Country differences in the diagnosis and management of coronary heart disease - a comparison between the US, the UK and Germany.
The way patients with coronary heart disease (CHD) are treated is partly determined by non-medical factors. There is a solid body of evidence that patient and physician characteristics influence doctors' management decisions. Relatively little is known about the role of structural issues in the decision making process. This study focuses on the question whether doctors' diagnostic and therapeutic decisions are influenced by the health care system in which they take place. This non-medical determinant of medical decision-making was investigated in an international research project in the US, the UK and Germany. Videotaped patients within an experimental study design were used. Experienced actors played the role of patients with symptoms of CHD. Several alternative versions were taped featuring the same script with patients of different sex, age and social status. The videotapes were shown to 384 randomly selected primary care physicians in the three countries under study. The sample was stratified on gender and duration of professional experience. Physicians were asked how they would diagnose and manage the patient after watching the video vignette using a questionnaire with standardised and open-ended questions. Results show only small differences in decision making between British and American physicians in essential aspects of care. About 90% of the UK and US doctors identified CHD as one of the possible diagnoses. Further similarities were found in test ordering and lifestyle advice. Some differences between the US and UK were found in the certainty of the diagnoses, prescribed medications and referral behaviour. There are numerous significant differences between Germany and the other two countries. German physicians would ask fewer questions, they would order fewer tests, prescribe fewer medications and give less lifestyle advice. Although all physicians in the three countries under study were presented exactly the same patient, some disparities in the diagnostic and patient management decisions were evident. Since other possible influences on doctors treatment decisions are controlled within the experimental design, characteristics of the health care system seem to be a crucial factor within the decision making process.


Replications in Psychology Research: How Often Do They Really Occur?
Recent controversies in psychology have spurred conversations about the nature and quality of psychological research. One topic receiving substantial attention is the role of replication in psychological science. Using the complete publication history of the 100 psychology journals with the highest 5-year impact factors, the current article provides an overview of replications in psychological research since 1900. This investigation revealed that roughly 1.6% of all psychology publications used the term replication in text. A more thorough analysis of 500 randomly selected articles revealed that only 68% of articles using the term replication were actual replications, resulting in an overall replication rate of 1.07%. Contrary to previous findings in other fields, this study found that the majority of replications in psychology journals reported similar findings to their original studies (i.e., they were successful replications). However, replications were significantly less likely to be successful when there was no overlap in authorship between the original and replicating articles. Moreover, despite numerous systemic biases, the rate at which replications are being published has increased in recent decades.


Long-term efficacy of intensive cycle ergometer exercise training program for advanced COPD patients.
Exercise training has been incorporated into the international guidelines for the treatment of chronic obstructive pulmonary disease (COPD). However, the long-term efficacy of the training program for patients with advanced COPD has never been evaluated in Thailand. To determine the long-term efficacy of intensive cycle ergometer exercise program on various clinical parameters of patients with advanced COPD. The patients with advanced COPD were separated into two groups: the intensive ergometer exercise program group and the control group. The clinical parameters of all the patients were assessed at baseline, every month for the first 3 months, and then every 3 months until they had completed the 24-month follow-up. Mann-Whitney U test was used to compare baseline mean differences between the groups. Repeated measure analysis was applied to determine the progress in all parameters during the entire follow-up period. Mean incase imputation method was applied to estimate the parameters of dropout cases. A total of 41 patients were enrolled: 27 in the intensive ergometer exercise program group and 14 in the control group. The intensive cycle ergometer exercise program group showed statistically significant improvements in muscle strength (from month 1 till the end of the study, month 24), endurance time (from month 1 till the end of measurement, month 12) and clinically significant improvements in 6-minute walk distance (from month 2 until month 9), dyspnea severity by transitional dyspnea index (from month 1 till the end of the study, month 24), and quality of life (from month 1 till the end of the study, month 24). There was no significant difference in survival rates between the groups. The intensive ergometer exercise training program revealed meaningful long-term improvements in various clinical parameters for up to 2 years. These promising results should encourage health care professionals to promote exercise training for patients with advanced COPD who have limited daily activities despite optimal medication control.


Species coexistence: macroevolutionary relationships and the contingency of historical interactions.
Evolutionary biologists since Darwin have hypothesized that closely related species compete more intensely and are therefore less likely to coexist. However, recent theory posits that species diverge in two ways: either through the evolution of 'stabilizing differences' that promote coexistence by causing individuals to compete more strongly with conspecifics than individuals of other species, or through the evolution of 'fitness differences' that cause species to differ in competitive ability and lead to exclusion of the weaker competitor. We tested macroevolutionary patterns of divergence by competing pairs of annual plant species that differ in their phylogenetic relationships, and in whether they have historically occurred in the same region or different regions (sympatric versus allopatric occurrence). For sympatrically occurring species pairs, stabilizing differences rapidly increased with phylogenetic distance. However, fitness differences also increased with phylogenetic distance, resulting in coexistence outcomes that were unpredictable based on phylogenetic relationships. For allopatric species, stabilizing differences showed no trend with phylogenetic distance, whereas fitness differences increased, causing coexistence to become less likely among distant relatives. Our results illustrate the role of species' historical interactions in shaping how phylogenetic relationships structure competitive dynamics, and offer an explanation for the evolution of invasion potential of non-native species.


Feline conjunctival microbiota in a shelter: effects of time, upper respiratory disease and famciclovir administration.
The aim of this study was to evaluate changes in the conjunctival microbiota of shelter-housed cats with time, upper respiratory disease (URD) and famciclovir administration. Cats were assigned to treatment groups on shelter entry. Healthy cats or cats with URD received ~30 mg/kg or ~90 mg/kg of famciclovir or placebo PO q12h for 7 days, or were untreated. Swabs were collected from ventral conjunctival fornices prior to (day 1) and immediately after (day 8) the treatment period. Microbiota analysis was conducted on 124 randomly selected swabs from healthy (56 swabs) or URD-affected (68 swabs) cats. Following DNA extraction and amplification of the V4 region of the 16S rRNA gene, sequences were assembled into operational taxonomic units (OTUs). Over-represented OTUs (as determined by linear discriminate analysis effect size), alpha and beta diversity, and median relative abundance of known feline ocular surface pathogens were assessed for the entire population and in 10 clinically relevant subpopulations of cats. Bacteria from 33 phyla and 70 genera were identified. Considering all cats, median relative abundance of Mycoplasma increased from day 1 to day 8, while Proteobacteria decreased. Community membership and structure (beta diversity) differed between days 1 and 8 for all famciclovir-treated cats (regardless of health status or dose) and healthy or URD-affected cats (regardless of famciclovir dose). Differences in taxonomic diversity within a sample (alpha diversity) between day 1 and day 8 were not detected in any subpopulations. Within 1 week of shelter entry, there were significant changes in community structure and membership of the feline conjunctival microbiota, with a shift towards over-representation of feline ocular surface pathogens. Although famciclovir may impact beta diversity of the feline conjunctival microbiota, absence of change in alpha diversity suggests minimal shift in individual cats.


Development of Scholarship Core Competencies for Pediatric Hospital Medicine Fellowship Programs.
The Pediatric Hospital Medicine (PHM) Fellowship Directors, recent fellowship graduates, and senior leaders in PHM have long identified training in scholarly activities as a key educational priority for fellowship training programs. We led a 2-day conference funded by the Agency for Healthcare Research and Quality to develop scholarship core competencies for PHM fellows. Participants included fellowship directors, national experts in PHM research, and representatives from key stakeholder organizations. Through engagement in large group presentations and small group iterative feedback and editing, participants created and refined a set of scholarship core competencies. After the conference, goals and objectives were edited and harmonized by conference leaders incorporating feedback from conference participants. Core competency development included 7 domains: (1) study design and execution, (2) data management, (3) principles of analytics, (4) critical appraisal of the medical literature, (5) ethics and responsible conduct of research, (6) peer review, dissemination, and funding, and (7) professionalism and leadership. Specific objectives for each goal were further organized into 3 levels to indicate core skills for all fellowship trainees (level 1), specialized and specific skills determined by fellow scholarly focus (level 2), and advanced skills for fellows interested in a clinical investigator career path (level 3). These newly developed scholarship core competencies provide a foundation for curricular development and implementation to ensure that the field continues to expand academically, given the 2-year training period and variable infrastructure across programs.


Human accelerated region 1 noncoding RNA is repressed by REST in Huntington's disease.
In the neurons of Huntington's disease (HD) patients, gene regulatory networks are disrupted by aberrant nuclear localization of the master transcriptional repressor REST. Emerging evidence suggests that, in addition to protein-coding genes, noncoding RNAs (ncRNAs) may also contribute to neurodegenerative processes. To discover ncRNAs that are involved in HD, we screened genome-wide data for novel, noncoding targets of REST. This identified human accelerated region 1 (HAR1), a rapidly evolving cis-antisense locus that is specifically transcribed in the nervous system. We show that REST is targeted to the HAR1 locus by specific DNA regulatory motifs, resulting in potent transcriptional repression. Consistent with other REST target genes, HAR1 levels are significantly lower in the striatum of HD patients compared with unaffected individuals. These data represent further evidence that noncoding gene expression changes accompany neurodegeneration in Huntington's disease.


The promoter for tomato 3-hydroxy-3-methylglutaryl coenzyme A reductase gene 2 has unusual regulatory elements that direct high-level expression.
The promoter region of tomato (Lycopersicon esculentum) 3-hydroxy-3-methylglutaryl coenzyme A reductase gene 2 (HMG2) has been analyzed using the transient expression of HMG2-luciferase fusions in red fruit pericarp. The mRNA for HMG2 accumulates to high level during fruit ripening, in a pattern that coincides with the synthesis of the carotenoid lycopene. Unlike most promoters, the region that is upstream of the HMG2 TATA element is not required for high-level expression. The 180-bp region containing the TATA element, the 5' untranslated region, and the translation start site are comparable in strength of the full-length 35S cauliflower mosaic virus promoter. Pyrimidine-rich sequences present in the 5' untranslated leader are important in regulating expression. Also, the ATG start region has been found to increase translation efficiency by a factor of 4 to 10. An alternative hairpin secondary structure has been identified surrounding the HMG2 initiator ATG, which could participate in the translational regulation of this locus. HMG2 appears to be a novel class of strong plant promoters that incorporate unusual, positive regulators of gene expression.


