Problem-solving therapy for depression and common mental disorders in Zimbabwe: piloting a task-shifting primary mental health care intervention in a population with a high prevalence of people living with HIV.
There is limited evidence that interventions for depression and other common mental disorders (CMD) can be integrated sustainably into primary health care in Africa. We aimed to pilot a low-cost multi-component 'Friendship Bench Intervention' for CMD, locally adapted from problem-solving therapy and delivered by trained and supervised female lay workers to learn if was feasible and possibly effective as well as how best to implement it on a larger scale. We trained lay workers for 8 days in screening and monitoring CMD and in delivering the intervention. Ten lay workers screened consecutive adult attenders who either were referred or self-referred to the Friendship Bench between July and December 2007. Those scoring above the validated cut-point of the Shona Symptom Questionnaire (SSQ) for CMD were potentially eligible. Exclusions were suicide risk or very severe depression. All others were offered 6 sessions of problem-solving therapy (PST) enhanced with a component of activity scheduling. Weekly nurse-led group supervision and monthly supervision from a mental health specialist were provided. Data on SSQ scores at 6 weeks after entering the study were collected by an independent research nurse. Lay workers completed a brief evaluation on their experiences of delivering the intervention. Of 395 potentially eligible, 33 (8%) were excluded due to high risk. Of the 362 left, 2% (7) declined and 10% (35) were lost to follow-up leaving an 88% response rate (n = 320). Over half (n = 166, 52%) had presented with an HIV-related problem. Mean SSQ score fell from 11.3 (sd 1.4) before treatment to 6.5 (sd 2.4) after 3-6 sessions. The drop in SSQ scores was proportional to the number of sessions attended. Nine of the ten lay workers rated themselves as very able to deliver the PST intervention. We have found preliminary evidence of a clinically meaningful improvement in CMD associated with locally adapted problem-solving therapy delivered by lay health workers through routine primary health care in an African setting. There is a need to test the effectiveness of this task-shifting mental health intervention in an appropriately powered randomised controlled trial. ISRCTN: ISRCTN25476759.


Structure-based inhibitors of tau aggregation.
Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau.


Shear-Enhanced Dispersion of a Wound Substance as a Candidate Mechanism for Variation Potential Transmission.
A variation potential (VP) is an electrical signal unique to plants that occurs in response to wounding or flaming. The propagation mechanism itself, however, is known not to be electrical. Here we examine the hypothesis that VP transmission occurs via the transport of a chemical agent in the xylem. We assume the electrical signal is generated locally by the activation of an ion channel at the plasma membrane of cells adjacent to the xylem. We work on the assumption that the ion channels are triggered when the chemical concentration exceeds a threshold value. We use numerical computations to demonstrate the combined effect of advection and diffusion on chemical transport in a tube flow, and propose shear-enhanced Taylor-Aris dispersion as a candidate mechanism to explain VP rates observed in experiments.


A Robust Noise Mitigation Method for the Mobile RFID Location in Built Environment.
The exact location of objects, such as infrastructure, is crucial to the systematic understanding of the built environment. The emergence and development of the Internet of Things (IoT) have attracted growing attention to the low-cost location scheme, which can respond to a dramatic increasing amount of public infrastructure in smart cities. Various Radio Frequency IDentification (RFID)-based locating systems and noise mitigation methods have been developed. However, most of them are impractical for built environments in large areas due to their high cost, computational complexity, and low noise detection capability. In this paper, we proposed a novel noise mitigation solution integrating the low-cost localization scheme with one mobile RFID reader. We designed a filter algorithm to remove the influence of abnormal data. Inspired the sampling concept, a more carefully parameters calibration was carried out for noise data sampling to improve the accuracy and reduce the computational complexity. To achieve robust noise detection results, we employed the powerful noise detection capability of the random sample consensus (RANSAC) algorithm. Our experiments demonstrate the effectiveness and advantages of the proposed method for the localization and noise mitigation in a large area. The proposed scheme has potential applications for location-based services in smart cities.


Datafication and accountability in public health: Introduction to a special issue.
In recent years and across many nations, public health has become subject to forms of governance that are said to be aimed at establishing accountability. In this introduction to a special issue, From Person to Population and Back: Exploring Accountability in Public Health, we suggest opening up accountability assemblages by asking a series of ostensibly simple questions that inevitably yield complicated answers: What is counted? What counts? And to whom, how and why does it count? Addressing such questions involves staying attentive to the technologies and infrastructures through which data come into being and are made available for multiple political agendas. Through a discussion of public health, accountability and datafication we present three key themes that unite the various papers as well as illustrate their diversity.


Comparison the percentage of detection of periarthritis in patients with rheumatoid arthritis using clinical examination or ultrasound methods.
This study aimed to compare the percentage of detection of periarthritis in patients with rheumatoid arthritis using clinical examination and ultrasound methods. This study is a cross-sectional study which was conducted in Al-Zahra Hospital (Isfahan, Iran) during 2014-2015. In our study, ninety patients were selected based on the American College of Rheumatology 2010 criteria. All patients were examined by a rheumatologist to find the existence of effusion, and the data were filled in the checklist. The ultrasonography for detecting effusion in periarticular structures was done by an expert radiologist with two methods, including high-resolution ultrasonography and power Doppler. The percentage of effusion existence found by physical examination was compared by sonography, and the Chi-square and t-tests were used for data analysis. The percentage of effusion found in areas with physical examination by rheumatologist was lower than the frequency distribution of effusions found by sonography (8.3% VS 14.2%) (P < 0.001). In sonography, rotator cuff tendonitis is the most common periarthritis. Other findings in sonography were biceps tendinitis (10 cases), wrist tendonitis (13 cases), olecranon bursitis (9 cases), golfers elbow (4 cases), tennis elbow (4 cases), trochanteric bursitis (6 cases), anserine bursitis (6 cases), prepatellar bursitis (11 cases), and ankle tendonitis (7 cases). Tenderness on physical examination was found in 15% of the cases, and the evidence of periarthritis was found in 21/7% through sonography (P < 0.001) and 34% through Doppler sonography (P < 0.001). The percentage of periarthritis detection by ultrasonography and power Doppler sonography was higher than clinical examination. Hence, the ultrasonography is more accurate than physical examination.


Understanding Epstein-Barr Virus Life Cycle with Proteomics: A Temporal Analysis of Ubiquitination During Virus Reactivation.
Epstein-Barr virus (EBV) is a human γ-herpesvirus associated with cancer, including Burkitt lymphoma, nasopharyngeal, and gastric carcinoma. EBV reactivation in latently infected B cells is essential for persistent infection whereby B cell receptor (BCR) activation is a physiologically relevant stimulus. Yet, a global view of BCR activation-regulated protein ubiquitination is lacking when EBV is actively replicating. We report here, for the first time, the long-term effects of IgG cross-linking-regulated protein ubiquitination and offer a basis for dissecting the cellular environment during the course of EBV lytic replication. Using the Akata-BX1 (EBV+) and Akata-4E3 (EBV-) Burkitt lymphoma cells, we monitored the dynamic changes in protein ubiquitination using quantitative proteomics. We observed temporal alterations in the level of ubiquitination at ∼150 sites in both EBV+ and EBV- B cells post-IgG cross-linking, compared with controls with no cross-linking. The majority of protein ubiquitination was downregulated. The upregulated ubiquitination events were associated with proteins involved in RNA processing. Among the downregulated ubiquitination events were proteins involved in apoptosis, ubiquitination, and DNA repair. These comparative and quantitative proteomic observations represent the first analysis on the effects of IgG cross-linking at later time points when the majority of EBV genes are expressed and the viral genome is actively being replicated. In all, these data enhance our understanding of mechanistic linkages connecting protein ubiquitination, RNA processing, apoptosis, and the EBV life cycle.


A single EBUS-TBNA procedure can support a large panel of immunohistochemical stains, specific diagnostic subtyping, and multiple gene analyses in the majority of non-small cell lung cancer cases.
Targeted therapies for pulmonary adenocarcinoma (ACA) necessitate specific subtyping and molecular testing of non-small cell lung carcinomas (NSCLC). However, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has decreased the tissue available for these assessments. While EBUS-TBNA specimens have previously been reported to successfully subtype NSCLC, allow immunohistochemistry (IHC), and support molecular diagnostics, no studies have documented the extent to which all objectives are possible in a single sample. Of 107 consecutive EBUS-TBNA specimens that were eligible for molecular testing, 98.8% had enough tissue for IHC, 80.2% received a definitive subtype, and 71.0% had both sufficient tissue to attempt molecular testing and technical success on multigene next-generation sequencing and ALK fluorescence in situ hybridization assays. Both subtyping and molecular diagnostics were possible in 57.9% of patients. The mean number of immunostains performed did not differ between patients with or without successful molecular testing (4.4 versus 4.6, P = .88). Only 40% of patients with insufficient tissue underwent repeat sampling. These findings indicate that a majority of EBUS-TBNA specimens provide sufficient tissue for subtyping pulmonary NSCLC, performing IHC, and completing multiple gene analyses. Although priorities must be assessed for each case individually, performance of IHC does not detract from completion of molecular diagnostics in general. Because most patients never undergo repeat sampling, the tissue yield of EBUS-TBNA should be improved to maximize evaluation for targeted therapies.


