Dependability of results in conference abstracts of randomized controlled trials in ophthalmology and author financial conflicts of interest as a factor associated with full publication.
Discrepancies between information in conference abstracts and full publications describing the same randomized controlled trial have been reported. The association between author conflicts of interest and the publication of randomized controlled trials is unclear. The objective of this study was to use randomized controlled trials in ophthalmology to evaluate (1) the agreement in the reported main outcome results by comparing abstracts and corresponding publications and (2) the association between the author conflicts of interest and publication of the results presented in the abstracts. We considered abstracts describing results of randomized controlled trials presented at the 2001-2004 Association for Research in Vision and Ophthalmology conferences as eligible for our study. Through electronic searching and by emailing abstract authors, we identified the earliest publication (journal article) containing results of each abstract's main outcome through November 2013. We categorized the discordance between the main outcome results in the abstract and its paired publication as qualitative (a difference in the direction of the estimated effect) or as quantitative. We used the Association for Research in Vision and Ophthalmology categories for conflicts of interest: financial interest, employee of business with interest, consultant to business with interest, inventor/developer with patent, and receiving ≥ 1 gift from industry in the past year. We calculated the relative risks (RRs) of publication associated with the categories of conflicts of interest for abstracts with results that were statistically significant, not statistically significant, or not reported. We included 513 abstracts, 230 (44.8 %) of which reached publication. Among the 86 pairs with the same main outcome domain at the same time point, 47 pairs (54.7 %) had discordant results: qualitative discordance in 7 pairs and quantitative discordance in 40 pairs. Quantitative discordance was indicated as < 10, 10-20, > 20 %, and unclear in 14, 5, 14, and 7 pairs, respectively. First authors reporting of one or more conflicts of interest was associated with a greater likelihood of publication (RR = 1.31; 95 % CI = 1.04 to 1.64) and a shorter time-to-publication (log-rank p = 0.026). First author conflicts of interests that were associated with publication were financial support (RR = 1.50; 95 % CI = 1.19 to 1.90) and one or more gifts (RR = 1.42; 95 % CI = 1.05 to 1.92). The association between conflicts of interest and publication remained, irrespective of the statistical significance of the results. More than half the abstract/publication pairs exhibited some amount of discordance in the main outcome results, calling into question the dependability of conference abstracts. Regardless of the main outcome results, the conflicts of interests of the abstract's first author were associated with publication.


Combined microRNA and mRNA expression analysis in pediatric multiple sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease.
Multiple sclerosis (MS) is a complex disease of the CNS that usually affects young adults, although 3-5% of cases are diagnosed in childhood and adolescence (hence called pediatric MS, PedMS). Genetic predisposition, among other factors, seems to contribute to the risk of the onset, in pediatric as in adult ages, but few studies have investigated the genetic 'environmentally naïve' load of PedMS. The main goal of this study was to identify circulating markers (miRNAs), target genes (mRNAs) and functional pathways associated with PedMS; we also verified the impact of miRNAs on clinical features, i.e. disability and cognitive performances. The investigation was performed in 19 PedMS and 20 pediatric controls (PCs) using a High-Throughput Next-generation Sequencing (HT-NGS) approach followed by an integrated bioinformatics/biostatistics analysis. Twelve miRNAs were significantly upregulated (let-7a-5p, let-7b-5p, miR-25-3p, miR-125a-5p, miR-942-5p, miR-221-3p, miR-652-3p, miR-182-5p, miR-185-5p, miR-181a-5p, miR-320a, miR-99b-5p) and 1 miRNA was downregulated (miR-148b-3p) in PedMS compared with PCs. The interactions between the significant miRNAs and their targets uncovered predicted genes (i.e. TNFSF13B, TLR2, BACH2, KLF4) related to immunological functions, as well as genes involved in autophagy-related processes (i.e. ATG16L1, SORT1, LAMP2) and ATPase activity (i.e. ABCA1, GPX3). No significant molecular profiles were associated with any PedMS demographic/clinical features. Both miRNAs and mRNA expressions predicted the phenotypes (PedMS-PC) with an accuracy of 92% and 91%, respectively. In our view, this original strategy of contemporary miRNA/mRNA analysis may help to shed light in the genetic background of the disease, suggesting further molecular investigations in novel pathogenic mechanisms.


Ability of medical students to calculate drug doses in children after their paediatric attachment.
Dose calculation errors constitute a significant part of prescribing errors which might have resulted from informal teaching of the topic in medical schools. To determine adequacy of knowledge and skills of drug dose calculations in children acquired by medical students during their clinical attachment in paediatrics. Fifty two 5th year medical students of the Lagos State University College of Medicine (LASUCOM), Ikeja were examined on drug dose calculations from a vial and ampoules of injections, syrup and suspension, and tablet formulation. The examination was with a structured questionnaire mostly in the form of multiple choice questions. Thirty-six (69.2%) and 30 (57.7%) students were taught drug dose calculation in neonatal posting and during ward rounds/ bed-side teaching, respectively. Less than 50% of the students were able to calculate the correct doses of each of adrenaline, gentamicin, chloroquine and sodium bicarbonate injections required by the patient. Dose calculation was however relatively better with adrenalin when compared with the other injections. The proportion of female students that calculated the correct doses of quinine syrup and cefuroxime suspension were significantly higher than those of their male counterparts (p<0.05 and p<0.01, respectively; Chi-square test). When doses calculated in mg/dose and mL/dose was compared for adrenalin injection and each of quinine syrup and cefuroxime suspension, there were significant differences (adrenaline and quinine, p=0.005; adrenaline and cefuroxime, p=0.003: Fischer's exact test). Dose calculation errors of similar magnitude to injections, syrup and suspension were also observed with tablet formulation. LASUCOM medical students lacked the basic knowledge of paediatric drug dose calculations but were willing to learn if the topic was formally taught. Drug dose calculations should be given a prominent consideration in the undergraduate medical curriculum in Nigeria.


Molecular Emissions from Stretched Excitation Pulse in Nanosecond Phase-Selective Laser-Induced Breakdown Spectroscopy of TiO2 Nanoaerosols.
In phase-selective laser-induced breakdown spectroscopy (PS-LIBS), gas-borne nanoparticles are irradiated with laser pulses (∼2.4 GW/cm2) resulting in breakdown of the nanoparticle phase but not the surrounding gas phase. In this work, the effect of excitation laser-pulse duration and energy on the intensity and duration of TiO2-nanoparticle PS-LIBS emission signal is investigated. Laser pulses from a frequency-doubled neodymium-doped yttrium aluminum garnet (Nd:YAG) laser (532 nm) are stretched from 8 ns (full width at half maximum, FWHM) up to ∼30 ns at fixed pulse energy using combinations of two optical cavities. The intensity of the titanium atomic emissions at around 500 nm wavelength increases by ∼60%, with the stretched pulse and emissions at around 482 nm, attributed to TiO, enhanced over 10 times. While the atomic emissions rise with the stretched laser pulse and decay around 20 ns after the end of the laser pulse, the TiO emissions reach their peak intensity at about 20 ns later and last longer. At low laser energy (i.e., 1 mJ/pulse, or 80 MW/cm2), the TiO emissions dominate, but their increase with laser energy is lower compared to the atomic emissions. The origin of the 482 nm emission is explored by examining several different aerosol setups, including Ti-O, Ti-N, and Ti-O-N from a spark particle generator and Ti-O-N-C-H aerosol from flame synthesis. The 482 nm emissions are attributed to electronically excited TiO, likely resulting from the reaction of excited titanium atoms with surrounding oxidizing (carbonaceous and/or radical) species. The effects of pulse length are attributed to the shift of absorption from the initial interaction with the particle to the prolonged interaction with the plasma through inverse bremsstrahlung.


Defining central themes in breast cancer biology by differential proteomics: conserved regulation of cell spreading and focal adhesion kinase.
Breast cancer is a highly heterogeneous disease, an observation that underscores the importance of elucidating conserved molecular characteristics, such as gene and protein expression, across breast cancer cell types toward providing a greater understanding of context-specific features central to this disease. Motivated by the goal of defining central biological themes across breast cancer cell subtypes, we conducted a global proteomic analysis of three breast cancer cell lines, MCF7, SK-BR-3, and MDA-MB-231, and compared these to a model of nontransformed mammary cells (MCF10A). Our results demonstrate modulation of proteins localized to the extracellular matrix, plasma membrane, and nucleus, along with coordinate decreases in proteins that regulate "cell spreading," a cellular event previously shown to be dysregulated in transformed cells. Protein interaction network analysis revealed the clustering of focal adhesion kinase (FAK), a fundamental regulator of cell spreading, with several proteins identified as mutually, differentially abundant across breast cancer cell lines that impact expression and activity of FAK, such as neprilysin and keratin 19. These analyses provide insights into conservation of protein expression across breast cancer cell subtypes, a subset of which warrants further investigation for their roles in the regulation of cell spreading and FAK in breast cancer.


A Fluoroscopic Credentialing/Safety Program at a Large Research Hospital.
The Brigham and Women's Hospital is an ~700 bed broad-scope licensed facility with a vigorous fluoroscopy service. Concomitant with this service is an equally robust quality management program to safeguard both patient and personnel from excessive radiation doses. The FDA, in an attempt to avoid serious skin injury for certain fluoroscopically guided procedures, issued a Public Health Advisory in 1994. Four years later the institutional Radiation Safety Committee voted to expand an existing fluoroscopic safety course to include a more formal credentialing/safety requirement. The specific parameters associated with this program follow.


