A critical meta-analysis of lens model studies in human judgment and decision-making.
Achieving accurate judgment ('judgmental achievement') is of utmost importance in daily life across multiple domains. The lens model and the lens model equation provide useful frameworks for modeling components of judgmental achievement and for creating tools to help decision makers (e.g., physicians, teachers) reach better judgments (e.g., a correct diagnosis, an accurate estimation of intelligence). Previous meta-analyses of judgment and decision-making studies have attempted to evaluate overall judgmental achievement and have provided the basis for evaluating the success of bootstrapping (i.e., replacing judges by linear models that guide decision making). However, previous meta-analyses have failed to appropriately correct for a number of study design artifacts (e.g., measurement error, dichotomization), which may have potentially biased estimations (e.g., of the variability between studies) and led to erroneous interpretations (e.g., with regards to moderator variables). In the current study we therefore conduct the first psychometric meta-analysis of judgmental achievement studies that corrects for a number of study design artifacts. We identified 31 lens model studies (N = 1,151, k = 49) that met our inclusion criteria. We evaluated overall judgmental achievement as well as whether judgmental achievement depended on decision domain (e.g., medicine, education) and/or the level of expertise (expert vs. novice). We also evaluated whether using corrected estimates affected conclusions with regards to the success of bootstrapping with psychometrically-corrected models. Further, we introduce a new psychometric trim-and-fill method to estimate the effect sizes of potentially missing studies correct psychometric meta-analyses for effects of publication bias. Comparison of the results of the psychometric meta-analysis with the results of a traditional meta-analysis (which only corrected for sampling error) indicated that artifact correction leads to a) an increase in values of the lens model components, b) reduced heterogeneity between studies, and c) increases the success of bootstrapping. We argue that psychometric meta-analysis is useful for accurately evaluating human judgment and show the success of bootstrapping.


Post-protein binding metal-mediated coupling of an acridine orange-based fluorophore.
The HEW lysozyme (Lys) and the fac-[Re(CO)(3)(H(2)O)(3)](+) complex (1) are used as a simple model system for the description of a new approach to the labelling polypeptides with fluorescent tags. The strategy takes advantage of the reaction of an acridine orange-based fluorophore (AO) with the non-native metal fragment 1 hybridized on the enzyme. A synthetic methodology for the quantitative metallation of the protein is first described and it is then shown that the exogenous metal complex can be exploited for the coupling of the fluorescent probe. All Lys-derived species were characterized by various spectroscopic techniques. It is shown that the approach does not significantly alter the activity of the final fluorescent metallo-protein conjugate (Lys2). The accumulation of Lys2 on Micrococcus lysodeikticus bacteria was observed via confocal laser scanning microscopy.


Rapid preclinical detection of sheeppox virus by a real-time PCR assay.
Sheeppox virus (SPPV) is a member of the Capripoxvirus (CaPV) genus of the Poxviridae family. Members of this genus, which also include goatpox and lumpy skin disease viruses, cause economically significant disease in sheep, goats, and cattle. A rapid diagnostic assay for CaPV would be useful for disease surveillance as well as for detection of CaPV in clinical samples and for outbreak management. Here we describe a fluorogenic probe hydrolysis (TaqMan) PCR assay designed for rapid detection of CaPV and tested on sheep experimentally infected with a virulent strain of SPPV. This assay can detect SPPV in buffy coats, nasal swabs, oral swabs, scabs, and skin lesions as well as in lung and lymph nodes collected at necropsy. This single-tube diagnostic assay can be performed in 2 h or less and can detect viral DNA in preclinical, clinical, and postmortem samples.


CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome.
Adrenocorticotropic hormone (ACTH)-independent hypercortisolism accounts for 15%-20% of cases of Cushing syndrome and always arises from primary adrenal disease. Computed tomographic (CT) and magnetic resonance (MR) imaging findings in 37 patients with primary adrenal Cushing syndrome were analyzed and correlated with pathologic findings. Hyperfunctioning adenomas (n = 24), together with functioning carcinomas (n = 10), accounted for 92% of cases. Adenomas had a significantly smaller mean size (3.5 vs 14.5 cm) and lower mean unenhanced CT attenuation value (11 vs 28 HU) than did carcinomas. The presence of necrosis, hemorrhage, and calcification favored a diagnosis of carcinoma. Six of 10 carcinoma patients had metastases at presentation. Two adenomas were seen within a myelolipoma, which was recognized at both CT and MR imaging due to its fat content, and two adenomas were of uncertain malignant potential. Bilateral disease--primary pigmented nodular adrenal dysplasia (PPNAD) (n = 2) and ACTH-independent macronodular adrenal hyperplasia (AIMAH) (n = 1)--had characteristic imaging features. In PPNAD, multiple tiny (2-5-mm) nodules were visible bilaterally, with no overall glandular enlargement and normal intervening adrenal tissue. In AIMAH, both glands were grossly enlarged and contained nodules up to 3 cm in diameter. Familiarity with the range of imaging appearances of the adrenal glands in primary adrenal Cushing syndrome may help establish the underlying diagnosis.


Chromosomes of Asian cyprinid fishes: cytogenetic analysis of two representatives of small paleotetraploid tribe Probarbini.
Polyploidy, although still poorly explored, represents an important evolutionary event in several cyprinid clades. Herein, Catlocarpio siamensis and Probarbus jullieni - representatives of the paleotetraploid tribe Probarbini, were characterized both by conventional and molecular cytogenetic methods. Alike most other paleotetraploid cyprinids (with 2n = 100), both species studied here shared 2n = 98 but differed in karyotypes: C. siamensis displayed 18m + 34sm + 46st/a; NF = 150, while P. jullieni exhibited 26m + 14sm + 58st/a; NF = 138. Fluorescence in situ hybridization (FISH) with rDNA probes revealed two (5S) and eight (18S) signals in C. siamensis, respectively, and six signals for both probes in P. jullieni. FISH with microsatellite motifs evidenced substantial genomic divergence between both species. The almost doubled size of the chromosome pairs #1 in C. siamensis and #14 in P. jullieni compared to the rest of corresponding karyotypes indicated chromosomal fusions. Based on our findings, together with likely the same reduced 2n = 98 karyotypes in the remainder Probarbini species, we hypothesize that the karyotype 2n = 98 might represent a derived character, shared by all members of the Probarbini clade. Besides, we also witnessed considerable changes in the amount and distribution of certain repetitive DNA classes, suggesting complex post-polyploidization processes in this small paleotetraploid tribe.


Meningococcal carriage prevalence in university students, 1824 years of age in Santiago, Chile.
Neisseria meningitidis invasive disease is a major public health problem. Pharyngeal carriage is considered a prerequisite for invasive infection. Prevalence reaches 10% in general population and up to 30% in the 20-24 years age group. The aim of this study was to asses pharyngeal carriage prevalence in healthy subjects aged 18-24 years, and as secondary endpoints evaluate known risk factors, to identify serogroups and sequence in the isolated strains. Cross-sectional study in 500 healthy subjects; students from Universidad de Chile aged 18-24 years, Santiago, Chile, October 2012. Each subject underwent a risk factor survey prior to throat culture sampling. Samples were processed in one central Microbiology Laboratory of Hospital Luis Calvo Mackenna and serogrouping and sequencing was performed at Instituto de Salud Pública de Chile. We obtained throat samples from 500 healthy subjects, 20 (4%) positive for N. meningitidis. Of positive strains 20% were serogroup B, 15% W and the rest non groupable. The median age was 20 years, 50% were men. Of the risk factors evaluated, 24% were current smokers, 16% shared a room, 72% had kissed someone during the last month, 64% had gone to pub and 76% had consumed alcohol in the same period of time. Literatures meningococcal carriage prevalence reaches up to 30% in people aged 18-24 years. Prevalence in our study was 4%. Different interpretations could be given; one could be the absence of overcrowding in our students because of the lack of dorms in our scholar system and also the characteristics of our enrolled group. Our results suggest the necessity to extend the study to other age groups and to other cities, to better understand the Chilean reality, as well as others regions of America, considering that these results cannot be extrapolated to another countries.


Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis.
Samples of serum, bile, and urine were collected simultaneously from patients with cholestasis of varying aetiology and from patients with cirrhosis; their bile acid composition was determined by gas/liquid chromatography and mass spectrometry. In cholestasis, the patterns in all three body fluids differed consistently and strikingly. In serum, cholic acid was the major bile acid and most bile acids (greater than 93%) were unsulphated, whereas, in urine, chenodeoxycholic was the major bile acid, and the majority of bile acids (greater than 60%) were sulphated. Secondary bile acids were virtually absent in bile, serum, and urine. The total amount of bile acids excreted for 24 hours correlated highly with the concentration of serum bile acids; in patients with complete obstruction, urinary excretion averaged 71-6 mg/24 h. In cirrhotic patients, serum bile acids were less raised, and chenodeoxycholic acid was the predominant acid. In healthy controls, serum bile acids were consistently richer in chenodeoxycholic acid than biliary bile acids, and no bile acids were present in urine. No unusual monohydroxy bile acids were present in patients with primary biliary cirrhosis, but, in several patients, there was a considerable amount of hyocholic acid present in the urinary bile acids. The analyses of individual bile acids in serum and urine did not appear to provide helpful information in the differential diagnosis of cholestasis. Thus, in cholestasis, conjugation of chenodeoxycholic acid with sulphate becomes a major biochemical pathway, urine becomes a major route of bile acid excretion, and abnormal bile acids are formed.


Replisome assembly at oriC, the replication origin of E. coli, reveals an explanation for initiation sites outside an origin.
This study outlines the events downstream of origin unwinding by DnaA, leading to assembly of two replication forks at the E. coli origin, oriC. We show that two hexamers of DnaB assemble onto the opposing strands of the resulting bubble, expanding it further, yet helicase action is not required. Primase cannot act until the helicases move 65 nucleotides or more. Once primers are formed, two molecules of the large DNA polymerase III holoenzyme machinery assemble into the bubble, forming two replication forks. Primer locations are heterogeneous; some are even outside oriC. This observation generalizes to many systems, prokaryotic and eukaryotic. Heterogeneous initiation sites are likely explained by primase functioning with a moving helicase target.


