Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism.
Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.


[Communication and interactive education in health and its application to the management of the diabetic patient].
This article analyzes the need for participation of the groups that are the recipients of health messages in order to make health education more effective. Taking the traditional educational approach as the point of departure, the different options for communication and education processes in this field are explored in depth. The participatory communication model, in which the subject plays the role of both transmitter and recipient, leads to the coproduction of health education messages. In light of the experience of the Diabetes Education Program of the National Endocrinology Institute of Cuba, a health education model based on a strategy of interactive communication is presented. Its objective is to develop in the patient the capability to think and decide about his or her health through discussion groups facilitated by a health care provider. In this model, the beneficiaries of the health message help shape its aim and content. The discussion centers on the patient, taking into account his or her real health needs and feelings. The results obtained with this methodology are reviewed, and it is concluded that this model opens new educational possibilities that will facilitate decision-making with regard to health and healthy lifestyles.


The nonstress test.
No currently available single test of fetal well-being is a universal, infallible clinical tool that stands apart from the more general context of the total pregnancy. It is tempting to place a substantial emphasis on the results of a test when medical decision-making is needed. Perhaps some sense of proportion should be invoked at this point, beginning with the recognition that fetal heart rate data, regardless of how they are obtained, provide a limited window to view the fetus and its environment. The fact remains that the relatively low incidence of real fetal compromise and subsequent poor outcomes biases the efficacy of the NST and other well-being tools. Most high-risk populations have a prevalence of poor outcomes of approximately 10 per cent; consequently, the target population for any assessment test is quite small. One must be reassured by the extremely large reported experience of Platt et al that nonstress testing is clinically useful in the overwhelming majority of cases. The NST appears to be an excellent predictor of the healthy fetus. The test is very good at predicting the fetus who does not require acute or premature obstetric intervention: it thereby prevents pregnancies from being subjected to unnecessary iatrogenic risks and from incurring tremendous medical and emotional costs. Can the NST be improved? I think that there is still considerable opportunity for making this test more effective and accurate. Our experience supports the concepts of standardized testing conditions, the use of baseline data in addition to reactivity alone, the prolongation of test sessions to achieve a more representative view of the fetus, and ultimately an automated analysis that will aid the clinician in making more reliable assessments of the fetal heart rate data present in the actual tracing. It would be useful to see the NST better integrated into management schemes that incorporate other assessment techniques as well as pertinent clinical data. The tendency to view the test as a "stand alone" modality has underscored weaknesses inherent in all surveillance methods that have a naturally limited perspective on complex developmental and adaptive problems. There is also a need for the development of academic standards so that collected experiences can be directly compared and communication of testing results made less ambiguous. These are some of the goals that should be set for the future and whose realization will effect better care for the unique population served by obstetricians.


An alternative approach to multiple genome comparison.
Genome comparison is now a crucial step for genome annotation and identification of regulatory motifs. Genome comparison aims for instance at finding genomic regions either specific to or in one-to-one correspondence between individuals/strains/species. It serves e.g. to pre-annotate a new genome by automatically transferring annotations from a known one. However, efficiency, flexibility and objectives of current methods do not suit the whole spectrum of applications, genome sizes and organizations. Innovative approaches are still needed. Hence, we propose an alternative way of comparing multiple genomes based on segmentation by similarity. In this framework, rather than being formulated as a complex optimization problem, genome comparison is seen as a segmentation question for which a single optimal solution can be found in almost linear time. We apply our method to analyse three strains of a virulent pathogenic bacteria, Ehrlichia ruminantium, and identify 92 new genes. We also find out that a substantial number of genes thought to be strain specific have potential orthologs in the other strains. Our solution is implemented in an efficient program, qod, equipped with a user-friendly interface, and enables the automatic transfer of annotations between compared genomes or contigs (Video in Supplementary Data). Because it somehow disregards the relative order of genomic blocks, qod can handle unfinished genomes, which due to the difficulty of sequencing completion may become an interesting characteristic for the future. Availabilty: http://www.atgc-montpellier.fr/qod.


Measurement of Strontium Monoxide in Methane-Air Flames.
The spectroscopy of alkaline earth metal compounds is stimulated by the use of these compounds in practical areas ranging from technology to medicine. Applications in the field of pyrotechnics were the motivation for a series of flame emission spectroscopy experiments with strontium-containing compounds. Specifically, strontium monoxide (SrO) was studied as a candidate radiator for the diagnosis of methane-air flames. Strontium monoxide emissions have been observed in flames with temperatures in the range 1200 K to 1600 K for two compounds: strontium hydroxide and strontium chloride. Comparisons are made of the measured SrO spectra to simulated spectra in the near-infrared region of 700 nm to 900 nm.


Superior Sagittal Venous Sinus Thrombosis in a Patient with Illicit Testosterone Use.
Cerebral venous sinus thrombosis is a challenging diagnosis due in part to its variable clinical presentation and rarity. The annual incidence ranges from 0.22 to 1.57 per 100,000. The etiology of such disease is related to hypercoagulability states. Although illicit androgen use is a well-known cause of prothrombotic states, its risk of causing cerebral venous sinus thrombosis has been infrequently reported. We present the case of a 33-year-old male with no known past medical history who presented to the emergency department (ED) with persistent seizure activity, neurological deficits, and history of worsening headaches who was found to have an extensive superior sagittal sinus thrombosis on imaging. Radiologic findings demonstrated pathognomonic findings of cord sign and delta sign, the previous being highly specific but of low incidence. An inconclusive hypercoagulability workup prompted further questioning which revealed illicit androgenic anabolic steroid use. Prompt treatment with anticoagulation and anti-seizure medication was pursued with full resolution of his neurologic symptomatology.


Glutamine reduces the expression of leukocyte integrins leukocyte function-associated antigen-1 and macrophage antigen-1 in mice exposed to arsenic.
Chronic arsenic exposure results in an increased oxidative stress and inflammation in the body. Glutamine (GLN) is an amino acid considered to have immunomodulatory effects and attenuate the inflammatory reaction. This study was designed to examine the effect of GLN supplementation on inflammatory-related leukocyte integrin expression and in vitro splenocyte cytokine production in mice exposed to arsenic. Mice were assigned to the control and experimental groups. The control group drank deionized water, whereas the experimental group drank deionized water containing 50 ppm of sodium arsenite. Each control and experimental group was further divided into 2 subgroups and fed diets for 5 weeks. One subgroup was fed a semipurified diet, whereas the other subgroup was fed a diet where part of the casein was replaced with GLN, which provided 25% of the total amino acid nitrogen. The results showed that plasma GLN levels of mice in the arsenic group were significantly lower than those in the control groups. Glutamine supplementation reversed the depletion of plasma GLN in the arsenic group. beta(2) intergins, including leukocyte function-associated antigen-1 and macrophage antigen-1 expressed by leukocytes, were significantly higher in the arsenic group than the control groups. Glutamine supplementation reduced leukocyte integrin expression in mice exposed to arsenic. There were no differences in interleukin 4, interleukin 6, interferon gamma, and tumor necrosis factor alpha production between the 2 arsenic groups when splenocytes were stimulated with mitogen. These results suggest that arsenic exposure results in depletion of plasma GLN and higher leukocyte integrin expression. Glutamine supplementation normalized the plasma GLN levels and reduced leukocyte leukocyte function-associated antigen-1 and macrophage antigen-1 expression. However, cytokine modulation may not be responsible for reducing leukocyte integrin expression in mice exposed to arsenic.


Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis.
The purpose of this study was to determine the cumulative incidence of lupus nephritis (LN) and the factors predictive of its occurrence in a multiethnic systemic lupus erythematosus (SLE) cohort. We studied 353 SLE patients as defined by the American College of Rheumatology (ACR) criteria (65 Hispanics, 93 African-Americans and 91 Caucasians). First, we determined the cumulative incidence of LN in all patients. Next, we determined the predictors for LN in those with nephritis occurring after diagnosis. The dependent variable, LN, was defined by: (1) A renal biopsy demonstrating World Health Organization (WHO), class II-V histopathology; and/or (2) proteinuria > or = 0.5 g/24 h or 3+ proteinuria attributable to SLE; and/or (3) one of the following features also attributable to SLE and present on two or more visits, which were performed at least 6 months apart--proteinuria > or = 2+, serum creatinine > or = 1.4 mg/dl, creatinine clearance < or = 79 ml/min, > or = 10 RBCs or WBCs per high power field (hpf), or > or = 3 granular or cellular casts per hpf. Independent variables assessed at diagnosis, and if absent, at baseline, were from four domains: sociodemographic, clinical, immunologic and immunogenetic (including the complete antibody profile and MHC class II alleles), and health habits. Variables with P < 0.05 by chi square analyses were entered into domain-specific stepwise logistic regression analyses controlling for disease duration, with LN as the dependent variable. Significant domain-specific regression variables (P < or = 0.1) were then entered into an overall model. The cumulative incidence of LN was 54.3% in all patients, and 35.3% for those developing LN after diagnosis. LN after diagnosis occurred in 43.1% of 65 Hispanics, 50.5% of 93 African-Americans, and 14.3% of 91 Caucasians, P < 0.0001. The duration of follow-up for those with LN after diagnosis was 5.5+/-2.4 vs 4.0+/-2.9 years for those without LN. Hispanic (odds ratio (OR) = 2.71, 95% confidence limits (CL) = 1.07-6.87, P < 0.04) and African-American ethnicities (OR = 3.13, 95% CL = 1.21-8.09, P < 0.02), not married or living together (OR = 3.45, 95% CL = 1.69-7.69, P < 0.0003), higher SLAM score (OR = 1.11, 95% CL = 1.02-1.19, P < 0.007), anti-dsDNA (OR = 3.14, 95% CL = 1.50-6.57, P < 0.0001) and anti-RNP (OR = 4.24, CL = 1.98-9.07, P < 0.0001) antibodies were shown to be significant predictors of the occurrence of LN. Repeated analyses excluding the patients with missing HLA data showed that absence of HLA-DQB1*0201 was also a significant predictor for the occurrence of LN (OR = 2.34, CL = 1.13-5.26, P < 0.04). In conclusion, LN occurred significantly more often in Hispanics and African-Americans with SLE. Sociodemographic, clinical and immunologic/immunogenetic factors seem to be predictive of LN occurring after the diagnosis of SLE has been made.


