Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry.
The neurobiological mechanisms underlying overeating in obesity are not understood. Here, we assessed the neurobiological responses to an Implantable Gastric Stimulator (IGS), which induces stomach expansion via electrical stimulation of the vagus nerve to identify the brain circuits responsible for its effects in decreasing food intake. Brain metabolism was measured with positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose in seven obese subjects who had the IGS implanted for 1-2 years. Brain metabolism was evaluated twice during activation (on) and during deactivation (off) of the IGS. The Three-Factor Eating Questionnaire was obtained to measure the behavioral components of eating (cognitive restraint, uncontrolled eating, and emotional eating). The largest difference was in the right hippocampus, where metabolism was 18% higher (P < 0.01) during the "on" than "off" condition, and these changes were associated with scores on "emotional eating," which was lower during the on than off condition and with "uncontrolled eating," which did not differ between conditions. Metabolism also was significantly higher in right anterior cerebellum, orbitofrontal cortex, and striatum during the on condition. These findings corroborate the role of the vagus nerve in regulating hippocampal activity and the importance of the hippocampus in modulating eating behaviors linked to emotional eating and lack of control. IGS-induced activation of regions previously shown to be involved in drug craving in addicted subjects (orbitofrontal cortex, hippocampus, cerebellum, and striatum) suggests that similar brain circuits underlie the enhanced motivational drive for food and drugs seen in obese and drug-addicted subjects, respectively.


Two-dimensional exit dosimetry using a liquid-filled electronic portal imaging device and a convolution model.
To determine the accuracy of two-dimensional exit dose measurements with an electronic portal imaging device, EPID, using a convolution model for a variety of clinically relevant situations. Exit doses were derived from portal dose images, obtained with a liquid-filled EPID at distances of 50 cm or more behind the patient, by using a convolution model. The resulting on- and off-axis exit dose values were first compared with ionization chamber exit dose measurements for homogeneous and inhomogeneous phantoms in open and wedged 4,8 and 18 MV photon beams. The accuracy of the EPID exit dose measurements was then determined for a number of anthropomorphic phantoms (lung and larynx) irradiated under clinical conditions and for a few patients treated in an 8 MV beam. The latter results were compared with in vivo exit dose measurements using diodes. The exit dose can be determined from portal images with an accuracy of 1.2% (1 SD) compared with ionization chamber measurements for open beams and homogeneous phantoms at all tested beam qualities. In the presence of wedges and for inhomogeneous phantoms the average relative accuracy slightly deteriorated to 1.7% (1 SD). For lung phantoms in a 4 MV beam a similar accuracy was obtained after refinement of our convolution model, which requires knowledge of the patient contour. Differences between diode and EPID exit dose measurements for an anthropomorphic lung phantom in an 8 MV beam were 2.5% at most, with an average agreement within 1% (1 SD). For larynx phantoms in a 4 MV beam exit doses obtained with an ionization chamber and EPID agreed within 1.5% (1 SD). Finally, exit doses in a few patients irradiated in an 8 MV beam could be determined with the EPID with an accuracy of 1.1% (1 SD) relative to exit dose measurements using diodes. Portal images, obtained with our EPID and analyzed with our convolution model, can be used to determine the exit dose distribution with an accuracy of 1.7% (1 SD) for most clinically relevant situations. EPID exit dosimetry is therefore a good alternative for diode dosimetry. The EPID system is a powerful tool in a dosimetric quality control programme during high dose/high precision radiotherapy.


Medication safety series: take charge!
Nurses have read the statistics on the numbers of prescription medications seniors take each day and the pitfalls and diverse problems that occur as a result. Various scenarios contribute to this problem: multiple healthcare providers prescribe medications; the use of over-the-counter products and herbs or alcohol cause medication interactions; and patients increase, decrease, skip, or repeat doses. When medications are not taken correctly, an increase in the number of physician or emergency department visits and hospitalizations results. Patients who come to a rehabilitation unit after joint replacement or hip-pinning surgery, stroke, or for treatment of other conditions may be prescribed medications that differ from the drugs they were taking at home. These patients and their families need to learn how to safely take their new medications. This presentation describes how five nurses developed a medication safety program consisting of four segments: Making Your Medication List; Talking to Your Healthcare Team About Your Medications; Safely Storing, Taking, and Destroying Your Medications; and Knowing the Difference Between Allergies, Side Effects, and Interactions. This article also describes the development of the script and PowerPoint program, lessons learned from the first presentation, and implications for rehabilitation nurses. The information presented in this series can help patients and families take charge of their medications. The team of community educators who wrote this article encourages the integration of this program into readers' local patient communities because standards of care and resources vary in the communities that nurses serve.


Surgical Management of Advanced Kidney Cancer: The Role of Cytoreductive Nephrectomy and Lymphadenectomy.
Despite the evolution of systemic therapy from the immunotherapy to targeted therapy eras, surgical management remains a mainstay of treatment of patients with locally advanced, lymph node-positive, and distant metastatic renal cell carcinoma. Balancing patient and disease characteristics with the potential morbidity of surgery has gained increasing attention to better define the role of cytoreductive nephrectomy and lymphadenectomy. In this review, we critically evaluate the literature for the potential therapeutic role of cytoreductive nephrectomy and lymphadenectomy in advanced kidney cancer, highlighting current evidence, limitations, and best-management practices. Although retrospective data supported a similar survival benefit for cytoreductive nephrectomy in the targeted therapy era as it did for the initial immunotherapy era (1992 to 2006), level 1 evidence from the randomized Clinical Trial to Assess the Importance of Nephrectomy (CARMENA) demonstrated no benefit for intermediate- and poor-risk patients in the setting of sunitinib therapy. Level 1 evidence among a favorable-risk subset is still awaited from the trial Targeted Therapy With or Without Nephrectomy in Metastatic Renal Cell Carcinoma: Liquid Biopsy for Biomarkers Discovery (TARIBO). Another trial, Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME), has compared upfront cytoreductive nephrectomy prior to targeted therapy with the initial initiation of targeted therapy followed by deferred cytoreductive nephrectomy. Lymphadenectomy is yet another controversial but less well-defined management option for patients with kidney cancer. The role of lymphadenectomy has been studied in both the localized and advanced settings over the past few decades, with a strong suggestion of no therapeutic benefit for patients with cT1-2N0M0 and cM1 disease, and with uncertain benefit in patients with high-risk disease (ie, locally advanced or cN1M0), leading to weak statements among clinical guidelines.


Evidence for the role of connexin 43-mediated intercellular communication in the process of intracortical bone resorption via osteocytic osteolysis.
Connexin 43 (Cx43) is the predominant gap junction protein in bone. Mice with a bone-specific deletion of Cx43 (cKO) have an osteopenic cortical phenotype. In a recent study, we demonstrated that cKO mice are resistant to bone loss induced by hindlimb suspension (HLS), an animal model of skeletal unloading. This protective effect occurred primarily as a result of lower osteoclast-mediated bone resorption. Interestingly, we also documented a significant increase in cortical osteocyte apoptosis and reduced sclerostin production. In the present study, we investigated whether osteocytic osteolysis - bone resorption by osteocytes within lacunae - is induced by HLS and the potential effect of Cx43 deficiency on this process during unloading. 6-month-old male Cx43 cKO or wild-type (WT) mice were subjected to three weeks of HLS (Suspended) or normal loading conditions (Control) (n = 5/group). Lacunar morphology and tartrate-resistant acid phosphatase (TRACP) staining were assessed on sections of femur cortical bone. Experimental groups were compared via two-way ANOVA. Empty lacunae were 26% larger in cKO-Control vs. WT-Control (p < 0.05), while there was no difference in the size of empty lacunae between Control and Suspended within WT or cKO (p > 0.05). Similarly, there was a trend (p = 0.06) for 11% larger lacunae containing viable osteocytes for cKO-Control vs. WT-Control, with no apparent effect of loading condition. There was no difference in the proportion of TRACP + cells between WT-Control and cKO-Control (p > 0.05); however, WT-Suspended mice had 246% more TRACP + osteocytes compared WT-Control mice (p < 0.05). There was no difference in TRACP staining between cKO-Control and cKO-Suspended (p > 0.05). Prior to undergoing apoptosis, osteocytes in cKO mice may be actively resorbing their respective lacunae via the process of osteocytic osteolysis. Interestingly, the proportion of TRACP + osteocytes increased dramatically following unloading of WT mice, an effect that was not observed in cKO mice subjected to HLS. The results of the present study provide initial evidence that osteocytic osteolysis is occurring in cortical bone in response to mechanical unloading. Furthermore, Cx43 deficiency appears to protect against osteocytic osteolysis in a manner similar to the inhibition of unloading-induced osteoclast activation that we have documented previously.


Structure of the bacteriophage lambda Ser/Thr protein phosphatase with sulfate ion bound in two coordination modes.
The protein phosphatase encoded by bacteriophage lambda (lambda PP) belongs to a family of Ser/Thr phosphatases (Ser/Thr PPases) that includes the eukaryotic protein phosphatases 1 (PP1), 2A (PP2A), and 2B (calcineurin). These Ser/Thr PPases and the related purple acid phosphatases (PAPs) contain a conserved phosphoesterase sequence motif that binds a dinuclear metal center. The mechanisms of phosphoester hydrolysis by these enzymes are beginning to be unraveled. To utilize lambda PP more effectively as a model for probing the catalytic mechanism of the Ser/Thr PPases, we have determined its crystal structure to 2.15 A resolution. The overall fold resembles that of PP1 and calcineurin, including a conserved beta alpha beta alpha beta structure that comprises the phosphoesterase motif. Substrates and inhibitors probably bind in a narrow surface groove that houses the active site dinuclear Mn(II) center. The arrangement of metal ligands is similar to that in PP1, calcineurin, and PAP, and a bound sulfate ion is present in two novel coordination modes. In two of the three molecules in the crystallographic asymmetric unit, sulfate is coordinated to Mn2 in a monodentate, terminal fashion, and the two Mn(II) ions are bridged by a solvent molecule. Two additional solvent molecules are coordinated to Mn1. In the third molecule, the sulfate ion is triply coordinated to the metal center with one oxygen coordinated to both Mn(II) ions, one oxygen coordinated to Mn1, and one oxygen coordinated to Mn2. The sulfate in this coordination mode displaces the bridging ligand and one of the terminal solvent ligands. In both sulfate coordination modes, the sulfate ion is stabilized by hydrogen bonding interactions with conserved arginine residues, Arg 53 and Arg 162. The two different active site structures provide models for intermediates in phosphoester hydrolysis and suggest specific mechanistic roles for conserved residues.


