Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients.
Famotidine has been posited as a potential treatment for coronavirus disease 2019 (COVID-19). We compared the incidence of COVID-19 outcomes (i.e., death and death or intensive services use) among hospitalized famotidine users vs proton pump inhibitors (PPIs) users, hydroxychloroquine users, or famotidine nonusers separately. We constructed a retrospective cohort study using data from COVID-19 Premier Hospital electronic health records. The study population was COVID-19 hospitalized patients aged 18 years or older. Famotidine, PPI, and hydroxychloroquine exposure groups were defined as patients dispensed any medication containing 1 of the 3 drugs on the day of admission. The famotidine nonuser group was derived from the same source population with no history of exposure to any drug with famotidine as an active ingredient before or on the day of admission. Time at risk was defined based on the intention-to-treat principle starting 1 day after admission to 30 days after admission. For each study comparison group, we fit a propensity score model through large-scale regularized logistic regression. The outcome was modeled using a survival model. We identified 2,193 users of PPI, 5,950 users of the hydroxychloroquine, 1,816 users of famotidine, and 26,820 nonfamotidine users. After propensity score stratification, the hazard ratios (HRs) for death were as follows: famotidine vs no famotidine HR 1.03 (0.89-1.18), vs PPIs: HR 1.14 (0.94-1.39), and vs hydroxychloroquine: 1.03 (0.85-1.24). Similar results were observed for the risk of death or intensive services use. We found no evidence of a reduced risk of COVID-19 outcomes among hospitalized COVID-19 patients who used famotidine compared with those who did not or compared with PPI or hydroxychloroquine users.


Is serological follow-up useful for patients with cutaneous Lyme borreliosis?
Serologic follow-up examinations are frequently performed in patients with erythema migrans, borrelial lymphocytoma, and acrodermatitis chronica atrophicans (the 3 dermatoborrelioses) to evaluate treatment efficacy. There is, however, substantial proof in the literature that antibody titer development after therapy is unpredictable and variable, and moreover it is largely uncorrelated with the clinical course and mode of antibiotic treatment. For example, persistent positive IgG and/ or IgM antibody titers do not indicate treatment failure. Thus, repeated serologic testing is of very limited value for assessing therapy efficacy, and therefore not recommended in the follow-up of dermatoborrelioses patients. Since cultivation of the etiologic agent, Borrelia burgdorferi sensu lato, and polymerase chain reaction are also inadequate for this purpose, the assessment of patients with cutaneous manifestations of Lyme borreliosis in the follow-up rests primarily on the clinical picture.


I-AUV Docking and Panel Intervention at Sea.
The use of commercially available autonomous underwater vehicles (AUVs) has increased during the last fifteen years. While they are mainly used for routine survey missions, there is a set of applications that nowadays can be only addressed by manned submersibles or work-class remotely operated vehicles (ROVs) equipped with teleoperated arms: the intervention applications. To allow these heavy vehicles controlled by human operators to perform intervention tasks, underwater structures like observatory facilities, subsea panels or oil-well Christmas trees have been adapted, making them more robust and easier to operate. The TRITON Spanish founded project proposes the use of a light-weight intervention AUV (I-AUV) to carry out intervention applications simplifying the adaptation of these underwater structures and drastically reducing the operational cost. To prove this concept, the Girona 500 I-AUV is used to autonomously dock into an adapted subsea panel and once docked perform an intervention composed of turning a valve and plugging in/unplugging a connector. The techniques used for the autonomous docking and manipulation as well as the design of an adapted subsea panel with a funnel-based docking system are presented in this article together with the results achieved in a water tank and at sea.


The Drosophila mei-S332 gene promotes sister-chromatid cohesion in meiosis following kinetochore differentiation.
The Drosophila mei-S332 gene acts to maintain sister-chromatid cohesion before anaphase II of meiosis in both males and females. By isolating and analyzing seven new alleles and a deficiency uncovering the mei-S332 gene we have demonstrated that the onset of the requirement for mei-S332 is not until late anaphase I. All of our alleles result primarily in equational (meiosis II) nondisjunction with low amounts of reductional (meiosis I) nondisjunction. Cytological analysis revealed that sister chromatids frequently separate in late anaphase I in these mutants. Since the sister chromatids remain associated until late in the first division, chromosomes segregate normally during meiosis I, and the genetic consequences of premature sister-chromatid dissociation are seen as nondisjunction in meiosis II. The late onset of mei-S332 action demonstrated by the mutations was not a consequence of residual gene function because two strong, and possibly null, alleles give predominantly equational nondisjunction both as homozygotes and in trans to a deficiency. mei-S332 is not required until after metaphase I, when the kinetochore differentiates from a single hemispherical kinetochore jointly organized by the sister chromatids into two distinct sister kinetochores. Therefore, we propose that the mei-S322 product acts to hold the doubled kinetochore together until anaphase II. All of the alleles are fully viable when in trans to a deficiency, thus mei-S332 is not essential for mitosis. Four of the alleles show an unexpected sex specificity.


Molecular epidemiology of Staphylococcus aureus in African children from rural and urban communities with atopic dermatitis.
Staphylococcus aureus has been associated with the exacerbation and severity of atopic dermatitis (AD). Studies have not investigated the colonisation dynamics of S. aureus lineages in African toddlers with AD. We determined the prevalence and population structure of S. aureus in toddlers with and without AD from rural and urban South African settings. We conducted a study of AD-affected and non-atopic AmaXhosa toddlers from rural Umtata and urban Cape Town, South Africa. S. aureus was screened from skin and nasal specimens using established microbiological methods and clonal lineages were determined by spa typing. Logistic regression analyses were employed to assess risk factors associated with S. aureus colonisation. S. aureus colonisation was higher in cases compared to controls independent of geographic location (54% vs. 13%, p < 0.001 and 70% vs. 35%, p = 0.005 in Umtata [rural] and Cape Town [urban], respectively). Severe AD was associated with higher colonisation compared with moderate AD (86% vs. 52%, p = 0.015) among urban cases. Having AD was associated with colonisation in both rural (odds ratio [OR] 7.54, 95% CI 2.92-19.47) and urban (OR 4.2, 95% CI 1.57-11.2) toddlers. In rural toddlers, living in an electrified house that uses gas (OR 4.08, 95% CI 1.59-10.44) or utilises kerosene and paraffin (OR 2.88, 95% CI 1.22-6.77) for heating and cooking were associated with increased S. aureus colonisation. However, exposure to farm animals (OR 0.3, 95% CI 0.11-0.83) as well as living in a house that uses wood and coal (OR 0.14, 95% CI 0.04-0.49) or outdoor fire (OR 0.31, 95% CI 0.13-0.73) were protective. Spa types t174 and t1476, and t272 and t1476 were dominant among urban and rural cases, respectively, but no main spa type was observed among controls, independent of geographic location. In urban cases, spa type t002 and t442 isolates were only identified in severe AD, t174 was more frequent in moderate AD, and t1476 in severe AD. The strain genotype of S. aureus differed by AD phenotypes and rural-urban settings. Continued surveillance of colonising S. aureus lineages is key in understanding alterations in skin microbial composition associated with AD pathogenesis and exacerbation.


Rapid expression of chemokines and proinflammatory cytokines in newly hatched chickens infected with Salmonella enterica serovar typhimurium.
Poultry meat and eggs contaminated with Salmonella enterica serovar Enteritidis or Salmonella enterica serovar Typhimurium are common sources of acute gastroenteritis in humans. However, the exact nature of the immune mechanisms protective against Salmonella infection in chickens has not been characterized at the molecular level. In the present study, bacterial colonization, development of pathological lesions, and proinflammatory cytokine and chemokine gene expression were investigated in the liver, spleen, jejunum, ileum, and cecal tonsils in newly hatched chickens 6, 12, 24, and 48 h after oral infection with Salmonella serovar Typhimurium. Very high bacterial counts were found in the ileum and cecal contents throughout the experiment, whereas Salmonella started to appear in the liver only from 24 h postinfection. Large numbers of heterophils, equivalent to neutrophils in mammals, and inflammatory edema could be seen in the lamina propria of the intestinal villi and in the liver. Interleukin 8 (IL-8), K60 (a CXC chemokine), macrophage inflammatory protein 1 beta, and IL-1 beta levels were significantly upregulated in the intestinal tissues and in the livers of the infected birds. However, the spleens of the infected birds show little or no change in the expression levels of these cytokines and chemokines. Increased expression of the proinflammatory cytokines and chemokines (up to several hundred-fold) correlated with the presence of inflammatory signs in those tissues. This is the first description of in vivo expression of chemokines and proinflammatory cytokines in response to oral infection with Salmonella in newly hatched chickens.


National School Lunch Program and School Breakfast Program: nutrition standards for all foods sold in school as required by the Healthy, Hunger-Free Kids Act of 2010. Interim final rule.
This interim final rule amends the National School Lunch Program and School Breakfast Program regulations to establish nutrition standards for all foods sold in schools, other than food sold under the lunch and breakfast programs. Amendments made by Section 208 of the Healthy, Hunger-Free Kids Act of 2010 (HHFKA) require the Secretary to establish nutrition standards for such foods, consistent with the most recent Dietary Guidelines for Americans, and directs the Secretary to consider authoritative scientific recommendations for nutrition standards; existing school nutrition standards, including voluntary standards for beverages and snack foods; current State and local standards; the practical application of the nutrition standards; and special exemptions for infrequent school-sponsored fundraisers (other than fundraising through vending machines, school stores, snack bars, à la carte sales and any other exclusions determined by the Secretary). In addition, this interim final rule requires schools participating in the National School Lunch Program and School Breakfast Program to make potable water available to children at no charge in the place where lunches are served during the meal service, consistent with amendments made by section 203 of the HHFKA, and in the cafeteria during breakfast meal service. This interim final rule is expected to improve the health and well-being of the Nation's children, increase consumption of healthful foods during the school day, and create an environment that reinforces the development of healthy eating habits.