Epidemiological and clinicopathological characteristics of lung cancer in a teaching hospital in Iran.
Lung cancer is one of the most commonly diagnosed cancers and the most frequent cause of cancer-related death worldwide. In Iran, it ranks second and third as the cancer-causing death in men and women, respectively. We carried out this study to find out the demographic, clinical, and histological characteristics and risk factors of lung cancer in a referral tertiary center in Iran. A retrospective study was conducted on cases of primary lung cancer based on the results of registered cancer reports of cytological and pathological specimens between March 2001 and March 2012. Demographic variables, clinical manifestations, histology and location of tumors were determined based on the data found in the medical records of each patient. Definite or probable etiologic factors were identified. Data analysis was performed with SPSS version 16 and a p-value ≤ 0.05 was considered as significant. A total of 203 patients, with a mean age of 65.7 years (SD=11.2), with primary lung cancer were identified, 81.3% being men. Of the total, 110 cases (54.2%) were living in urban areas. In 53.2% of cases, the site of tumor was on the right side and in 72.9% of cases the lesion was centrally located. The histological types of lung cancer were squamous cell carcinoma (SCC) in 107 cases (52.7%), adenocarcinoma (AC) in 30 cases (14.8%), and small cell carcinoma (SC) in 27 cases (13.3%). Significant correlations between the gender and residence, smoking, and the histological type and location (central or peripheral) of tumor were found. The percentage of smokers was 75.2% in men and 15.8% in women. Smoking was the most important risk factor and squamous cell carcinoma the most common histological type of lung cancer in our study. Male sex and being a smoker was associated with histological types of SCC while being nonsmoker had relationship with adenocarcinoma.


The TiltMeter app is a novel and accurate measurement tool for the weight bearing lunge test.
The weight bearing lunge test is increasing being used by health care clinicians who treat lower limb and foot pathology. This measure is commonly established accurately and reliably with the use of expensive equipment. This study aims to compare the digital inclinometer with a free app, TiltMeter on an Apple iPhone. This was an intra-rater and inter-rater reliability study. Two raters (novice and experienced) conducted the measurements in both a bent knee and straight leg position to determine the intra-rater and inter-rater reliability. Concurrent validity was also established. Allied health practitioners were recruited as participants from the workplace. A preconditioning stretch was conducted and the ankle range of motion was established with the weight bearing lunge test position with firstly the leg straight and secondly with the knee bent. The measurement device and each participant were randomised during measurement. The intra-rater reliability and inter-rater reliability for the devices and in both positions were all over ICC 0.8 except for one intra-rater measure (Digital inclinometer, novice, ICC 0.65). The inter-rater reliability between the digital inclinometer and the tilmeter was near perfect, ICC 0.96 (CI: 0.898-0.983); Concurrent validity ICC between the two devices was 0.83 (CI: -0.740 to 0.445). The use of the Tiltmeter app on the iPhone is a reliable and inexpensive tool to measure the available ankle range of motion. Health practitioners should use caution in applying these findings to other smart phone equipment if surface areas are not comparable.


Anatomico-radiological study of the borderline sella.
Multidirectional thin section tomography was performed on 62 excised sphenoidal bones. The pituitary gland was then sectioned and examined microscopically for evidence of microadenoma, cellular hyperplasia or cysts. There is absolutely no meaningful correlation between the radiological and the histological findings. Minor sellar changes in the form of slight irregularity of the lamina dura, asymmetry of the sellar floor or thinning of the dorsum sellae may be found in the absence of any histopathological abnormality.


Reasons for refusing parenteral therapy: a qualitative study of patients with pulmonary arterial hypertension.
While parenteral prostacyclin (pPCY) therapy, delivered either subcutaneously or intravenously, is recommended for pulmonary arterial hypertension patients with severe or rapidly developing disease, some patients refuse this treatment. This study aimed to understand, directly from patients with pulmonary arterial hypertension, why pPCY was refused and, in some cases, later accepted. Interviews were conducted with 25 pulmonary arterial hypertension patients who previously refused pPCY therapy (Group A: Refused/Never initiated (n = 9) and Group B: Refused/Initiated (n = 16)). Patients in both groups believed that pPCY could improve their symptoms, slow disease progression, and provide them a greater ability to perform activities. Reasons for refusal included concern over side effects and the perceived limitations of pPCY on daily activities. Group A perceived their decision as a balance between quality of life and prolonging life and most acknowledged they would reconsider pPCY if other treatment options were exhausted. Group B cited they initiated therapy due to a worsening of symptoms, disease progression, to improve quality of life, to be there for their family, or a desire to live. Following initiation, Group B indicated their experience met expectations with reduced symptoms, slowed disease progression, and perception of improved survival; concerns related to pPCY were described as manageable. Given the efficacy of pPCY therapy, clinicians should apply knowledge of these findings in clinical practice. Patients noted improvements to parenteral pump technologies to include smaller size, water resistance, and implantability may increase their acceptance of this modality. Development efforts should focus on technologies that increase the acceptance of pPCY when indicated.


Serum microRNAs are promising novel biomarkers.
Circulating nucleic acids (CNAs) offer unique opportunities for early diagnosis of clinical conditions. Here we show that microRNAs, a family of small non-coding regulatory RNAs involved in human development and pathology, are present in bodily fluids and represent new effective biomarkers. After developing protocols for extracting and quantifying microRNAs in serum and other body fluids, the serum microRNA profiles of several healthy individuals were determined and found to be similar, validating the robustness of our methods. To address the possibility that the abundance of specific microRNAs might change during physiological or pathological conditions, serum microRNA levels in pregnant and non pregnant women were compared. In sera from pregnant women, microRNAs associated with human placenta were significantly elevated and their levels correlated with pregnancy stage. Considering the central role of microRNAs in development and disease, our results highlight the medically relevant potential of determining microRNA levels in serum and other body fluids. Thus, microRNAs are a new class of CNAs that promise to serve as useful clinical biomarkers.


[Polybrominated diphenyl ether flame retardants in foodstuffs and human milk].
Polybrominated diphenyl ethers (PBDEs) have been used worldwide as additive flame retardants in polymeric materials. Commercial products consist predominantly of deca-, octa-, and pentabromodiphenyl ether mixtures. PBDEs are resistant to degradation in the natural environment and Penta-BDE in particular accumulates in the fatty tissues of fish, birds and mammals (including humans). Several toxic effects on the thyroid system or on neurodevelopment have been reported in experimental animals exposed to PBDEs. It is likely that human exposure is predominantly through the ingestion of contaminated food and/or mother's milk. The potential health effects of dietary exposure to PBDEs have now become a great concern because of the increasing PBDE levels in the biosphere. In this review, published information on the toxicology of PBDEs, levels in foodstuffs and human milk, and analytical methods has been compiled.


Microfiber Release to Water, Via Laundering, and to Air, via Everyday Use: A Comparison between Polyester Clothing with Differing Textile Parameters.
Textiles are one of the major sources of microplastic pollution to aquatic environments and have also been reported in dry and wet atmospheric deposition. There is still a lack of information on the direct release of microfibers from garments to the air and on the influence of textile characteristics including structure, type of yarn, and twist. The present study examines microfiber emissions directly to the air and to water as a consequence of laundering. Polyester garments with different textile characteristics were examined including various material compositions, fabric structure, yarn twist, fiber type, and hairiness. Scaling up our data indicates release of microfibers per person per year to the air is of a similar order of magnitude to that released to wastewater by laundering. The lowest releases to both air and water were recorded for a garment with a very compact woven structure and highly twisted yarns made of continuous filaments, compared with those with a looser structure (knitted, short staple fibers, lower twist). Our results demonstrate for the first time that direct release of microfibers from garments to air as a consequence of wear is of equal importance to releases to water. Currently there is considerable interest in interventions focused on capture from wastewater. However, our results suggest more effective interventions are likely to result from changes in textile design that could reduce emissions to both air and water.


Changes in the relation of self-efficacy beliefs and behaviors across development.
Many social science theories that examine the connection between beliefs and behaviors assume that belief constructs will predict behaviors similarly across development. Converging research implies that this assumption may not be tenable across all ages or all belief constructs. Thus, to test this implication, the relation between behavior and beliefs about the self was examined in 2 independent data sets with 2 different constructs: aggression and achievement. The respondents were 6-18 years of age and predominately Caucasian. Results using quasi-simplex structural equation models suggest that self-beliefs become more strongly related to behavior as children grow older independent of the reliability of the measures used. Possible limitations in the use of self-report methodology with young children are discussed.


Ghrelin is produced by and directly activates corticotrope cells from adrenocorticotropin-secreting adenomas.
In Cushing's disease, ACTH hypersecretion by pituitary corticotrope adenoma cells and resulting hypercortisolism is accompanied by a severely blunted GH secretory response. Interestingly, in Cushing's disease, ghrelin markedly increases plasma ACTH, whereas its stimulatory action on GH secretion is reduced. Although the reported expression of ghrelin receptors (GHS-R) in corticotrope tumors offers a potential mechanism for ghrelin-induced ACTH hypersecretion, studies on the direct effects of synthetic GH secretagogues on corticotropinoma cells offered contradictory results. To evaluate the direct action of ghrelin on corticotropinoma cells from two patients with Cushing's disease, we measured its effect on free cytosolic calcium concentration ([Ca(2+)](i)). Additionally, expression of GHS-R and its ligand ghrelin was examined in these cells and in five additional corticotropinomas. Ghrelin (10(-6) m) induced a marked [Ca(2+)](i) increase in 89.5% (case 1; n = 19 cells) and 85% (case 2; n = 13 cells) of corticotropinoma cells. Moreover, RT-PCR showed that expression of GHS-R isoforms is accompanied by that of ghrelin in all seven corticotrope adenomas examined. Importantly, double immunogold electron microscopy revealed that ghrelin is costored within ACTH secretory vesicles in densely granulated adenomatous corticotropes. These results constitute the first demonstration that ghrelin acts directly on corticotrope tumor cells derived from patients with Cushing's disease. The presence of ghrelin and GHS-R suggests that pituitary ghrelin may play an autocrine/paracrine role in regulating ACTH release in Cushing's disease. Our findings provide a plausible cellular basis for the exaggerated ACTH response to ghrelin in Cushing's disease and suggest novel research strategies to develop medical treatments for this disease.


Gene activation without histone acetylation in Drosophila melanogaster.
Chromosomal puffing, generally believed to represent gene activation in Drosophila, was induced in the presence of radioactively labeled acetate. There is no preferential uptake of these labeled molecules in regions of gene activation. It is concluded that the acetylation of histones does not play a general role in the regulation of RNA synthesis in Drosophila melanogaster.