Global architecture of the F-actin cytoskeleton regulates cell shape-dependent endothelial mechanotransduction.
Uniaxial stretch is an important biophysical regulator of cell morphology (or shape) and functions of vascular endothelial cells (ECs). However, it is unclear whether and how cell shape can independently regulate EC mechanotransductive properties under uniaxial stretch. Herein, utilizing a novel uniaxial cell-stretching device integrated with micropost force sensors, we reported the first experimental evidence showing cell shape-dependent EC mechanotransduction via cytoskeleton (CSK) contractile forces in response to uniaxial stretch. Combining experiments and theoretical modeling from first principles, we showed that it was the global architecture of the F-actin CSK that instructed the cell shape-dependent EC mechanotransductive process. Furthermore, a cell shape-dependent nature was relayed in EC mechanotransduction via dynamic focal adhesion (FA) assembly. Our results suggested a novel mechanotransductive process in ECs wherein the global architecture of the F-actin CSK, governed by cell shape, controls mechanotransduction via CSK contractile forces and force-dependent FA assembly under uniaxial stretch.


Compositional, nutritional, and functional characteristics of instant teas produced from low- and high-quality black teas.
Two types of instant teas produced from low- and high-quality black teas were examined for their proximate composition, dietary fiber, minerals, water-soluble vitamins, total phenolic content, various antioxidant assays, phenolics (flavanols, condensed phenolics, and phenolic acids), alkaloids, and carotenoids as well as taste-active compounds (sugars, organic acids, and free amino acids). Some variations, albeit to different extents, were observed (p < 0.05) among these parameters between instant teas produced from low- and high-quality black teas. With respect to proximate composition, carbohydrate was the predominant component (56.68-59.84 g/100 g), followed by protein (19.31-19.86 g/100 g). Ash, moisture, and, to a lesser extent, dietary fiber and fat were also present in both instant teas. Thirteen minerals, four water-soluble vitamins, six flavanols, two alkaloids, three condensed phenolics, one phenolic acid, and one carotenoid were identified. Total phenolic content varied between 17.35 and 17.82 g of gallic acid equivalents (GAE)/100 g instant tea. With regard to antioxidant activities, three different assays such as oxygen radical absorbance capacity (ORAC), trolox equivalent antioxidant capacity (TEAC), and cupric ion reducing antioxidant capacity (CUPRAC) were measured. No significant differences (p > 0.05) in total phenolic, ORAC, TEAC, and CUPRAC contents between low- and high-quality instant teas were observed. With regard to taste-active compounds, 3 sugars, 5 organic acids, and 18 free amino acids were positively identified, of which fructose, tannic acid, and theanine predominated, respectively. The present work suggests that despite some differences, instant teas produced from low- and high-quality black teas should not be distinguished on the basis of their compositional, nutritional, and functional characteristics as well as taste-active compounds.


Site-selective chemical protein glycosylation protects from autolysis and proteolytic degradation.
Glycosylation is often cited as having a stabilizing effect upon proteins with respect to proteolysis, thermolysis and other forms of degradation. We present here a model study on an autolytic protease that has been chemically glycosylated to produce single glycoforms. The resulting glycosylated enzymes are more stable with respect to their own autolytic degradation and that by other proteases. Kinetic parameters for protease activity with respect to the degradation of small-molecule amide substrate reveal no significant change in inherent activity thereby suggesting that reduced autolysis and proteolysis are a consequence of stabilization, perhaps by steric blockade of cleavage points or alteration of local unfolding kinetics. Variation in glycan identity suggests that greater glycan size leads to greater stabilization.


Development of Economic Thresholds for Sugarcane Aphid (Hemiptera: Aphididae) in Susceptible Grain Sorghum Hybrids.
Sugarcane aphid, Melanaphis sacchari Zehtner (Hemiptera: Aphididae), outbreaks on grain sorghum were first detected in the United States in 2013. The spread of sugarcane aphid across the sorghum-producing regions of North America necessitated increased insecticide use to mitigate economic loss. A field experiment to develop economic thresholds for sugarcane aphid was conducted 15 times across seven locations across the southern United States during 3 yr (2014-2016). Grain sorghum hybrids were evaluated by measuring yield in response to a range of aphid infestations. Yield-aphid population density relationships were described by linear function, which facilitated calculating economic injury levels and economic thresholds. The slopes of the yield-aphid density regressions were significant, negative, and relatively stable across locations, years, and agronomic conditions. The relationships aggregated into two groups, populations that exhibited relatively slow and fast population growth, and common economic injury levels were determined using control costs and market values of grain. Average economic injury levels of 37 and 102 aphids per leaf were most applicable to the two groupings of sorghum/aphid relationships and aphid population growth. Using field-based sugarcane aphid population doubling time estimated from weekly observations of aphid densities, economic thresholds were calculated, ranging from 19 to 132 aphids per leaf across the 15 locations-years. Without site-specific knowledge of a slow-growing aphid population and given cost and market price variability of the system, a 40 aphid per leaf threshold is most prudent to use across the range of hybrid, environmental, and market conditions experienced in this study.


Formation of surface nanodroplets facing a structured microchannel wall.
Surface nanodroplets are important units for lab-on-a-chip devices, compartmentalised catalytic reactions, high-resolution near-field imaging, and many others. Solvent exchange is a simple solution-based bottom-up approach for producing surface nanodroplets by displacing a good solvent of the droplet liquid by a poor one in a narrow channel in the laminar regime. The droplet size is controlled by the solution composition and the flow conditions during the solvent exchange. In this paper, we investigated the effects of local microfluidic structures on the formation of surface nanodroplets. The microstructures consist of a microgap with a well-defined geometry, embedded on the opposite microchannel wall, facing the substrate where nucleation takes place. For a given channel height, the dimensionless control parameters were the Peclet number of the flow, the ratio between the gap height and the channel height, and the aspect ratio between the gap length and the channel height. We found and explained three prominent features in the surface nanodroplet distribution at the surface opposite to the microgap: (i) enhanced volume of the droplets; (ii) asymmetry as compared to the location of the gap in the spatial droplet distribution with increasing Pe; (iii) reduced exponent of the effective scaling law of the droplet size with Pe. The droplet size also varied with the aspect and height ratios of the microgap at a given Pe value. Our simulations of the profile of oversaturation in the channel reveal that the droplet size distribution may be attributed to the local flow patterns induced by the gap. Finally, in a tapered microchannel, a gradient of surface nanodroplet size was obtained. Our work shows the potential for controlling nanodroplet size and spatial organization on a homogeneous surface in a bottom-up approach by simple microfluidic structures.


Anatomy and biomechanics of the medial side of the knee and their surgical implications.
In order to reconstruct the medial knee to restore the original biomechanical function of its ligamentous structures, a thorough understanding of its anatomic placement and relationship with surrounding structures is required. To restore the knee to normal kinematics, the diagnosis and surgical approach have to be aligned, to successfully reconstruct the area of injury. Three important ligaments maintain primary medial knee stability: the superficial medial collateral ligament, posterior oblique ligament, and deep medial collateral ligament. It is important not to exclude the assistance that other ligaments of the medial knee provide, including support of patellar stability by the medial patellofemoral ligament and multiligamentous hamstring tendon attachments. Valgus gapping and medial knee stability is accounted for collectively by every primary medial knee stabilizing structure. The following will review the principal medial knee anatomic and biomechanical properties.


Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants.
This study aimed to determine lamivudine disposition in infants and to construct an appropriate dose adjustment for age, given the widespread use of lamivudine for both the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and the treatment of HIV-infected infants. Using a pooled-population approach, the pharmacokinetics of lamivudine in HIV-exposed or -infected infants from four Pediatric AIDS Clinical Trials Group studies were assessed. Ninety-nine infants provided 559 plasma samples for measurement of lamivudine concentrations. All infants received combination antiretroviral therapy including lamivudine dosed at 2 mg/kg of body weight every 12 h (q12h) for the first 4 to 6 weeks of life and at 4 mg/kg q12h thereafter. Lamivudine's apparent clearance was 0.25 liter/h/kg at birth, doubling by 28 days. In the final model, age and weight were the only significant covariates for lamivudine clearance. While lamivudine is predominantly renally eliminated, the serum creatinine level was not an independent covariate in the final model, possibly because it was confounded by age. Inclusion of interoccasion variability for bioavailability improved the individual subject clearance prediction over the age range studies. Simulations based on the final model predicted that by the age of 4 weeks, 90% of infant lamivudine concentrations with the standard 2 mg/kg dose of lamivudine fell below the adult median concentration. This population pharmacokinetic analysis affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg q12 h at the age of 4 weeks for infants with normal maturation of renal function will provide optimal lamivudine exposure, potentially contributing to more successful therapy.