Disparities in the receipt of robot-assisted radical prostatectomy: between-hospital and within-hospital analysis using 2009-2011 California inpatient data.
Despite the rapid proliferation of robot-assisted radical prostatectomy (RARP), little attention has been paid to patient utilisation of this newest surgical innovation and barriers that may result in disparities in access to RARP. The goal of this study is to identify demographic and economic factors that decrease the likelihood of patients with prostate cancer (PC) receiving RARP. A retrospective, pooled, cross-sectional study was conducted using 2009-2011 California State Inpatient Data and American Hospital Association data. Patients who were diagnosed with PC and underwent radical prostatectomy (RP) from 225 hospitals in California were identified, using ICD-9-CM diagnosis and procedure codes. Patients' likelihood of receiving RARP was associated with patient and hospital characteristics using the two models: (1) between-hospital and (2) within-hospital models. Multivariate binomial logistic regression was used for both models. The first model predicted patient access to RARP-performing hospitals versus non-RARP-performing hospitals, after adjusting for patient and hospital-level covariates (between-hospital variation). The second model examined the likelihood of patients receiving RARP within RARP-performing hospitals (within-hospital variation). Among 20,411 patients who received RP, 13,750 (67.4%) received RARP, while 6661 (32.6%) received non-RARP. This study found significant differences in access to RARP-performing hospitals when race/ethnicity, income and insurance status were compared, after controlling for selected confounding factors (all p<0.001). For example, Hispanic, Medicare and Medicaid patients were more likely to be treated at non-RARP-performing hospitals versus RARP-performing hospitals. Within RARP-performing hospitals, Medicaid patients had 58% lower odds of receiving RARP versus non-RARP (adjusted OR 0.42, p<0.001). However, there were no significant differences by race/ethnicity or income within RARP-performing hospitals. Significant differences exist by race/ethnicity and payer status in accessing RARP-performing hospitals. Furthermore, payer status continues to be an important predictor of receiving RARP within RARP-performing hospitals.


Diagnosis of thyroid metastasis in cancer patients with thyroid mass by fine needle aspiration cytology and ultrasonography.
Thyroid metastasis is generally thought to be infrequent. To evaluate its occurrence, fine needle aspiration cytology and ultrasound of the thyroid gland were performed in nonthyroid cancer patients with thyroid mass. A total of 20 nonthyroid cancer patients (6 males and 14 females with a mean age of 55 +/- 7 years) with thyroid mass were examined with thyroid ultrasound and fine needle aspiration cytology. Their underlying malignancies included lung cancer in 10 patients, breast cancer in 7 patients, cervical cancer in 2 patients and colon cancer in 1 patient. Thyroid metastases were diagnosed in 4 patients (20%), 2 with breast cancer and 2 with lung cancer. For 3 of them, thyroid ultrasound showed solitary hypoechoic nodule, and in 1 case, multiple nodular lesions were demonstrated in each lobe. In addition, neck lymph nodes were noted in 3 patients. In the remaining 16 cancer patients, thyroid ultrasound showed either multiple or solitary nodular goiter change with no neck lymph node involvement. Fine needle aspiration cytology (FNAC) yielded nonthyroid adenocarcinoma in 4 metastatic cases. The 2 breast cancer patients received finally total thyroidectomy and were still alive 1 year after operation. While in the other 2 lung cancer cases, only supportive treatment were given due to advanced stages and the patients died within months. Thyroid metastases could occur at a high frequency in nonthyroid cancer patients with thyroid mass from our small series. By combining FNAC with ultrasound, a clinical diagnosis of thyroid metastasis is attainable in cancer patients with thyroid mass.


Epidemiology of malaria in endemic areas.
Malaria infection is still to be considered a major public health problem in those 106 countries where the risk of contracting the infection with one or more of the Plasmodium species exists. According to estimates from the World Health Organization, over 200 million cases and about 655.000 deaths have occurred in 2010. Estimating the real health and social burden of the disease is a difficult task, because many of the malaria endemic countries have limited diagnostic resources, especially in rural settings where conditions with similar clinical picture may coexist in the same geographical areas. Moreover, asymptomatic parasitaemia may occur in high transmission areas after childhood, when anti-malaria semi-immunity occurs. Malaria endemicity and control activities are very complex issues, that are influenced by factors related to the host, to the parasite, to the vector, to the environment and to the health system capacity to fully implement available anti-malaria weapons such as rapid diagnostic tests, artemisinin-based combination treatment, impregnated bed-nets and insecticide residual spraying while waiting for an effective vaccine to be made available.


Cloning, Expression and Purification of Penicillin Binding Protein2a (PBP2a) from Methicillin Resistant Staphylococcus aureus: A Study on Immunoreactivity in Balb/C Mouse.
Staphylococcus aureus (S. aureus) is a major nosocomial pathogen and the infection with this organism in human is increasing due to the spread of antibiotic resistant strains. One of the resistance mechanisms of S. aureus comprises modification in binding proteins to penicillin. Vaccine strategy may be useful in controlling the infections induced by this organism. This study aimed at developing and producing the recombinant protein PBP2a as a vaccine candidate and evaluating the related humoral immune response in a murine model. A 242 bp fragment of mecA gene was amplified by PCR from S. aureus COL strain and then cloned into prokaryotic expression vector pET-24a. For expression of recombinant protein, pET24a-mec plasmid was transformed into competent E. coli BL21 (DE3) cells. Recombinant protein was over expressed with 1 mM isopropythio-β-D-galctoside (IPTG) and purified using Ni-NTA agarose. SDS-PAGE and western blotting were carried out to confirm protein expression. For immunization of experimental groups, Balb/c mice were injected subcutaneously with 20 µg of recombinant PBP2a three times with three weeks intervals. The sera of experimental groups were collected three weeks after the last immunization and then specific antibodies were evaluated by ELISA method. Successful cloning of mecA was confirmed by colony-PCR, enzymatic digestion, and sequencing. SDS-PAGE and western blot analysis showed that recombinant protein with molecular weight of 13 kDa is over expressed. In addition, high titer of specific antibody against PBP2a in vaccinated mice was developed as compared with the control group and confirmed the immunogenicity of the vaccine candidate. Results suggest that PBP2a recombinant induced specific antibodies and can be used as Staphylococcal vaccine candidate after further studies.


Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation.
Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC. The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of CNR1 and CNR2 in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS). In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure. Cannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.


Optimal counter-current exchange networks.
We present a general analysis of exchange devices linking their efficiency to the geometry of the exchange surface and supply network. For certain parameter ranges, we show that the optimal exchanger consists of densely packed pipes which can span a thin sheet of large area (an "active layer"), which may be crumpled into a fractal surface and supplied with a fractal network of pipes. We derive the efficiencies of such exchangers, showing the potential for significant gains compared to regular exchangers (where the active layer is flat), using parameters relevant to biological systems.


Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy.
Activation of cellular Ca2+ signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca2+-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death. We found that activity and expression of a second Ca2+-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy. CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.


Between-Session Reliability of Common Strength- and Power-Related Measures in Adolescent Athletes.
The purpose of this study was to investigate the between-session reliability of common strength- and power-related measures in adolescent athletes. Seventeen adolescent athletes (males: n = 8: age 17.1 ± 2.2 years; height 175.6 ± 3.5 cm; mass 80.2 ± 3.6 kg; females: n = 9; age 16.9 ± 2.6 years; height 178.5 ± 4.3 cm; mass 71.5 ± 4.5 kg) participated in this study. Isokinetic dynamometry, isometric mid-thigh pull (IMTP), countermovement jump (CMJ), and horizontal jumps (standing broad jump (SBJ) and single-leg hop (SLH)) were each performed twice on separate days, seven days apart. Reliability was assessed by intraclass correlation coefficient (ICC), coefficient of variation (%CV), standard error of measurement (SEM), and smallest detectable difference (SDD). Intraclass correlation coefficients and CV demonstrated acceptable between-session reliability for all measures (ICC > 0.63; CV < 11%), except rate of force development and impulse measures during bilateral and unilateral stance IMTP. Smallest detectable differences demonstrated that changes in performance of >7% CMJ height, >8% SLH distance, >10% in peak isometric force, and >5% in isokinetic peak torques should be considered meaningful, when assessing adolescent athletes.


A survey of street children in northern Tanzania: how abuse or support factors may influence migration to the street.
In October 2006, a survey was undertaken of youth "on the streets" in the Arusha and Kilimanjaro regions of Tanzania (n = 1,923). The question of interest was if street children who live on streets full-time differ concerning reports of abuse and support, compared to reports of children who are only part-time on the streets, and to children who don't self-identify as "street children" at all. Results show full-time street children reporting significantly more abuse than part-time counterparts, or children who were not street children (mean difference = -1.44, P < .001). Concerning support scores, non-street children and part-time street children reported significantly more support from their family than full-time street children (mean difference = 1.70, P < .001). This information identifies possible reasons why vulnerable children migrate to live on the streets in the urban areas, and contributes to the limited literature and data on this subject.