A new method for carbon isotopic analysis of protein.
The reaction of ninhydrin with amino acids can be used in carbon isotopic studies of protein. The reaction can be applied to extract as carbon dioxide only peptide-bonded carbon in proteinaceous material, thus avoiding most, if not all, contaminants. Test radiocarbon dates on ancient bone indicate that the method provides reliable ages, and stable carbon isotopic data suggest that our understanding of isotopic dietary reconstruction needs detailed examination. The technique should also be useful in biochemical tracing experiments and in global carbon budget studies, and the underlying principle may be applicable to other isotopes and molecules.


Zebrafish mutants provide insights into Apolipoprotein B functions during embryonic development and pathological conditions.
Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs, and LDLs and is essential for their production. Defects in ApoB synthesis and secretion result in several human diseases, including abetalipoproteinemia and familial hypobetalipoproteinemia (FHBL1). In addition, ApoB-related dyslipidemia is linked to nonalcoholic fatty liver disease (NAFLD), a silent pandemic affecting billions globally. Due to the crucial role of APOB in supplying nutrients to the developing embryo, ApoB deletion in mammals is embryonic lethal. Thus, a clear understanding of the roles of this protein during development is lacking. Here, we established zebrafish mutants for 2 apoB genes: apoBa and apoBb.1. Double-mutant embryos displayed hepatic steatosis, a common hallmark of FHBL1 and NAFLD, as well as abnormal liver laterality, decreased numbers of goblet cells in the gut, and impaired angiogenesis. We further used these mutants to identify the domains within ApoB responsible for its functions. By assessing the ability of different truncated forms of human APOB to rescue the mutant phenotypes, we demonstrate the benefits of this model for prospective therapeutic screens. Overall, these zebrafish models uncover what are likely previously undescribed functions of ApoB in organ development and morphogenesis and shed light on the mechanisms underlying hypolipidemia-related diseases.


Retinal disorders in northern Brazilian patients treated with chloroquine assessed by multifocal ERG.
The effects of chloroquine intake on the retinal function in a Brazilian population of patients were assessed by multifocal electroretinography. Twenty-four randomly chosen eyes of patients treated with chloroquine for rheumatoid arthritis and systemic lupus erythematosus were examined using multifocal electroretinography (mfERG). Control measurements were acquired from 21 randomly chosen eyes of age-matched healthy subjects. None of the study participants had an inherited retinal disease or a Snellen visual acuity reduced to less than 20/40. In patients and control subjects, cumulative chloroquine dose, total daily dose, duration of treatment, retinal examination, visual field defects, visual acuity, and the mfERG were assessed. The average amplitudes and implicit times of the N1, P1, and P2 components of the mfERGs were measured in the central hexagon (R1) and in five rings (R2-R6). The values measured in patients and normal subjects were compared. The P1 amplitudes in R2 were significantly decreased in the patients. In addition, the amplitudes of N1 and N2 in R1 were significantly smaller in the patients. The implicit times of none of the components were significantly different between patients and controls. The response amplitude was not significantly correlated with cumulative dose and duration of intake. There was no correlation with retinal appearance, visual field, and visual acuity. In agreement with earlier data, the central mfERG amplitudes were decreased in chloroquine patients indicating functional alterations in the retina. These changes are also present in a Brazilian population suggesting that the effects of chloroquine are general and that genetic background and life circumstances probably have, if at all, only little effect.


Mindfulness disposition and default-mode network connectivity in older adults.
An extensive body of research defines the default-mode network (DMN) to be one of the critical networks of the human brain, playing a pivotal functional role in processes of internal mentation. Alterations in the connectivity of this network as a function of aging have been found, with reductions associated with functional ramifications for the elderly population. This study examined associations between integrity of the DMN and trait levels of mindfulness disposition, defined by our ability to exert attentional and emotional control in the present moment, and, thereby, bring awareness to immediate experiences. Twenty-five older adults participated in the study and underwent a brief functional magnetic resonance imaging session and filled out questionnaires related to their overall health and mindfulness disposition. Mindfulness disposition was associated with greater connectivity of the DMN, specifically, in the dorsal posterior cingulate cortex and the precuneus. Mindfulness disposition, thus, explains variance in the connectivity of one of the more intrinsic networks of the human brain, known to be critical for promoting self-relevant mental explorations and building cognitive and affective control.


The biochemical effects of ischemia-reperfusion injury in the ipsilateral and contralateral testes of rats and the protective role of melatonin.
Testicular torsion (TT) is a serious urologic emergency that is observed in adolescent males and that can lead to infertility if left untreated. The ischemia-reperfusion (I/R) injury due to TT has been implicated in the pathogenesis of testicular damage. We investigated the effects of melatonin on oxidative damage in the ipsilateral and contralateral testes of rats induced by unilateral TT. A total of 21 prepubertal male Wistar albino rats were divided into three groups, each consisting of seven rats. In Group 1 (SHAM group): a sham operation to the left testis and bilateral orchiectomy were performed. In Group 2 (I/R group): I/R injury was created by rotating the left testis 720° in a clockwise direction for 2 h and detorsing the testis after 2 h. Group 3 (I/R + MEL group): rats were subjected to I/R injury and one-shot melatonin injection (50 mg kg?1, intraperitoneal (i.p.)). The testes of the rats were excised bilaterally in all groups. The testicular tissue activities of antioxidant catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase enzymes (GSH-Px), and the tissue levels of malondialdehyde (MDA), protein carbonyl (PC) and nitric oxide (NO) were determined. Administration of melatonin caused a significant decrease in lipid peroxidation and enzyme activities in the ipsilateral testis when compared with the control group (P < 0.05). All of the changes in the enzyme activities of the contralateral testis were insignificant (P > 0.05). MDA levels were signifi cantly altered in the contralateral testis (P = 0.009). Melatonin administration decreased the deleterious effects of I/R injury in the ipsilateral torted testes of the rats. The contralateral testes were slightly affected by unilateral TT.


Identification of late larval stage developmental checkpoints in Caenorhabditis elegans regulated by insulin/IGF and steroid hormone signaling pathways.
Organisms in the wild develop with varying food availability. During periods of nutritional scarcity, development may slow or arrest until conditions improve. The ability to modulate developmental programs in response to poor nutritional conditions requires a means of sensing the changing nutritional environment and limiting tissue growth. The mechanisms by which organisms accomplish this adaptation are not well understood. We sought to study this question by examining the effects of nutrient deprivation on Caenorhabditis elegans development during the late larval stages, L3 and L4, a period of extensive tissue growth and morphogenesis. By removing animals from food at different times, we show here that specific checkpoints exist in the early L3 and early L4 stages that systemically arrest the development of diverse tissues and cellular processes. These checkpoints occur once in each larval stage after molting and prior to initiation of the subsequent molting cycle. DAF-2, the insulin/insulin-like growth factor receptor, regulates passage through the L3 and L4 checkpoints in response to nutrition. The FOXO transcription factor DAF-16, a major target of insulin-like signaling, functions cell-nonautonomously in the hypodermis (skin) to arrest developmental upon nutrient removal. The effects of DAF-16 on progression through the L3 and L4 stages are mediated by DAF-9, a cytochrome P450 ortholog involved in the production of C. elegans steroid hormones. Our results identify a novel mode of C. elegans growth in which development progresses from one checkpoint to the next. At each checkpoint, nutritional conditions determine whether animals remain arrested or continue development to the next checkpoint.


3D Cascaded Convolutional Networks for Multi-vertebrae Segmentation.
Automatic approach to vertebrae segmentation from computed tomography (CT) images is very important in clinical applications. As the intricate appearance and variable architecture of vertebrae across the population, cognate constructions in close vicinity, pathology, and the interconnection between vertebrae and ribs, it is a challenge to propose a 3D automatic vertebrae CT image segmentation method. The purpose of this study was to propose an automatic multi-vertebrae segmentation method for spinal CT images. Firstly, CLAHE-Threshold-Expansion was preprocessed to improve image quality and reduce input voxel points. Then, 3D coarse segmentation fully convolutional network and cascaded finely segmentation convolutional neural network were used to complete multi-vertebrae segmentation and classification. The results of this paper were compared with the other methods on the same datasets. Experimental results demonstrated that the Dice similarity coefficient (DSC) in this paper is 94.84%, higher than the V-net and 3D U-net. Method of this paper has certain advantages in automatically and accurately segmenting vertebrae regions of CT images. Due to the easy acquisition of spine CT images. It was proven to be more conducive to clinical application of treatment that uses our segmentation model to obtain vertebrae regions, combining with the subsequent 3D reconstruction and printing work.


A subset of host B lymphocytes controls melanoma metastasis through a melanoma cell adhesion molecule/MUC18-dependent interaction: evidence from mice and humans.
Host immunity affects tumor metastasis but the corresponding cellular and molecular mechanisms are not entirely clear. Here, we show that a subset of B lymphocytes (termed B-1 population), but not other lymphocytes, has prometastatic effects on melanoma cells in vivo through a direct heterotypic cell-cell interaction. In the classic B16 mouse melanoma model, one mechanism underlying this phenomenon is a specific up-regulation and subsequent homophilic interaction mediated by the cell surface glycoprotein MUC18 (also known as melanoma cell adhesion molecule). Presence of B-1 lymphocytes in a panel of tumor samples from melanoma patients directly correlates with MUC18 expression in melanoma cells, indicating that the same protein interaction exists in humans. These results suggest a new but as yet unrecognized functional role for host B-1 lymphocytes in tumor metastasis and establish a biochemical basis for such observations. Our findings support the counterintuitive central hypothesis in which a primitive layer of the immune system actually contributes to tumor progression and metastasis in a mouse model and in melanoma patients. Given that monoclonal antibodies against MUC18 are in preclinical development but the reason for their antitumor activity is not well understood, these translational results are relevant in the setting of human melanoma and perhaps of other cancers.