[Long-term observation of a case of organoid naevus phakomatosis (Schimmelpenning-Feuerstein-Mims syndrome)].
The course of an organoid naevus phakomatosis (Schimmelpenning-Feuerstein-Mims syndrome) was observed in one patient over 25 years. Although the syndrome was fully developed, it has so far remained relatively benign, without limiting the patient's ability to work. During the course of the disease various investigations were carried out (CT, brain scintigrams, chromosome analysis). These confirm that the outstanding feature consisting of fibrous bone dysplasia of the skull continues to progress into adult life. In addition, the presence of intracerebral calcification could be demonstrated. Examination of the chromosomes suggests that further similar cases should also be examined, since the aetiology and pathogenesis of this phakomatosis are still unknown.


The Effect of Larval Diet on Adult Survival, Swarming Activity and Copulation Success in Male Aedes aegypti (Diptera: Culicidae).
Control of Aedes aegypti (L.) (Diptera: Culicidae) populations is vital for reducing the transmission of several pervasive human diseases. The success of new vector control technologies will be influenced by the fitness of laboratory-reared transgenic males. However, there has been relatively little published data on how rearing practices influence male fitness in Aedes mosquitoes. In the laboratory, the effect of larval food availability on adult male fitness was tested, using a range of different fitness measures. Larval food availability was demonstrated to be positively correlated with adult body size. Larger males survived longer and exhibited greater swarming activity. As a consequence, larger males may have more mating opportunities in the wild. However, we also found that within a swarm larger males did not have an increased likelihood of copulating with a female. The outcome of the mating competition experiments depended on the methodology used to mark the males. These results show that fitness assessment can vary depending on the measure analyzed, and the methodology used to determine it. Continued investigation into these fitness measures and methodologies, and critically, their utility for predicting male performance in the field, will increase the efficiency of vector control programs.


Interactive toxic effects of heavy metals and humic acids on Vibrio fischeri.
The effect of humic acids (HAs) on the toxicity of copper, zinc, and lead was investigated using the photobacterium Vibrio fischeri (Microtox test) as a test organism. The effects of HAs on metal toxicity were evaluated as functions of time and concentration in pure compound solutions. The toxicities of copper and lead were generally comparable, while the toxicity of zinc was lower than those of the other two metals. The toxicity of copper decreased with the addition of HAs, while the toxicity of zinc remained almost constant. On the other hand, the toxicity of lead increased, depending on the concentration of HAs. The interactive effects between copper and zinc and between lead and zinc were synergistic, while the interactive effect between copper and lead on the bioluminescence of V. fischeri was additive. The presence of HAs caused relatively high toxicity reduction in the binary mixtures of zinc and copper or zinc and lead, while the toxicity reduction in the case of the binary mixture of copper and lead was negligible.


[T-cell panniculitis-like lymphoma of the subcutaneous fat: clinicomorphological and immunohistochemical analysis].
3 cases of T-cell panniculitis-like lymphoma of the subcutaneous fat are reported. Clinical, histological and immunohistochemical findings are presented. Histologically, we found lobular structure, atypical small and middle-size lymphoid cells, angiocentric growth, erythrophagocytosis. Immunohistochemically it was a cytotoxic phenotype of atypical T-cells. T-cell panniculitis-like lymphoma is a special variant of non-Hodgkin's lymphoma which is diagnosed immunohistochemically.


Mobile Health for Pediatric Weight Management: Systematic Scoping Review.
The prevalence and consequences of obesity among children and adolescents remain a leading global public health concern, and evidence-based, multidisciplinary lifestyle interventions are the cornerstone of treatment. Mobile electronic devices are widely used across socioeconomic categories and may provide a means of extending the reach and efficiency of health care interventions. We aimed to synthesize the evidence regarding mobile health (mHealth) for the treatment of childhood overweight and obesity to map the breadth and nature of the literature in this field and describe the characteristics of published studies. We conducted a systematic scoping review in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews, by searching nine academic databases in addition to gray literature for studies describing acceptability, usability, feasibility, effectiveness, adherence, or cost-effectiveness of interventions assessing mHealth for childhood obesity treatment. We also hand searched the reference lists of relevant articles. Studies aimed at the prevention of overweight or obesity were excluded, as were studies in which mHealth was not the primary mode of treatment delivery for at least one study arm or was not independently assessed. A random portion of all abstracts and full texts was double screened by a second reviewer to ensure consistency. Data were charted according to study characteristics, including design, participants, intervention content, behavior change theory (BCT) underpinning the study, mode of delivery, and outcomes measured. We identified 42 eligible studies assessing acceptability (n=7), usability (n=2), feasibility or pilot studies (n=15), treatment effect (n=17), and fidelity (n=1). Change in BMI z-scores or percentiles was most commonly measured, among a variety of dietary, physical activity, psychological, and usability or acceptability measures. SMS, mobile apps, and wearable devices made up the majority of mobile interventions, and 69% (29/42) of the studies specified a BCT used. Pediatric weight management using mHealth is an emerging field, with most work to date aimed at developing and piloting such interventions. Few large trials are published, and these are heterogeneous in nature and rarely reported according to the Consolidated Standards of Reporting Trials for eHealth guidelines. There is an evidence gap in the cost-effectiveness analyses of such studies.


Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects.
We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects. We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin:cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL. Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.


SAMHD1 protects cancer cells from various nucleoside-based antimetabolites.
Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (AML) cells to the cytotoxicity of cytarabine (ara-C), the most important drug in AML treatment. Ara-C is intracellularly converted by the canonical dNTP synthesis pathway to ara-CTP, which serves as a substrate but not an allosteric activator of SAMHD1. Using an AML mouse model, we show here that wild type but not catalytically inactive SAMHD1 reduces ara-C treatment efficacy in vivo. Expanding the clinically relevant substrates of SAMHD1, we demonstrate that THP-1 CRISPR/Cas9 cells lacking a functional SAMHD1 gene showed increased sensitivity to the antimetabolites nelarabine, fludarabine, decitabine, vidarabine, clofarabine, and trifluridine. Within this Extra View, we discuss and build upon both these and our previously reported findings, and propose SAMHD1 is likely active against a variety of nucleoside analog antimetabolites present in anti-cancer chemotherapies. Thus, SAMHD1 may constitute a promising target to improve a wide range of therapies for both hematological and non-haematological malignancies.


Electromechanical properties of relaxor ferroelectric P(VDF-TrFE-CFE)-P(VDF-CTFE) blends.
Electromechanical properties of the relaxor ferroelectric poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [P(VDF-TrFE-CFE)] terpolymer blended with a small amount of poly(vinylidene fluoride-chlorotrifluoroethylene) [P(VDF-CTFE)] copolymer, which possesses a much higher elastic modulus than that of the neat terpolymer, were investigated. It was observed that the presence of small amount of P(VDF-CTFE) does not affect the microstructure of the crystalline phase. However, the uniaxially stretched blended films show a slight increase in the crystallinity and increased or similar induced polarization at high electric fields compared with the neat terpolymer, likely caused by the interface effect. Consequently, for blends with P(VDF-CTFE) less than 5 wt%, the transverse strains S1 along the stretching direction for uniaxially stretched blended films are nearly the same as those of neat P(VDF-TrFE-CFE), whereas the elastic modulus along the S1-direction increases with the P(VDF-CTFE) content. As a result, the blended films exhibit a higher elastic energy density and electromechanical coupling factor k31 compared with the neat terpolymer.


A humanized UGT1 mouse model expressing the UGT1A1*28 allele for assessing drug clearance by UGT1A1-dependent glucuronidation.
Humanized mice that express the human UDP-glucuronosyltransferase (UGT) 1 locus have been developed in a Ugt1-null background as a model to improve predictions of human UGT1A-dependent drug clearance. Enzyme kinetic parameters (K(m) and V(max)) and pharmacokinetic properties of three probe drugs were compared using wild-type and humanized UGT1 mice that express the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28)) Ugt1(-/-) mice]. The well characterized substrate for UGT1A1, 7-ethyl-10-hydroxy-camptothecin (SN-38), showed the greatest difference in parent drug exposure ( approximately 3-fold increase) and clearance ( approximately 3-fold decrease) in Tg(UGT1(A1*28)) Ugt1(-/-) mice after intravenous administration compared with wild-type and phenobarbital-treated animals. In contrast, the clearance of the UGT2B7 substrate (-)-17-allyl-4, 5alpha-epoxy-3, 14-dihydroxymorphinan-6-one (naloxone) was not altered in Tg(UGT1(A1*28)) Ugt1(-/-) mice. In addition, pharmacokinetic parameters with 1-(4-fluorophenyl)3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (ezetimibe, Zetia; Merck & Co., Whitehouse Station, NJ), considered to be a major substrate for UGT1A1, showed small to no dependence on UGT1A1-directed glucuronidation. Enzyme kinetic parameters assessed for SN-38, ezetimibe, and naloxone using liver microsomes prepared from wild-type and Tg(UGT1(A1*28)) Ugt1(-/-) mice showed patterns consistent with the in vivo pharmacokinetic data. For SN-38 glucuronidation, V(max) decreased 5-fold in Tg(UGT1(A1*28)) Ugt1(-/-) mouse liver microsomes compared with microsomes prepared from wild-type mice, and decreased 10-fold compared with phenobarbital-treated Tg(UGT1(A1*28)) Ugt1(-/-) mice. These differences are consistent with SN-38 glucuronidation activities using HLMs isolated from individuals genotyped as UGT1A1*1 or UGT1A1*28. For ezetimibe and naloxone the differences in V(max) were minimal. Thus, Tg(UGT1(A1*28)) Ugt1(-/-) mice can serve as a pharmacokinetic model to further investigate the effects of UGT1A1 expression on drug metabolism.