Associations of Toll-Like Receptor and β-Defensin Polymorphisms with Measures of Periodontal Disease (PD) in HIV+ North American Adults: An Exploratory Study.
Polymorphisms in toll-like receptor (TLR) and β-defensin (DEFB) genes have been recognized as potential genetic factors that can influence susceptibility to and severity of periodontal diseases (PD). However, data regarding associations between these polymorphisms and PD are still scarce in North American populations, and are not available in HIV+ North American populations. In this exploratory study, we analyzed samples from HIV+ adults (n = 115), who received primary HIV care at 3 local outpatient HIV clinics and were monitored for PD status. We genotyped a total of 41 single nucleotide polymorphisms (SNPs) in 8 TLR genes and copy number variation (CNV) in DEFB4/103A. We performed regression analyses for levels of 3 periodontopathogens in subgingival dental plaques (Porphyromonas gingivalis [Pg], Treponema denticola [Td], and Tannerella forsythia [Tf]) and 3 clinical measures of PD (periodontal probing depth [PPD], gingival recession [REC], and bleeding on probing [BOP]). In all subjects combined, 2 SNPs in TLR1 were significantly associated with Td, and one SNP in TLR2 was significantly associated with BOP. One of the 2 SNPs in TLR1 was significantly associated with Td in Caucasians. In addition, another SNP in TLR1 and a SNP in TLR6 were also significantly associated with Td and Pg, respectively, in Caucasians. All 3 periodontopathogen levels were significantly associated with PPD and BOP, but none was associated with REC. Instrumental variable analysis showed that 8 SNPs in 6 TLR genes were significantly associated with the 3 periodontopathogen levels. However, associations between the 3 periodontopathogen levels and PPD or BOP were not driven by associations with these identified SNPs. No association was found between DEFB4/103A CNV and any periodontopathogen level or clinical measure in all samples, Caucasians, or African Americans. Our exploratory study suggests a role of TLR polymorphisms, particularly TLR1 and TLR6 polymorphisms, in PD in HIV+ North Americans.


[Involvement of nitrogen oxide in the cerebral vasoconstriction during respiration with high pressure oxygen].
High pressure oxygen evokes a cerebral vasoconstriction and diminishes cerebral blood flow with the aid of mechanisms which are not yet sufficiently studied. We were checking a hypothesis that the hyperbaric oxygen (HBO2) inactivates cerebral nitrogen oxide (NO), interrupts its basal relaxing effect, and evokes a vasoconstriction. In our experiments, HBO2 decreased cerebral blood flow depending on the pressure. Inhibiting the NO-synthase weakened basal vasorelaxation in breathing with atmosphere air and eliminated the vasoconstriction in exposure to the HBO2. Inactivation of O2 prevented the HBO2-induced vasoconstriction. The data obtained reveal that diminishing of cerebral blood flow in HBO is related to the NO inactivation and weakening of its basal vasorelaxing effect. Possible mechanisms of the NO inactivation may involve its reaction with oxygen and superoxide anion which lead to diminishing of the tissue NO concentration and weakening of its vasorelaxing effect.


Site-specific detection of protein secondary structure using 2D IR dihedral indexing: a proposed assembly mechanism of oligomeric hIAPP.
Human islet amyloid polypeptide (hIAPP) aggregates into fibrils through oligomers that have been postulated to contain α-helices as well as β-sheets. We employ a site-specific isotope labeling strategy that is capable of detecting changes in dihedral angles when used in conjunction with 2D IR spectroscopy. The method is analogous to the chemical shift index used in NMR spectroscopy for assigning protein secondary structure. We introduce isotope labels at two neighbouring residues, which results in an increased intensity and positive frequency shift if those residues are α-helical versus a negative frequency shift in β-sheets and turns. The 2D IR dihedral index approach is demonstrated for hIAPP in micelles for which the polypeptide structure is known, using pairs of 13C18O isotope labels L12A13 and L16V17, along with single labeled control experiments. Applying the approach to aggregation experiments performed in buffer, we show that about 27-38% of hIAPP peptides adopt an α-helix secondary structure in the monomeric state at L12A13, prior to aggregation, but not at L16V17 residues. At L16V17, the kinetics are described solely by the monomer and fiber conformations, but at L12A13 the kinetics exhibit a third state that is created by an oligomeric intermediate. Control experiments performed with a single isotope label at A13 exhibit two-state kinetics, indicating that a previously unknown change in dihedral angle occurs at L12A13 as hIAPP transitions from the intermediate to fiber structures. We propose a mechanism for aggregation, in which helices seed oligomer formation via structures analogous to leucine rich repeat proteins.


Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain.
Chronic pain is common in the United States and prescribed opioid analgesics use for noncancer pain has increased dramatically in the past two decades, possibly accounting for the current opioid addiction epidemic. Co-morbid drug use in those prescribed opioid analgesics is common, but there are few data on polysubstance use patterns. We explored patterns of use of cigarette, alcohol, and illicit drugs in HIV-infected people with chronic pain who were prescribed opioid analgesics. We conducted a secondary data analysis of screening interviews conducted as part of a parent randomized trial of financial incentives to improve HIV outcomes among drug users. In a convenience sample of people with HIV and chronic pain, we collected self-report data on demographic characteristics; pain; patterns of opioid analgesic use (both prescribed and illicit); cigarette, alcohol, and illicit drug use (including cannabis, heroin, and cocaine) within the past 30 days; and current treatment for drug use and HIV. Almost half of the sample of people with HIV and chronic pain reported current prescribed opioid analgesic use (N = 372, 47.1%). Illicit drug use was common (N = 505, 63.9%), and cannabis was the most commonly used illicit substance (N = 311, 39.4%). In multivariate analyses, only cannabis use was significantly associated with lower odds of prescribed opioid analgesic use (adjusted odds ratio = 0.57; 95% confidence interval: 0.38-0.87). Conclusions/Importance: Our data suggest that new medical cannabis legislation might reduce the need for opioid analgesics for pain management, which could help to address adverse events associated with opioid analgesic use.


Minimal residual disease studies by flow cytometry in acute leukemia.
Minimal residual disease (MRD) assays are increasingly important in the clinical management of patients with acute leukemia. Among the methods available for monitoring MRD, flow cytometry holds great promise for clinical application because of its simplicity and wide availability. Several studies have demonstrated strong correlations between MRD levels by flow cytometry during clinical remission and treatment outcome, lending support to the reliability of this approach. Flow-cytometric detection of MRD is based on the identification of immunophenotypic combinations expressed on leukemic cells but not on normal hematopoietic cells. Its sensitivity depends on the specificity of the immunophenotypes used to track leukemic cells and on the number of cells available for study. Immunophenotypes that allow detection of 1 leukemic cell in 10,000 normal cells can be identified in at least 90% of patients with acute lymphoblastic leukemia; immunophenotypes that allow detection of 1 leukemic cell in 1,000-10,000 normal cells can be identified in at least 85% of patients with acute myeloid leukemia. Identification of new markers of leukemia by gene array technology should lead to the design of simple and reliable antibody panels for universal monitoring of MRD. Here we review the relative advantages and disadvantages of flow cytometry for MRD studies, as well as results obtained in correlative studies with treatment outcome.


International outbreak investigation of Salmonella Heidelberg associated with in-flight catering.
Rapid and wide dispersal of passengers after flights makes investigation of flight-related outbreaks challenging. An outbreak of Salmonella Heidelberg was identified in a group of Irish travellers returning from Tanzania. Additional international cases sharing the same flight were identified. Our aim was to determine the source and potential vehicles of infection. Case-finding utilized information exchange using experts' communication networks and national surveillance systems. Demographic, clinical and food history information was collected. Twenty-five additional cases were identified from Ireland, The Netherlands, Norway, USA and Canada. We conducted a case-control study which indicated a significant association between illness and consumption of milk tart (OR 10.2) and an egg dish (OR 6) served on-board the flight. No food consumed before the flight was associated with illness. Cases from countries other than Ireland provided supplementary information that facilitated the identification of likely vehicles of infection. Timely, committed international collaboration is vital in such investigations.


Notch3 overexpression promotes anoikis resistance in epithelial ovarian cancer via upregulation of COL4A2.
Ovarian cancer is a lethal disease with the majority of diagnosed women having distant metastases. Interestingly, although Notch3 overexpression has been correlated with poor survival in epithelial ovarian cancer (EOC), little is known about its mechanism of action. Data show that Notch3 specifically promotes anoikis resistance. In addition, data indicate a positive role for focal adhesion kinase (FAK) as well as downstream signaling kinases such as Akt and Erk 1/2 in promoting anchorage-independent growth. Mechanistically, both mRNA transcript and protein levels of type IV collagen (COL4A2) are reduced when Notch3 levels are decreased and exogenous collagen IV supplementation reverses the anoikis sensitivity. Reduction of COL4A2 expression by RNAI-mediated knockdown induces cell death. Finally, elevated Notch3 expression levels correlate with higher COL4A2 expression in human ovarian tumor specimens. These data highlight type IV collagen as a novel therapeutic target for metastatic EOC. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/11/25/1541-7786.MCR-14-0334/F1.large.jpg


Effect of plasmapheresis on hyperviscosity-related retinopathy and retinal hemodynamics in patients with Waldenstrom's macroglobulinemia.
Waldenström's macroglobulinemia (WM) is characterized by an overproduction of immunoglobulin M (IgM), which can lead to a hyperviscosity syndrome (HVS) and HVS-related retinopathy. Plasmapheresis is known to reduce serum viscosity (SV) and IgM levels. The purpose of this study was to investigate the effects of plasmapheresis on HVS-related retinopathy and retinal hemodynamic parameters in patients with WM. Nine patients with HVS due to WM were studied. SV and plasma IgM levels were measured before and after plasmapheresis treatment. The patients were evaluated for HVS-related retinopathy, and hemodynamic changes in a major temporal retinal vein by laser Doppler, before and after plasmapheresis. Plasmapheresis resulted in significant reductions in serum IgM (46.5% +/- 18.0%, mean +/- SD; P = 0.0009) and SV (44.7% +/- 17.3%, P = 0.002). HVS-related retinopathy improved in all patients after plasmapheresis. After treatment, the venous diameter decreased in each patient by an average of 15.3% +/- 5.8% (P = 0.0001). A significant (P = 0.0004) 55.2% +/- 22.5% increase in retinal venous blood speed accompanied the decreases in diameter. There was no significant change in the retinal blood flow rate after treatment. The percentage decreases in SV in the patients were significantly correlated with the percentage decreases in venous blood column diameter (P = 0.031, R(2) = 0.51). HVS triggers a distinctive retinopathy with a central retinal vein occlusion (CRVO)-like appearance. However, the retinal blood flow is not decreased as in CRVO, but remains at normal levels. Plasmapheresis is effective in reversing HVS-related retinopathy and in reducing abnormal venous dilatation.