Renal transcription of high-affinity type-2 cationic amino acid transporter is up-regulated in LPS-stimulated rodents.
Sepsis stimulates renal nitric oxide (NO) biosynthesis through up-regulation of inducible NO synthase (iNOS) expression. Type-2 cationic amino acid transporter (CAT-2) mediation of trans-membrane L-arginine (L-Arg) transportation has been identified as one of the crucial regulatory mechanisms involved in the formation of NO by iNOS. We had previously shown that CAT-2B, a high-affinity alternative-spliced transcript of the CAT-2, is involved in induced NO biosynthesis by iNOS (Nitric Oxide, 2002). In this present study, we sought to assess the effects of sepsis on the expression of CAT-2B in lipopolysaccharide (LPS)-stimulated rat kidney. Forty rats were randomized to either a normal saline (N/S)-treated group or a LPS-treated group. Renal NO production was determined using chemiluminescence. Semi-quantitative RT-PCR was used to determine the mRNA concentrations of iNOS and L-Arg transporters (CAT-1, CAT-2 and CAT-2B) in kidney. Lipopolysaccharide-coinduced iNOS, CAT-2 and CAT-2B mRNA expression in kidney and caused renal NO overproduction. A significant linear regression relationship was defined between renal NO concentrations and iNOS, CAT-2 and CAT-2B, respectively. On the contrary, CAT-1 expression was not affected by LPS-stimulation. We provide the first evidence to illustrate that sepsis/septic shock induces the transcription of high-affinity CAT-2B in renal tissues. Transcription of iNOS, CAT-2 and CAT-2B correlates well with renal NO biosynthesis. Regulation of L-Arg uptake by modulating the expression regulation of induced CAT-2 and CAT-2B might be a potential target for therapies against renal pathologic conditions related to NO overproduction.


Lower serum total bilirubin concentration is associated with higher prevalence of gestational diabetes mellitus in Japanese pregnant women.
We aimed to clarify the pathophysiological significance of total bilirubin (TB) in gestational diabetes mellitus (GDM). This was a cross-sectional study that included 616 pregnant Japanese women (368 normal glucose tolerance [NGT] and 248 GDM). Serum TB concentration, homeostasis model assessment of insulin resistance (HOMA-IR), and other clinical parameters were compared in NGT and GDM women. TB concentration was also compared according to the number of abnormal OGTT values. Logistic regression analysis was used to evaluate the association between TB and GDM prevalence. A multiple linear regression model was used to evaluate the association between TB and HOMA-IR. TB concentrations were significantly lower in GDM women than in NGT women. This result did not change after adjustments for TB sampling timing were made. Out of 248 GDM women, the prevalences of 1- and 2/3- abnormal OGTT values (1- and 2/3-AV) GDM were 72.2% (n = 179) and 27.8% (n = 69), respectively. In the multiple comparisons, TB concentrations were significantly lower in women with 2/3-AV GDM than in women with NGT and 1-AV GDM. Multiple logistic regression analysis showed that TB was a significantly associated factor for 2/3-AV, but not for total GDM. HOMA-IR was significantly higher in GDM women than in NGT women. The univariate, but not multivariate, analysis showed that TB was a significantly associated factor for HOMA-IR. Our findings suggest that hypobilirubinemia may be involved in the pathogenesis of GDM.


Symbiotic Burkholderia Species Show Diverse Arrangements of nif/fix and nod Genes and Lack Typical High-Affinity Cytochrome cbb3 Oxidase Genes.
Genome analysis of fourteen mimosoid and four papilionoid beta-rhizobia together with fourteen reference alpha-rhizobia for both nodulation (nod) and nitrogen-fixing (nif/fix) genes has shown phylogenetic congruence between 16S rRNA/MLSA (combined 16S rRNA gene sequencing and multilocus sequence analysis) and nif/fix genes, indicating a free-living diazotrophic ancestry of the beta-rhizobia. However, deeper genomic analysis revealed a complex symbiosis acquisition history in the beta-rhizobia that clearly separates the mimosoid and papilionoid nodulating groups. Mimosoid-nodulating beta-rhizobia have nod genes tightly clustered in the nodBCIJHASU operon, whereas papilionoid-nodulating Burkholderia have nodUSDABC and nodIJ genes, although their arrangement is not canonical because the nod genes are subdivided by the insertion of nif and other genes. Furthermore, the papilionoid Burkholderia spp. contain duplications of several nod and nif genes. The Burkholderia nifHDKEN and fixABC genes are very closely related to those found in free-living diazotrophs. In contrast, nifA is highly divergent between both groups, but the papilionoid species nifA is more similar to alpha-rhizobia nifA than to other groups. Surprisingly, for all Burkholderia, the fixNOQP and fixGHIS genes required for cbb3 cytochrome oxidase production and assembly are missing. In contrast, symbiotic Cupriavidus strains have fixNOQPGHIS genes, revealing a divergence in the evolution of two distinct electron transport chains required for nitrogen fixation within the beta-rhizobia.


Childhood maltreatment among Hispanic women in the United States: an examination of subgroup differences and impact on psychiatric disorder.
Prevalence rates of childhood maltreatment among Hispanic women in the United States are presented separately for nativity status and ethnic origin subgroups, and the associations between different types of maltreatment and the development of anxiety and depressive disorders are examined. Analyses used self-report data from 1,427 Hispanic women who participated in the National Latino and Asian American Survey. Foreign-born Hispanic women compared to U.S.-born Hispanic women reported significantly lower rates of sexual assault and witnessing interpersonal violence, and a significantly higher rate of being beaten. Ethnic subgroups reported similar rates of maltreatment, with the exception of rape. Bivariate analyses were remarkably consistent in that regardless of nativity status or ethnic subgroup, each type of maltreatment experience increased the risk of psychiatric disorder. In multivariate models controlling for all types of victimization and proxies of acculturation, having been beaten and witnessing interpersonal violence remained significant predictors of both disorders, but sexual abuse increased risk of anxiety only. A significant interaction effect of family cultural conflict and witnessing violence on anxiety provided very limited support for the hypothesis that acculturation moderates the influence of maltreatment on mental health outcomes. Implications for culturally relevant prevention and intervention approaches are presented.


Solid-phase polarization matrixes for dynamic nuclear polarization from homogeneously distributed radicals in mesostructured hybrid silica materials.
Mesoporous hybrid silica-organic materials containing homogeneously distributed stable mono- or dinitroxide radicals covalently bound to the silica surface were developed as polarization matrixes for solid-state dynamic nuclear polarization (DNP) NMR experiments. For TEMPO-containing materials impregnated with water or 1,1,2,2-tetrachloroethane, enhancement factors of up to 36 were obtained at ∼100 K and 9.4 T without the need for a glass-forming additive. We show that the homogeneous radical distribution and the subtle balance between the concentration of radical in the material and the fraction of radicals at a sufficient inter-radical distance to promote the cross-effect are the main determinants for the DNP enhancements we obtain. The material, as well as an analogue containing the poorly soluble biradical bTUrea, is used as a polarizing matrix for DNP NMR experiments of solutions containing alanine and pyruvic acid. The analyte is separated from the polarization matrix by simple filtration.


Nitric oxide does not modulate the hyperpolarization-activated current, I(f), in ventricular myocytes from spontaneously hypertensive rats.
: In sinoatrial (SA) node cells, nitric oxide (NO) exerts a dual effect on the hyperpolarization-activated current, I(f), i.e. in basal conditions NO enhances I(f) whereas in the presence of beta-adrenergic stimulation it decreases it. Recent studies have shown that I(f) is present in ventricular myocytes from hypertrophied or failing hearts where it may promote abnormal automaticity. Since these pathological conditions are associated with increased sympathetic tone and upregulation of myocardial NO production, we set out to investigate whether I(f) is similarly modulated by NO in hypertrophied ventricular myocytes. Left ventricular myocytes were isolated from 18-20-month-old spontaneously hypertensive rats (SHRs). Membrane current was measured under whole-cell or amphotericin-perforated patch-clamp conditions, at 35 degrees C. Application of diethylamine-NO (DEA-NO, 1-100 microM) did not alter the amplitude or voltage dependence of activation of I(f) under basal conditions (half-activation voltage, V(h): control -82.9+/-2.6, DEA-NO -84.0+/-2.6 mV). Similarly, I(f) was not affected by the inhibition of endogenous NO production (L-NMMA, 500 microM) or guanylate cyclase (ODQ, 10 microM). Forskolin (10 microM) or isoprenaline (100 nM) elicited a positive shift in V(h) but subsequent application of DEA-NO did not further affect the properties of I(f). Our results show that, unlike in SA node cells, in SHR ventricular myocytes basal and adrenergically stimulated I(f) is not modulated by exogenous NO or by constitutive NO or cGMP production.


Small, highly active DNAs that hydrolyze DNA.
DNA phosphoester bonds are exceedingly resistant to hydrolysis in the absence of chemical or enzymatic catalysts. This property is particularly important for organisms with large genomes, as resistance to hydrolytic degradation permits the long-term storage of genetic information. Here we report the creation and analysis of two classes of engineered deoxyribozymes that selectively and rapidly hydrolyze DNA. Members of class I deoxyribozymes carry a catalytic core composed of only 15 conserved nucleotides and attain an observed rate constant (k(obs)) of ~1 min(-1) when incubated near neutral pH in the presence of Zn(2+). Natural DNA sequences conforming to the class I consensus sequence and structure were found that undergo hydrolysis under selection conditions (2 mM Zn(2+), pH 7), which demonstrates that the inherent structure of certain DNA regions might promote catalytic reactions, leading to genomic instability.


