Critical role of deadenylation in regulating poly(A) rhythms and circadian gene expression.
The mammalian circadian clock is deeply rooted in rhythmic regulation of gene expression. Rhythmic transcriptional control mediated by the circadian transcription factors is thought to be the main driver of mammalian circadian gene expression. However, mounting evidence has demonstrated the importance of rhythmic post-transcriptional controls, and it remains unclear how the transcriptional and post-transcriptional mechanisms collectively control rhythmic gene expression. In mouse liver, hundreds of genes were found to exhibit rhythmicity in poly(A) tail length, and the poly(A) rhythms are strongly correlated with the protein expression rhythms. To understand the role of rhythmic poly(A) regulation in circadian gene expression, we constructed a parsimonious model that depicts rhythmic control imposed upon basic mRNA expression and poly(A) regulation processes, including transcription, deadenylation, polyadenylation, and degradation. The model results reveal the rhythmicity in deadenylation as the strongest contributor to the rhythmicity in poly(A) tail length and the rhythmicity in the abundance of the mRNA subpopulation with long poly(A) tails (a rough proxy for mRNA translatability). In line with this finding, the model further shows that the experimentally observed distinct peak phases in the expression of deadenylases, regardless of other rhythmic controls, can robustly cluster the rhythmic mRNAs by their peak phases in poly(A) tail length and abundance of the long-tailed subpopulation. This provides a potential mechanism to synchronize the phases of target gene expression regulated by the same deadenylases. Our findings highlight the critical role of rhythmic deadenylation in regulating poly(A) rhythms and circadian gene expression.


Comparative immediate effect of different yoga asanas on heart rate and blood pressure in healthy young volunteers.
This study planned to compare immediate cardiovascular effects of different yoga asanas in healthy young volunteers. Heart rate (HR), systolic pressure (SP), and diastolic pressure (DP), blood pressure (BP), were recorded using the non invasive blood pressure (NIBP) apparatus in 22 healthy young subjects, before and after the performance of Dhanurasana (DA), Vakrasana (VA) (both sides), Janusirasasana (JSA) (both sides), Matsyasana and Shavasana for 30 s. HR and BP were further recorded during supine recovery at 2, 4, 6, 8, and 10 min. A repeated measure of ANOVA was used for statistical analysis. There were significant changes in HR and BP both immediately after the Asanas as well as during the recovery period. Overall comparisons of ∆% changes immediately after the performance of the Asanas revealed significant differences with regard to HR that increased significantly after DA. In the recovery phase, there were significant intergroup differences from 2 min onward in both SP and DP. The decrease of SP after VA (right side) (VA-R) was significantly greater than Shavasana (4(th), 6(th), and 8(th) min) and JSA (left side) (JSA-L) at 6(th) and 8(th) min. DP decreased significantly after performing JSA-L compared to VA-R at the 6(th) and 8(th) min. The cardiovascular changes immediately after the Asanas and during the recovery phase reveal inherent differences between the selected postures. The rise of HR in DA may be attributed to increased sympathetic response due to the relative difficulty of the posture as well as abdominal compression occurring in it. The effect of supine relaxation is more pronounced after the performance of the Asanas as compared to mere relaxation in Shavasana. This may be attributed to a normalization and resultant homeostatic effect occurring due to a greater, healthier de-activation of the autonomic nervous system occurring towing to the presence of prior activation. There were also subtle differences between the right sided and left sided performance of VA and JSA that may be occurring due to the different internal structures being either compressed or relaxed on either side. Our study provides initial evidence of differential cardiovascular effects of Asanas and subtle differences between right and left sided performance. Further, cardiovascular recovery is greater after the performance of the Asanas as compared to shavasan; thus, implying a better response when effort precedes relaxation.


Body mass index at different adult ages, weight change, and colorectal cancer risk in the National Institutes of Health-AARP Cohort.
The authors investigated the relations of body mass index at different ages and adult weight change to incident colorectal cancer risk in the prospective National Institutes of Health-AARP Diet and Health Study (1995-1996), using a subcohort with repeated recall weights (273,679 participants; mean baseline age = 62.8 years). During 2,509,662 person-years follow-up, 4076 incident colorectal cancers were ascertained. For men, an increased risk of colon cancer but not rectal cancer was associated with body mass index at baseline age (per 5-kg/m(2) increase, hazard ratio (HR) = 1.18, 95% confidence interval (CI): 1.11, 1.25), at age 50 years (HR = 1.18, 95% CI: 1.10, 1.26), and at age 35 years (HR = 1.16, 95% CI: 1.07, 1.25) but less so at age 18 years. Weight gained between the ages of 18 and 35 years and between 18 years of age and the baseline age was associated with an increased risk of colon cancer in men (per 0.5-kg/year increase, HR = 1.18, 95% CI: 1.11, 1.25 and HR = 1.29, 95% CI: 1.16, 1.56, respectively). For women, relations throughout were weaker than those observed for men. These findings suggest that weight gains during early to middle adulthood have important influences on colon cancer risk, especially in men.


Drosophila-associated bacteria differentially shape the nutritional requirements of their host during juvenile growth.
The interplay between nutrition and the microbial communities colonizing the gastrointestinal tract (i.e., gut microbiota) determines juvenile growth trajectory. Nutritional deficiencies trigger developmental delays, and an immature gut microbiota is a hallmark of pathologies related to childhood undernutrition. However, how host-associated bacteria modulate the impact of nutrition on juvenile growth remains elusive. Here, using gnotobiotic Drosophila melanogaster larvae independently associated with Acetobacter pomorumWJL (ApWJL) and Lactobacillus plantarumNC8 (LpNC8), 2 model Drosophila-associated bacteria, we performed a large-scale, systematic nutritional screen based on larval growth in 40 different and precisely controlled nutritional environments. We combined these results with genome-based metabolic network reconstruction to define the biosynthetic capacities of Drosophila germ-free (GF) larvae and its 2 bacterial partners. We first established that ApWJL and LpNC8 differentially fulfill the nutritional requirements of the ex-GF larvae and parsed such difference down to individual amino acids, vitamins, other micronutrients, and trace metals. We found that Drosophila-associated bacteria not only fortify the host's diet with essential nutrients but, in specific instances, functionally compensate for host auxotrophies by either providing a metabolic intermediate or nutrient derivative to the host or by uptaking, concentrating, and delivering contaminant traces of micronutrients. Our systematic work reveals that beyond the molecular dialogue engaged between the host and its bacterial partners, Drosophila and its associated bacteria establish an integrated nutritional network relying on nutrient provision and utilization.


A perspective on the role of emerging technologies for the propagation of companion animals, non-domestic and endangered species.
Assisted reproductive technologies (ART) have been used successfully in humans, domestic and laboratory species for many years. In contrast, our limited knowledge of basic reproductive physiology has restricted the application of ART in companion animal, non-domestic and endangered species (CANDES). Although there are numerous benefits, and in some cases a necessity, for applying ART for the reproductive and genetic management of CANDES, the challenges encountered with even the most basic procedures have limited the rate of progress. In this foreword we discuss the status of conventional ART, such as artificial insemination and in vitro fertilisation, as well as their benefits and inherent difficulties when applied to CANDES. It is upon these techniques, and ultimately our knowledge of basic reproductive physiology, that the success of emerging technologies, such as those described in this special issue, are dependent for success.


Evaluation of implementation, compliance and acceptance of partial smoking bans among hospitality workers before and after the Swiss Tobacco Control Act.
The World Health Organization recommends uniform comprehensive smoking bans in public places. In Switzerland, regulations differ between various areas and are mostly incomplete for hospitality venues. As ambiguous regulations offer more leeway for implementation, we evaluated the Swiss regulations with respect to their effects on implementation, acceptance and compliance among hospitality workers. In our longitudinal study, a standardized, self-administered questionnaire was mailed to a sample of 185 hospitality workers before and 4-6 month after the smoking ban came into effect. The matched longitudinal sample comprised 71 participants (repeated response rate 38.4%). We developed a seven-item acceptance scale. Logistic regressions were performed to explore the factors associated with acceptance. Acceptance of smoking bans was influenced by smoking status and perceived annoyance with second-hand smoke in private. Although not statistically significant (P = 0.09), we found some indications that post-ban acceptance increased in an area with strict regulations, whereas it decreased in two areas with less stringent regulations. Tobacco bans in Swiss hospitality venues are still in a period of consolidation. The incomplete nature of the law may also have had a negative impact on the development of greater acceptance.


Evaluation of laparoscopic vs robotic partial nephrectomy using the margin, ischemia and complications score system: a retrospective single center analysis.
To evaluate differences between Laparoscopic Partial Nephrectomy (LPN) and Robot-Assisted Partial Nephrectomy (RAPN) using the Margin, Ischemia and Complications (MIC) score system and to evaluate factors related with MIC success. Single centre retrospective study on 258 LPN and 58 RAPN performed between January 2012 and January 2014. Success was defined when surgical margins was negative, Warm Ischemia Time (WIT) was ≤ 20 minutes and no major complications occurred. Mann-Whitney-U and Pearson χ2 correlation were used to compare LPN and RAPN. A matched pair comparison was also performed. Spearman correlation (Rho) was used to evaluate the relationship between clinical, intra and post-operative and pathological patients characteristics with MIC score. A binary regression analysis was also performed to evaluate independent factors associated with MIC success. The MIC rate in LPN and RAPN was 55% and 65.5% respectively. No differences in clinical, intra and post-operative outcomes between groups were found. Clinical tumor size (p-value: < 0.001; OR: 0.829; 95% CI: 0.697-0.987), PADUA score (p-value: < 0.001; OR: 0.843; 95% CI: 0.740-0.960), PADUA risk groups (intermediate; p-value: < 0.001; OR: 0.416; 95% CI: 0.238- 0.792; high: p-value: < 0.001; OR: 0.356; 95% CI: 0.199- 0.636), WIT (p-value: < 0.001; OR: 0.598; 95% CI: 0.530- 0.675) were independently associated with MIC. eGFR (< 60 vs ≥ 60 ml/min per 1.73 m2: p-value: < 0.001; OR: 3.356; 95% CI: 1.701-6.621) and Fuhrman nuclear grade (p-value: 0.014; OR: 1.798; 95% CI:1.129-2.865) were also independently associated with MIC. MIC score system is a simple and useful tool to report and to compare different surgical approach.