Oncostatin m is produced in adipose tissue and is regulated in conditions of obesity and type 2 diabetes.
Adipose tissue is a highly active endocrine organ that secretes many factors that affect other tissues and whole-body metabolism. Adipocytes are responsive to several glycoprotein 130 (gp130) cytokines, some of which have been targeted as potential antiobesity therapeutics. Oncostatin M (OSM) is a gp130 family member known to inhibit adipocyte differentiation in vitro, but its effects on other adipocyte properties are not characterized. The expression of OSM in white adipose tissue (WAT) has not been evaluated in the context of obesity. Thus, our objective was to examine the expression of adipose tissue OSM in obese animals and humans. OSM expression was examined in adipose tissues from mice with diet-induced and genetic obesity and in obese humans as well as in fractionated adipose tissue from mice. Murine adipocytes were used to examine OSM receptor expression and the effects of OSM on adipocytes, including the secretion of factors such as plasminogen activator inhibitor 1 and IL-6, which are implicated in metabolic diseases. OSM expression is increased in rodent and human obesity/type 2 diabetes mellitus. In humans, OSM levels correlate with body weight and insulin and are inversely correlated with glucose disposal rate as measured by hyperinsulinemic-euglycemic clamp. OSM is not produced from the adipocytes in WAT but derives from cells in the stromovascular fraction, including F4/80(+) macrophages. The specific receptor of OSM, OSM receptor-β, is expressed in adipocytes and adipose tissue and increased in both rodent models of obesity examined. OSM acts on adipocytes to induce the expression and secretion of plasminogen activator inhibitor 1 and IL-6. These data indicate that WAT macrophages are a source of OSM and that OSM levels are significantly induced in murine and human obesity/type 2 diabetes mellitus. These studies suggest that OSM produced from immune cells in WAT acts in a paracrine manner on adipocytes to promote a proinflammatory phenotype in adipose tissue.


Learning a weighted sequence model of the nucleosome core and linker yields more accurate predictions in Saccharomyces cerevisiae and Homo sapiens.
DNA in eukaryotes is packaged into a chromatin complex, the most basic element of which is the nucleosome. The precise positioning of the nucleosome cores allows for selective access to the DNA, and the mechanisms that control this positioning are important pieces of the gene expression puzzle. We describe a large-scale nucleosome pattern that jointly characterizes the nucleosome core and the adjacent linkers and is predominantly characterized by long-range oscillations in the mono, di- and tri-nucleotide content of the DNA sequence, and we show that this pattern can be used to predict nucleosome positions in both Homo sapiens and Saccharomyces cerevisiae more accurately than previously published methods. Surprisingly, in both H. sapiens and S. cerevisiae, the most informative individual features are the mono-nucleotide patterns, although the inclusion of di- and tri-nucleotide features results in improved performance. Our approach combines a much longer pattern than has been previously used to predict nucleosome positioning from sequence-301 base pairs, centered at the position to be scored-with a novel discriminative classification approach that selectively weights the contributions from each of the input features. The resulting scores are relatively insensitive to local AT-content and can be used to accurately discriminate putative dyad positions from adjacent linker regions without requiring an additional dynamic programming step and without the attendant edge effects and assumptions about linker length modeling and overall nucleosome density. Our approach produces the best dyad-linker classification results published to date in H. sapiens, and outperforms two recently published models on a large set of S. cerevisiae nucleosome positions. Our results suggest that in both genomes, a comparable and relatively small fraction of nucleosomes are well-positioned and that these positions are predictable based on sequence alone. We believe that the bulk of the remaining nucleosomes follow a statistical positioning model.


Interactive effects of environmental stress and inbreeding on reproductive traits in a wild bird population.
1. Conservation biologists are concerned about the interactive effects of environmental stress and inbreeding because such interactions could affect the dynamics and extinction risk of small and isolated populations, but few studies have tested for these interactions in nature. 2. We used data from the long-term population study of song sparrows Melospiza melodia on Mandarte Island to examine the joint effects of inbreeding and environmental stress on four fitness traits that are known to be affected by the inbreeding level of adult birds: hatching success, laying date, male mating success and fledgling survival. 3. We found that inbreeding depression interacted with environmental stress to reduce hatching success in the nests of inbred females during periods of rain. 4. For laying date, we found equivocal support for an interaction between parental inbreeding and environmental stress. In this case, however, inbred females experienced less inbreeding depression in more stressful, cooler years. 5. For two other traits, we found no evidence that the strength of inbreeding depression varied with environmental stress. First, mated males fathered fewer nests per season if inbred or if the ratio of males to females in the population was high, but inbreeding depression did not depend on sex ratio. Second, fledglings survived poorly during rainy periods and if their father was inbred, but the effects of paternal inbreeding and rain did not interact. 6. Thus, even for a single species, interactions between the inbreeding level and environmental stress may not occur in all traits affected by inbreeding depression, and interactions that do occur will not always act synergistically to further decrease fitness.


Animal models of transcranial direct current stimulation: Methods and mechanisms.
The objective of this review is to summarize the contribution of animal research using direct current stimulation (DCS) to our understanding of the physiological effects of transcranial direct current stimulation (tDCS). We comprehensively address experimental methodology in animal studies, broadly classified as: (1) transcranial stimulation; (2) direct cortical stimulation in vivo and (3) in vitro models. In each case advantages and disadvantages for translational research are discussed including dose translation and the overarching "quasi-uniform" assumption, which underpins translational relevance in all animal models of tDCS. Terminology such as anode, cathode, inward current, outward current, current density, electric field, and uniform are defined. Though we put key animal experiments spanning decades in perspective, our goal is not simply an exhaustive cataloging of relevant animal studies, but rather to put them in context of ongoing efforts to improve tDCS. Cellular targets, including excitatory neuronal somas, dendrites, axons, interneurons, glial cells, and endothelial cells are considered. We emphasize neurons are always depolarized and hyperpolarized such that effects of DCS on neuronal excitability can only be evaluated within subcellular regions of the neuron. Findings from animal studies on the effects of DCS on plasticity (LTP/LTD) and network oscillations are reviewed extensively. Any endogenous phenomena dependent on membrane potential changes are, in theory, susceptible to modulation by DCS. The relevance of morphological changes (galvanotropy) to tDCS is also considered, as we suggest microscopic migration of axon terminals or dendritic spines may be relevant during tDCS. A majority of clinical studies using tDCS employ a simplistic dose strategy where excitability is singularly increased or decreased under the anode and cathode, respectively. We discuss how this strategy, itself based on classic animal studies, cannot account for the complexity of normal and pathological brain function, and how recent studies have already indicated more sophisticated approaches are necessary. One tDCS theory regarding "functional targeting" suggests the specificity of tDCS effects are possible by modulating ongoing function (plasticity). Use of animal models of disease are summarized including pain, movement disorders, stroke, and epilepsy.


Isoniazid Prophylactic Therapy for the Prevention of Tuberculosis in HIV Infected Adults: A Systematic Review and Meta-Analysis of Randomized Trials.
Infection with Human Immunodeficiency virus (HIV) is an important risk factor for Tuberculosis (TB). Anti-Retroviral Therapy (ART) has improved the prognosis of HIV and reduced the risk of TB infected patients. Isoniazid Preventive Therapy (IPT) aims to reduce the development of active TB in patients with latent TB. Systematically review and synthesize effect estimates of IPT for TB prevention in adult HIV patients. Secondary objectives were to assess the effect of IPT on HIV disease progression, all-cause mortality and adverse drug reaction (ADR). Electronic databases were searched to identify relevant articles in English available by September 11th 2015. Research articles comparing IPT to placebo or no treatment in HIV infected adults using randomized clinical trials. A qualitative review included study-level information on randomization and treatment allocation. Effect estimates were pooled using random-effects models to account for between-study heterogeneity. This review assessed ten randomized clinical trials that assigned 7619 HIV patients to IPT or placebo. An overall 35% of TB risk reduction (RR = 0.65, 95% CI (0.51, 0.84)) was found in all participants, however, larger benefit of IPT was observed in Tuberculin Skin Test (TST) positive participants, with pooled relative risk reduction of 52% [RR = 0.48; 95% CI (0.29, 0.82)] and with a prediction interval ranging from 0.13 to 1.81. There was no statistically significant effect of IPT on TB occurrence in TST negative or unknown participants. IPT also reduced the risk of HIV disease progression in all participants (RR = 0.69; 95% CI (0.48, 0.99)) despite no benefits observed in TST strata. All-cause mortality was not affected by IPT although participants who had 12 months of IPT tend to have a reduced risk (RR = 0.65; 95% CI(0.47, 0.90)). IPT had an elevated, yet statistically non-significant, risk of adverse drug reaction [RR = 1.20; 95% CI (1.20, 1.71)]. Only a single study assessed the effect of IPT in combination with ART in preventing TB and occurrence of multi-drug resistant tuberculosis. IPT use substantially contributes in preventing TB in persons with HIV in general and in TST positive individuals in particular. More evidence is needed to explain discrepancies in the protective effect of IPT in these individuals.