Adjuvant therapy for resected gallbladder cancer.
Gallbladder cancer, one of the family of biliary tract cancers, has a poor prognosis. Adjuvant therapy comprising radiotherapy, chemotherapy plus radiation therapy and systemic chemotherapy may all play a role in improving survival. Most extant data on adjuvant therapy are retrospective studies or meta-analyses based on these studies. Recently, a phase III study demonstrated that capecitabine is a standard treatment option for biliary tract cancers, including gallbladder cancer. Ongoing studies investigating chemotherapy, novel surgical strategies, immunotherapy, molecular-targeted therapies using molecular profiling have been developed. This review summarises current status and future perspectives of adjuvant therapy for gallbladder cancer.


In vivo measurement of changes in venous blood-oxygenation with high resolution functional MRI at 0.95 tesla by measuring changes in susceptibility and velocity.
High-resolution functional imaging experiments at 0.95 Tesla have been performed to determine the changes in oxygen saturation in pial veins during motor activation by measuring both flow and susceptibility changes in the blood. Averaging across subjects, mean values for the change of the oxygenation level, deltaY = 0.16 +/- 0.08 (n = 7) and deltaY = 0.13 +/- 0.09 (n = 4), were obtained from the susceptibility sensitive and the flow sensitive acquisitions, respectively. The results suggest that the increase in blood flow is largely uncoupled from the oxygen consumption. The quoted errors reflect mainly the intersubject variability. In addition, low-resolution echo planar imaging (EPI) measurements were performed on the same volunteers to quantify signal intensity changes. Using the measured change in oxygenation, the observed signal changes in the EPI experiments can be attributed to a 5% venous blood volume.


Cardiovascular disease: Psychological, social, and behavioral influences: Introduction to the special issue.
Although deaths due to cardiovascular diseases have declined significantly since the 1970s, they remain the most common cause of morbidity and mortality in the United States. A large number of cardiovascular risk factors, such as smoking, obesity, and sedentary lifestyle, are modifiable. Psychologists and other behavioral scientists and practitioners are engaged in not only understanding the mechanistic links between behaviors and cardiovascular health but also developing effective interventions for improving health. The purpose of this special issue is to highlight some of the more innovative psychological research in cardiovascular health promotion, disease prevention, and management. Articles included in this issue focus on 2 primary areas. First, cutting-edge research on the current state of knowledge of modifiable health behaviors and their impact on cardiovascular health include articles on e-cigarette use as a putative risk factor, psychological factors involved in adherence to medications, the role of sleep in cardiovascular health, and innovative approaches to enhancing the treatment and recovery of patients with cardiovascular diseases. Second, outstanding research identifying the mechanisms by which psychological factors such as stress, depression, and anxiety impact cardiovascular disease include an overview of the current state of science examining psychological comorbidities that can accompany cardiovascular disease and influence outcomes, discussion of the neurocognitive processes that connect stress appraisal with biological functioning and diseases processes, and the role of genetics on behavioral interventions and clinical decision-making in the context of behavioral weight loss treatments. Our goal with these innovative articles is to stimulate additional advances in cardiovascular behavioral medicine. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Morusin alleviates mycoplasma pneumonia via the inhibition of Wnt/β-catenin and NF-κB signaling.
Morusin has been traditionally used for the treatment of Mycoplasma pneumoniae pneumonia (MPP), but the underlying mechanism remains elusive. The present study aimed to explore the mechanism by which morusin achieves efficacy on mycoplasma pneumonia. Mycoplasma pneumonia model was established in BALB/c mouse and the effects of morusin were evaluated in the model. Compared with the model group, DNA amount of M. pneumoniae decreased by 24.6 ± 3.14% and 47.6 ± 6.78% in low morusin (20 mg/kg) and high morusin (50 mg/kg) groups, respectively (P<0.05). Moreover, morusin treatment led to decreased levels of pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor α and increased level of anti-inflammatory IL-10 in mice lung tissue. Furthermore, morusin treatment inhibited the activation of Wnt/β-catenin and NF-κB pathways in mice lung tissue. Taken together, our results suggest that morusin relieves mycoplasma pneumonia via the inhibition of the activation of Wnt/β-catenin and NF-κB pathways, and is a potential natural agent for the treatment of mycoplasma pneumonia.


Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting.
Acute infection increases the risk of arterial cardiovascular events, but effects on venous thromboembolic disease are less well established. Our aim was to investigate whether acute infections transiently increase the risk of venous thromboembolism. We used the self-controlled case-series method to study the risk of first deep vein thrombosis (DVT) (n=7278) and first pulmonary embolism (PE) (n=3755) after acute respiratory and urinary tract infections. Data were obtained from records from general practices who had registered patients with the UK's Health Improvement Network database between 1987 and 2004. The risks of DVT and PE were significantly raised, and were highest in the first two weeks, after urinary tract infection. The incidence ratio for DVT was 2.10 (95% CI 1.56-2.82), and that for PE 2.11 (1.38-3.23). The risk gradually fell over the subsequent months, returning to the baseline value after 1 year. The risk of DVT was also higher after respiratory tract infection, but possible diagnostic misclassification precluded a reliable estimate of the risk of PE after respiratory infection. Acute infections are associated with a transient increased risk of venous thromboembolic events in a community setting. Our results confirm that infection should be added to the list of precipitants for venous thromboembolism, and suggest a causal relation.


GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment.
The mechanical properties of the tumor microenvironment are emerging as attractive targets for the development of therapies. Tamoxifen, an agonist of the G protein-coupled estrogen receptor (GPER), is widely used to treat estrogen-positive breast cancer. Here, we show that tamoxifen mechanically reprograms the tumor microenvironment through a newly identified GPER-mediated mechanism. Tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells (PSCs) in the tumor microenvironment of pancreatic cancer in an acto-myosin-dependent manner via RhoA-mediated contractility, YAP deactivation, and GPER signaling. This hampers the ability of PSCs to remodel the extracellular matrix and to promote cancer cell invasion. Tamoxifen also reduces the recruitment and polarization to the M2 phenotype of tumor-associated macrophages. Our results highlight GPER as a mechanical regulator of the tumor microenvironment that targets the three hallmarks of pancreatic cancer: desmoplasia, inflammation, and immune suppression. The well-established safety of tamoxifen in clinics may offer the possibility to redirect the singular focus of tamoxifen on the cancer cells to the greater tumor microenvironment and lead a new strategy of drug repurposing.


Early cretaceous dinosaurs from the sahara.
A major question in Mesozoic biogeography is how the land-based dinosaurian radiation responded to fragmentation of Pangaea. A rich fossil record has been uncovered on northern continents that spans the Cretaceous, when continental isolation reached its peak. In contrast, dinosaur remains on southern continents are scarce. The discovery of dinosaurian skeletons from Lower Cretaceous beds in the southern Sahara shows that several lineages of tetanuran theropods and broad-toothed sauropods had a cosmopolitan distribution across Pangaea before the onset of continental fragmentation. The distinct dinosaurian faunas of Africa, South America, and Asiamerica arose during the Cretaceous by differential survival of once widespread lineages on land masses that were becoming increasingly isolated from one another.


Revisiting the Role of the Fusiform Face Area in Expertise.
The fusiform face area (FFA) is considered to be a highly specialized brain module because of its central importance for face perception. However, many researchers claim that the FFA is a general visual expertise module that distinguishes between individual examples within a single category. Here, I circumvent the shortcomings of some previous studies on the FFA controversy by using chess stimuli, which do not visually resemble faces, together with more sensitive methods of analysis such as multivariate pattern analysis. I also extend the previous research by presenting chess positions, complex scenes with multiple objects, and their interrelations to chess experts and novices as well as isolated chess objects. The first experiment demonstrates that chess expertise modulated the FFA activation when chess positions were presented. In contrast, single chess objects did not produce different activation patterns among experts and novices even when the multivariate pattern analysis was used. The second experiment focused on the single chess objects and featured an explicit task of identifying the chess objects but failed to demonstrate expertise effects in the FFA. The experiments provide support for the general expertise view of the FFA function but also extend the scope of our understanding about the function of the FFA. The FFA does not merely distinguish between different exemplars within the same category of stimuli. More likely, it parses complex multiobject stimuli that contain numerous functional and spatial relations.


Assessment of DNA damage in welders using comet and micronucleus assays.
Welding technology is widely used in pressurized containers, thermal power plants, refineries, chemical facilities and steel structures. Welders are exposed to a number of hazardous compounds such as ultraviolet (UV) radiation, electromagnetic fields, toxic metals and polycyclic aromatic hydrocarbons (PAHs). In the present study, 48 welders and an equal number of control subjects were evaluated for DNA damage in the whole blood and isolated lymphocytes using the comet assay. The genotoxic damage in buccal epithelial cells of subjects was determined by micronucleus (MN) assay. Metal(loids) such as Cr, Mn, Ni, Cu, As, Cd and Pb levels in blood samples were evaluated by using Inductively Coupled Plasma-Mass Spectrometer (ICP-MS). Results of this study showed that DNA damage in blood, isolated lymphocytes, and buccal epithelial cells were significantly higher in workers compared to the controls. Also, these workers had remarkably higher blood Cr, Cu, Cd, Ni and Pb levels. These results showed that occupational exposure to welding fumes may cause genotoxic damage that can lead to important health problems in the workers. More extensive epidemiological studies should be performed that enable the assessment of health risk in welding industry.


