, and physician's global assessment, but only the change in ESR (29 mm/h on baseline and 25 mm/h at week 24) reached statistical significance (p = 0.03). No change was observed in the other disease activity variables. No significant improvement in any disease activity variable of active AS was observed during treatment with Salofalk except for the ESR. Many side effects were seen.


Daily consumption of cranberry improves endothelial function in healthy adults: a double blind randomized controlled trial.
Background: Previous studies indicate cardiovascular health benefits of cranberry juice consumption. However, whether daily consumption of whole cranberries will have sustained vascular benefits in healthy individuals is currently unknown. Objective: To investigate the vascular effects of acute and daily consumption of freeze dried whole cranberry in healthy men and how effects relate to circulating cranberry (poly)phenol metabolites. Methods: A double-blind, parallel-group, randomized controlled trial was conducted in 45 healthy male adults randomly allocated to 1 month daily consumption of either cranberry (9 g powder solubilized in water equivalent to 100 g of fresh cranberries, 525 mg total (poly)phenols) or control (9 g powder, no (poly)phenols). Flow-mediated dilation (FMD, primary outcome), pulse wave velocity (PWV), aortic augmentation index (AIx), blood pressure, heart rate, blood lipids, and blood glucose were assessed at baseline and at 2 h on day 1 and after 1 month. Plasma and 24 h-urine were analyzed before and after treatment using targeted quantitative LC-MS methods including 137 (poly)phenol metabolites. Results: Cranberry consumption significantly increased FMD at 2 h and 1-month (1.1% (95% CI: 1.1%, 1.8%); ptreatment ≤ 0.001; ptreatment × time = 0.606) but not PWV, AIx, blood pressure, heart rate, blood lipids, and glucose. Of the 56 and 74 (poly)phenol metabolites quantified in plasma and urine, 13 plasma and 13 urinary metabolites significantly increased 2 h post-consumption and on day 1, respectively, while 4 plasma and 13 urinary metabolites were significantly higher after 1-month of cranberry consumption, in comparison with control. A multi-variable stepwise linear regression analysis showed that plasma cinnamic acid-4'-glucuronide, 4-hydroxybenzoic acid-3-sulfate, 2,5-dihydroxybenzoic acid, 3'-hydroxycinnamic acid, and 5-O-caffeoylquinic acid were significant independent predictors of 2 h FMD effects (R2 = 0.71), while 3'-hydroxycinnamic acid, 4-methoxycinnamic acid-3'-glucuronide, 3-(4'-methoxyphenyl)propanoic acid 3'-sulfate, and 3-(4'-methoxyphenyl)propanoic acid 3'-glucuronide predicted the 1-month FMD effects (R2 = 0.52). Conclusions: Acute and daily consumption of whole cranberry powder for 1 month improves vascular function in healthy men and this is linked with specific metabolite profiles in plasma. The National Institutes of Health (NIH)-randomized trial records held on the NIH ClinicalTrials.gov website (NCT02764749). https://clinicaltrials.gov/ct2/show/NCT02764749.


Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells.
Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O(6)-methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation. Exposure to IFN-β induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-β sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-β receptors, R1 and R2, are required for IFN-β-mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible to IFN-β sensitization. Gene expression profiling following IFN-β treatment revealed strong upregulation of IFN-β-associated genes, including a proapoptotic gene cluster, but did not alter stemness-associated expression signatures. Caspase activity and inhibition studies revealed the proapoptotic genes to mediate glioma cell sensitization to exogenous death ligands by IFN-β, but not to temozolomide or irradiation, indicating distinct pathways of death sensitization mediated by IFN-β. Thus, IFN-β is a potential adjunct to glioblastoma treatment that may target the GIC population. IFN-β operates independently of MGMT-mediated resistance, classical apoptosis-regulatory networks, and stemness-associated gene clusters.


MosaicIA: an ImageJ/Fiji plugin for spatial pattern and interaction analysis.
Analyzing spatial distributions of objects in images is a fundamental task in many biological studies. The relative arrangement of a set of objects with respect to another set of objects contains information about potential interactions between the two sets of objects. If they do not "feel" each other's presence, their spatial distributions are expected to be independent of one another. Spatial correlations in their distributions are indicative of interactions and can be modeled by an effective interaction potential acting between the points of the two sets. This can be used to generalize co-localization analysis to spatial interaction analysis. However, no user-friendly software for this type of analysis was available so far. We present an ImageJ/Fiji plugin that implements the complete workflow of spatial pattern and interaction analysis for spot-like objects. The plugin detects objects in images, infers the interaction potential that is most likely to explain the observed pattern, and provides statistical tests for whether an inferred interaction is significant given the number of objects detected in the images and the size of the space within which they can distribute. We benchmark and demonstrate the present software using examples from confocal and PALM single-molecule microscopy. The present software greatly simplifies spatial interaction analysis for point patterns, and makes it available to the large user community of ImageJ and Fiji. The presented showcases illustrate the usage of the software.


The Association of the Parent-Child Language Acculturation Gap with Obesity and Cardiometabolic Risk in Hispanic/Latino Youth: Results from the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth).
Hispanic/Latino youth are disproportionately burdened by obesity and have a high prevalence of prediabetes and dyslipidemia. Differences in parent and child acculturation related to language use and preference (i.e., language acculturation) are associated with adverse cardiometabolic health behaviors, but no study has examined associations with cardiometabolic markers. To determine whether discordance in parent-child language acculturation (parent-child acculturation gap) was associated with poor youth cardiometabolic health. Hispanic/Latino 8-16-year-olds (n = 1,466) and parents from the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth) were examined. Mean scores for the Brief ARSMA-II's Anglo (AOS) and Latino (LOS) Orientation Scales represented language acculturation. Cardiometabolic markers included youth body mass index (BMI) percentile, blood pressure percentiles, and dysglycemia and hyperlipidemia measures. Missing data were imputed. Survey-weighted multivariable linear regression examined the association of youth, parent, and youth × parent (the acculturation gap) AOS and LOS scores separately with each cardiometabolic marker. Youth reported greater English and lower Spanish use than parents. Greater discordance in AOS scores was associated with elevated BMI percentile only (p-for-interaction < .01). The LOS acculturation gap was not associated with any outcome. Adjustment for acculturative stress, family functioning and closeness, parenting style, and youth's diet and physical activity did not alter findings. Removal of nonsignificant acculturation gaps did not indicate an association between individual youth or parent AOS or LOS scores and any cardiometabolic marker. Discordance in Hispanic/Latino parent-child dyads' English use may relate to increased risk for childhood obesity. Future studies should identify mediators of this association.