A blueprint of pain curriculum across prelicensure health sciences programs: one NIH Pain Consortium Center of Excellence in Pain Education (CoEPE) experience.
To improve U.S. pain education and promote interinstitutional and interprofessional collaborations, the National Institutes of Health Pain Consortium has funded 12 sites to develop Centers of Excellence in Pain Education (CoEPEs). Each site was given the tasks of development, evaluation, integration, and promotion of pain management curriculum resources, including case studies that will be shared nationally. Collaborations among schools of medicine, dentistry, nursing, pharmacy, and others were encouraged. The John D. Loeser CoEPE is unique in that it represents extensive regionalization of health science education, in this case in the region covering the states of Washington, Wyoming, Alaska, Montana, and Idaho. This paper describes a blueprint of pain content and teaching methods across the University of Washington's 6 health sciences schools and provides recommendations for improvement in pain education at the prelicensure level. The Schools of Dentistry and Physician Assistant provide the highest percentage of total required curriculum hours devoted to pain compared with the Schools of Medicine, Nursing, Pharmacy, and Social Work. The findings confirm the paucity of pain content in health sciences curricula, missing International Association for the Study of Pain curriculum topics, and limited use of innovative teaching methods such as problem-based and team-based learning. Findings confirm the paucity of pain education across the health sciences curriculum in a CoEPE that serves a large region in the United States. The data provide a pain curriculum blueprint that can be used to recommend added pain content in health sciences programs across the country.


Neural mechanisms underlying target detection in a dragonfly centrifugal neuron.
Visual identification of targets is an important task for many animals searching for prey or conspecifics. Dragonflies utilize specialized optics in the dorsal acute zone, accompanied by higher-order visual neurons in the lobula complex, and descending neural pathways tuned to the motion of small targets. While recent studies describe the physiology of insect small target motion detector (STMD) neurons, little is known about the mechanisms that underlie their exquisite sensitivity to target motion. Lobula plate tangential cells (LPTCs), a group of neurons in dipteran flies selective for wide-field motion, have been shown to take input from local motion detectors consistent with the classic correlation model developed by Hassenstein and Reichardt in the 1950s. We have tested the hypothesis that similar mechanisms underlie the response of dragonfly STMDs. We show that an anatomically characterized centrifugal STMD neuron (CSTMD1) gives responses that depend strongly on target contrast, a clear prediction of the correlation model. Target stimuli are more complex in spatiotemporal terms than the sinusoidal grating patterns used to study LPTCs, so we used a correlation-based computer model to predict response tuning to velocity and width of moving targets. We show that increasing target width in the direction of travel causes a shift in response tuning to higher velocities, consistent with our model. Finally, we show how the morphology of CSTMD1 allows for impressive spatial interactions when more than one target is present in the visual field.


Long integration time for accelerating and decelerating visual, tactile and visuo-tactile stimuli.
The human visual system is good at discriminating speed but not acceleration. However, as speed is seldom constant, it is important to be able to extract speed in conditions of acceleration and deceleration. We measured visual, tactile and bimodal speed-matching over a wide range of accelerations and decelerations in a 2IFC procedure. Both visual and tactile stimuli were generated on physical wheels etched with a sinusoidal profile. During different experimental sessions the wheels could be seen, or touched, or both. Comparisons between different unimodal and bimodal matched speeds revealed similar integration times for the two modalities, in both cases around one second, suggesting that it occurs at a relatively high level of processing. Bimodal precision of speed discrimination was better than unimodal discrimination, as predicted by the maximum likelihood model of optimal integration.


Development and validation of a Food Choices Score for use in weight-loss interventions.
Weight loss results from an energy deficit, although the quality of food choices making up the diet may also be important. The aim of the present study was to develop and validate a diet quality tool based on food categories to monitor dietary change in clinical weight-loss settings. The Food Choices Score (FCS) was based on seventeen food categories, each scoring up to five points, totalling 85. In addition to content validity, the tool was validated using (1) two energy-deficit diet models (6500 and 7400 kJ) assuring nutrient and food-group targets and (2) dietary data from two weight-loss trials (n 189). First, the diet models confirmed that an optimal score of 85 was achievable. Second, change in scores was compared with weight loss achieved at 3 months. The trial data produced a mean FCS of 42·6 (sd 8·6), increasing to 49·1 (sd 7·6) by 3 months. Participants who lost weight achieved a higher FCS at 3 months than those who did not (P= 0·027), and there was an even greater improvement in the FCS (P= 0·024) in participants losing ≥ 5 % body weight than in those losing < 5 %. A greater change in the FCS (Δ ≥ 7) resulted in a greater change in BMI (P =0·044), and score change was correlated with weight change (P= 0·023). Participants with the highest scores ( ≥ 56 v. ≤ 44/85) consumed more fruit (P< 0·001) and low-fat dairy foods (P =0·004), less fatty meat (P< 0·001), non-whole-grain cereals (P< 0·001), non-core foods and drinks (NCFD) (P< 0·001), less energy (P =0·018), less dietary fat (P< 0·001) and more dietary fibre (P= 0·013). Weight loss was 35·5 % less likely to be achieved with every increase in the serves of NCFD (P =0·004) in the study sample. The FCS is a valid tool for assessing diet quality in clinical weight-loss settings.


[Double purse-string craft around the inner cuff: a new technique for an immediate start of CAPD].
Background: In order to minimize the risk of leakage and displacement, international guidelines recommend that catheter insertion should be performed at least 2 weeks before beginning CAPD. However, the optimal duration of the break-in period is not defined yet. Methods: From January 2011 to December 2018, 135 PD catheter insertions in 125 patients (90 men and 35 women, mean age 62,02 ± 16,7) were performed in our centre with the double purse-string technique. Seventy-seven straight double-cuffed Tenckhoff catheter were implanted semi-surgically on midline under umbilicus by a trocar and 58 were surgically implanted through rectus muscle. In all patients CAPD was started within 24 hours from catheter placement, without a break-in procedure. We recorded all mechanical and infective catheter-related complications during the 3 first months after initiation of CAPD and the catheter survival rates. Results: During the first 3 months the overall incidence of peri-catheter leakages, catheter dislocations, peritonitis and exit-site infections was 2,96% (4/135), 1,48% (2/135), 10.3% (14/135) and 2.96% (4/135), respectively. No bleeding events, bowel perforations or hernia formations were reported. The catheter survival censored for deaths, kidney transplant, loss of ultrafiltration and inability was 74,7% at 48 months. There was no difference in the incidence of any mechanical or infectious complications and catheter survival between the semi-surgical and the surgical groups. Conclusions: Double purse-string technique allows an immediate start of CAPD both with semi-surgical and surgical catheter implantation. This technique is a safe and feasible approach in all patients who refer to peritoneal dialysis.


High payload delivery of optical imaging and photodynamic therapy agents to tumors using phthalocyanine-reconstituted low-density lipoprotein nanoparticles.
To improve the labeling efficiency of a low-density lipoprotein (LDL)-based photosensitizer (PS) for achieving high probe to protein payload, a tetra-t-butyl silicon phthalocyanine bearing two oleate moieties at its axial positions, SiPcBOA, is designed and synthesized. Using this novel strategy, SiPcBOA reconstituted LDL (r-SiPcBOA-LDL) with a very high payload (SiPcBOA to LDL molar ratio >3000 to 35001:1) is obtained. Using electron microscopy, we find reconstituted LDL (rLDL) with such a high payload essentially retains the mean particle size of native LDL. Since acetylated LDL binds to scavenger receptors of endothelial and microglial cells instead of LDLR, SiPcBOA reconstituted acetylated LDL (r-SiPcBOA-AcLDL) is also prepared to serve as a negative control to validate the LDL receptor (LDLR) targeting specificity. Confocal microscopy studies demonstrate that the internalization of r-SiPcBOA-LDL by human hepatoblastoma G2 (HepG2) tumor cells is mediated by LDLR pathway. The in vitro photodynamic therapy (PDT) response of HepG2 cells to r-SiPcBOA-LDL is compared to SiPcBOA (free drug control) using a clonogenic assay. The slopes of the linear regression fit to the logarithmic data for these two plots are significantly different from each other (p=0.0007), indicating greatly enhanced efficacy of LDLR-targeted PDT.


Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart.
Stem cells are important in the maintenance and repair of adult tissues. A population of cells, termed side population (SP) cells, has stem cell characteristics as they have been shown to contribute to diverse lineages. In this study, we confirm that Abcg2 is a determinant of the SP cell phenotype. Therefore, we examined Abcg2 expression during murine embryogenesis and observed robust expression in the blood islands of the E8.5 yolk sac and in developing tissues including the heart. During the latter stages of embryogenesis, Abcg2 identifies a rare cell population in the developing organs. We further establish that the adult heart contains an Abcg2 expressing SP cell population and these progenitor cells are capable of proliferation and differentiation. We define the molecular signature of cardiac SP cells and compare it to embryonic stem cells and adult cardiomyocytes using emerging technologies. We propose that the cardiac SP cell population functions as a progenitor cell population for the development, maintenance, and repair of the heart.


Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression.
Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.


