Medication reconciliation interventions in ambulatory care: A scoping review.
The published literature on medication reconciliation (MR) interventions, outcomes, and facilitators in ambulatory care settings is reviewed. A scoping review was conducted to characterize ambulatory care-based MR research in terms of study design, elements of interventions, and outcomes examined. English-language articles on comparative studies of MR programs targeting adults in ambulatory care settings were identified using data sources including MEDLINE, PreMEDLINE, EMBASE, and International Pharmaceutical Abstracts. For each study, steps undertaken in the MR process were extracted. The Cochrane Effective Practice and Organisation of Care (EPOC) taxonomy was used to classify types of interventions; taxonomies for reported outcomes and factors facilitating implementation of MR initiatives were developed by the authors. From among 2062 publications screened, 15 were included in the review. In 13 studies, multiple data sources were used to compile a "best possible medication history" (BPMH); however, the BPMH was shared with external healthcare providers in only 4 studies and with patients in only 5 studies. Most reported MR interventions were classified into two EPOC domains: professional (predominantly educational outreach visits and patient reminders) and organizational (predominantly provider-oriented interventions). Process outcomes were reported in 12 studies, with correct performance of MR being the most commonly evaluated process outcome, and 9 studies identified factors that facilitated MR implementation. Few studies have examined clinical outcomes of MR in ambulatory care settings, with the majority of pertinent reports focusing instead on process outcomes. Facilitators of successful MR interventions have been identified at the patient, staff, and clinic setting levels.


Modeling multivariate survival data by a semiparametric random effects proportional odds model.
In this article, the focus is on the analysis of multivariate survival time data with various types of dependence structures. Examples of multivariate survival data include clustered data and repeated measurements from the same subject, such as the interrecurrence times of cancer tumors. A random effect semiparametric proportional odds model is proposed as an alternative to the proportional hazards model. The distribution of the random effects is assumed to be multivariate normal and the random effect is assumed to act additively to the baseline log-odds function. This class of models, which includes the usual shared random effects model, the additive variance components model, and the dynamic random effects model as special cases, is highly flexible and is capable of modeling a wide range of multivariate survival data. A unified estimation procedure is proposed to estimate the regression and dependence parameters simultaneously by means of a marginal-likelihood approach. Unlike the fully parametric case, the regression parameter estimate is not sensitive to the choice of correlation structure of the random effects. The marginal likelihood is approximated by the Monte Carlo method. Simulation studies are carried out to investigate the performance of the proposed method. The proposed method is applied to two well-known data sets, including clustered data and recurrent event times data.


Predetermining value analysis of the prehospital phase procedures in trauma victims survival.
The aim of this study was to analyze the determining value of the procedures carried out during prehospital care in the survival time of traffic accident victims. Data of 175 victims with Revised Trauma Score pound 11, cared for and transported by advanced life support to tertiary referral hospitals, were submitted to Kaplan-Meier Survival Analysis and to Cox proportional hazards model. Four procedure groups associated with survival were identified: basic circulatory; advanced respiratory; volume replaced and medication. Until hospital discharge, the victims who underwent orotracheal intubation and chest compressions showed 3.6 and 6.4 times higher death hazards, respectively. The need for definitive airway and cardiopulmonary resuscitation in the prehospital phase was predetermining with higher death hazard. The less than 1000 ml intravenous fluid replacement was the only predetermining factor with protective power against death hazard.


Positive ion chemistry of esters of carboxylic acids in air plasma at atmospheric pressure.
Ionization of esters of carboxylic acids RCOOR' (R = H, alkyl; R' = alkyl) within the air plasma of the Atmospheric Pressure Chemical Ionization (APCI) source occurs largely via H(+)-transfer and, to a minor extent, via NO(+) association. The protonated ester MH(+) is normally observed as M(2)H(+) and as higher aggregates (M(3)H(+), M(3)H(+)(H(2)O)) also at high source temperature. The behavior of M(2)H(+) upon collisional activation is consistent with the reported dissociation of proton-bound dimers to MH(+) species that, in turn, fragment according to the known paths of lowest energy. In addition, other important product ions form within the plasma, some in very high relative abundance, which are attributed to ion-molecule condensation reactions between neutral M and either MH(+) or M(2)H(+) resulting in the elimination of CO, R'OH, alkene from the alkoxy moiety of the ester and HCOOH. A general scheme is proposed to account for the experimental observations, which suggest that the encounter complex formed between MH(+) and M or between M(2)H(+) and M may either collisionally relax to the protonated dimer or trimer, respectively, or react via covalent bond forming and cleaving steps to eliminate stable neutral molecules. The proposed scheme is supported by both the observed concentration dependence and the temperature dependence of the products relative abundances within the plasma. Such reactions can be the dominant process, as in the case of formate esters. A second significant ionization route involves addition of NO(+) to form M(n)NO(+) (n = 1, 2, 3). An additional product corresponding to [M(2)NO(+) - CO(2)] is also observed with iso- and n-butyl formate esters.