Single-molecule force measurement via optical tweezers reveals different kinetic features of two BRaf mutants responsible for cardio-facial-cutaneous (CFC) syndrome.
BRaf (B- Rapid Accelerated Fibrosarcoma) protein is an important serine/threonine-protein kinase. Two domains on BRaf can independently bind its upstream kinase, Ras (Rat Sarcoma) protein. These are the Ras binding domain (RBD) and cysteine-rich-domain (CRD). Herein we use customized optical tweezers to compare the Ras binding process in two pathological mutants of BRaf responsible for CFC syndrome, abbreviated BRaf (A246P) and BRaf (Q257R). The two mutants differ in their kinetics of Ras-binding, though both bind Ras with similar increased overall affinity. BRaf (A246P) exhibits a slightly higher Ras/CRD unbinding force and a significantly higher Ras/RBD unbinding force versus the wild type. The contrary phenomenon is observed in the Q257R mutation. Simulations of the unstressed-off rate, koff (0), yield results in accordance with the changes revealed by the mean unbinding force. Our approach can be applied to rapidly assess other mutated proteins to deduce the effects of mutation on their kinetics compared to wild type proteins and to each other.


A genetic epilepsy rat model displays endophenotypes of psychosis.
The incidence of psychosis is increased in people with epilepsy, including idiopathic generalized epilepsies. To study the biological basis for this co-morbidity, we compared GAERS, a genetic rat model of absence epilepsy, to non-epileptic control rats (NEC). Mature, 14-week old GAERS showed enhanced amphetamine-induced locomotor hyperactivity - a feature also present in young (6-week old) GAERS prior to epilepsy onset. Prepulse inhibition and its disruption by psychotropic drugs did not differ between strains, although GAERS displayed elevated startle responses at both epileptic and pre-epileptic ages. The frontoparietal cortex of GAERS displayed a twofold increase in the power of gamma (30-80 Hz) oscillations, a proposed neurophysiological correlate of psychosis. Radioligand binding autoradiography demonstrated reduced densities of dopamine transporters in the caudate nucleus and nucleus accumbens core and of dopamine D2 receptors in the caudate nucleus. GAERS provide an opportunity to study the neurodevelopmental, genetic and therapeutic aspects of psychiatric comorbidities associated with epilepsy.


Development of a safety net medical home scale for clinics.
Existing tools to measure patient-centered medical home (PCMH) adoption are not designed for research evaluation in safety-net clinics. Develop a scale to measure PCMH adoption in safety-net clinics. Cross-sectional survey. Sixty-five clinics in five states. Fifty-two-item Safety Net Medical Home Scale (SNMHS). The total score ranges from 0 (worst) to 100 (best) and is an average of multiple subscales (0-100): Access and Communication, Patient Tracking and Registry, Care Management, Test and Referral Tracking, Quality Improvement, and External Coordination. The scale was tested for internal consistency reliability and tested for convergent validity using The Assessment of Chronic Illness Care (ACIC) and the Patient-Centered Medical Home Assessment (PCMH-A). The scale was applied to centers in the sample. In addition, linear regression models were used to measure the association between clinic characteristics and medical home adoption. The SNMHS had high internal consistency reliability (Cronbach's alpha = 0.84). The SNMHS score correlated moderately with the ACIC score (r = 0.64, p < 0.0001) and the PCMH-A (r = 0.56, p < 0.001). The mean SNMHS score was 61 ± SD 13. Among the subscales, External Coordination (66 ± 16) and Access and Communication (65 ± 14) had the highest mean scores, while Quality Improvement (55 ± 17) and Care Management (55 ± 16) had lower mean scores. Clinic characteristics positively associated with total SNMHS score were having more providers (β 15.8 95% CI 8.1-23.4 >8 provider FTEs compared to <4 FTEs) and participation in financial incentive programs (β 8.4 95% 1.6-15.3). The SNMHS demonstrated reliability and convergent validity for measuring PCMH adoption in safety-net clinics. Some clinics have significant PCMH adoption. However, room for improvement exists in most domains, especially for clinics with fewer providers.


Metacognition and persecutory delusions: tests of a metacognitive model in a clinical population and comparisons with non-patients.
BACKGROUND. A metacognitive approach to the conceptualization of paranoia as a strategy for managing interpersonal threat has gained some support in studies of non-clinical populations. This study reports a clinical validation of the Beliefs about Paranoia Scale (BaPS), a self-report measure to assess metacognitive beliefs about paranoia. We aimed to replicate the factor structure of a brief version of the measure and test the specific hypotheses that positive beliefs about paranoia would predict levels of suspiciousness, and that negative beliefs about paranoia would predict problematic persecutory delusions. METHOD. A total of 122 patients meeting criteria for a diagnosis of a schizophrenia spectrum disorder completed the questionnaire assessing beliefs about paranoia. In addition, 61 of the participants were administered the Structured Clinical Interview for DSM-IV, and 60 were administered the Positive and Negative Syndromes of Schizophrenia Scale. One hundred and seventy-eight non-patients were also recruited (an undergraduate sample). RESULTS. Principal components factor analysis showed that the three-factor solution was replicated (comprising negative beliefs about paranoia, paranoia as a survival strategy, and normalizing beliefs). This measure showed good internal consistency (alphas ranged from .85 to .91). Correlational analyses revealed that positive beliefs about paranoia were positively associated with levels of suspiciousness, and independent t tests showed that negative beliefs about paranoia were significantly higher in patients with a diagnosis of schizophrenia meeting criteria for persecutory delusions in comparison to those without. Analyses of covariance showed that patients scored higher than non-patients on both positive and negative beliefs, but logistic regression did not demonstrate that co-occurrence of these beliefs predicted patient status. CONCLUSIONS. Three of our four hypotheses were confirmed, suggesting that a metacognitive approach to the conceptualization of paranoia as a strategy for managing interpersonal threat may have some utility for understanding clinical paranoia. Such a model is described and the clinical implications of the findings are also discussed.


COPII-cargo interactions direct protein sorting into ER-derived transport vesicles.
Vesicles coated with coat protein complex II (COPII) selectively transport molecules (cargo) and vesicle fusion proteins from the endoplasmic reticulum (ER) to the Golgi complex. We have investigated the role of coat proteins in cargo selection and recruitment. We isolated integral membrane and soluble cargo proteins destined for transport from the ER in complexes formed in the presence of Sar1 and Sec23/24, a subset of the COPII components, and GTP or GMP-PNP. Vesicle fusion proteins of the vSNARE family and Emp24, a member of a putative cargo carrier family, were also found in COPII complexes. The inclusion of amino-acid permease molecules into the complex depended on the presence of Shr3, a protein required for the permease to leave the ER. Resident ER proteins Sec61, BiP (Kar2) and Shr3 were not included in the complexes, indicating that the COPII components bound specifically to vesicle cargo. COPII-cargo complexes and putative cargo adaptor-cargo complexes were also isolated from COPII vesicles. Our results indicate that cargo packaging signals and soluble cargo adaptors are recognized by a recruitment complex comprising Sar1-GTP and Sec23/24.


A Difficult Decision: Atypical JC Polyomavirus Encephalopathy in a Kidney Transplant Recipient.
A number of cerebral manifestations are associated with JC polyomavirus (JCPyV) which are diagnosed by detection of JCPyV in cerebrospinal fluid (CSF), often with the support of cerebral imaging. Here we present an unusual case of a kidney transplant patient presenting with progressive neurological deterioration attributed to JCPyV encephalopathy. Quantitative polymerase chain reaction JCPyV was used prospectively and retrospectively to track the viral load within the patient blood, urine, CSF, and kidney sections. A JCPyV VP1 enzyme-linked immunosorbent assay was used to measure patient and donor antibody titers. Immunohistochemical staining was used to identify active JCPyV infection within the kidney allograft. JC polyomavirus was detected in the CSF at the time of presentation. JC polyomavirus was not detected in pretransplant serum, however viral loads increased with time, peaking during the height of the neurological symptoms (1.5E copies/mL). No parenchymal brain lesions were evident on imaging, but transient cerebral venous sinus thrombosis was present. Progressive decline in neurological function necessitated immunotherapy cessation and allograft removal, which led to decreasing serum viral loads and resolution of neurological symptoms. JC polyomavirus was detected within the graft's collecting duct cells using quantitative polymerase chain reaction and immunohistochemical staining. The patient was JCPyV naive pretransplant, but showed high antibody titers during the neurological symptoms, with the IgM decrease paralleling the viral load after graft removal. We report a case of atypical JCPyV encephalopathy associated with cerebral venous sinus thrombosis and disseminated primary JCPyV infection originating from the kidney allograft. Clinical improvement followed removal of the allograft and cessation of immunosuppression.


Hospitals caring for rural Aboriginal patients: holding response and denial.
To investigate how policy requiring cultural respect and attention to health equity is implemented in the care of rural and remote Aboriginal people in city hospitals. Interviews with 26 staff in public hospitals in Adelaide, South Australia, were analysed (using a framework based on cultural competence) to identify their perceptions of the enabling strategies and systemic barriers against the implementation of official policy in the care of rural Aboriginal patients. The major underlying barriers were lack of knowledge and skills among staff generally, and the persistent use of 'business as usual' approaches in their hospitals, despite the clear need for proactive responses to the complex care journeys these patients undertake. Staff reported a sense that while they are required to provide responsive care, care systems often fail to authorise or guide necessary action to enable equitable care. Staff caring for rural Aboriginal patients are required to respond to complex particular needs in the absence of effective authorisation. We suggest that systemic misinterpretation of the principle of equal treatment is an important barrier against the development of culturally competent organisations. WHAT IS KNOWN ABOUT THIS TOPIC?: The care received by Aboriginal patients is less effective than it is for the population generally, and access to care is poorer. Those in rural and remote settings experience both severe access barriers and predictable complexity in their patient care journeys. This situation persists despite high-level policies that require tailored responses to the particular needs of Aboriginal people. WHAT DOES THIS PAPER ADD?: Staff who care for these patients develop skills and modify care delivery to respond to their particular needs, but they do so in the absence of systematic policies, procedures and programs that would 'build in' or authorise the required responsiveness. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS?: Systematic attention, at hospital and clinical unit level, to operationalising high policy goals is needed. The framework of cultural competence offers relevant guidance for efforts (at system, organisation and care delivery levels) to improve care, but requires organisations to address misinterpretation of the principle of equal treatment.