Artifact removal in physiological signals--practices and possibilities.
The combination of reducing birth rate and increasing life expectancy continues to drive the demographic shift toward an aging population. This, in turn, places an ever-increasing burden on healthcare due to the increasing prevalence of patients with chronic illnesses and the reducing income-generating population base needed to sustain them. The need to urgently address this healthcare "time bomb" has accelerated the growth in ubiquitous, pervasive, distributed healthcare technologies. The current move from hospital-centric healthcare toward in-home health assessment is aimed at alleviating the burden on healthcare professionals, the health care system and caregivers. This shift will also further increase the comfort for the patient. Advances in signal acquisition, data storage and communication provide for the collection of reliable and useful in-home physiological data. Artifacts, arising from environmental, experimental and physiological factors, degrade signal quality and render the affected part of the signal useless. The magnitude and frequency of these artifacts significantly increases when data collection is moved from the clinic into the home. Signal processing advances have brought about significant improvement in artifact removal over the past few years. This paper reviews the physiological signals most likely to be recorded in the home, documenting the artifacts which occur most frequently and which have the largest degrading effect. A detailed analysis of current artifact removal techniques will then be presented. An evaluation of the advantages and disadvantages of each of the proposed artifact detection and removal techniques, with particular application to the personal healthcare domain, is provided.


Perceived learning outcome: the relationship between experience, realism and situation awareness during simulator training.
Navigation errors are a frequent cause of serious accidents and work-related injuries among seafarers. The present study investigated the effects of experience, perceived realism, and situation awareness (SA) on the perceived learning outcome of simulator-based navigation training. Thirty-two Norwegian Navy officer cadets were assigned to a low and a high mental workload conditions based on previous educational and navigational experience. In the low mental workload condition, experience (negatively associated), perceived realism, and subjective SA explained almost half of the total variance in perceived learning outcome. A hierarchical regression analysis showed that only subjective SA made a unique contribution to the learning outcome. In the high mental workload condition, perceived realism and subjective SA together explained almost half of the variance in perceived learning outcome. Furthermore, both perceived realism and subjective SA were shown to make an independent contribution to perceived learning outcomes. The results of this study show that in order to enhance the learning outcomes from simulator training it is necessary to design training procedures and scenarios that enable students to achieve functional fidelity and to generate and maintain SA during training. This can further improve safety and reduce the risk of maritime disasters.


Genome Organization and Adaptive Potential of Archetypal Organophosphate Degrading Sphingobium fuliginis ATCC 27551.
Sphingobium fuliginis ATCC 27551, previously classified as Flavobacterium sp. ATCC 27551, degrades neurotoxic organophosphate insecticides and nerve agents through the activity of a membrane-associated organophosphate hydrolase. This study was designed to determine the complete genome sequence of S. fuliginis ATCC 27551 to unravel its degradative potential and adaptability to harsh environments. The 5,414,624 bp genome with a GC content of 64.4% is distributed between two chromosomes and four plasmids and encodes 5,557 proteins. Of the four plasmids, designated as pSF1, pSF2, pSF3, and pSF4, only two (pSF1 and pSF2) are self-transmissible and contained the complete genetic repertoire for a T4SS. The other two plasmids (pSF3 and pSF4) are mobilizable and both showed the presence of an oriT and relaxase-encoding sequences. The sequence of plasmid pSF3 coincided with the previously determined sequence of pPDL2 and included an opd gene encoding organophosphate hydrolase as a part of the mobile element. About 15,455 orthologous clusters were identified from among the cumulatively annotated genes of 49 Sphingobium species. Phylogenetic analysis done using the core genome consisting of 802 orthologous clusters revealed a close relationship between S. fuliginis ATCC 27551 and bacteria capable of degradation of polyaromatic hydrocarbon compounds. Genes coding for transposases, efflux pumps conferring resistance to heavy metals, and TonR-type outer membrane receptors are selectively enriched in the genome of S. fuliginis ATCC 27551 and appear to contribute to the adaptive potential of the organism to challenging and harsh environments.


Preconception Maternal Iodine Status Is Positively Associated with IQ but Not with Measures of Executive Function in Childhood.
Adverse effects of severe maternal iodine deficiency in pregnancy on fetal brain development are well-established, but the effects of milder deficiency are uncertain. Most studies examine iodine status in pregnancy; less is known about iodine nutrition before conception. We examined relations between maternal preconception iodine status and offspring cognitive function, within a prospective mother-offspring cohort. Maternal iodine status was assessed through the use of the ratio of iodine:creatinine concentrations (I/Cr) in spot urine samples [median (IQR) period before conception 3.3 y (2.2-4.7 y)]. Childhood cognitive function was assessed at age 6-7 y. Full-scale IQ was assessed via the Wechsler Abbreviated Scale of Intelligence, and executive function through the use of tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Analyses (n = 654 mother-child dyads) were adjusted for potential confounders including maternal intelligence, education, and breastfeeding duration. The median (IQR) urinary iodine concentration was 108.4 µg/L (62.2-167.8 µg/L) and the I/Cr ratio 114 µg/g (76-164 µg/g). The preconception I/Cr ratio was positively associated with child IQ, before and after adjustment for potential confounding influences [β = 0.13 (95% CI: 0.04, 0.21)/SD, P = 0.003]. 8.9% of women had a preconception urinary I/Cr ratio <50 µg/g; compared with those with an I/Cr ratio ≥150 µg/g, the IQ of their offspring was 0.49 (95% CI: 0.79, 0.18) SD lower. There were no associations with the executive function outcomes assessed via CANTAB, before or after adjustment for confounders. The positive association between iodine status before conception and child IQ provides some support for demonstrated links between low maternal iodine status in pregnancy and poorer cognitive function reported in other studies. However, given the negative effects on school performance previously observed in children born to iodine-deficient mothers, the lack of associations with measures of executive function in the present study was unexpected. Further data are needed to establish the public health importance of low preconception iodine status.


Placing the newborn on the maternal abdomen increases the volume of umbilical cord blood collected.
Haematopoietic stem cell transplantation is an important therapy for certain haematological and malignant disorders. Umbilical cord blood contains a high proportion of potentially transplantable haematopoietic progenitor cells. However, the use of cord blood stem cell transplantation is limited by the low number of stem cells obtainable from a single cord blood donor. The aim of our study was to investigate the possibility that procedures during delivery might influence the number of umbilical cord blood haematopoietic progenitor cells available for transplantation. We assessed the effects of upper and lower positions of the newborn infant on the yield of cord blood stem cells in 51 vaginal deliveries. Neonates in the upper position group were placed by the midwife on the maternal abdomen immediately after birth, while those in the lower position group were placed on the delivery table, below the maternal introitus. The total volume of cord blood and the total number of CD34+ cells collected from babies in the upper position group were significantly higher than those from babies in the lower position group. There were no significant differences in cord blood haemoglobin levels and white blood cell counts between the two groups, nor were there any adverse effects in the newborn infants. The simple manoeuvre of placing the newborn on the maternal abdomen after delivery may thus increase the yield of transplantable haematopoietic progenitor cells in cord blood.


A Phase II Study of Irinotecan and Etoposide as Treatment for Refractory Metastatic Breast Cancer.
The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events. As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC). This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen. We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy. Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.


A new method to determine trabecular bone elastic properties and loading using micromechanical finite-element models.
The apparent mechanical behavior of trabecular bone depends on properties at the tissue or trabecular level. Many investigators have attempted to determine trabecular tissue properties and loading. However, accuracy and applicability of all methods reported are limited. The small size of the trabeculae and a possible size effect are complicating factors when using traditional testing methods on single trabeculae. Other methods reported, using models that describe the trabecular structure, are of limited value because they consider bone as a repetitive structure in order to describe a reasonably large region of bone. The present study introduces a new finite-element method strategy that enables analysis of reasonably large regions of trabecular bone in full detail. The method uses three-dimensional serial reconstruction techniques to construct a large-scale FE model, by directly converting voxels to elements. A 5 mm cube of trabecular bone was modeled in this way, resulting in a FE model that consists of 296,679 elements. Special strategies were developed to solve the set of equations that results from the FE approach. Using this model in combination with experimental apparent data taken from the literature, the upper and lower boundaries for the tissue modulus were calculated to be 10.1 and 2.23 GPa, respectively. From the local stress and strain distributions it was concluded that the deformation mode of the trabeculae in the present cube was predominantly in bending. It was concluded that the method developed offers new perspectives for the study of trabecular bone.


Optimal design of antireflection coatings with different metrics.
We consider the problem of designing antireflection coatings by numerical optimization methods with merit functions in different metrics. The dependence of the optimal solution on the metrics is investigated through numerical experiments on several types of coatings, using the average and maximal values of the reflected power in the regions of interest. The results confirm existing statements and provide a few new findings, e.g., some specific metrics can yield particularly better solutions than others.