Treatment algorithm in cancer-associated thrombosis: Canadian expert consensus.
Management of anticoagulant therapy for the treatment of venous thromboembolism (vte) in cancer patients is complex because of an increased risk of recurrent vte and major bleeding complications in those patients relative to the general population. Subgroups of patients with cancer also show variation in their risk for recurrent vte and adverse bleeding events. Accordingly, a committee of 10 Canadian clinical experts developed the consensus risk- stratification treatment algorithm presented here to provide guidance on tailoring anticoagulant treatment choices for the acute and extended treatment of symptomatic and incidental vte, to prevent recurrent vte, and to minimize the bleeding risk in patients with cancer. During a 1-day live meeting, a systematic review of the literature was performed, and a draft treatment algorithm was developed. The treatment algorithm was refined through the use of a Web-based platform and a series of online teleconferences. Clinicians using this treatment algorithm should consider the bleeding risk, the type of cancer, and the potential for drug-drug interactions in addition to informed patient preference in determining the most appropriate treatment for patients with cancer-associated thrombosis. Anticoagulant therapy should be regularly reassessed as the patient's cancer status and management change over time.


Arsenic, organic foods, and brown rice syrup.
Rice can be a major source of inorganic arsenic (Asi) for many sub-populations. Rice products are also used as ingredients in prepared foods, some of which may not be obviously rice based. Organic brown rice syrup (OBRS) is used as a sweetener in organic food products as an alternative to high-fructose corn syrup. We hypothesized that OBRS introduces As into these products. We determined the concentration and speciation of As in commercially available brown rice syrups and in products containing OBRS, including toddler formula, cereal/energy bars, and high-energy foods used by endurance athletes. We used inductively coupled plasma mass spectrometry (ICP-MS) and ion chromatography coupled to ICP-MS to determine total As (Astotal) concentrations and As speciation in products purchased via the Internet or in stores in the Hanover, New Hampshire, area. We found that OBRS can contain high concentrations of Asi and dimethyl-arsenate (DMA). An "organic" toddler milk formula containing OBRS as the primary ingredient had Astotal concentrations up to six times the U.S. Environmental Protection Agency safe drinking water limit. Cereal bars and high-energy foods containing OBRS also had higher As concentrations than equivalent products that did not contain OBRS. Asi was the main As species in most food products tested in this study. There are currently no U.S. regulations applicable to As in food, but our findings suggest that the OBRS products we evaluated may introduce significant concentrations of Asi into an individual's diet. Thus, we conclude that there is an urgent need for regulatory limits on As in food.


Molecular and Functional Insights into the Regulation of d-Galactonate Metabolism by the Transcriptional Regulator DgoR in Escherichia coli.
d-Galactonate, an aldonic sugar acid, is used as a carbon source by Escherichia coli, and the structural dgo genes involved in its metabolism have previously been investigated. Here, using genetic, biochemical and bioinformatics approaches, we present the first detailed molecular and functional insights into the regulation of d-galactonate metabolism in E. coli K-12 by the transcriptional regulator DgoR. We found that dgoR deletion accelerates the growth of E. coli in d-galactonate concomitant with the strong constitutive expression of dgo genes. In the dgo locus, sequence upstream of dgoR alone harbors the d-galactonate-inducible promoter that likely drives the expression of all dgo genes. DgoR exerts repression on the dgo operon by binding two inverted repeats overlapping the dgo promoter. Binding of d-galactonate induces a conformational change in DgoR to derepress the dgo operon. The findings from our work firmly place DgoR in the GntR family of transcriptional regulators: DgoR binds an operator sequence [5'-TTGTA(G/C)TACA(A/T)-3'] matching the signature of GntR family members that recognize inverted repeats [5'-(N) yGT(N) xAC(N) y -3', where x and y indicate the number of nucleotides, which varies], and it shares critical protein-DNA contacts. We also identified features in DgoR that are otherwise less conserved in the GntR family. Recently, missense mutations in dgoR were recovered in a natural E. coli isolate adapted to the mammalian gut. Our results show these mutants to be DNA binding defective, emphasizing that mutations in the dgo-regulatory elements are selected in the host to allow simultaneous induction of dgo genes. The present study sets the basis to explore the regulation of dgo genes in additional enterobacterial strains where they have been implicated in host-bacterium interactions.IMPORTANCE d-Galactonate is a widely prevalent aldonic sugar acid. Despite the proposed significance of the d-galactonate metabolic pathway in the interaction of enteric bacteria with their hosts, there are no details on its regulation even in Escherichia coli, which has been known to utilize d-galactonate since the 1970s. Here, using multiple methodologies, we identified the promoter, operator, and effector of DgoR, the transcriptional repressor of d-galactonate metabolism in E. coli We establish DgoR as a GntR family transcriptional regulator. Recently, a human urinary tract isolate of E. coli introduced in the mouse gut was found to accumulate missense mutations in dgoR Our results show these mutants to be DNA binding defective, hence emphasizing the role of the d-galactonate metabolic pathway in bacterial colonization of the mammalian gut.


Estimation of Purkinje trees from electro-anatomical mapping of the left ventricle using minimal cost geodesics.
The electrical activation of the heart is a complex physiological process that is essential for the understanding of several cardiac dysfunctions, such as ventricular tachycardia (VT). Nowadays, patient-specific activation times on ventricular chambers can be estimated from electro-anatomical maps, providing crucial information to clinicians for guiding cardiac radio-frequency ablation treatment. However, some relevant electrical pathways such as those of the Purkinje system are very difficult to interpret from these maps due to sparsity of data and the limited spatial resolution of the system. We present here a novel method to estimate these fast electrical pathways from the local activations maps (LATs) obtained from electro-anatomical maps. The location of Purkinje-myocardial junctions (PMJs) is estimated considering them as critical points of a distance map defined by the activation maps, and then minimal cost geodesic paths are computed on the ventricular surface between the detected junctions. Experiments to validate the proposed method have been carried out in simplified and realistic simulated data, showing good performance on recovering the main characteristics of simulated Purkinje networks (e.g. PMJs). A feasibility study with real cases of fascicular VT was also performed, showing promising results.


Signs and Symptoms of Ocular Surface Disease: The Reasons for Patient Dissatisfaction with Glaucoma Treatments.
Ocular Surface Disease (OSD) and hyperemia are the most common adverse events of topical ocular medications. While active compounds may cause allergic reactions or irritation, preservatives, which are intended to prevent bacterial growth, are toxic as well. Therefore, the most recent glaucoma medications no longer contain preservatives. Despite this, local tolerability may still impact treatment compliance and patient quality of life. We conducted an observational, multi-center, international, cross-sectional study in 793 treated and stabilized glaucoma patients to assess patient satisfaction and local tolerability of their treatment. The vast majority (93.7%) of patients was satisfied or very satisfied with their treatment in terms of tolerability and only 6.3% were dissatisfied. However, ophthalmological examination showed a high frequency of ocular signs: conjunctival hyperemia (32%), OSD (42.5%) and positive conjunctival fluorescein staining (10.3%). Additionally, patients reported symptoms upon instillation (31.4%) and between instillations (57.3%); 25.1% of patients were using tear substitutes. All signs and symptoms were significantly (p<0.001) associated with patient dissatisfaction. A logistic regression model indicated that dissatisfaction was higher in patients with symptoms upon instillation and in those using tear substitutes (OR: 3.03 and 4.63, respectively). The mean patient tolerability score to treatment was 82.7±16.1 on a 100-point visual analogue scale. In conclusion, even if patients may be highly satisfied with their current treatment, most of them present ocular signs and symptoms. A treatment change should be considered in case of clinical signs or patient-reported symptoms.


Contrasting temporal difference and opportunity cost reinforcement learning in an empirical money-emergence paradigm.
Money is a fundamental and ubiquitous institution in modern economies. However, the question of its emergence remains a central one for economists. The monetary search-theoretic approach studies the conditions under which commodity money emerges as a solution to override frictions inherent to interindividual exchanges in a decentralized economy. Although among these conditions, agents' rationality is classically essential and a prerequisite to any theoretical monetary equilibrium, human subjects often fail to adopt optimal strategies in tasks implementing a search-theoretic paradigm when these strategies are speculative, i.e., involve the use of a costly medium of exchange to increase the probability of subsequent and successful trades. In the present work, we hypothesize that implementing such speculative behaviors relies on reinforcement learning instead of lifetime utility calculations, as supposed by classical economic theory. To test this hypothesis, we operationalized the Kiyotaki and Wright paradigm of money emergence in a multistep exchange task and fitted behavioral data regarding human subjects performing this task with two reinforcement learning models. Each of them implements a distinct cognitive hypothesis regarding the weight of future or counterfactual rewards in current decisions. We found that both models outperformed theoretical predictions about subjects' behaviors regarding the implementation of speculative strategies and that the latter relies on the degree of the opportunity costs consideration in the learning process. Speculating about the marketability advantage of money thus seems to depend on mental simulations of counterfactual events that agents are performing in exchange situations.