BMP4 regulates the hematopoietic stem cell niche.
Bone morphogenetic protein 4 (BMP4) is required for mesoderm commitment to the hematopoietic lineage during early embryogenesis. However, deletion of BMP4 is early embryonically lethal and its functional role in definitive hematopoiesis is unknown. Consequently, we used a BMP4 hypomorph to investigate the role of BMP4 in regulating hematopoietic stem cell (HSC) function and maintaining steady-state hematopoiesis in the adult. Reporter gene expression shows that Bmp4 is expressed in cells associated with the hematopoietic microenvironment including osteoblasts, endothelial cells, and megakaryocytes. Although resting hematopoiesis is normal in a BMP4-deficient background, the number of c-Kit+, Sca-1+, Lineage- cells is significantly reduced. Serial transplantation studies reveal that BMP4-deficient recipients have a microenvironmental defect that reduces the repopulating activity of wild-type HSCs. This defect is even more pronounced in a parabiosis model that demonstrates a profound reduction in wild-type hematopoietic cells within the bone marrow of BMP4-deficient recipients. Furthermore, wild-type HSCs that successfully engraft into the BMP4-deficient bone marrow show a marked decrease in functional stem cell activity when tested in a competitive repopulation assay. Taken together, these findings indicate BMP4 is a critical component of the hematopoietic microenvironment that regulates both HSC number and function.


Haptoglobin elutes from human atherosclerotic coronary arteries--a potential marker of arterial pathology.
Molecules which egress from atherosclerotic arteries may function as plasma markers of arterial pathology, but such egress has not been proven with living human coronary arteries. We hypothesised that proteins eluting from the arterial wall may discriminate between atherosclerotic and non-atherosclerotic coronary arteries. During cardiac bypass surgery, 155 sequential fractions of antegradely flushed coronary cardioplegia solution were collected by balloon-cuffed catheter from the coronary sinus in subjects with angiographically extensive (n=30) or minor (n=7) coronary disease. Although plasma was the major source of protein in heavily blood-contaminated samples, under conditions of low blood contamination (<0.5 mg/ml red cell Haemoglobin) coronary circulation-derived protein was detected. N-terminal sequencing of a major 40 kDa band detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated 100% homology with beta chain of Haptoglobin (Hpt). Comparison of perfusates from patients with and without significant coronary disease found that the concentration of Hpt was markedly increased in perfusates from atherosclerotic coronary arteries (0.099+/-0.017 microg Hpt/microg Hb) relative to controls (0.016+/-0.008 microg Hpt/microg Hb, P=0.0027). Analysis of peripheral plasma samples of the same subjects, and of a separate cohort of patients, confirmed greater Hpt in those with angiographic coronary disease than in those without disease. Proteins such as Hpt elute from the human coronary vascular bed and may differentiate between arteries with minor or extensive atherosclerosis. Although the suitability of Hpt as a circulating plasma marker for atherosclerosis remains to be established, the approach used in the present study may permit identification of diverse plasma-detectable markers of atherosclerosis, and the subsequent non-invasive evaluation of in vivo arterial pathology.


Lifestyle interventions for the treatment of urinary incontinence in adults.
Low cost, non-invasive alterations in lifestyle are frequently recommended by healthcare professionals or those presenting with incontinence. However, such recommendations are rarely based on good evidence. The objective of the review was to determine the effectiveness of specific lifestyle interventions (i.e. weight loss; dietary changes; fluid intake; reduction in caffeinated, carbonated and alcoholic drinks; avoidance of constipation; stopping smoking; and physical activity) in the management of adult urinary incontinence. We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE in process, and handsearching of journals and conference proceedings (searched 3 July 2013), and the reference lists of relevant articles. We incorporated the results of these searches fully in the review. We undertook an updated search of the Specialised Register, which now includes searches of ClinicalTrials.gov and WHO ICTRP, on 27 October 2014; potentially eligible studies from this search are currently awaiting classification. Randomised and quasi-randomised studies of community-based lifestyle interventions compared with no treatment, other conservative therapies, or pharmacological interventions for the treatment of urinary incontinence in adults. Two authors independently assessed study quality and extracted data. We collected information on adverse effects from the trials. Data were combined in a meta-analysis when appropriate. We assessed the quality of the evidence using the GRADE approach. We included 11 trials in the review, involving a total of 5974 participants.Four trials involving 4701 women compared weight loss programmes with a control intervention. Low quality evidence from one trial suggested that more women following weight loss programmes reported improvement in symptoms of incontinence at six months (163/214 (76%) versus 49/90 (54%), risk ratio (RR) 1.40, 95% confidence interval (CI) 1.14 to 1.71), and this effect was sustained at 18 months (N = 291, 75% versus 62%, RR not estimable, reported P value 0.02). No data were available for self-reported cure and quality of life. One of the weight loss trials involving 1296 women reported very low quality evidence for a reduction in weekly urinary incontinence a mean of 2.8 years after following a lifestyle weight loss intervention that had been compared with a pharmacological weight loss intervention.Three trials involving 181 women and 11 men compared change in fluid intake with no change. Limited, very low quality evidence suggested that symptom-specific quality of life scores improved when fluid intake was reduced, although some people reported headaches, constipation or thirst. A further three trials involving 160 women and nine men compared reduction in caffeinated drinks with no change, and one trial involving 42 women compared a soy-rich diet with soy-free diet. However, it was not possible to reach any conclusions about the effects of these changes, due to methodological limitations, that resulted in very low quality evidence.Adverse effects appeared relatively uncommon for all interventions studied.All included studies had a high or unclear risk of bias across all bias parameters, but most notably for allocation concealment. The main factors for our downgrading of the evidence were risk of bias, indirect evidence (less than 12 months of follow-up; and not all participants having confirmed urinary incontinence at baseline in some studies), and imprecise results with wide confidence intervals.Other interventions such as reduction in consumption of sweetened fizzy or diet drinks; reduction in alcohol consumption; avoiding constipation; smoking cessation; restricting strenuous physical forces; or reducing high levels of, or increasing low levels of, physical activity, could not be assessed in this review, as no evidence from randomized controlled trials or quasi-randomised trials was available. Evidence for the effect of weight loss on urinary incontinence is building and should be a research priority. Generally, there was insufficient evidence to inform practice reliably about whether lifestyle interventions are helpful in the treatment of urinary incontinence.