Quantitative fluorescence tomography using a trimodality system: in vivo validation.
A fully integrated trimodality fluorescence, diffuse optical, and x-ray computed tomography (FT/DOT/XCT) system for small animal imaging is reported in this work. The main purpose of this system is to obtain quantitatively accurate fluorescence concentration images using a multimodality approach. XCT offers anatomical information, while DOT provides the necessary background optical property map to improve FT image accuracy. The quantitative accuracy of this trimodality system is demonstrated in vivo. In particular, we show that a 2-mm-diam fluorescence inclusion located 8 mm deep in a nude mouse can only be localized when functional a priori information from DOT is available. However, the error in the recovered fluorophore concentration is nearly 87%. On the other hand, the fluorophore concentration can be accurately recovered within 2% error when both DOT functional and XCT structural a priori information are utilized together to guide and constrain the FT reconstruction algorithm.


Telomerase activity in gastric cancer.
Although many genetic alterations have been reported in gastric cancer, it is not known whether all gastric tumors are capable of indefinite proliferative potential, e.g., immortality. The expression of telomerase and stabilization of telomeres are concomitant with the attainment of immortality in tumor cells; thus, the measurement of telomerase activity in clinically obtained tumor samples may provide important information useful both as a diagnostic marker to detect immortal cancer cells in clinical materials and as a prognostic indicator of patient outcome. Telomerase activity was analyzed in 66 primary gastric cancers with the use of a PCR-based assay. The majority of tumors (85%) displayed telomerase activity, but telomerase was undetectable in 10 tumors (15%), 8 of which were early stage tumors. Most of the tumors with telomerase activity were large and of advanced stages, including metastases. Survival rate of patients of tumors with detectable telomerase activity was significantly shorter than that of those without telomerase activity. Alterations of telomere length (reduced/elongated terminal restriction fragments) were detected in 14 of 66 (21%) gastric cancers, and all 14 had telomerase activity. Cellular DNA contents revealed that all 22 aneuploid tumors had detectable telomerase activity. The present results indicate that telomerase activation may be required as a critical step in the multigenetic process of tumorigenesis, and that telomerase is frequently but not always activated as a late event in gastric cancer progression.


The development, validation, and testing of a health outcomes burn questionnaire for infants and children 5 years of age and younger: American Burn Association/Shriners Hospitals for Children.
The 12-member American Burn Association/Shriners Hospitals for Children Outcomes Task Force was charged with developing a health outcomes questionnaire for use in children 5 years of age and younger that was clinically based and valid. A 55-item form was tested using a cross-sectional design on the basis of a range of 184 infants and children between 0 and 5 years of age at 8 burn centers, nationally. A total of 131 subjects completed a follow-up health outcomes questionnaire 6 months after the baseline assessment. A comparison group of 285 normal nonburn children was also obtained. Internal consistency reliability of the scales ranged from 0.74 to 0.94. Tests of clinical validity were significant in the hypothesized direction for the majority of scales for length of hospital stay, duration since the burn, percent of body surface area burned, overall clinician assessment of severity of burn injury, and number of comorbidities. The criterion validity of the instrument was supported using the Child Developmental Inventories for Burn Children in early childhood and preschool stages of development comparing normal vs abnormal children. The instrument was sensitive to changes over time following a clinical course observed by physicians in practice. The Health Outcomes Burn Questionnaire for Infants and Children 5 years of age and younger is a clinically based reliable and valid assessment tool that is sensitive to change over time for assessing burn outcomes in this age group.


Figs--the earliest known ancient drug for cutaneous anthrax.
Anthrax is an often fatal bacterial infection, occurring in cutaneous, inhalational, gastrointestinal, and meningeal forms. Evaluation of anthrax treatment from ancient history may help healthcare providers to handle this serious disease more efficiently. To evaluate the biblical descriptions of anthrax, focusing on its therapy in ancient times. All biblical texts associated with anthrax were examined and passages relating to this disease were studied closely. Biblical passages such as: "Take a cluster of figs. And they took and laid it on the boil [anthrax], and he recovered," and "Let them take a cluster of figs, and lay it upon the boil [anthrax], and he shall recover," convincingly indicate that figs have healing properties in cutaneous anthrax lesions. On the basis of this study, the National Institutes of Health together with the pharmaceutical industry may consider to work on isolation of compounds from fig plants to develop products against cutaneous and possibly other forms of anthrax once screening tests are completed.


Subcutaneous injection of IFN alpha-2b for COVID-19: an observational study.
The global pandemic of coronavirus disease 2019 (COVID-19) infection is ongoing and associated with high mortality. The aim of this study was to investigate the efficacy and safety of subcutaneous injection of interferon alpha-2b (IFN alpha-2b) combined with lopinavir/ritonavir (LPV/r) in the treatment of COVID-19 infection, compared with that of using LPV/r alone. Patients diagnosed with laboratory-confirmed COVID-19 infection in Wuhan Red Cross hospital during the period from January 23, 2020 to March 19, 2020 were included. The length of stay, the time to viral clearance and adverse reactions during hospitalization were compared between patients using oral LPV/r and combined therapy of LPV/r and subcutaneous injection of IFN alpha-2b. A total of 22 patients were treated with LPV/r alone and 19 with combined therapy with subcutaneous injection of IFN alpha-2b. The average length of hospitalization in the combination group was shorter than that of LPV/r group (16 ± 9.7 vs 23 ± 10.5 days; P = 0.028). Moreover, the days of hospitalization in early intervention group decreased from 25 ± 8.5 days to 10 ± 2.9 days compared with delayed intervention group (P = 0.001). Combined therapy with IFN alpha-2b also significantly reduced the duration of detectable virus in the upper respiratory tract. No patient in each group was transferred to intensive care unit (ICU) or died during the treatment. There was no significant difference in the adverse effect composition between two groups. Subcutaneous injection of IFN alpha-2b combined with LPV/r shortened the length of hospitalization and accelerated viral clearance in COVID-19 patients, which deserves further investigation in clinical practice.


Increased amygdala response to shame in remitted major depressive disorder.
Proneness to self-blaming moral emotions such as shame and guilt is increased in major depressive disorder (MDD), and may play an important role in vulnerability even after symptoms have subsided. Social psychologists have argued that shame-proneness is relevant for depression vulnerability and is distinct from guilt. Shame depends on the imagined critical perception of others, whereas guilt results from one's own judgement. The neuroanatomy of shame in MDD is unknown. Using fMRI, we compared 21 participants with MDD remitted from symptoms with no current co-morbid axis-I disorders, and 18 control participants with no personal or family history of MDD. The MDD group exhibited higher activation of the right amygdala and posterior insula for shame relative to guilt (SPM8). This neural difference was observed despite equal levels of rated negative emotional valence and frequencies of induced shame and guilt experience across groups. These same results were found in the medication-free MDD subgroup (N = 15). Increased amygdala and posterior insula activations, known to be related to sensory perception of emotional stimuli, distinguish shame from guilt responses in remitted MDD. People with MDD thus exhibit changes in the neural response to shame after symptoms have subsided. This supports the hypothesis that shame and guilt play at least partly distinct roles in vulnerability to MDD. Shame-induction may be a more sensitive probe of residual amygdala hypersensitivity in MDD compared with facial emotion-evoked responses previously found to normalize on remission.


A prospective controlled multicentre study of clarithromycin in pregnancy.
Clarithromycin is a relatively new macrolide antibiotic with an action spectrum similar to that of erythromycin. Its main indications for use are for upper and lower respiratory and skin and soft tissue infections. Little is known about its safety in pregnancy, although animal reproductive studies found an increased rate of cardiovascular anomalies, cleft palate, and embryonic loss. Human data, limited to case reports and one small uncontrolled study, cannot allow evidence based counseling of pregnant women who were exposed to the drug before finding out they were pregnant. Pregnant women who had been counseled on the use of clarithromycin by five centers, were matched for age, smoking, and alcohol use with a control group of pregnant women who were exposed to nonteratogenic antibiotics. A total of 157 women were followed up. Of these, 122 were exposed to the drug in the first trimester. There were no significant differences found between the two groups in the rates of major and minor malformations; 2.3 versus 1.4% for major (p = 0.86) and 5.4 versus 4.9% for minor (p = 0.96). Spontaneous abortion rates in the exposed group was significantly different, higher (14%) than in the control group (7%) (p = 0.04). This first prospective controlled study of exposure to clarithromycin in pregnancy suggests that this agent does not increase the rate of major malformations above the baseline risk of 1-3%. The higher rate of reported spontaneous abortions, although still within the expected baseline rate, may warrant further study.