Rodentborne fungal pathogens in wetland agroecosystem.
The past few decades have witnessed an overwhelming increase in the incidence of fungal infections, particularly in immunocompromised individuals. Consequently, zoonotic diseases, especially through rodents constitute a prominent group among the emerging diseases. Rodents are commensal to man and related health risks are common. Water rats (Rattus norvegicus) are typical to Vembanadu-Kol wetland agroecosystems, where they can act as a good carrier nexus for pathogens. The present study evaluates the carrier status of water rats with respect to fungal pathogens. A total of fifty two fungi covering eighteen families were isolated. Among the isolates, eight were dermaptophytes and Chrysosporium sp. (89.18%) was the frequent isolate. The source-wise analyses showed an increased isolation from ventral hair (67 isolates). Water rats of Vembanadu-Kol wetland agroecosystem are potent carrier of dermaptophytes and other opportunistic fungi, and strong carrier paths are existing too.


SPIN90 associates with mDia1 and the Arp2/3 complex to regulate cortical actin organization.
Cell shape is controlled by the submembranous cortex, an actomyosin network mainly generated by two actin nucleators: the Arp2/3 complex and the formin mDia1. Changes in relative nucleator activity may alter cortical organization, mechanics and cell shape. Here we investigate how nucleation-promoting factors mediate interactions between nucleators. In vitro, the nucleation-promoting factor SPIN90 promotes formation of unbranched filaments by Arp2/3, a process thought to provide the initial filament for generation of dendritic networks. Paradoxically, in cells, SPIN90 appears to favour a formin-dominated cortex. Our in vitro experiments reveal that this feature stems mainly from two mechanisms: efficient recruitment of mDia1 to SPIN90-Arp2/3 nucleated filaments and formation of a ternary SPIN90-Arp2/3-mDia1 complex that greatly enhances filament nucleation. Both mechanisms yield rapidly elongating filaments with mDia1 at their barbed ends and SPIN90-Arp2/3 at their pointed ends. Thus, in networks, SPIN90 lowers branching densities and increases the proportion of long filaments elongated by mDia1.


Rapid flip-flop of oleic acid across the plasma membrane of adipocytes.
Nonesterified long-chain fatty acids may enter cells by free diffusion or by membrane protein transporters. A requirement for proteins to transport fatty acids across the plasma membrane would imply low partitioning of fatty acids into the membrane lipids, and/or a slower rate of diffusion (flip-flop) through the lipid domains compared to the rates of intracellular metabolism of fatty acids. We used both vesicles of the plasma membrane of adipocytes and intact adipocytes to study transmembrane fluxes of externally added oleic acid at concentrations below its solubility limit at pH 7.4. Binding of oleic acid to the plasma membrane was determined by measuring the fluorescent fatty acid-binding protein ADIFAB added to the external medium. Changes in internal pH caused by flip-flop and metabolism were measured by trapping a fluorescent pH indicator in the cells. The metabolic end products of oleic acid were evaluated over the time interval required for the return of intracellular pH to its initial value. The primary findings were that (i) oleic acid rapidly binds with high avidity in the lipid domains of the plasma membrane with an apparent partition coefficient similar to that of protein-free phospholipid bilayers; (ii) oleic acid rapidly crosses the plasma membrane by the flip-flop mechanism (both events occur within 5 s); and (iii) the kinetics of esterification of oleic acid closely follow the time dependence of the recovery of intracellular pH. Any postulated transport mechanism for facilitating translocation of fatty acid across the plasma membrane of adipocytes, including a protein transporter, would have to compete with the highly effective flip-flop mechanism.


Associations of context-specific sitting time with markers of cardiometabolic risk in Australian adults.
High volumes of sitting time are associated with an elevated risk of type 2 diabetes and cardiovascular disease, and with adverse cardiometabolic risk profiles. However, previous studies have predominately evaluated only total sitting or television (TV) viewing time, limiting inferences about the specific cardiometabolic health impacts of sitting accumulated in different contexts. We examined associations of sitting time in four contexts with cardiometabolic risk biomarkers in Australian adults. Participants (n = 3429; mean ± SD age 58 ± 10 years) were adults without clinically diagnosed diabetes or cardiovascular disease from the 2011-2012 Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Multiple linear regressions examined associations of self-reported context-specific sitting time (occupational, transportation, TV-viewing and leisure-time computer use) with a clustered cardiometabolic risk score (CMR) and with individual cardiometabolic risk biomarkers (waist circumference, BMI, resting blood pressure, triglycerides, HDL- and LDL-cholesterol, and fasting and 2-h post-load plasma glucose). Higher CMR was significantly associated with greater TV-viewing and computer sitting time (b [95%CI] = 0.07 [0.04, 0.09] and 0.06 [0.03, 0.09]), and tended to be associated with higher occupational and transport sitting time (0.01 [- 0.01, 0.03] and 0.03 [- 0.00, 0.06]), after adjustment for potential confounders. Furthermore, keeping total sitting time constant, accruing sitting via TV-viewing and computer use was associated with significantly higher CMR (0.05 [0.02, 0.08] and 0.04 [0.01, 0.06]), accruing sitting in an occupational context was associated with significantly lower CMR (- 0.03 [- 0.05, - 0.01]), while no significant association was seen for transport sitting (0.00 [- 0.03, 0.04]). Results varied somewhat between the respective biomarkers; however, higher sitting time in each domain tended to be associated detrimentally with individual biomarkers except for fasting glucose (non-significant associations) and systolic blood pressure (a beneficial association was observed). Overall, associations were stronger for TV-viewing and computer use, and weaker for occupational sitting. Higher context-specific sitting times tended to be detrimentally associated, albeit modestly, with CMR and several cardiometabolic risk biomarkers. There was some evidence suggesting that the context in which people sit is relevant above and beyond total sitting time. Methodological issues notwithstanding, these findings may assist in identifying priorities for sitting-reduction initiatives, in order to achieve optimal cardiometabolic health benefits.


Central dimensions of clinical practice evaluation: efficiency, appropriateness and effectiveness--II.
That a treatment selected for a given condition works, or that it works better than alternative treatments, or that it was selected because it works as well as but is cheaper than alternative treatments, should be of pivotal concern to clinicians and is of central concern to patients and to health care managers. Attempts to address these concerns have resulted in what is now widely termed the 'effectiveness movement'. The protagonists of the movement have been concerned to create a culture of evaluation and inquiry within which the formulation of evidence-based clinical guidelines and their introduction into routine practice have played a prominent part. The need to ensure cost effectiveness of clinical intervention has been at least as emphasized as the need to ensure the clinical effectiveness of health care interventions. Although cost-effectiveness analyses are now an indispensable feature of practice guideline formulation and treatment evaluation, few studies have examined any deterioration in patient outcome associated with successful cost containment. An adequate understanding of the concept of clinical effectiveness and the associated aims of the 'effectiveness movement' is central to an understanding of the future nature and extent of health service provision, not simply in the UK but also internationally. Having examined the concepts of efficiency and appropriateness previously (O'Neill, Miles & Polychronis 1996, Journal of Evaluation in Clinical Practice 2, 13-27) we move in this second of two articles to a detailed explanation of the concept of effectiveness, and to an examination of the derivation and use of clinical practice guideline, concluding with a consideration of the role of practice guidelines in ensuring the cost effectiveness of health care intervention. The reservation is expressed that a 'guidelines culture', when established, will be manipulated by health care commissioners for largely political purposes, creating a systematic bias in the purchasing process that will actively disadvantage a range of patient groups.


Mechanisms and current treatments of urogenital dysfunction in multiple sclerosis.
The majority of patients with multiple sclerosis (MS) suffer from lower urinary tract symptoms and sexual dysfunction at some stage of the disease. This has a negative impact on the quality of life of patients as well as causing concern to caregivers and family. Neurologists can now treat most of these symptoms by a number of pharmacological and nonpharmacological methods. This review presents the neuroanatomy, neurophysiology, neuropharmacology and pathophysiology of the urinary bladder and sexual organs, and the biological mechanisms underlying urogenital dysfunction in MS patients. Current treatment options for urinary and sexual dysfunction are reviewed. As most urogenital symptoms of MS can now be treated by conservative means, expert urological or gynaecological consultation should be requested only if more aggressive diagnostic or therapeutic measures are needed.