Pseudomonas aeruginosa MifS-MifR Two-Component System Is Specific for α-Ketoglutarate Utilization.
Pseudomonas aeruginosa is a Gram-negative, metabolically versatile opportunistic pathogen that elaborates a multitude of virulence factors, and is extraordinarily resistant to a gamut of clinically significant antibiotics. This ability, in part, is mediated by two-component regulatory systems (TCS) that play a crucial role in modulating virulence mechanisms and metabolism. MifS (PA5512) and MifR (PA5511) form one such TCS implicated in biofilm formation. MifS is a sensor kinase whereas MifR belongs to the NtrC superfamily of transcriptional regulators that interact with RpoN (σ54). In this study we demonstrate that the mifS and mifR genes form a two-gene operon. The close proximity of mifSR operon to poxB (PA5514) encoding a ß-lactamase hinted at the role of MifSR TCS in regulating antibiotic resistance. To better understand this TCS, clean in-frame deletions were made in P. aeruginosa PAO1 creating PAO∆mifS, PAO∆mifR and PAO∆mifSR. The loss of mifSR had no effect on the antibiotic resistance profile. Phenotypic microarray (BioLOG) analyses of PAO∆mifS and PAO∆mifR revealed that these mutants were unable to utilize C5-dicarboxylate α-ketoglutarate (α-KG), a key tricarboxylic acid cycle intermediate. This finding was confirmed using growth analyses, and the defect can be rescued by mifR or mifSR expressed in trans. These mifSR mutants were able to utilize all the other TCA cycle intermediates (citrate, succinate, fumarate, oxaloacetate or malate) and sugars (glucose or sucrose) except α-KG as the sole carbon source. We confirmed that the mifSR mutants have functional dehydrogenase complex suggesting a possible defect in α-KG transport. The inability of the mutants to utilize α-KG was rescued by expressing PA5530, encoding C5-dicarboxylate transporter, under a regulatable promoter. In addition, we demonstrate that besides MifSR and PA5530, α-KG utilization requires functional RpoN. These data clearly suggests that P. aeruginosa MifSR TCS is involved in sensing α-KG and regulating its transport and subsequent metabolism.


The strong-migration limit in geographically structured populations.
Some strong-migration limits are established for geographically structured populations. A diploid monoecious population is subdivided into a finite number of colonies, which exchange migrants. The migration pattern is fixed and ergodic, but otherwise arbitrary. Generations are discrete and nonoverlapping; the analysis is restricted to a single locus. In all the limiting results, an effective population number Ne (less than or equal to NT) appears instead of the actual total population number NT. 1. If there is no selection, every allele mutates at rate u to types not preexisting in the population, and the (finite) subpopulation numbers Ni are very large, then the ultimate rate and pattern of convergence of the probabilities of allelic identity are approximately the same as for panmixia. If, in addition, the Ni are proportional to 1/u, as NT leads to infinity, the equilibrium probabilities of identity converge to the panmictic value. 2. With a finite number of alleles, any mutation pattern, an arbitrary selection scheme for each colony, and the mutation rates and selection of coefficients proportional to 1/NT, let Pj be the frequency of the allele Aj in the entire population, averaged with respect to the stationary distribution of the backward migration matrix M. As NT leads to infinity, the deviations of the allelic frequencies in each of the subpopulations from Pj converge to zero; the usual panmictic mutation-selection diffusion is obtained for Pj, with the selection intensities averaged with respect to the stationary distribution of M. In both models, Ne = NT and all effects of population subdivision disappear in the limit if, and only if, migration does not alter the subpopulation numbers.


The relative importance of online victimization in understanding depression, delinquency, and substance use.
This article explores the relationship between online and offline forms of interpersonal victimization, with depressive symptomatology, delinquency, and substance use. In a national sample of 1,501 youth Internet users (ages 10-17 years), 57% reported some form of offline interpersonal victimization (e.g., bullying, sexual abuse), and 23% reported an online interpersonal victimization (i.e., sexual solicitation and harassment) in the past year. Nearly three fourths (73%) of youth reporting an online victimization also reported an offline victimization. Virtually all types of online and offline victimization were independently related to depressive symptomatology, delinquent behavior, and substance use. Even after adjusting for the total number of different offline victimizations, youth with online sexual solicitation were still almost 2 times more likely to report depressive symptomatology and high substance use. Findings reiterate the importance of screening for a variety of different types of victimization in mental health settings, including both online and offline forms.


Validation of isoleucine utilization targets in Plasmodium falciparum.
Intraerythrocytic malaria parasites can obtain nearly their entire amino acid requirement by degrading host cell hemoglobin. The sole exception is isoleucine, which is not present in adult human hemoglobin and must be obtained exogenously. We evaluated two compounds for their potential to interfere with isoleucine utilization. Mupirocin, a clinically used antibacterial, kills Plasmodium falciparum parasites at nanomolar concentrations. Thiaisoleucine, an isoleucine analog, also has antimalarial activity. To identify targets of the two compounds, we selected parasites resistant to either mupirocin or thiaisoleucine. Mutants were analyzed by genome-wide high-density tiling microarrays, DNA sequencing, and copy number variation analysis. The genomes of three independent mupirocin-resistant parasite clones had all acquired either amplifications encompassing or SNPs within the chromosomally encoded organellar (apicoplast) isoleucyl-tRNA synthetase. Thiaisoleucine-resistant parasites had a mutation in the cytoplasmic isoleucyl-tRNA synthetase. The role of this mutation in thiaisoleucine resistance was confirmed by allelic replacement. This approach is generally useful for elucidation of new targets in P. falciparum. Our study shows that isoleucine utilization is an essential pathway that can be targeted for antimalarial drug development.


Geographical variation in reproductive character displacement in mate choice by male sailfin mollies.
Female Amazon mollies, Poecilia formosa, are a unisexual species that reproduce by gynogenesis. They must coexist and mate with males of other species (usually the mollies Poecilia latipinna or Poecilia mexicana) to induce embryogenesis, but inheritance is strictly maternal. We examined the mating preference of the male sailfin molly, P. latipinna, for female sailfin mollies versus Amazon mollies, P. formosa. We compared the mating preferences of sympatric and allopatric populations collected throughout the Gulf Coast of North America. Male P. latipinna from six populations sympatric with Amazon mollies showed a significantly greater strength of preference for conspecific sailfin females than males from five populations that were allopatric with Amazon mollies. These results provide strong evidence for reproductive character displacement of male mate choice in sympatry. Furthermore, the large geographical range of populations that we tested revealed variation among populations within sympatry and allopatry, indicating that it is important to evaluate a large number of populations when examining reproductive character displacement.


Factors predictive of neonatal thrombocytopenia in pregnant women with immune thrombocytopenia.
To determine predictive factors for neonatal thrombocytopenia in deliveries with immune thrombocytopenia (ITP), we conducted a retrospective study at a tertiary hospital between 1997 and 2013. During this period, 30 women with ITP delivered 44 children. Neonatal thrombocytopenia (<100 × 10(9)/L) at birth was observed in seven neonates; four of these cases were severe (<50 × 10(9)/L). No cases were complicated by intracranial hemorrhage, and there was no neonatal mortality. Platelet counts at birth of neonates born to mothers, who had first been diagnosed with ITP during pregnancy were significantly higher than those born to mothers diagnosed with ITP before pregnancy. There were significant correlations between neonatal platelet counts in the first and second siblings at birth (P = 0.015) and at nadir (P = 0.035). Platelet counts of neonates born vaginally were significantly more likely to decline after birth than those delivered by cesarean section (13/16 vs. 10/23, P = 0.024). In conclusion, diagnosis of ITP before pregnancy was significantly associated with neonatal thrombocytopenia, and the platelet count of an older sibling is a strong predictor for that of the next baby. The delivery mode may be an indicator of the timing of platelet count nadir after birth.


[The influence of metformin and N-acetylcysteine on mammographic density in postmenopausal women].
Mammographic breast density (MBD) value is currently one of the strong predictors for mammary carcinoma development. There are also other conditions predisposing to MBD increase with hormone-related markers different from those used in breast cancer, while pharmacological methods for MBD reduction are few and still considered experimental. In the current study 25 postmenopausal women received daily for a median 10.5 months 1-1.5 g of antidiabetic biguanide metformin (siofor) (n = 14) or 400-600 mg of antigenotoxic drug N-acetylcysteine (n = 11). In both groups MBD was measured before and after treatment. The effects of both drugs were quite similar. Metformin use lead to lower MBD in 4 of 14 (28.5%) women with mean MBD decrease of -1,24% (absolute dynamics) and -5.03% (relative value). In N-acetylcysteine group this effect was observed in 27.3% of cases, with -2.0% absolute dynamics and -6.1% relative dynamics. In metformin group the most evident absolute and relative dynamics was observed in patients with no signs of metabolic syndrome, -10.86% compared to -2.45%. In 7 women the metformin use also lead to decrease of dense and increase of non-dense areas on digital scans, leading to decrease in dense to non-dense area volume ratio. Therefore, the similar effects of metformin and N-acetylcysteine are probably explained mostly not by insulin resistance elimination by metformin, but by altered cell proliferation, apoptosis and DNA repair.


Characteristics of spatial memory span: is there an analogy to the word length effect, based on movement time?
In studies of verbal short-term memory it has been shown that the length of words to be remembered affects the size of memory span. This word-length effect is attributed to relationships between the rate of rehearsal of verbal material and the time it takes to speak the words being rehearsed. For spatial memory span there may also be an internal rehearsal system linked to overt responding, and if there is a strong analogy to be drawn between the verbal and spatial domains then movement time between spatial targets should predict the number of spatial locations that can be recalled. In the experiments reported here the time taken to move between spatial targets is varied by altering the size of targets and the distance between them. No difference between span performance on a nine-block spatial span task were found, either on immediate recall or on recall after an interval. When recall is of items from an array of 27, grouped in nine sets of three, with only one location in any set being presented on any trial, there is an effect of display size. This effect is consonant with the argument that movement time is related to spatial rehearsal, but other explanations are also possible. However, if recall in this task is scored over the nine sets rather than over the 27 items, then there is no difference between the displays. The results indicate that performance on the normal nine-block spatial-span task cannot be predicted by movement time.