Work environments and HIV prevention: a qualitative review and meta-synthesis of sex worker narratives.
Sex workers (SWs) experience a disproportionately high burden of HIV, with evidence indicating that complex and dynamic factors within work environments play a critical role in mitigating or producing HIV risks in sex work. In light of sweeping policy efforts to further criminalize sex work globally, coupled with emerging calls for structural responses situated in labour and human-rights frameworks, this meta-synthesis of the qualitative and ethnographic literature sought to examine SWs' narratives to elucidate the ways in which physical, social and policy features of diverse work environments influence SWs' agency to engage in HIV prevention. We conducted a meta-synthesis of qualitative and ethnographic studies published from 2008 to 2014 to elucidate SWs' narratives and lived experiences of the complex and nuanced ways in which physical, social, and policy features of indoor and outdoor work environments shape HIV prevention in the sex industry. Twenty-four qualitative and/or ethnographic studies were included in this meta-synthesis. SWs' narratives revealed the nuanced ways that physical, social, and policy features of work environments shaped HIV risk and interacted with macrostructural constraints (e.g., criminalization, stigma) and community determinants (e.g., sex worker empowerment initiatives) to shape SWs' agency in negotiating condom use. SWs' narratives revealed the ways in which the existence of occupational health and safety standards in indoor establishments, as well as protective practices of third parties (e.g., condom promotion) and other SWs/peers were critical ways of enhancing safety and sexual risk negotiation within indoor work environments. Additionally, working in settings where negative interactions with law enforcement were minimized (e.g., working in decriminalized contexts or environments in which peers/managers successfully deterred unjust policing practices) was critical for supporting SWs' agency to negotiate HIV prevention. Policy reforms to remove punitive approaches to sex work, ensure supportive workplace standards and policies, and foster SWs' ability to work collectively are recommended to foster the realization of SWs' health and human rights across diverse settings. Future qualitative and mixed-methods research is recommended to ensure that HIV policies and programmes are grounded in SWs' voices and realities, particularly in more under-represented regions such as Eastern Europe and Sub-Saharan Africa.


Validation and sensitivity of the FINE Bayesian network for forecasting aquatic exposure to nano-silver.
The adaptive nature of the Forecasting the Impacts of Nanomaterials in the Environment (FINE) Bayesian network is explored. We create an updated FINE model (FINEAgNP-2) for predicting aquatic exposure concentrations of silver nanoparticles (AgNP) by combining the expert-based parameters from the baseline model established in previous work with literature data related to particle behavior, exposure, and nano-ecotoxicology via parameter learning. We validate the AgNP forecast from the updated model using mesocosm-scale field data and determine the sensitivity of several key variables to changes in environmental conditions, particle characteristics, and particle fate. Results show that the prediction accuracy of the FINEAgNP-2 model increased approximately 70% over the baseline model, with an error rate of only 20%, suggesting that FINE is a reliable tool to predict aquatic concentrations of nano-silver. Sensitivity analysis suggests that fractal dimension, particle diameter, conductivity, time, and particle fate have the most influence on aquatic exposure given the current knowledge; however, numerous knowledge gaps can be identified to suggest further research efforts that will reduce the uncertainty in subsequent exposure and risk forecasts.


High-output cardiac failure associated with an iliac artery aneurysm and arteriovenous fistula. A case report.
Rupture of an aneurysm into a major vein is an uncommon complication, and the resulting arteriovenous fistula frequently causes high-output cardiac failure as a presenting symptom. A patient with high-output cardiac failure refractory to conservative treatment and an aortic and left iliac artery aneurysm and associated arteriovenous fistula between the left common iliac artery and vein is presented. The fistula was confirmed by transfemoral arteriography. Successful resection of the aneurysm and closure of the fistula resulted in dramatic clinical improvement. Careful monitoring of cardiovascular function with a Swan-Ganz catheter, before, during and after operation contributed to a satisfactory result.


Adnexal masses requiring surgical intervention in women with advanced cervical cancer.
Surgical evaluation of adnexal masses in patients with cervical cancer can be considered in order to optimize treatment outcomes and rule out a second pathologic process. Our objective was to review treatment patterns and outcomes in women with advanced cervical cancer (ACC) and an adnexal mass. A retrospective review was performed with IRB approval of patients treated for advanced cervical cancer at our institution between 1990 and 2011. Patients were identified using institutional databases and tumor registries. Descriptive statistics were performed using Microsoft Excel 2011 and Instat was used to perform Fisher's exact test and student T-tests. Two hundred twenty eight patients with stage IIB-IVB cervical cancer were identified, 50 (22%) of whom had an adnexal mass on initial imaging studies (31 stage IIB, 15 stage IIIB, 3 stage IVA, 3 stage IVB). The mean follow up time of patients with adnexal masses was 22 months (range 3-128 months). Thirteen of 50 (26%) patients underwent surgical evaluation of the adnexal mass. Six were found to have cervical cancer metastatic to the adnexae, while seven had benign adnexal lesions. Thirty-seven of 50 (74%) patients were conservatively managed. All 37 women had cystic masses <8 cm or complex masses <5 cm in size. Thirty-four of the 37 (92%) patients had resolution of their adnexal mass and 3 were deemed stable on follow up imaging. Twenty three percent of surgically managed patients and 57% of conservatively managed patients had disease recurrence (p=0.05). There were no recurrences in the adnexa. Twelve percent of women with ACC and an adnexal mass have ovarian metastases. Patients with cystic masses less than 8 cm and complex masses less than 5 cm in size can be expectantly managed.


Reconstructing the origins of praying mantises (Dictyoptera, Mantodea): the roles of Gondwanan vicariance and morphological convergence.
A comprehensive taxonomic sampling of Mantodea (praying mantises), covering virtually all higher-level groups, was assembled to reconstruct the phylogeny of the order. Sequence data were generated from five mitochondrial and four nuclear loci (12S rRNA, 16S rRNA, 18S rRNA, 28S rRNA, Histone III, Cytochrome Oxidase I & II, NADH dehydrogenase subunit 4, and Wingless) for 329 mantis exemplars along with seven cockroach and eight termite species. Only seven of 14 families, 14 of 33 subfamilies, and seven of 14 tribes were recovered as monophyletic, indicating that phylogeny is largely incongruent with classification. Mapping biogeographical regions on the phylogeny demonstrated that our results adhere closer to biogeographical distributions than to classification. Specific patterns in distribution suggest that major morphological convergences have confounded taxonomists' ability to reconstruct natural groups. A major revision of higher-level relationships is in order through a comprehensive investigation of morphology and molecular data. We found that major mantis lineages diverged prior to and during the isolation of geographical regions and subsequent ecomorphic specializations within these regions may have led to convergences in morphology. Divergence time estimation places the origin of Mantodea at the beginning of the Jurassic with most modern mantises originating on Gondwana in the Cretaceous. The first major divergence among modern mantises occurred as a result of the north-south splitting of South America and Africa. Subsequent divergences resulted from the breakup of Gondwana. The position of the Indian subcontinent appears to be central to the diversification of Afrotropical and Indomalayan mantises while Antarctica may have served as the conduit for the mantis invasions into South America and Australasia. When India separated from Antarctica and drifted north it distributed mantis lineages back into the Afrotropics and carried a diverse taxonomic assemblage to Asia.


Bradycardia seen in children with Crimean-Congo hemorrhagic fever.
Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic viral disease with a high mortality rate. In clinical practice, we observed bradycardia in some pediatric patients with CCHF during the clinical course. So we aimed to report CCHF cases that presented bradycardia during the clinical course and the relation of bradycardia with the clinical findings and ribavirin therapy. Charts of all hospitalized pediatric CCHF patients were reviewed with respect to age, sex, history of tick bite or history of removing a tick, other risk factors for CCHF transmission, and interval between the tick bite and the onset of symptoms. Outcomes and clinical and laboratory findings and medications were recorded for each patient. We searched the patient records for information regarding the existence of bradycardia. Bradycardia was accepted as the heart rate 2 standard deviations (SD) lower than the suspected heart rate based on age. Fifty-two patients (mean age 11.2 ± 4.4 years, 31 female) were enrolled into the study. Bradycardia was seen in seven patients. Six patients with bradycardia were male and only one was female, and the mean age was 13.1 ± 1.6 years. It was observed that male gender is frequent among patients with bradycardia, as compared with those without bradycardia (p=0.01). Bleeding was found to be more frequent in patients with bradycardia (p=0.02). There were significant differences between the bradycardia and nonbradycardia groups with regard to the requirements for fresh frozen plasma transfusion, the number of platelet suspension given, requirement for intravenous immune globulin (IVIG) and in the days of stay in hospital (p=0.01, p=0.03, p=0.03, p=0.04, respectively). Reversible bradycardia might be seen in the clinical course of pediatric CCHF patients, and the clinicians must be aware of this finding. The possibility that ribavirin may potentiate bradycardia cannot be assessed without a placebo-control study. So further studies may help to reveal the cause of the bradycardia, the disease itself, or the ribavirin therapy. Hence this study supports the need for a randomized, placebo-controlled study to assess intravenous ribavirin in treating CCHF and to support approval of the drug.


Antibiotic translocation through porins studied in planar lipid bilayers using parallel platforms.
In general, the method of choice to characterize the conductance properties of channel-forming bacterial porins is electrophysiology. Here, the classical method is to reconstitute single porins into planar lipid bilayers to derive functional information from the observed channel conductance. In addition to an estimated pore size, ion selectivity or transport properties in general are of importance. For the latter, measuring the ion current fluctuation can provide some information about the mode of transport of charged molecules penetrating the proteins. For instance, increasing the external voltage modifies the residence time in the channel: charged molecules with the ability to permeate through channels will travel faster whereas non-permeating molecules get pushed to the constriction zone with enhanced residence time. Here, we are interested in the ability of antibiotics to permeate channels and compare different techniques to reveal fast events.