A global framework for action to improve the primary care response to chronic non-communicable diseases: a solution to a neglected problem.
Although in developing countries the burden of morbidity and mortality due to infectious diseases has often overshadowed that due to chronic non-communicable diseases (NCDs), there is evidence now of a shift of attention to NCDs. Decreasing the chronic NCD burden requires a two-pronged approach: implementation of the multisectoral policies aimed at decreasing population-level risks for NCDs, and effective and affordable delivery of primary care interventions for patients with chronic NCDs. The primary care response to common NCDs is often unstructured and inadequate. We therefore propose a programmatic, standardized approach to the delivery of primary care interventions for patients with NCDs, with a focus on hypertension, diabetes mellitus, chronic airflow obstruction, and obesity. The benefits of this approach will extend to patients with related conditions, e.g. those with chronic kidney disease caused by hypertension or diabetes. This framework for a "public health approach" is informed by experience of scaling up interventions for chronic infectious diseases (tuberculosis and HIV). The lessons learned from progress in rolling out these interventions include the importance of gaining political commitment, developing a robust strategy, delivering standardised interventions, and ensuring rigorous monitoring and evaluation of progress towards defined targets. The goal of the framework is to reduce the burden of morbidity, disability and premature mortality related to NCDs through a primary care strategy which has three elements: 1) identify and address modifiable risk factors, 2) screen for common NCDs and 3) and diagnose, treat and follow-up patients with common NCDs using standard protocols. The proposed framework for NCDs borrows the same elements as those developed for tuberculosis control, comprising a goal, strategy and targets for NCD control, a package of interventions for quality care, key operations for national implementation of these interventions (political commitment, case-finding among people attending primary care services, standardised diagnostic and treatment protocols, regular drug supply, and systematic monitoring and evaluation), and indicators to measure progress towards increasing the impact of primary care interventions on chronic NCDs. The framework needs evaluation, then adaptation in different settings. A framework for a programmatic "public health approach" has the potential to improve on the current unstructured approach to primary care of people with chronic NCDs. Research to establish the cost, value and feasibility of implementing the framework will pave the way for international support to extend the benefit of this approach to the millions of people worldwide with chronic NCDs.


Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells.
Human T cells that express a T cell antigen receptor (TCR) containing γ-chain variable region 9 and δ-chain variable region 2 (Vγ9Vδ2) recognize phosphorylated prenyl metabolites as antigens in the presence of antigen-presenting cells but independently of major histocompatibility complex (MHC), the MHC class I-related molecule MR1 and antigen-presenting CD1 molecules. Here we used genetic approaches to identify the molecule that binds and presents phosphorylated antigens. We found that the butyrophilin BTN3A1 bound phosphorylated antigens with low affinity, at a stoichiometry of 1:1, and stimulated mouse T cells with transgenic expression of a human Vγ9Vδ2 TCR. The structures of the BTN3A1 distal domain in complex with host- or microbe-derived phosphorylated antigens had an immunoglobulin-like fold in which the antigens bound in a shallow pocket. Soluble Vγ9Vδ2 TCR interacted specifically with BTN3A1-antigen complexes. Accordingly, BTN3A1 represents an antigen-presenting molecule required for the activation of Vγ9Vδ2 T cells.


If we share data, will anyone use them? Data sharing and reuse in the long tail of science and technology.
Research on practices to share and reuse data will inform the design of infrastructure to support data collection, management, and discovery in the long tail of science and technology. These are research domains in which data tend to be local in character, minimally structured, and minimally documented. We report on a ten-year study of the Center for Embedded Network Sensing (CENS), a National Science Foundation Science and Technology Center. We found that CENS researchers are willing to share their data, but few are asked to do so, and in only a few domain areas do their funders or journals require them to deposit data. Few repositories exist to accept data in CENS research areas.. Data sharing tends to occur only through interpersonal exchanges. CENS researchers obtain data from repositories, and occasionally from registries and individuals, to provide context, calibration, or other forms of background for their studies. Neither CENS researchers nor those who request access to CENS data appear to use external data for primary research questions or for replication of studies. CENS researchers are willing to share data if they receive credit and retain first rights to publish their results. Practices of releasing, sharing, and reusing of data in CENS reaffirm the gift culture of scholarship, in which goods are bartered between trusted colleagues rather than treated as commodities.


Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer.
Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)) versus high-dose-rate endorectal brachytherapy (EBT). Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5-fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P < 0.001). There was a trend towards higher rate of pathologic CR for EBT (P = 0.06). Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P = 0.025). Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes.


SU-E-T-321: Dynamic Modulated Brachytherapy.
We introduced the concept of Dynamic Modulated Brachytherapy (DMBT) for rectal cancer, last year. To continue our work, we studied different shield designs and investigated the system's tolerance against systematic setup errors. As previously presented, our system uses a cylindrical tungsten shield to create a directional radiation profile, which is modulated through translation and rotation using a specialized robotic arm. We used Monte Carlo simulations and an in-house gradient projection optimization algorithm to look at key design parameters. First, we used ideal phantoms to study treatment quality from shield radii ranging 0.5-1.5 cm in 0.25 cm increments. Second, using 36 patient plans, the dependence on radial source position within the shield was studied. We also analyzed the tolerance of the system to systematic setup errors by simulating dose distributions from possible inaccuracies. These included translational and rotational errors as well as possible Ir-192 source misplacements by the afterloading system. Changes in shield radius followed steady patterns. Increasing the radius showed a consistent increase in dose conformality to the tumor volume and better sparing to surrounding tissues. However, there was also a linear increase in total dwell time. There was a trade off to changing the radial position of the source. As the source is brought away from the center, there is a decrease in conformality to the tumor volume, but sparing to healthy tissues was increased and there is a decrease in total dwell time. We found that any potential setup errors for our system, within anticipated margins, had negligible effects on the dose distributions (< 3% deviation). Various parameters for shield designs must be balanced for an effective DMBT application. It was found that the system is highly robust against systematic setup uncertainties.


Selection and characterization of DNA aptamers for detection of glutamate dehydrogenase from Clostridium difficile.
Rapid and accurate diagnosis of Clostridium difficile infections (CDI) is crucial for patient treatment, infection control and epidemiological monitoring. As an important antigen, glutamate dehydrogenase (GDH) has been proposed as a preliminary screening test target for CDI. However, current assays based on GDH activity or GDH immunoassays have suboptimal sensitivity and specificity. Herein, we describe the selection and characterization of single-stranded DNA aptamers that specifically target GDH. After 10 rounds of selection, high-throughput sequencing was used to identify enriched aptamer candidates. Of 10 candidates, three aptamers for GDH were identified. Gel shift assays showed that these aptamers exhibited low nanomolar affinities. One aptamer was optimized based on structural analysis and further engineered into a structure-switching fluorescence signaling aptamer, wherein desorption from reduced graphene oxide (RGO) upon binding of GDH led to an increase in fluorescence emission. This method allowed for quantitative detection of GDH with a detection limit of 1 nM, providing great potential for its further application in CDI diagnosis.


The nuclear envelope and gene organization in parasitic protozoa: Specializations associated with disease.
The parasitic protozoa Trypanosoma brucei and Plasmodium falciparum are lethal human parasites that have developed elegant strategies of immune evasion by antigenic variation. Despite the vast evolutionary distance between the two taxa, both parasites employ strict monoallelic expression of their membrane proteins, variant surface glycoproteins in Trypanosomes and the var, rif and stevor genes in Plasmodium, in order to evade their host's immune system. Additionally, both telomeric location and epigenetic controls are prominent features of these membrane proteins. As such, telomeres, chromatin structure and nuclear organization all contribute to control of gene expression and immune evasion. Here, we discuss the importance of epigenetics and sub-nuclear context for the survival of these disease-causing parasites.


Identification of a novel herpesvirus associated with a penile proliferative lesion in a beluga (Delphinapterus leucas).
The carcass of an adult male beluga (Delphinapterus leucas) was found beach cast in 2008 on the shore of the St. Lawrence Estuary at Rivière-Ouelle, Quebec, Canada. The carcass was transported to the Faculté de médecine vétérinaire of the Université de Montréal for postmortem examination. Aspiration pneumonia was the probable cause of death. Necropsy revealed a focal papilloma-like penile lesion, characterized by focal mucosal thickening with disorganization of the epithelial layers and lymphoplasmacytic infiltration. A pan-herpesvirus nested PCR assay on frozen tissue from the penile lesion was positive. The PCR product sequencing revealed a partial herpesvirus DNA polymerase (DPOL) gene sequence of 600 nucleotides. Its nearest nucleotide identity was with the partial DPOL gene of an alphaherpesvirus, bovine herpesvirus 5 (79.5% identity). It also shared high identity with several other marine mammal herpesviruses (50.2 to 77.3% identity). This new herpesvirus was tentatively named beluga whale herpesvirus (BWHV). Virus isolation was unsuccessful. The pathogenic potential of BWHV is unknown, but the evaluation of archived tissues suggests that the virus is endemic in the St. Lawrence Estuary beluga population.


Dysfunctional neural network of spatial working memory contributes to developmental dyscalculia.
The underlying neural mechanisms of developmental dyscalculia (DD) are still far from being clearly understood. Even the behavioral processes that generate or influence this heterogeneous disorder are a matter of controversy. To date, the few studies examining functional brain activation in children with DD mainly focus on number and counting related tasks, whereas studies on more general cognitive domains that are involved in arithmetical development, such as working memory are virtually absent. There are several studies showing a close relationship between DD and spatial working memory [Camos, V. (2008). Low working memory capacity impedes both efficiency and learning of number transcoding in children. Journal of Experimental Child Psychology, 99(1), 37-57; McLean, J. F., & Hitch, G. J. (1999). Working memory impairments in children with specific arithmetic learning difficulties. Journal of Experimental Child Psychology, 74(3), 240-260; Rosselli, M., Matute, E., Pinto, N., & Ardila, A. (2006). Memory abilities in children with subtypes of dyscalculia. Developmental Neuropsychology, 30(3), 801-818; Siegel, L. S., & Ryan, E. B. (1989). The development of working memory in normally achieving and subtypes of learning disabled children. Child Development, 60(4), 973-980]. The relationship between these two mechanisms is still matter of debate, but this study follows the assumption that poor spatial working memory capacity may hinder the acquisition of spatial number representations in children with DD [Geary, D. C. (1993). Mathematical disabilities: Cognitive, neuropsychological, and genetic components. Psychological Bulletin, 114(2), 345-362; von Aster, M., & Shalev, R. S. (2007). Number development and developmental dyscalculia. Developmental Medicine and Child Neurology, 49(11), 868-873]. Using functional MRI the current study compares brain activity associated with spatial working memory processes in 8-10-year-old children with DD and normally achieving controls. Both groups showed significant spatial working memory related activity in a network including occipital and parietal regions. Children with DD showed weaker neural activation compared to the control group during a spatial working memory task in the right intraparietal sulcus (IPS), the right insula and the right inferior frontal lobe. Performance tests outside the scanner showed impaired working memory proficiency in children with DD. Bringing behavioral performance and neural activity together we found significant correlations of right IPS activity with performance on the verbal digit span forward and the spatial Corsi Block Tapping test. Our findings demonstrate for the first time an involvement of spatial working memory processes in the neural underpinnings of DD. These poor spatial working memory processes may inhibit the formation of spatial number representations (mental numberline) as well as the storage and retrieval of arithmetical facts.