Studying the impact of COVID-19 mitigation policies on childhood obesity, health behaviors, and disparities in an observational cohort: Protocol for the COVID-19 Family Study.
COVID-19 pandemic control policies, including school closures, suspended extra-curricular activities, and social distancing, were introduced to prevent viral transmission, and disrupted children's daily routines, health behaviors, and wellness. This observational cohort study among 697 families with children or adolescents, based on the Family Stress Model, aims to: 1) evaluate pre- to during-pandemic changes in child health behaviors (diet, physical activity, sleep) and weight gain, 2) identify mechanisms explaining the changes, and 3) determine projected healthcare costs on weight gain and obesity. Each aim includes an examination by racial and ethnic, socioeconomic, and geographic disparities. The study employs a mixed methods design, recruiting children and their caregivers from two obesity prevention trials halted in 2020. Enrolled participants complete annual surveys to assess child health behaviors, family resources, routines, and demographics, and home environment in 2020-2022. Height and weight are measured annually in 2021-2022. Annual semi-structured interviews are conducted within a subsample to understand mechanisms of observed changes. Multilevel mixed models and mediation analyses are used to examine changes in child health behaviors and weight gain and mechanisms underlying the changes. Qualitative data are analyzed within and across time points and integrated with quantitative findings to further explain mechanisms. Markov models are used to determine healthcare costs for unhealthy child behaviors and weight gain. Findings from this study will aid in understanding pandemic-related changes in child health behaviors and weight status and will provide insights for the implementation of future programs and policies to improve child and family wellness.


Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice.
Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.


Abdominal myomectomy for infertility: a comprehensive review.
To obtain estimates of the effect of abdominal myomectomy on infertility, information from studies published in the English language literature between 1982 and 1996 was retrieved. Articles were identified through hand and computerized searches using Medline. A total of 27 trials, all published in peer-reviewed journals, was identified, of which four were excluded from the analysis because of methodological limitations. All studies were non-comparative and only nine were prospective. The sample size was generally limited, the mean number of patients included being 49 and the mean number of infertile subjects 26. All patients were followed for at least 12 months after surgery in 12 studies. The combined estimate of pregnancy rates across prospective studies based on a total of 138 observed subjects was 57% [95% confidence interval (CI), 48-65%]. Time to conception varied from a mean of 8 to 20 months. Survival analysis was used in only three studies, with cumulative rates ranging from 57 to 67% at 1 year, and 63% at 5 years. The overall conception rate among seven prospective studies in which only women with otherwise unexplained infertility were recruited was 61% (95% CI, 51-70%) compared with 38% (95% CI, 20-59%) in two prospective studies that included patients with causes of infertility in addition to myomas (chi2(1) = 4.25, P = 0.04; mean difference = 23%, 95% CI, 1-43%; OR = 2.47, 95% CI, 1.03-5.94). The conception rate ranged from 58 to 65% in the three studies of women with only intramural and/or subserous fibroids and were respectively 53 and 70% in the two that considered only patients with submucous myomas. Data on recurrence after myomectomy were reported in 13 articles, with rates varying from 4 to 47%. According to the available evidence, slightly less than two-thirds of women with uterine leiomyomas and otherwise unexplained infertility conceived after myomectomy. However, comparison with expectant management is needed before drawing definitive conclusions on the effectiveness of this time-honoured conservative surgical procedure.


Penumonic presentation of brucellosis.
Brucellosis is a rare disease in children. Lung involvement is an uncommon presentation of brucellosis. The authors are presenting a child with brucellosis, who presented with predominant pulmonary involvement. It was an eight-year-old child who was referred to us a case of non-resolving pneumonia. Brucella agglutination test was suggestive of brucellosis. He responded to the combination of doxycycline and rifampicin.


Rsc14-controlled expression of MNN6, MNN4 and MNN1 regulates mannosylphosphorylation of Saccharomyces cerevisiae cell wall mannoproteins.
ybl006cDelta was selected using an Alcian-blue-based screen aimed to identify nonessential genes involved in the regulation of mannosylphosphorylation. When cells of this deletant were mixed with the cationic dye Alcian blue in a typical assay, they remained white, indicating a low number of mannosylphosphate groups on the cell surface. ybl006cDelta cells did not show any defect in growth rate nor in the glycosylation or secretion rate of the major exoglucanase Exg1. Transcriptome analysis of ybl006cDelta using macroarrays showed at least two-fold changes in the expression of 52 genes (<0.9% of the genome). Three of these have previously been reported to be directly (MNN6 and MNN4) or indirectly (MNN1) implicated in the transfer of mannosylphosphate to the N- and O-oligosaccharides. Alterations in the expression of these genes were confirmed by Northern analysis. YBL006C product was recently identified as a subunit (Rsc14) of the RSC chromatin-remodelling complex of Saccharomyces cerevisiae. It follows that remodelling of chromatin can be an important regulatory mechanism for the maturation of cell wall mannoproteins.


The effect of lactic acid bacteria isolates on the urinary tract pathogens to infants in vitro.
Urinary tract infections are common clinical problems in children, even though lots of treatment strategies have been tried. Many studies of the application of probiotics for urinary tract infection in female adults exist, but there is a lack of studies in children. The aims of this study were to screen probiotic strains for inhibiting the uropathogens in vitro, to find candidates for in vivo study. Nine strains of E. coli were isolated from children with urinary tract infection and six uropathogens were obtained from Korean Collection for Type Cultures and American Type Culture Collection. Also 135 lactic acid bacteria (LAB) strains were isolated from healthy children, and were identified through physiologic, biochemical methods, 16S rDNA PCR, and data analysis. And with agar disk diffusion assay technique the antimicrobial activities of these LAB strains against those uropathogens were examined. Three strains of separated LAB strains demonstrated major antimicrobial activity against all the uropathogens. In the agar disk diffusion assay technique, antimicrobial activities increased most in the 4th day culture broth with separated Lactobacillus. In summary, some LAB can be used as candidates to develop the probiotic microorganisms that inhibit uropathogens in children, and are expected to be applied to treatment and prevention of pediatric urinary tract infection.


Surgical management of splenic hydatidosis.
This study was conducted to evaluate the surgical management of splenic hydatidosis in an area where the disease is endemic. Over a period of 16 years, 26 patients with splenic hydatidosis underwent surgery in our department. Preoperative investigations included plain abdominal X-ray, serology, ultrasonography, and computed tomography. In our series, splenic hydatidosis represented 3.5% of total abdominal hydatidosis. The majority of patients presented with abdominal discomfort and palpable swelling in the left hypochondrium. Twenty-two patients were operated on electively and 4 as emergency cases, including 2 with ruptured hydatids and 2 with infected hydatids of the spleen. Isolated splenic hydatid cysts were present in 21 patients, associated liver hydatid cysts in 4, and diffuse abdominal hydatidosis in 1 patient. All patients underwent splenectomy except for one patient who initially had partial splenectomy for a lower polar cyst. This patient also ended up undergoing a splenectomy for postoperative hemorrhage. One patient died on the sixth postoperative day (mortality rate 3.8%) as a result of multiorgan failure, and 4 developed minor complications (morbidity 15.4%). Splenic hydatidosis, although rare, is the third most common type of hydatidosis after liver and lung hydatidosis. This entity should thus be kept in mind when encountering a splenic cyst especially in areas where the disease is endemic. A splenectomy remains the treatment of choice because it demonstrates low morbidity and mortality rates.


[A light-hardened polymeric material for metal-plastic whole-cast fixed dentures].
Self-hardening material for metal plastic permanent dentures, has been developed by the Central Research Institute of Dentistry for the first time in Russia. Its physicomechanical properties are described and the results of toxicological trials are presented. The new material is superior in wear resistance to foreign analogs Kulzer Dentacolor and ESPE Visio-Gem. Toxicological studies demonstrated the biological inertness of the material during long contact with the internal media of human organism and the absence of toxic, sensitizing, and mutagenic action.


Long-term survival of ischemic cerebrovascular disease in the acute inflammatory stroke study, a hospital-based cohort described by TOAST and ASCO.
Ischemic cerebrovascular disease (ICVD) comprises multiple etiological phenotypes that share common clinical characteristics. Etiological classification of patients with ICVD is of major clinical interest to achieve optimal medical treatment and predict prognosis. The TOAST classification system has been widely used to describe stroke etiology but provides restricted phenotypic homogeneity within groups. The ASCO classification system has introduced a new approach in phenotypic classification, and aims to describe clinical characteristics without merging concurrent comorbidities. Inflammatory processes have been suggested to mediate stroke etiology and pathology. The Acute Inflammatory Stroke Study (AISS), a hospital-based cohort, is here introduced and described by TOAST and ASCO classification systems. The aim of this first analysis of AISS was to investigate long-term mortality in relation to ischemic stroke subtypes, and clinical and biochemical markers. AISS consecutively follows patients on 6 occasions up to 1 year after stroke onset. Complete workup according to ASCO comprised CT or MRI of the head, ECG, duplex of the extracranial arteries or CT/MR angiography and ultrasound of the heart. Level 2 evidence was required in each domain to obtain a comparable system to TOAST (ASCO2). Clinical and biochemical characteristics and mortality rates were documented and compared by the two classification systems. Of 142 patients consecutively evaluated and recruited in the study, a total of 101 ICVD patients (ischemic stroke, n = 84; transient ischemic attack, n = 17) were included in the final analysis. Agreement between ASCO2 and TOAST was very good. During the mean observation period of 28 months, 26 patients died. The 1- and 4-year mortality rates were 0 and 4% for large artery atherosclerosis (LAA); 23 and 36% for cardioembolism (CE); 0% for small artery occlusion (SAO); 63 and 100% for the subtype with unknown etiology due to incomplete workup (Unknown), and 12 and 29% for the cryptogenic subtype. As for the ASCO2 groups, the 1- and 4-year mortality rates were 0 and 6% in LAA, 25 and 36% in CE, 0% in SAO, 0 and 14% in LAA + CE, 0% in SAO + CE, 16 and 36% in the subgroup with undetermined etiology despite complete workup, and 56 and 100% in Unknown. Regression analysis showed that age, white blood cell count, fibrinogen and bilirubin, but not etiological subgroup, were independent predictors of mortality. Our findings indicate that clinical and biochemical markers may differentiate phenotypically homogeneous etiological subtypes and predict long-term mortality. Further studies with larger patient numbers are needed to investigate possible causative mechanisms.