Paracrine interaction between adipose-derived stromal cells and cranial suture-derived mesenchymal cells.
Adipose-derived stromal cells are a potential cell source for the successful healing of skeletal defects. In this study, the authors sought to investigate the potential for cranial suture-derived mesenchymal cells to promote the osteogenic differentiation of adipose-derived stromal cells. Various reports have previously examined the unique in vitro attributes of suture-derived mesenchymal cells; this study sought to extend those findings. Suture-derived mesenchymal cells were isolated from wild-type mice (n = 30) from both fusing posterofrontal and patent sagittal sutures. Cells were placed in Transwell inserts with human adipose-derived stromal cells (n = 5 patients) with osteogenic differentiation medium with or without recombinant Noggin (10 to 400 ng/ml). Specific gene expression of osteogenic markers and Hedgehog pathway were assayed; standard osteogenic assays (alkaline phosphatase and alizarin red staining) were performed. All assays were performed in triplicate. Both posterofrontal and sagittal suture-derived mesenchymal cells induced osteogenic differentiation of adipose-derived stromal cells (p < 0.05). Posterofrontal suture-derived mesenchymal cells induced adipose-derived stromal cell osteogenesis to a greater degree than sagittal suture-derived mesenchymal cells (p < 0.05). This was accompanied by an increase in bone morphogenetic protein expression (p < 0.05). Finally, recombinant Noggin mitigated the pro-osteogenic effects of co-culture accompanied by a reduction in Hedgehog signaling (p < 0.05). Suture-derived mesenchymal cells secrete paracrine factors that induce osteogenic differentiation of multipotent stromal cells (human adipose-derived stromal cells). Cells derived from the fusing posterofrontal suture do this to a significantly greater degree than cells from the patent sagittal suture. Enhanced bone morphogenetic protein and Hedgehog signaling may underlie this paracrine effect.


Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies.
The term nephronophthisis-related ciliopathies (NPHP-RC) describes a group of rare autosomal-recessive cystic kidney diseases, characterised by broad genetic and clinical heterogeneity. NPHP-RC is frequently associated with extrarenal manifestations and accounts for the majority of genetically caused chronic kidney disease (CKD) during childhood and adolescence. Generation of a molecular diagnosis has been impaired by this broad genetic heterogeneity. However, recently developed high-throughput exon sequencing techniques represent powerful and efficient tools to screen large cohorts for dozens of causative genes. Therefore, we performed massively multiplexed targeted sequencing using the modified molecular inversion probe strategy (MIPs) in an international cohort of 384 patients diagnosed with NPHP-RC. As a result, we established the molecular diagnoses in 81/384 unrelated individuals (21.1%). We detected 127 likely disease-causing mutations in 18 of 34 evaluated NPHP-RC genes, 22 of which were novel. We further compared a subgroup of current findings to the results of a previous study in which we used an array-based microfluidic PCR technology in the same cohort. While 78 likely disease-causing mutations were previously detected by the array-based microfluidic PCR, the MIPs approach identified 94 likely pathogenic mutations. Compared with the previous approach, MIPs redetected 66 out of 78 variants and 28 previously unidentified variants, for a total of 94 variants. In summary, we demonstrate that the modified MIPs technology is a useful approach to screen large cohorts for a multitude of established NPHP genes in order to identify the underlying molecular cause. Combined application of two independent library preparation and sequencing techniques, however, may still be indicated for Mendelian diseases with extensive genetic heterogeneity in order to further increase diagnostic sensitivity.


Digital microscopy using phase-shifting digital holography with two reference waves.
A lensless, coherent optical microscope is described that uses a version of phase-shifting digital holography (PSDH) in conjunction with a field backpropagation algorithm to form coherent images of transmission-type objects. The PSDH is implemented by use of only two reference waves, in contrast with the usual implementation that requires four quadrature phase-shifting reference waves. Therefore only two digital holograms need to be recorded, and the complexity of the microscopic system is reduced. Experimental results are presented that compare images generated from conventional Gabor digital holography, two-reference-wave PSDH, and conventional white-light microscopy.


Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism.
To compare relative bioavailability of Synthroid, Levoxine (Levoxine has been renamed Levoxyl), and 2 generic levothyroxine sodium preparations. Single-blind (primary investigators blinded), randomized, 4-way crossover trial. Ambulatory care. Twenty-two women with hypothyroidism who were clinically and chemically euthyroid and were receiving levothyroxine sodium, 0.1 or 0.15 mg. All patients received each of the 4 levothyroxine products for 6-week periods in the same dosage as their prestudy regimen with no washout period. The order of the drug sequences was randomly determined before study initiation. Area under the curve, time to peak serum concentrations, and peak serum concentrations of thyroxine, triiodothyronine, and free thyroxine index for all 4 products. All data analyses were completed prior to unblinding of the product codes. No significant differences between the 4 products were found in area under the curve or peak serum concentrations of total thyroxine, total triiodothyronine, or free thyroxine index. Although Synthroid produced a more rapid rise in total serum triiodothyronine concentration and a higher total peak serum triiodothyronine concentration than the other products, these differences were not statistically significant (P=.08). The Food and Drug Administration criterion for relative bioequivalence within 90% confidence intervals (0.8-1.25) was demonstrated (P<.05) for all pairs of products. Relative bioequivalence of 0.95 to 1.07 was demonstrated, tighter than the current bioequivalence criterion for oral formulations. The 4 generic and brand-name levothyroxine preparations studied are different but are bioequivalent by current Food and Drug Administration criteria and are interchangeable in the majority of patients receiving thyroxine replacement therapy. Further investigation is required to determine whether our results are equally applicable to all existing levothyroxine preparations.


The Egypt National Perinatal/Neonatal Mortality Study 2000.
To estimate stillbirth, perinatal (PMR) and neonatal mortality rates (NMR) in Egypt and to assign main causes of death. Data were collected from a representative sample of women who gave birth from 17,521 households which were included in the Egypt Demographic and Health Survey (EDHS) 2000. Comparisons were made between three systems for classifying causes of death. The NMR was 25 per 1000 live births (17 early and eight late). Half the deaths occurred in the first two days of life. Neonatal causes of death were pre-maturity (39%), asphyxia (18%), infections (7%), congenital malformation (6%) and unclassified (29%). The PMR was 34 per 1000 births, mainly attributed to: asphyxia (44%) and prematurity (21%). The revised Wigglesworth classification agreed well with the physicians except the panel attributed more deaths to infections (20%). The WHO verbal autopsy algorithm left 48% of deaths unclassified. Infant mortality in Egypt is showing an epidemiological transition with a significant decrease in mortality, resulting in a disproportionate percentage of deaths in the first week of life. Infant mortality in Egypt declined 64% from 124 per 1000 between 1974 and 1978 to 44 per 1000 between 1995 and 1999, the decline being greatest among older infants; 55% of all infant deaths occurred during the neonatal period. The neonatal mortality rate in this study was estimated to be 25 per 1000 live births.


Coronary artery disease in diabetic patients with lower-extremity arterial disease: disease characteristics and survival. A report from the Coronary Artery Surgery Study (CASS) registry.
Patients who have diabetes and lower-extremity arterial disease (LEAD) are at an increased risk of dying from coronary artery disease (CAD). This study was undertaken to: 1) define the clinical and arteriographic factors associated with LEAD among diabetic patients; 2) determine the long-term survival and predictors of mortality of diabetic patients with LEAD, compared to those without LEAD; and 3) determine if the presence of LEAD is an independent risk factor for mortality among diabetic patients with CAD. A total of 263 diabetic patients from the Coronary Artery Surgery Study (CASS) registry with LEAD, who were > or = 50 years of age, and who had arteriographically proven CAD, were identified and followed for a mean of 12.8 years. A total of 1,349 comparably aged diabetic patients from the CASS registry with CAD and no evidence of LEAD were followed for an equivalent period of time. Compared with diabetic patients without LEAD, diabetic patients with LEAD were characterized by the presence of cerebrovascular disease, a high rate of current smoking, elevated systolic blood pressure, high grades of angina pectoris, and digitalis use. Severity of epicardial CAD and extent of CAD were not independent predictors of the presence of LEAD. On follow-up, diabetic patients with LEAD had significantly higher mortality (mostly cardiovascular) than diabetic patients without LEAD, with a median survival of 8.1 and 10.9 years, respectively. On multivariate analysis, age, the number of significantly narrowed coronary arteries, and the presence of left ventricular dysfunction predicted mortality in both subsets of diabetic patients. Among all the diabetic patients with CAD, the presence of LEAD was an independent risk factor for mortality. Diabetic patients with LEAD have a higher mortality rate (mostly cardiovascular) than diabetic patients without LEAD, despite no apparent anatomic differences in the severity and extent of CAD. This suggests that factors associated with the presence of LEAD, other than the anatomy of the coronary circulation, may play a role in determining survival among diabetic patients with LEAD and CAD.


Analysing the operative experience of basic surgical trainees in Ireland using a web-based logbook.
There is concern about the adequacy of operative exposure in surgical training programmes, in the context of changing work practices. We aimed to quantify the operative exposure of all trainees on the National Basic Surgical Training (BST) programme in Ireland and compare the results with arbitrary training targets. Retrospective analysis of data obtained from a web-based logbook (http://www.elogbook.org) for all general surgery and orthopaedic training posts between July 2007 and June 2009. 104 trainees recorded 23,918 operations between two 6-month general surgery posts. The most common general surgery operation performed was simple skin excision with trainees performing an average of 19.7 (± 9.9) over the 2-year training programme. Trainees most frequently assisted with cholecystectomy with an average of 16.0 (± 11.0) per trainee. Comparison of trainee operative experience to arbitrary training targets found that 2-38% of trainees achieved the targets for 9 emergency index operations and 24-90% of trainees achieved the targets for 8 index elective operations. 72 trainees also completed a 6-month post in orthopaedics and recorded 7,551 operations. The most common orthopaedic operation that trainees performed was removal of metal, with an average of 2.90 (± 3.27) per trainee. The most common orthopaedic operation that trainees assisted with was total hip replacement, with an average of 10.46 (± 6.21) per trainee. A centralised web-based logbook provides valuable data to analyse training programme performance. Analysis of logbooks raises concerns about operative experience at junior trainee level. The provision of adequate operative exposure for trainees should be a key performance indicator for training programmes.