Metabolic rates, swimming capabilities, thermal niche and stress response of the lumpfish, Cyclopterus lumpus.
The lumpfish (Cyclopterus lumpus) is a semi-pelagic globiform teleost native to the North Atlantic with a ventral suction disc that allows for attachment onto surfaces. Some local populations are in decline and the species has recently become important in salmonid sea cages as cleaner fish. Little is known about the basal physiology of the lumpfish, and a characterization of thermal performance, aerobic capacity, swimming behaviour and stress response is therefore warranted. In the present study, swim tunnel respirometry was performed on lumpfish acclimated to 3, 9 or 15°C. Higher temperatures were also attempted, but at 18°C their behaviour became erratic and 15% of the fish died over 3 weeks of acclimation. Water current tolerance was assessed in two size classes (∼75 g and ∼300 g) both with and without the ability to voluntarily use the ventral suction disc. Lastly, blood samples were taken from resting, exhausted and recovered fish to assess haematological effects of exercise stress. Lumpfish had relatively low aerobic scopes that increased slightly with temperature. Critical swimming speed was poor, increasing within the tested temperatures from 1.3 to 1.7 body lengths s-1 in 300 g fish. They struggled to remain sucked onto surfaces at currents above 70-110 cm s-1, depending on size. Acute stress effects were modest or non-existent in terms of changes in cortisol, lactate, glucose, erythrocytes and ion balance. These results describe a typical sluggish and benthic species, which is contradictory to the pelagic nature of lumpfish in large parts of its lifecycle.


Evaluation of fracture resistance in aqueous environment under dynamic loading of lithium disilicate restorative systems for posterior applications. Part 2.
The goals of part 2 of the study presented here were 1) to assess whether there is a difference in failure mode of different thicknesses (2.0, 1.5, 1.0, and 0.5 mm) of anatomically standardized full contour monolithic lithium disilicate restorations for posterior teeth, and 2) to assess if there is a difference among various crown thicknesses when these restorations are subjected to dynamic load forces common for posterior teeth. Four groups (n = 10), each with a different thickness of anatomically appropriate all-ceramic crowns, were to be tested as established from the statistical analysis of the preliminary phase. Group 1: 2.0 mm; group 2: 1.5 mm; group 3: 1.0 mm; group 4: 0.5 mm. The specimens were adhesively luted to the corresponding die, and underwent dynamic cyclic loading (380 to 390 N) completely submerged in an aqueous environment until a failure was noted by graphic recording and continuous monitoring. There was a statistically significant difference of the fatigue cycles to failure among four groups (p < 0.001; Kruskal-Wallis test). The mean number of cycles to fail for 2.0 mm specimens was 17 times more than the mean number of cycles to fail for 1.0 mm specimens and 1.5 times more than the mean number of cycles to fail for 1.5 mm specimens. The 0.5 mm specimens failed with one cycle of loading. A qualitative characteristic noted among the 2.0 mm specimens was wear of the area of indenter contact followed by shearing of the material and/or crack propagation. Based on the findings of this study, it may be reasonable to consider a crown thickness of 1.5 mm or greater for clinical applications of milled monolithic lithium disilicate crowns for posterior single teeth.


Exploring Extracellular Vesicles Biogenesis in Hypothalamic Cells through a Heavy Isotope Pulse/Trace Proteomic Approach.
Studies have shown that the process of extracellular vesicles (EVs) secretion and lysosome status are linked. When the lysosome is under stress, the cells would secrete more EVs to maintain cellular homeostasis. However, the process that governs lysosomal activity and EVs secretion remains poorly defined and we postulated that certain proteins essential for EVs biogenesis are constantly synthesized and preferentially sorted to the EVs rather than the lysosome. A pulsed stable isotope labelling of amino acids in cell culture (pSILAC) based quantitative proteomics methodology was employed to study the preferential localization of the newly synthesized proteins into the EVs over lysosome in mHypoA 2/28 hypothalamic cell line. Through proteomic analysis, we found numerous newly synthesized lysosomal enzymes-such as the cathepsin proteins-that preferentially localize into the EVs over the lysosome. Chemical inhibition against cathepsin D promoted EVs secretion and a change in the EVs protein composition and therefore indicates its involvement in EVs biogenesis. In conclusion, we applied a heavy isotope pulse/trace proteomic approach to study EVs biogenesis in hypothalamic cells. The results demonstrated the regulation of EVs secretion by the cathepsin proteins that may serve as a potential therapeutic target for a range of neurological disorder associated with energy homeostasis.


Insula and Amygdala Atrophy Are Associated With Functional Impairment in Subjects With Presbycusis.
Hearing loss is an important risk factor for dementia. However, the mechanisms that relate these disorders are still unknown. As a proxy of this relationship, we studied the structural brain changes associated with functional impairment in activities of daily living in subjects with age related hearing loss, or presbycusis. One hundred eleven independent, non-demented subjects older than 65 years recruited in the ANDES cohort were evaluated using a combined approach including (i) audiological tests: hearing thresholds and cochlear function measured by pure tone averages and the distortion product otoacoustic emissions respectively; (ii) behavioral variables: cognitive, neuropsychiatric, and functional impairment in activities of daily living measured by validated questionnaires; and (iii) structural brain imaging-assessed by magnetic resonance imaging at 3 Tesla. The mean age of the recruited subjects (69 females) was 73.95 ± 5.47 years (mean ± SD) with an average educational level of 9.44 ± 4.2 years of schooling. According to the audiometric hearing thresholds and presence of otoacoustic emissions, we studied three groups: controls with normal hearing (n = 36), presbycusis with preserved cochlear function (n = 33), and presbycusis with cochlear dysfunction (n = 38). We found a significant association (R 2 D = 0.17) between the number of detected otoacoustic emissions and apathy symptoms. The presbycusis with cochlear dysfunction group had worse performance than controls in global cognition, language and executive functions, and severe apathy symptoms than the other groups. The neuropsychiatric symptoms and language deficits were the main determinants of functional impairment in both groups of subjects with presbycusis. Atrophy of insula, amygdala, and other temporal areas were related with functional impairment, apathy, and language deficits in the presbycusis with cochlear dysfunction group. We conclude that (i) the neuropsychiatric symptoms had a major effect on functional loss in subjects with presbycusis, (ii) cochlear dysfunction is relevant for the association between hearing loss and behavioral impairment, and (iii) atrophy of the insula and amygdala among other temporal areas are related with hearing loss and behavioral impairment.


Separation of peptides with polyionic nanosponges for MALDI-MS analysis.
A polymer brush consisting of 70% poly(N-isopropylacrylamide) (PNIPAAM) and 30% polymethacrylic acid (PMAA) was synthesized from gold substrates with a "grafting from" AIBN-type free-radical initiator. Fractionation of two peptides, bradykinin and buccalin, was accomplished in less than 120 s by placing a 30 pM (pH approximately 6.2) droplet onto the polymer brush substrate. The eluant containing the anionic buccalin is pipetted away for MALDI analysis while the cationic bradykinin adsorbed to the swollen anionic brush and was subsequently released by adding a droplet of formic acid to the substrate. This caused the brush to collapse and release the bradykinin, much like squeezing a sponge; these nanosponge substrates exhibited very high loading capacity (>2.0 mg/mL) compared to plasma-polymer-modified MALDI substrates. Ellipsometric measurements showed that complementary peptides adsorb rapidly while those of the same charge do not, and MALDI-MS analysis of the two fractions showed separation of both peptides. The adsorption of bradykinin was monitored over time, and 85% of the peptide had been adsorbed to the nanosponge in 1 min from a 0.5 mg/mL aqueous solution.


Idiotypic self binding of a dominant germline idiotype (T15). Autobody activity is affected by antibody valency.
We have previously described (1-3) an IgM antibody that binds to PC, expresses the T15 idiotype, and binds also to itself or T15 if insolubilized. Because of the simultaneous presence of complementary idiotopes and paratopes this type of antibody has been termed autobody. The self binding involves the antigen-binding site because the F(ab')2 fragment of T15, PC, and no other haptens inhibit the self binding. DNA sequence analysis of 11E7-1 using primer extension cDNA sequencing showed that the variable sequences of H and L chains of 11E7-1 are identical to the germline sequence of the prototype T15 idiotype. Furthermore, monomeric and dimeric T15 IgA were shown to bind to insolubilized T15 and other T15+ antibodies including 11E7-1. Thus, the self-binding activity is an inherent property of the T15 germline sequence. The self binding is highly dependent on the polymeric state of the binding antibody since the IgM pentamer of 11E7-1 is about three fold more effective than the T15 dimer and 50 times more than the T15 monomer. These data suggest that the self-binding activity of a germline-encoded idiotype may play an important role in the biology of its expression, and more specifically, may be responsible for the establishment of its dominant expression.