Extended haplodiploidy hypothesis.
Evolution of altruistic behavior was a hurdle for the logic of Darwinian evolution. Soon after Hamilton formalized the concept of inclusive fitness, which explains how altruism can evolve, he suggested that the high sororal relatedness brought by haplodiploidy could be why Hymenopterans have a high prevalence in eusocial species, and why helpers in Hymenoptera are always female. Later it was noted that in order to capitalize on the high sororal relatedness, helpers would need to direct help toward sisters, and this would bias the population sex ratio. Under a 1:3 males:females sex ratio, the inclusive fitness valuation a female places on her sister, brother, and an own offspring are equal-apparently removing the benefit of helping over independent reproduction. Based on this argumentation, haplodiploidy hypothesis has been considered a red herring. However, here we show that when population sex ratio, cost of altruism, and population growth rate are considered together, haplodiploidy does promote female helping even with female-biased sex ratio, due the lowered cost of altruism in such populations. Our analysis highlights the need to re-evaluate the role of haplodiploidy in the evolution of helping, and the importance of fully exploring the model assumptions when comparing interactions of population sex ratios and social behaviors.


Spontaneous wrinkle emergence in nascent eumelanin thin films.
Self-patterning processes originated by physical stimuli have been extensively documented in thin films, whereas spontaneous wrinkling phenomena due to chemical transformation processes are, to the best of our knowledge, unprecedented. Herein we report a case of spontaneous polymerization-driven surface nano-patterning (∼500 nm) that develops in smooth thin solid films of 5,6-dihydroxyindole (DHI), a major precursor of eumelanin polymers, over a time scale of 30 to 60 days in air at room temperature. The phenomenon can be observed only above a critical film thickness of ∼250 nm and it is affected by exposure to ammonia vapors causing acceleration of the oxidation process. The thickness-dependent onset of wrinkling can be attributed to non-homogeneous rates of oxidation through the film causing slow swelling/expansion of the inner layers followed by fast stiffening and cross-linking in the outer layer exposed to higher oxygen levels.


Insulin restores neuronal nitric oxide synthase expression in streptozotocin-induced diabetic rats.
Nitric oxide (NO) is known to play an important role in the pathophysiology of insulin-dependent diabetic mellitus (IDDM). In an attempt to investigate the relation between insulin and NO in IDDM, the present study employed male Wistar rats to induce IDDM by intravenous injection of streptozotocin (STZ). Four groups of rats were used; untreated normal control group, insulin treated STZ group, vehicle-treated STZ control, and one group of age-matched rats which were orally supplied with glucose to increase plasma glucose (glucose-challenged rats). Changes of the activity and gene expression of neuronal nitric oxide synthase (nNOS) were examined in cerebellum and kidney of these groups. The activity of nNOS in cerebellum, determined by conversion of [3H] L-arginine to [3H] L-citrulline, in STZ-induced diabetic rats was markedly lower than normal rats. Insulin treatment reversed the nNOS activity. Similar reversion by insulin treatment was also obtained in the gene expression of nNOS. However, the activity and gene expression of nNOS in glucose-challenged rats were not different from those in normal rats. The role of hyperglycemia can thus be ruled out. These findings indicated that an impairment of nNOS in the brain of rats with IDDM is mainly due to the absence of insulin.


Different drug survival of first line tumour necrosis factor inhibitors in radiographic and non-radiographic axial spondyloarthritis: a multicentre retrospective survey.
Good drug survival of tumour necrosis factor inhibitors (TNFi) has been shown in axial spondyloarthritis (axSpA) patients treated in real-life setting. However, few studies have compared drug survival of the first TNF inhibitor between radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) patients in real-world clinical practice. The aim of this work was to evaluate the effectiveness by assessing the retention rate of first-line TNFi in r-axSpA and nr-axSpA patients. Baseline predictive factors for TNFi discontinuation were also evaluated. We retrospectively assessed axSpA patients, who underwent first line therapy with TNFi. Demographic and clinical data was obtained through structured interview, review of medical records and physical examination. Disease activity indices such as the Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score evaluating C Reactive Protein (ASDAS-CRP), Leeds Enthesitis Index (LEI) were assessed at baseline. Moreover Health Assessment QuestionnaireDisability Index (HAQ), erythrocyte sedimentation rate (ESR, mm/h), CRP (mg/dl) and HLA-B27 were recorded as well. Data on x-ray and magnetic resonance imaging of the sacroiliac joints were also collected. Drug retention rates were analysed using Kaplan-Meier curves; log-rank test was performed to demonstrate differences in the survival functions. Cox regression models were used to estimate the inference of several disease and clinical characteristics on drug discontinuation. Drug survival of first-line TNFi was significantly lower in patients who had nr-axSpA than in those with r-axSpA (p=0.005). HLA-B27 frequency was higher in patients with x-ray sacroiliitis than in those with nr-axSpA (p=0.01) as well as mean CRP serum level (p=0.0001), whereas both mean BASDAI and LEI score were higher in patients with nr-axSpA than in those with r-axSpA (p=0.018 and p=0.007, respectively). Global retention rate in our cohort was 60.34% with mean survival time (MST) of 58.68 months (95% CI 47.93-69.42). MST for patients diagnosed with r-axSpA was 66.79 months (95% CI 53.54-80.04) and 39.05 months (95% CI 24.12-53.99) for those with nr-axSpA. Moreover, nr-axSpA (HR 1.620), higher BMI (HR 1.093) and BASFI, (HR 1.192) had an impact on drug discontinuation, whereas HLA-B27 presence (HR. 0.523) had protective effect. Effectiveness of TNFi, seems to be lower in nr-axSpA patients than in those with r-axSpA. In addition obesity and functional disability negatively impact the persistence on first line TNFi in axSpA patients in real life setting.


Application of biotechnology to the study of molluscan hosts of animal parasites.
The intimate and complex relationship that exists between man and mollusc makes the group an ideal target for the application of biotechnology. The paper discusses and reviews the application of both the conventional and new molecular techniques to the study of the molluscan hosts of animal parasites. The remarkable advances in molluscan biology which have occurred during the past two decades as a consequence of conventional technological methods are noted and applications pertinent to problems in Southeast Asia are cited. Applications of new biotechniques, including those of molecular biology, to problems of the host-parasite interaction are discussed. Examples of how the new biotechnology may resolve present and future problems in applied malacology are presented.


When are burns not accidental?
One hundred and ninety five children aged up to 6 years with burns and scalds (30 non-accidental and 165 accidental) were studied retrospectively. The history, presentation, and other typical injuries assisted the diagnosis of abuse. Scalds accounted for 81% of accidents and 25% of the cases of abuse, and burns for 17% and 44%, respectively. Scalds usually followed spillage from kitchen containers in accidents and forced tap water immersion in cases of abuse. Burns in cases of both accidents and abuse resulted from contact with a wide range of household appliances, including room heaters. Attention is drawn to the back of the hand as an important site in cases of abuse, as well as the legs, buttocks, and feet. It is speculated that the low level of reporting of this form of child abuse reflects failure of diagnosis.


genetic determinants of intrinsic colistin tolerance in Acinetobacter baumannii.
Acinetobacter baumannii is a leading cause of multidrug-resistant infections worldwide. This organism poses a particular challenge due to its ability to acquire resistance to new antibiotics through adaptation or mutation. This study was undertaken to determine the mechanisms governing the adaptability of A. baumannii to the antibiotic colistin. Screening of a transposon mutant library identified over 30 genes involved in inducible colistin resistance in A. baumannii. One of the genes identified was lpsB, which encodes a glycosyltransferase involved in lipopolysaccharide (LPS) synthesis. We demonstrate that loss of LpsB function results in increased sensitivity to both colistin and cationic antimicrobial peptides of the innate immune system. Moreover, LpsB is critical for pathogenesis in a pulmonary model of infection. Taken together, these data define bacterial processes required for intrinsic colistin tolerance in A. baumannii and underscore the importance of outer membrane structure in both antibiotic resistance and the pathogenesis of A. baumannii.


[Morbidity in Chagas' disease. IV. Longitudinal study of 10 years in Pains and Iguatama, Minas Gerais, Brazil].
An evolutive study of the "case-control" type was carried out in an endemic area of Chagas' disease in Minas Gerais State, Brazil, using two cross-section evaluations with an interval of ten years between them (1974-1984). Patients were paired for sex and age. In the first cross-section study 264 pairs one with a positive serology and the other with a negative serology for T. cruzi antibodies were included. In the second evaluation, ten years later, 235 patients among those with previous positive serology and 216 with negative serology were located, but only 110 pairs could be recomposed and reexamined (clinical examination, ECG and Rx of the heart and esophagus). The incidence of chagasic cardiopathy in the cases with positive serology but previously assymptomatic was 38.3% during the ten year period. On the other hand there was a deterioration in 24% of the patients with chagasic cardiopathy since the first examination. Considering all clinical forms of the disease in 34.5% of the patients the clinical situation deteriorated, in 57.3% there was no change and in 8.2% the situation improved. The general mortality in the period was 23% in the chagasic group and 10.6% in the control group, but the lethality by cardiopathy was 17% in chagasic group and only 23.3% in the control group. The mortality was twice as high in males than in females, mainly in the age group from 30 to 59 years.