Selectivity of post-translational modification in biotinylated proteins: the carboxy carrier protein of the acetyl-CoA carboxylase of Escherichia coli.
Biotin-dependent enzymes contain a biotinyl-lysine residue in a conserved sequence motif, MKM, located in a surface hairpin turn in one of the two beta-sheets that make up the domain. A sub-gene encoding the 82-residue C-terminal biotinyl domain from the biotin carboxy carrier protein of acetyl-CoA carboxylase from Escherichia coli as a fusion protein with glutathione S-transferase was created and over-expressed in E. coli. The biotinyl domain was readily released by cleavage with thrombin. Five mutant domains were created in which the conserved MKM motif was systematically replaced: by MAK and KAM, in which the target lysine is moved one place; by KKM and MKK, in which a second potential site for biotinylation is introduced; and by DKA, the motif found in the correspondingly conserved site of lipoylation in the structurally related lipoyl domains of 2-oxo acid dehydrogenase multienzyme complexes. No biotinylation of the MAK or KAM mutants was observed in vivo or by purified biotinyl protein ligase in vitro; in the KKM and MKK mutants, only one lysine residue, presumed to be that in its native position in the hairpin turn, was found to be biotinylated in vivo and in vitro. The DKA mutant was not biotinylated in vivo, but was partly lipoylated and octanoylated. It was also a poor substrate for lipoylation in vitro catalysed by the E. coli lipoyl protein ligase encoded by the lplA gene. The flanking sequence in the MKM motif is important, but not crucial, and appears to have been conserved in part to be compatible with the subsequent carboxylation reactions of biotin-dependent enzymes. The DKA motif, displayed in the hairpin loop, is sufficient to address lipoylation in E. coli but probably by a pathway different from that mediated by the lplA-dependent ligase. The recognition of the structurally homologous lipoyl and biotinyl domains by the appropriate ligase evidently has a major structural component to it, notably the positioning of the target lysine residue in the exposed hairpin loop, but there appear to be additional recognition sites elsewhere on the domains.


Polymorphisms in the vitamin A receptor and innate immunity genes influence the antibody response to rubella vaccination.
Genetic polymorphisms play an important role in rubella vaccine-induced immunity. We genotyped 714 healthy children after 2 age-appropriate doses of rubella-containing vaccine for 142 potential single-nucleotide polymorphisms (SNPs). Specific polymorphisms in the vitamin A receptor, retinoic acid-inducible gene I (RIG-I), and tripartite motif 5 and 22 (TRIM5 and TRIM22) genes were significantly associated with rubella vaccine humoral immunity. The minor allele of the rs4416353 in the vitamin A receptor gene was associated with an allele dose-related decrease (P = .019) in rubella antibody response. The minor allele of rs6793694, in the vitamin A receptor gene, was associated with an allele dose-related antibody decrease (p = .039). The minor variant of nonsynonymous SNP rs10813831 (Arg7Cys) in the RIG-I gene was associated with an allele dose-related decrease in rubella antibody level from 37.4 to 28.0 IU/mL (P = .035), whereas increased representation of the minor allele of the 5'UTR SNP (rs3824949, P = .015) in the antiretroviral TRIM5 gene was associated with an allele dose-related increase in rubella antibody. It is of particular interest that the nonsynonymous SNP rs3740996 (His43Tyr) in the TRIM5 gene was associated with variations in rubella antibody response (P = .016) after having been previously found to play a significant functional role. These findings further expand our immunogenetic understanding of mechanisms of rubella vaccine-induced immunity.


Polar decomposition of the Mueller matrix: a polarimetric rule of thumb for square-profile surface structure recognition.
In this research, the polar decomposition (PD) method is applied to experimental Mueller matrices (MMs) measured on two-dimensional microstructured surfaces. Polarization information is expressed through a set of parameters of easier physical interpretation. It is shown that evaluating the first derivative of the retardation parameter, δ, a clear indication of the presence of defects either built on or dug in the scattering flat surface (a silicon wafer in our case) can be obtained. Although the rule of thumb thus obtained is established through PD, it can be easily implemented on conventional surface polarimetry. These results constitute an example of the capabilities of the PD approach to MM analysis, and show a direct application in surface characterization.


Use of blood glucose data by families of children and adolescents with IDDM.
Prospective evaluation of the use of blood glucose test results for treatment actions by families of youth with IDDM. Forty-seven patients with IDDM used reflectance meters with memory for SMBG for 28 days. Parents kept weekly diaries of six types of uses of SMBG data. We collected SMBG data from the reflectance meters, HbA1 and serum fructosamine assays, and measures of behavioral factors that could affect use of SMBG data. Families recorded a mean of 4.85 data-based actions during the 28-day study, and 74% of the families reported at least one such action. Fifty percent of recorded actions consisted of management of hypoglycemia and, among the remainder, only 18% were anticipatory, proactive actions. Partial correlation analysis showed that families with more frequent use of SMBG data had less parent-child conflict about diabetes, more diabetes knowledge, and better overall treatment adherence. Use of SMBG data was unrelated to objective indices of the need for treatment adjustments or to diabetic control. Most families made active use of their SMBG data, but few of these actions were proactive. Behavioral factors were stronger predictors of family use of SMBG data than were objective indices of the need for treatment adjustments. The results illustrate the need for further research on use of SMBG data and methods to enhance its impact on diabetic control.