Forecasting risk of tick-borne encephalitis (TBE): using data from wildlife and climate to predict next year's number of human victims.
Over the past quarter century, the incidence of tick-borne encephalitis (TBE) has increased in most European nations. However, the number of humans stricken by the disease varies from year to year. A method for predicting major increases and decreases is needed. We assembled a 25-y database (1984-2008) of the number of human TBE victims and wildlife and climate data for the Stockholm region of Sweden, and used it to create easy-to-use mathematical models that predict increases and decreases in the number of humans stricken by TBE. Our best model, which uses December precipitation and mink (Neovison vison, formerly Mustela vison) bagging figures, successfully predicted every major increase or decrease in TBE during the past quarter century, with a minimum of false alarms. However, this model was not efficient in predicting small increases and decreases. Predictions from our models can be used to determine when preventive and adaptive programmes should be implemented. For example, in years when the frequency of TBE in humans is predicted to be high, vector control could be intensified where infested ticks have a higher probability of encountering humans, such as at playgrounds, bathing lakes, barbecue areas and camping facilities. Because our models use only wildlife and climate data, they can be used even when the human population is vaccinated. Another advantage is that because our models employ data from previously-established databases, no additional funding for surveillance is required.


Work-related and psychological determinants of multisite musculoskeletal pain.
Musculoskeletal pain is associated with occupational physical activities and psychosocial risk factors. We evaluated the relative importance of work-related and psychological determinants of the number of -anatomical sites affected by musculoskeletal pain in a cross-sectional survey. The survey focused on musculoskeletal pain in six body regions (low-back, neck, shoulder, elbow, wrist-hand, and knee) among 224 nurses, 200 office workers and 140 postal clerks in Crete, Greece (response rate 95%). Information was collected about demographic characteristics, occupational physical load, psycho-social aspects of work, perceptions about the causes of pain, mental health, somatization, and experience of pain in the past 12 months. We used Poisson regression to assess associations of risk factors with the number of painful anatomical sites and explored interactions using classification and regression trees (CART). Two-thirds of the study sample reported pain in >or=2 body sites during the past 12 months, and in 23%, >3 sites were affected. The number of painful anatomical sites was strongly related to both physical load at work and somatization (with relative risks increased 5-fold or more for frequent and disabling multisite pain) and was also significantly associated with work-related psychosocial factors and beliefs about work causation. The CART analysis suggested that somatization was the leading determinant of the number of painful body sites. In the population studied, pain at multiple anatomical sites was common and strongly associated with somatization, which may have a more important influence on multisite pain than pain that is limited to a single anatomical site.


Caveolin-1 is a modulator of fibroblast activation and a potential biomarker for gastric cancer.
Stromal fibroblasts play an important role in chronic cancer-related inflammation and the development as well as progression of malignant diseases. However, the difference and relationship between inflammation-associated fibroblasts (IAFs) and cancer-associated fibroblasts (CAFs) are poorly understood. In this study, gastric cancer-associated fibroblasts (GCAFs) and their corresponding inflammation-associated fibroblasts (GIAFs) were isolated from gastric cancer (GC) with chronic gastritis and cultured in vitro. These activated fibroblasts exhibited distinct secretion and tumor-promoting behaviors in vitro. Using proteomics and bioinformatics techniques, caveolin-1 (Cav-1) was identified as a major network-centric protein of a sub-network consisting of 121 differentially expressed proteins between GIAFs and GCAFs. Furthermore, immunohistochemistry in a GC cohort showed significant difference in Cav-1 expression score between GIAFs and GCAFs and among patients with different grades of chronic gastritis. Moreover, silencing of Cav-1 in GIAFs and GCAFs using small interfering RNA increased the production of pro-inflammatory and tumor-enhancing cytokines and chemokines in conditioned mediums that elevated cell proliferation and migration when added to GC cell lines AGS and MKN45 in vitro. In addition, Cav-1 status in GIAFs and GCAFs independently predicted the prognosis of GC. Our findings indicate that Cav-1 loss contributes to the distinct activation statuses of fibroblasts in GC microenvironment and gastritis mucosa, and Cav-1 expression in both GCAFs and GIAFs may serve as a potential biomarker for GC progression.


Striking sequence similarity in inter- and intra-specific comparisons of class I SLG alleles from Brassica oleracea and Brassica campestris: implications for the evolution and recognition mechanism.
Self-incompatibility in Brassica is controlled by a single multi-allelic locus (S locus), which contains at least two highly polymorphic genes expressed in the stigma: an S glycoprotein gene (SLG) and an S receptor kinase gene (SRK). The putative ligand-binding domain of SRK exhibits high homology to the secretory protein SLG, and it is believed that SLG and SRK form an active receptor kinase complex with a self-pollen ligand, which leads to the rejection of self-pollen. Here, we report 31 novel SLG sequences of Brassica oleracea and Brassica campestris. Sequence comparisons of a large number of SLG alleles and SLG-related genes revealed the following points. (i) The striking sequence similarity observed in an inter-specific comparison (95.6% identity between SLG14 of B. oleracea and SLG25 of B. campestris in deduced amino acid sequence) suggests that SLG diversification predates speciation. (ii) A perfect match of the sequences in hypervariable regions, which are thought to determine S specificity in an intra-specific comparison (SLG8 and SLG46 of B. campestris) and the observation that the hypervariable regions of SLG and SRK of the same S haplotype were not necessarily highly similar suggests that SLG and SRK bind different sites of the pollen ligand and that they together determine S specificity. (iii) Comparison of the hypervariable regions of SLG alleles suggests that intragenic recombination, together with point mutations, has contributed to the generation of the high level of sequence variation in SLG alleles. Models for the evolution of SLG/SRK are presented.


Leg lengthening and femoral-offset reduction after total hip arthroplasty: where is the problem - stem or cup positioning?
Background Restoration of femoral offset (FO) and leg length is an important goal in total hip arthroplasty (THA) as it improves functional outcome. Purpose To analyze whether the problem of postoperative leg lengthening and FO reduction is related to the femoral stem or acetabular cup positioning or both. Material and Methods Between September 2010 and April 2013, 172 patients with unilateral primary osteoarthritis treated with THA were included. Postoperative leg-length discrepancy (LLD) and global FO (summation of cup and FO) were measured by two observers using a standardized protocol for evaluation of antero-posterior plain hip radiographs. Patients with postoperative leg lengthening ≥10 mm (n = 41) or with reduced global FO >5 mm (n = 58) were further studied by comparing the stem and cup length of the operated side with the contralateral side in the lengthening group, and by comparing the stem and cup offset of the operated side with the contralateral side in the FO reduction group. We evaluated also the inter-observer and intra-observer reliability of the radiological measurements. Results Both observers found that leg lengthening was related to the stem positioning while FO reduction was related to the positioning of both the femoral stem and acetabular cup. Both inter-observer reliability and intra-observer reproducibility were moderate to excellent (intra-class correlation co-efficient, ICC ≥0.69). Conclusion Post THA leg lengthening was mainly caused by improper femoral stem positioning while global FO reduction resulted from improper positioning of both the femoral stem and the acetabular cup.


Effect of lifibrol on the metabolism of low density lipoproteins and cholesterol.
Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL-receptor pathway through a different mechanisms which remains to be determined.


Rhizosecretion of stele-synthesized glucosinolates and their catabolites requires GTR-mediated import in Arabidopsis.
Casparian strip-generated apoplastic barriers not only control the radial flow of both water and ions but may also constitute a hindrance for the rhizosecretion of stele-synthesized phytochemicals. Here, we establish root-synthesized glucosinolates (GLS) are in Arabidopsis as a model to study the transport routes of plant-derived metabolites from the site of synthesis to the rhizosphere. Analysing the expression of GLS synthetic genes in the root indicate that the stele is the major site for the synthesis of aliphatic GLS, whereas indole GLS can be synthesized in both the stele and the cortex. Sampling root exudates from the wild type and the double mutant of the GLS importers GTR1 and GTR2 show that GTR-mediated retention of stele-synthesized GLS is a prerequisite for the exudation of both intact GLS and their catabolites into the rhizosphere. The expression of the GTRs inside the stele, combined with the previous observation that GLS are exported from biosynthetic cells, suggest three possible routes of stele-synthesized aliphatic GLS after their synthesis: (i) GTR-dependent import to cells symplastically connected to the cortical cells and the rhizosphere; (ii) GTR-independent transport via the xylem to the shoot; and (iii) GTR-dependent import to GLS-degrading myrosin cells at the cortex. The study suggests a previously undiscovered role of the import process in the rhizosecretion of root-synthesized phytochemicals.


Overlooked non-motor symptoms in myasthenia gravis.
Patients with myasthenia gravis (MG) may have various non-motor symptoms in addition to fatigability and weakness of skeletal muscles. Thymomas contain abundant immature thymocytes and developing CD4 and CD8 T cells. Thymomas are found in 15-25% of patients with MG and are associated with severe symptoms. We suggest that non-motor symptoms are based on the autoimmune disorders probably owing to an abnormal T cell repertoire from thymomas. Using previously reported cases and cases from our multicentre cooperative study, we review the clinical characteristics of patients with thymoma-associated MG who have non-motor symptoms. CD8 T cell cytotoxicity against haematopoietic precursor cells in bone marrow and unidentified autoantigens in hair follicles lead to the development of pure red cell aplasia, immunodeficiency and alopecia areata. In contrast, neuromyotonia, limbic encephalitis, myocarditis and taste disorders are autoantibody-mediated disorders, as is MG. Autoantibodies to several types of voltage-gated potassium channels and the related molecules can evoke various neurological and cardiac disorders. About 25% of patients with thymoma-associated MG have at least one non-motor symptom. Non-motor symptoms affect many target organs and result in a broad spectrum of disease, ranging from the impairment of quality of life to lethal conditions. Since relatively little attention is paid to non-motor symptoms in patients with thymoma-associated MG, the symptoms may be overlooked by many physicians. Early diagnosis is important, since non-motor symptoms can be treatable. A complete understanding of non-motor symptoms is necessary for the management of patients with thymoma-associated MG.