Respondent driven sampling of wheelchair users: A lack of traction?
Internationally, wheelchair users are an emerging demographic phenomenon, due to their increased prevalence and rapidly increasing life-span. While having significant healthcare implications, basic robust epidemiological information about wheelchair users is often lacking due, in part, to this population's 'hidden' nature. Increasingly popular in epidemiological research, Respondent Driven Sampling (RDS) provides a mechanism for generating unbiased population-based estimates for hard-to-reach populations, overcoming biases inherent within other sampling methods. This paper reports the first published study to employ RDS amongst wheelchair users. Between October 2015 and January 2016, a short, successfully piloted, internet-based national survey was initiated. Twenty seeds from diverse organisations were invited to complete the survey then circulate it to peers within their networks following a well-defined protocol. A predetermined reminder protocol was triggered when seeds or their peers failed to respond. All participants were entered into a draw for an iPad. Overall, 19 people participated (nine women); 12 initial seeds, followed by seven second-wave participants arising from four seeds . Completion time for the survey ranged between 7 and 36 minutes. Despite repeated reminders, no further people were recruited. While New Zealand wheelchair user numbers are unknown, an estimated 14% of people have physical impairments that limited mobility. The 19 respondents generated from adopting the RDS methodology here thus represents a negligible fraction of wheelchair users in New Zealand, and an insufficient number to ensure equilibrium required for unbiased analyses. While successful in other hard-to-reach populations, applying RDS methodology to wheelchair users requires further consideration. Formative research exploring areas of network characteristics, acceptability of RDS, appropriate incentive options, and seed selection amongst wheelchair users is needed.


[Integrins and metalloproteinases: an efficient collaboration in the invasive process].
During the invasive process, tumor cells must move through the extracellular matrix. They have to adhere to the extracellular matrix components, then proteolyse them and migrate on their fragments. This implicates integrins and proteinases, namely metalloproteinases. Numerous experiments which had been performed on various models, namely malignant melanomas proved that integrins have a major role in the transduction of signals from the outside to the inside of the cells, such signals enhancing the expression of the metalloproteinases or, in the contrary, inhibiting it. The modifications of this expression are dependent of extracellular matrix components and may be induced by the linking of specific antibodies to integrins. In some instances, the integrins localized on the tumor cell surface may act as receptors for extracellular matrix proteins and metalloproteinases at once, that may give to tumor cells an higher efficiency in the invasive process. Such mechanisms may result in interesting clinical perspectives for the control of metalloproteinases regulation in pathological processes.


One-versus two-incision ACL reconstruction. A prospective, randomized study.
This study compares the early functional outcomes of anterior cruciate ligament (ACL) reconstruction using a one-incision endoscopic technique versus a two-incision arthroscopically assisted technique. Thirty patients with chronic ACL-deficient knees were randomly assigned to either group 1 (one-incision technique; 15 patients) or group 2 (two-incision technique; 15 patients). Middle third ipsilateral patellar tendon was used in all reconstructions. All patients followed the same home-based accelerated rehabilitation protocol. The International Knee Documentation Committee scoring system was used to assess pre- and postoperative knee function. The mean length of follow-up was 17 months for group 1 and 15 months for group 2. Three patients were lost to follow-up in group 2. Patients in group 1 achieved a mean one-leg hop value of 89% of the uninjured side while group 2 patients averaged 92%. The mean side-to-side difference in anterior tibial translation was 2 mm in both groups at manual maximum translation. The mean isokinetic quadriceps strength at 300 degrees/second of the operated side 1 year after surgery was 83% of normal for group 1 versus 73% for group 2. Both groups achieved maximum range of motion within 3 months. There was no statistically significant difference between the outcomes of the one- and two-incision techniques for ACL reconstruction. All patients in both groups had improved stability and function of their operative knees compared with their preoperative condition.


In silico experiment with an-antigen-toll like receptor-5 agonist fusion construct for immunogenic application to Helicobacter pylori.
Helicobacter pylori colonize the gastric mucosa of half of the world's population. Although it is classified as a definitive type I carcinogen by World Health Organization, there is no effective vaccine against this bacterium. H. pylori evade the host immune response by avoiding toll-like detection, such as detection via toll-like receptor-5 (TLR-5). Thus, a chimeric construct consisting of selected epitopes from virulence factors that is incorporated into a TLR-5 ligand (Pseudomonas flagellin) could result in more potent innate and adaptive immune responses. Based on the histocompatibility antigens of BALB/c mice, in silico techniques were used to select several fragments from H. pylori virulence factors with a high density of B- and T-cell epitopes. These segments consist of cytotoxin-associated geneA (residue 162-283), neutrophil activating protein (residue 30-135) and outer inflammatory protein A (residue 155-268). The secondary and tertiary structure of the chimeric constructs and other bioinformatics analyses such as stability, solubility, and antigenicity were performed. The chimeric construct containing antigenic segments of H. pylori proteins was fused with the D3 domain of Pseudomonas flagellin. This recombinant chimeric gene was optimized for expression in Escherichia coli. The in silico results showed that the conserved C- and N-terminal domains of flagellin and the antigenicity of selected fragments were retained. In silico analysis showed that Pseudomonas flagellin is a suitable platform for incorporation of an antigenic construct from H. pylori. This strategy may be an effective tool for the control of H. pylori and other persistent infections.


Improved reflectance reconstruction for multispectral imaging by combining different techniques.
In multispectral imaging system, one of the most important tasks is to accurately reconstruct the spectral reflectance from system responses. We propose such a new method by combing three most frequently used techniques, i.e., wiener estimation, pseudo-inverse, and finite-dimensional modeling. The weightings of these techniques are calculated by minimizing the combined standard deviation of both spectral errors and colorimetric errors. Experimental results show that, in terms of color difference error, the performance of the proposed method is better than those of the three techniques. It is found that the simple averaging of the reflectance estimates of these three techniques can also yield good color accuracy.


A comparison of discharge teaching on the consequences of brain injury.
Cognitive dysfunction is a common consequence of brain injury. Frequently, however, this phenomenon is not discussed with family caregivers before the patient's discharge from the acute care setting. A discharge teaching videotape was developed, which presented how the most common cognitive dysfunctions experienced postbrain injury affect activities of daily living. The ability to extrapolate appropriate patient care techniques after receiving discharge instructions on cognitive dysfunctions was tested by a posttest only experimental design study using a control and experimental group. The results indicated that family caregivers who received instruction on cognitive dysfunction were more informed about brain injury-induced behavior and better prepared to help loved ones compensate for cognitive dysfunctions.


Concepts and strategies for scaling up focused prevention for sex workers in India.
To describe the concepts, strategies and field results of a project to scale up prevention programmes and services for female sex workers (FSWs) in Karnataka, India. A strategy was developed to scale up urban sex worker interventions in 18 districts in the southern Indian state of Karnataka. Macro-level coverage objectives were defined by mapping the urban locations where FSWs operate and estimating their population size. Prevention programmes were initiated in the urban locations that contained at least 90% of the estimated urban FSW population in each district. Within each location, a micro-planning process was used by FSW peer educators and outreach workers to design local outreach and service delivery plans. An estimated 48 973 FSWs were distributed across 1551 locations and 6232 spots. Outreach was conducted by 1043 peer educators. Services were provided through 170 drop-in centres, 93 programme-run clinics, 110 outreach clinics and 157 referral clinics. Within the first 3 years of the programme the cumulative number of individual FSWs contacted at least once was >78 000, with monthly contact established with 81% of the in situ population; >45 000 FSWs had visited a clinic and >10 000 visited monthly. Direct and indirect condom distribution by the programme amounted to more than 30 per contacted FSW, which is estimated to meet the condom requirement. A strategy that involves geographically defined coverage and micro-level outreach planning can rapidly and effectively provide outreach and services to large dispersed FSW populations.


Intraosseous schwannoma of the humerus: a rarity yet warrants consideration.
Intraosseous schwannoma is extremely rare that it is not often considered among differential diagnosis for an osteolytic lesion, especially in long bones of the extremities. Amounting to less than 0.2% of all primary bone tumours and less than 200 cases reported so far, with only 3 cases involving the humerus, we hereby report the fourth case. In addition to its rarity, this was the only case of an intraosseous schwannoma involving the humerus bone which presented with a pathological fracture in a 45-year-old woman after sustaining a trivial trauma. Radiological examination revealed a geographic type of osteolytic lesion in distal shaft region of the left humerus. Only a histopathological examination helped in revealing and confirming the diagnosis of an intraosseous schwannoma. Treatment of the tumour with complete excision with bone graft reconstruction and osteosynthesis yields good results with very low risk of recurrence.


Ginsenoside Rg1 protects rat cardiomyocyte from hypoxia/reoxygenation oxidative injury via antioxidant and intracellular calcium homeostasis.
Ginsenoside Rg1 is a major active ingredient of Panax notoginseng radix which has demonstrated a number of pharmacological actions including a cardioprotective effect in vivo. This study investigated the protective effect and mechanism of ginsenoside Rg1 in cardiomyocytes hypoxia/reoxygenation (H/R) model. Pretreatment with ginsenoside Rg1 (60-120 microM) reduced lactate dehydrogenase release and increased cell viability in a dose-dependent manner. Fluorescence analysis demonstrated ginsenoside Rg1 reduced intracellular ROS and suppressed the intracellular [Ca(2+)] level. Cell lysate detected an increase of T-SOD, CAT, and GSH levels. The myocardial protection of ginsenoside Rg1 during H/R is partially due to its antioxidative effect and intracellular calcium homeostasis.