When should functional neuroimaging techniques be used in the diagnosis and management of Alzheimer's dementia? A decision analysis.
Functional neuroimaging, including positron emission tomography (PET), has been proposed for use in diagnosing Alzheimer's disease-related dementia (AD). The objective of this study was identify the circumstances under which PET scanning for the diagnosis of AD maximizes health outcomes. A Markov-model-based decision analysis was conducted using estimates derived from the literature on AD epidemiology, the accuracy of PET, and donepezil treatment efficacy. The target population for the analysis was assumed to be US men and women who either have mild AD or are asymptomatic but at an elevated risk of developing AD owing to disease in a first-degree relative (parent or sibling). The time horizon was the patient lifetime. We compared treatment 1) based on an American Academy of Neurology (AAN) clinical evaluation either alone; 2) in combination with PET scanning; or 3) empirically based on a family history. Outcomes measures were life expectancy, quality-adjusted life-years (QALYs), and (severe) dementia-free life expectancy (SDFLE). For both patient populations, treating all patients based on an AAN evaluation without further testing using PET resulted in the greatest gains in life expectancy, QALYs, and SDFLEs. PET-based testing was the second preferred strategy compared to no intervention. The rankings of the strategies were sensitive to severity of treatment complications: analyses of hypothetical treatments with the potential for severe complications indicated that testing was preferred if the treatment was effective but had moderate complications. These results suggest that current treatments, which are relatively benign and may slow progression of disease, should be offered to patients who are identified as having AD based solely on an AAN clinical evaluation. A clinical evaluation that includes functional neuroimaging based testing will be warranted, however, when new treatments that are effective at slowing disease progression but have the potential for moderate to severe complications become available.


Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial.
There is a growing literature on the biological and clinical effects of pulsed electromagnetic fields. Some studies suggest that electromagnetic therapies may be useful in the treatment of chronic illnesses. This study is a follow-up to a placebo controlled pilot study in which multiple sclerosis (MS) patients exposed to weak, extremely low frequency pulsed electromagnetic fields showed significant improvements on a composite symptom measure. To evaluate the effects of a pulsed electromagnetic therapy on MS related fatigue, spasticity, bladder control, and overall quality of life. A multi-site, double-blind, placebo controlled, crossover trial. Each subject received 4 weeks of the active and placebo treatments separated by a 2-week washout period. The University of Washington Medical Center in Seattle Wash, the Neurology Center of Fairfax in Fairfax, Va, and the headquarters of the Multiple Sclerosis Association of America in Cherry Hill, NJ. 117 patients with clinically definite MS. Daily exposure to a small, portable pulsing electromagnetic field generator. The MS Quality of Life Inventory (MSQLI) was used to assess changes in fatigue, bladder control, spasticity, and a quality of life composite. Paired t-tests were used to assess treatment differences in the 117 subjects (81% of the initial sample) who completed both treatment sessions. Improvements in fatigue and overall quality of life were significantly greater on the active device. There were no treatment effects for bladder control and a disability composite, and mixed results for spasticity. Evidence from this randomized, double-bind, placebo controlled trial is consistent with results from smaller studies suggesting that exposure to pulsing, weak electromagnetic fields can alleviate symptoms of MS. The clinical effects were small, however, and need to be replicated. Additional research is also needed to examine the possibility that ambulatory patients and patients taking interferons for their MS may be most responsive to this kind of treatment.


Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane.
Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR.


Reduced Levels of Cerebrospinal Fluid/Plasma Aβ40 as an Early Biomarker for Cerebral Amyloid Angiopathy in RTg-DI Rats.
The accumulation of fibrillar amyloid β-protein (Aβ) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer's disease. Presently, the clinical diagnosis of this condition relies on neuroimaging markers largely associated with cerebral macro/microbleeds. However, these are markers of late-stage disease detected after extensive cerebral vascular amyloid accumulation has become chronic. Recently, we generated a novel transgenic rat model of CAA (rTg-DI) that recapitulates multiple aspects of human CAA disease with the progressive accumulation of cerebral vascular amyloid, largely composed of Aβ40, and the consistent emergence of subsequent microbleeds. Here, we investigated the levels of Aβ40 in the cerebrospinal fluid (CSF) and plasma of rTg-DI rats as CAA progressed from inception to late stage disease. The levels of Aβ40 in CSF and plasma precipitously dropped at the early onset of CAA accumulation at three months of age and continued to decrease with the progression of disease. Notably, the reduction in CSF/plasma Aβ40 levels preceded the emergence of cerebral microbleeds, which first occurred at about six months of age, as detected by in vivo magnetic resonance imaging and histological staining of brain tissue. These findings support the concept that reduced CSF/plasma levels of Aβ40 could serve as a biomarker for early stage CAA disease prior to the onset of cerebral microbleeds for future therapeutic intervention.


Neural organization of the median ocellus of the dragonfly. II. Synaptic structure.
Two types of presumed synaptic contacts have been recognized by electron microscopy in the synaptic plexus of the median ocellus of the dragonfly. The first type is characterized by an electron-opaque, button-like organelle in the presynaptic cytoplasm, surrounded by a cluster of synaptic vesicles. Two postsynaptic elements are associated with these junctions, which we have termed button synapses. The second synaptic type is characterized by a dense cluster of synaptic vesicles adjacent to the presumed presynaptic membrane. One postsynaptic element is observed at these junctions. The overwhelming majority of synapses seen in the plexus are button synapses. They are found most commonly in the receptor cell axons where they synaptically contact ocellar nerve dendrites and adjacent receptor cell axons. Button synapses are also seen in the ocellar nerve dendrites where they appear to make synapses back onto receptor axon terminals as well as onto adjacent ocellar nerve dendrites. Reciprocal and serial synaptic arrangements between receptor cell axon terminals, and between receptor cell axon terminals and ocellar nerve dendrites are occasionally seen. It is suggested that the lateral and feedback synapses in the median ocellus of the dragonfly play a role in enhancing transients in the postsynaptic responses.


Least-squares analysis of the Mueller matrix.
In a single-mode fiber excited by light with a fixed polarization state, the output polarizations obtained at two different optical frequencies are related by a Mueller matrix. We examine least-squares procedures for estimating this matrix from repeated measurements of the output Stokes vector for a random set of input polarization states. We then apply these methods to the determination of polarization mode dispersion and polarization-dependent loss in an optical fiber. We find that a relatively simple formalism leads to results that are comparable with those of far more involved techniques.