Why Word Learning is not Fast.
Upon fast mapping, children rarely retain new words even over intervals as short as 5 min. In this study, we asked whether the memory process of encoding or consolidation is the bottleneck to retention. Forty-nine children, mean age 33 months, were exposed to eight 2- or-3-syllable nonce neighbors of words in their existing lexicons. Didactic training consisted of six exposures to each word in the context of its referent, an unfamiliar toy. Productions were elicited four times: immediately following the examiner's model, and at 1-min-, 5-min-, and multiday retention intervals. At the final two intervals, the examiner said the first syllable and provided a beat gesture highlighting target word length in syllables as a cue following any erred production. The children were highly accurate at immediate posttest. Accuracy fell sharply over the 1-min retention interval and again after an additional 5 min. Performance then stabilized such that the 5-min and multiday posttests yielded comparable performance. Given this time course, we conclude that it was not the post-encoding process of consolidation but the process of encoding itself that presented the primary bottleneck to retention. Patterns of errors and responses to cueing upon error suggested that word forms were particularly vulnerable to partial decay during the time course of encoding.


Biogas desulfurization and biogas upgrading using a hybrid membrane system--modeling study.
Membrane gas permeation using glassy membranes proved to be a suitable method for biogas upgrading and natural gas substitute production on account of low energy consumption and high compactness. Glassy membranes are very effective in the separation of bulk carbon dioxide and water from a methane-containing stream. However, the content of hydrogen sulfide can be lowered only partially. This work employs process modeling based upon the finite difference method to evaluate a hybrid membrane system built of a combination of rubbery and glassy membranes. The former are responsible for the separation of hydrogen sulfide and the latter separate carbon dioxide to produce standard-conform natural gas substitute. The evaluation focuses on the most critical upgrading parameters like achievable gas purity, methane recovery and specific energy consumption. The obtained results indicate that the evaluated hybrid membrane configuration is a potentially efficient system for the biogas processing tasks that do not require high methane recoveries, and allows effective desulfurization for medium and high hydrogen sulfide concentrations without additional process steps.


Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD).
Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (> or = 3, 1-2 or <1) or CD4 (> or = 3 or <3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (<400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively. Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) and 'Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P<0.001] and reporting 'Other' HIV exposures experienced reduced suppression (OR=0.28; P<0.001). Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites with VL testing less than once per year.


What to do and what not to do in serological diagnosis of pertussis: recommendations from EU reference laboratories.
Bordetella pertussis-specific antibodies can be detected by enzyme-linked immunosorbent assays (ELISAs) or multiplex immunoassays. Assays use purified or mixed antigens, and only pertussis toxin (PT) is specific for B. pertussis. The interpretation of results can be based on dual-sample or single-sample serology using one or two cut-offs. The EU Pertstrain group recommends that: (i) ELISAs and multiplex immunoassays should use purified non-detoxified PT as an antigen, that they should have a broad linear range and that they should express results quantitatively in International Units per millilitre (IU/ml); (ii) a single or dual diagnostic cut-off for single-serum serology using IgG-anti-PT between 50 and 120 IU/ml should be used, and diagnostic serology cannot be validly interpreted for one year after vaccination with acellular pertussis (aP) vaccines; (iii) IgA-anti-PT should only be used with indeterminate IgG-anti-PT levels or when a second sample cannot be obtained. This group discourages using: (i) other antigens in routine diagnostics, as they are not specific; (ii) micro-agglutination, due to its lack of sensitivity; (iii) immunoblots for pertussis serodiagnosis, as results cannot be quantified; (iv) other methods, such as complement fixation or indirect immunofluorescence, due to their low sensitivity and/or specificity.


Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules.
Breast cancer (BC) arises commonly in women with metabolic dysfunction. The underlying mechanism by which glycemic load can exert its action on tumor metastasis is under investigated. In this study we showed that glycemic microenvironment alters the expression of three classes of proteins, VEGF and its receptors, cell to cell, and cell to extracellular matrix (ECM) adhesion proteins in MDA-MB-231 parental cells and its two metastatic variants to the bone and brain (MDA-MB-231BO and MDA-MB-231BR, respectively). Using western blotting, we showed that VEGFR2 levels were higher in these variant cells and persisted in the cells under extreme hypoglycemia. Hypoglycemia did not alter VEGFR2 expression per se but rather suppressed its posttranslational glycosylation. This was reversed rapidly upon the restoration of glucose, and cyclohexamide (CHX) treatment demonstrated that this deglycosylated VEGFR2 was not a product of de-novo protein synthesis. VEGFR2 co-receptor Neuropilin-1 was up-regulated four-fold in all MDA-MB-231 cells (parental and two variants) compared to VEGFR2 expression, and was also susceptible to glycemic changes but resistant to CHX treatment for up to 72 hrs. Hypoglycemia also resulted in a significant decrease in specific catenin, cadherin, and integrin proteins, as well as cellular proliferation and colony forming ability. However, MDA-MB-231BR cells showed a unique sensitivity to hypo/hyperglycemia in terms of morphological changes, colony formation ability, integrin β3 expression and secreted VEGF levels. In conclusion, this study can be translated clinically to provide insight into breast cancer cell responses to glycemic levels relevant for our understanding of the interaction between diabetes and cancer.


Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity.
British dietary recommendations are to decrease total fat intake to less than 30 % of daily energy intake and saturated fat to less than 10 %. In practice, it is difficult for people to make these changes. It may be easier to encourage people to switch from a diet rich in saturated fatty acids to one rich in polyunsaturated fatty acids. A total of 17 subjects - six people with Type II (non-insulin-dependent) diabetes mellitus, six non-obese and five obese people without diabetes - were randomised to spend two 5-week periods on a diet rich in saturated or in polyunsaturated fatty acids, in a crossover design. At the start of the study and after each dietary period, we assessed abdominal fat distribution using magnetic resonance imaging, insulin sensitivity using hyperinsulinaemic-euglycaemic clamps and fasting lipid parameters. Dietary compliance, assessed by weekly 3-day dietary records and measurement of biochemical markers, was good. Energy and fat intake appeared to be reduced on the diet rich in polyunsaturated fatty acids although body weights did not change. Insulin sensitivity and plasma low density lipoprotein cholesterol concentrations improved with the diet rich in polyunsaturated fatty acids compared with the diet rich in saturated fatty acids. There was also a decrease in abdominal subcutaneous fat area. If this result is confirmed in longer-term studies, this dietary manipulation would be more readily achieved by the general population than the current recommendations and could result in considerable improvement in insulin sensitivity, reducing the risk of developing Type II diabetes.


A person-centered approach to achievement goal orientations in competitive tennis players: Associations with motivation and mental toughness.
Research on achievement goal orientations in sport has typically relied on the use of variable-centered approaches that tend to overlook population heterogeneity. In this study, we used a person-centered approach to identify subgroups of competitive tennis players according to unique combinations of achievement goal orientations and tested for subgroup differences in motivation and mental toughness. A sample of 323 competitive tennis athletes (69.35% male) between 15 and 25 years of age (17.60 ± 2.40 years, mean ± SD) completed the 3 × 2 Achievement Goal Questionnaire for Sport, Sport Motivation Scale II, and Mental Toughness Index. Latent profile analysis was used to identify unique combinations of achievement goal orientations. Comparisons between latent subgroups on autonomous motivation, controlled motivation, and mental toughness were performed using analysis of variance. Latent profile analysis supported 3 distinct patterns of achievement goal profiles that were primarily distinguishable based on valence of competence (i.e., approach vs. avoidance). Analyses of variance indicated that athletes who were classified into subgroups that endorsed approach types of goals (regardless of the types of avoidance goals they endorsed) reported higher levels of autonomous motivation and mental toughness. Results indicated that athletes tend to pursue a number of achievement goals collectively rather than in isolation. Although approach goals are more commonly linked to adaptive psychological functioning and positive outcomes, avoidance goals may also be associated with desirable psychological characteristics if they are pursued in conjunction with approach types of achievement goals.


Link Prediction Investigation of Dynamic Information Flow in Epilepsy.
As a brain disorder, epilepsy is characterized with abnormal hypersynchronous neural firings. It is known that seizures initiate and propagate in different brain regions. Long-term intracranial multichannel electroencephalography (EEG) reflects broadband ictal activity under seizure occurrence. Network-based techniques are efficient in discovering brain dynamics and offering finger-print features for specific individuals. In this study, we adopt link prediction for proposing a novel workflow aiming to quantify seizure dynamics and uncover pathological mechanisms of epilepsy. A dataset of EEG signals was enrolled that recorded from 8 patients with 3 different types of pharmocoresistant focal epilepsy. Weighted networks are obtained from phase locking value (PLV) in subband EEG oscillations. Common neighbor (CN), resource allocation (RA), Adamic-Adar (AA), and Sorenson algorithms are brought in for link prediction performance comparison. Results demonstrate that RA outperforms its rivals. Similarity, matrix was produced from the RA technique performing on EEG networks later. Nodes are gathered to form sequences by selecting the ones with the highest similarity. It is demonstrated that variations are in accordance with seizure attack in node sequences of gamma band EEG oscillations. What is more, variations in node sequences monitor the total seizure journey including its initiation and termination.