Laparoscopic marsupialization of a giant posttraumatic splenic cyst.
Nonparasitic cysts are rare clinical lesions of the spleen. Causes include congenital malformations and trauma. Historically, management has entailed partial or total splenectomy using an open approach. Recently, laparoscopic approaches have been developed. In this report, we describe laparoscopic marsupialization of a giant splenic cyst (diameter > 15 cm). A 25-year-old African-American man presented with a 9-month history of early satiety, constipation, and left upper quadrant pain. Additionally, he reported blunt trauma to the abdomen 2 years earlier. Physical examination revealed a large, fixed, nontender left upper quadrant mass. Computed tomography scan confirmed a simple cyst within the spleen, measuring 20 x 25 cm. Echinococcus and Entamoeba histolytica serologies were negative. Laparoscopic exploration was performed. Four liters of brown fluid were aspirated and intraoperative cytology confirmed a nonparasitic cyst. The cyst wall was excised and the cavity was packed with omentum. The patient's recovery was uneventful, and he was discharged to home tolerating a regular diet on postoperative day 3. At 6-month follow-up, the patient was asymptomatic and showed no evidence of recurrence. Nonparasitic splenic cysts are rare lesions. Laparoscopic marsupialization is safe and effective for giant nonparasitic splenic cysts and should be considered the treatment of choice.


Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation.
Big mitogen-activated protein kinase 1 (BMK1) is a new member of mitogen-activated protein kinase (MAPK) family. In the present study, we investigated whether glial cell line-derived neurotrophic factor (GDNF) can induce activation of BMK1 through RET tyrosine kinase. Its activation reached a maximal level at 30 min and continued at least for 120 min after GDNF stimulation. In addition, we detected BMK1 activation in NIH3T3 cells expressing RET with a multiple endocrine neoplasia (MEN) 2A mutation. The level of BMK1 activation markedly decreased by replacement of tyrosine 1062 with phenylalanine (designated Y1062F) in RET, indicating the importance of downstream signaling via tyrosine 1062. However, although both RAS/MAPK and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways are activated via tyrosine 1062, BMK1 activation by GDNF was not significantly impaired by treatment with an MEK1 inhibitor, PD98059, or two distinct PI3-K inhibitors, LY294002 and wortmannin, suggesting that the RAS and PI3-K signaling pathways are not crucial for BMK1 activation by GDNF. Moreover, luciferase reporter assays revealed that RET-MEN2A mutant proteins can activate the MEF2C transcription factor that is known to be a cellular target for BMK1, and that its activation is impaired by the Y1062F mutation or by expression of a dominant negative form of MEK5.


Quantification of the association between intervertebral disk calcification and disk herniation in Dachshunds.
To quantify the association between intervertebral disk calcification and disk herniation in Dachshunds. Longitudinal study. 61 Dachshunds that had been radiographically screened for calcification of intervertebral disks at 2 years of age in other studies. Thirty-seven of the dogs had survived to the time of the present study and were > or = 8 years of age; 24 others had not survived. Radiographic examination of 36 surviving dogs was performed, and information on occurrence of disk calcification at 2 years of age were obtained from records of all 61 Dachshunds. Information on occurrence of disk herniation between 2 and 8 years of age was obtained from owners via questionnaire. Associations between numbers of calcified disks and disk herniation were analyzed via maximum likelihood logistic regression. Disk calcification at 2 years of age was a significant predictor of clinical disk herniation (odds ratio per calcified disk, 1.42; 95% confidence interval, 1.19 to 1.81). Number of calcified disks in the full vertebral column was a better predictor than number of calcified disks between vertebrae T10 and L3. Numbers of calcified disks at > or = 8 years of age and at 2 years of age were significantly correlated. Number of calcified disks at 2 years of age was a good predictor of clinical disk herniation in Dachshunds. Because of the high heritability of disk calcification, it is possible that an effective reduction in occurrence of severe disk herniation in Dachshunds could be obtained by selective breeding against high numbers of calcified disks at 2 years of age.


Effects of apolipoprotein E genotypes on the development of exfoliation syndrome.
Apolipoprotein E (apo E) is directly involved in the amyloid deposition and fibril formation and is present in many cerebral and systemic amyloidoses immunologically. It is encoded by a polymorphic gene and it has three common alleles-epsilon2, epsilon3, and epsilon4. Exfoliation syndrome (XFS) is characterized by the deposition throughout the body of focal fibrillogranular aggregates in which there have been some reports of amyloid or amyloid-like features. We evaluated the possible association between apo E polymorphism and the occurrence of XFS. Using High Pure PCR Template Preparation Kits, genomic DNAs were extracted from whole blood and apo E polymorphisms were determined by using Lightcycler-Apo E Mutation Detection Kits in 76 patients with XFS and 74 controls. The E2/E2, E2/E3 and E2/E4 genotypes (OR 29.9, 95% CI 3.1-293.7; OR 56.1, 95% CI 12.5-252.7; OR 43.9, 95% CI 7.4-257.6, respectively) and the in2 allele are found to have an increased risk of developing XFS (p=0.0001); whereas the in3 allele was found to be protective (p=0.0001). Apo E polymorphism and the presence of in2 allele are seem to be significantly associated with the development of XFS.


Heart rate-independent energetics and systolic pressure-volume area in dog heart.
Left ventricular (LV) systolic pressure-volume area (PVA), a new measure of total mechanical energy for the contraction, linearly correlates with its oxygen consumption per beat (VO2) regardless of contraction mode in a canine heart with stable chronotropism and inotropism. PVA is the area in the pressure-volume (PV) diagram circumscribed by the end-systolic and end-diastolic PV relation curves and the systolic segment of the PV loop and has dimensions of energy. We investigated whether primary changes in heart rate would affect the VO2-PVA relation. In the excised cross-circulated canine heart with left ventricular load controlled with a servo pump, we changed heart rate by pacing to compare the VO2-PVA relations at low [124 +/- 17 (SD) min-1] and high (193 +/- 23) heart rates. In 15 left ventricles, VO2 (ml O2 X beat-1 X 100 g LV-1) was (1.75 +/- 0.57) X 10(-5) PVA (mmHg X ml X beat-1 X 100 g LV-1) + 0.031 +/- 0.011 (ml O2 X beat-1 X 100 g LV-1). The VO2-PVA relation was virtually independent of heart rate in individual hearts. We conclude that the load-independent VO2-PVA relationship is not affected by chronotropism in a given canine left ventricle.


Development of colorimetric HTS assay of cytochrome p450 for ortho-specific hydroxylation, and engineering of CYP102D1 with enhanced catalytic activity and regioselectivity.
A current challenge in high-throughput screening (HTS) of hydroxylation reactions by P450 is a fast and sensitive assay for regioselective hydroxylation against millions of mutants. We have developed a solid-agar plate-based HTS assay for screening ortho-specific hydroxylation of daidzein by sensing formaldehyde generated from the O-dealkylation reaction. This method adopts a colorimetric dye, pararosaniline, which has previously been used as an aldehyde-specific probe within cells. The rationale for this method lies in the fact that the hydroxylation activity at ortho-carbon position to COH correlates with a linear relationship to O-dealkylation activity on chemically introduced methoxy group at the corresponding COH. As a model system, a 4',7-dihydroxyisoflavone (daidzein) hydroxylase (CYP102D1 F96V/M246I), which catalyzes hydroxylation at ortho positions of the daidzein A/B-ring, was examined for O-dealklyation activity, by using permethylated daidzein as a surrogate substrate. By using the developed indirect bishydroxylation screening assay, the correlation coefficient between O-dealkylation and bishydroxylation activity for the template enzyme was 0.72. For further application of this assay, saturation mutants at A273/G274/T277 were examined by mutant screening with a permethylated daidzein analogue substrate (A-ring inactivated in order to find enhanced 3'-regioselectiviy). The whole-cell biotransformation of daidzein by final screened mutant G1 (A273H/G274E/T277G) showed fourfold increased conversion yield, with 14.3 mg L(-1) production titer and greatly increased 3'-regioselectiviy (3'/6=11.8). These results show that there is a remarkably high correlation (both in vitro and in vivo), thus suggesting that this assay would be ideal for a primary HTS assay for P450 reactions.


4Pi microscopy of type A with 1-photon excitation in biological fluorescence imaging.
We demonstrate that oil immersion lenses with a semi-aperture angle >/= 74 degrees enable 4Pi confocal fluorescence microscopy of type A with 1 photon excitation. The axial sidelobes amount to < 50 % of the main diffraction maximum, implying that lobe induced artifacts can be removed from the image data. The advancement reported herein enables a relative inexpensive implementation of 4Pi microscopy, providing axially superresolved 3D-imaging in transparent samples. As an example, we show dual-color 4Pi images of double stained Golgi stacks in a mammalian cell with 110 nm axial resolution. The resolution can be further enhanced to values slightly below 100 nm by image deconvolution.


Ruthenium(0) nanoparticles supported on xonotlite nanowire: a long-lived catalyst for hydrolytic dehydrogenation of ammonia-borane.
Ruthenium(0) nanoparticles supported on xonotlite nanowire (Ru(0)@X-NW) were prepared by the ion exchange of Ru(3+) ions with Ca(2+) ions in the lattice of xonotlite nanowire followed by their reduction with sodium borohydride in aqueous solution at room temperature. Ru(0)@X-NW were characterized by a combination of advanced analytical techniques. The results show that (i) highly dispersed ruthenium(0) nanoparticles of 4.4 ± 0.4 nm size were formed on the surface of xonotlite nanowire, (ii) Ru(0)@X-NW show high catalytic activity in hydrogen generation from the hydrolytic dehydrogenation of ammonia borane with a turnover frequency value up to 135 min(-1) at 25.0 ± 0.1 °C. (iii) They provide unprecedented catalytic life time (TTO = 134,100) for hydrogen generation from the hydrolysis of ammonia borane at 25.0 ± 0.1 °C. (iv) The results of a kinetic study on the hydrogen generation from the hydrolysis of ammonia borane were also reported including the activation energy of 77 ± 2 kJ mol(-1) for this reaction.