NF-AB, a liver-specific and cytokine-inducible nuclear factor that interacts with the interleukin-1 response element of the rat alpha 1-acid glycoprotein gene.
The 142-bp cytokine response element of the rat alpha 1-acid glycoprotein (AGP) gene is a complex of several additively contributing regulatory sequences. By using deletions and point mutations, a minimal interleukin-1 (IL-1) response element was localized to the region from positions 1 to 36 within the 5'-most AB fragment of the cytokine response element. Two distinct sequence motifs were contained within this element, both of which were required to achieve full IL-1 response in rat and human hepatoma cells. This element showed a minor response to phorbol ester treatment only in human hepatoma cells. Southwestern (DNA-protein) blot analysis of nuclear proteins of rat liver and hepatoma cells revealed the presence of a heat-labile nuclear factor (NF-AB). NF-AB migrated as a basic protein with an apparent molecular mass of 37 kDa and bound specifically to the DNA sequence at positions 10 to 37 of the AB fragment. The NF-AB binding activity was detected neither in the cytoplasmic fraction of rat hepatoma cells nor in nuclear extracts from control or acute-phase rat kidney. The binding activity of NF-AB correlated with the transcriptional activity of the endogenous AGP gene in rat liver and hepatoma cells. Nuclear extract from human HepG2 cells showed a similar binding activity with an apparent molecular mass of 34.5 kDa. The human NF-AB binding activity was detectable only after 13 h of cytokine treatment and was not induced by phorbol ester. Tissue distribution, DNA sequence binding specificity, and kinetics of cytokine induction of NF-AB do not coincide with the characteristics of any other described factors that have been associated with cytokine regulation. Therefore, NF-AB is considered a new candidate involved in IL-1 regulation of the rat AGP gene.


Vibration phases estimation based on multi-channel interferometry for ISAL.
Target vibration introduces unexpected vibration phases in the echo signal of inverse synthetic aperture LADAR (ISAL). The vibration phases cause the imaging results to be defocused. How to estimate the vibration phases has always been one of the difficulties in ISAL imaging, and there has not been an effective solution. In this paper, two methods are proposed to estimate the vibration phases in different situations. The method based on multi-channel along-track interferometry (MCATI method) is for some cases that the target velocity vector is parallel to some baselines of ISAL. The method based on orthogonal interferometry (OI method) is for other cases that the target velocity vector is not parallel to any baseline of ISAL. In addition, a high signal to noise ratio (SNR) is essential for the MCATI and OI methods to get high estimation accuracy. Therefore, a large power-aperture product should be carefully considered in the ISAL system design. Furthermore, on the condition of low SNR, range cell accumulation is also helpful to reduce the influence of noise. Take the ISAL, which is utilized to image the satellite in 500 km orbit, as an example, the estimation accuracy can satisfy the demand of synthetic aperture imaging with 0 dB single-pulse SNR and 300 range cell accumulation. The proposed methods are verified with simulation and experiment.


Raised intrathecal levels of APRIL and BAFF in patients with systemic lupus erythematosus: relationship to neuropsychiatric symptoms.
The tumour necrosis factor (TNF) family ligands BAFF (B-cell activating factor of TNF family) and APRIL (a proliferation-inducing ligand) are essential for B-cell survival and function. Elevated serum levels of BAFF and APRIL have been reported earlier in patients with systemic lupus erythematosus (SLE). Since autoantibody formation in the central nervous system (CNS) is a distinct feature of neuropsychiatric SLE (NPSLE), we have investigated whether NPSLE is associated with an enhanced intrathecal production of APRIL and BAFF. Levels of BAFF and APRIL in cerebrospinal fluid (CSF) and serum from healthy controls, SLE patients without CNS involvement, and patients with NPSLE were determined by enzyme-linked immunosorbent assay. Interleukin-6 (IL-6) levels were determined by an IL-6-specific bioassay. SLE patients had levels of APRIL in CSF that were more than 20-fold higher and levels of BAFF in CSF that were more than 200-fold higher than those of healthy controls. Separate analyses of SLE patients with and without CNS involvement revealed that NPSLE patients had enhanced levels of APRIL in CSF. BAFF and APRIL were likely produced locally in the CNS as CSF and serum levels did not correlate. Moreover, CSF levels of APRIL correlated with BAFF but not with IL-6, suggesting that APRIL and BAFF in the CNS are regulated together but that they are produced independently of IL-6. To our knowledge this is the first study to show elevated levels of BAFF and APRIL in CSF of SLE patients. APRIL was augmented in NPSLE patients compared with SLE patients without CNS involvement. APRIL and BAFF antagonists breeching the blood-brain barrier therefore could have beneficial effects on SLE patients, in particular patients with NPSLE.


[Effect of the GABA receptor blockader bicuculline on the action of fenibut and diazepam].
Fenibut (100 mg/kg) suppressed the motility and emotional reactivity but did not possess any antiaggressive properties, whereas diazepam (2.5 mg/kg) did increase the motility and reduced aggressiveness in rats. Bicuculline (1.25 mg/kg) itself did not cause any behavioral changes, although it was capable of antagonizing the effects of diazepam and to potentiate those of fenibut. Bicuculline attenuated the GABA rise but did not influence the increased content of HVA and DOPAC after fenibut. The importance of the bicuculline-insensitive mechanisms in the action of fenibut and bicuculline-sensitive ones in the action of diazepam is discussed.


Toxicological Profiling of Potential Shikimate Kinase Inhibitors Against Mycobacterium tuberculosis.
Over the last decade, Mycobacterium tuberculosis has mutated into a putative 'superbug', as treatments against it have failed due to increasing antimicrobial resistance. As a result, the rising incidence of multidrug-resistant tuberculosis (MDR-TB) is posing a significant public health threat, thus, the need to develop effective drugs for MDR-TB has become an urgent priority. To identify new drug candidates for the treatment of MDR-TB, the present study was based on mycobacterial shikimate kinase (MtSK) as the pharmacological target. One hundred potential MtSK inhibitors were identified from literature and database searches to identify compounds that were designed to specifically function as MtSK antagonists. The ADME properties of these compounds were evaluated by using the SwissADME web tool. ProTox-II software was also used to investigate any potential endocrine disrupting effects, mediated through their interaction with oestrogenic and/or androgenic receptors. This study also aimed to predict LD50 values of potential drug candidates that would be active against the standard H37Rv strain of M. tuberculosis, by using the ProTox-II in silico tool. The molecules for which no structural hazard alerts were identified with these software tools were further subjected to molecular docking analyses and molecular dynamic simulations to estimate their ability to interact with the MtSK enzyme. Preliminary results from SwissADME indicated that 30 molecules were drug-like, due to their physicochemical and pharmacokinetic properties. However, subsequent analysis with ToxTree and ProTox-II indicated that only three of these 30 drug-like molecules were suitable for taking forward into further in vitro experiments. This study, which is based on the use of commonly used open-source in silico tools, identified new MtSK ligands for potential use in the development of new drugs for the therapeutic management of tuberculosis. An initial prediction of their safety profile was also generated.


Long-term survival of Japanese patients transported to an emergency department because of syncope.
Cardiovascular disease mortality is affected by ethnic differences and is lower in Japan than in Western countries. Although patients with cardiac syncope have significantly higher mortality than patients with noncardiac syncope in Western countries, no such phenomenon has been described in Japan. The aim of this study is to clarify the long-term mortality of patients with syncope who are brought to an emergency department (ED) in Japan. This retrospective observational study was conducted on patients treated in the ED of Keio University Hospital in Tokyo. Nine hundred twelve consecutive patients who presented with syncope were identified. The patients were classified into 2 groups according to the cause of syncope: cardiac syncope and noncardiac syncope. Follow-up information about mortality was obtained from mailed questionnaires and medical records. Mortality data were analyzed using the actuarial life-table method and a Cox proportional hazards model. Follow-up information was obtained for 715 patients. The median follow-up period was 38 months, during which 63 patients died. At 5 years, the 23.1% (95% confidence interval [CI] 12.7% to 33.4%) mortality of the patients with cardiac syncope was significantly higher than the 8.2% (95% CI 5.5% to 10.9%) mortality of the patients with noncardiac syncope (P<.0001). The incidence of cardiac death among the patients with cardiac syncope was 17.2% (95% CI 7.8% to 26.5%) compared with 0.9% (95% CI 0% to 1.8%) in the noncardiac syncope group (P<.0001). Cardiac syncope was an independent predictor of overall mortality and cardiac mortality (relative risk 2.81 [95% CI 1.53 to 5.16], 18.74 [95% CI 5.90 to 59.52]). Cardiac syncope is associated with higher mortality than noncardiac syncope in this Japanese patient population.


circCPA4 acts as a prognostic factor and regulates the proliferation and metastasis of glioma.
Circular RNAs (circRNAs) are reported to play vital roles in tumour process and might be potential prognostic biomarkers and therapeutic targets for tumours. But the expression and function of circRNAs in glioma remain unclear. Here, we performed circRNA microarray analysis of glioma tissues and matched normal brain tissue samples to explore the circRNA profile in glioma. GO analysis, KEGG and Reactom pathway analysis of linear mRNA transcripts corresponding to circRNAs were performed to study the involved biological process and pathways. The clinical significance of the selected circRNA was investigated by Kaplan-Meier survival analysis. Relevant biological function, such as cell proliferation and metastasis, was detected in vitro and in vivo. And possible mechanism of the regulatory function of the selected circRNA in glioma was explored. We found that circCPA4 (hsa_circ_0082374) up-regulated the most in glioma tissues and high levels of circCPA4 were positively related to poor outcome of glioma. And knockdown of circCPA4 suppresses cell proliferation and metastasis in glioma. Moreover, circCPA4 interacts with let-7 and serves as a sponge for let-7. Through the competitive endogenous RNA (ceRNA) mechanism, circCPA4 sponges let-7 to regulate the expression of CPA4 and glioma progression. The circCPA4/let-7/CPA4 axis regulates glioma progression by ceRNA mechanism, and circCPA4 could be a novel prognostic biomarker and target for glioma treatment.