Metallothionein in Brain Disorders.
Metallothioneins are a family of proteins which are able to bind metals intracellularly, so their main function is to regulate the cellular metabolism of essential metals. There are 4 major isoforms of MTs (I-IV), three of which have been localized in the central nervous system. MT-I and MT-II have been localized in the spinal cord and brain, mainly in astrocytes, whereas MT-III has been found mainly in neurons. MT-I and MT-II have been considered polyvalent proteins whose main function is to maintain cellular homeostasis of essential metals such as zinc and copper, but other functions have also been considered: detoxification of heavy metals, regulation of gene expression, processes of inflammation, and protection against free radicals generated by oxidative stress. On the other hand, the MT-III has been related in events of pathogenesis of neurodegenerative diseases such as Parkinson and Alzheimer. Likewise, the participation of MTs in other neurological disorders has also been reported. This review shows recent evidence about the role of MT in the central nervous system and its possible role in neurodegenerative diseases as well as in brain disorders.


"Toxic pleasures": A study of eating out behavior in Arab female university students and its associations with psychological distress and disordered eating.
University years are a critical period in which young people establish independence and adopt lasting health behaviors. The aim of this study was to estimate the associations between eating out, psychological distress, and disordered eating behaviors among young Arab females in Qatar a rapidly developing small nation. A cross-sectional probability-based survey of 1615 Qatar University's female students assessed the frequency of eating out (main independent variable) and other eating behaviors in relation to two main dependent variables, disordered eating and psychological distress, which were measured using the Eating Attitudes Test and the Kessler Psychological Distress Scale, respectively. Multivariable logistic-regression analyses were used to estimate these two main associations with and without adjustment for other potential confounding variables, including the main effects of psychological distress and disordered eating on each other. Of the students, 45% reported eating out 3 times or more a week. Furthermore, approximately 18% screened positive for disordered eating and 33% reported high levels of psychological distress in the past 30 days. After adjustment for other variables, eating out 5 times or more a week was not significantly associated with the odds of disordered eating (OR 1.21, p = 0.32). However, eating out 5 times or more per week was significantly associated with odds of having psychological distress (OR 1.46, p = 0.03). Both psychological distress and disordered eating were strongly associated with each other (OR 2.58, p < 0.001).


Antimicrobial and micronutrient interventions for the management of infants under 6 months of age identified with severe malnutrition: a literature review.
Infants under 6 months (U6M) contribute a significant proportion of the burden and mortality of severe malnutrition globally. Evidence of underlying aetiology in this population is sparse, but it is known that the group includes ex-preterm and low birthweight (LBW) infants. They represent a unique population given their dependence on breastmilk or a safe, secure alternative. Nutrition agencies and health providers struggle to make programming decisions on which interventions should be provided to this group based upon the 2013 WHO Guidelines for the 'Management of Severe Acute Malnutrition in Infants and Young Children' since there are no published interventional trial data focussed on this population. Interim guidance for this group might be informed by evidence of safety and efficacy in adjacent population groups. A narrative literature review was performed of systematic reviews, meta-analyses and randomised controlled trials of antimicrobial and micronutrient interventions (antibiotics, deworming, vitamin A, vitamin D, iron, zinc, folic acid and oral rehydration solution (ORS) for malnutrition) across the population groups of low birthweight/preterm infants, infants under 6 months, infants and children over 6 months with acute malnutrition or through supplementation to breastfeeding mothers. Outcomes of interest were safety and efficacy, in terms of mortality and morbidity. Ninety-four articles were identified for inclusion within this review. None of these studied interventions exclusively in severely malnourished infants U6M. 64% reported on the safety of studied interventions. Significant heterogeneity was identified in definitions of study populations, interventions provided, and outcomes studied. The evidence for efficacy and safety across population groups is reviewed and presented for the interventions listed. The direct evidence base for medical interventions for severely malnourished infants U6M is sparse. Our review identifies a specific need for accurate micronutrient profiling and interventional studies of micronutrients and oral fluid management of diarrhoea amongst infants U6M meeting anthropometric criteria for severe malnutrition. Indirect evidence presented in this review may help shape interim policy and programming decisions as well as the future research agenda for the management of infants U6M identified as malnourished.


The neural basis of error detection: conflict monitoring and the error-related negativity.
According to a recent theory, anterior cingulate cortex is sensitive to response conflict, the coactivation of mutually incompatible responses. The present research develops this theory to provide a new account of the error-related negativity (ERN), a scalp potential observed following errors. Connectionist simulations of response conflict in an attentional task demonstrated that the ERN--its timing and sensitivity to task parameters--can be explained in terms of the conflict theory. A new experiment confirmed predictions of this theory regarding the ERN and a second scalp potential, the N2, that is proposed to reflect conflict monitoring on correct response trials. Further analysis of the simulation data indicated that errors can be detected reliably on the basis of post-error conflict. It is concluded that the ERN can be explained in terms of response conflict and that monitoring for conflict may provide a simple mechanism for detecting errors.


DACT2 is frequently methylated in human gastric cancer and methylation of DACT2 activated Wnt signaling.
Dapper, Dishevelled-associated antagonist of β-catenin (DACT), is a key regulator of Wnt signaling pathway. The purpose of this study is to explore the epigenetic changes and the function ofDACT2 in human gastric cancer (GC). Eight human gastric cancer cell lines, 167 cases of primary gastric cancer and 8 cases of normal gastric mucosa were involved in this study. In addition, methylation Specific PCR (MSP), semi-quantitative RT-PCR, colony formation assay, flow cytometry assay, siRNA, immunofluorescence techniques and xenograft mice models were employed. The results indicate that DACT2 is frequently methylated in human primary gastric cancer (55.7%), and that methylation of DACT2 is associated with lost or reduction in its expression (X(2) test, P<0.01). We found that DACT2 expression was regulated by promoter region hypermethylation. Methylation of DACT2 is associated with tumor differentiation, invasion and intravascular cancerous emboli (X(2) test, P<0.05, P<0.05 and P<0.05). In gastric cancer patients treated with 5-FU and cisplatin, the five-year survival rates are higher in DACT2 methylated cases. DACT2 inhibits cell proliferation, migration and invasion in gastric cancer cells and suppresses gastric cancer xenografts in mice. Restoration of DACT2 expression inhibits both canonical and noncanonical WNT signaling in SGC7901 cells. Restoration of DACT2 expression sensitized gastric cancer cells to paclitaxel and 5-FU. In conclusion, DACT2 is frequently methylated in human gastric cancer and DACT2 expression is silenced by promoter region hypermethylation. DACT2 suppressed gastric cancer proliferation, invasion and metastasis by inhibiting Wnt signaling both in vitro and in vivo.


Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies.
The disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) was identified recently as the TDP-43 (TAR DNA-binding protein 43), thereby providing a molecular link between these two disorders. In FTLD-U and ALS, TDP-43 is redistributed from its normal nuclear localization to form cytoplasmic insoluble aggregates. Moreover, pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate C-terminal fragments (CTFs). However, the specific cleavage site(s) and the biochemical properties as well as the functional consequences of pathological TDP-43 CTFs remained unknown. Here we have identified the specific cleavage site, Arg(208), of a pathological TDP-43 CTF purified from FTLD-U brains and show that the expression of this and other TDP-43 CTFs in cultured cells recapitulates key features of TDP-43 proteinopathy. These include the formation of cytoplasmic aggregates that are ubiquitinated and abnormally phosphorylated at sites found in FTLD-U and ALS brain and spinal cord samples. Furthermore, we observed splicing abnormalities in a cell culture system expressing TDP-43 CTFs, and this is significant because the regulation of exon splicing is a known function of TDP-43. Thus, our results show that TDP-43 CTF expression recapitulates key biochemical features of pathological TDP-43 and support the hypothesis that the generation of TDP-43 CTFs is an important step in the pathogenesis of FTLD-U and ALS.


Non-uniform displacement within the Achilles tendon during passive ankle joint motion.
An initial step in the understanding of Achilles tendon dynamics is to investigate the effects of passive motion, thereby minimising muscle activation and reducing internal joint forces. Internal tendon dynamics during passive ankle joint motion have direct implications for clinical rehabilitation protocols after Achilles tendon surgery. The aim of this study was to test the hypothesis that tendon tissue displacement is different in different layers of the Achilles tendon during controlled passive ankle joint movements. Ultrasound imaging was conducted on the right Achilles tendon of nine healthy recreationally active males. Standardised isokinetic passive dorsi-plantar-flexion movements were performed with a total range of motion of 35°. The tendon was divided into superficial, central and deep layers in the resulting B-mode ultrasound images viewed in the sagittal plane. A block-matching speckle tracking algorithm was applied post-process, with kernels for the measurement of displacement placed in each of the layers. The mean (SD) displacement of the Achilles tendon during passive dorsiflexion was 8.4 (1.9) mm in the superficial layer, 9.4 (1.9) mm in the central portion and 10.4 (2.1) mm in the deep layer, respectively. In all cases, the movement of the deep layer of the tendon was greater than that of the superficial one (P < 0.01). These results, achieved in vivo with ultrasonographic speckle tracking, indicated complex dynamic differences in different layers of the Achilles tendon, which could have implications for the understanding of healing processes of tendon pathologies and also of normal tendon function.