Fluorescence imaging for the demarcation of basal cell carcinoma tumor borders.
Basal cell carcinoma (BCC) is a common malignancy accounting for 80% of all nonmelanoma skin cancers. Mohs micrographic surgery (MMS) is considered superior to alternative treatments, but the procedure is time consuming and costly. Alternative simpler techniques to facilitate accurate tumor demarcation are therefore in demand. Fluorescence imaging following application of 5-aminolevulinic acid is a noninvasive diagnostic technique that gives rapid information about the superficial extent of the skin tumor. To ascertain whether fluorescence imaging improves the clinical tumor border assessment by investigating the consistency between tumor size determination by MMS, clinical assessment, and fluorescence imaging. Eighteen patients with histologically verified nodular BCCs on the face scheduled for MMS were included in the study. The night before the surgical procedure, 5-aminolevulinic methyl ester cream was applied to the lesion. The following morning, tumor borders were determined clinically (clinical size), after illumination with Wood's light (fluorescence size), and by the tumor defect left on the skin surface following removal of the MMS specimen (Mohs size). The median tumor sizes were 93.05 mm2 (Mohs size), 61.05 mm2 (clinical size), and 72.75 mm2 (fluorescence size). The interclass correlation coefficients between Mohs size and fluorescence size was 0.984 and Mohs size and clinical size was 0.752. Tumor border estimation by fluorescence imaging and clinical assessment underestimate the genuine tumor size determined by MMS; however, the fluorescence size showed a higher degree of consistency with the Mohs size than did the clinical size.


Ruthenium polypyridyl complexes as inducer of ROS-mediated apoptosis in cancer cells by targeting thioredoxin reductase.
TrxR is an NADPH-dependent selenoenzyme upregulated in a number of cancers. It plays a pivotal role in cancer progression and represents an increasingly attractive target for anticancer drugs. The limitations of cisplatin in cancer treatment have motivated the extensive investigation to other metal complexes, especially ruthenium (Ru) complexes. In this study, we present the in vitro biological evaluation of four Ru(II) polypridyl complexes with diimine ligands, namely, [Ru(bpy)3](2+) (1), [Ru(phen)3](2+) (2), [Ru(ip)3](2+) (3), [Ru(pip)3](2+) (4) (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, ip = imidazole[4,5-f][1,10]phenanthroline, pip = 2-phenylimidazo[4,5-f][1,10]phenanthroline), and demonstrate that they exhibit antiproliferative activities against A375 human melanoma cells through inhibition of TrxR. As the planarity of the structure increases, their TrxR-inhibitory effects and in vitro anticancer activities were enhanced. Among them, complex 4 exhibited higher antiproliferative activity than cisplatin, and the TrxR-inhibitory potency of 4 was more effective than auranofin, a positive TrxR inhibitor. Complex 4 suppressed the cancer cell growth through induction of apoptosis as evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Moreover, complex 4 was able to localize in mitochondria and therein induced ROS-dependent apoptosis by inhibition of TrxR activity. Activation of MAPKs, AKT, DNA damage-mediated p53 phosphorylation and inhibition of VEGFR signaling were also triggered in cells exposed to complex 4. On the basis of this evidence, we suggest that Ru polypyridyl complexes could be developed as TrxR-targeted agents that demonstrate application potentials for treatment of cancers.


An Explorative Biomarker Study for Vaccine Responsiveness after a Primary Meningococcal Vaccination in Middle-Aged Adults.
Prevention of infectious diseases in the elderly is essential to establish healthy aging. Yet, immunological aging impairs successful vaccination of the elderly. Predictive biomarkers for vaccine responsiveness in middle-aged adults may help to identify responders and non-responders before reaching old age. Therefore, we aimed to determine biomarkers associated with low and high responsiveness toward a primary vaccination in middle-aged adults, for which a tetravalent meningococcal vaccine was used as a model. Middle-aged adults (50-65 years of age, N = 100), receiving a tetravalent meningococcal vaccination, were divided into low and high responders using the functional antibody titers at 28 days postvaccination. A total of 48 parameters, including absolute numbers of immune cells and serum levels of cytokines and biochemical markers, were determined prevaccination in all participants. Heat maps and multivariate redundancy analysis (RDA) were used to reveal immune phenotype characteristics and associations of the low and high responders. Several significant differences in prevaccination immune markers were observed between the low and high vaccine responders. Moreover, RDA analysis revealed a significant association between the prevaccination immune phenotype and vaccine responsiveness. In particular, our analysis pointed at high numbers of CD4 T cells, especially naïve CD4 and regulatory T subsets, to be associated with low vaccine responsiveness. In addition, low responders showed lower prevaccination IL-1Ra levels than high responders. This explorative biomarker study shows associations between the prevaccination immune phenotype and vaccine responsiveness after a primary meningococcal vaccination in middle-aged adults. Consequently, these results provide a basis for predictive biomarker discovery for vaccine responsiveness that will require validation in larger cohort studies.


Investigating regional variation of respiratory infections in a general practice syndromic surveillance system.
Established surveillance systems can follow trends in community disease and illness over many years. However, within England there are known regional differences in healthcare utilisation, which can affect interpretation of trends. Here, we explore regional differences for a range of respiratory conditions using general practitioner (GP) consultation data. Daily data for respiratory conditions were extracted from a national GP surveillance system. Average daily GP consultation rates per 100 000 registered patient population were calculated by each region of England and for each study year (2013-17). Consultation rates and incidence rate ratios were also calculated for each condition by deprivation quintile and by rural, urban, and conurbation groups. Upper and lower respiratory tract infections and asthma were higher in the North and the Midlands than in London and the South, were highest in the most deprived groups and tended to be higher in more urban areas. Influenza-like illness was highest in the least deprived and rural areas. There are consistent differences in GP consultation rates across the English regions. This work has improved our understanding and interpretation of GP surveillance data at regional level and will guide more accurate public health messages.


Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma.
To determine if osteosarcoma cells express chemokine receptors and if their presence or absence relates to clinical features. Using fluorescent quantitative real-time PCR, the pattern of 17 chemokine receptors in 3 osteosarcoma cell lines and 68 osteosarcoma patient samples was analyzed. The expression of the chemokine receptors was generally low among the cell lines. In the high-grade osteosarcoma patient samples (n = 47), CXCR4 was the most commonly expressed (63%) and its expression level was inversely correlated to overall survival (P < 0.0001), event-free survival (P < 0.001), and metastasis-free survival (MFS; P = 0.002). There was also a correlation between the expression level of CXCR4 and the presence of metastasis at diagnosis (P = 0.002). CCR7 was expressed in 43% of the samples and its expression level was inversely correlated with overall survival (P = 0.03) and MFS (P = 0.007). CCR10 mRNA expression level was inversely correlated with MFS (P = 0.009). There was no association between the expression of CXCR4, CCR7, and CCR10. Of the 26 samples studied for stromal cell-derived factor-1 expression, 77% expressed it, but there was no correlation with the clinical variables or CXCR4 expression. Multivariate analysis revealed that mRNA expression level of CXCR4 was the only significant variable for overall survival (P = 0.0006), event-free survival (P = 0.004), and MFS (P = 0.025). These data suggest that CXCR4 could be useful as a prognostic factor and as a predictor of potential metastatic development in osteosarcoma. If further studies confirm that it is relevant to metastases in this disease, it could represent a new therapeutic target.


Effects of genotype and environment on the antioxidant properties of hard winter wheat bran.
Recent consumer interest in controlling and preventing chronic diseases through improved diet has promoted research on the bioactive components of agricultural products. Wheat is an important agricultural and dietary commodity worldwide with known antioxidant properties concentrated mostly in the bran fraction. The objective of this study was to determine the relative contributions of genotype (G) and growing environment (E) to hard winter wheat bran antioxidant properties, as well as correlations of these properties to growing conditions. Bran samples of 20 hard winter wheat varieties grown in two locations were examined for their free radical scavenging capacities against DPPH, ABTS cation, peroxyl (ORAC), and superoxide anion radicals and chelating properties, as well as their total phenolics and phenolic acid compositions. Results showed significant differences for all antioxidant properties tested and multiple significant correlations between these properties. A factorial designed analysis of variance for these data and pooled previously published data showed similar results for four of the six antioxidant properties, indicating that G effects were considerably larger than E effects for chelating capacity and DPPH radical scavenging properties, whereas E was much stronger than G for ABTS cation radical scavenging capacity and total phenolics, although small interaction effects (GxE) were significant for all antioxidant properties analyzed. Results also showed significant correlations between temperature stress or solar radiation and some antioxidant properties. These results indicate that each antioxidant property of hard winter wheat bran is influenced differently by genotype and growing conditions.


Cost-effectiveness of open versus endovascular repair of abdominal aortic aneurysm in the OVER trial.
This study was conducted to determine the costs and comparative cost-effectiveness of two methods of abdominal aortic aneurysm (AAA) repair in the Open Versus Endovascular Repair (OVER) Veterans Affairs (VA) Cooperative Study, a multicenter randomized trial of 881 patients. The primary outcomes of this analysis were mean total health care cost per life-year and per quality-adjusted life-year (QALY) from randomization to 2 years after. QALYs were calculated from EuroQol (EQ)-5D questionnaires collected at baseline and annually. Health care utilization data were obtained directly from patients and from national VA and Medicare data sources. VA costs were obtained from national VA sources using methods previously developed by the VA Health Economics Resource Center. Costs for non-VA care were determined from Medicare claims data or billing data from the patient's health care providers. After 2 years of follow-up, mean life-years were 1.78 in the endovascular repair group and 1.74 in the open repair group (difference, 0.04; 95% confidence interval [CI], -0.03 to 0.09; P = .29). Mean QALYs were 1.462 in the endovascular group and 1.461 in the open group (difference adjusting for baseline EQ-5D score, 0.006; 95% CI, -0.038 to 0.052; P = .78). Mean graft costs were higher in the endovascular group ($14,052 vs $1363; P < .001), but length of stay was shorter (5.0 vs 10.5 days; P < .001), resulting in a lower mean cost of the hospital admission for the AAA procedure in the endovascular repair group of $37,068 vs $42,970 (difference, -$5901; 95% CI, -$12,135 to -$821; P = .04). After 2 years, total health care costs remained lower in the endovascular group, but the difference was no longer significant (-$5019; 95% CI, -$16,720 to $4928; P = .35). The probability of endovascular repair being less costly and more effective was 70.9% for life-years and 51.4% for QALYs. In this multicenter randomized trial, endovascular AAA repair resulted in lower cost and better survival than open repair after the initial hospitalization for repair; but after 2 years, survival, quality of life, and costs were not significantly different between the two treatments.


Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior.
Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected. The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.


Childhood body mass index in relation to future risk of oesophageal adenocarcinoma.
Middle-aged obese adults are at substantially elevated risk of oesophageal adenocarcinoma. It is unclear whether this risk originates earlier in life. We assessed associations between childhood body mass index (BMI) and height-measured annually between ages 7 and 13-with adult oesophageal adenocarcinoma in a cohort from the Copenhagen School Health Records Register. Analyses included 255 053 children born during 1930-1971. Danish Cancer Registry linkage provided outcomes. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression. During 5.4 million person-years of follow-up, 254 (216 males) incident oesophageal adenocarcinomas occurred. At each examined age, cancer risk increased linearly per unit BMI z-score, although associations were only statistically significant for ages 9-13. The HR for the age of 13 years was 1.31 (95% CI: 1.13, 1.51) per unit BMI z-score. Associations were similar in men and women and across birth cohorts. Childhood height was not related to cancer risk in men but was in women, although these analyses included just 38 female cases. HRs per unit height z-score at the age of 13 years were 1.04 (0.90, 1.19) in males and 1.77 (1.27, 2.47) in females, with similar results observed at the other examined ages. Individuals with higher childhood BMI were at elevated risk of oesophageal adenocarcinoma, even though these cancers occurred many decades later in life. Although the mechanisms require further investigation, our findings provide additional evidence for the long-term health risks of childhood obesity.


Cue-interaction effects in contingency judgments using the streamed-trial procedure.
The authors previously described a procedure that permits rapid, multiple within-participant assessments of the contingency between a cue and an outcome (the "streamed-trial" procedure, Crump, Hannah, Allan, & Hord, 2007). In the present experiments, the authors modified this procedure to investigate cue-interaction effects, replicating conventional findings in both the one- and two-phase blocking paradigms. The authors show that the streamed-trial procedure is not restricted to the geometric forms used as cues and outcomes by Crump et al., and that it can incorporate the conventional allergy stimuli, where food is the cue and an allergic reaction is the outcome. The authors discuss the value of the streamed-trial procedure as a method for advancing our theoretical understanding of cue-interaction effects.


Immunotherapy with plasmid DNA encoding mycobacterial hsp65 in association with chemotherapy is a more rapid and efficient form of treatment for tuberculosis in mice.
Tuberculosis (TB) remains a threat for public health, killing around 3 million people a year. Despite the fact that most cases can be cured with antibiotics, the treatment is long and patients relapse if chemotherapy is not continued for at least 6 months. Thus, a better characterization of the working principles of the immune system in TB and identification of new immunotherapeutic products for the development of shorter regimens of treatment are essential to achieve an effective management of this disease. In the present work, we demonstrate that immunotherapy with a plasmid DNA encoding the Mycobacterium leprae 65 kDa heat-shock protein (hsp65) in order to boost the efficiency of the immune system, is a valuable adjunct to antibacterial chemotherapy to shorten the duration of treatment, improve the treatment of latent TB infection and be effective against multidrug-resistant bacilli (MDR-TB). We also showed that the use of DNA-hsp65 alone or in combination with other drugs influence the pathway of the immune response or other types of inflammatory responses and should augment our ability to alter the course of immune response/inflammation as needed, evidencing an important target for immunization or drug intervention.


When less is more and more is less in brief motivational interventions: characteristics of intervention content and their associations with drinking outcomes.
Brief motivational interventions (BMIs) that aim to reduce alcohol use and related problems have been widely implemented in college settings. BMIs share common principles, but vary in specific content. Thus far, the variation in content has not been thoroughly understood in relation to intervention outcomes. The present study addressed this gap by examining variation in breadth of BMI content (i.e., total number of components covered), the extent to which content was personalized to participants, and the interaction between breadth and personalization in relation to treatment outcomes. Data (N = 6,047 participants across 31 separate BMI conditions) came from an integrative data analysis (IDA) study featuring individual-level data from a broad sample of 24 BMI studies of college students. Participants were assessed at baseline and at least 1 follow-up point, conducted up to 12 months postbaseline. Structural equation modeling revealed a significant interaction effect between breadth and personalization of BMI content on alcohol use and related problems at the long-term follow-up (6-12 months) but not at the short-term follow-up (1-3 months). Results indicated that "more is better" for reducing both alcohol use and related problems when BMIs were highly personalized to participants. For less personalized BMIs, coverage of more components was associated with increases in both alcohol use and problems. Findings point to the importance of strategically designing BMIs to maximize their impact on drinking outcomes in college students.


Preventing Musculoskeletal Disorders in Factory Workers: Evaluating a New Eight Minute Stretching Program.
A preshift stretching program was implemented to evaluate its effectiveness in preventing work-related musculoskeletal disorders (WMSD). Workers in a Midwestern factory were assessed for WMSDs before and after the new 8-min stretching program was implemented. Aggregate WMSD data were evaluated and sick days used from the start of the new program were compared with the same 60-day period the previous year. Potential cost savings were also assessed. The researchers found a significant decline in injury rates and time-off requests. Cost savings were noted for both the employer and employees. Additional studies with more workers, as well as longitudinal designs are recommended to verify the findings in this program evaluation study.


Breast cancer cell targeting by prenylation inhibitors elucidated in living animals with a bioluminescence reporter.
Inhibitors of protein prenylation, including prenyltransferase inhibitors and aminobisphosphonates such as zoledronic acid, are being investigated intensively as therapeutics in cancer and other diseases. Determining whether prenylation inhibitors directly or indirectly target tumor and/or host cells is key to understanding therapeutic mechanisms. To determine which cell types can be targeted directly by distinct classes of prenylation inhibitors in vivo, we describe herein the development and implementation of a sensitive and pharmacologically specific bioluminescence-based imaging reporter that is inducible by prenylation inhibitors. In mouse xenograft models of breast cancer, using reporter-bearing mammary fat pad- or bone-localized tumor cells, we show that a prenyltransferase inhibitor robustly induces reporter activity in vivo. In contrast, zoledronic acid, a bone-associated aminobisphosphonate that exerts adjuvant chemotherapeutic activity in patients with breast cancer, fails to induce reporter activity in tumor cells of either model. Although a prenyltransferase inhibitor can directly target breast cancer cells in vivo, zoledronic acid and related aminobisphosphonates are likely to exert antitumor activity indirectly by targeting host cells. Accordingly, these findings shift attention toward the goal of determining which host cell types are targeted directly by aminobisphosphonates to exert adjuvant chemotherapeutic activity.


Food-related parenting practices and adolescent weight status: a population-based study.
To examine food-related parenting practices (pressure-to-eat and food restriction) among mothers and fathers of adolescents and associations with adolescent weight status within a large population-based sample of racially/ethnically and socioeconomically diverse parent-adolescent pairs. Adolescents (N = 2231; 14.4 years old [SD = 2.0]) and their parents (N = 3431) participated in 2 coordinated population-based studies designed to examine factors associated with weight status and weight-related behaviors in adolescents. Adolescents completed anthropometric measurements and surveys at school. Parents (or other caregivers) completed questionnaires via mail or phone. Findings suggest that the use of controlling food-related parenting practices, including pressure-to-eat and restriction, is common among parents of adolescents. Mean restriction levels were significantly higher among parents of overweight and obese adolescents compared with nonoverweight adolescents. However, levels of pressure-to-eat were significantly higher among nonoverweight adolescents. Results indicate that fathers are more likely than mothers to engage in pressure-to-eat behaviors and boys are more likely than girls to be on the receiving end of parental pressure-to-eat. Parental report of restriction did not differ significantly by parent or adolescent gender. No significant interactions by race/ethnicity or socioeconomic status were seen in the relationship between restriction or pressure-to-eat and adolescent weight status. Given that there is accumulating evidence for the detrimental effects of controlling feeding practices on children's ability to self-regulate energy intake, these findings suggest that parents should be educated and empowered through anticipatory guidance to encourage moderation rather than overconsumption and emphasize healthful food choices rather than restrictive eating patterns.