Monodisperse magnetic core/shell microspheres with Pd nanoparticles-incorporated-carbon shells.
This work reports a hard self-template method to synthesize core/shell like Fe3O4@C microparticles, in which the Pd nanocrystals can be alternatively incorporated into the carbon shells. The Fe3O4@polyaniline core/shell microspheres were first synthesized as the precursor by in situ polymerization of aniline onto the surface of the Fe3O4 microspheres. In a subsequent carbonization of the precursor under a vacuum oven, the Fe3O4 core was preserved and the polyaniline shell transferred into carbon shells enveloping the magnetic sphere, forming magnetic Fe3O4@C microspheres. The Pd ions could be impregnated into the polyaniline shell, and thus the obtained composites were transformed into Fe3O4@C/Pd microspheres under the same vacuum heating progress. The as-obtained system demonstrates superparamagnetic characteristics, which would benefit its potential application in nanocatalysts. This strategy provides an efficient approach for tailoring core/shell materials with desired functionalities and structures by adjusting the precursors and structure-directing agents.


Activation of MMP-9 by human lung epithelial cells in response to the cystic fibrosis-associated pathogen Burkholderia cenocepacia reduced wound healing in vitro.
Burkholderia cepacia complex is a group of bacterial pathogens that cause opportunistic infections in cystic fibrosis (CF). The most virulent of these is Burkholderia cenocepacia. Matrix metalloproteinases (MMPs) are upregulated in CF patients. The aim of this work was to examine the role of MMPs in the pathogenesis of B. cepacia complex, which has not been explored to date. Real-time PCR analysis showed that B. cenocepacia infection upregulated MMP-2 and MMP-9 genes in the CF lung cell line CFBE41o- within 1 h, whereas MMP-2, -7, and -9 genes were upregulated in the non-CF lung cell line 16HBE14o-. Conditioned media from both cell lines showed increased MMP-9 activation following B. cenocepacia infection. Conditioned media from B. cenocepacia-infected cells significantly reduced the rate of wound healing in confluent lung epithelia (P < 0.05), in contrast to conditioned media from Pseudomonas aeruginosa-infected cells, which showed predominant MMP-2 activation. Treatment of control conditioned media from both cell lines with the MMP activator 4-aminophenylmercuric acetate (APMA) also resulted in clear activation of MMP-9 and to a much lesser extent MMP-2. APMA treatment of control media also delayed the repair of wound healing in confluent epithelial cells. Furthermore, specific inhibition of MMP-9 in medium from cells exposed to B. cenocepacia completely reversed the delay in wound repair. These data suggest that MMP-9 plays a role in the reduced epithelial repair observed in response to B. cenocepacia infection and that its activation following B. cenocepacia infection contributes to the pathogenesis of this virulent pathogen.


Participation and performance trends in ultracycling.
Participation and performance trends have been investigated in ultramarathons and ultratriathlons but not in ultracycling. The aim of the present study was to investigate (1) participation and performance trends in ultraendurance cyclists, (2) changes in cycling speed over the years, and (3) the age of the fastest male and female ultraendurance cyclists. Participation and performance trends in the 5000 km Race Across America (RAAM) and in two RAAM-qualifier races - the 818 km Furnace Creek 508 in the United States and the 715 km Swiss Cycling Marathon in Europe - were investigated using linear regression analyses and analyses of variance. On average, ~41% of participants did not finish either the RAAM or the Furnace Creek 508, whereas ~26% did not finish the Swiss Cycling Marathon. Female finishers accounted for ~11% in both the RAAM and the Furnace Creek 508 but only ~3% in the Swiss Cycling Marathon. The mean cycling speed of all finishers remained unchanged during the studied periods. The winner's average speed was faster for men than for women in the RAAM (22.6 ± 1.1 km · h(-1) versus 18.4 ± 1.7 km · h(-1), respectively; average speed difference between male and female winners, 25.0% ± 11.9%), the Swiss Cycling Marathon (30.8 ± 0.8 km · h(-1) versus 24.4 ± 1.9 km · h(-1), respectively; average speed difference between male and female winners, 27.8% ± 9.4%), and the Furnace Creek 508 (27.4 ± 1.6 km · h(-1) versus 23.4 ± 3.0 km · h(-1), respectively; average speed difference between male and female winners, 18.4% ± 13.9%). In both the Furnace Creek 508 and the Swiss Cycling Marathon, ~46% of the finishers were aged between 35 and 49 years. The mean age of winners, both male and female, across the years in the Furnace Creek 508 and in the Swiss Cycling Marathon was 37 ± 10 years. These findings in ultracycling races showed that (1) ~26%-40% of starters were unable to finish, (2) the percentage of female finishers was ~3%-11%, (3) the gender difference in performance was ~18%-28%, and (4) ~46% of the successful finishers were master athletes. Future studies need to investigate the reasons for the low female participation and focus on the age-related performance decline in other ultraendurance events in order to confirm that master athletes are predisposed to ultraendurance performances.


B(OCH2CF3)3-mediated direct amidation of pharmaceutically relevant building blocks in cyclopentyl methyl ether.
The use of B(OCH2CF3)3 for mediating direct amidation reactions of a wide range of pharmaceutically relevant carboxylic acids and amines is described, including numerous heterocycle-containing examples. An initial screen of solvents for the direct amidation reaction suggested that cyclopentyl methyl ether, a solvent with a very good safety profile suitable for use over a wide temperature range, was an excellent replacement for the previously used solvent acetonitrile. Under these conditions amides could be prepared from 18 of the 21 carboxylic acids and 18 of the 21 amines examined. Further optimisation of one of the low yielding amidation reactions (36% yield) via a design of experiments approach enabled an 84% yield of the amide to be obtained.


Floral adaptation to local pollinator guilds in a terrestrial orchid.
Studies of local floral adaptation in response to geographically divergent pollinators are essential for understanding floral evolution. This study investigated local pollinator adaptation and variation in floral traits in the rewarding orchid Gymnadenia odoratissima, which spans a large altitudinal gradient and thus may depend on different pollinator guilds along this gradient. Pollinator communities were assessed and reciprocal transfer experiments were performed between lowland and mountain populations. Differences in floral traits were characterized by measuring floral morphology traits, scent composition, colour and nectar sugar content in lowland and mountain populations. The composition of pollinator communities differed considerably between lowland and mountain populations; flies were only found as pollinators in mountain populations. The reciprocal transfer experiments showed that when lowland plants were transferred to mountain habitats, their reproductive success did not change significantly. However, when mountain plants were moved to the lowlands, their reproductive success decreased significantly. Transfers between populations of the same altitude did not lead to significant changes in reproductive success, disproving the potential for population-specific adaptations. Flower size of lowland plants was greater than for mountain flowers. Lowland plants also had significantly higher relative amounts of aromatic floral volatiles, while the mountain plants had higher relative amounts of other floral volatiles. The floral colour of mountain flowers was significantly lighter compared with the lowland flowers. Local pollinator adaptation through pollinator attraction was shown in the mountain populations, possibly due to adaptation to pollinating flies. The mountain plants were also observed to receive pollination from a greater diversity of pollinators than the lowland plants. The different floral phenotypes of the altitudinal regions are likely to be the consequence of adaptations to local pollinator guilds.


Light-induced superconductivity in a stripe-ordered cuprate.
One of the most intriguing features of some high-temperature cuprate superconductors is the interplay between one-dimensional "striped" spin order and charge order, and superconductivity. We used mid-infrared femtosecond pulses to transform one such stripe-ordered compound, nonsuperconducting La(1.675)Eu(0.2)Sr(0.125)CuO(4), into a transient three-dimensional superconductor. The emergence of coherent interlayer transport was evidenced by the prompt appearance of a Josephson plasma resonance in the c-axis optical properties. An upper limit for the time scale needed to form the superconducting phase is estimated to be 1 to 2 picoseconds, which is significantly faster than expected. This places stringent new constraints on our understanding of stripe order and its relation to superconductivity.


Rural-urban disparity in lung function parameters of Nigerian children: effects of socio-economic, nutritional and housing factors.
The effect of socio-demographic and nutritional factors on lung functions of African children is poorly studied. This study set out to determine the effects of these factors on lung functions of Nigerian school children. Rural and urban secondary schools students in Ilesa, Nigeria were selected by multistage sampling. The socio-demographic, nutritional status as well as lung function parameters measured using incentive Spirometry (MIR Spirolab III srl, Italy) of the children were obtained and compared among the rural and urban children. A total of 250 children (128 rural and 122 urban) aged 9 to 17 years participated in the study over a 12 month period. Mean (SD) age was 12.6 (1.9) years and Male: Female 1:1.1. The urban children were heavier, taller and have larger lung volumes than their age and sex matched rural counterpart. Stunted rural males [Mean (SD) FVC 1.8 (0.3) L vs. 2.2 (0.6) L t-test = 2.360; p = 0.022], underweight females [Mean (SD) FVC 1.8 (0.4) L vs. 2.2 (0.6) L; t-test = 2.855; p = 0.006] and those exposed to unclean fuel [Mean (SD) FVC 2.1 (0.6) L vs. 2.4 (0.5) L; t-test = 2.079; p = 0.041] had significantly lower lung volumes compared to their counterparts without these conditions. Undernutrition, low socio-economic class and use of unclean fuels adversely affect the lung functions of Nigerian children. Improved standard of living, use of clean fuel and adequate nutrition may ensure better lung health among these children.


Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.


Interactions Between Two Invertebrate Pathogens: An Endophytic Fungus and an Externally Applied Bacterium.
The members of family Noctuidae exist in diverse environments and many species from this group are of agriculture importance, particularly Helicoverpa spp. Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) is a major pest of many legumes and cereal crops. Due to environmental and regulatory concerns, safe alternatives to broad spectrum chemical insecticides are needed for the control of key noctuid pests such as H. armigera. A strain of Beauveria bassiana (Cordycipitaceae: Hypocreales) was evaluated for its ability to colonize endophytically in chickpea plants, and its effectiveness against second (L2) and fourth (L4) larval instars of H. armigera. B. bassiana was inoculated to chickpea plants through injection and endophytic establishment was confirmed by re-isolating the fungi from leaf samples. A detached leaf assay was used to evaluate pathogenicity. Bacillus thuringiensis was also applied to both larval stages through leaf dip method. In a novel approach, combined treatments of bacteria and endophytic fungi were compared with single-pathogen treatments. Relative to the single treatments, the combined pathogen treatments exhibited an increase in larval mortality, and decrease in pupation, adult emergence and egg eclosion. Specifically, synergistic effects on mortality were observed when larvae were exposed to simultaneous application of B. bassiana (1 × 108 conidia ml-1) with B. thuringiensis (0.75 μg ml-1). Both instars exhibited varying level of growth, development, frass production, diet consumption and fecundity when exposed to the chickpea leaves inoculated with endophytic B. bassiana and dipped with sub-lethal doses of B. thuringiensis. These findings indicate that the integrated application of endophytic colonized B. bassiana and B. thuringiensis can be effectively used against H. armigera.


Novel flicker-sensitive visual circuit neurons inhibited by stationary patterns.
Many animals use visual motion cues for navigating within their surroundings. Both flies and vertebrates compute local motion by temporal correlation of neighboring photoreceptors, via so-called elementary motion detectors (EMDs). In the fly lobula plate and the vertebrate visual cortex the output from many EMDs is pooled in neurons sensitive to wide-field optic flow. Although the EMD has been the preferred model for more than 50 years, recent work has highlighted its limitations in describing some visual behaviors, such as responses to higher-order motion stimuli. Non-EMD motion processing may therefore serve an important function in vision. Here, we describe a novel neuron class in the fly lobula plate that clearly does not derive its input from classic EMDs. The centrifugal stationary inhibited flicker excited (cSIFE) neuron is strongly excited by flicker, up to very high temporal frequencies. The non-EMD driven flicker sensitivity leads to strong, nondirectional responses to high-speed, wide-field motion. Furthermore, cSIFE is strongly inhibited by stationary patterns, within a narrow wavelength band. cSIFE's outputs overlap with the inputs of well described optic flow-sensitive lobula plate tangential cells (LPTCs). Driving cSIFE affects the active dendrites of LPTCs, and cSIFE may therefore play a large role in motion vision.


An acute injection of Porphyromonas gingivalis lipopolysaccharide modulates the OPG/RANKL system and interleukin-6 in an ovariectomized mouse model.
In the present study, we attempted to develop a simulated model to explore the causal effects of periodontal pathogens on skeletal homeostasis in postmenopausal osteoporosis. Fifty-three female adult ICR mice were randomly assigned to an experimental group (ovariectomized) or a control group. A single injection of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS, ATCC 33277) or Escherichia coli lipopolysaccharide (E. coli-LPS) was administered intraperitoneally 4 weeks after an ovariectomy. Concentrations of interleukin-6 (IL-6), osteoprotegerin (OPG), and the receptor activator of nuclear factor-kappaB ligand (RANKL) in serum were subsequently analyzed using an enzyme-linked immunosorbent assay (ELISA). Under stimulation with P. gingivalis-LPS or E. coli-LPS, the concentration of OPG rose in both groups. The serum level of RANKL showed a decreasing trend 24 h after the injection in both groups. After injection of P. gingivalis-LPS in both the experimental and control animals, the OPG : RANKL ratio increased 24 h after the booster (22.26-620.99, P < 0.05). The serum level of IL-6 in the experimental group significantly increased 1-6 h after administration of E. coli-LPS and 1-3 h after administration of P. gingivalis-LPS (P < 0.05). A single booster injection of P. gingivalis-LPS induced short-term changes in OPG, RANKL, and IL-6 serum levels in this ovariectomized mouse model.


Fluorescent nitric oxide donor for the detection and killing of Pseudomonas aeruginosa.
The epidemic of multidrug-resistant bacteria calls for the improvement of both detection methods for bacterial infections and methods of treatment. Nitric oxide is a known potent antibacterial agent, but due to its gaseous and highly reactive nature, it is difficult to incorporate into a stable antibacterial compound. In this paper, we synthesize a nitric oxide donor attached to a fluorescent compound, creating a material that can both detect and kill the deadly multi-drug resistant bacteria strain Pseudomonas aeruginosa. Detection occurs through a bacterial enzyme-activated color change, showing a clear and obvious change from blue to yellow under UV light. The synthesized compound spontaneously releases 853 μmol of nitric oxide/g from a 10 mM initial concentration. Antibacterial efficacy studies after exposing Pseudomonas aeruginosa to a 10 mM dose of the synthesized compound show a 55-75% reduction in bacteria after 24 hours. This work is the first instance of a small molecule dual-function material that can both detect and kill bacteria.


Anatomical registration and three-dimensional visualization of low and high-resolution pan-colonic manometry recordings.
Colonic propagating sequences (PS) are important for the movement of colonic content and defecation, and aberrant PS patterning has been associated with slow transit constipation. However, because these motor patterns are typically recorded over long periods (24 h +), the visualization of PS spatiotemporal patterning is difficult. Here, we develop a novel method for displaying pan-colonic motility patterns. A 3D mesh representing the geometry of the human colon was created as follows: (i) Human colon images from the Visible Human Dataset were digitized to create a 3D data cloud, and (ii) A surface mesh was fitted to the cloud using a least-squares minimization technique. Colonic manometry catheters were placed in the ascending colon of healthy controls and patients with slow transit constipation (STC), with the aid of a colonoscope. The colonic manometry data were interpolated and mapped to the model according to the following anatomical landmarks: cecum, hepatic flexure, splenic flexure, sigmoid-descending junction, and anus. These 3D images clearly and intuitively communicate characteristics of normal and abnormal colonic motility. Specifically we have shown the reduced amplitude of the antegrade propagating pressure waves (PPW) throughout the colon and reduced frequency of PPWs at the mid-colon in patients with STC. A novel method for the 3D visualization of PS is presented, providing an intuitive method for representing a large volume of physiological data. These techniques can be used to display frequency, amplitude or velocity data, and will help to convey regions of abnormally in patient populations.


Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism.
In mammals, the catabolic pathway of phenylalanine and tyrosine is found in liver (hepatocytes) and kidney (proximal tubular cells). There are well-described human diseases associated with deficiencies of all enzymes in this pathway except for maleylacetoacetate isomerase (MAAI), which converts maleylacetoacetate (MAA) to fumarylacetoacetate (FAA). MAAI is also known as glutathione transferase zeta (GSTZ1). Here, we describe the phenotype of mice with a targeted deletion of the MAAI (GSTZ1) gene. MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy. This observation suggested that either accumulating MAA is not toxic or an alternate pathway for MAA metabolism exists. A complete redundancy of MAAI could be ruled out because substrate overload of the tyrosine catabolic pathway (administration of homogentisic acid, phenylalanine, or tyrosine) resulted in renal and hepatic damage. However, evidence for a partial bypass of MAAI activity was also found. Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI. Double mutants showed predominant renal injury, indicating that this organ is the primary target for the accumulated compound(s) resulting from MAAI deficiency. A glutathione-mediated isomerization of MAA to FAA independent of MAAI enzyme was demonstrated in vitro. This nonenzymatic bypass is likely responsible for the lack of a phenotype in nonstressed MAAI mutant mice.


Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer.
The MHC class I chain-related molecules (MICs) have previously been shown to be induced on most epithelial tumor cells. Engagement of MIC by the activating immune receptor NKG2D triggers NK cells and augments antigen-specific CTL anti-tumor immunity. The MIC-NKG2D system was proposed to participate in epithelial tumor immune surveillance. Paradoxically, studies suggest that tumors may evade MIC-NKG2D-mediated immunity by MIC shedding-induced impairment of effector cell function. Here we demonstrate the first evidence to our knowledge of a significant correlation of MIC shedding and deficiency in NK cell function with the grade of disease in prostate cancer. MIC is widely expressed in prostate carcinoma. The presence of surface target MIC, however, is counteracted by shedding. A significant increase in serum levels of soluble MIC (sMIC) and deficiency in NK cell function was shown in patients with advanced cancer. Finally, the deficiency in NK cell function can be overcome by treatment with IL-2 or IL-15 in vitro. Our results suggest that (a) deficiency in MIC-NKG2D immune surveillance may contribute to prostate cancer progression, (b) sMIC may be a novel biomarker for prostate cancer, and (c) using cytokines to restore MIC-NKG2D-mediated immunity may have clinical significance for prostate cancer in cell-based adaptive immunotherapy.