Cost-Effectiveness Analysis of Surgical versus Medical Treatment of Prolactinomas.
Background Few studies address the cost of treating prolactinomas. We performed a cost-utility analysis of surgical versus medical treatment for prolactinomas. Materials and Methods We determined total hospital costs for surgically and medically treated prolactinoma patients. Decision-tree analysis was performed to determine which treatment produced the highest quality-adjusted life years (QALYs). Outcome data were derived from published studies. Results Average total costs for surgical patients were $19,224 ( ± 18,920). Average cost for the first year of bromocriptine or cabergoline treatment was $3,935 and $6,042, with $2,622 and $4,729 for each additional treatment year. For a patient diagnosed with prolactinoma at 40 years of age, surgery has the lowest lifetime cost ($40,473), followed by bromocriptine ($41,601) and cabergoline ($70,696). Surgery also appears to generate high health state utility and thus more QALYs. In sensitivity analyses, surgery appears to be a cost-effective treatment option for prolactinomas across a range of ages, medical/surgical costs, and medical/surgical response rates, except when surgical cure rates are ≤ 30%. Conclusion Our single institution analysis suggests that surgery may be a more cost-effective treatment for prolactinomas than medical management for a range of patient ages, costs, and response rates. Direct empirical comparison of QALYs for different treatment strategies is needed to confirm these findings.


Methods for Early Control of Abdominal Hemorrhage: An Assessment of Potential Benefit.
Noncompressible truncal hemorrhage (NCTH) after injury is associated with a mortality increase that is unchanged during the past 20 years. Current treatment consists of rapid transport and emergent intervention. Three early hemorrhage control interventions that may improve survival are placement of a resuscitative endovascular balloon occlusion of the aorta (REBOA), injection of intracavitary self-expanding foam, and application of the Abdominal Aortic Junctional Tourniquet (AAJT™). The goal of this work was to ascertain whether patients with uncontrolled abdominal or pelvic hemorrhage might benefit by the early or prehospital use of one of these interventions. This was a single-center retrospective study of patients who received a trauma laparotomy from 2013 to 2015. Operative reports were reviewed. The probable benefit of each hemorrhage control method was evaluated for each patient based on the location(s) of injury and the severity of their physiologic derangement. The potential scope of applicability of each control method was then directly compared. During the study period, 9,608 patients were admitted; 402 patients required an emergent trauma laparotomy. REBOA was potentially beneficial for hemorrhage control in 384 (96%) of patients, foam in 351 (87%), and AAJT in 35 (9%). There was no statistically significant difference in the potential scope of applicability between REBOA and foam (ρ = .022). There was a significant difference between REBOA and AAJT (ρ < .001) and foam and AAJT™ (ρ < .001). The external surface location of signs of injury did not correlate with the internal injury location identified during laparotomy. Early use of REBOA and foam potentially benefits the largest number of patients with abdominal or pelvic bleeding and may have widespread applicability for patients in the preoperative, and potentially the prehospital, setting. AAJT may be useful with specific types of injury. The site of bleeding must be considered before the use of any of these tools.


Implementation of wavelength reusing upstream service based on distributed intensity conversion in ultrawideband-over-fiber system.
We propose and demonstrate a simple scheme for generating the ultrawideband (UWB) signals and reusing the wavelength for upstream service simultaneously by using a distributed polarization modulation-to-intensity modulation convertor. Through adjusting the static phase difference between transverse electric and transverse magnetic modes of the optical carrier (OC) and the angle between the polarization direction of the OC and the principal axis of the polarizers, the UWB doublet-like signals were generated. Meanwhile, the error-free transmission of the upstream signals with bit rate of 1.25 Gbit/s over 10 km fiber is achieved. The power penalty resulting from the interference of downstream signals is less than 0.3 dB.


Current views on genetics and epigenetics of cholesterol gallstone disease.
Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.


Contrasting predictors of poor antiretroviral therapy outcomes in two South African HIV programmes: a cohort study.
Many national antiretroviral therapy (ART) programmes encourage providers to identify and address baseline factors associated with poor treatment outcomes, including modifiable adherence-related behaviours, before initiating ART. However, evidence on such predictors is scarce, and providers judgement may often be inaccurate. To help address this evidence gap, this observational cohort study examined baseline factors potentially predictive of poor treatment outcomes in two ART programmes in South Africa, with a particular focus on determinants of adherence. Treatment-naïve patients starting ART were enrolled from a community and a workplace ART programme. Potential baseline predictors associated with poor treatment outcomes (defined as viral load > 400 copies/ml or having discontinued treatment by six months) were assessed using logistic regression. Exposure variables were organised for regression analysis using a hierarchical framework. 38/227 (17%) of participants in the community had poor treatment outcomes compared to 47/117 (40%) in the workplace. In the community, predictors of worse outcomes included: drinking more than 20 units of alcohol per week, having no prior experience of chronic medications, and consulting a traditional healer in the past year (adjusted odds ratio [aOR] 15.36, 95% CI 3.22-73.27; aOR 2.30, 95%CI 1.00-5.30; aOR 2.27, 95% CI 1.00-5.19 respectively). Being male and knowing someone on ART were associated with better outcomes (aOR 0.25, 95%CI 0.09-0.74; aOR 0.44, 95%CI 0.19-1.01 respectively). In the workplace, predictors of poor treatment outcomes included being uncertain about the health effects of ART and a traditional healer's ability to treat HIV (aOR 7.53, 95%CI 2.02-27.98; aOR 4.40, 95%CI 1.41-13.75 respectively). Longer pre-ART waiting time (2-12 weeks compared to <2 weeks) predicted better treatment outcomes (aOR 0.13, 95% CI 0.03-0.56). Baseline predictors of poor treatment outcomes were largely unique to each programme, likely reflecting different populations and pathways to HIV care. In the workplace, active promotion of HIV testing may have extended ART to individuals who, without provider initiation, would not have spontaneously sought care. As provider-initiated testing makes ART available to individuals less motivated to seek care, patients may need additional adherence support, especially addressing uncertainty about the health benefits of ART.


Genetics and functional imaging: effects of APOE, BDNF, COMT, and KIBRA in aging.
Increasing evidence from cross-sectional and longitudinal molecular-genetic studies suggests that effects of common genetic variations on cognitive functioning increase with aging. We review the influence of candidate genes on brain functioning in old age, focusing on four genetic variations that have been extensively investigated: APOE, BDNF, COMT, and KIBRA. Similar to the behavioral evidence, there are reports from age-comparative studies documenting stronger genetic effects on measures of brain functioning in older adults compared to younger adults. This pattern suggests disproportionate impairments of neural processing among older individuals carrying disadvantageous genotypes. We discuss various factors, including gene-gene interactions, study population characteristics, lifestyle factors, and diseases, that need to be considered in future studies and may help understand inconsistent findings in the extant literature.