On Solving the Problem of Identifying Unreliable Sensors Without a Knowledge of the Ground Truth: The Case of Stochastic Environments.
The purpose of this paper is to propose a solution to an extremely pertinent problem, namely, that of identifying unreliable sensors (in a domain of reliable and unreliable ones) without any knowledge of the ground truth. This fascinating paradox can be formulated in simple terms as trying to identify stochastic liars without any additional information about the truth. Though apparently impossible, we will show that it is feasible to solve the problem, a claim that is counter-intuitive in and of itself. One aspect of our contribution is to show how redundancy can be introduced, and how it can be effectively utilized in resolving this paradox. Legacy work and the reported literature (for example, in the so-called weighted majority algorithm) have merely addressed assessing the reliability of a sensor by comparing its reading to the ground truth either in an online or an offline manner. Unfortunately, the fundamental assumption of revealing the ground truth cannot be always guaranteed (or even expected) in many real life scenarios. While some extensions of the Condorcet jury theorem [9] can lead to a probabilistic guarantee on the quality of the fused process, they do not provide a solution to the unreliable sensor identification problem. The essence of our approach involves studying the agreement of each sensor with the rest of the sensors, and not comparing the reading of the individual sensors with the ground truth-as advocated in the literature. Under some mild conditions on the reliability of the sensors, we can prove that we can, indeed, filter out the unreliable ones. Our approach leverages the power of the theory of learning automata (LA) so as to gradually learn the identity of the reliable and unreliable sensors. To achieve this, we resort to a team of LA, where a distinct automaton is associated with each sensor. The solution provided here has been subjected to rigorous experimental tests, and the results presented are, in our opinion, both novel and conclusive.


Benefits of audibility for listeners with severe high-frequency hearing loss.
A consonant identification test was carried out with 10 hearing-impaired listeners under various low-pass filter conditions. Subjects were also tested for cochlear dead regions with the TEN test. All subjects had moderate-to-severe high-frequency hearing losses. Consonant recognition was tested under conditions in which the speech signals were highly audible to subjects for frequencies up to the low-pass filter cut-off. Extensive dead regions were found for one subject with the TEN test. The remaining subjects may have had dead regions above 3 kHz, because of the severity of their hearing losses, but these could not be demonstrated with the TEN test. Average consonant scores for the subject group improved significantly (p<0.05) with increasing audibility of high-frequency components of the speech signal. There were no cases of speech perception being reduced with increasing bandwidth. Nine of the subjects showed improvements in scores with increasing audibility, whereas the remaining subject showed little change in scores. For this subject, speech perception results were consistent with the TEN test findings. In general, the results suggest that listeners with severe high-frequency losses are often able to make some use of high-frequency speech cues if these cues can be made audible.


An automated method for 'clumped-isotope' measurements on small carbonate samples.
Clumped-isotope geochemistry deals with the state of ordering of rare isotopes in molecules, in particular with their tendency to form bonds with other rare isotopes rather than with the most abundant ones. Among its possible applications, carbonate clumped-isotope thermometry is the one that has gained most attention because of the wide potential of applications in many disciplines of earth sciences. Clumped-isotope thermometry allows reconstructing the temperature of formation of carbonate minerals without knowing the isotopic composition of the water from which they were formed. This feature enables new approaches in paleothermometry. The currently published method is, however, limited by sample weight requirements of 10-15 mg and because measurements are performed manually. In this paper we present a new method using an automated sample preparation device coupled to an isotope ratio mass spectrometer. The method is based on the repeated analysis (n = 6-8) of 200 microg aliquots of sample material and completely automated measurements. In addition, we propose to use precisely calibrated carbonates spanning a wide range in Delta(47) instead of heated gases to correct for isotope effects caused by the source of the mass spectrometer, following the principle of equal treatment of the samples and standards. We present data for international standards (NBS 19 and LSVEC) and different carbonates formed at temperatures exceeding 600 degrees C to show that precisions in the range of 10 to 15 ppm (1 SE) can be reached for repeated analyses of a single sample. Finally, we discuss and validate the correction procedure based on high-temperature carbonates instead of heated gases.


The evolution of ontogenetic allometric trajectories in mammalian domestication.
Morphological divergence of domesticated as compared to wild forms must result from changes in the ontogenetic process. Species-specific tests for heterochrony have rejected a single explanation of domestic forms representing juveniles of their wild relatives. Ontogenetic allometric trajectories for 12 pairs of wild and domestic mammals were examined using skull growth data for 1070 specimens, including representatives from all lineages in which domestication has occurred. A suite of tests were performed to quantify allometric disparity in wild and domestic forms and assess the extent and patterning of modification to allometric trajectories. Domestication has modified postnatal ontogenetic allometric trajectories in mammals, and has generated disparity, achieved through lengthening of trajectory slopes and alteration to slope angles. Allometric disparity was similar for domestic forms compared to their wild relatives, whereas the magnitude of dispersion along allometric vectors differed between precocial mammals and altricial mammals, underscoring the importance of life history and shared evolutionary history in patterns of ontogenetic variation. The results verify the importance of scaling in the morphological changes associated with domestication. The response to domestication for all measured trajectory parameters was variable across species, suggesting multiple pathways of change.


The presence of Pneumocystis jirovecii DNA in plasma is associated with a higher mortality rate in patients with AIDS-associated Pneumocystis pneumonia.
To examine the relationship between Pneumocystis jirovecii DNA (PJ-DNA) levels in blood from AIDS-associated Pneumocystis pneumonia (AIDS-PCP) and mortality, and to correlate mitochondrial large subunit rRNA (mtLSUrRNA) gene polymorphism with mortality, we performed a retrospective study including AIDS-PCP patients between 2014 and 2016 from one hospital in China. PJ-DNA in plasma was measured by nested polymerase chain reaction (PCR) of the mtLSUrRNA gene and in positive specimens we further detected the level of PJ-DNA using qPCR. Polymorphisms were observed at two positions (85 and 248) of the mtLSUrRNA gene by sequencing. The PJ-DNA positivity rate for survivors and nonsurvivors was 13.64% (9/66) and 78.57% (11/14) (P ≤ .001), respectively. Using multivariate analysis, we found that lactate dehydrogenase, PaO2, albumin and PJ-positive in blood were independent predictors of death (P = .011; P = .042; P = .01; P ≤ .001, respectively). The PJ-DNA level in the nonsurvivor group (n = 11) was higher than that of the survivor group (n = 9) (54610.3copies/ ml vs. 934.5 copies/ml, P = .006). Nine had genotype 1, and 88.89% (8/9) patients died. Of nine with genotype 3, 11.11% (1/9) died (P = .003). In conclusion, high PJ-DNA level detected by analyzing plasma and mtLSUrRNA genotype 1 are strongly associated with death in AIDS-PCP patients.


Examining the job search-turnover relationship: the role of embeddedness, job satisfaction, and available alternatives.
This study examined factors that may help explain under what conditions employee job search effort may most strongly (or weakly) predict subsequent turnover. As predicted, the job search-turnover relationship was stronger when employees had lower levels of job embeddedness and job satisfaction and higher levels of available alternatives. These findings suggest that there may be a number of factors interacting to influence employees' turnover decisions, indicating greater complexity to the process than described in prominent sequential turnover models.


Thrombophilias as risk factors for disorders of pregnancy and fetal damage.
Inherited thrombophilias have been suggested as a possible condition of increased susceptibility to adverse pregnancy outcomes. Although there is no consensus on the association between the factor V Leiden mutation and early (less than 10 weeks) pregnancy loss, the evidence suggests an association between the mutation and second-, and third-trimester fetal loss and severe preeclampsia. At present the relationship between the prothrombin G20210A mutation and inherited thrombophilias and adverse pregnancy outcomes remains controversial. Due to the low prevalence, AT and PC deficiencies have been rarely found as the cause of complicated pregnancy, whereas increased risk for preeclampsia and fetal losses has been found in relation to PS deficiency. Concerning the association between pathological pregnancies and PAI-1 4G/5G deletion/insertion polymorphism, only few controversial data are available. A meta-analysis of ten case-control studies suggested an association between hyperhomocysteinemia, MTHFR C677T mutation and repeated pregnancy losses before 16 weeks. Recently a role for Angiotensin Converting Enzyme I/D polymorphism in obstetrical complications has been suggested.


Hospital mortality and thirty day readmission among patients with non-acute myocardial infarction related cardiogenic shock.
Cardiogenic shock (CS) in absence of acute myocardial infarction (AMI) has significant morbidity and mortality. This population of patients has been excluded from prior major randomized trials and observational studies. We included patients with CS in absence of AMI from the 2013-14 HCUP's National Readmission Database. 30-day readmissions were studied and etiology for readmission was identified by using ICD-9CM codes in primary diagnosis field. Multivariable mixed effect logistic regression models were created to identify predictors of 30-day readmission and in-hospital mortality, respectively. We studied 38,198 index admissions with non-AMI CS, with an in-hospital mortality of 35.4%. Mean age, length and cost of stay were 63.6 years, 16.9 days and 69,947$, respectively among survivors of index admission. Among those discharged, 22.6% were readmitted within 30 days with >50% readmissions occurring within 11-days. Cardiovascular etiologies (42.3%), especially heart failure (24.0%) comprised the commonest reason for readmission. Among non-cardiac causes were infectious (11.7%) and respiratory (9.2%) etiologies. Older age (50-64 years odds ratio:1.29, 65-79 years, OR:1.59, ≥80 years OR:2.69), ventilator use (OR:4.25), sepsis (OR:1.12), use of short term devices (intra-aortic balloon pump OR:2.67, Impella/TandemHeart OR:4.84, extracorporeal membrane oxygenation OR:3.68) and non-ischemic cardiomyopathy(OR:0.65) were among the predictors of in-hospital mortality. Older age (65-79 years, OR:1.25, ≥80 years OR:1.41), male sex (OR:1.08), and ventilator use (OR:1.21) predicted higher 30-day readmission. Both, in-hospital mortality and 30-day readmission among those admitted for non-AMI CS were significantly elevated. The majority of readmissions were due to non-cardiovascular causes. Identifying high-risk factors may help devise strategies to improve quality of care and reduce adverse outcome rates.


Human cardiac progenitor cells engineered with Pim-I kinase enhance myocardial repair.
The goal of this study was to demonstrate the enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for the treatment of myocardial infarction. Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation, and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration. hCPCs isolated from the myocardium of heart failure patients undergoing left ventricular assist device implantation were engineered to express green fluorescent protein (hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential were performed with immunocompromised mice by using intramyocardial adoptive transfer injection after infarction. Myocardial structure and function were monitored by echocardiographic and hemodynamic assessment for 20 weeks after delivery. hCPCe and hCPCeP expressing luciferase were observed by using bioluminescence imaging to noninvasively track persistence. hCPCeP exhibited augmentation of reparative potential relative to hCPCe control cells, as shown by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrated increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe was revealed by bioluminescence imaging at up to 8 weeks post-delivery. Genetic engineering of hCPCs with Pim-1 enhanced repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of hCPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells in pre-clinical settings.