Current approaches to gastric cancer in Peru and Mexico.
In Peru, the incidence of gastric cancer is reported to be around 15.8 per 100,000 inhabitants and it is the second most common oncological disease in men and the third one in women. Additionally, a high mortality index was reported, especially among poor people. To address this issue, in 2008, Peru initiated several insurance treatment plans of oncological diseases with promising results. In Mexico, there is a high predominance of gastric cancer in male gender compared to female gender, even reaching a 2/1 ratio, and the detection rate of early gastric cancer is low (10% to 20%) which results in a mainly palliative treatment with an overall survival rate in 5 years about 10% to 15% only. In Peru, the average age at diagnosis is around 62.96±14.75 years old and the most frequent symptoms includes abdominal pain, indigestion, loss of appetite, weight loss and gastrointestinal bleeding, while in Mexico, some studies reported an average age at diagnosis around 60.3±4.1 years old (range, 23-78 years old) and the most frequent symptoms were postprandial fullness (74.4%), abdominal pain (37.2%), weight loss (18.6%), and melena (4.6%). The anemia rate was 65.1% with a mean Hb level of 6.14 g/dL. In Peru, the most common gastric cancer type is the intestinal-type adenocarcinoma (around 34%), followed by the diffuse-type adenocarcinoma (18.7%), whilst among Mexicans, the diffuse-type was reported in 55.2% of cases, the intestinal-type was reported in 28.2% and the undifferentiated-type corresponded to 6%. In both, Peru and Mexico, 90% of the associated factors includes tabaquismo, diets rich in salt, smoked foods, and a sedentary lifestyle. Family inheritance and advanced age and pharmacological-resistant Helicobacter pylori infection are also important. Poverty has been heavily associated with a higher incidence of gastric cancer. The management of gastric cancer patients in Peru is carried out by general surgeons or general surgical oncologists. In recent years, efforts have been made by the Peruvian government to establish specialized surgical centers which resulted in an improvement in morbidity and mortality rates, as well as an increase in the retrieval of lymph nodes. In Mexico, during the last 5 years, D1+ has been reported to be the most predominant lymphadenectomy-type, particularly in specialized surgical services. There have been a decrease in mortality rate from 7.5 per 100,000 inhabitants in 2000 to 5.6 per 1,000,000 inhabitants in 2012. Additional steps in order to continue improving gastric cancer management in Peru and Mexico are needed.


An anatomically comprehensive atlas of the adult human brain transcriptome.
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ∼900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography-the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.


A group-theoretical approach to enumerating magnetoelectric and multiferroic couplings in perovskites.
A group-theoretical approach is used to enumerate the possible couplings between magnetism and ferroelectric polarization in the parent Pm{\overline 3}m perovskite structure. It is shown that third-order magnetoelectric coupling terms must always involve magnetic ordering at the A and B sites which either transforms both as R-point or both as X-point time-odd irreducible representations (irreps). For fourth-order couplings it is demonstrated that this criterion may be relaxed allowing couplings involving irreps at X-, M- and R-points which collectively conserve crystal momentum, producing a magnetoelectric effect arising from only B-site magnetic order. In this case, exactly two of the three irreps entering the order parameter must be time-odd irreps and either one or all must be odd with respect to inversion symmetry. It is possible to show that the time-even irreps in this triad must transform as one of: X1+, M3,5- or R5+, corresponding to A-site cation order, A-site antipolar displacements or anion rocksalt ordering, respectively. This greatly reduces the search space for type-II multiferroic perovskites. Similar arguments are used to demonstrate how weak ferromagnetism may be engineered and a variety of schemes are proposed for coupling this to ferroelectric polarization. The approach is illustrated with density functional theory calculations on magnetoelectric couplings and, by considering the literature, suggestions are given of which avenues of research are likely to be most promising in the design of novel magnetoelectric materials.


Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice.
Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.


Total mercury in fish, sediments and soil from the River Pra Basin, southwestern Ghana.
Total Mercury (Hg) concentrations were determined in soil, river sediments and six (6) species of fish from the River Pra Basin in southwestern Ghana by Cold Vapour Atomic Absorption Spectrometry. Mercury concentration (microg g(-1)) ranged from 0.042 to 0.145 for soil: from 0.390 to 0.707 for sediments and from <0.001 to 0.370 for fish. All the fish samples had Hg concentration below the World Health Organisation (WHO) permissible limit of 0.5 microg g(-1) whereas all the sediment samples had levels higher than the US-EPA value of 0.2 microg g(-1). The results obtained from this study showed that fish from River Pra Basin are unlikely to constitute any significant mercury exposure to the public through consumption. No apparent trend of increasing mercury concentration along the main river as it flows downward toward the sea was observed.


Biochemical properties of a plastidial DNA polymerase of rice.
Plastids are organelles unique to plant cells and are responsible for photosynthesis and other metabolic functions. Despite their important cellular roles, relatively little is known about the mechanism of plastidial DNA replication and repair. Recently, we identified a novel DNA polymerase in Oryza Sativa L. (OsPOLP1, formerly termed OsPolI-like) that is homologous to prokaryotic DNA polymerase Is (PolIs), and suggested that this polymerase might be involved in plastidial DNA replication and repair. Here, we propose to rename the plant PolI homologs as DNA polymerase pi (POLP), and investigate the biochemical properties of full-length OsPOLP1. The purified OsPOLP1 elongated both DNA and RNA primer hybridized to a DNA template, and possessed a 3' exonuclease activity. Moreover, OsPOLP1 displayed high processivity and fidelity, indicating that this polymerase has the biochemical characteristics appropriate for DNA replication. We found that POLPs have two extra sequences in the polymerase domain that are absent in prokaryotic PolIs. Deletion of either insert from OsPOLP1 caused a decrease in DNA synthetic activity, processivity, and DNA binding activity. In addition, OsPOLP1 efficiently catalyzed strand displacement on nicked DNA with a 5'-deoxyribose phosphate, suggesting that this enzyme might be involved in a repair pathway similar to long-patch base excision repair. These results provide insights into the possible role of POLPs in plastidial DNA replication and repair.


Field evaluation of the diagnostic performance of EasyScan GO: a digital malaria microscopy device based on machine-learning.
Microscopic examination of Giemsa-stained blood films remains the reference standard for malaria parasite detection and quantification, but is undermined by difficulties in ensuring high-quality manual reading and inter-reader reliability. Automated parasite detection and quantification may address this issue. A multi-centre, observational study was conducted during 2018 and 2019 at 11 sites to assess the performance of the EasyScan Go, a microscopy device employing machine-learning-based image analysis. Sensitivity, specificity, accuracy of species detection and parasite density estimation were assessed with expert microscopy as the reference. Intra- and inter-device reliability of the device was also evaluated by comparing results from repeat reads on the same and two different devices. This study has been reported in accordance with the Standards for Reporting Diagnostic accuracy studies (STARD) checklist. In total, 2250 Giemsa-stained blood films were prepared and read independently by expert microscopists and the EasyScan Go device. The diagnostic sensitivity of EasyScan Go was 91.1% (95% CI 88.9-92.7), and specificity 75.6% (95% CI 73.1-78.0). With good quality slides sensitivity was similar (89.1%, 95%CI 86.2-91.5), but specificity increased to 85.1% (95%CI 82.6-87.4). Sensitivity increased with parasitaemia rising from 57% at < 200 parasite/µL, to ≥ 90% at > 200-200,000 parasite/µL. Species were identified accurately in 93% of Plasmodium falciparum samples (kappa = 0.76, 95% CI 0.69-0.83), and in 92% of Plasmodium vivax samples (kappa = 0.73, 95% CI 0.66-0.80). Parasite density estimates by the EasyScan Go were within ± 25% of the microscopic reference counts in 23% of slides. The performance of the EasyScan Go in parasite detection and species identification accuracy fulfil WHO-TDR Research Malaria Microscopy competence level 2 criteria. In terms of parasite quantification and false positive rate, it meets the level 4 WHO-TDR Research Malaria Microscopy criteria. All performance parameters were significantly affected by slide quality. Further software improvement is required to improve sensitivity at low parasitaemia and parasite density estimations. Trial registration ClinicalTrials.gov number NCT03512678.


Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity.
Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP, which encodes TAGAP, a guanosine triphosphatase (GTPase)-activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes' adhesion to the cortex through their β1-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection. Tagap physically interacted with the cytoplasmic domain of plexin-D1 and directly stimulated the activity and signaling of the GTPase RhoA. In addition, Tagap indirectly mediated the activation of Cdc42 in response to the binding of sema3E to plexin-D1. Both RhoA and Cdc42 are key mediators of cytoskeletal and integrin dynamics in thymocytes. Knockdown of Tagap in mice suppressed the sema3E- and plexin-D1-mediated release of thymocytes that adhered within the cortex through β1-containing integrins. This suppression led to the impaired translocation of thymocytes from the cortex to the medulla and resulted in the formation of ectopic medullary structures within the thymic cortex. Our results suggest that TAGAP variation modulates the risk of autoimmunity by altering thymocyte migration during thymic selection.


Tuberculosis in migrants - screening, surveillance and ethics.
Tuberculosis (TB) is the leading infectious cause of human mortality and is responsible for nearly 2 million deaths every year. It is often regarded as a 'silent killer' because it predominantly affects the poor and marginalized, and disease outbreaks occur in 'slow motion' compared to Ebola or coronavirus 2 (COVID-19). In low incidence countries, TB is predominantly an imported disease and TB control in migrants is pivotal for countries to progress towards TB elimination in accordance with the World Health Organisations (WHO's) End TB strategy. This review provides a brief overview of the different screening approaches and surveillance processes that are in place in low TB incidence countries. It also includes a detailed discussion of the ethical issues related to TB screening of migrants in these settings and the different interests that need to be balanced. Given recognition that a holistic approach that recognizes and respects basic human rights is required to end TB, the review considers the complexities that require consideration in low-incidence countries that are aiming for TB elimination.