Multiple, objectively measured sleep dimensions including hypoxic burden and chronic kidney disease: findings from the Multi-Ethnic Study of Atherosclerosis.
Poor sleep may contribute to chronic kidney disease (CKD) through several pathways, including hypoxia-induced systemic and intraglomerular pressure, inflammation, oxidative stress and endothelial dysfunction. However, few studies have investigated the association between multiple objectively measured sleep dimensions and CKD. We investigated the cross-sectional association between sleep dimensions and CKD among 1895 Multi-Ethnic Study of Atherosclerosis Sleep Ancillary Study participants who completed in-home polysomnography, wrist actigraphy and a sleep questionnaire. Using Poisson regression models with robust variance, we estimated separate prevalence ratios (PR) and 95% CIs for moderate-to-severe CKD (glomerular filtration rate <60 mL/min/1.73 m2 or albuminuria >30 mg/g) among participants according to multiple sleep dimensions, including very short (≤5 hours) sleep, Apnoea-Hypopnoea Index and sleep apnoea-specific hypoxic burden (SASHB) (total area under the respiratory event-related desaturation curve divided by total sleep duration, %min/hour)). Regression models were adjusted for sociodemographic characteristics, health behaviours and clinical characteristics. Of the 1895 participants, mean age was 68.2±9.1 years, 54% were women, 37% were white, 28% black, 24% Hispanic/Latino and 11% Asian. Several sleep metrics were associated with higher adjusted PR of moderate-to-severe CKD: very short versus recommended sleep duration (PR=1.40, 95% CI 1.06 to 1.83); SASHB (Box-Cox transformed SASHB: PR=1.06, 95% CI 1.02 to 1.12); and for participants in the highest quintile of SASHB plus sleep apnoea: PR=1.28, 95% CI 1.01 to 1.63. Sleep apnoea associated hypoxia and very short sleep, likely representing independent biological mechanisms, were associated with a higher moderate-to-severe CKD prevalence, which highlights the potential role for novel interventions.


Metric-based vs peer-reviewed evaluation of a research output: Lesson learnt from UK's national research assessment exercise.
There is a general inquisition regarding the monetary value of a research output, as a substantial amount of funding in modern academia is essentially awarded to good research presented in the form of journal articles, conferences papers, performances, compositions, exhibitions, books and book chapters etc., which, eventually leads to another question if the value varies across different disciplines. Answers to these questions will not only assist academics and researchers, but will also help higher education institutions (HEIs) make informed decisions in their administrative and research policies. To examine both the questions, we applied the United Kingdom's recently concluded national research assessment exercise known as the Research Excellence Framework (REF) 2014 as a case study. All the data for this study is sourced from the openly available publications which arose from the digital repositories of REF's results and HEFCE's funding allocations. A world leading output earns between £7504 and £14,639 per year within the REF cycle, whereas an internationally excellent output earns between £1876 and £3659, varying according to their area of research. Secondly, an investigation into the impact rating of 25315 journal articles submitted in five areas of research by UK HEIs and their awarded funding revealed a linear relationship between the percentage of quartile-one journal publications and percentage of 4* outputs in Clinical Medicine, Physics and Psychology/Psychiatry/Neuroscience UoAs, and no relationship was found in the Classics and Anthropology/Development Studies UoAs, due to the fact that most publications in the latter two disciplines are not journal articles. The findings provide an indication of the monetary value of a research output, from the perspectives of government funding for research, and also what makes a good output, i.e. whether a relationship exists between good quality output and the source of its publication. The findings may also influence future REF submission strategies in HEIs and ascertain that the impact rating of the journals is not necessarily a reflection of the quality of research in every discipline, and this may have a significant influence on the future of scholarly communications in general. According to the author's knowledge, this is the first time an investigation has estimated the monetary value of a good research output.


Prefrontal brain network connectivity indicates degree of both schizophrenia risk and cognitive dysfunction.
Cognitive dysfunction is a core feature of schizophrenia, and persons at risk for schizophrenia may show subtle deficits in attention and working memory. In this study, we investigated the relationship between integrity of functional brain networks and performance in attention and working memory tasks as well as schizophrenia risk. A total of 235 adults representing 3 levels of risk (102 outpatients with schizophrenia, 70 unaffected first-degree relatives of persons with schizophrenia, and 63 unrelated healthy controls [HCs]) completed resting-state functional magnetic resonance imaging and a battery of attention and working memory tasks (Brief Test of Attention, Hopkins Verbal Learning Test, and Brief Visuospatial Memory Test) on the same day. Functional networks were defined based on coupling with seeds in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and primary visual cortex. Networks were then dissected into regional clusters of connectivity that were used to generate individual interaction matrices representing functional connectivity within each network. Both patients with schizophrenia and their first-degree relatives showed cognitive dysfunction compared with HCs. First canonicals indicated an inverse relationship between cognitive performance and connectivity within the DLPFC and MPFC networks. Multivariate analysis of variance revealed multivariate main effects of higher schizophrenia risk status on increased connectivity within the DLPFC and MPFC networks. These data suggest that excessive connectivity within brain networks coupled to the DLPFC and MPFC, respectively, accompany cognitive deficits in persons at risk for schizophrenia. This might reflect compensatory reactions in neural systems required for cognitive processing of attention and working memory tasks to brain changes associated with schizophrenia.


Vector competence of eastern and western forms of Psorophora columbiae (Diptera: Culicidae) mosquitoes for enzootic and epizootic Venezuelan equine encephalitis virus.
Venezuelan equine encephalitis virus (VEEV) continues to circulate enzootically in Mexico with the potential to re-emerge and cause disease in equines and humans in North America. We infected two geographically distinct mosquito populations of eastern Psorophora columbiae form columbiae (Chiapas, Mexico and Texas, United States) and one mosquito population of western Psorophora columbiae form toltecum (California, United States) with epizootic and enzootic IE VEEV and epizootic IAB VEEV. We detected no differences between epizootic and enzootic IE viruses in their ability to infect any of the mosquito populations analyzed, which suggested that neither species selects for epizootic IE viruses. Psorophora columbiae f. columbiae (Texas) were significantly less susceptible to infection by epizootic IE than Ps. columbiae f. columbiae (Mexico). Psorophora columbiae f. toltecum populations were more susceptible than Ps. columbiae f. columbiae populations to epizootic IE and IAB viruses.


Determination of clenbuterol in pork and potable water samples by molecularly imprinted polymer through the use of covalent imprinting method.
A novel molecularly imprinted polymer (MIP) for efficient separation and concentration of clenbuterol (CLB) was synthesized by covalent imprinting approach using CLB derivative as functional monomer. The MIPs synthesized were characterized by scanning electron microscope, nitrogen adsorption analysis, Fourier transform infrared spectrometer, and thermo-gravimetric analysis. The binding experimental results showed that the MIPs synthesized had fast adsorption kinetic (20 min at 25 mg L(-1)), high adsorption capacity and specific recognition ability for the analyte. In addition, the MIPs synthesized were successfully used as solid-phase sorbent for CLB sample preparation to be analyzed by high performance liquid chromatography with ultraviolet detector. Under optimized experimental conditions, the linear range of the calibration curve was 5-80 μg L(-1) (R(2) = 0.9938). The proposed method was also applied to the analysis of CLB in pork and potable water samples.


Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies.
To quantify the link between lower, subclinically symptomatic, levels of psychological distress and cause-specific mortality in a large scale, population based study. Individual participant meta-analysis of 10 large prospective cohort studies from the Health Survey for England. Baseline psychological distress measured by the 12 item General Health Questionnaire score, and mortality from death certification. 68,222 people from general population samples of adults aged 35 years and over, free of cardiovascular disease and cancer, and living in private households in England at study baseline. Death from all causes (n = 8365), cardiovascular disease including cerebrovascular disease (n = 3382), all cancers (n = 2552), and deaths from external causes (n = 386). Mean follow-up was 8.2 years (standard deviation 3.5). We found a dose-response association between psychological distress across the full range of severity and an increased risk of mortality (age and sex adjusted hazard ratio for General Health Questionnaire scores of 1-3 v score 0: 1.20, 95% confidence interval 1.13 to 1.27; scores 4-6: 1.43, 1.31 to 1.56; and scores 7-12: 1.94, 1.66 to 2.26; P<0.001 for trend). This association remained after adjustment for somatic comorbidity plus behavioural and socioeconomic factors. A similar association was found for cardiovascular disease deaths and deaths from external causes. Cancer death was only associated with psychological distress at higher levels. Psychological distress is associated with increased risk of mortality from several major causes in a dose-response pattern. Risk of mortality was raised even at lower levels of distress.


N-acetylcysteine decreases severity of acute pancreatitis in mice.
Oxidative stress plays a major role in the early stage of acute pancreatitis. This study assessed the effects of N-acetylcysteine (NAC), a reduced glutathione (GSH) provider and a direct scavenger of reactive oxygen intermediates, in the course of acute pancreatitis in mice. Acute pancreatitis (AP) was induced by intraperitoneal (i.p.) injections of cerulein. Mice received NAC (1,000 mg/kg, i.p.) every 3 h, starting either 1 h before the first cerulein injection (prophylactic group) or 1 h after the first cerulein injection (therapeutic group), or i.p. saline injections for controls. Severity of AP was evaluated by histology, serum hydrolase levels, and serum and intrapancreatic levels of MCP-1 and interleukin 6 (IL-6). Pancreatic conjugated dienes and intrapancreatic and intrahepatic GSH levels were measured to assess the local and systemic oxidative processes. Acute pancreatitis was also induced with a CDE diet in controls and mice receiving either both NAC ad libidum in drinking water and 1,000 mg/kg i.p. injection once daily. The severity of pulmonary lesions was assessed by arterial blood gases (pO2) and intrapulmonary myeloperoxidase (MPO content) measurements as well as the survival of mice. The severity of cerulein-induced AP was significantly decreased in the prophylactic group compared with the therapeutic and control groups. Prophylactic administration of NAC also decreased the intrapancreatic levels of conjugated dienes compared with controls. The intrapancreatic and systemic release of MCP- 1 and IL-6 was also decreased in the prophylactic group 3 and 6 hours after AP induction. In addition, NAC pretreatment also reduced hepatic IL-6 production at 3 and 6 hours after starting cerulein challenge. In CDE-induced AP, the severity of lung injury (hypoxemia, MPO content) was decreased, and survival was improved by NAC. NAC administered in a prophylactic protocol limits the severity of experimental acute pancreatitis in mice, as well as its systemic complications and related mortality.