Get real in individual participant data (IPD) meta-analysis: a review of the methodology.
Individual participant data (IPD) meta-analysis is an increasingly used approach for synthesizing and investigating treatment effect estimates. Over the past few years, numerous methods for conducting an IPD meta-analysis (IPD-MA) have been proposed, often making different assumptions and modeling choices while addressing a similar research question. We conducted a literature review to provide an overview of methods for performing an IPD-MA using evidence from clinical trials or non-randomized studies when investigating treatment efficacy. With this review, we aim to assist researchers in choosing the appropriate methods and provide recommendations on their implementation when planning and conducting an IPD-MA.


Priming tool actions: Are real objects more effective primes than pictures?
Humans are faster to grasp an object such as a tool if they have previewed the same object beforehand. This priming effect is strongest when actors gesture the use of the tool rather than simply move it, possibly because the previewed tool activates action-specific routines in dorsal-stream motor networks. Here, we examined whether real tools, which observers could physically act upon, serve as more potent primes than two-dimensional images of tools, which do not afford physical action. Participants were presented with a prime stimulus that could be either a real tool or a visually matched photograph of a tool. After a brief delay, participants interacted with a real tool target, either by 'grasping to move,' or 'grasping to use' it. The identities of the prime and target tools were either the same (congruent trials; e.g., spatula-spatula) or different (incongruent trials; e.g., whisk-spatula). As expected, participants were faster to initiate grasps during trials when they had to move the tool rather than gesture its use. Priming effects were observed for grasp-to-use, but not grasp-to-move, responses. Surprisingly, however, both pictures of tools and real tools primed action responses equally. Our results indicate that tool priming effects are driven by pictorial cues and their implied actions, even in the absence of volumetric cues that reflect the tangibility and affordances of the prime.


Effects of melatonin treatment in septic newborns.
Free radicals have been implicated in the pathogenesis of neonatal sepsis and its complications. This study was conducted to determine the changes in the clinical status and the serum levels of lipid peroxidation products [malondialdehyde (MDA) and 4-hydroxylalkenals (4-HDA)] in 10 septic newborns treated with the antioxidant melatonin given within the first 12 h after diagnosis. Ten other septic newborns in a comparable state were used as "septic" controls, while 10 healthy newborns served as normal controls. A total of 20 mg melatonin was administered orally in two doses of 10 mg each, with a 1-h interval. One blood sample was collected before melatonin administration and two additional blood samples (at 1 and 4 h) were collected after melatonin administration to assess serum levels of lipid peroxidation products. Serum MDA + 4-HDA concentrations in newborns with sepsis were significantly higher than those in healthy infants without sepsis; in contrast, in septic newborns treated with melatonin there was a significant reduction (p < 0.05) of MDA + 4-HDA to the levels in the normal controls at both 1 and 4 h (p < 0.05). Melatonin also improved the clinical outcome of the septic newborns as judged by measurement of sepsis-related serum parameters after 24 and 48 h. Three of 10 septic children who were not treated with melatonin died within 72 h after diagnosis of sepsis; none of the 10 septic newborns treated with melatonin died. To our knowledge, this is the first study where melatonin was given to human newborns.


Safety evaluation of repeated intravenous infusion of sinoporphyrin with and without PDT in rats.
Photodynamic therapy (PDT) is a promising antineoplastic modality in the oncology field. We assessed the safety of repeated intravenous administrations of sinoporphyrin, a porphyrin derivative, with and without illumination in rats. Toxicokinetic studies of single and multiple administrations of sinoporphyrin were also carried out. Sprague-Dawley rats were randomly assigned to the dark-toxicity and PDT groups. Animals in the dark toxicity group received an i.v. infusion of sinoporphyrin at 3 doses: 2 mg kg-1, 6 mg kg-1, and 18 mg kg-1. The PDT group included 2 doses of sinoporphyrin (2 mg kg-1 and 18 mg kg-1), and the rats received 60 J of 630 nm laser illumination 24 h after photosensitizer infusion. The treatments were repeated every 7 days for 5 cycles and were followed by a 14-day recovery period. Systematic analyses were conducted at the end of treatment and recovery periods. Blood samples were obtained 5 min, 30 min, 2 h, 8 h, 24 h, 48 h, 72 h, and 96 h after the first and fifth treatments for toxicokinetic studies. Sinoporphyrin-PDT led to the death of one out of 270 rats; the dead animal had been treated with 18 mg kg-1 sinoporphyrin and died at the end of the fifth PDT treatment. Liver injury, the primary toxicity observed in the study, was identified using biochemical tests, necropsy, and histopathology. Elevated white blood cell and neutrophil counts were found in the rats in both the dark toxicity and PDT groups. Skin lesions at the illumination site were obvious in the PDT group. Pigment deposits were detected in multiple organs such as the liver, spleen, lymph nodes, and ovaries in the 6 mg kg-1 and 18 mg kg-1 groups. No other abnormalities were observed. The toxicokinetic parameters of single and multiple sinoporphyrin administrations were calculated and compared. Repeated sinoporphyrin administrations both alone and in combination with laser illumination were tolerable, and all toxicities were transient. The no observed adverse effect level (NOAEL) for repeated sinoporphyrin administration and sinoporphyrin-PDT was 6 mg kg-1 and 2 mg kg-1, respectively. Further studies are warranted.


Teaching acceptance and mindfulness to improve the lives of the obese: a preliminary test of a theoretical model.
Obesity is a growing epidemic. Weight control interventions can achieve weight loss, but most is regained over time. Stigma and low quality of life are significant problems that are rarely targeted. A new model aimed at reducing avoidant behavior and increasing psychological flexibility, has shown to be relevant in the treatment of other chronic health problems and is worth examining for improving the lives of obese persons. Patients who had completed at least 6 months of a weight loss program (N = 84) were randomly assigned to receive a 1-day, mindfulness and acceptance-based workshop targeting obesity-related stigma and psychological distress or be placed on a waiting list. At a 3-month follow-up, workshop participants showed greater improvements in obesity-related stigma, quality of life, psychological distress, and body mass, as well as improvements in distress tolerance, and both general and weight-specific acceptance and psychological flexibility. Effects on distress, stigma, and quality of life were above and beyond the effects due to improved weight control. Mediational analyses indicated that changes in weight-specific acceptance coping and psychological flexibility mediated changes in outcomes. Results provide preliminary support for the role of acceptance and mindfulness in improving the quality of life of obese individuals while simultaneously augmenting their weight control efforts.


Extraction and quantification of polyphenols from kinnow (Citrus reticulate L.) peel using ultrasound and maceration techniques.
An investigation was carried out to extract polyphenols from the peel of kinnow (Citrus reticulate L.) by maceration and ultrasound-assisted extraction (UAE) techniques. The antioxidant potential of these polyphenols was evaluated using ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and superoxide radical scavenging assays; and their antimicrobial activity was assessed against bacterial strains Staphyloccoccus aureus, Bacillus cereus, and Salmonella typhimurium. The highest extraction yield was obtained through the solvent ethanol at 80% concentration level, whereas UAE was a more efficient technique and yielded comparatively higher polyphenol contents than maceration. Maximum polyphenols were extracted with 80% methanol [32.48 mg gallic acid equivalent (GAE)/g extract] using UAE, whereas minimum phenolics (8.64 mg GAE/g extract) were obtained with 80% ethyl acetate through the maceration technique. Elevated antioxidant activity of kinnow peel extracts was exhibited in three antioxidant assays, where 80% methanolic extracts showed the highest antioxidant activity (27.67±1.11mM/100 g for FRAP) and the highest scavenging activity, 72.83±0.65% and 64.80±0.91% for DPPH and superoxide anion radical assays, respectively. Strong correlations between total polyphenols and antioxidant activity were recorded. Eleven phenolic compounds-including five phenolic acids and six flavonoids-were identified and quantified by high performance liquid chromatography. Ferulic acid and hesperidin were the most abundant compounds whereas caffeic acid was the least abundant phenolic compound in kinnow peel extracts. Maximum inhibition zone was recorded against S. aureus (16.00±0.58 mm) whereas minimum inhibition zone was noted against S. typhimurium (9.00±1.16 mm). It was concluded that kinnow mandarin peels, being a potential source of phenolic compounds with antioxidant and antimicrobial properties, may be used as an ingredient for the preparation of functional foods.


Validation of a method for measuring the short-term rate of urea synthesis after an amino acid load.
The response of the plasma concentration of urea to the oral and intravenous administration of alanine was studied in healthy adult humans. The instantaneous rate of urea synthesis was calculated by using a model-dependent procedure. The errors in this procedure were calculated and it was shown that analytical precision and sampling frequency, and the estimates of the distribution volume and elimination fluxes, were adequate to determine the synthesis parameters. A direct test of the compartmental model was made by the intravenous injection of exogenous urea. The one-compartment model with first-order elimination gave a good fit to the experimental results at times greater than 8 min after the injection. Both oral and intravenous loads of alanine had dose-dependent effects on the rate of urea synthesis. There was no evidence of a limit to the maximum possible rate of urea synthesis in these experiments and the values obtained were similar to published results for different stimuli and methods of measurement. The rate of synthesis increased more rapidly after intravenous loads and subjective side-effects were less severe. The intravenous administration of alanine appears to be a suitable stimulus for urea synthesis.


Acute Dehydration Impairs Performance and Physiological Responses in Highly Trained Judo Athletes.
Background: The present study investigated highly trained male judo athletes and how a 5% body mass dehydration affects their judo-specific performance and physiological responses. Methods: Nine highly trained international-level male judo athletes who are weight-cyclers voluntarily participated in the study. The study had a controlled crossover design in nature. Athletes completed three sessions, including a familiarisation session and two experimental sessions (dehydration (DEHY) and control (CON)) with judo-specific tests, including maximal handgrip strength test (HGS), judogi grip strength tests (JGST), and the Special Judo Fitness Test (SJFT). Results: Intergroup analysis revealed a significant increase in urine specific gravity (USG) and decreased body mass following DEHY condition compared to CON. Furthermore, significant decreases were determined in HGS, JGSTs, and a number of throws in the first and third series of SJFTs, as well as higher heart rate (HR) responses in the second and third series of SJFT and worse SJFT index in DEHY condition (p < 0.05). Conclusions: We concluded that 5% dehydration of body mass led to impairment in dynamic and isometric strength in upper limbs and in judo-specific performance, as well as elevated HR during the SJFT.