Ab Initio calculations of even oxygen isotopes with chiral two-plus-three-nucleon interactions.
We formulate the in-medium similarity renormalization group (IM-SRG) for open-shell nuclei using a multireference formalism based on a generalized Wick theorem introduced in quantum chemistry. The resulting multireference IM-SRG (MR-IM-SRG) is used to perform the first ab initio study of all even oxygen isotopes with chiral nucleon-nucleon and three-nucleon interactions, from the proton to the neutron drip lines. We obtain an excellent reproduction of experimental ground-state energies with quantified uncertainties, which is validated by results from the importance-truncated no-core shell model and the coupled cluster method. The agreement between conceptually different many-body approaches and experiment highlights the predictive power of current chiral two- and three-nucleon interactions, and establishes the MR-IM-SRG as a promising new tool for ab initio calculations of medium-mass nuclei far from shell closures.


Small-animal PET of tumors with (64)Cu-labeled RGD-bombesin heterodimer.
The overexpression of gastrin-releasing peptide receptor (GRPR) in various tumor types suggests that GRPR is an attractive target for cancer imaging and therapy with radiolabeled bombesin analogs. We recently reported the ability of (18)F-labeled RGD-bombesin heterodimer to be used for dual integrin alpha(v)beta(3)- and GRPR-targeted imaging. To further investigate the synergistic effect of the dual-receptor targeting of peptide heterodimers, we evaluated (64)Cu-labeled RGD-bombesin for PET imaging of tumors. RGD-bombesin was coupled with 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the conjugates were labeled with (64)Cu. The in vitro and in vivo characteristics of (64)Cu-NOTA-RGD-bombesin were compared with those of (64)Cu-NOTA-RGD, (64)Cu-NOTA-bombesin, and (64)Cu-DOTA-RGD-bombesin. (64)Cu-NOTA-RGD-bombesin and (64)Cu-DOTA-RGD-bombesin had comparable dual integrin alpha(v)beta(3)- and GRPR-binding affinities in vitro, both of which were slightly lower than RGD for integrin binding and bombesin for GRPR binding. (64)Cu-NOTA-RGD-bombesin possessed significantly higher tumor uptake than did (64)Cu-NOTA-RGD, (64)Cu-NOTA-bombesin, the mixture of (64)Cu-NOTA-RGD and (64)Cu-NOTA-bombesin, or (64)Cu-DOTA-RGD-bombesin in PC-3 prostate cancer. (64)Cu-NOTA-RGD-bombesin also showed improved in vivo kinetics such as lower liver and intestinal activity accumulation than did the bombesin tracers. (64)Cu-NOTA-RGD-bombesin also outperformed (64)Cu-NOTA-RGD in a 4T1 murine mammary carcinoma model that expresses integrin on tumor vasculature but no GRPR in tumor tissue, which had no uptake of (64)Cu-NOTA-bombesin. Compared with other tracers, (64)Cu-NOTA-RGD-bombesin showed favorable in vivo kinetics and enhanced tumor uptake, which warrants its further investigation for targeting tumors that express integrin or GRPR or that coexpress integrin and GRPR for imaging and therapeutic applications. The synergistic effect of RGD-bombesin heterodimers observed in this study also encourages further investigations of novel heterodimers recognizing other cell surface receptors for tumor targeting.


Expression of a Neurospora crassa zinc transporter gene in transgenic Nicotiana tabacum enhances plant zinc accumulation without co-transport of cadmium.
Zinc (Zn) is an essential micronutrient required for growth and development of all organisms. Deficiency of Zn in humans is widespread, affecting 25% of world population and efforts are underway to develop crop plants with high levels of Zn in their edible parts. When strategies for enhancing Zn in crop plants are designed, it is essential to exclude cadmium (Cd), a toxic analogue of Zn. In the present work, a high affinity and high specificity zinc transporter gene (tzn1) from Neurospora crassa was cloned and introduced into Nicotiana tabacum with the objective of enhancing the potential of plants for zinc acquisition. When grown in hydroponic medium spiked with (65) Zn, transgenic plants showed enhanced accumulation of Zn (up to 11 times) compared to control plants, which was confirmed further by environmental scanning electron microscopy coupled with Energy Dispersive X-ray analysis. More importantly, no significant difference in uptake of Cd(2+), Fe(2+), Ni(2+), Cu(2+), Mn(2+) and Pb(2+) between the transgenic and control plants was observed. The present studies have shown that Neurospora crassa tzn1 is a potential candidate gene for developing transgenic plants for improving Zn uptake, without co-transport of Cd and may have implications in Zn phytofortification and phytoremediation.


Simultaneous intake of beta-glucan and plant stanol esters affects lipid metabolism in slightly hypercholesterolemic subjects.
Intake of food products rich in water-soluble fiber beta-glucan and products enriched with plant stanol esters lower serum cholesterol. Combining 2 functional food ingredients into one food product may achieve additional reductions of serum cholesterol. Our objective was to investigate the effects of a simultaneous intake of beta-glucan plus plant stanol esters on lipid metabolism in mildly hypercholesterolemic volunteers. In a randomized, controlled, 3-period crossover study, 40 mildly hypercholesterolemic men and women received muesli in random order twice a day for 4 wk, which provided, in total, 5 g control fiber from wheat (control muesli), 5 g oat beta-glucan (beta-glucan muesli), or 5 g oat beta-glucan plus 1.5 g plant stanols (combination muesli). beta-Glucan muesli decreased serum LDL cholesterol by 5.0% compared with control muesli (P = 0.013). Combination muesli reduced LDL cholesterol by 9.6% compared with control muesli (P < 0.001), and by 4.4% compared with beta-glucan muesli (P = 0.036). Serum HDL cholesterol and triacylglycerol concentrations did not differ after the 3 treatments. Compared with control muesli, beta-glucan muesli increased bile acid synthesis (P = 0.043) and decreased cholesterol absorption (P = 0.011). Addition of plant stanols did not influence bile acid synthesis but decreased cholesterol absorption (P < 0.001) and raised cholesterol synthesis (P = 0.016) compared with control muesli, and the plant stanols decreased cholesterol absorption compared with beta-glucan muesli (P = 0.004). The combination muesli decreased serum concentrations of sitostanol compared with control muesli (P = 0.010). Plasma concentrations of lipid-soluble antioxidants did not differ after the 3 treatments. beta-Glucan muesli effectively lowered serum LDL cholesterol concentrations. The addition of plant stanol esters to beta-glucan-enriched muesli further lowered serum LDL cholesterol, although effects were slightly less than predicted.


Development and evaluation of a novel fast broad-range PCR and sequencing assay (FBR-PCR/S) using dual priming oligonucleotides targeting the ITS/LSU gene regions for rapid diagnosis of invasive fungal diseases: multi-year experience in a large Canadian healthcare zone.
This study evaluated the performance of a novel fast broad range PCR and sequencing (FBR-PCR/S) assay for the improved diagnosis of invasive fungal disease (IFD) in high-risk patients in a large Canadian healthcare region. A total of 114 clinical specimens (CS) including bronchoalveolar lavages (BALs) were prospectively tested from 107 patients over a 2-year period. Contrived BALs (n = 33) inoculated with known fungi pathogens were also tested to increase diversity. Patient characteristics, fungal stain and culture results were collected from the laboratory information system. Dual-priming oligonucleotide (DPO) primers targeted to the internal transcribed spacer (ITS) (~ 350 bp) and large subunit (LSU) (~ 550 bp) gene regions were used to perform FBR-PCR/S assays on extracted BALs/CS. The performance of the molecular test was evaluated against standard microbiological methods and clinical review for the presence of IFD. The 107 patients were predominantly male (67, 62.6%) with a mean age of 59 years (range = 0-85 years): 74 (69.2%) patients had at least one underlying comorbidity: 19 (34.5%) had confirmed and 12 (21.8%) had probable IFD. Culture recovered 66 fungal isolates from 55 BALs/CS with Candida spp. and Aspergillus spp. being most common. For BALs, the molecular assay vs. standard methods had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), and efficiency of 88.5% vs.100%, 100% vs. 61.1%, 100% vs. 88.5%, 61.1% vs. 100%, and 90.2% for both. For other CS, the molecular assay had similar performance to standard methods with sensitivity, specificity, PPV, NPV and efficiency of 66.7%, 87.0%, 66.7%, 87.0% and 81.3% for both methods. Both methods also performed similarly, regardless of whether CS stain/microscopy showed yeast/fungal elements. FBR-PCR/S assays results were reported in ~ 8 h compared to fungal cultures that took between 4 and 6 weeks. Rapid molecular testing compared to standard methods have equivalent diagnostic efficiency but improves clinical utility by reporting a rapid species-level identification the same dayshift (~ 8 h).


Stability and in vivo safety of gold, titanium nitride and parylene C coatings on NdFeB magnets implanted in muscles towards a new generation of myokinetic prosthetic limbs.
Rare earth magnets are the elective choice when high magnetic field density is required and they are particularly intriguing for inclusion in implantable devices. A safe implantation of NdFeB magnets in muscles would enable the control of limb prostheses using a myokinetic interface i.e., direct control of artificial limb movements by means of magnetic tracking of residual muscle contractions. However, myokinetic prosthesis control is prevented by NdFeB magnets poor biocompatibility, at present. Here we investigated three biocompatible materials as NdFeB magnet coating candidates, namely gold, titanium nitride and parylene C, which have not been analyzed in a systematic way for this purpose, so far. In vitro testing in a tissue-mimicking environment and upon contact with C2C12 myoblasts enabled assessment of the superiority of parylene C coated magnets in terms of corrosion prevention and lack of cytotoxicity. In addition, parylene C coated magnets implanted in rabbit muscles for 28 days confirmed, both locally and systemically, their biocompatibility, with a lack of irritation and toxicity associated with the implant. These findings pave the way towards the development of implantable devices based on permanent magnets and of a new generation of limb prostheses.


[From Virchow's cellular pathology to modern molecular pathology].
Evolution of Virchow's cellular pathology into molecular biology and molecular pathology due to achievements of cytology, biochemistry (histochemistry), immunology (immunomorphology) and genetics as well as new opportunities opened by integration of these disciplines (electron histochemistry, immunohistochemistry, immunogenetics, etc.).