Histopathologic and immunochemical features of lattice corneal dystrophy type III.
We examined seven corneas from five patients with a new form of lattice corneal dystrophy (designated lattice corneal dystrophy type III) by light and electron microscopy. Numerous amyloid deposits were scattered throughout the corneal stroma, some of which were much larger than those usually observed in either lattice corneal dystrophy type I or II; these were located predominantly midway between the epithelium and the endothelium. Image analysis disclosed that the cross-sectional size of the large stromal amyloid deposits was significantly greater than those in age-matched patients with lattice corneal dystrophy type I. All patients had a discontinuous band of amyloid (15 to 25 micron wide) in the superficial stroma beneath Bowman's layer, which usually had only one or two small disruptions. Descemet's membrane and the endothelium were normal. The stromal deposits, which were composed of 10-nm diameter fibrils typical of amyloid, stained positively with Congo red after the histologic sections were pretreated with dilute potassium permanganate. Immunohistochemical studies on formalin-fixed, paraffin-embedded tissue indicated that only some deposits reacted weakly with antibodies to amyloid protein AA. The deposits stained positively with antibodies to protein AP and negatively with antibodies to kappa and lambda immunoglobulin light chains.


Influence of arrangement order ratio on the magneto-optical properties of one-dimensional microcavity structures.
The dependence of the optical responses of microcavity-type one-dimensional (1D) photonic crystals and 1D magnetophotonic crystals (1D-MPCs) on the arrangement order ratio (AOR), which is the ratio of the first and second layers' refractive indexes of Bragg reflectors, is studied. It is demonstrated that the optical properties of two microcavity structures resulting from exchanging the order of Bragg reflector layers so that they have the same optical contrast ratios and different AORs would be different. This difference will be more noticeable in the case of microcavity type 1D-MPCs. Regarding the arrangement-dependent magneto-optical properties of the structures, we can propose the efficient Bragg reflectors with high transmittance enhanced Faraday rotation.


Transcriptional analysis of the Bacillus subtilis teichuronic acid operon.
The cell walls of Gram-positive bacteria consist primarily of a macromolecular matrix comprising similar amounts of peptidoglycan and covalently attached anionic polymers. Under most growth conditions the anionic polymers of Bacillus subtilis are principally teichoic acids; in strain 168 these include a polyglycerol teichoic acid and a glucose/galactosamine-containing teichoic acid. However, when cultures are subjected to phosphate stress the bacterium induces a complex series of responses, one of which is the replacement of at least part of the wall teichoic acid with teichuronic acid, a non-phosphate-containing anionic polymer. In this paper the construction of a transcriptional reporter strain that facilitates the monitoring of the promoter region upstream of the tua operon involved in teichuronic acid synthesis and its controlled expression are reported. The expression of the tua operon was monitored in both phosphate-starved, non-growing batch cultures and phosphate-limited continuous cultures. We show that the transcription of the operon correlates well with the anionic polymer composition of the cell walls.


Intramedullary arthrodesis of the knee in the treatment of sepsis after TKR.
Infection is a devastating complication following total knee replacement (TKR). In the majority of cases, single- or two-stage revision has excellent results in eradicating infection and restoring function. Rarely, recurrent infection requires alternative treatments such as resection, amputation, or arthrodesis. A review of infections following TKR treated at two joint replacement centers identified 29 cases of resistant knee sepsis treated with a long intramedullary fusion nail. Clinical outcome and radiographs were reviewed at an average follow-up of 48 months (13-114). After the initial intramedullary arthrodesis union occurred in 24 of 29 patients (83%). The average time to fusion was 6 months (3-18 months). Failures included two cases of nail breakage, one of which subsequently achieved fusion following revision nailing, and three cases of recurrent infection requiring nail removal and permanent resection. At a minimum 2-year follow-up, 28% of the patients that achieved fusion complained of pain in the fused knee, 28% complained of ipsilateral hip pain, and two patients complained of contralateral knee pain. Four of the 25 fused patients (16%) remained nonambulatory after fusion, 17 required walking aids (68%) and only four ambulated unassisted. There was no association between age, number of previous procedures, the use of two-stage versus single stage technique, or infecting organism and failure of arthrodesis. Intramedullary arthrodesis is a viable treatment for refractory infection after TKR. Patients undergoing fusion should be informed of the potential for nonunion, recurrence of infection, pain in the ipsilateral extremity, and the long-term need for walking aids.


Biodiversity ensures plant-pollinator phenological synchrony against climate change.
Climate change has the potential to alter the phenological synchrony between interacting mutualists, such as plants and their pollinators. However, high levels of biodiversity might buffer the negative effects of species-specific phenological shifts and maintain synchrony at the community level, as predicted by the biodiversity insurance hypothesis. Here, we explore how biodiversity might enhance and stabilise phenological synchrony between a valuable crop, apple and its native pollinators. We combine 46 years of data on apple flowering phenology with historical records of bee pollinators over the same period. When the key apple pollinators are considered altogether, we found extensive synchrony between bee activity and apple peak bloom due to complementarity among bee species' activity periods, and also a stable trend over time due to differential responses to warming climate among bee species. A simulation model confirms that high biodiversity levels can ensure plant-pollinator phenological synchrony and thus pollination function.


Cyclic deposition of calcium salts during growth of cholesterol gallstones.
Some cholesterol gallstones contain darkly pigmented centers or peripheral concentric pigmented bands. We examined the cross-sectional surface of three cholesterol gallstones which contained both central and peripheral pigmented areas with electron-probe microanalysis (EPM) and energy dispersive x-ray microanalysis (EDXA) to determine the elemental composition of the pigmented regions. Linear EPM across the cross-sectional surface of the stones demonstrated that most of the pigmented regions of all three stones had high Ca and P signals; the non-pigmented intervening areas had markedly lower or no detectable Ca and P signals. In two of the three stones, high O signals coincided with the high Ca and P signals suggesting that both calcium bilirubinate and calcium phosphate were present in these pigmented areas. EDXA of the central and peripheral pigmented areas of each stone confirmed the presence of a high Ca signal. Our results demonstrate that in some cholesterol gallstones there is cyclic deposition of calcium bilirubinate and other calcium salts.


Vitamin D supplementation in children with asthma: a systematic review and meta-analysis.
Epidemiologic studies suggest an association between vitamin D deficiency and atopic diseases, including asthma. The objective of this study was to systematically review the benefits and harms of vitamin D supplementation in children with asthma. We used standard Cochrane systematic review methodology. The search strategy included an electronic search in February 2013 of MEDLINE and EMBASE. Two reviewers completed in duplicate and independently study selection, data abstraction, and assessment of risk of bias. We pooled the results of trials using a random-effects model. We assessed the quality of evidence by outcome using the GRADE methodology. Four trials with a total of 149 children met eligibility criteria. The trials had major methodological limitations. Given the four studies reporting on asthma symptoms used different instruments to measure that outcome, we opted not to conduct a meta-analysis. Three of those studies reported improvement in asthma symptoms in the vitamin D supplemented group study, while the fourth reported no effect (very low quality evidence). For the lung function outcome, a meta-analysis of two trials assessing post treatment FEV-1 found a mean difference of 0.54 liters per second (95% CI -5.28; 4.19; low quality evidence). For the vitamin D level outcome, a meta-analysis of three trials found a mean difference of 6.56 ng/ml (95% CI -0.64; 13.77; very low quality evidence). The available very low to low quality evidence does not confirm or rule out beneficial effects of vitamin D supplementation in children with asthma. Large-scale, well-designed and executed randomized controlled trials are needed to better understand the effectiveness and safety of vitamin D in children with asthma.


Rod photoreceptor transduction is affected in central retinal vein occlusion associated with iris neovascularization.
Patients with central retinal vein occlusion who later develop iris neovascularization show changes in the amplitude, the timing, and the sensitivity of the electroretinogram beta wave. We determined the extent to which rod photoreceptor dysfunction contributes to these changes by recording single-flash electroretinograms from both eyes of 52 patients with unilateral central retinal vein occlusion and fitting the leading edges of alpha waves with a model of rod phototransduction. Eyes with central retinal vein occlusion showed reductions in photoreceptor gain but no changes in photoreceptor amplitude when compared with the fellow eyes. The reductions were larger in eyes that developed iris neovascularization and were predictive of this complication. Photoreceptor gain reductions accounted for only part of the beta-wave timing delays and sensitive loss; the remainder is attributed to functional loss in the inner nuclear layer.


Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme.
Ets transcription factors have Ets DNA binding domains, that have a winged helix-turn-helix structure. ETS-1, the founding member of the family, is regulated by the Ras and Ca2+ signaling pathways and is implicated in various physiological processes leading to cell growth, differentiation and apoptosis. We have identified ETS-1 interacting factors with a yeast two-hybrid screen. The majority of the positive clones turned out to encode the human homologue of the yeast ubiquitin-conjugating enzymes UBC9 and Hus5. In two different yeast assays, ETS-1 interacted with huUBC9. In an in vitro GST 'pull-down' assay, ETS-1 and several other Ets family members complexed with huUBC9. Interestingly, in mammalian cells, coexpression of huUBC9 resulted in a substantial increase in the transcriptional activity of ETS-1. Coexpressed huUBC9 did not affect the ETS-1 protein level, and moreover, a point mutation at Cys93, an amino acid known to be essential for ubiquitination, did not abolish the stimulation of the ETS-1 transcriptional activity. Our results indicate that the modulation of ETS-1 activity by huUBC9 results from processes other than ubiquitination and ETS-1 stabilization.