An Introduced Crop Plant Is Driving Diversification of the Virulent Bacterial Pathogen Erwinia tracheiphila.
Erwinia tracheiphila is the causal agent of bacterial wilt of cucurbits, an economically important phytopathogen affecting an economically important phytopathogen affecting few cultivated Cucurbitaceae few cultivated Cucurbitaceae host plant species in temperate eastern North America. However, essentially nothing is known about E. tracheiphila population structure or genetic diversity. To address this shortcoming, a representative collection of 88 E. tracheiphila isolates was gathered from throughout its geographic range, and their genomes were sequenced. Phylogenomic analysis revealed three genetic clusters with distinct hrpT3SS virulence gene repertoires, host plant association patterns, and geographic distributions. Low genetic heterogeneity within each cluster suggests a recent population bottleneck followed by population expansion. We showed that in the field and greenhouse, cucumber (Cucumis sativus), which was introduced to North America by early Spanish conquistadors, is the most susceptible host plant species and the only species susceptible to isolates from all three lineages. The establishment of large agricultural populations of highly susceptible C. sativus in temperate eastern North America may have facilitated the original emergence of E. tracheiphila into cucurbit agroecosystems, and this introduced plant species may now be acting as a highly susceptible reservoir host. Our findings have broad implications for agricultural sustainability by drawing attention to how worldwide crop plant movement, agricultural intensification, and locally unique environments may affect the emergence, evolution, and epidemic persistence of virulent microbial pathogens.IMPORTANCEErwinia tracheiphila is a virulent phytopathogen that infects two genera of cucurbit crop plants, Cucurbita spp. (pumpkin and squash) and Cucumis spp. (muskmelon and cucumber). One of the unusual ecological traits of this pathogen is that it is limited to temperate eastern North America. Here, we complete the first large-scale sequencing of an E. tracheiphila isolate collection. From phylogenomic, comparative genomic, and empirical analyses, we find that introduced Cucumis spp. crop plants are driving the diversification of E. tracheiphila into multiple lineages. Together, the results from this study show that locally unique biotic (plant population) and abiotic (climate) conditions can drive the evolutionary trajectories of locally endemic pathogens in unexpected ways.


Teat lesions and their relationship to intramammary infections on small-scale dairy farms in Kiambu district in Kenya.
Mammary gland quarters of 139 lactating dairy cows from small-scale dairy herds were examined visually and by palpation for teat lesions and by California mastitis test (CMT) and bacterial culture for subclinical mastitis. Teat lesions were observed in 97 teats. These included teat chaps (39.2%), teat papillomas (23.7%), teat erosions (22.7%), teat fistulae (5.1%), inverted teats (5.1%) and blocked teats (4.2%). According to the CMT, the prevalence of subclinical mastitis was 33.4% in all the mammary gland quarters, 71.0% in quarters with teat lesions and 24.5% in quarters without teat lesions. There was a significant (P < 0.01) association between teat lesions and the prevalence of subclinical mastitis. The mammary gland quarters with teat lesions were 7.2 times more likely to have a positive CMT (P < 0.01) and 5.6 times more likely to have bacterial organisms (P < 0.01) isolated from them than those without any teat lesions. The bacterial organisms most frequently isolated from the CMT-positive milk samples from both the mammary gland quarters with teat lesions and those without teat lesions were Staphylococcus aureus (50.0%), Streptococcus spp. (34.8%) and Arcanobacterium pyogenes (6.2%).


Early life child exposure and the risk of multiple sclerosis: a population based study.
The precise aetiology of multiple sclerosis (MS) is yet to be conclusively determined, but both genes and environment and interactions thereof are important. It has been suggested that early life child exposure influences MS susceptibility. Here, in a population-based cohort, we investigated whether infant day care attendance influences the subsequent risk to develop MS. We identified 379 MS index cases and 101 spousal controls, all of whom were a single child (i.e. they had no biological sibs, half-sibs, step-sibs, adopted sibs) from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of infant day care attendance was compared for index cases and controls and the results were not statistically significant. Exposure to other infants during early childhood thus does not appear to be a risk factor for MS.


Development of a visio-haptic integrated dental training simulation system.
The use of haptic devices in the medical field has become widespread in the last decade. In this study, a visio-haptic dental training system is developed using haptic and stereoscopic devices. Several advantages are offered by such a simulation system, including effective learning without any fear of making mistakes on a patient, possibility of repeating various dental operations, ease of evaluating student performance, and low-cost dental training even without an instructor. In this study, the biomechanical properties of enamel, dentin, pulp, and caries were modeled, and the parameters were fine-tuned to provide more realistic haptic sensations. Maxillary and mandibular dental arches and various dental instruments such as mouth mirror, probe, and dental drills were modeled in a 3D virtual environment. Probing and cavity preparation on teeth were implemented in the training system. Various graphical rendering methods (Surface Rendering in CPU, Iso-Surface Rendering, and Ray-Casting in GPU) were implemented and compared in performance. The implementation details and the software structure used are described. Finally, detailed performance tests by a group of dentists are conducted, and the results of these tests are presented. The performance tests found that dentists have a strong motivation to use the system and that in the aspects of usability, clarity, effectiveness, help/support provided, and satisfaction, the users' responses were above average.


Ultrasound-based testing of tendon mechanical properties: a critical evaluation.
In the past 20 years, the use of ultrasound-based methods has become a standard approach to measure tendon mechanical properties in vivo. Yet the multitude of methodological approaches adopted by various research groups probably contribute to the large variability of reported values. The technique of obtaining and relating tendon deformation to tensile force in vivo has been applied differently, depending on practical constraints or scientific points of view. Divergence can be seen in 1) methodological considerations, such as the choice of anatomical features to scan and to track, force measurements, or signal synchronization; and 2) in physiological considerations related to the viscoelastic behavior or length measurements of tendons. Hence, the purpose of the present review is to assess and discuss the physiological and technical aspects connected to in vivo testing of tendon mechanical properties. In doing so, our aim is to provide the reader with a qualitative analysis of ultrasound-based techniques. Finally, a list of recommendations is proposed for a number of selected issues.


The fetal origins of hypertension: a systematic review and meta-analysis of the evidence from animal experiments of maternal undernutrition.
Numerous experiments in animals have been performed to investigate the effect of prenatal undernutrition on the development of hypertension in later life, with inconclusive results. We systematically reviewed animal studies examining the effects of maternal undernutrition on SBP, DBP, and mean arterial blood pressure (BP) in offspring. A search was performed in Medline and Embase to identify articles that reported on maternal undernutrition and hypertension in experimental animal studies. Summary estimates of the effect of undernutrition on SBP, DBP, and mean arterial BP were obtained through meta-analysis. Of the 6151 articles identified, 194 were considered eligible after screening titles and abstracts. After detailed evaluation, 101 met the inclusion criteria and were included in the review. Both maternal general and protein undernutrition increased SBP [general undernutrition: 14.5 mmHg, 95% confidence interval (CI) 10.8-18.3; protein undernutrition: 18.9 mmHg, 95% CI 16.1-21.8] and mean arterial BP (general undernutrition: 5.0 mmHg, 95% CI 1.4-8.6; protein undernutrition: 10.5 mmHg, 95% CI 6.7-14.2). There was substantial heterogeneity in the results. DBP was increased by protein undernutrition (9.5 mmHg, 95% CI 2.6-16.3), whereas general undernutrition had no significant effect. The results of this meta-analysis generally support the view that in animals, maternal undernutrition--both general and protein--results in increased SBP and mean arterial BP. DBP was only increased after protein undernutrition. The results depended strongly on the applied measurement technique and animal model.


Simultaneous 19F-1H medium resolution NMR spectroscopy for online reaction monitoring.
Medium resolution nuclear magnetic resonance (MR-NMR) spectroscopy is currently a fast developing field, which has an enormous potential to become an important analytical tool for reaction monitoring, in hyphenated techniques, and for systematic investigations of complex mixtures. The recent developments of innovative MR-NMR spectrometers are therefore remarkable due to their possible applications in quality control, education, and process monitoring. MR-NMR spectroscopy can beneficially be applied for fast, non-invasive, and volume integrating analyses under rough environmental conditions. Within this study, a simple 1/16″ fluorinated ethylene propylene (FEP) tube with an ID of 0.04″ (1.02mm) was used as a flow cell in combination with a 5mm glass Dewar tube inserted into a benchtop MR-NMR spectrometer with a 1H Larmor frequency of 43.32MHz and 40.68MHz for 19F. For the first time, quasi-simultaneous proton and fluorine NMR spectra were recorded with a series of alternating 19F and 1H single scan spectra along the reaction time coordinate of a homogeneously catalysed esterification model reaction containing fluorinated compounds. The results were compared to quantitative NMR spectra from a hyphenated 500MHz online NMR instrument for validation. Automation of handling, pre-processing, and analysis of NMR data becomes increasingly important for process monitoring applications of online NMR spectroscopy and for its technical and practical acceptance. Thus, NMR spectra were automatically baseline corrected and phased using the minimum entropy method. Data analysis schemes were designed such that they are based on simple direct integration or first principle line fitting, with the aim that the analysis directly revealed molar concentrations from the spectra. Finally, the performance of 1/16″ FEP tube set-up with an ID of 1.02mm was characterised regarding the limit of detection (LOQ (1H)=0.335molL-1 and LOQ (19F)=0.130molL-1 for trifluoroethanol in D2O (single scan)) and maximum quantitative flow rates up to 0.3mLmin-1. Thus, a series of single scan 19F and 1H NMR spectra acquired with this simple set-up already presents a valuable basis for quantitative reaction monitoring.