Clinical Evaluation of a Multiplex PCR for the Detection of Salmonella enterica Serovars Typhi and Paratyphi A from Blood Specimens in a High-Endemic Setting.
Enteric fever is a major public health concern in endemic areas, particularly in infrastructure-limited countries where Salmonella Paratyphi A has emerged in increasing proportion of cases. We aimed to evaluate a method to detect Salmonella Typhi (S. Typhi) and Salmonella Paratyphi A (S. Paratyphi A) in febrile patients in Bangladesh. We conducted a prospective study enrolling patients with fever > 38°C admitted to two large urban hospitals and two outpatient clinics located in Dhaka, Bangladesh. We developed and evaluated a method combining short culture with a new molecular assay to simultaneously detect and differentiate S. Typhi and S. Paratyphi A from other Salmonella directly from 2 to 4 mL of whole blood in febrile patients (n = 680). A total of 680 cases were enrolled from the four participating sites. An increase in the detection rate (+38.8%) in S. Typhi and S. Paratyphi A was observed with a multiplex polymerase chain reaction (PCR) assay, and absence of non-typhoidal Salmonella detection was reported. All 45 healthy controls were culture and PCR negative, generating an estimated 92.9% of specificity on clinical samples. When clinical performance was assessed in the absence of blood volume prioritization for testing, a latent class model estimates clinical performance ≥ 95% in sensitivity and specificity with likelihood ratio (LR) LR+ > 10 and LR- < 0.1 for the multiplex PCR assay. The alternative method to blood culture we developed may be useful alone or in combination with culture or serological tests for epidemiological studies in high disease burden settings and should be considered as secondary endpoint test for future vaccine trials.


Evaluation of Maternal Risk Factors in Neonatal Hyperbilirubinemia.
Diagnosis and timely treatment of neonatal jaundice and prevention of dangerous side effects of pathologic neonatal jaundice remain a serious debate. The first step in prevention of jaundice is the identification of predisposing factors. The present study aims to systematically review the maternal risk factors of neonatal hyperbilirubinemia. For this study, we searched databases including Science Direct, Cochrane Library, ISI, PubMed and Google Scholar from 1993 to 2017. The keywords searched based on MESH included hyperbilirubinemia, jaundice, infants, mothers and risk factors. The present systematic review was conducted on studies reporting maternal risk factors for neonatal jaundice. The inclusion criteria were: study on neonates; examination of maternal factors or both maternal and neonatal factors. Papers associated with the diagnosis and treatment of neonatal jaundice were excluded from the study, as well as those articles for which only abstracts were available. The limitations of this study include lack of access to all relevant articles, lack of qualified reports in some papers, and the limitation in number of articles related to maternal risk factors, and therefore inability to judge accurately about their effects on neonatal jaundice. Of 500 searched articles, 17 articles (1 prospective article, 2 retrospective papers, 12 cross-sectional papers and 2 historical cohort articles) were finally investigated. Maternal risk factors included hypertension, diabetes, type of delivery, vaginal bleeding, premature rupture of membranes (PROM), maternal age, lack of initiation of feeding during the first hours of life, inappropriate breastfeeding techniques and presence of maternal breast problems. The most common maternal risk factors for neonatal jaundice were prematurity, blood type incompatibilities, preeclampsia, hypertension, diabetes mellitus, vaginal bleeding, delivery problems (type of delivery, labor injuries, delivery at home, skin ecchymosis, and cephalohematoma), mothers and community cultural beliefs (use of traditional supplements), breast problems, and decrease in breastfeeding.


Statins and hepatic steatosis: perspectives from the Dallas Heart Study.
Non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease are independently associated. Due to the efficacy of 3-hydroxy 3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the prevention of cardiovascular disease, increasing interest has been shown in establishing the safety of these drugs in NAFLD. In this study, the relationship between statin use, hepatic triglyceride content (HTGC), and serum alanine aminotransferase (ALT) levels was examined in 2,264 Dallas Heart Study participants who were using no lipid-lowering agent (n = 2,124) or using only a statin for lipid management (n = 140). Statin use was not associated with a greater frequency of hepatic steatosis (38% vs. 34%) or elevated serum ALT (15% vs. 13%) by a pair-matched analysis. Statin use was also not associated with a greater prevalence of elevated serum ALT among subjects with hepatic steatosis (n = 638). This finding persisted when controlling for possible sample bias as a result of current prescribing practices for statins. Among subjects with serum lipid abnormalities who were not using a statin, hepatic steatosis was present in 60% of those with mixed hyperlipidemia and 83% of those with both mixed hyperlipidemia and an elevated serum ALT. In conclusion, statin use was not associated with a higher frequency of hepatic steatosis or serum ALT abnormalities, even among those with hepatic steatosis. Individuals meeting criteria for statin therapy are likely to have coexistent hepatic steatosis.


Photoelectrochemical water splitting with mesoporous hematite prepared by a solution-based colloidal approach.
Sustainable hydrogen production through photoelectrochemical water splitting using hematite (alpha-Fe(2)O(3)) is a promising approach for the chemical storage of solar energy, but is complicated by the material's nonoptimal optoelectronic properties. Nanostructuring approaches have been shown to increase the performance of hematite, but the ideal nanostructure giving high efficiencies for all absorbed light wavelengths remains elusive. Here, we report for the first time mesoporous hematite photoelectodes prepared by a solution-based colloidal method which yield water-splitting photocurrents of 0.56 mA cm(-2) under standard conditions (AM 1.5G 100 mW cm(-2), 1.23 V vs reversible hydrogen electrode, RHE) and over 1.0 mA cm(-2) before the dark current onset (1.55 V vs RHE). The sintering temperature is found to increase the average particle size, and have a drastic effect on the photoactivity. X-ray photoelectron spectroscopy and magnetic measurements using a SQUID magnetometer link this effect to the diffusion and incorporation of dopant atoms from the transparent conducting substrate. In addition, examining the optical properties of the films reveals a considerable change in the absorption coefficient and onset properties, critical aspects for hematite as a solar energy converter, as a function of the sintering temperature. A detailed investigation into hematite's crystal structure using powder X-ray diffraction with Rietveld refinement to account for these effects correlates an increase in a C(3v)-type crystal lattice distortion to the improved optical properties.