Pair formation in the herbivorous rabbitfish Siganus doliatus.
This study investigated the basis of pair formation in the abundant herbivorous rabbitfish Siganus doliatus on Orpheus Island, Great Barrier Reef. Pair formation was the most common social system in S. doliatus, with 67.4% of all individuals occurring in pairs. Pairs were stable (i.e. individuals remained with the same partner throughout the study) and pair members were found within 5 m of each other 82.9% of the time. Of the examined pairs, 25% were homosexual resulting in a proportion of heterosexual pairs (75%) that was significantly lower than expected if pairs were formed solely for reproductive reasons. Therefore, although reproduction appears to be the main driver of pair formation in S. doliatus, other factors are likely to influence this behaviour. The high density of individuals on the reef crest (5.7 ± 0 .9 individuals 200 m(-2); mean ± s.e.) and extensively overlapping home ranges of pairs indicated that the defence of territories plays no role in pair formation. Instead, it appears that pair formation in S. doliatus is driven, in part, by other, non-reproductive, ecological factors. It is suggested that pair formation allows for increased vigilance against predation and enables S. doliatus to execute a novel feeding behaviour.


Prenatal and postnatal exposures to endocrine disrupting chemicals and timing of pubertal onset in girls and boys: a systematic review and meta-analysis.
Globally, the ages at pubertal onset for girls and boys have been decreasing during recent decades, partly attributed to excess body fat accumulation. However, a growing body of literature has recognized that endocrine disrupting chemicals (EDCs) may play an important role in this global trend, but the association has not yet been fully established. EDCs can interfere with normal hormone function and metabolism and play a role in pubertal onset. We aimed to systematically identify and evaluate the current evidence on the timing of pubertal onset in girls and boys following prenatal or postnatal exposures to xenobiotic EDCs. Following PRISMA guidelines, we performed a systematic literature search of original peer-reviewed publications in the PubMed database through a block search approach using a combination of index MeSH and free text search terms. Publications were considered if they covered biomarkers of prenatal or postnatal exposures to xenobiotic EDCs (European Commission's list of category 1 EDCs) measured in maternal or child biospecimen and pubertal onset defined by the progression of the following milestones (and assessed in terms of the following measures): menarche (age), thelarche (Tanner staging) and pubarche (Tanner staging), in girls, and genital stage (Tanner staging), testicular volume (ml) and pubarche (Tanner staging), in boys. The literature search resulted in 703 references, of which we identified 52 publications fulfilling the eligibility criteria for the qualitative trend synthesis and 23 publications for the meta-analysis. The qualitative trend synthesis provided data on 103 combinations of associations between prenatal or postnatal exposure to EDC compounds groups and puberty outcomes and the meta-analysis enabled 18 summary risk estimates of meta-associations. Statistically significant associations in the qualitative trend synthesis suggested that postnatal exposure to phthalates may be associated with earlier thelarche and later pubarche. However, we did not find consistent evidence in the meta-analysis for associations between timing of pubertal onset in girls and boys and exposures to any of the studied xenobiotic EDCs. We were not able to identify specific pre- or postnatal windows of exposure as particularly critical and susceptible for effects of EDCs. Current evidence is subject to several methodological challenges and inconsistencies and evidence on specific exposure-outcome associations remains too scarce to firmly confirm EDC exposure as a risk factor for changes in age of pubertal onset in the general child population. To create a more uniform foundation for future comparison of evidence and to strengthen pooled studies, we recommend the use of more standardized approaches in the choice of statistical analyses, with exposure transformations, and in the definitions and assessments of puberty outcomes. The impact of mixtures of EDC exposures on the association also remains unestablished and would be valuable to elucidate for prenatal and postnatal windows of exposure. Future large, longitudinal epidemiological studies are needed to clarify the overall association.


Factors Affecting Contrast-Detail Performance in Computed Tomography: A Review.
This article reports on recent research findings into the factors that influence the detectability performance of different systems of computed tomography (CT) scanners. These systems include multidetector CT (MDCT) of different slice numbers, dual-source CT (DSCT), and cone-beam CT (CBCT). The introduction of more slices for MDCT, DSCT, and the new technology of CBCT increases the need to optimize the image quality and to examine the potential reduction of radiation doses to the patient. Low-contrast detail detectability is a method that has proven to be an appropriate evaluation method for this purpose. However, it is essential to recognize factors that affect detectability performance and understand how these factors influence image quality and radiation dose. It is argued that deep understanding of the influences of these factors is the key to image quality optimization in terms of contrast-detail detectability and radiation dose reduction. The purpose of this article is, therefore, to specify these factors and to explain their influence on detectability performance and hence on CT image quality. Further low-contrast detail studies are required to optimize imaging performance of different CT systems and scanners.


Biosynthesis of Drug Glucuronide Metabolites in the Budding Yeast Saccharomyces cerevisiae.
Glucuronidation is one of the most common pathways in mammals for detoxification and elimination of hydrophobic xenobiotic compounds, including many drugs. Metabolites, however, can form active or toxic compounds, such as acyl glucuronides, and their safety assessment is often needed. The absence of efficient means for in vitro synthesis of correct glucuronide metabolites frequently limits such toxicological analyses. To overcome this hurdle we have developed a new approach, the essence of which is a coexpression system containing a human, or another mammalian UDP-glucuronosyltransferases (UGTs), as well as UDP-glucose-6-dehydrogenase (UGDH), within the budding yeast, Saccharomyces cerevisiae. The system was first tested using resting yeast cells coexpressing UGDH and human UGT1A6, 7-hydroxycoumarin as the substrate, in a reaction medium containing 8% glucose, serving as a source of UDP-glucuronic acid. Glucuronides were readily formed and recovered from the medium. Subsequently, by selecting suitable mammalian UGT enzyme for the coexpression system we could obtain the desired glucuronides of various compounds, including molecules with multiple conjugation sites and acyl glucuronides of several carboxylic acid containing drugs, namely, mefenamic acid, flufenamic acid, and zomepirac. In conclusion, a new and flexible yeast system with mammalian UGTs has been developed that exhibits a capacity for efficient production of various glucuronides, including acyl glucuronides.


Implementation of Pediatric Emergency Care Applied Research Network Guidelines for Traumatic Brain Injury in a Rural Tertiary Care Center.
To evaluate changes in imaging practices for pediatric head trauma after publication of the Pediatric Emergency Care Applied Research Network (PECARN) guidelines, explore areas for quality improvement regarding neuroradiology referrals. We also sought to determine the prevalence of incidental findings discovered on computed tomographies (CTs) attained for minor head trauma and ascertain disposition in these cases. This retrospective study was conducted at a rural academic center and included 156 children who received CTs for head trauma between 2005 and 2015. Subjects were divided into 2 groups: pre-PECARN publication and post-PECARN publication. Electronic medical records were reviewed to determine whether or not head CTs were obtained according to PECARN guidelines. The proportion of scanned cases and incidental findings in each group was then compared. Significantly more subjects met PECARN criteria for head CT during the pre-PECARN period (67.1% vs 50.6%, P = 0.04). Among those who met PECARN criteria, severe mechanism of injury was the most common criterion met in both groups (43.8% pre-PECARN and 26.5% post-PECARN). Nine (5.7%) subjects had incidental findings (similar for both study periods), of which 3 prompted additional diagnostic testing or invasive intervention. Among those who did not meet PECARN criteria, the most common mechanism of injury was fall (<3 ft). Implementation of PECARN guidelines at our center remained limited in the 5 years after publication of this practice guide. Clinically insignificant incidental findings were often detected and may heighten patient anxiety.


Computer-assisted instruction: a survey on the attitudes of osteopathic medical students.
To investigate the views of osteopathic medical students on their preferred learning methods, their current use of computers as an educational tool, and their attitudes regarding the role of computers in medical education, based on their skill level. A 27-item questionnaire was distributed to first-through fourth-year osteopathic medical students. Items asked students to assess their levels of computer skills and experience, their current use of computers as an educational tool, and their attitudes regarding the role of computers in medical education. Of the 246 students (80% of enrolled students) who responded to the questionnaire, a majority (129 [53%]) rated themselves as having intermediate computer skills, and the remaining students rated their skills as basic (69 [28%]) or advanced (46 [19%]). Most students (176 [72%]) felt that they learned best by both hearing and seeing or reading new material, that they learned more easily from a printed page than a computer screen, and that live lectures provided them with the best opportunity for learning. However, when compared with students who have basic and intermediate computer skills, students with advanced computer skills were more in favor of computer-assisted instruction and testing as well as a school requirement to own a computer and to use a laptop computer in class. Students' opinions of the importance of computer technology in medical education seem to be based mainly on their self-assessed technical competency levels. Understanding this dynamic may aid medical educators in the implementation of computer-assisted instruction.


Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.
Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group. In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.