Magnetic resonance imaging documentation of coexistent traumatic locked facets of the cervical spine and disc herniation.
The coexistence of traumatic locked facets of the cervical spine and a herniated disc is not well described. The authors present a series of patients with traumatic locked facets who demonstrated a high incidence of associated disc herniation documented on magnetic resonance (MR) imaging. Thirteen patients with either unilateral (four cases) of bilateral (nine cases) locked facets of the cervical spine were analyzed retrospectively. Immediate closed reduction using traction and/or manipulation was attempted in the first nine cases treated and was successful in only three; however, the procedure was abandoned in three cases due to deterioration in the patient's clinical status. In the subsequent four patients, an MR image was obtained prior to attempts at closed reduction. All patients underwent MR imaging of the cervical spine. Of eight consecutive cases treated at the University of Michigan, frank disc herniation with fragmented disc in the canal was found in five while pathological disc bulging was found in the other three. All five cases contributed by other institutions had concurrent disc herniation. This series illustrates the importance of using MR imaging to document the presence of a herniated disc during the initial evaluation of a patient with traumatic locked facets of the cervical spine and prior to attempted reduction of the locked facets. Experience indicates that closed reduction of facet dislocation associated with disc rupture may result in increased spinal cord compression and neurological deficit. If a herniated disc is discovered, anterior discectomy and fusion would be favored as the initial therapy over attempts at closed reduction or operative posterior reduction.


Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study.
Drug toxicity is a hurdle to drug development and to clinical translation of basic research. Antiepileptic drugs such as carbamazepine (CBZ) and selective serotonin reuptake inhibitors such as sertraline (SRT) are commonly co-prescribed to patients with epilepsy and comorbid depression. Because SRT may interfere with cytochrome P450 (CYP) enzyme activity and CYPs have been implicated in the conversion of CBZ to reactive cytotoxic metabolites, we investigated in vitro models to determine whether SRT affects the neurotoxic potential of CBZ and the mechanisms involved. Human fetal brain-derived dopaminergic neurons, human brain microvascular endothelial cells (HBMECs), and embryonic kidney (HEK) cells were used to evaluate cytotoxicity of CBZ and SRT individually and in combination. Nitrite and glutathione (GSH) levels were measured with drug exposure. To validate the role of CYP3A4 in causing neurotoxicity, drug metabolism was compared to cell death in HEK CYP3A4 overexpressed and cells pretreated with the CYP3A4 inhibitor ketoconazole. In all cellular systems tested, exposure to CBZ (127 μM) or SRT (5 μM) alone caused negligible cytotoxicity. By contrast CBZ, tested at a much lower concentration (17 μM) in combination with SRT (5 μM), produced prominent cytotoxicity within 15 min exposure. In neurons and HBMECs, cytotoxicity was associated with increased nitrite levels, suggesting involvement of free radicals as a pathogenetic mechanism. Pretreatment of HBMECs with reduced GSH or with the GSH precursor N-acetyl-L-cysteine prevented cytotoxic response. In HEK cells, the cytotoxic response to the CBZ + SRT combination correlated with the rate of CBZ biotransformation and production of 2-hydroxy CBZ, further suggesting a causative role of reactive metabolites. In the same system, cytotoxicity was potentiated by overexpression of CYP3A4, and prevented by CYP3A4 inhibitor. These results demonstrate an unexpected neurotoxic interaction between CBZ and SRT, apparently related to increased CYP3A4-mediated production of reactive CBZ metabolites. The potential clinical implications of these findings are discussed.


Axonal sodium channel NaV1.2 drives granule cell dendritic GABA release and rapid odor discrimination.
Dendrodendritic synaptic interactions between olfactory bulb mitral and granule cells represent a key neuronal mechanism of odor discrimination. Dendritic release of gamma-aminobutyric acid (GABA) from granule cells contributes to stimulus-dependent, rapid, and accurate odor discrimination, yet the physiological mechanisms governing this release and its behavioral relevance are unknown. Here, we show that granule cells express the voltage-gated sodium channel α-subunit NaV1.2 in clusters distributed throughout the cell surface including dendritic spines. Deletion of NaV1.2 in granule cells abolished spiking and GABA release as well as inhibition of synaptically connected mitral cells (MCs). As a consequence, mice required more time to discriminate highly similar odorant mixtures, while odor discrimination learning remained unaffected. In conclusion, we show that expression of NaV1.2 in granule cells is crucial for physiological dendritic GABA release and rapid discrimination of similar odorants with high accuracy. Hence, our data indicate that neurotransmitter-releasing dendritic spines function just like axon terminals.


Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission.
For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.


Liver transplantation in the treatment of bleeding esophageal varices.
From March 1980 to July 1987, 1000 patients with various end-stage liver diseases received orthotopic liver transplants. Of the 1000 patients, three hundred two had definite histories of bleeding from esophageal varices before transplantation. There were 287 patients with nonalcoholic liver diseases and 15 patients with alcoholic cirrhosis. All patients had very poor liver function, which was the main indication for liver transplantation. One- through 5-year actuarial survival rates of the 302 patients were 79%, 74%, 71%, 71%, and 71%, respectively. These survival rates are far better than those obtained with other available modes of treatment for bleeding varices when liver disease is advanced. Long-term sclerotherapy is the treatment of primary choice for bleeding varices. Patients in whom sclerotherapy fails should be considered for liver transplantation unless clear contraindications exist.


Impact of rainfed agriculture on spatio-temporal patterns of water balance and the interaction between groundwater and surface water in sub-humid plains.
The expansion of rainfed agriculture, especially soybean cultivation in sub-humid plains, alters water balance and the exchange between groundwater-surface water (GW-SW). However, to date, there are no studies that analyze how these anthropic disturbances affect hydrological connectivity in these systems, especially the GW-SW interactions. The objective of this study is to analyze how the increase in rainfed agriculture affects the spatio-temporal patterns of the water balance and the GW-SW interaction. For this analysis, a coupled GW-SW flow model was implemented under land use and land cover (LULC) scenarios, to quantify the spatio-temporal dynamics for different components of water balance and GW-SW interactions for the upper creek basin of Del Azul. A simulation was carried out for a period of 13 years (2003-2015) on a daily scale and it was contrasted through three multitemporal LULC maps. The results point that substitution of natural pastures, the reduction of winter crops and the decrease of crop rotation, due to the increase of soybean monoculture in the basin under study, modifies the water balance, especially the annual rates of surface runoff and soil moisture which may increase between 3.5 and 9.4 % and between 1.4 and 4.4 % respectively, thus increasing the annual streamflows between 2.6 and 6.8 % and the groundwater heads between 0.2 and 0.6 m. This leads to changes in the hetereogeneity of the GW-SW interaction, a reduction between 0.3 and 3 % is observed in the discharge from the Pampeano aquifer to the Del Azul stream, while the recharge rates from the Del Azul stream to the Pampeano aquifer increase between 2 and 17.8 %. The application of the SWAT-MODFLOW model under LULC scenarios, improves the prediction of the regional hydrologic connectivity on sub-humid plains, because the hydrological processes occurring in the surface and non-saturated zone are governed by shallow groundwater dynamics.


Catalytic Asymmetric α-Alkylation of Ketones with Unactivated Alkyl Halides.
A catalytic, enantioselective method for direct α-alkylation of ketones with unactivated alkyl halides is realized by employing an α-enolizable ketone in a nickel-catalyzed C(sp3)-C(sp3) cross-coupling reaction. The key to the success is attributed to a unique bimetallic ligand. A variety of acyclic ketones and unactivated alkyl iodides can serve as suitable substrates under mild conditions to generate chiral ketones with α-quaternary carbon stereocenters in high yields with good enantioselectivities. A range of transformations based on the ketone moiety are also demonstrated to show the potential application of this method. Preliminary mechanistic studies support a dinickel-catalyzed cross-coupling mechanism.


Acute exposure to boron in Nile tilapia (Oreochromis niloticus): Median-lethal concentration (LC50), blood parameters, DNA fragmentation of blood and sperm cells.
Recently, Boron (B) contamination of aquatic ecosystem has received considerable critical attention due to its toxic effects at high concentrations on plants as well as animals. Previous studies on toxic effects of B have not dealt with DNA damages in blood and sperm cells of Nile tilapia (Oreochromis niloticus), together with blood parameters. This study consisted of two successive experiments purposes to determine these findings, including the median-lethal concentration (LC50) of B for Nile tilapia. In the first one, at 96 h, LC50 of B for Nile tilapia was 141.42 mg L-1 B. In the second one, Nile tilapia were treated with five elevated B concentrations (1, 5, 25, 50 and 100 mg L-1 B) and hematological, serum biochemical parameters, and DNA damages of Nile tilapia in these treatments were determined comparing with the control after 14 days of exposure. Hematological parameters (red blood cell count, hematocrit, and hemoglobin) were similar to each other in all groups while serum biochemical parameters (glucose, total protein, cholesterol, alkaline phosphatase, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase) in B treatments, especially in 50 and 100 mg L-1 B groups, were found significantly higher (P < 0.05). DNA fragmentation was detected in all blood cells in ≥25 mg L-1 B treatments, while all sperm cells in 100 mg L-1 B treatments. These results demonstrated the harmful effects of B at high concentration (50 and 100 mg L-1 B) on the DNA integrity of blood and sperm cells, and also the serum biochemical parameters.