BdWRKY38 is required for the incompatible interaction of Brachypodium distachyon with the necrotrophic fungus Rhizoctonia solani.
Rhizoctonia solani is a soil-borne necrotrophic fungus that causes sheath blight in grasses. The basal resistance of compatible interactions between R. solani and rice is known to be modulated by some WRKY transcription factors (TFs). However, genes and defense responses involved in incompatible interaction with R. solani remain unexplored, because no such interactions are known in any host plants. Recently, we demonstrated that Bd3-1, an accession of the model grass Brachypodium distachyon, is resistant to R. solani and, upon inoculation with the fungus, undergoes rapid induction of genes responsive to the phytohormone salicylic acid (SA) that encode the WRKY TFs BdWRKY38 and BdWRKY44. Here, we show that endogenous SA and these WRKY TFs positively regulate this accession-specific R. solani resistance. In contrast to a susceptible accession (Bd21), the infection process in the resistant accessions Bd3-1 and Tek-3 was suppressed at early stages before the development of fungal biomass and infection machinery. A comparative transcriptome analysis during pathogen infection revealed that putative WRKY-dependent defense genes were induced faster in the resistant accessions than in Bd21. A gene regulatory network (GRN) analysis based on the transcriptome dataset demonstrated that BdWRKY38 was a GRN hub connected to many target genes specifically in resistant accessions, whereas BdWRKY44 was shared in the GRNs of all three accessions. Moreover, overexpression of BdWRKY38 increased R. solani resistance in Bd21. Our findings demonstrate that these resistant accessions can activate an incompatible host response to R. solani, and BdWRKY38 regulates this response by mediating SA signaling.


Gastrointestinal and liver adverse effects of drugs used for treating IBD.
Drugs used for treating inflammatory bowel disease are known to have a number of gastrointestinal and liver adverse effects. 5-ASA products are relatively safe and have few adverse events. In contrast sulfasalazine has side effects in 11-40% of treated patients including fatigue, nausea, abdominal pain and diarrhoea. Glucocorticoids can induce or propagate peptic ulcers and upper GI bleeding especially in combination with NSAIDs. Thioguanins may have severe gastrointestinal side effects including gastrointestinal complaints (in up to 12%), hepatotoxicity (up to 4%) and pancreatitis (1%). Nodular regenerative hyperplasia (NRH) is an important potential side effect of thiopurine therapy especially in men with Crohn's disease after ileocecal resection. NRH may ultimately lead to portal hypertension. A major concern of methotrexate therapy in IBD besides myelosuppression and pulmonary fibrosis is hepatotoxicity. 5mg of folic acid substitution per week potentially decreases gastrointestinal side effects by 80% without interfering with the efficacy of methotrexate. Besides renal dysfunction, tremor, hirsutism, hypertension and gum hyperplasia cyclosporine is known to have a number of gastrointestinal side effects that occur with less frequency such as diarrhoea (up to 8%) nausea and vomiting (up to 10%) and hepatotoxicity in 1-4%. Rare gastrointestinal adverse events are gastritis and peptic ulcers. Paying attention to these potential deleterious side effects is mandatory for physicians treating IBD patients.


A simulated annealing algorithm for prioritized multiobjective optimization--implementation in an adaptive model predictive control configuration.
This paper presents a new stochastic algorithm for solving hierarchical multiobjective optimization problems. The algorithm is based on the simulated annealing concept and returns a single solution that corresponds to the lexicographic ordering approach. The algorithm optimizes simultaneously the multiple objectives by assigning a different initial temperature to each one, according to its position in the hierarchy. A major advantage of the proposed method is its low computational cost. This is very critical, particularly, for online applications, where the time that is available for decision making is limited. The method is tested in a number of benchmark problems, which illustrate its ability to find near-optimal solutions even in nonconvex multiobjective optimization problems. The results are comparable with those that are produced by state-of-the-art multiobjective evolutionary algorithms, such as the Nondominated Sorting Genetic Algorithm II. The algorithm is further applied to the solution of a large-scale problem that is formulated online, when a multiobjective adaptive model predictive control (MPC) configuration is adopted. This particular control scheme involves an adaptive discrete-time model of the system, which is developed using the radial-basis-function neural-network architecture. A key issue in the success of the adaptation strategy is the introduction of a persistent excitation constraint, which is transformed to a top-priority objective. The overall methodology is applied to the control problem of a pH reactor and proves to be superior to conventional MPC configurations.


Construction and bootstrap analysis of DNA fingerprinting-based phylogenetic trees with the freeware program FreeTree: application to trichomonad parasites.
The Win95/98/NT program FreeTree for computation of distance matrices and construction of phylogenetic or phenetic trees on the basis of random amplified polymorphic DNA (RAPD), RFLP and allozyme data is presented. In contrast to other similar software, the program FreeTree (available at http://www.natur.cuni.cz/~flegr/programs/freetree or http://ijs.sgmjournals.org/content/vol51/issue3/) can also assess the robustness of the tree topology by bootstrap, jackknife or operational taxonomic unit-jackknife analysis. Moreover, the program can be also used for the analysis of data obtained in several independent experiments performed with non-identical subsets of taxa. The function of the program was demonstrated by an analysis of RAPD data from 42 strains of 10 species of trichomonads. On the phylogenetic tree constructed using FreeTree, the high bootstrap values and short terminal branches for the Tritrichomonas foetus/suis 14-strain branch suggested relatively recent and probably clonal radiation of this species. At the same time, the relatively lower bootstrap values and long terminal branches for the Trichomonas vaginalis 20-strain branch suggested more ancient radiation of this species and the possible existence of genetic recombination (sexual reproduction) in this human pathogen. The low bootstrap values and the star-like topology of the whole Trichomonadidae tree confirm that the RAPD method is not suitable for phylogenetic analysis of protozoa at the level of higher taxa. It is proposed that the repeated bootstrap analysis should be an obligatory part of any RAPD study. It makes it possible to assess the reliability of the tree obtained and to adjust the amount of collected data (the number of random primers) to the amount of phylogenetic signals in the RAPD data of the taxon analysed. The FreeTree program makes such analysis possible.


Cellular localization and associations of the major lipolytic proteins in human skeletal muscle at rest and during exercise.
Lipolysis involves the sequential breakdown of fatty acids from triacylglycerol and is increased during energy stress such as exercise. Adipose triglyceride lipase (ATGL) is a key regulator of skeletal muscle lipolysis and perilipin (PLIN) 5 is postulated to be an important regulator of ATGL action of muscle lipolysis. Hence, we hypothesized that non-genomic regulation such as cellular localization and the interaction of these key proteins modulate muscle lipolysis during exercise. PLIN5, ATGL and CGI-58 were highly (>60%) colocated with Oil Red O (ORO) stained lipid droplets. PLIN5 was significantly colocated with ATGL, mitochondria and CGI-58, indicating a close association between the key lipolytic effectors in resting skeletal muscle. The colocation of the lipolytic proteins, their independent association with ORO and the PLIN5/ORO colocation were not altered after 60 min of moderate intensity exercise. Further experiments in cultured human myocytes showed that PLIN5 colocation with ORO or mitochondria is unaffected by pharmacological activation of lipolytic pathways. Together, these data suggest that the major lipolytic proteins are highly expressed at the lipid droplet and colocate in resting skeletal muscle, that their localization and interactions appear to remain unchanged during prolonged exercise, and, accordingly, that other post-translational mechanisms are likely regulators of skeletal muscle lipolysis.


Spatio-temporal reference model of Caenorhabditis elegans embryogenesis with cell contact maps.
The nematode Caenorhabditis elegans has been used as a model for developmental biology for decades. Still, the few publicly available spatio-temporal (4D) data sets have conflicting information regarding variability of cell positions and are not well-suited for a standard 4D embryonic model, due to compression. We have recorded six uncompressed embryos, and determined their lineage and 4D coordinates, including nuclear radii, until the end of gastrulation. We find a remarkable degree of stability in the cell positions, as well as little rotational movement, which allowed us to combine the data into a single reference model of C. elegans embryogenesis. Using Voronoi decomposition we generated the list of all predicted cell contacts during early embryogenesis and calculated these contacts up to the approximately 150 cell stage, and find that about 1500 contacts last 2.5 min or longer. The cell contact map allows for comparison of multiple 4D data sets, e.g., mutants or related species, at the cellular level. A comparison of our uncompressed 4D model with a compressed embryo shows that up to 40% of the cell contacts can be different. To visualize the 4D model interactively we developed a software utility. Our model provides an anatomical resource and can serve as foundation to display 4D expression data, a basis for developmental systems biology.


Tobacco Industry Marketing Exposure and Commercial Tobacco Product Use Disparities among American Indians and Alaska Natives.
Background: Non-Hispanic American Indians and Alaska Natives (NH AI/AN) have the highest commercial tobacco use (CTU) among U.S. racial/ethnic groups. Tobacco marketing is a risk factor, however few studies examine it among NH AI/AN. Objective: We identified prevalence of tobacco industry marketing exposure and correlates of CTU among NH AI/AN compared to other racial/ethnic groups. Methods: Data were from wave 1 (2013-2014; N = 32,320) of the Population Assessment of Tobacco and Health Study, analyzing self-reported exposure to tobacco ads from stores, tobacco package displays, direct mail and email marketing. Correlates of CTU were identified and interactions between racial/ethnic groups and tobacco marketing were assessed. Results: NH AI/AN (n = 955) had a higher prevalence of exposure to retail tobacco ads (64.5% vs 59.3%; p < 0.05), mail (20.2% vs.14.3%; p < 0.001) and email (17.0% vs.10.6%; p < 0.001) marketing than NH Whites (n = 19,297). Adjusting for tobacco use and related risk factors, exposure to email marketing remained higher among NH AI/AN than NH Whites. Interactions between racial/ethnic groups and marketing exposures on CTU were nonsignificant. CTU was higher among NH AI/AN than NH Whites and among adults who reported exposure to tobacco ads, mail, and email marketing. Conclusions/importance: There is higher tobacco marketing exposure in stores and via mail for NH AI/AN. Email marketing exposure was higher, even after controlling for tobacco-related risk factors. The tobacco industry may be targeting NH AI/AN through emails, which include coupons and other marketing promotions. Culturally relevant strategies that counter-act tobacco industry direct marketing tactics are needed to reduce disparities in this population.