Kava: a comprehensive review of efficacy, safety, and psychopharmacology.
Kava (Piper methysticum) is a South Pacific psychotropic plant medicine that has anxiolytic activity. This effect is achieved from modulation of GABA activity via alteration of lipid membrane structure and sodium channel function, monoamine oxidase B inhibition, and noradrenaline and dopamine re-uptake inhibition. Kava is available over the counter in jurisdictions such as the USA, Australia and New Zealand. Due to this, a review of efficacy, safety and clinical recommendations is advised. To conduct a comprehensive review of kava, in respect to efficacy, psychopharmacology, and safety, and to provide clinical recommendations for use in psychiatry to treat generalized anxiety disorder (GAD). A review was conducted using the electronic databases MEDLINE, CINAHL, PsycINFO and the Cochrane Library during mid 2010 of search terms relating to kava and GAD. A subsequent forward search was conducted of key papers using Web of Science cited reference search. The current weight of evidence supports the use of kava in treatment of anxiety with a significant result occurring in four out of six studies reviewed (mean Cohen's d = 1.1). Safety issues should however be considered. Use of traditional water soluble extracts of the rhizome (root) of appropriate kava cultivars is advised, in addition to avoidance of use with alcohol and caution with other psychotropic medications. Avoidance of high doses if driving or operating heavy machinery should be mandatory. For regular users routine liver function tests are advised. While current evidence supports kava for generalized anxiety, more studies are required to assess comparative efficacy and safety (on the liver, cognition, driving, and sexual effects) versus established pharmaceutical comparators.


Effects of preoperative aspirin on cardiocerebral and renal complications in non-emergent cardiac surgery patients: a sub-group and cohort study.
Postoperative cardiocerebral and renal complications are a major threat for patients undergoing cardiac surgery. This study was aimed to examine the effect of preoperative aspirin use on patients undergoing cardiac surgery. An observational cohort study was performed on consecutive patients (n = 1879) receiving cardiac surgery at this institution. The patients excluded from the study were those with preoperative anticoagulants, unknown aspirin use, or underwent emergent cardiac surgery. Outcome events included were 30-day mortality, renal failure, readmission and a composite outcome--major adverse cardiocerebral events (MACE) that include permanent or transient stroke, coma, perioperative myocardial infarction (MI), heart block and cardiac arrest. Of all patients, 1145 patients met the inclusion criteria and were divided into two groups: those taking (n = 858) or not taking (n = 287) aspirin within 5 days preceding surgery. Patients with aspirin presented significantly more with history of hypertension, diabetes, peripheral arterial disease, previous MI, angina and older age. With propensity scores adjusted and multivariate logistic regression, however, this study showed that preoperative aspirin therapy (vs. no aspirin) significantly reduced the risk of MACE (8.4% vs. 12.5%, odds ratio [OR] 0.585, 95% CI 0.355-0.964, P = 0.035), postoperative renal failure (2.6% vs. 5.2%, OR 0.438, CI 0.203-0.945, P = 0.035) and dialysis required (0.8% vs. 3.1%, OR 0.230, CI 0.071-0.742, P = 0.014), but did not significantly reduce 30-day mortality (4.1% vs. 5.8%, OR 0.744, CI 0.376-1.472, P = 0.396) nor it increased readmissions in the patients undergoing cardiac surgery. Preoperative aspirin therapy is associated with a significant decrease in the risk of MACE and renal failure and did not increase readmissions in patients undergoing non-emergent cardiac surgery.


Evaluating the NCCN Clinical Criteria for Recommending BRCA1 and BRCA2 Genetic Testing in Patients With Breast Cancer.
Background: Mutations in the BRCA1 and BRCA2 genes predispose individuals to a significantly elevated risk for breast and ovarian cancers. Identification of these individuals allows for proper screening, management, and testing of at-risk relatives. NCCN has established clinical criteria for recommending BRCA1/2 testing. Patients and Methods: A retrospective chart review of 1,123 patients with breast cancer was performed to evaluate the positive predictive values (PPVs) of 14 individual criteria for predicting BRCA1/2 mutations. Results: Two criteria had PPVs significantly below 10%. Only 2 of 115 patients who were recommended for testing based solely on the criterion of "diagnosed with breast cancer at ≤45 years of age" had pathogenic mutations at a PPV of 1.6% (95% CI, 0.2%-6.0%). Additionally, 0 of 37 individuals who underwent testing based on the criterion, "diagnosed with breast cancer at any age with ≥2 close blood relatives with breast cancer at any age" tested positive (95% CI, 0%-9%). Overall, meeting >1 criterion has a PPV of 12%, whereas meeting only 1 criterion has a PPV of 3.2% (95% CI, 1.6%-5.7%), significantly below 10% (P<.0001) for predicting BRCA1/2 positivity. Conclusions: Patients with breast cancer meeting >1 criterion constitute a population significantly enriched for BRCA1/2 mutations, whereas those meeting only 1 criterion test positive at a rate similar to unselected patients with breast cancer. These data will inform ongoing discussions regarding how to best implement BRCA1/2 genetic testing.


Genetic variation and dynamics of hepatitis C virus replicons in long-term cell culture.
Hepatitis C virus (HCV) genomic sequences are known to vary widely among HCV strains, but to date there have been few reports on the genetic variations and dynamics of HCV in an experimental system of HCV replication. In this study, a genetic analysis of HCV replicons obtained in long-term culture of two HCV replicon cells (50-1 and 1B-2R1), which were established from two HCV strains, 1B-1 and 1B-2, respectively, was performed. One person cultured 50-1 cells for 18 months, and two people independently cultured 50-1 cells for 12 months. 1B-2R1 cells were also cultured for 12 months. The whole nucleotide sequences of the three independent replicon RNA clones obtained at several time points were determined. It was observed that genetic mutations in both replicons accumulated in a time-dependent manner, and that the mutation rates of both replicons were approximately 3.0 x 10(-3) base substitutions/site/year. The genetic diversity of both replicons was also enlarged in a time-dependent manner. The colony formation assay by transfection of total RNAs isolated from both replicon cells at different time points into naive HuH-7 cells revealed that the genetic mutations accumulating with time in both replicons apparently improved colony formation efficiency. Taken together, these results suggest that the HCV replicon system is useful for the analysis of evolutionary dynamics and variations of HCV. Using this replicon cell culture system, it was demonstrated further that neither ribavirin nor its derivative mizoribine accelerated the mutation rate or the increase in the genetic diversity of HCV replicon.


Effects of Regular Physical Activity on the Immune System, Vaccination and Risk of Community-Acquired Infectious Disease in the General Population: Systematic Review and Meta-Analysis.
Regular physical activity is the prime modality for the prevention of numerous non-communicable diseases and has also been advocated for resilience against COVID-19 and other infectious diseases. However, there is currently no systematic and quantitative evidence synthesis of the association between physical activity and the strength of the immune system. To examine the association between habitual physical activity and (1) the risk of community-acquired infectious disease, (2) laboratory-assessed immune parameters, and (3) immune response to vaccination. We conducted a systemic review and meta-analysis according to PRISMA guidelines. We searched seven databases (MEDLINE, Embase, Cochrane CENTRAL, Web of Science, CINAHL, PsycINFO, and SportDiscus) up to April 2020 for randomised controlled trials and prospective observational studies were included if they compared groups of adults with different levels of physical activity and reported immune system cell count, the concentration of antibody, risk of clinically diagnosed infections, risk of hospitalisation and mortality due to infectious disease. Studies involving elite athletes were excluded. The quality of the selected studies was critically examined following the Cochrane guidelines using ROB2 and ROBINS_E. Data were pooled using an inverse variance random-effects model. Higher level of habitual physical activity is associated with a 31% risk reduction (hazard ratio 0.69, 95% CI 0.61-0.78, 6 studies, N = 557,487 individuals) of community-acquired infectious disease and 37% risk reduction (hazard ratio 0.64, 95% CI 0.59-0.70, 4 studies, N = 422,813 individuals) of infectious disease mortality. Physical activity interventions resulted in increased CD4 cell counts (32 cells/µL, 95% CI 7-56 cells/µL, 24 studies, N = 1112 individuals) and salivary immunoglobulin IgA concentration (standardised mean difference 0.756, 95% CI 0.146-1.365, 7 studies, N = 435 individuals) and decreased neutrophil counts (704 cells/µL, 95% CI 68-1340, 6 studies, N = 704 individuals) compared to controls. Antibody concentration after vaccination is higher with an adjunct physical activity programme (standardised mean difference 0.142, 95% CI 0.021-0.262, 6 studies, N = 497 individuals). Regular, moderate to vigorous physical activity is associated with reduced risk of community-acquired infectious diseases and infectious disease mortality, enhances the first line of defence of the immune system, and increases the potency of vaccination. The original protocol was prospectively registered with PROSPERO (CRD42020178825).


microRNA 421 induces apoptosis of c-33a cervical cancer cells via down-regulation of Bcl-xL.
Cervical cancer is a life-threatening condition. MicroRNAs (miRNAs) can promote or inhibit cell death and proliferation. The present study investigated the effect of miRNA 421 on the growth and apoptosis of cervical cancer cells. miRNA 421 and control miRNA were synthesized and transfected into c-33a cervical cancer cells. A thiazolyl blue tetrazolium bromide assay, caspase-3 activity, and flow cytometry were used to study the effects of miRNA 421 on c-33a cell growth, and apoptosis. Small interfering RNA targeting Bcl-xL was synthesized and transfected into c-33a cells along with miRNA 421. Bcl-xL expression and cell apoptosis were then measured by western blot and flow cytometry, respectively. Transfection of miRNA 421 into c-33a cells reduced their growth, promoted their apoptosis (measured by increased phosphatidylserine eversion), activated caspase-3, and decreased Bcl-xL expression. Silencing and overexpression of Bcl-xL enhanced and inhibited miRNA 421-induced apoptosis of c-33a cells, respectively. miRNA 421 induces c-33a cell apoptosis via down-regulation of Bcl-xL, suggesting that this latter might be used as a potential clinical target.