Microspectroscopic SERS detection of interleukin-6 with rationally designed gold/silver nanoshells.
Rationally designed gold/silver nanoshells (Au/Ag-NS) with plasmon resonances optimized for red laser excitation in order to minimize autofluorescence from clinical samples exhibit scattering cross-sections, which are ca. one order of magnitude larger compared with solid quasi-spherical gold nanoparticles (Au-NPs) of the same size. Hydrophilic stabilization and sterical accessibility for subsequent bioconjugation of Au/Ag-NS is achieved by coating their surface with a self-assembled monolayer (SAM) of rationally designed Raman reporter molecules comprising terminal mono- and tri-ethylene glycol (EG) spacers, respectively. The stability of the hydrophilically stabilized metal colloid was tested under different conditions. In contrast to metal colloids coated with a SAM without terminal EG spacers, the hydrophilically stabilized SERS particles do not aggregate under physiologically relevant conditions, i.e., buffer solutions with high ionic strength. Using these rationally designed SERS particles in conjunction with a microspectroscopic acquisition scheme, a sandwich immunoassay for the sensitive detection of interleukin-6 (IL-6) was developed. Several control experiments demonstrate the high specificity of the assay towards IL-6, with a lowest detectable concentration of ca. 1 pg mL(-1). The signal strength of the Au/Ag-NS is at least one order of magnitude higher compared with hydrophilically stabilized, non-aggregated solid quasi-spherical Au-NPs of the same size.


Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein.
Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides-besides transcription-an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP-together with the RBM4 splicing factor-in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.


Phthalates and other additives in plastics: human exposure and associated health outcomes.
Concern exists over whether additives in plastics to which most people are exposed, such as phthalates, bisphenol A or polybrominated diphenyl ethers, may cause harm to human health by altering endocrine function or through other biological mechanisms. Human data are limited compared with the large body of experimental evidence documenting reproductive or developmental toxicity in relation to these compounds. Here, we discuss the current state of human evidence, as well as future research trends and needs. Because exposure assessment is often a major weakness in epidemiological studies, and in utero exposures to reproductive or developmental toxicants are important, we also provide original data on maternal exposure to phthalates during and after pregnancy (n = 242). Phthalate metabolite concentrations in urine showed weak correlations between pre- and post-natal samples, though the strength of the relationship increased when duration between the two samples decreased. Phthalate metabolite levels also tended to be higher in post-natal samples. In conclusion, there is a great need for more human studies of adverse health effects associated with plastic additives. Recent advances in the measurement of exposure biomarkers hold much promise in improving the epidemiological data, but their utility must be understood to facilitate appropriate study design.


Exploring the personal and professional factors associated with student evaluations of tenure-track faculty.
Tenure-track faculty members in the United States are evaluated on their performance in both research and teaching. In spite of accusations of bias and invalidity, student evaluations of teaching have dominated teaching evaluation at U.S. universities. However, studies on the topic have tended to be limited to particular institutional and disciplinary contexts. Moreover, in spite of the idealistic assumption that research and teaching are mutually beneficial, few studies have examined the link between research performance and student evaluations of teaching. In this study, we conduct a large scale exploratory analysis of the factors associated with student evaluations of teachers, controlling for heterogeneous institutional and disciplinary contexts. We source public student evaluations of teaching from RateMyProfessor.com and information regarding career and contemporary research performance indicators from the company Academic Analytics. The factors most associated with higher student ratings were the attractiveness of the faculty and the student's interest in the class; the factors most associated with lower student ratings were course difficulty and whether student comments mentioned an accent or a teaching assistant. Moreover, faculty tended to be rated more highly when they were young, male, White, in the Humanities, and held a rank of full professor. We observed little to no evidence of any relationship, positive or negative, between student evaluations of teaching and research performance. These results shed light on what factors relate to student evaluations of teaching across diverse contexts and contribute to the continuing discussion teaching evaluation and faculty assessment.


Atopic dermatitis and cytokines: the immunoregulatory and therapeutic implications of cytokines in atopic dermatitis--part II: negative regulation and cytokine therapy in atopic dermatitis.
Atopic dermatitis is an immunologic disease that results in allergic inflammations of the skin. Cytokines are involved in the negative regulation of immunopathogenesis of atopic dermatitis. Negative immune regulation is also achieved by immune cells in addition to cytokines which are subsequently regulated by a counter-regulatory mechanism. Allergen tolerance is an important aspect of the treatment of atopic dermatitis. Recently, the IL-27, IL-21, and IL-10 cytokines were found to be important components of the counter regulatory mechanism that terminates immune response, and protects the host from excessive immune responses. IL-10 and TGF-β are well-known to be involved in the immune tolerance. IL-10 and IFN-γ are promising cytokines with respect to the prevention of allergen sensitization and the induction of allergen-specific tolerance. In particular, IFN-γ has unique tolerogenic effects with respect to pre-sensitized allergens, especially in atopic dermatitis. In this review, the role of cytokines in the immune tolerance and relevant patents are reviewed, and therapeutic strategies are presented based on the immunologic architecture of AD.


Combined pharmacokinetics of gentamicin in pony mares after a single intravenous and intramuscular administration.
Healthy mature pony mares (n = 6) were given a single dose of gentamicin (5 mg/kg of body weight) IV or IM 8 days apart. Venous blood samples were collected at 0, 5, 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 40, and 48 hours after IV injection of gentamicin, and at 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, and 30 hours after IM injection of gentamicin. Gentamicin serum concentration was determined by a liquid-phase radioimmunoassay. The combined data of IV and IM treatments were analyzed by a nonlinear least-square regression analysis program. The kinetic data were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the correlation of determination. The distribution phase half-life was 0.12 +/- 0.02 hour and postdistribution phase half-life was 1.82 +/- 0.22 hour. The volume of the central compartment was 115.8 +/- 6.0 ml/kg, volume of distribution at steady state was 188 +/- 9.9 ml/kg, and the total body clearance was 1.27 +/- 0.18 ml/min/kg. Intramuscular absorption was rapid with a half-life for absorption of 0.64 +/- 0.14 hour. The extent of absorption was 0.87 +/- 0.14. Kinetic calculations predicted that IM injections of 5 mg of gentamicin/kg every 8 hours would provide average steady-state serum concentrations of 7.0 micrograms/ml, with maximum and minimum steady-state concentrations of 16.8 and 1.1 micrograms/ml, respectively.


[New approach to the interpretation of vibrational spectra of microbial cells].
IR-technique was applied to study baker's yeast cell and its envelope fragments. The quantitative evaluation of spectra was made using the polysaccharide band at 1070 cm-1 as the bench one. The comparison of the spectra of the whole cells and of the envelope fragments suggested that the spectrum of the yeast cell was governed by the composition of its envelope only. ATR-spectra of the whole cells and of envelope debris were obtained and the comparison of these with the "absorption" ones made it possible to conclude that the yeast cells vibration spectrum was for the most part the reflection spectrum governed by the composition of the cell envelope rather than the absorption one.


Effect of endurance swimming on the lactate kinetics of rainbow trout.
The lactate turnover rate of rainbow trout (Oncorhynchus mykiss) was measured by bolus injection of [U-14C]lactate at rest and during prolonged swimming at 85% Ucrit to determine the importance of this metabolic fuel for endurance locomotion in fish, to assess whether lactate exchange between white and red muscle could be a possible mechanism for supplying oxidizable fuel to their lateral red muscle, and to compare the contribution of lactate to total energy provision between teleost and mammalian species. Turnover rate only increased from 4.41 +/- 0.33 to 9.71 +/- 1.69 mumol kg-1 min-1 between rest and prolonged swimming, and the contribution of lactate oxidation to total metabolism declined during exercise. Lactate exchange between white and red muscle is, therefore, not a significant mechanism to fuel the active lateral red musculature during prolonged swimming. The lactate turnover rate of teleosts is one or two orders of magnitude lower than in mammals of equivalent size, but lactate has the same importance as a fuel in both vertebrate groups. However, lactate turnover rate and oxidation rate do not scale with body mass in the same fashion as does metabolic rate. The slope of the mammalian relationship for whole-body lactate turnover and oxidation is much lower (0.58) than the slope of the classic relationship for metabolic rate (0.75), indicating that lactate is a much more important oxidative substrate for small than for large animals.


Stress induced by recombinant protein production in Escherichia coli.
Strong production of recombinant proteins interferes with cellular processes in many ways. Drainage of precursors and energy urges the cell to readjust metabolic fluxes and enzyme composition, stress responses are induced, and hence the cellular activity is shifted from growth to reorganisation of biomass. This may result in inhibition of growth or low level of product accumulation. The extent of the bacterial stress response is determined by the specific properties of the recombinant protein, and by the rates of transcription and translation. Taking into account the capacities of the host for protein processing and physiological adaptation, production schemes can be developed that enhance volumetric productivity and sustainability of the process.


Comparative analysis of anticholinergic burden scales to explain iatrogenic cognitive impairment and self-reported side effects in the euthymic phase of bipolar disorders: Results from the FACE-BD cohort.
Bipolar disorders (BD) are characterized by cognitive impairment during the euthymic phase, to which treatments can contribute. The anticholinergic properties of medications, i.e., the ability of a treatment to inhibit cholinergic receptors, are associated with cognitive impairment in elderly patients and people with schizophrenia but this association has not been well characterized in individuals with remitted BD. Moreover, the validity of only one anticholinergic burden scale designed to assess the anticholinergic load of medications has been tested in BD. In a literature review, we identified 31 existing scales. We first measured the associations between 27 out of the 31 scales and objective cognitive impairment in bivariable regressions. We then adjusted the bivariable models with covariates: the scales significantly associated with cognitive impairment in bivariable and multiple logistic regressions were defined as having good concurrent validity to assess cognitive impairment. In a sample of 2,031 individuals with euthymic BD evaluated with a neuropsychological battery, two scales had good concurrent validity to assess cognitive impairment, whereas chlorpromazine equivalents, lorazepam equivalents, the number of antipsychotics, or the number of treatments had not. Finally, similar analyses with subjective anticholinergic side-effects as outcome variables reported 14 scales with good concurrent validity to assess self-reported peripheral anticholinergic side-effects and 13 to assess self-reported central anticholinergic side-effects. Thus, we identified valid scales to monitor the anticholinergic burden in BD, which may be useful in estimating iatrogenic cognitive impairment in studies investigating cognition in BD.