Ecological opportunity in adaptive radiation of Galápagos endemic land snails.
The classic evolutionary hypothesis of ecological opportunity proposes that both heterogeneity of resources and freedom from enemies promote phenotypic divergence as a response to increased niche availability. Although phenotypic divergence and speciation have often been inferred to be the primary consequences of the release from competition or predation that accompanies a shift to a new adaptive zone, increased phenotypic variation within species is expected to represent the first stage resulting from such a shift. Using measures of intraspecific morphological variation of 30 species of Galápagos endemic land snails in a phylogenetically controlled framework, we show that the number of local congeners and the number of local plant species are associated with lower and higher intraspecific phenotypic variation, respectively. In this clade, ecological opportunity thus explicitly links the role of competition from congeners and the heterogeneity of resources to the extent of intraspecific phenotypic divergence as adaptive radiation proceeds.


Auditory event-related potentials (ERPs) and mismatch negativity (MMN) in healthy children and those with attention-deficit or tourette/tic symptoms.
The study compares 5 auditory event-related potential (ERP) components (P1 to P3) after 3 tones differing in pitch and rarity, and contrasts the mismatch negativity (MMN) between them in 12 children with attention-deficit hyperactivity disorder (ADHD; mean 10.2 years of age), 12 healthy controls pairwise matched for age (controls), and 10 with Chronic Tic or Tourette Syndrome (TS). Topographic recordings were derived from 19 scalp electrodes. Four major effects are reported. (a) Shorter latencies in ADHD patients were evident as early as 100 ms. (b) Both ADHD and TS groups showed very large P2 components where the maxima were shifted anteriorly. The differences in the later potentials were of a topographical nature. (c) Frontal MMN was non-significantly larger in the ADHD group but normalized data showed a left rather than a right frontal bias as in control subjects. Maxima for TS were usually posterior. (d) ADHD patients did not show the usual right-biased P3 asymmetry nor the frontal versus parietal P3 latency difference. From these results it is suggested that ADHD patients process perceptual information faster from an early stage (N1). Further, along with the TS group, ADHD patients showed an unusually marked inhibitory phase in processing (P2), interpreted as a reduction of the normal controls on further processing. Later indices of stimulus processing (N2-P3) showed a frontal impairment in TS and a right hemisphere impairment in ADHD patients. These are interpreted in terms of the difficulties in sustaining attention experienced by both ADHD and TS patients.


The spread of sleep loss influences drug use in adolescent social networks.
Troubled sleep is a commonly cited consequence of adolescent drug use, but it has rarely been studied as a cause. Nor have there been any studies of the extent to which sleep behavior can spread in social networks from person to person to person. Here we map the social networks of 8,349 adolescents in order to study how sleep behavior spreads, how drug use behavior spreads, and how a friend's sleep behavior influences one's own drug use. We find clusters of poor sleep behavior and drug use that extend up to four degrees of separation (to one's friends' friends' friends' friends) in the social network. Prospective regression models show that being central in the network negatively influences future sleep outcomes, but not vice versa. Moreover, if a friend sleeps </=7 hours, it increases the likelihood a person sleeps < or =7 hours by 11%. If a friend uses marijuana, it increases the likelihood of marijuana use by 110%. Finally, the likelihood that an individual uses drugs increases by 19% when a friend sleeps < or =7 hours, and a mediation analysis shows that 20% of this effect results from the spread of sleep behavior from one person to another. This is the first study to suggest that the spread of one behavior in social networks influences the spread of another. The results indicate that interventions should focus on healthy sleep to prevent drug use and targeting specific individuals may improve outcomes across the entire social network.


Use of rainfall and sea surface temperature monitoring for malaria early warning in Botswana.
Improved prediction, prevention, and control of epidemics is a key technical element of the Roll Back Malaria partnership. We report a methodology for assessing the importance of climate as a driver of inter-annual variability in malaria in Botswana, and provide the evidence base for inclusion of climate information in a national malaria early warning system. The relationships of variability in rainfall and sea surface temperatures (SSTs) to malaria incidence are assessed at the national level after removing the impact of non-climatic trends and a major policy intervention. Variability in rainfall totals for the period December-February accounts for more than two-thirds of the inter-annual variability in standardized malaria incidence in Botswana (January-May). Both rainfall and annual malaria anomalies in December-February are significantly related to SSTs in the eastern Pacific, suggesting they may be predictable months in advance using seasonal climate forecasting methodologies.


Quality of referrals and guideline compliance for time to consultation at an acute neurovascular clinic.
The Age, Blood pressure, Clinical features, Duration of symptoms, Diabetes (ABCD2) score can be used to predict early recurrent stroke risk following Transient ischemic attack (TIA). Given that recurrent stroke risk can be as high as 20% in the first week, international guidelines recommend "high-risk" TIAs (ABCD2 >3) be seen by specialist services such as dedicated acute neurovascular clinics within 24 hours. The goal of this study was to examine the associations of both quality of referrals to a specialist acute clinic and of "guideline congruence" of time-to-clinic consultation after TIA/minor stroke. We hypothesized high-quality referrals containing key clinical elements would be associated with greater guideline congruence. A retrospective analysis of referrals to an acute neurovascular clinic within a tertiary care hospital of consecutive patients with TIA/minor stroke. Quality of general practitioner and emergency department referrals was defined on the basis of information content enabling ABCD2-based risk stratification by the clinic triage service. Time-to-clinic consultation was used to define "guideline congruence." Referrals of 148 consecutive eligible patients were reviewed. Sixty-six percent of cases were subsequently neurologist-diagnosed as TIA or minor stroke. Seventy-nine percent were referred by general practitioners. Fifty-three percent of referrals were of high quality, but quality was not associated with guideline congruence. Of the high-risk patients, only 3.6% were seen at the clinic within 24 hours of index event and 31.3% within 24 hours of referral. Current guidelines are pathophysiologically logical and evidence based, but are difficult to implement. Improving quality of primary-secondary communication by improved referral quality is unlikely to improve guideline compliance. Alternative strategies are needed to reduce recurrent stroke risk after TIA/minor stroke.


Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737.
Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet Pim kinase inhibitors seem to have only limited effects on prostate cancer cell survival. Because overexpression of Bcl-2 family members are implicated in chemotherapeutic resistance in prostate cancer, we investigated the cooperative effects of Pim kinase inhibition with ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5'-cap dependent translation and decreasing protein half life. In addition, Pim inhibition transcriptionally increased levels of the BH3 protein Noxa by activating the unfolded protein response (UPR), lead to eIF-2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 protein activity. Notably, these specific protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies.


MicroRNAs dysregulated in breast cancer preferentially target key oncogenic pathways.
MicroRNA (miRNA) dysregulation has been associated with numerous cancers including breast cancer. The dysregulation of miRNAs in cancer has been shown to perturb various pathways, with oncogenic effects. Here we investigate the relationship between dysregulated miRNAs and pathways involved in breast cancer by integrating miRNA and mRNA expression data. From a list of dysregulated miRNAs, we started by selecting the subset that appear to be regulating genes differentially expressed in breast cancer vs. normal tissue. Individually and as a group, this subset was found to target several canonical oncogenic pathways including the p53 signalling pathway, MAPK signalling pathway, TGFβ signalling pathway, focal adhesion and cell cycle progression. These results suggest that the dysregulation of miRNAs in breast cancer not only results in widespread changes to gene expression, but also the dysregulation of key oncogenic pathways.


Unconstrained Pose-Invariant Face Recognition Using 3D Generic Elastic Models.
Classical face recognition techniques have been successful at operating under well-controlled conditions; however, they have difficulty in robustly performing recognition in uncontrolled real-world scenarios where variations in pose, illumination, and expression are encountered. In this paper, we propose a new method for real-world unconstrained pose-invariant face recognition. We first construct a 3D model for each subject in our database using only a single 2D image by applying the 3D Generic Elastic Model (3D GEM) approach. These 3D models comprise an intermediate gallery database from which novel 2D pose views are synthesized for matching. Before matching, an initial estimate of the pose of the test query is obtained using a linear regression approach based on automatic facial landmark annotation. Each 3D model is subsequently rendered at different poses within a limited search space about the estimated pose, and the resulting images are matched against the test query. Finally, we compute the distances between the synthesized images and test query by using a simple normalized correlation matcher to show the effectiveness of our pose synthesis method to real-world data. We present convincing results on challenging data sets and video sequences demonstrating high recognition accuracy under controlled as well as unseen, uncontrolled real-world scenarios using a fast implementation.


Vasorelaxant effect of resin-based, single-bottle dentin bonding systems.
Single-bottle dentin bonding systems are currently in wide use. Because these materials are sometimes inadvertently placed on microscopic pulp exposures while at other times deliberately on frank exposures, their effects on pulpal soft tissues need to be evaluated. The present study assessed the vascular effects of 3M Single Bond (3MSB) and Prime & Bond NT (PBNT), using rat aortic ring preparations. It is hypothesized that these bonding agents induce relaxation of these preparations. Both 3MSB and PBNT caused endothelium-dependent and -independent relaxations in a concentration-dependent manner. The endothelium-dependent relaxation was associated with the release of nitric oxide. However, the responses to both agents did not involve the generation of prostanoids or KATP channel activation. At relatively low concentrations, the responses of endothelium-denuded tissues to 3MSB were greater than those to PBNT, indicating certain differences in the vascular action between these products. The data suggest that 3MSB and PBNT interfere with vascular function by causing vasorelaxation via mechanisms occurring in the smooth muscle and endothelium, including the release of nitric oxide. Among others, this effect may promote bleeding if these adhesives are placed on pulp exposures.