Lysosomal membrane stability plays a major role in the cytotoxic activity of the anti-proliferative agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT).
The potent and selective anti-tumor agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), localizes in lysosomes and forms cytotoxic copper complexes that generate reactive oxygen species (ROS), resulting in lysosomal membrane permeabilization (LMP) and cell death. Herein, the role of lysosomal membrane stability in the anti-tumor activity of Dp44mT was investigated. Studies were performed using molecules that protect lysosomal membranes against Dp44mT-induced LMP, namely heat shock protein 70 (HSP70) and cholesterol. Up-regulation or silencing of HSP70 expression did not affect Dp44mT-induced LMP in MCF7 cells. In contrast, cholesterol accumulation in lysosomes induced by the well characterized cholesterol transport inhibitor, 3-β-[2-(diethyl-amino)ethoxy]androst-5-en-17-one (U18666A), inhibited Dp44mT-induced LMP and markedly and significantly (p<0.001) reduced the ability of Dp44mT to inhibit cancer cell proliferation (i.e., increased the IC(50)) by 140-fold. On the other hand, cholesterol extraction using methyl-β-cyclodextrin enhanced Dp44mT-induced LMP and significantly (p<0.01) increased its anti-proliferative activity. The protective effect of U18666A in increasing lysosomal cholesterol and preventing the cytotoxic activity of Dp44mT was not due to induced autophagy. Instead, U18666A was found to decrease lysosomal turnover, resulting in autophagosome accumulation. Moreover, preincubation with U18666A did not prevent the ability of Dp44mT to induce autophagosome synthesis, indicating that autophagic initiation via Dp44mT occurs independently of LMP. These studies demonstrate the significance of lysosomal membrane stability in relation to the ability of Dp44mT to execute tumor cell death and overcome pro-survival autophagy. Hence, lysosomal-dependent cell death induced by Dp44mT serves as an important anti-tumor strategy. These results are important for comprehensively understanding the mechanism of action of Dp44mT.


Novel vascular molecule involved in monocyte adhesion to aortic endothelium in models of atherogenesis.
Adhesion of monocytes to the endothelium in lesion-prone areas is one of the earliest events in fatty streak formation leading to atherogenesis. The molecular basis of increased monocyte adhesion is not fully characterized. We have identified a novel vascular monocyte adhesion-associated protein, VMAP-1, that plays a role in adhesion of monocytes to activated endothelium. Originally selected for its ability to block binding of a mouse monocyte-like cell line (WEHI78/24) to cytokine- or LPS-stimulated cultured mouse endothelial cells in vitro, antiVMAP-1 mAb LM151 cross-reacts with rabbit endothelium and blocks binding of human monocytes to cultured rabbit aortic endothelial cells stimulated with minimally modified low density lipoprotein, thought to be a physiologically relevant atherogenic stimulus. Most importantly, LM151 prevents adhesion of normal monocytes and monocytoid cells to intact aortic endothelium from cholesterol-fed rabbits in an ex vivo assay. VMAP-1 is a 50-kD protein. Immunohistology of vessels reveals focal constitutive expression in aorta and other large vessels. VMAP-1 is thus a novel vascular adhesion-associated protein that appears to play a critical role in monocyte adhesion to aortic endothelial cells in atherogenesis in vivo.


Curcumin: a new cell-permeant inhibitor of the inositol 1,4,5-trisphosphate receptor.
Curcumin (diferuoylmethane or 1,7-bis (4-hydroxy-3-methoxyphenol)-1,6-hepatadiene-3,5-dione) is the active ingredient of the spice turmeric. Curcumin has been shown to have a number of pharmacological and therapeutic uses. This study shows that curcumin is a potent inhibitor of the inositol 1,4,5-trisphosphate-sensitive Ca2+ channel (InsP3 receptor). In porcine cerebellar microsomes, the extent of InsP3-induced Ca2+ release (IICR) is almost completely inhibited by 50 microM curcumin (IC50 = 10 microM). As the extent of IICR cannot be restored back to control levels by the addition of excess InsP3 and since it has little effect on [3H]InsP3 binding to cerebellar microsomes, this inhibition is likely to be non-competitive in nature. IICR in cerebellar microsomes is biphasic consisting of a fast and slow component. The rate constants for the two components are both reduced by curcumin to similar extents (by about 70% of control values at 40 microM curcumin). In addition, curcumin also reduces agonist (ATP)-stimulated Ca2+ mobilization from intact HL-60 cells, indicating that curcumin is cell permeant. However, since it also affects intracellular Ca2+ pumps and possibly ryanodine receptors, it may lead to complex Ca2+ transient responses within cells, which may well explain some of its putative therapeutic properties.


Contact transfer of engineered nanomaterials in the workplace.
This study investigates the potential spread of cadmium selenide quantum dots in laboratory environments through contact of gloves with simulated dry spills on laboratory countertops. Secondary transfer of quantum dots from the contaminated gloves to other substrates was initiated by contact of the gloves with different materials found in the laboratory. Transfer of quantum dots to these substrates was qualitatively evaluated by inspection under ultraviolet illumination. This secondary contact resulted in the delivery of quantum dots to all the evaluated substrates. The amount of quantum dots transferred was quantified by elemental analysis. The residue containing quantum dots picked up by the glove was transferred to at least seven additional sections of the pristine substrate through a series of sequential contacts. These results demonstrate the potential for contact transfer as a pathway for spreading nanomaterials throughout the workplace, and that 7-day-old dried spills are susceptible to the propagation of nanomaterials by contact transfer. As research and commercialization of engineered nanomaterials increase worldwide, it is necessary to establish safe practices to protect workers from the potential for chronic exposure to potentially hazardous materials. Similar experimental procedures to those described herein can be adopted by industries or regulatory agencies to guide the development of their nanomaterial safety programmes.


Problem and non-problem gamblers: a cross-sectional clustering study by gambling characteristics.
Gambling characteristics are factors that could influence problem gambling development. The aim of this study was to identify a typology of gamblers to frame risky behaviour based on gambling characteristics (age of initiation/of problem gambling, type of gambling: pure chance/chance with pseudoskills/chance with elements of skill, gambling online/offline, amount wagered monthly) and to investigate clinical factors associated with these different profiles in a large representative sample of gamblers. The study is a cross-sectional analysis to the baseline data of the french JEU cohort study (study protocol : Challet-Bouju et al, 2014). Recruitment (April 2009 to September 2011) involved clinicians and researchers from seven institutions that offer care for or conduct research on problem gamblers (PG). Participants were recruited in gambling places, and in care centres. Only participants who reported gambling in the previous year between 18 and 65 years old were included.Participants gave their written informed consent, it was approved by the French Research Ethics Committee. The participants were 628 gamblers : 256 non-problem gamblers (NPG), 169 problem gamblers without treatment (PGWT) and 203 problem gamblers seeking treatment (PGST). Six clustering models were tested, the one with three clusters displayed a lower classification error rate (7.92%) and was better suited to clinical interpretation : 'Early Onset and Short Course' (47.5%), 'Early Onset and Long Course' (35%) and 'Late Onset and Short Course' (17.5%). Gambling characteristics differed significantly between the three clusters. We defined clusters through the analysis of gambling variables, easy to identify, by psychiatrists or by physicians in primary care. Simple screening concerning these gambling characteristics could be constructed to prevent and to help PG identification. It is important to consider gambling characteristics : policy measures targeting gambling characteristics may reduce the risk of PG or minimise harm from gambling. NCT01207674 (ClinicalTrials.gov); Results.


A screening tool for vulnerability assessment of pesticide leaching to groundwater for the islands of Hawaii, USA.
This paper describes an updated version of a screening tool for groundwater vulnerability assessment to evaluate pesticide leaching to groundwater, based on a revised version of the attenuation factor. The tool has been implemented in a geographical information system (GIS) covering the major islands of the state of Hawaii, USA. The Hawaii Department of Agriculture currently uses the tool in their pesticide evaluation process as a first-tier screening tool. The basic soil properties and pesticide properties necessary to compute the index, and estimates of their uncertainty, are included in the GIS. Uncertainties in soil and pesticide properties are accounted for using first-order uncertainty analysis. Classifications of pesticides as 'likely', 'uncertain' or 'unlikely' to leach are made on the basis of the uncertainty and a comparison of the revised attenuation factor with values and uncertainties of two reference chemicals. The reference chemicals represent what are considered to be a 'leachable' and a 'non-leachable' pesticide under Hawaii conditions. It is concluded that the tool is suitable for screening new and already used pesticides for the islands of Hawaii. However, the tool is associated with uncertainties that are not accounted for, so a conservative approach with respect to interpretation of the results and selection of pesticide parameters used in the tool is recommended.


Informed consent practices for surgical care at university teaching hospitals: a case in a low resource setting.
Informed consent in medical practice is essential and a global standard that should be sought at all the times doctors interact with patients. Its intensity would vary depending on the invasiveness and risks associated with the anticipated treatment. To our knowledge there has not been any systematic review of consent practices to document best practices and identify areas that need improvement in our setting. The objective of the study was to evaluate the informed consent practices of surgeons at University teaching Hospitals in a low resource setting. A cross-sectional study conducted at three university teaching hospitals in Uganda. Self-guided questionnaires were left at a central location in each of the surgical departments after verbally communicating to the surgeons of the intention of the study. Filled questionnaires were returned at the same location by the respondents for collection by the research team. In addition, 20 in-depth interviews were held with surgeons and a review of 384 patients' record files for informed consent documentation was done. A total of 132 (62.1%) out of 214 questionnaires were completed and returned. Respondents were intern doctors, residents and specialists from General surgery, Orthopedic surgery, Ear, Nose and Throat, Ophthalmology, Dentistry, Obstetrics and Gynaecology departments. The average working experience of respondents was 4.8 years (SD 4.454, range 0-39 years). 48.8% of the respondents said they obtained consent all the time surgery is done while 51.2% did not obtain consent all the time. Many of the respondents indicated that informed consent was not obtained by the surgeon who operated the patient but was obtained either at admission or by nurses in the surgical units. The consent forms used in the hospitals were found to be inadequate and many times signed at admission before diagnosing the patient's disease. Informed consent administration and documentation for surgical health care is still inadequate at University teaching hospitals in Uganda.