A hyperboliod representation of the bone-marrow interface within 3D NMR images of trabecular bone: applications to skeletal dosimetry.
Recent advances in physical models of skeletal dosimetry utilize high-resolution NMR microscopy images of trabecular bone. These images are coupled to radiation transport codes to assess energy deposition within active bone marrow irradiated by bone- or marrow-incorporated radionuclides. Recent studies have demonstrated that the rectangular shape of image voxels is responsible for cross-region (bone-to-marrow) absorbed fraction errors of up to 50% for very low-energy electrons (<50 keV). In this study, a new hyperboloid adaptation of the marching cube (MC) image-visualization algorithm is implemented within 3D digital images of trabecular bone to better define the bone-marrow interface, and thus reduce voxel effects in the assessment of cross-region absorbed fractions. To test the method, a mathematical sample of trabecular bone was constructed, composed of a random distribution of spherical marrow cavities, and subsequently coupled to the EGSnrc radiation code to generate reference values for the energy deposition in marrow or bone. Next, digital images of the bone model were constructed over a range of simulated image resolutions, and coupled to EGSnrc using the hyperboloid MC (HMC) algorithm. For the radionuclides 33P, 117mSn, 131I and 153Sm, values of S(marrow<--bone) estimated using voxel models of trabecular bone were shown to have relative errors of 10%, 9%, <1% and <1% at a voxel size of 150 microm. At a voxel size of 60 microm, these errors were 6%, 5%, <1% and <1%, respectively. When the HMC model was applied during particle transport, the relative errors on S(marrow<--bone) for these same radionuclides were reduced to 7%, 6%, <1% and <1% at a voxel size of 150 microm, and to 2%, 2%, <1% and <1% at a voxel size of 60 microm. The technique was also applied to a real NMR image of human trabecular bone with a similar demonstration of reductions in dosimetry errors.


Neural mechanisms of attention become more specialised during infancy: Insights from combined eye tracking and EEG.
The Fixation Shift Paradigm (FSP) measures infants' ability to shift gaze from a central fixation stimulus to a peripheral target (e.g. Hood & Atkinson, 1993: Infant Behavior and Development, 16(4), 405-422). Cortical maturation has been suggested as crucial for the developing ability to shift attention. This study investigated the development of neural mechanisms by combining EEG with simultaneous eye tracking during FSP testing, in typically developing infants aged between 1 and 8 months. The most prominent neural response was a frontal positivity which occurred only in the hemisphere contralateral to the target in the youngest infants but became more ipsilateral with age. This changing lateralisation was associated with improving ability to shift attention (decreasing saccade latencies and fewer 'sticky fixations'-failures to disengage attention from the central target). These findings suggest that the lateralisation of neural responses develops during infancy, possibly due to developing intracortical connections, allowing infants to shift attention more efficiently. Successful use of combined simultaneous remote eye tracking and EEG to measure infant attention shifts. Neural responses involved in attention shifts change in the first year of life. The lateralisation of EEG responses changes with age in the first year of life. Frontal cortex is involved in attention shifts from around 2 months of age.


Effect of feeding glyphosate-tolerant (roundup-ready events GA21 or nk603) corn compared with reference hybrids on feedlot steer performance and carcass characteristics.
Three experiments were conducted to compare the feeding value of genetically enhanced corn (Roundup Ready corn events GA21 and nk603) with nontransgenic hybrids. The four treatments included two separate reference hybrids (REF), the near-isogenic control hybrid (CON), and the genetically enhanced corn (RR), resulting in two preplanned comparisons of CON vs. RR and RR vs. the average of REF. In Exp. 1 (RR event GA21), 175 steers (BW = 427 kg) were fed in 25 pens with seven pens per corn hybrid, except CON, which contained four pens due to limited quantities of that hybrid. In Exp. 2 (RR event nk603), 196 steers (BW = 420 kg) were fed in 28 pens with seven pens per corn. In Exp. 3 (RR event nk603), 200 steers were fed in 20 pens, with a similar treatment design to Exp. 2 and five pens per corn. All experiments were conducted as completely randomized designs and utilized corn produced at University of Illinois (Exp. 1 and 2) and University of Nebraska (Exp. 3) research farms under identity-preserved protocols. In all experiments, DMI, ADG, and feed efficiency were similar (P > 0.30) between RR and REF. In Exp. 1 and Exp. 2, RR was not different (P > 0.25) than CON for growth performance. In Exp. 3, RR was not different from CON for ADG and DMI (P > 0.15) or for feed efficiency (P = 0.08). No differences were observed between RR and CON or RR and REF for carcass weight, longissimus dorsi area, and marbling scores in any of the experiments. Subtle differences were observed between RR and either CON or REF for fat depth in each experiment; however, cattle fed RR were not consistently greater and varied from either the CON or the REF (but not both contrasts) within an experiment. Based on these results, insertion of glyphosate-tolerant genes had no significant effect on nutritive quality of corn. Performance and carcass characteristics were not influenced, which suggests that Roundup Ready corn is similar to conventional, nontransgenic corn when fed to finishing feedlot cattle.


Cardiac hybrid imaging: state-of-the-art.
The field of noninvasive cardiac imaging has experienced enormous advances including computerized tomography coronary angiography (CTCA). Invasive angiography remains the anatomic standard of reference but it is associated with a non-negligible peri-procedural morbidity and mortality which suggests confining its use to patients who will benefit from a revascularization procedure. Many factors that are beyond the simple quantification of diameter narrowing and therefore cannot be fully assessed with luminology will eventually determine whether or not a given lesion produces stress-induced ischemia. Myocardial perfusion scintigraphy by single photon emission computerized tomography (SPECT) is one of the most widely used and well established noninvasive tools for the diagnosis of ischemic heart disease. Although positron emission tomography (PET) offers a higher accuracy than SPECT its use is often limited to large centers. This article explains the great potential of cardiac hybrid imaging which allows a comprehensive evaluation of coronary artery disease as it combines both morphological and functional information by fusing either SPECT or PET with CTCA. SPECT/CT and PET/CT hybrid imaging can provide entirely noninvasively unique information which helps improving diagnostic assessment and risk stratification and also impacts decision making with regard to revascularization in patients with coronary artery disease.


Central neural control of blood pressure and cardiac arrhythmias during subarachnoid hemorrhage in rats.
Sudden death may follow subarachnoid hemorrhage which indicates involvement of neural mechanisms connected with the cardiovascular system. Since various regions of the brain mediate blood pressure and heart rate changes, these parameters and heart rhythm could be affected due to a subarachnoid hemorrhage near the circle of Willis which surrounds the hypothalamus, the highest center for autonomic control. To investigate this in the control group, intracranial pressure, blood pressure, and electrocardiogram were measured before and after a simulated subarachnoid hemorrhage; blood pressure and electrocardiogram were measured following midcollicular lesions in the decerebrate group both before and after a subarachnoid hemorrhage. The results demonstrate that an increase in systemic arterial blood pressure and premature ventricular contractions (with respect to unlesioned group, p less than 0.04) are mediated by forebrain areas and require the integrity of neuroanatomical connections with structures that are caudal to the midbrain. Since bradycardia and other electrocardiographic abnormalities could still be produced after midcollicular lesioning it is suggested that they can be mediated via the brainstem only without involvement of more rostral areas and may occur due to increased intracranial pressure.


Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT).
Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients. A multicenter, randomized, international, 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder, 26.8% of whom were refractory to previous treatment, who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation. To equalize clinical contact across treatments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomization, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts. Suicidal behavior was assessed at each visit. Primary end points included suicide attempts (including those that led to death), hospitalizations to prevent suicide, and a rating of "much worsening of suicidality" from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved. Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P =.03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P =.03), required hospitalizations (82 vs 107; P =.05) or rescue interventions (118 vs 155; P =.01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P =.01) or anxiolytics or soporifics (301 vs 331; P =.03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P =.73). Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.


Natural killer T cells: a bridge to tolerance or a pathway to rejection?
Over the past 20 years, natural killer T (NKT) cells have been shown to play an important role in both innate and adaptive immune responses. In this review, the potential role of NKT cells in transplantation will be discussed, particularly their role in rejection and the induction of a state of tolerance.


The amobarbital sodium interview in conversion disorders: use of video feedback in therapy.
The prognosis in treating acute conversion disorder is good, but it demands considerable time in the form of an intensive, and often extensive, hospital stay. With the increasing trend to limiting hospital stays, the family practitioner working with a psychiatrist in the hospital setting is pressured to find new approaches in order to limit the use of inpatient units. The authors describe a case of classic conversion disorder and outline a successful approach that uses a video recording of the interview, during which the patient is under the influence of amobarbital sodium. The videotape then provides valuable feedback during future therapy sessions in the treatment of this persistent disorder.


Dynamic range enhancement of a novel phase-locked coherent optical phase demodulator.
We report on a novel cancellation technique, for reducing the nonlinearity associated with the tracking phase-modulator in recently proposed phase-locked coherent demodulator for phase modulated analog optical links. The proposed cancellation technique is input RF signal power and frequency independent leading to a significant increase in dynamic range of the coherent demodulator. Furthermore, this technique demonstrates that large values of the signal-to-intermodulation ratio of the demodulated signal can be obtained even though the tracking phase modulator is fairly nonlinear, and thereby relaxing the linearity requirements for the tracking phase modulator. A new model is developed and the calculated results are in good agreement with measurements.