Expression of unusual immunophenotype combinations in acute myelogenous leukemia.
Immunophenotypes for 272 patients with acute myelogenous leukemia (AML) were analyzed using a panel of 22 antibodies. Numerical evidence for unusual coexpressions (present in normal marrow at < or = 0.1%) of surface markers on > or = 10% of the blast cells was found in 85% of all cases. Asynchronous expression of myeloid differentiation antigens occurred in 70% of the cases. Unusual coexpression of T-lymphoid, B-lymphoid, or natural killer (NK) markers with myeloid markers occurred in 38%, 13%, and 21%, respectively, of all AML cases. Two- and three-color analyses confirmed coexpression in 15 of 15 cases, and indicated that these percentages are an underestimate, because coexpression can be demonstrated in cases without numerical overlap. These data indicate that the unusual coexpression of normal differentiation antigens is a common occurrence in AML. Markers in 12 of 13 patients were similar between presentation and relapse, and in two patients, unusual phenotypes detected at first relapse were shown at second relapse, indicating these immunophenotypes are stable in the majority of AML patients. Significant correlations were found between t(8;21) cytogenetics and coexpression of CD19 with CD15 or CD34, t(9;22) and coexpression of CD19 and CD34, and t(15;17) and coexpression of CD2 and myeloid antigens. Multiparameter fluorescence analysis allows detection of unusual phenotypes when the blast counts are < 5% (classical remission). Analysis of 16 patients in remission indicated the presence of presentation phenotypes in 0.2% to 7.9% of the lymphocyte + blast light scatter region, representing 0.03% to 1.4% of the total nucleated marrow cells. Of the 16 patients with > or = 4 months follow-up after detection of these cells, 6 of 6 patients with > or = 0.2% unusual presentation phenotypic marrow cells have relapsed, while 9 of 10 patients with < 0.2% remain in remission. The detection of cells with the unusual presentation phenotype may reflect residual AML cells, and their increase may predict relapse.


Effects of β-blockers and anxiety on complication rates after acute myocardial infarction.
Anxiety is common after acute myocardial infarction and increases the number of complications and the length of stay in the hospital. Anxiety-induced activation of the sympathetic nervous system is hypothesized to be an underlying cause of increased complication rates. Little is known about whether use of β-blockers eliminates the effects of anxiety on complication rate and length of stay. To compare number of complications and length of stay among nonanxious and anxious patients receiving β-blockers during hospitalization. A total of 322 patients with acute myocardial infarction participated in this study within 48 hours of hospital admission. Patients completed the Brief Symptom Inventory to assess anxiety level. After discharge, medical records were reviewed to determine use of β-blockers, type and number of complications, and length of stay. Most patients (96%) were treated with less than 200 mg daily of metoprolol. Anxious patients had more complications (mean [SD], 1.43 [0.15] vs 0.73 [.09], P ≤ .01) and longer stays (7.0 [0.49] vs 5.7 [0.36] days, P < .05) than did nonanxious patients. To test whether the dose of β-blocker made a difference, the interaction between daily dose and anxiety score was tested. No interaction was found between metoprolol dose and anxiety score, and no main effect was found for metoprolol dose. Anxious patients had more complications and longer stays than did nonanxious patients. The administration of metoprolol did not eliminate this relationship, perhaps because patients did not receive a sufficient dose of metoprolol to counter the effect of anxiety.


Modified Genta triple stain for identifying Helicobacter pylori.
To evaluate whether lead nitrate could replace uranyl nitrate in the Genta stain for H pylori without sacrificing the advantages of the triple stain (Steiner silver impregnation combined with Alcian blue and haematoxylin/eosin (H&E)). A comparison was made in 16 specimens between the original triple stain and the revised version. One pathologist evaluated all sections. Direct substitution of lead nitrate for uranium nitrate produced well stained organisms without interfering with H&E or Alcian blue staining. No difference was found in the ability to identify bacteria in 11 cases with H pylori density of 1 or 2 (on a scale of 0 to 5). The potential chemical and radiological hazards associated with uranium nitrate can be eliminated by using lead nitrate without sacrificing the advantages obtained by using the triple stain.


High incidence of herpes zoster in patients with systemic lupus erythematosus: an immunological analysis.
The incidence of herpes zoster was determined in patients with systemic lupus erythematosus (SLE) and the cellular and humoral immunity to varicella zoster virus (VZV) investigated in 45 of these 92 patients. The incidence of herpes zoster was high, occurring in 40 patients (43%), though it was benign in all. Patients with SLE who had had zoster showed significantly higher antibody titres than normal subjects. On the other hand, only 13 of 43 (30%) patients with SLE showed positive delayed hypersensitivity skin reactions to VZV antigen, despite a history of infections with VZV, whereas all 15 normal subjects had positive reactions. Skin reactions to VZV correlated directly with the ratio of OKT4+ to OKT8+ T cells and inversely with the dose of corticosteroids. These results suggest that the high incidence of herpes zoster in patients with SLE is probably due to defects in cellular immunity and that normal or higher titres of antibodies to VZV will not act as a preventive against zoster. In addition, reactivation of VZV, whether symptomatic or not, seemed often to occur in patients with SLE.


ENPP1 processes protein ADP-ribosylation in vitro.
ADP-ribosylation is a conserved post-translational protein modification that plays a role in all major cellular processes, particularly DNA repair, transcription, translation, stress response and cell death. Hence, dysregulation of ADP-ribosylation is linked to the physiopathology of several human diseases including cancers, diabetes and neurodegenerative disorders. Protein ADP-ribosylation can be reversed by the macrodomain-containing proteins PARG, TARG1, MacroD1 and MacroD2, which hydrolyse the ester bond known to link proteins to ADP-ribose as well as consecutive ADP-ribose subunits; targeting this bond can thus result in the complete removal of the protein modification or the conversion of poly(ADP-ribose) to mono(ADP-ribose). Recently, proteins containing the NUDIX domain - namely human NUDT16 and bacterial RppH - have been shown to process in vitro protein ADP-ribosylation through an alternative mechanism, converting it into protein-conjugated ribose-5'-phosphate (R5P, also known as pR). Though this protein modification was recently identified in mammalian tissues, its physiological relevance and the mechanism of generating protein phosphoribosylation are currently unknown. Here, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) as the first known mammalian enzyme lacking a NUDIX domain to generate pR from ADP-ribose on modified proteins in vitro. Thus, our data show that at least two enzyme families - Nudix and ENPP/NPP - are able to metabolize protein-conjugated ADP-ribose to pR in vitro, suggesting that pR exists and may be conserved from bacteria to mammals. We also demonstrate the utility of ENPP1 for converting protein-conjugated mono(ADP-ribose) and poly(ADP-ribose) into mass spectrometry-friendly pR tags, thus facilitating the identification of ADP-ribosylation sites.


Analysis of the sensitivity of absorbed light and incident light profile to various canopy architecture and stand conditions.
We analyzed the effect of simplifying assumptions in canopy representation of radiation transfer models, comparing modeled diffuse non-interceptance and photosynthetic photon flux density with measurements at different layers of complex pine-broadleaved canopy with large seasonal variation of leaf area index. The most detailed model included clumping of trees (i.e., stand density) and a vertical specification of leaf angle distribution and shoot clumping. A less detailed model replaced the vertically specified variables with their means. The most parsimonious model accounted for neither shoot clumping nor stand density. The vertical specification of shoot clumping and leaf angle distribution only slightly improved vertical and seasonal openness and light estimates over using mean values. Further simplification had little effect on total absorbed light but was more risky for estimates of the vertical distributions of openness and light absorbed by the canopy, which will affect photosynthesis estimates due to the non-linearity of photosynthetic light response. Including woody surfaces in winter, when leaf area was low, was essential for reproducing the measurements correctly. A sensitivity analysis showed that ignoring (i) shoot clumping could result in a substantial overestimation of total absorbed light with errors increasing with decreasing leaf area and (ii) stand density in sparse stands could lead to substantial overestimation of total absorbed light, and the effect is largely independent of leaf area. Also, (iii) the effect of changing leaf angle distribution increased with decreasing leaf area, and was larger and more persistent along the leaf area range with increasing shoot clumping. Overall, accounting for the effect of tree clumping on absorbed light is most important in stands composed of species where leaves are not very clumped (e.g., broadleaved). However, even in forests with highly clumped shoots (i.e., coniferous), an accurate estimation of absorbed light distribution in stands requires incorporation of stand density in the model.


Vps35-dependent recycling of Trem2 regulates microglial function.
Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11. When Vps35 is knocked down, Trem2 accumulated in the lysosomes but was not degraded. More importantly, Vps35 deficiency leads to excessive lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and IL-6 production, which can be abolished by Trem2 overexpression. Furthermore, R47H Trem2, an AD-associated mutant, failed to interact with Vps35 and became unstable compared with wild-type Trem2. Our study suggests that Vps35/retromer is responsible for recycling of Trem2 in the regulation of microglial function such as proinflammatory responses, whereas R47H mutation impairs Trem2 trafficking, which might contribute to AD.


Cellular interactions and metabolism of aflatoxin: an update.
The aflatoxins are a group of closely related mycotoxins that are widely distributed in nature. The most important of the group is aflatoxin B1 (AFB1), which has a range of biological activities, including acute toxicity, teratogenicity, mutagenicity and carcinogenicity. In order for AFB1 to exert its effects, it must be converted to its reactive epoxide by the action of the mixed function mono-oxygenase enzyme systems (cytochrome P450-dependent) in the tissues (in particular, the liver) of the affected animal. This epoxide is highly reactive and can form derivatives with several cellular macromolecules, including DNA, RNA and protein. Cytochrome P450 enzymes may additionally catalyse the hydroxylation (to AFQ1 and AFM1) and demethylation (to AFP1) of the parent AFB1 molecule, resulting in products less toxic than AFB1. Conjugation of AFB1 to glutathione (mediated by glutathione S-transferase) and its subsequent excretion is regarded as an important detoxification pathway in animals. Resistance to AFB1 toxicity has been interpreted in terms of levels and activities of these detoxifying pathways. This article reviews the multiple reactions and effects attributed to aflatoxin, with particular reference to the interaction of aflatoxin with nucleic acids and proteins, and the contribution this mycotoxin has in disease development and in the promotion of hepatocellular carcinoma (HCC). The anti-mutagenic properties of several dietary factors are also considered in this article. Undoubtedly, the most important aspect of aflatoxin action is its putative role in the development of human cancer, in particular, HCC. Recently, there has been a renewed interest in this aspect and experimental evidence is rapidly accumulating at the molecular level, indicating aflatoxin as an important consideration in the aetiology of human HCC.