Curcumin Suppresses Proliferation and Migration and Induces Apoptosis on Human Placental Choriocarcinoma Cells via ERK1/2 and SAPK/JNK MAPK Signaling Pathways.
Curcumin, a natural pigment for yellow color that originates from turmeric, is a diarylheptanoid widely studied for its anti-inflammatory, anti-angiogenic, anti-oxidant and anti-cancer effects on cells. In placental diseases including preeclampsia and preterm birth, curcumin reduces pro-inflammatory cytokines. Even though curcumin is regarded as a novel chemotherapeutic agent with strong apoptotic effects based on phenolic structure, little is known about its functional effects on choriocarcinoma. Therefore, in the present study, we investigated the chemotherapeutic effects of curcumin on choriocarcinoma cells (JAR and JEG3), which are valuable placental models. The results showed that curcumin decreased viability of choriocarcinoma cells in a dose-dependent manner. In addition, proliferative and migratory characteristics of JAR and JEG3 cells were inhibited by curcumin treatment and curcumin-induced apoptotic effects which were assessed using TUNEL and annexin V/propidium iodide (PI) staining. Moreover, curcumin decreased depolarization of mitochondrial membrane based on JC-1 staining and changed expression of apoptotic proteins. Phosphorylation of mitogen-activated protein kinases responsible for regulation of anti-cancer effects of curcumin were examined for dose- and time-dependent effects. The ERK1/2 and SAPK/JNK and their downstream molecules including P90RSK and c-Jun, respectively, were activated by curcumin. Moreover, pharmacological inhibitors of ERK1/2 (U0126) and SAPK/JNK (SP600125) suppressed ERK1/2 and SAPK/JNK activation respectively, and blockage of P38 MAPK by its inhibitor (SB203580) had a synergistic effect with curcumin. These results indicate that curcumin acts as a novel chemotherapeutic agent on human placental choriocarcinoma cells via activation of ERK1/2 and SAPK/JNK signal transduction cascades.


A subjective distance between stimuli: quantifying the metric structure of representations.
As subjects perceive the sensory world, different stimuli elicit a number of neural representations. Here, a subjective distance between stimuli is defined, measuring the degree of similarity between the underlying representations. As an example, the subjective distance between different locations in space is calculated from the activity of rodent's hippocampal place cells and lateral septal cells. Such a distance is compared to the real distance between locations. As the number of sampled neurons increases, the subjective distance shows a tendency to resemble the metrics of real space.


[Clinical and molecular features of cardial gastric cancer associated to Epstein Barr virus].
Mortality caused by cardial gastric cancer in Chile, is increasing. Previously we demonstrated an association between Epstein Barr virus and this specific location of gastric cancer. To perform a clinical and molecular characterization of cardial gastric cancer associated to Epstein Barr virus. Epstein Barr virus was identified in 93 cardial gastric tumors, by in situ hybridization. Clinical and pathological features, survival and expression of p53 and c-erbB2 were compared between tumors with or without the presence of the virus. Twenty two (23.6%) tumors expressed Epstein Barr virus. No difference in sex or age of patients with tumors positive or negative for the virus was observed. Epstein Barr positive tumors had a tendency to have a higher frequency of Bormann III endoscopic appearance and a lower frequency of p53 accumulation (p=0.06). Five years survival was 67% and 42% of tumors positive and negative for the presence of the virus, respectively (p=0.57). Our results, although not significant, show a tendency towards unique characteristics of cardial gastric tumors associated to Epstein Barr.


Azobenzene-based inhibitors of human carbonic anhydrase II.
Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant K i. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K i = 25-65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.


Continuous intraoperative temperature measurement and surgical site infection risk: analysis of anesthesia information system data in 1008 colorectal procedures.
To investigate the association between intraoperative temperature and surgical site infection (SSI) in colorectal surgery with anesthesia information system data. Continuously measured intraoperative anesthesia information system temperature data for adult abdominal colorectal surgery procedures at a large tertiary center for 1 year were linked to 30-day American College of Surgeons National Surgical Quality Improvement Program SSI outcomes. Univariable and multivariable analyses of SSI to descriptive temperature statistics, absolute and relative temperature threshold times, and other clinically relevant variables were performed. Overall, 1008 patients (48% female, median age: 53 years) underwent major colorectal procedures (7% emergent, 72% open, 173 ± 95 minutes mean procedure time) with median intraoperative temperature 36.0°C, using active rewarming in 92% and 1-hour presurgical antibiotic administration in 91%. Thirty-day overall and organ/space infection rates were 17.4% (175) and 8.5% (86). Maximum, minimum, ending, and median temperatures were similar for those with or without SSI (36.6°C vs 36.5°C, 34.9°C vs 35.0°C, 36.4°C vs 36.2°C, and 36.1°C vs 36.0°C, P = not significant) and percent minutes using incremental cutoffs failed to correlate SSI with temperature. Absolute minutes for higher temperature cutoffs correlated with SSI because of longer procedure times. On multivariable analysis, factors associated with SSI were preoperative diabetes [odds ratio: 1.81 (1.07-3.07), P = 0.022] and blood loss of more than 500 mL [odds ratio: 1.61 (1.01-2.58), P = 0.047]. Although active rewarming remains an accepted and valid process measure, highly granular anesthesia information system temperature data did not demonstrate a correlation between temperature measures and SSI. SSI prevention efforts should focus on more efficacious interventions as opposed to currently mandated publicly reported normothermia measures.


A tamoxifen inducible knock-in allele for investigation of E2A function.
E-proteins are transcription factors important for the development of a variety of cell types, including neural, muscle and lymphocytes of the immune system. E2A, the best characterized E-protein family member in mammals, has been shown to have stage specific roles in cell differentiation, lineage commitment, proliferation, and survival. However, due to the complexity of E2A function, it is often difficult to separate these roles using conventional genetic approaches. Here, we have developed a new genetic model for reversible control of E2A protein activity at physiological levels. This system was created by inserting a tamoxifen-responsive region of the estrogen receptor (ER) at the carboxyl end of the tcfe2a gene to generate E2AER fusion proteins. We have characterized and analyzed the efficiency and kinetics of this inducible E2AER system in the context of B cell development. B cell development has been shown previously to be blocked at an early stage in E2A deficient animals. Our E2AER/ER mice demonstrated this predicted block in B cell development, and E2AER DNA binding activity was not detected in the absence of ligand. In vitro studies verified rapid induction of E2AER DNA binding activity upon tamoxifen treatment. While tamoxifen treatment of E2AER/ER mice showed inefficient rescue of B cell development in live animals, direct exposure of bone marrow cells to tamoxifen in an ex vivo culture was sufficient to rescue and support early B cell development from the pre-proB cell stage. The E2AER system provides inducible and reversible regulation of E2A function at the protein level. Many previous studies have utilized over-expression systems to induce E2A function, which are complicated by the toxicity often resulting from high levels of E2A. The E2AER model instead restores E2A activity at an endogenous level and in addition, allows for tight regulation of the timing of induction. These features make our E2AER ex vivo culture system attractive to study both immediate and gradual downstream E2A-mediated events.


Early Pleistocene third metacarpal from Kenya and the evolution of modern human-like hand morphology.
Despite discoveries of relatively complete hands from two early hominin species (Ardipithecus ramidus and Australopithecus sediba) and partial hands from another (Australopithecus afarensis), fundamental questions remain about the evolution of human-like hand anatomy and function. These questions are driven by the paucity of hand fossils in the hominin fossil record between 800,000 and 1.8 My old, a time interval well documented for the emergence and subsequent proliferation of Acheulian technology (shaped bifacial stone tools). Modern and Middle to Late Pleistocene humans share a suite of derived features in the thumb, wrist, and radial carpometacarpal joints that is noticeably absent in early hominins. Here we show that one of the most distinctive features of this suite in the Middle Pleistocene to recent human hand, the third metacarpal styloid process, was present ∼1.42 Mya in an East African hominin from Kaitio, West Turkana, Kenya. This fossil thus provides the earliest unambiguous evidence for the evolution of a key shared derived characteristic of modern human and Neandertal hand morphology and suggests that the distinctive complex of radial carpometacarpal joint features in the human hand arose early in the evolution of the genus Homo and probably in Homo erectus sensu lato.


Direct visualization of receptor arrays in frozen-hydrated sections and plunge-frozen specimens of E. coli engineered to overproduce the chemotaxis receptor Tsr.
We have recently reported electron tomographic studies of sections obtained from chemically fixed E. coli cells overproducing the 60-kDa chemotaxis receptor Tsr. Membrane extracts from these cells prepared in the presence of Tween-80 display hexagonally close-packed microcrystalline assemblies of Tsr, with a repeating unit large enough to accommodate six Tsr molecules arranged as trimers of receptor dimers. Here, we report the direct visualization of the Tsr receptor clusters in (i) vitrified cell suspensions of cells overproducing Tsr, prepared by rapid plunge-freezing, and (ii) frozen-hydrated sections obtained from cells frozen under high pressure. The frozen-hydrated sections were generated by sectioning at -150 degrees C using a diamond knife with a 25 degrees knife angle, with nominal thicknesses ranging from 20 to 60 nm. There is excellent correspondence between the spatial arrangement of receptors in thin frozen-hydrated sections and the arrangements found in negatively stained membrane extracts and plunge-frozen cells, highlighting the potential of using frozen-hydrated sections for the study of macromolecular assemblies within cells under near-native conditions.


Benzodiazepines as a Monotherapy in Depressive Disorders: A Systematic Review.
The aim of this paper was to perform a systematic review and, when feasible, a meta-analysis of randomized controlled trials (RCT) which used benzodiazepines (BZD) as a monotherapy versus placebo, antidepressant drugs (AD), or both. Keyword searches were conducted for identifying RCT comparing BZD and AD, and/or placebo in the treatment of depression, using electronic databases from their inception up to April 2017. We selected reports of RCT in which BZD were compared to AD and/or placebo in the treatment of adult patients with a primary diagnosis of depressive disorder or anxious depression. When feasible, data were subjected to meta-analysis. A total of 38 studies met the criteria for inclusion and were then included in the systematic review. Only 1 study concerned a newer AD, fluvoxamine. For the meta-analysis, we submitted data on response rate from 22 RCT, considering BZD versus placebo (8 comparisons) and BZD versus tricyclic antidepressants (TCA) (20 comparisons). There was a lack of significant differences as to response rate between BZD and placebo, as well as between BZD and TCA. Analysis of individual studies disclosed that, in more than half of the studies comparing BZD to TCA and/or placebo, BZD were significantly more effective than placebo and as effective as TCA. BZD are a therapeutic option in anxious depression and there are no indications that AD are preferable. There is a pressing need for RCT of adequate methodological quality and follow-up comparing BZD to second-generation AD and placebo in anxious depression.