Nonrandom association of free iron with membranes of sickle and beta-thalassemic erythrocytes.
To further define the nature of abnormal iron deposits on the membranes of pathologic red blood cells, we have used sickle cell anemia (HbSS), HbSC, and beta-thalassemic erythrocytes (RBCs) to prepare inside-out membranes (IOM) and insoluble membrane aggregates (AGGs) containing coclustered hemichrome and band 3. Study of IOM from HbSC and thalassemic patients showed that amounts of heme iron and, especially, free iron were much higher in patients who had undergone surgical splenectomy. The membrane AGGs from HbSS and beta-thalassemic RBCs contained much more globin than heme, with this discrepancy being variable from patient to patient. Although these AGGs were enriched (compared with the ghosts from which they were derived) for heme, as expected, less than 10% of total ghost heme was recovered in them. Remarkably, these AGGs also were enriched for nonheme iron, markedly so in some patients. Iron binding studies showed that the association of free iron with these hemichrome/band 3 AGGs is explained by the fact that free iron binds to denatured hemoglobin. These results document that free iron is nonrandomly associated with the membranes of sickle and beta-thalassemic RBCs. Whether this plays a causative role in the premature removal of such cells from the circulation remains to be seen.


Invasive in vivo measurement of rear-, mid- and forefoot motion during walking.
The aim of this work was to use bone anchored external markers to describe the kinematics of the tibia, fibula, talus, calcaneus, navicular, cuboid, medial cuneiform, first and fifth metatarsals during gait. Data were collected from six subjects. There was motion at all the joints studied. Movement between the talus and the tibia showed the expected predominance of sagittal plane motion, but the talocalcaneal joint displayed greater variability than expected in its motion. Movement at the talonavicular joint was greater than at the talocalcaneal joint and motion between the medial cuneiform and navicular was far greater than expected. Motion between the first metatarsal and the medial cuneiform was less than motion between the fifth metatarsal and cuboid. Overall the data demonstrated the complexity of the foot and the importance of the joints distal to the rearfoot in its overall dynamic function.


Opiate analgesia: evidence for mediation by a subpopulation of opiate receptors.
Naloxazone, a hydrazone derivative of the opiate antagonist naloxone, has a high affinity for opiate receptor binding sites. Naloxazone injections reduce opiate receptor binding to extensively washed mouse brain membranes for more than 24 hours, suggesting that the effect is irreversible. High-affinity binding sites are abolished by this treatment, whereas low-affinity sites are unaffected. Naloxazone treatment blocks the analgesic effects of morphine for at least 24 hours but does not prevent death from high doses of morphine. Thus analgesic but nonlethal opiate effects may be mediated by the high-affinity subpopulation of opiate receptors.


Widening disparities in cigarette smoking by race/ethnicity across education level in the United States.
Reducing tobacco use is an important public health objective. It is the largest preventable cause of death and disease, yet inequalities remain. This study examines combined educational and racial/ethnic disparities in the United States related to cigarette smoking for the three largest racial/ethnic groups (African Americans, Hispanics/Latinos, and non-Hispanic Whites). Data included nine Tobacco Use Supplements to the Current Population Surveys (TUS-CPS) conducted in the United States from 1992/1993-2018 for four smoking metrics: ever smoking rates, current smoking rates, consumption (cigarettes per day), and quit ratios. Across all TUS-CPS samples, there were 9.5% African Americans, 8.8% Hispanics/Latinos, and 81.8% non-Hispanic Whites who completed surveys. Findings revealed that lower educational attainment was associated with increased ever and current smoking prevalence over time across all racial/ethnic groups, and education-level disparities within each race/ethnicity widened over time. Disparities in ever and current smoking rates between the lowest and highest categories of educational attainment (less than a high school education vs. completion of college) were larger for African Americans and non-Hispanic Whites than Hispanics/Latinos. Non-Hispanic Whites had the highest cigarette consumption across all education levels over time. College graduates had the highest quit ratios for all racial/ethnic groups from 1992 to 2018, with quit ratios significantly increasing for Hispanics/Latinos and non-Hispanic Whites, but not African Americans. In conclusion, educational disparities in smoking have worsened over time, especially among African Americans and Hispanics/Latinos. Targeted tobacco control efforts could help reduce these disparities to meet public health objectives, although racial/ethnic disparities may persist regardless of educational attainment.


Neurophysiological assessment of skeletal muscle fatigue in patients with congestive heart failure.
Recent research has demonstrated that patients with congestive heart failure (CHF) exhibit significant functional impairment of skeletal muscle and that these changes may be important determinants of exercise capacity. Although muscle strength may be mildly reduced, the most significant abnormality is markedly enhanced muscle fatigue. The goal of the present study is to determine whether accelerated fatigue is caused by impaired muscle activation, as a result of inadequate central motor drive or neuromuscular transmission, or by a change in the muscle itself. The study population consisted of nine patients with New York Heart Association class I-III CHF and eight sedentary, age- and sex-matched control subjects. Maximal voluntary contraction force of the foot dorsiflexors (primarily the tibialis anterior) was quantified as a measure of muscle strength, isometric endurance was quantified by the time required for force to decline to 60% of maximal during a sustained maximal contraction, and dynamic endurance was defined as the number of maximal contractions required for force to decline to 60% of maximal under a protocol of six repetitions per minute with an incremental duty cycle. The degree of central motor drive failure was quantified by the degree of force augmentation produced by a superimposed tetanic stimulus delivered to the peroneal nerve during the initial maximal voluntary contraction and at the time when force during the sustained isometric contraction declined to 60% of maximal. Neuromuscular junction transmission was examined by quantifying the amplitude of the compound muscle action potential (M wave) in response to a single nerve stimulus during fatiguing exercise. Muscle strength was relatively preserved in the CHF patients versus the control subjects (93 +/- 41 versus 105 +/- 34 lb; p = NS), but isometric endurance (time to decline to 60%, 34 +/- 15 versus 54 +/- 19 seconds; p less than 0.02) and dynamic endurance (number of repetitions before decline to 60%, 30 +/- 6 versus 43 +/- 7 contractions; p less than 0.001) were both impaired. Tetanic nerve stimulation increased force by similar degrees in the two groups, and the amplitude of the M wave did not decline in either group during exercise. These findings indicate that enhanced muscle fatigue in patients with CHF is not caused by impaired central motor drive or an abnormality of neuromuscular junction transmission but rather by an abnormality in the muscle itself.