Effect of adding the herb Achillea millefolium on mouthwash on chemotherapy induced oral mucositis in cancer patients: A double-blind randomized controlled trial.
Oral mucositis (OM) is a debilitating side-effect of chemotherapy. It has different complications, including impairment of drinking, eating and even talking, sometimes so severe that physician stops the therapy. Investigating the effect of Achillea millefolium distillate solution in the treatment of chemotherapy-induced OM. In this randomized controlled trial, 56 cancer patients with chemotherapy-induced OM were randomly assigned into control and experimental groups in similar blocks based on the severity of OM. The experimental group gargled 15 mL of a mixture of routine solution and distilled A. millefolium 4 times a day for 14 days while the control group gargled 15 mL of routine solution. The severity of OM was assessed at three times before, 7 and 14 days after intervention. Data was analyzed using Wilcoxon, Kruskal-Wallis, Mann-Whitney U, Friedman, Chi-square and Fisher's exact tests. The mean severity score of OM was 2.39 ± 0.875 in both groups at start of the study that was changed to 1.07 ± 0.85 and 0.32 ± 0.54 in the intervention group in days 7 and 14 (p < 0.001). However, the severity of OM was increased to 2.75 ± 0.87 and 2.89 ± 0.956 in the control group respectively (p < 0.001). A. millefolium distillate healed OM much more than the routine solution. Therefore, it is suggested to be used in patients with chemotherapy-induced OM. The study was registered in the Iranian Registry of Clinical Trials, Number: IRCT2013092214729N1.


Development of a new vaccine for the prevention of Lassa fever.
Recent importation of Lassa fever into Germany, the Netherlands, the United Kingdom, and the United States by travelers on commercial airlines from Africa underscores the public health challenge of emerging viruses. Currently, there are no licensed vaccines for Lassa fever, and no experimental vaccine has completely protected nonhuman primates against a lethal challenge. We developed a replication-competent vaccine against Lassa virus based on attenuated recombinant vesicular stomatitis virus vectors expressing the Lassa viral glycoprotein. A single intramuscular vaccination of the Lassa vaccine elicited a protective immune response in nonhuman primates against a lethal Lassa virus challenge. Vaccine shedding was not detected in the monkeys, and none of the animals developed fever or other symptoms of illness associated with vaccination. The Lassa vaccine induced strong humoral and cellular immune responses in the four vaccinated and challenged monkeys. Despite a transient Lassa viremia in vaccinated animals 7 d after challenge, the vaccinated animals showed no evidence of clinical disease. In contrast, the two control animals developed severe symptoms including rashes, facial edema, and elevated liver enzymes, and ultimately succumbed to the Lassa infection. Our data suggest that the Lassa vaccine candidate based on recombinant vesicular stomatitis virus is safe and highly efficacious in a relevant animal model that faithfully reproduces human disease.


Evidence for redundancy but not trans factor-cis element coevolution in the regulation of Drosophila Yp genes.
In Drosophila melanogaster and the endemic Hawaiian species D. grimshawi three Yolk protein (Yp) genes are expressed in a similar sex- and tissue-specific pattern. In contrast, DNA sequence comparisons of promoter/enhancer regions show low levels of similarity. We tested the functional significance of these observations by transforming D. melanogaster with the genomic region that includes the divergently transcribed D. grimshawi DgYp1 and DgYp2 genes; we found that the introduced genes were expressed in female fat body and in ovaries but not in males. Moreover, we found D. grimshawi proteins in the hemolymph and accumulating in ovaries. Using reporter constructs we showed that the intergenic region from D. grimshawi was sufficient to drive accurate expression, but some low level of ectopic expression was seen in males. Transforming D. melanogaster with constructs bearing deletions within the D. grimshawi intergenic region revealed only subtle effects in the overall level of expression, suggesting a high level of redundancy. Testing mutants in the sex-specific regulator doublesex revealed that it is capable of repressing the DgYp genes in males. Together, these data show that D. melanogaster trans-acting factors can regulate the in vivo pattern of DgYp expression and support the notion of a redundant and complex system of cis-acting elements.


Who fears the HPV vaccine, who doesn't, and why? an experimental study of the mechanisms of cultural cognition.
The cultural cognition thesis holds that individuals form risk perceptions that reflect their commitments to contested views of the good society. We conducted a study that used the dispute over mandatory HPV vaccination to test the cultural cognition thesis. Although public health officials have recommended that all girls aged 11 or 12 be vaccinated for HPV-a sexually transmitted virus that causes cervical cancer-political controversy has blocked adoption of mandatory school-enrollment vaccination programs in all but one state. An experimental study of a large sample of American adults (N = 1,538) found that cultural cognition generates disagreement about the risks and benefits of the vaccine through two mechanisms: biased assimilation, and the credibility heuristic. We discuss theoretical and practical implications.


Effects of dietary forage and calf starter on ruminal pH and transcriptomic adaptation of the rumen epithelium in Holstein calves during the weaning transition.
We investigated the relationship between ruminal pH and transcriptomic adaptation of the rumen epithelium (RE) of calves fed calf starter with and without forage during the weaning transition. Holstein calves were assigned to groups fed calf starter either with forage (HAY group, n = 3) or without forage (CON group, n = 4). Ruminal pH was measured continuously, and rumen fluid and epithelium were collected 3 wk after weaning. mRNA expression profiles of the RE were examined by one-color microarray. Differentially expressed genes (DEGs) were investigated using the Ingenuity Pathway Analysis (IPA). Mean and maximum ruminal pH were significantly (P < 0.05) higher, and the duration of pH < 5.8 during 1 day was significantly (P < 0.05) shorter, in the HAY group. The proportion of ruminal acetate and the acetate-to-propionate ratio were significantly (P < 0.05) lower in the CON group. DEGs encoding transcription regulators (SREBP1), insulin-like growth factor binding proteins (IGFBP7 and CTGF), ketogenic enzymes (HMGCL, BDH1, and BDH2), and a transporter (SLC16A3) were identified (P < 0.05) between the two groups. A growth factor (TGFB1) and signaling pathway (EGF and EGFR) were activated as upstream regulators. These results suggest that dietary forage alleviates ruminal acidosis, and the decrease in ruminal pH may damage the RE, leading to changes in gene expression to repair the damage. Furthermore, rumen development may be regulated by growth factor (TGFB1) and signaling pathways (EGF and IGFBP) for adaptation to feeding on calf starter with and without forage during the weaning transition.


Regulation of neurogenesis by interkinetic nuclear migration through an apical-basal notch gradient.
The different cell types in the central nervous system develop from a common pool of progenitor cells. The nuclei of progenitors move between the apical and basal surfaces of the neuroepithelium in phase with their cell cycle, a process termed interkinetic nuclear migration (INM). In the retina of zebrafish mikre oko (mok) mutants, in which the motor protein Dynactin-1 is disrupted, interkinetic nuclei migrate more rapidly and deeply to the basal side and more slowly to the apical side. We found that Notch signaling is predominantly activated on the apical side in both mutants and wild-type. Mutant progenitors are, thus, less exposed to Notch and exit the cell cycle prematurely. This leads to an overproduction of early-born retinal ganglion cells (RGCs) at the expense of later-born interneurons and glia. Our data indicate that the function of INM is to balance the exposure of progenitor nuclei to neurogenic versus proliferative signals.


Revisiting the taxonomy and evolution of pathogenicity of the genus Leptospira through the prism of genomics.
The causative agents of leptospirosis are responsible for an emerging zoonotic disease worldwide. One of the major routes of transmission for leptospirosis is the natural environment contaminated with the urine of a wide range of reservoir animals. Soils and surface waters also host a high diversity of non-pathogenic Leptospira and species for which the virulence status is not clearly established. The genus Leptospira is currently divided into 35 species classified into three phylogenetic clusters, which supposedly correlate with the virulence of the bacteria. In this study, a total of 90 Leptospira strains isolated from different environments worldwide including Japan, Malaysia, New Caledonia, Algeria, mainland France, and the island of Mayotte in the Indian Ocean were sequenced. A comparison of average nucleotide identity (ANI) values of genomes of the 90 isolates and representative genomes of known species revealed 30 new Leptospira species. These data also supported the existence of two clades and 4 subclades. To avoid classification that strongly implies assumption on the virulence status of the lineages, we called them P1, P2, S1, S2. One of these subclades has not yet been described and is composed of Leptospira idonii and 4 novel species that are phylogenetically related to the saprophytes. We then investigated genome diversity and evolutionary relationships among members of the genus Leptospira by studying the pangenome and core gene sets. Our data enable the identification of genome features, genes and domains that are important for each subclade, thereby laying the foundation for refining the classification of this complex bacterial genus. We also shed light on atypical genomic features of a group of species that includes the species often associated with human infection, suggesting a specific and ongoing evolution of this group of species that will require more attention. In conclusion, we have uncovered a massive species diversity and revealed a novel subclade in environmental samples collected worldwide and we have redefined the classification of species in the genus. The implication of several new potentially infectious Leptospira species for human and animal health remains to be determined but our data also provide new insights into the emergence of virulence in the pathogenic species.