Ascending aortic stenosis selectively increases action potential-induced Ca2+ influx in epicardial myocytes of the rat left ventricle.
A decrease of the transient outward potassium current (Ito) has been observed in cardiac hypertrophy and contributes to the altered shape of the action potential (AP) of hypertrophied ventricular myocytes. Since the shape and duration of the ventricular AP are important determinants of the Ca2+ influx during the AP (QCa), we investigated the effect of ascending aortic stenosis (AS) on QCa in endo- and epicardial myocytes of the left ventricular free wall using the AP voltage-clamp technique. In sham-operated animals, QCa was significantly larger in endocardial compared to epicardial myocytes (803 +/- 65 fC pF(-1), n = 27 vs. 167 +/- 32 fC pF(-1), n = 38, P < 0.001). Ascending aortic stenosis significantly increased QCa in epicardial myocytes (368 +/- 54 fC pF(-1), n = 42, P < 0.05), but did not alter QCa in endocardial myocytes (696 +/- 65 fC pF(-1), n = 26). Peak and current-voltage relation of the AP-induced Ca2+ current were unaffected by AS. However, the time course of the current-voltage relation was significantly prolonged in epicardial myocytes of AS animals. Model calculations revealed that the increase in QCa can be ascribed to a prolonged opening of the activation gate, whereas an increase in inactivation prevents an excessive increase in QCa. In conclusion, AS significantly increased AP-induced Ca2+ influx in epicardial but not in endocardial myocytes of the rat left ventricle.


The impact of causal attribution on stigmatizing attitudes toward a person who stutters.
This study investigated the impact of providing low control (biological) and high control (psychobehavioral) causal explanations for stuttering on a variety of stigma related variables including blame, anger, social distance, stereotypes, dislike, sympathy, willingness to help, and perceptions of potential for recovery for a hypothetical person who stutters. One hundred and sixty-five university students read one of three vignettes describing a person who stutters with different descriptions about the cause of stuttering (low control, high control, and a control group in which no explanation was given) and answered a series of self-report measures assessing stigmatizing attitudes and perceived potential for recovery. The controllable explanation for stuttering led to more blame compared to the uncontrollable explanation and no explanation. The controllable explanation resulted in higher levels of anger and stereotypes compared to no explanation. There were no significant differences between uncontrollable explanations and no explanation on any of the stigma related variables of interest. Uncontrollable explanations increased prognostic pessimism compared to controllable explanations. Self-reported familiarity and closeness with people who stutter was significantly related to more positive attitudes toward a hypothetical person who stutters. Reducing the belief that stuttering is ultimately caused by psychobehavioral factors will reduce blame toward people who stutter. However, providing biological explanations for stuttering is not effective for reducing stigma compared to no explanation at all, and could increase prognostic pessimism. Biological explanations for stuttering should be provided to inform clients and society about current research findings, however this information must be given carefully and be balanced with evidence that people who stutter can make great progress with appropriate, personalized therapy that addresses the multidimensionality of the disorder. As a result of reading this paper, readers should be able to: (1) describe how causal attributions impact attitudes toward individuals with disabilities (2) summarize the effects of providing a biological explanation for stuttering on stigmatizing attitudes toward a person who stutters (3) summarize the effects of providing a psychobehavioral explanation for stuttering on stigmatizing attitudes toward a person who stutters, (4) discuss how familiarity and closeness toward people who stutter relates to stigmatizing attitudes toward a person who stutters.


Validation of one-mile walk equations for the estimation of aerobic fitness in British military personnel under the age of 40 years.
To provide an accurate estimate of peak oxygen uptake (VO2 peak) for British Royal Navy Personnel aged between 18 and 39, comparing a gold standard treadmill based maximal exercise test with a submaximal one-mile walk test. Two hundred military personnel consented to perform a treadmill-based VO2 peak test and two one-mile walk tests round an athletics track. The estimated VO2 peak values from three different one-mile walk equations were compared to directly measured VO2 peak values from the treadmill-based test. One hundred participants formed a validation group from which a new equation was derived and the other 100 participants formed the cross-validation group. Existing equations underestimated the VO2 peak values of the fittest personnel and overestimated the VO2 peak of the least aerobically fit by between 2% and 18%. The new equation derived from the validation group has less bias, the highest correlation with the measured values (r = 0.83), and classified the most people correctly according to the Royal Navy's Fitness Test standards, producing the fewest false positives and false negatives combined (9%). The new equation will provide a more accurate estimate of VO2 peak for a British military population aged 18 to 39.


Molecular mechanism of voltage sensing in voltage-gated proton channels.
Voltage-gated proton (Hv) channels play an essential role in phagocytic cells by generating a hyperpolarizing proton current that electrically compensates for the depolarizing current generated by the NADPH oxidase during the respiratory burst, thereby ensuring a sustained production of reactive oxygen species by the NADPH oxidase in phagocytes to neutralize engulfed bacteria. Despite the importance of the voltage-dependent Hv current, it is at present unclear which residues in Hv channels are responsible for the voltage activation. Here we show that individual neutralizations of three charged residues in the fourth transmembrane domain, S4, all reduce the voltage dependence of activation. In addition, we show that the middle S4 charged residue moves from a position accessible from the cytosolic solution to a position accessible from the extracellular solution, suggesting that this residue moves across most of the membrane electric field during voltage activation of Hv channels. Our results show for the first time that the charge movement of these three S4 charges accounts for almost all of the measured gating charge in Hv channels.


Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering.
Computational prediction has become an indispensable aid in the processes of engineering and designing proteins for various biotechnological applications. With the tremendous progress in more powerful computer hardware and more efficient algorithms, some of in silico tools and methods have started to apply the more realistic description of proteins as their conformational ensembles, making protein dynamics an integral part of their prediction workflows. To help protein engineers to harness benefits of considering dynamics in their designs, we surveyed new tools developed for analyses of conformational ensembles in order to select engineering hotspots and design mutations. Next, we discussed the collective evolution towards more flexible protein design methods, including ensemble-based approaches, knowledge-assisted methods, and provable algorithms. Finally, we highlighted apparent challenges that current approaches are facing and provided our perspectives on their further development.


Adsorption and desorption of uranium(VI) onto humic acids derived from uranium-enriched lignites.
Humic acids (HAs) were extracted and characterized from three kinds of uranium-enriched lignites from Yunnan province, China. Batch experiments were used to study the adsorption and desorption behavior of uranium (VI) onto these HAs and a commercial HA. The results showed that the optimum pH level at which all the HAs adsorbed uranium(VI) ranged from 5 to 8. The high uranium content of the HAs was released into the solution at the pH values between 1 and 3; when the HA dosage was 2.5 g L-1, the maximum concentration of uranium was 44.14 μg L-1. This shows that HAs derived from uranium-enriched lignites may present a potential environmental risk when used in acidic conditions. The experimental data were found to comply with the pseudo-second-order kinetic model, and the adsorption isotherms fit the Langmuir and Freundlich models well. The desorption experiments revealed that the sorption mechanism was controlled by the complex interactions between the organic ligands of the HAs and uranium(VI). The uranium present in the HAs may not affect the adsorption capacity of the uranium(VI), but the carboxylic and phenolic hydroxyl groups in the HAs play a significant role in controlling the adsorption capacity.


Evidence of oligogenic inheritance in nephronophthisis.
Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the NPHP1, NPHP2, NPHP3, and NPHP4 genes. In our previous studies involving 44 families, we detected two mutations in one of the NPHP1-4 genes. Here, we detected in six families two mutations in either NPHP1, NPHP3, or NPHP4, and identified a third mutation in one of the other NPHP genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in NPHP2 and a second mutation in NPHP3. Finally, we detected the presence of a single mutation in nine families, suggesting that the second recessive mutation may be in another as yet unidentified NPHP gene. Our findings suggest that oligogenicity may occur in cases of nephronophthisis.


Biallelic FBXW7 knockout induces AKAP8-mediated DNA damage in neighbouring wildtype cells.
Colorectal cancer possesses marked intratumoral heterogeneity. While subclonal interactions between Vogelstein driver mutations have been extensively studied, less is known about competitive or cooperative effects between subclonal populations with other cancer driver mutations. FBXW7 is a cancer driver mutation which is present in close to 17% of colorectal cancer cells. In this study, we generated isogenic FBXW7 mutant cells using CRISPR-Cas9. We identified an upregulation of oxidative phosphorylation and DNA damage in FBXW7 mutant cells, which surprisingly proliferated at a decreased rate compared to wildtype cells. To determine subclonal interactions, wildtype and mutant FBXW7 cells were cocultured using a Transwell system. Wildtype cells cocultured with FBXW7 mutant cells similarly developed DNA damage which was not observed when wildtype cells were co-cultured with other wildtype cells, suggesting that FBXW7 mutant cells were inducing DNA damage in neighbouring wildtype cells. Using mass spectrometry, we identified AKAP8 as being secreted by FBXW7 mutant cells into the coculture media. Furthermore, overexpression of AKAP8 in wildtype cells recapitulated the DNA damage phenotype observed during coculture, while co-culture of wildtype cells with double mutant FBXW7-/-/AKAP8-/- cells abrogated the DNA damage phenotype. Here, we describe a hitherto unknown phenomenon of AKAP8-mediated DNA damage from FBXW7 mutant to neighbouring wildtype cells. Our findings demonstrate the importance of elucidating the local effect of cancer driver mutations between subclonal populations.