Mutation in the Arabidopsis PASTICCINO1 gene, which encodes a new FK506-binding protein-like protein, has a dramatic effect on plant development.
The pasticcino (pas) mutants of Arabidopsis thaliana are a new class of plant developmental mutants; members of this class show ectopic cell proliferation in cotyledons, extra layers of cells in the hypocotyl, and an abnormal apical meristem. This phenotype is correlated with both cell division and cell elongation defects. There are three complementation groups of pas mutants (pas1, pas2, and pas3, with, respectively 2, 1, and 4 alleles). Here we describe in more detail the pas1-1 allele, which was obtained by insertional mutagenesis. The PAS1 gene has been cloned and characterized; it encodes an immunophilin-like protein similar to the p59 FK506-binding protein (FKBP52). PAS1 is characterized by an FKBP-like domain and three tetratricopeptide repeat units. Although the presence of immunophilins in plants has already been demonstrated, the pas1-1 mutant represents the first inactivation of an FKBP-like gene in plants. PAS1 expression is altered in pas1 mutants and in the pas2 and pas3 mutants. The expression of the PAS1 gene is increased in the presence of cytokinins, a class of phytohormones originally discovered because of their ability to stimulate cell division. These results are of particular relevance as they show for the first time that an FKBP-like protein plays an important role in the control of plant development.


Developmental dyslexia: an update on genes, brains, and environments.
The science of reading and developmental dyslexia has experienced spectacular advances during the last few years. Five aspects of this research are discussed in the article. (1) The holistic phenomenon of reading is complex. Many lower-level psychological processes (e.g., phonemic awareness, phonological decoding, ability to process stimuli rapidly and automatize this process, memory, ability to recognize words) contribute to a single act of reading. Conceptualizing the complex process of reading through its partly overlapping but partly independent components--which contribute to, but do not fully explain, the holistic process of reading--provides an excellent model for understanding complex hierarchies of higher mental functions. Those who master reading skills successfully and those who have difficulties doing so differ in a wide range of reading-related processes. The central deficit experienced by poor readers appears to be related to phonological processing (a complex hierarchy of functions related to processing phonemes), whereas characteristics of automatization processes seem to moderate the reading outcome for people whose phonological skills are weak. (2) There are new data addressing models of dyslexia in languages other than English. The most fascinating finding is that the model implicating phonological deficit as central to dyslexia, and the lack of ability to automatize as leading to troubled reading, appears to be universal, regardless of the specific language. However, there is an interaction effect between the characteristics of a particular language and the developmental model of dyslexia. In phonologically more difficult languages (e.g., English), the most pronounced weakness appears to occur in phonological processing, whereas in phonologically easier languages (e.g., German), the crucial role in the manifestation of dyslexia is played by the lack of the skills needed to achieve automatization. (3) There is abundant evidence that reading (i.e., any single act of reading as well as reading as a holistic process) is "cooked" by the brain. Although no unified brain map of reading has been developed, some specific areas of the brain have been implicated in different reading-related cognitive processes by different laboratories and on different samples. (4) Indisputable evidence has been accumulated suggesting the involvement of the genome in developmental dyslexia. As of now, specific regions of the genome have been identified as being intimately involved with a number of different reading-related processes. Today the field of developmental dyslexia is the only area of genetic studies of human abilities and disabilities in which linkages to the genome have been robustly replicated in independent laboratories. (5) Finally, evidence suggests that developmental dyslexia might be only one of the manifestations of a deep, underlying, anatomical syndrome. The comorbidity of developmental dyslexia with both internalizing and externalizing behavioral disturbances, as well as with other learning disabilities, underscores the need for wide-ranging cognitive and behavioral approaches in the remediation programs offered to dyslexic children.


The roles of transforming growth factor-β, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours (Review).
Primary liver tumours have a high incidence and mortality. The most important forms are hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both can occur together in the mixed phenotype hepatocellular-cholangiocarcinoma. Liver progenitor cells (LPCs) are bipotential stem cells activated in case of severe liver damage and are capable of forming both cholangiocytes and hepatocytes. Possibly, alterations in Wnt, transforming growth factor-β, Notch and hypoxia pathways in these LPCs can cause them to give rise to cancer stem cells, capable of driving tumourigenesis. In this review, we summarize and discuss current knowledge on the role of these pathways in LPC activation and differentiation during hepatocarcinogenesis.


The effects of delay duration on visual working memory for orientation.
We used a delayed-estimation paradigm to characterize the joint effects of set size (one, two, four, or six) and delay duration (1, 2, 3, or 6 s) on visual working memory for orientation. We conducted two experiments: one with delay durations blocked, another with delay durations interleaved. As dependent variables, we examined four model-free metrics of dispersion as well as precision estimates in four simple models. We tested for effects of delay time using analyses of variance, linear regressions, and nested model comparisons. We found significant effects of set size and delay duration on both model-free and model-based measures of dispersion. However, the effect of delay duration was much weaker than that of set size, dependent on the analysis method, and apparent in only a minority of subjects. The highest forgetting slope found in either experiment at any set size was a modest 1.14°/s. As secondary results, we found a low rate of nontarget reports, and significant estimation biases towards oblique orientations (but no dependence of their magnitude on either set size or delay duration). Relative stability of working memory even at higher set sizes is consistent with earlier results for motion direction and spatial frequency. We compare with a recent study that performed a very similar experiment.


Obesity: a neuroimmunometabolic perspective.
Neuroimmunology and immunometabolism are burgeoning topics of study, but the intersection of these two fields is scarcely considered. This interplay is particularly prevalent within adipose tissue, where immune cells and the sympathetic nervous system (SNS) have an important role in metabolic homeostasis and pathology, namely in obesity. In the present Review, we first outline the established reciprocal adipose-SNS relationship comprising the neuroendocrine loop facilitated primarily by adipose tissue-derived leptin and SNS-derived noradrenaline. Next, we review the extensive crosstalk between adipocytes and resident innate immune cells as well as the changes that occur in these secretory and signalling pathways in obesity. Finally, we discuss the effect of SNS adrenergic signalling in immune cells and conclude with exciting new research demonstrating an immutable role for SNS-resident macrophages in modulating SNS-adipose crosstalk. We posit that the latter point constitutes the existence of a new field - neuroimmunometabolism.