Clinical management of Staphylococcus aureus bacteraemia.
Staphylococcus aureus bacteraemia is one of the most common serious bacterial infections worldwide. In the UK alone, around 12,500 cases each year are reported, with an associated mortality of about 30%, yet the evidence guiding optimum management is poor. To date, fewer than 1500 patients with S aureus bacteraemia have been recruited to 16 controlled trials of antimicrobial therapy. Consequently, clinical practice is driven by the results of observational studies and anecdote. Here, we propose and review ten unanswered clinical questions commonly posed by those managing S aureus bacteraemia. Our findings define the major areas of uncertainty in the management of S aureus bacteraemia and highlight just two key principles. First, all infective foci must be identified and removed as soon as possible. Second, long-term antimicrobial therapy is required for those with persistent bacteraemia or a deep, irremovable focus. Beyond this, the best drugs, dose, mode of delivery, and duration of therapy are uncertain, a situation compounded by emerging S aureus strains that are resistant to old and new antibiotics. We discuss the consequences on clinical practice, and how these findings define the agenda for future clinical research.


Beryllium, an adjuvant that promotes gamma interferon production.
Beryllium is associated with a human pulmonary granulomatosis characterized by an accumulation of CD4(+) T cells in the lungs and a heightened specific lymphocyte proliferative response to beryllium (Be) with gamma interferon (IFN-gamma) release (i.e., a T helper 1 [Th1] response). While an animal model of Be sensitization is not currently available, Be has exhibited adjuvant effects in animals. The effects of Be on BALB/c mice immunized with soluble leishmanial antigens (SLA) were investigated to determine if Be had adjuvant activity for IFN-gamma production, an indicator of the Th1 response. In this strain of Leishmania-susceptible BALB/c mice, a Th2 response is normally observed after in vivo SLA sensitization and in vitro restimulation with SLA. If interleukin-12 (IL-12) is given during in vivo sensitization with SLA, markedly increased IFN-gamma production and decreased IL-4 production are detected. We show here that when beryllium sulfate (BeSO(4)) was added during in vivo sensitization of BALB/c mice with SLA and IL-12, significantly increased IFN-gamma production and decreased IL-4 production from lymph node and spleen cells were detected upon in vitro SLA restimulation. No specific responses were observed to Be alone. Lymph node and spleen cells from all mice proliferated strongly and comparably upon in vitro restimulation with SLA and with SLA plus Be; no differences were noted among groups of mice that received different immunization regimens. In vivo, when Be was added to SLA and IL-12 for sensitization of BALB/c mice, more effective control of Leishmania infection was achieved. This finding has implications for understanding not only the development of granulomatous reactions but also the potential for developing Be as a vaccine adjuvant.


Quantitative Trait Locus (QTL) meta-analysis and comparative genomics for candidate gene prediction in perennial ryegrass (Lolium perenne L.).
In crop species, QTL analysis is commonly used for identification of factors contributing to variation of agronomically important traits. As an important pasture species, a large number of QTLs have been reported for perennial ryegrass based on analysis of biparental mapping populations. Further characterisation of those QTLs is, however, essential for utilisation in varietal improvement programs. A bibliographic survey of perennial ryegrass trait-dissection studies identified a total of 560 QTLs from previously published papers, of which 189, 270 and 101 were classified as morphology-, physiology- and resistance/tolerance-related loci, respectively. The collected dataset permitted a subsequent meta-QTL study and implementation of a cross-species candidate gene identification approach. A meta-QTL analysis based on use of the BioMercator software was performed to identify two consensus regions for pathogen resistance traits. Genes that are candidates for causal polymorphism underpinning perennial ryegrass QTLs were identified through in silico comparative mapping using rice databases, and 7 genes were assigned to the p150/112 reference map. Markers linked to the LpDGL1, LpPh1 and LpPIPK1 genes were located close to plant size, leaf extension time and heading date-related QTLs, respectively, suggesting that these genes may be functionally associated with important agronomic traits in perennial ryegrass. Functional markers are valuable for QTL meta-analysis and comparative genomics. Enrichment of such genetic markers may permit further detailed characterisation of QTLs. The outcomes of QTL meta-analysis and comparative genomics studies may be useful for accelerated development of novel perennial ryegrass cultivars with desirable traits.


Capillary refilling time in newborns--optimal pressing time, sites of testing and normal values.
Aspects of capillary refilling time (CRT) in newborns, such as pressing time, sites of testing, normal values and difference between observers were assessed. CRT was measured in 280 term newborns, divided into 7 groups of 40 each, varying pressing time (from 1 to 7 s) was applied. CRT was measured in midpoints of forehead and sternum and plantar surface of heel (defined as head, chest and heel). No statistically significant difference was found between 3 and 7 s pressing time groups. The data points of the CRT of the head and chest approached normality, whilst those of the heel were widely scattered. Normal CRT in newborns is <3 s. No significant difference between two observers in head and chest CRT values was found.


The cognitive correlates of functional status: a review from the Committee on Research of the American Neuropsychiatric Association.
This report reviews the state of the literature and opportunities for research related to the cognitive correlates of functional status. The prediction of functional capacity on the basis of cognitive test performance is an important aspect of neuropsychological assessment. Moreover, functional impairment or "disability" is an essential part of dementia case finding. Nevertheless, relatively little attention has been given to the empirical study of the specific cognitive correlates of functional outcomes. What literature is available suggests that 1) the variance in functional status that can be specifically attributed to cognition is surprisingly modest; 2) some cognitive domains may be more relevant to functional capacity than others; 3) some measures of executive control function are relatively strong correlates of functional capacities, particularly medical or financial decision-making; and 4) "general" cognitive screening tests are surprisingly strong correlates of functional status. These findings are of particular significance to dementia case finding, epidemiology, and treatment. The extensive literature on functional status has yet to be integrated with the equally extensive literature on cognitive assessment. Better integration of cognitive and functional assessments would offer greater clinical utility. However, psychometric batteries may have to be redesigned to maximize their capacity to capture the variance in functional outcomes.


miR-145 Inhibits Th9 Cell Differentiation by Suppressing Activation of the PI3K/Akt/mTOR/p70S6K/HIF-1α Pathway in Malignant Ascites from Liver Cancer.
Our previous experiments confirmed that T helper type 9 (Th9) cells were involved in the occurrence and development of malignant ascites caused by liver cancer. The current study investigated the mechanism underlying microRNA (miR-145)-mediated inhibition of Th9 cells in an malignant ascites model with liver cancer. CD4+ T cells were induced to differentiate Th9 cells after transfection with miR-145 mimics or negative control. A malignant ascites mouse model was transfected with miR-145agomir or negative control. Th9 cells were detected by flow cytometry. Enzyme-linked immunosorbent assay was applied to detect the interleukin 9 (IL-9) cytokine and hypoxia-inducible factor 1 alpha (HIF-1α). RT-PCR was used to detect the expression of miR-145 and phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase/HIF-1α (PI3K/Akt/mTOR/p70S6K/HIF-1α) mRNA. Western blotting and immunofluorescence were performed to detect the expression of PI3K/Akt/mTOR/p70S6K/HIF-1α-related proteins. In vitro experiments showed that miR-145 inhibited Th9 cell polarization, HIF-1α expression, and PI3K/Akt/mTOR/p70S6K pathway activation. In the malignant ascites mouse model, miR-145 also demonstrated inhibitory effects on Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. miR-145 may inhibit Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. These findings suggest a novel therapeutic target for malignant ascites from liver cancer.


Study of Knowledge, Attitudes, and Practices Toward Risk Factors and Early Detection of Noncommunicable Diseases Among Rural Women in India.
In recognition of the growing burden of noncommunicable diseases (NCDs), including cancer, we assessed the knowledge, attitudes, and practices of rural women in low-resourced countries toward common NCDs and the barriers they face in receiving NCD early detection services. The study was conducted in a rural block of India using the Rapid Assessment and Response Evaluation ethnographic assessment, which included in-depth interviews of key health officials; focus group discussions with women, men, teachers, and health workers from the block; and a knowledge, attitudes, and practices questionnaire survey. The home-based survey was conducted among 1,192 women selected from 50 villages of the block using a two-stage randomization process and stratified to 30- to 44-year and 45- to 60-year age-groups. Our study revealed low awareness among women with regard to tobacco as a risk factor; hypertension, diabetes, and cancer as major health threats; and the importance of their early detection. Only 4.8% of women reported to have ever consumed tobacco, and many others consumed smokeless tobacco without knowing that the preparations contained tobacco. Only 27.3% and 11.5% of women had any knowledge about breast and cervical cancer, respectively, and only a few could describe at least one common symptom of either cancer. Self-reported diagnosis of hypertension and diabetes was significantly lower than the reported national prevalence. Only 0.9% and 1.3% of women reported having had a breast examination or gynecologic checkup, respectively, in the past 5 years. Low female empowerment and misconceptions were major barriers. Barriers need to be addressed to improve uptake of NCD early detection services.


Serum cytokine profiles in patients with adult onset Still's disease.
Adult onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by fever, arthritis, and rash. Although the pathogenesis is not known, immunologically mediated inflammation occurs in active AOSD. To evaluate the pathogenesis and disease activity of AOSD, we measured serial serum concentrations of several cytokines in patients with active and inactive disease. Seventeen patients diagnosed as having AOSD were enrolled. We analyzed clinical and laboratory findings retrospectively. Serial serum samples were obtained from 14 patients with active and inactive AOSD. Interleukin 18 (IL-18), soluble IL-2 receptor (sIL-2R), IL-6, interferon-g (IFN-g), and IL-8 were determined by ELISA. Serum levels of IL-18, IFN-g, and IL-8 were significantly higher in patients with AOSD than in healthy controls (p < 0.01), but there were no significant differences between patients with active and inactive AOSD. Serum sIL-2R levels tended to be higher in the active state than in healthy controls, but there was no statistically significant difference between the 2 groups. Serum sIL-2R levels decreased significantly with antiinflammatory therapy (p < 0.05). Serum IL-18 and sIL-2R levels correlated significantly with serum ferritin levels in the active AOSD group (p < 0.05). Overproduction of IL-18 may contribute to the pathogenic mechanism of AOSD, and serum sIL-2R levels may be used as a marker for monitoring disease activity in AOSD.