Non-asymptotic Properties of Individualized Treatment Rules from Sequentially Rule-Adaptive Trials.
Learning optimal individualized treatment rules (ITRs) has become increasingly important in the modern era of precision medicine. Many statistical and machine learning methods for learning optimal ITRs have been developed in the literature. However, most existing methods are based on data collected from traditional randomized controlled trials and thus cannot take advantage of the accumulative evidence when patients enter the trials sequentially. It is also ethically important that future patients should have a high probability to be treated optimally based on the updated knowledge so far. In this work, we propose a new design called sequentially rule-adaptive trials to learn optimal ITRs based on the contextual bandit framework, in contrast to the response-adaptive design in traditional adaptive trials. In our design, each entering patient will be allocated with a high probability to the current best treatment for this patient, which is estimated using the past data based on some machine learning algorithm (for example, outcome weighted learning in our implementation). We explore the tradeoff between training and test values of the estimated ITR in single-stage problems by proving theoretically that for a higher probability of following the estimated ITR, the training value converges to the optimal value at a faster rate, while the test value converges at a slower rate. This problem is different from traditional decision problems in the sense that the training data are generated sequentially and are dependent. We also develop a tool that combines martingale with empirical process to tackle the problem that cannot be solved by previous techniques for i.i.d. data. We show by numerical examples that without much loss of the test value, our proposed algorithm can improve the training value significantly as compared to existing methods. Finally, we use a real data study to illustrate the performance of the proposed method.


[Acupuncture in edema of the extremities following radiation or combination therapy of cancer of the breast and uterus].
Acupuncture was carried out in 141 sufferers from late-onset radiation injuries to skin and soft tissues. 122 patients (86%) revealed clinical manifestations of edema of varying gravity in arms and legs, while 19 (14%) suffered radiation-induced neuritis or plexitis unaccompanied by edema. Radionuclide and rheographic studies as well as evaluation of hemostatic function showed acupuncture to be an effective treatment for edema and pain. It also improved lymph flow, rheovasographic indexes and normalized hemostasis. The best results were obtained in cases of stage I-II edema.


Interviewer Involvement in Sample Selection Shapes the Relationship Between Response Rates and Data Quality.
Several studies have shown that high response rates are not associated with low bias in survey data. This paper shows that, for face-to-face surveys, the relationship between response rates and bias is moderated by the type of sampling method used. Using data from Rounds 1 through 7 of the European Social Survey, we develop two measures of selection bias, then build models to explore how sampling method, response rate, and their interaction affect selection bias. When interviewers are involved in selecting the sample of households or respondents for the survey, high reported response rates can in fact be a sign of poor data quality. We speculate that the positive association detected between response rates and selection bias is because of interviewers' incentives to select households and respondents who are likely to complete the survey.


Systematic identification of risk factors for Alzheimer's disease through shared genetic architecture and electronic medical records.
Alzheimer's disease (AD) is one of the leading causes of death for older people in US with rapidly increasing incidence. AD irreversibly and progressively damages the brain, but there are treatments in clinical trials to potentially slow the development of AD. We hypothesize that the presence of clinical traits, sharing common genetic variants with AD, could be used as a non-invasive means to predict AD or trigger for administration of preventative therapeutics. We developed a method to compare the genetic architecture between AD and traits from prior GWAS studies. Six clinical traits were significantly associated with AD, capturing 5 known risk factors and 1 novel association: erythrocyte sedimentation rate (ESR). The association of ESR with AD was then validated using Electronic Medical Records (EMR) collected from Stanford Hospital and Clinics. We found that female patients and with abnormally elevated ESR were significantly associated with higher risk of AD diagnosis (OR: 1.85 [1.32-2.61], p=0.003), within 1 year prior to AD diagnosis (OR: 2.31 [1.06-5.01], p=0.032), and within 1 year after AD diagnosis (OR: 3.49 [1.93-6.31], p<0.0001). Additionally, significantly higher ESR values persist for all time courses analyzed. Our results suggest that ESR should be tested in a specific longitudinal study for association with AD diagnosis, and if positive, could be used as a prognostic marker.


Acute myeloid leukemia after adjuvant breast cancer therapy in older women: understanding risk.
The purpose of this study was to determine the risk of developing acute myeloid leukemia (AML) after adjuvant chemotherapy for breast cancer in older women. Data from the Surveillance, Epidemiology, and End Results-Medicare linked database were used for women diagnosed with nonmetastatic breast cancer from 1992 to 2002. The primary end point was a claim with an inpatient or outpatient diagnosis of AML (International Classification of Diseases ninth revision, codes 205 to 208), comparing patients treated with and without adjuvant chemotherapy, and by differing chemotherapy regimens. The cumulative hazard of AML was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to determine factors independently associated with the development of AML. In this observational study, there were 64,715 patients: 10,130 received adjuvant chemotherapy and 54,585 did not. The median patient age was 75.6 years (range, 66 to 104 years). The mean follow-up was 54.8 months (range, 13 to 144 months). The absolute risk of developing AML at 10 years after any adjuvant chemotherapy for breast cancer was 1.8% versus 1.2% for women who had not received chemotherapy. The adjusted hazard ratio for AML with adjuvant chemotherapy versus none was 1.53 (95% CI, 1.14 to 2.06). Granulocyte colony-stimulating factor (G-CSF) within the first year of diagnosis did not convey a significantly increased risk of AML (hazard ratio, 1.14; 95% CI, 0.67 to 1.92). There is a small but real increase in AML after adjuvant chemotherapy for breast cancer in older women. This study may underestimate the true incidence because myelodysplastic syndrome cannot be identified through claims. G-CSF use within the first year of diagnosis does not convey an increased risk of AML in older women.


Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease.
Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumours. Haemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma and pheochromocytomas are the most common tumours. The absence of treatment for VHL leads to the need of repeated surgeries as the only option for these patients. Targeting VHL-derived tumours with drugs with reduced side effects is urgent to avoid repeated CNS surgeries. Recent reports have demonstrated that propranolol, a β-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control haemangioblastoma growth in VHL disease given its antiangiogenic effects that were recently demonstrated by us. The main objective of the present study was the assessment of the efficacy and safety of propranolol on retinal haemangioblastoma in von Hippel-Lindau disease (VHL). 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily. Patients were evaluated every 3 months for 12 months, at Virgen de la Salud Hospital (Toledo). The patients had juxtapapillary or peripheral haemangioblastomas but had refused standard treatments. Propranolol was initiated with a progressive increase up to a final dose of 120 mg daily. All tumours remained stable, and no new tumours appeared. The reabsorption of retinal exudation was noted in the two patients having exudates. No adverse effects were recorded. VEGF and miRNA 210 levels were monitored in the plasma of patients as possible biomarkers of VHL. These levels decreased in all cases from the first month of treatment. Although more studies are necessary, the results of this work suggest that propranolol is a drug to be considered in the treatment of VHL patients with retinal haemangioblastomas. VEGF and miRNA 210 could be used as biomarkers of the VHL disease activity. The study has a clinical trial design and was registered at EU Clinical Trials Register and Spanish Clinical Studies Registry, EudraCT Number: 2014-003671-30 . Registered 2 September 2014.


Mesenchymal stem cells inhibit multiple myeloma cells via the Fas/Fas ligand pathway.
Cell-based therapy represents a new frontier in the treatment of a wide variety of human diseases traditionally associated with morbidity outcomes, including those involving inflammation, autoimmunity, tissue damage, and cancer. However, the use of mesenchymal stem cells (MSCs) to treat multiple myeloma (MM) bone disease has raised concerns. Specifically, evidence has shown that infused MSCs might support tumor growth and metastasis. In this study, we used a standard disseminated MM model in mice to identify the in vivo effects of intravenous MSC infusion. In addition, a series of in vitro co-culture assays were preformed to explore whether Fas/Fas ligand (Fas-L) is involved in the inhibitory effects of MSCs on MM cells. In the MM mouse model, treatment of MSCs with highly expressed Fas ligand (Fas-L high MSCs) showed remarkable inhibitory effects on MM indenization in terms of extending the mouse survival rate and inhibiting tumor growth, bone resorption in the lumbus and collum femoris, and MM cell metastasis in the lungs and kidneys. In addition, reduced proliferation and increased apoptosis of MM cells was observed when co-cultured with Fas-L high MSCs in vitro. Furthermore, mechanistically, the binding between Fas and Fas-L significantly induced apoptosis in MM cells, as evidenced through an increase in the expression of apoptosis marker and Fas in MM cells. In contrast, Fas-L null MSCs promote MM growth. These data suggest that Fas/Fas-L-induced MM apoptosis plays a crucial role in the MSC-based inhibition of MM growth. Although whether MSCs inhibit or promote cancer growth remains controversial, the levels of Fas-L expression in MSCs determine, at least partially, the effects of MSCs on MM cell growth.