Simultaneous quantification of anidulafungin and caspofungin in plasma by an accurate and simple liquid chromatography tandem mass-spectrometric method.
Echinocandins are a valuable addition for the treatment of invasive fungal infections, as they are efficacious, demonstrate low toxicity, and have limited drug-drug interactions. In specific clinical situations when altered pharmacokinetics can be expected or dosing guidelines are conflicting, it may be useful to measure concentrations. For this purpose, a liquid chromatography tandem mass-spectrometric method to measure anidulafungin and caspofungin in ethylenediaminetetraacetic acid plasma was developed. The method was developed on a Thermo Fisher TSQ Quantum LC-MS/MS. For separation, a BetaBasic C4 (100 mm × 3.0 mm; 5 μm) analytical column was used. Sample preparation consisted of protein precipitation directly in the autosampler vial. The internal standard aculeacin A is structurally related, not used in humans, and commercially available. The method was validated according to the guidelines for bioanalytical method validation of the Food and Drug Administration. The method was accurate (bias ranging from -3.0% to 1.9%) and precise (within-run and between-run coefficients of variation of 2.2% to 7.7% and 1.6% to 9.0%, respectively). All calibration curves were linear over a range of 0.5-10.0 mg/L for anidulafungin and 0.1-20.0 mg/L for caspofungin, and if necessary, samples can be diluted 10-fold. The samples were stable for 3 freeze-thaw cycles, with a bias ranging from 0.6% to 11%. The maximum bias from the worst storage condition, 72 hours at room temperature, was -14.7%. In patient samples, anidulafungin peak concentrations ranged from 2.8 to 8.6 mg/L (n = 20) and trough concentrations ranged from 1.0 to 4.7 mg/L (n = 79). The measured caspofungin concentrations ranged from 1.9 to 7.3 mg/L (n = 20). The method developed has a straightforward sample preparation and uses a structural analog as the internal standard. This method has been applied successfully for the measurement of anidulafungin and caspofungin concentrations in patient samples, both for clinical practice and for research.


Effects of side-chain interdigitation on stability: an environmentally, electrically, and thermally stable semiconducting polymer.
A polymeric semiconductor, poly(3,6-dihexyl-[2,2']bi[thieno[3,2-b]thiophene]) (PDHTT), was synthesized and tested as an active layer in organic thin film transistors (OTFTs). This semiconductor showed considerable potential for use in commercial electronic devices because of its superior characteristics, particularly its good stability. PDHTT-based OTFTs exhibited high stability in air, retaining their initial performance after exposure to 70% relative humidity for 50 days; they were also stable under repeated electrical stress and even after exposure to temperatures as high as 250 °C. We attribute the remarkable stability of PDHTT OTFTs to the relatively low highest occupied molecular orbital (5.1 eV) level of the polymer and its highly interdigitated structure in the thin film state.


Alteration of an amino acid residue outside the active site of the ricin A chain reduces its toxicity towards yeast ribosomes.
Yeast transformants containing integrated copies of a galactose-regulated, ricin toxin A chain (RTA) expression plasmid were constructed and used in an attempt to isolate RTA-resistant yeast mutants. Analysis of RNA from mutant strains demonstrated that approximately half contained ribosomes that had been partially modified by RTA, although all the strains analysed transcribed full-length RTA RNA. The mutant strains could have mutations in yeast genes giving rise to RTA-resistant ribosomes or they could contain alterations within the RTA-encoding DNA causing production of mutant toxin. Ribosomes isolated from mutant strains were shown to be susceptible to RTA modification in vitro suggesting that the strains contain alterations in RTA. This paper describes the detailed analysis of one mutant strain which has a point mutation that changes serine 203 to asparagine in RTA protein. Although serine 203 lies outside the proposed active site of RTA its alteration leads to the production of RTA protein with a greatly reduced level of ribosome modifying activity. This decrease in activity apparently allows yeast cells to survive expression of RTA as only a proportion of the ribosomes become modified. We demonstrate that the mutant RTA preferentially modifies 26S rRNA in free 60S subunits and has lower catalytic activity compared with native RTA when produced in Escherichia coli. Such mutations provide a valuable means of identifying residues important in RTA catalysis and of further understanding the precise mechanism of action of RTA.


Nonribosomal peptides protect Pseudomonas nunensis 4A2e from amoebal and nematodal predation.
The rhizosphere is a highly competitive environment forcing bacteria to evolve strategies to oppose their enemies. The production of toxic secondary metabolites allows bacteria to counteract predators. In this study, we describe the anti-predator armamentarium of the soil-derived bacterium Pseudomonas nunensis 4A2e. Based on a genome mining approach, we identified several biosynthetic gene clusters coding for nonribosomal peptide synthetases. Generation of gene deletion mutants of the respective clusters shows a loss of defense capabilities. We isolated the novel lipopeptides keanumycin D and nunapeptins B and C, and fully elucidated their structures by a combination of in-depth mass spectrometry experiments, stable isotope labelling, and chemical synthesis. Additionally, investigation of the quorum sensing-dependent biosynthesis allowed us to elucidate parts of the underlying regulation of the biosynthetic machinery. Ecology-inspired bioassays highlight the role of these peptides as a defence strategy against protozoans and led us to find a previously unknown function against the bacterivorous nematode Oscheius myriophilus.


[Kinetics of neutrophil granulocytes].
The kinetics of neutrophilic granulocytes are briefly reviewed. The cell traverses 3 compartments during its life cycle. After a phase of proliferation and maturation in the bone marrow for a period of about 10 days, it enters the blood for an average period of 10-12 h and then migrates into tissues where it survives for an unknown length of time. Although a quantitative understanding of normal neutrophil kinetics has emerged, our knowledge of disorders of neutropoiesis is limited. Progress in the diagnosis and treatment of disorders of neutropoiesis is anticipated with improved methods of assessing quantitatively abnormal production and its regulation.


Lack of association between serological evidence of past Coxiella burnetii infection and incident ischaemic heart disease: nested case-control study.
Coxiella burnetii causes the common worldwide zoonotic infection, Q fever. It has been previously suggested that patients who had recovered from acute Q fever (whether symptomatic or otherwise) may be at increased risk of ischaemic heart disease. We undertook this study to determine if past infection with Coxiella burnetii, the aetiological agent of Q fever, is a risk factor for the subsequent development of ischaemic heart disease. A nested case-control study within the Prospective Epidemiological Study of Myocardial Infarction (PRIME). The PRIME study is a cohort study of 10,593 middle-aged men undertaken in France and Northern Ireland in the 1990s. A total of 335 incident cases of ischaemic heart disease (IHD) were identified and each case was matched to 2 IHD free controls. Q fever seropositivity was determined using a commercial IgG ELISA method. Seroprevalence of Q fever in the controls from Northern Ireland and France were 7.8% and 9.0% respectively. No association was seen between seropositivity and age, smoking, lipid levels, or inflammatory markers. The unadjusted odds ratio (95% CI) for Q fever seropositivity in cases compared to controls was 0.95 (0.59, 1.57). The relationship was substantially unaltered following adjustment for cardiovascular risk factors and potential confounders. Serological evidence of past infection with C. burnetii was not found to be associated with an increased risk of IHD.


Field testing alternative criteria for chronic migraine.
The criteria for chronic migraine (CM), as proposed by the Second Edition of the International Classification of Headache Disorders (ICHD-2) is very restrictive, excluding most patients that evolve from episodic migraine. In this study we empirically tested three recent proposals for revised criteria for CM. We included individuals with transformed migraine (TM) with or without medication overuse, according to the criteria proposed by Silberstein and Lipton. All individuals had headache calendars for at least three consecutive months. We assessed the proportion of subjects that fulfilled ICHD-2 criteria for CM or probable chronic migraine with probable medication overuse (CM+). We also tested three proposals for making the CM criteria more inclusive. In proposal 1, CM/CM + would require at least 15 days of migraine or probable migraine per month. Proposal 2 suggests that CM/CM + would be classified in those with >or= 15 days of headache per month, where at least 50% of these days are migraine or probable migraine. Proposal 3 suggests that CM/CM + would be classified in those with chronic daily headache and at least 8 days of migraine or probable migraine per month. Among TM sufferers, 399 (62.5%) had TM with medication overuse, and just 10.2% were classified as CM+ 158 (37.5%) had TM without medication overuse; just nine (5.6%) met current ICHD-2 criteria for CM. Using the alternative criteria, proposal 1 included 48.7% of patients with TM without medication overuse; proposal 2 captured 88%, and proposal 3 classified 94.9% of these patients. For TM with medication overuse, the proportions for proposals 1-3 were, respectively, 37%, 81% and 91%. The differences were statistically significant, favouring proposal 3. Consistently, criteria for CM and CM+ should be revised to require at least 8 days of migraine or probable migraine per month, in individuals with 15 or more days of headache per month.


Chlorophagy is ATG gene-dependent microautophagy process.
Autophagy delivers cytosolic components to lysosomes and the vacuole for degradation. This pathway prevents starvation through bulk degradation and recycling of cytoplasmic components, and maintains cellular homeostasis through selective elimination of damaged proteins and organelles. Autophagic delivery processes are categorized into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy. During macroautophagy, nascent, double membrane-bound vesicles termed autophagosomes sequester a portion of cytoplasm and deliver it to the vacuole/lysosomes. Molecular genetic studies in budding yeasts have identified a set of AUTOPHAGY (ATG) genes required for autophagosome formation. Although microautophagy involves the direct lysosomal/vacuolar engulfment and incorporation of a target into the lumen rather than the formation of autophagosomes, the membrane dynamics and possible roles of ATGs during microautophagy are under investigation. Our recent study revealed an ATG-dependent microautophagy process in plants, during which chloroplasts damaged by high visible light (HL) are selectively eliminated. Here, we discuss the membrane dynamics of the plant microautophagy that enables the transport of whole chloroplasts into the vacuole.