Direct dating of lithic surface artifacts using luminescence.
Archaeological surface assemblages composed of lithic scatters comprise a large proportion of the archaeological record. Dating such surface artifacts has remained inherently difficult owing to the dynamic nature of Earth-surface processes affecting these assemblages and because no satisfactory chronometric dating technique exists that can be directly applied to constrain the timing of artifact manufacture, discard, and thus human use of the landscape. Here, we present a dating approach based on optically stimulated luminescence (OSL)-OSL rock-surface burial dating-and apply it to a lithic surface scatter in Tibet. We generate OSL burial ages (age-depth profiles) for each artifact, outline the methodological complexities, and consider the artifact burial ages in the context of local-scale Earth-surface dynamics. The oldest age cluster between 5.2 and 5.5 thousand years is likely related to quarrying activities at the site and thus represents the oldest chronometric age constraints for human presence on the south-central Tibetan plateau.


Evaluation of commercial enzyme immunoassay (EIA) and immunofluorescent antibody (FA) test kits for detection of Cryptosporidium oocysts of species other than Cryptosporidium parvum.
A commercial enzyme immunoassay (EIA) (ProSpect Rapid Assay), a direct immunofluorescence antibody (IFA) test for stool testing (MERIFLUOR Cryptosporidium/Giardia), and an indirect IFA test for environmental testing (Hydrofluor-Combo Cryptosporidium/Giardia) were evaluated for detection of low public health risk Cryptosporidium oocyst isolates, and for C. parvum oocyst isolates from human and bovine feces that represent a high public health risk. There was no cross-reactivity of EIA with ova of eight medically important helminths, three Eimeria species oocysts, Sarcocystis cruzi sporocysts, and two Candida sp. isolates. All nine snake oocyst isolates (C. serpentis), two of seven lizard oocyst isolates, one turtle oocyst isolate, two avian oocyst isolates (turkey, C. meleagridis), one C. wrairi oocyst isolate from guinea pigs, one C. muris oocyst isolate from hyrax, one heifer C. muris isolate, and two C. muris-like oocyst isolates from a camel were positive by both IFA tests; six of these 19 oocyst isolates were EIA-positive. There was no difference in the sensitivity and specificity between direct and indirect IFA tests. The sensitivity of the EIA and both IFA tests to the C. parvum oocysts was 100%. The EIA showed less cross-reactivity with the non-C. parvum oocysts (24%) than direct or indirect IFA (76%), and was less sensitive to those isolates (20%) than both IFA tests (63%). A simulated sampling model for high and low public health risk Cryptosporidium oocysts showed that the low risk oocyst isolates may constitute up to 35% of all positive environmental samples by direct or indirect IFA determination, and up to 12% of all EIA positive samples. This study indicates a superiority of direct and indirect IFA and EIA for screening of human-or-bovine-origin fecal specimens, whereas testing of environmental samples may lead to misidentification of medically important isolates. The results demonstrated that the EIA kit can more accurately identify environmental samples containing oocytes pathogenic for humans than both IFA tests. The specificity of commercially available diagnostic kits to C. parvum should be critically examined for cross-species identification before they are recommended or adopted for use in testing environmental samples.


Morbidity of tamoxifen-perceptions of patients and healthcare professionals.
There is little published data comparing patients' and doctors' perceptions of tamoxifen-related morbidity and toxicity, in particular in terms of side-effects which are not medically serious but which disrupt quality of life. We undertook a questionnaire-based study of 210 randomly selected, disease-free pre- and post-menopausal breast cancer patients to assess perceived morbidity whilst taking tamoxifen. We also questioned 143 healthcare professionals, including nurses, GPs and oncologists, on their opinions of tamoxifen-related side-effects. This study suggests that patients experience significant morbidity while taking adjuvant tamoxifen but will tolerate this for the sake of anticipated benefits. Healthcare professionals particularly hospital-based doctors and specialist nurses tend to overestimate the prevalence and severity of tamoxifen-associated symptoms.


[Multifactorial analysis of risk factors for low birth weight in Salvador, Bahia].
This study is a multifactorial analysis of the risk factors for low birthweight in a group of newborns in an urban area of Brazil. A total of 1023 infants born in four maternity units in Salvador, Bahia, between July 1987 and February 1988 were included in the study. The sources of information were clinical histories and interviews with the mothers in the maternity units. The analysis was by means of logistic regression. In the final model the risk factors were the following: maternal age less than 21 years or more than 35; gestational age less than 38 weeks; unfavorable outcome of an earlier pregnancy; interval of 12 months or less since prior birth; tobacco smoking; and hypertension. The population attributable risk values for the risk factors included in the final model are presented. These factors should be used to identify pregnant women at high risk of giving birth to a low-birthweight baby, in order to provide them with more prenatal care.


Radiofrequency electromagnetic field exposure and non-specific symptoms of ill health: a systematic review.
This article is a systematic review of whether everyday exposure to radiofrequency electromagnetic field (RF-EMF) causes symptoms, and whether some individuals are able to detect low-level RF-EMF (below the ICNIRP [International Commission on Non-Ionizing Radiation Protection] guidelines). Peer-reviewed articles published before August 2007 were identified by means of a systematic literature search. Meta-analytic techniques were used to pool the results from studies investigating the ability to discriminate active from sham RF-EMF exposure. RF-EMF discrimination was investigated in seven studies including a total of 182 self-declared electromagnetic hypersensitive (EHS) individuals and 332 non-EHS individuals. The pooled correct field detection rate was 4.2% better than expected by chance (95% CI: -2.1 to 10.5). There was no evidence that EHS individuals could detect presence or absence of RF-EMF better than other persons. There was little evidence that short-term exposure to a mobile phone or base station causes symptoms based on the results of eight randomized trials investigating 194 EHS and 346 non-EHS individuals in a laboratory. Some of the trials provided evidence for the occurrence of nocebo effects. In population based studies an association between symptoms and exposure to RF-EMF in the everyday environment was repeatedly observed. This review showed that the large majority of individuals who claims to be able to detect low level RF-EMF are not able to do so under double-blind conditions. If such individuals exist, they represent a small minority and have not been identified yet. The available observational studies do not allow differentiating between biophysical from EMF and nocebo effects.


Withania somnifera chemotype NMITLI 101R significantly increases the efficacy of antileishmanial drugs by generating strong IFN-γ and IL-12 mediated immune responses in Leishmania donovani infected hamsters.
Withania somnifera (L.) Dunal (Solanaceae), commonly known as Ashwagandha, is one of the most important medicinal plant in the traditional Indian medical systems. Pharmacological studies have established that root extracts of W. somnifera contain several bioactive constituents called withanolides. The plant has long been used for its several beneficial properties and recently as an immunomodulator. A combination therapy including a potential and safe immunostimulant with lower doses of effective drug, which can reduce the parasitic burden and simultaneously can produce an enhancement of adaptive immunity, has proven to be significantly a more effective approach than immunotherapy or drug therapy alone. Evaluation of the immunostimulatory effect of W. somnifera chemotype NMITLI 101R when used in combination with ED50 doses of antileishmanial drugs in Leishmania donovani infected hamsters. Infected animals were administered with chemotype 101R(30mg/kg × 15 days) either alone or in combination with ED50 doses of miltefosine (10mg/kg × 5 days), paromomycin (30mg/kg × 5 days) or amphotericin B (0.5mg/kg × 5 days). The treated animals were euthanized on days 30 and 60 post-treatment (p.t.) and checked for parasite clearance, delayed type hypersensitivity (DTH) response, cytokine and inducible nitric oxide synthase levels by real-time PCR, nitric oxide (NO) production, reactive oxygen species (ROS) generation, lymphoproliferative and antibody responses. The group of animals that received 101R and ED50 dose of miltefosine showed optimum inhibition of parasite multiplication (∼98%) by day 60 p.t. followed by the group that received 101R plus paromomycin (∼94%) and 101R plus amphotericin B (∼93%). The efficacy was well supported by the increased inducible NO synthase mRNA transcript, strong IFN-γand IL-12 mediated Th1 immune responses and significantly suppressed levels of Th2 cytokines (IL-4, IL-10 and TGF-β). Additionally, same therapy also induced significant increase in the level of NO production, ROS generation, Leishmania specific IgG2 antibody along with profound DTH and strong T-cell responses as compared with all the other treated groups. Our results suggest that combination of chemotype 101R with ED50 doses of antileishmanial drugs may provide a promising alternative for the cure of visceral leishmaniasis with significant restoration of the host immune response.


Tissue regeneration in vivo within recombinant spidroin 1 scaffolds.
One of the major tasks of tissue engineering is to produce tissue grafts for the replacement or regeneration of damaged tissue, and natural and recombinant silk-based polymer scaffolds are promising candidates for such grafts. Here, we compared two porous scaffolds made from different silk proteins, fibroin of Bombyx mori and a recombinant analog of Nephila clavipes spidroin 1 known as rS1/9, and their biocompatibility and degradation behavior in vitro and in vivo. The vascularization and intergrowth of the connective tissue, which was penetrated with nerve fibers, at 8 weeks after subcutaneous implantation in Balb/c mice was more profound using the rS1/9 scaffolds. Implantation of both scaffolds into bone defects in Wistar rats accelerated repair compared to controls with no implanted scaffold at 4 weeks. Based on the number of macrophages and multinuclear giant cells in the subcutaneous area and the number of osteoclasts in the bone, regeneration was determined to be more effective after the rS1/9 scaffolds were implanted. Microscopic examination of the morphology of the matrices revealed differences in their internal microstructures. In contrast to fibroin-based scaffolds, the walls of the rS1/9 scaffolds were visibly thicker and contained specific micropores. We suggest that the porous inner structure of the rS1/9 scaffolds provided a better micro-environment for the regenerating tissue, which makes the matrices derived from the recombinant rS1/9 protein favorable candidates for future in vivo applications.