Discrepancy analysis between crystallized and fluid intelligence tests: a novel method to detect mild cognitive impairment in patients with asymptomatic carotid artery stenosis.
The present study was conducted to accurately determine the presence of mild cognitive impairment, which is often difficult to evaluate using only simple tests. Our approach focused on discrepancy analysis of fluid intelligence relative to crystallized intelligence using internationally recognized neuropsychological tests. One-hundred and five patients diagnosed with asymptomatic carotid artery stenosis were assessed. The neuropsychological tests included the two subtests (information and picture completion) of Wechsler Adult Intelligence Scale-Revised (WAIS-R-two-subtests): crystallized intelligence tests and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (immediate memory, visuospatial/constructional, language, attention, delayed memory and total score) as fluid intelligence tests. Discrepancy analysis was used to assess cognitive impairment. The score for RBANS was subtracted from the score for WAIS-R-two-subtests, and if the score difference was greater than the 5% confidence limit for statistical significance, it was defined as a decline in cognitive function. The WAIS-R-two-subsets was within normal limits when compared with the standardized values. However, all RBANS domains showed significant declines. Frequencies of decline in each RBANS domain were as follows: 69 patients (66%) in immediate memory, 26 (25%) in visuospatial/constructional, 54 (51%) in language, 63 (60%) in attention, 54 (51%) in delayed memory and 78 (74%) in the total score. Moreover, 99 patients (94%) showed decline in at least one RBANS domain. Cognitive function is only preserved in a few patients with asymptomatic carotid artery stenosis. Mild cognitive impairment can be precisely detected by performing the discrepancy analysis between crystallized and fluid intelligence tests.


Substance use, mental health and dual disorders on pregnancy: Results of prevalence and treatment rates in a developed country.
Smoking and substance use during pregnancy are major preventable causes of mortality and morbidity, having a bidirectional and deleterious relationship with the mental health of the mother and child. As part of the WOMAP (Woman Mental Health and Addictions on Pregnancy) initiative, our study aimed to describe the prevalence of co-occurring mental illness and substance use problems, diagnoses and severity of those considered at risk and rates of treatment.A screening of 2,014 pregnant women was done using the AC-OK scale and they were asked about their smoking habits and services use for mental health/substance abuse. Of these, 170 women were considered at risk of co-occurring mental illness and substance use problems (≥ 2 positive responses to the AC-OK-Mental Health subscale, ≥ 1 positive response to the AC-OK-Substance Abuse subscale and/or smoking more than once a month and no use of specialized services) and were assessed with a more extensive battery of measures (Patient Health Questionnaire [PHQ-9], General Anxiety Disorder [GAD-7], Posttraumatic stress disorder [PTSD] Checklist for DSM-5 [PCL-5], Alcohol Use Disorders Identification Test [AUDIT], Drug Abuse Screening Test [DAST] and Fagerström).In the last year, 614 women (30.5%) smoked tobacco (42.5% daily) and 9.8% were positive for both substance use and mental illness per the AC-OK. Only 11.1% of them received specific treatment in the previous three months while another 13.6% were scheduled to attend services in the following month. From the subsample assessed in depth, 62(36.5%) endorsed at least moderate depression, 35(20.6%) endorsed at least moderate anxiety, 32(18.8%) endorsed PTSD on the PCL, and 37 out of 88 alcohol users scored above the threshold in AUDIT (≥ 3). In conclusion, high prevalence and low treatment rates suggest that effective detection mechanisms should be integrated into usual care, allowing for early interventions.


Hybrid vanadate waveguiding configurations for extreme optical confinement and efficient polarization management in the near-infrared.
Vanadate materials such as CaVO3 and SrVO3 were recently proposed as promising alternatives to their conventional transparent conducting oxide counterparts owing to the superior capability for simultaneous realization of high optical transparency and high electrical conductivity originating from strong electron-electron interactions. Here we show that, in addition to their remarkable optoelectronic properties as conducting materials, their incorporation into planar waveguiding configurations could enable outstanding optical performance that is otherwise difficult to achieve with conventional material building blocks, especially metals. Starting from the guided wave at a single CaVO3/dielectric interface, the unique dispersion relationship and propagation property of the fundamental mode are revealed and compared to the conventional surface plasmon polariton associated with a silver/dielectric planar configuration. The superior confinement capability and the unique modal attenuation of the CaVO3-based waveguiding platform are further demonstrated via investigating silicon-based hybrid guiding schemes integrated with a CaVO3 nanostructure. By leveraging the pronounced polarization dependent loss in the hybrid configuration, an ultra-compact TE-pass polarizer is numerically demonstrated at telecommunication wavelengths. This transformative design features a reduced footprint and enhanced optical performance when benchmarked against the current state-of-the-art in hybrid silicon polarizers. The combination of these vanadate materials with traditional waveguiding platforms thereby opens new avenues towards miniaturized functional integrated photonic devices, and potentially enables a variety of intriguing applications at the sub-diffraction-limited scale.


Subclinical hyperthyroidism and pregnancy outcomes.
Subclinical hyperthyroidism has long-term sequelae that include osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis or thyroid failure. The objective of this study was to evaluate pregnancy outcomes in women with suppressed thyroid-stimulating hormone (TSH) and normal free thyroxine (fT(4)) levels. All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, underwent thyroid screening by chemiluminescent TSH assay. Women with TSH values at or below the 2.5th percentile for gestational age and whose serum fT(4) levels were 1.75 ng/dL or less were identified to have subclinical hyperthyroidism. Those women screened and delivered of a singleton infant weighing 500 g or more were analyzed. Pregnancy outcomes in women identified with subclinical hyperthyroidism were compared with those in women whose TSH values were between the 5th and 95th percentiles. A total of 25,765 women underwent thyroid screening and were delivered of singleton infants. Of these, 433 (1.7%) were considered to have subclinical hyperthyroidism, which occurred more frequently in African-American and/or parous women. Pregnancies in women with subclinical hyperthyroidism were less likely to be complicated by hypertension (adjusted odds ratio 0.66, 95% confidence interval 0.44-0.98). All other pregnancy complications and perinatal morbidity or mortality were not increased in women with subclinical hyperthyroidism. Subclinical hyperthyroidism is not associated with adverse pregnancy outcomes. Our results indicate that identification of subclinical hyperthyroidism and treatment during pregnancy is unwarranted. II-2.


The composite face illusion.
Few findings in cognitive science have proved as influential as the composite face effect. When the top half of one face is aligned with the bottom half of another, and presented upright, the resulting composite arrangement induces a compelling percept of a novel facial configuration. Findings obtained using composite face procedures have contributed significantly to our understanding of holistic face processing, the detrimental effects of face inversion, the development of face perception, and aberrant face perception in clinical populations. Composite paradigms continue to advance our knowledge of face perception, as exemplified by their recent use for investigating the perceptual mechanisms underlying dynamic face processing. However, the paradigm has been the subject of intense scrutiny, particularly over the last decade, and there is a growing sense that the composite face illusion, whilst easy to illustrate, is deceptively difficult to measure and interpret. In this review, we provide a focussed overview of the existing composite face literature, and identify six priorities for future research. Addressing these gaps in our knowledge will aid the evaluation and refinement of theoretical accounts of the illusion.


Effects of parathyroid hormone on sodium and calcium transport in the dog nephron.
1. The effect of purified bovine parathyroid hormone on renal tubular reabsorption of sodium and calcium has been studied by micropuncture in intact and recently thyroparathyroidectomized dogs. 2. Parathyroid hormone increased the rejection of sodium and calcium proportionately at the late proximal tubule in both intact and operated dogs. 3. In both groups of dogs, there was increased delivery of sodium and calcium to the distal tubule after the hormone. However, the Ca/Na ratio decreased, suggesting some selective enhancement of calcium reabsorption before the superficial distal puncture site. 4. In the final urine, the Ca/Na ratio decreased highly significantly in both groups of dogs, indicating a further selective effect of parathyroid hormone on calcium reabsorption in or beyond the distal convoluted tubule.


Cardioprotection with ischemic preconditioning and MLA: role of adenosine-regulating enzymes?
Both ischemic preconditioning and pretreatment with the endotoxin derivative monophosphoryl lipid A (MLA) protect the heart against infarction, yet the cellular mechanisms responsible for the cardioprotection achieved with either intervention are unknown. Using pentobarbital-anesthetized dogs, we tested the hypothesis that increased activity of 5'-nucleotidase (5'-NT), the enzyme that catalyzes the formation of adenosine from AMP, may play a role. Twenty-two dogs underwent 1 h of coronary occlusion and 4 h of reperfusion: eight controls received no intervention, seven animals were preconditioned with four 5-min episodes of brief ischemia, and seven received MLA (35 micrograms/kg iv) 24 h previously. Collateral blood flow was measured by injection of radiolabeled microspheres, infarct size was delineated by tetrazolium staining, and myocardial 5'-NT activities were measured by quantifying the release of adenosine from AMP. Despite comparable values of collateral blood flow in all groups, infarct size was reduced in preconditioned and MLA-treated dogs vs. controls. In addition, 5'-NT activities were increased throughout the heart with preconditioning and MLA treatment. However, single and multivariate regression analyses revealed no correlation between infarct size and 5'-NT activities for either treatment group. In fact, in the preconditioned cohort, animals with the highest enzyme activities developed the largest infarcts. This dissociation between infarct size and 5'-NT suggests that increased activity of 5'-NT is not the mechanism by which preconditioning or MLA treatment protects the canine heart against infarction.