High throughput discovery of new fouling-resistant surfaces.
A novel high throughput method for synthesis and screening of customized protein-resistant surfaces was developed. This method is an inexpensive, fast, reproducible and scalable approach to synthesize and screen protein-resistant surfaces appropriate for a specific feed. The method is illustrated here by combining a high throughput platform (HTP) approach together with our patented photo-induced graft polymerization (PGP) method developed for facile modification of commercial poly(aryl sulfone) membranes. We demonstrate that the HTP-PGP approach to synthesize and screen fouling-resistant surfaces is general, and thus provides the capability to develop surfaces optimized for specific feeds. Surfaces were prepared via graft polymerization onto poly(ether sulfone) (PES) membranes and were evaluated using a protein adsorption assay followed by pressure-driven filtration. We have employed the HTP-PGP approach to confirm previously reported successful monomers and to develop new antifouling surfaces from a library of 66 monomers for four different challenges of interest to the biotechnology community: hen egg-white lysozyme, supernatant from Chinese Hamster Ovary (CHO) cells in phosphate buffered saline (PBS) solution as a model cell suspension, and immunoglobulin G (IgG) precipitated in the absence and presence of bovine serum albumin (BSA) in high salt solution as a model precipitation process.


COVID-19 in a cohort of pregnant women and their descendants, the MOACC-19 study.
The Mother and Child COVID-19 study is a cohort recruiting pregnant women and their children in Cantabria, North of Spain, during COVID-19 pandemic in order to ascertain consequences of SARS-CoV-2 infection on pregnant women and their descendants. This article reports the cohort profile and preliminary results as recruitment is still open. Three subcohorts can be identified at recruitment. Subcohort 1 includes women giving birth between 23 March and 25 May 2020; they have been retrospectively recruited and could have been exposed to COVID-19 only in their third trimester of pregnancy. Subcohort 2 includes women giving birth from 26 May 2020 on; they are being prospectively recruited and could have been exposed to COVID-19 in both their second and third trimesters of pregnancy. Subcohort 3 includes women in their 12 week of pregnancy prospectively recruited from 26 May 2020 on; they could have been exposed to COVID-19 anytime in their pregnancy. All women are being tested for SARS-CoV-2 infection using both RT-PCR for RNA detection and ELISA for anti-SARS-CoV-2 antibodies. All neonates are being tested for antibodies using immunochemoluminiscency tests; if the mother is tested positive for SARS-CoV-2 RNA, a nasopharyngeal swab is also obtained from the child for RT-PCR analysis. As of 22 October, 1167 women have been recruited (266, 354 and 547 for subcohorts 1, 2 and 3, respectively). Fourteen women tested positive to SARS-CoV-2 RNA by the day of delivery. All 14 children born from these women tested negative for SARS-CoV-2 RNA. Children from women included in subcohort 3 are expected to be recruited by the end of 2020. Children will be followed-up for 1 year in order to ascertain the effect that COVID-19 on their development.


Wernicke's encephalopathy with atypical findings on MR imaging.
Wernicke's encephalopathy (WE) is a disease usually related to chronic alcoholism. The clinical diagnosis is often difficult to establish. MR imaging is a highly sensitive method for detecting lesions associated with Wernicke's encephalopathy. We report a case of atypical manifestation of hyperintense lesions on magnetic resonance imaging (MRI) in a 60-year-old male patient with Wernicke's encephalopathy.


Promiscuous seven transmembrane receptors sensing L-α-amino acids.
A number of nutrient sensing seven trans-membrane (7TM) receptors have been identified and characterized over the past few years. While the sensing mechanisms to carbohydrates and free fatty acids are well understood, the molecular basis of amino acid sensing has recently come to the limelight. The present review describes the current status of promiscuous L-α-amino acid sensors, the calcium sensing receptor (CaSR), the GPRC6A receptor, the T1R1/T1R3 receptor and also their molecular pharmacology, expression pattern and physiological significance.


[Effect of ciglitazone on THP-1 macrophage CD36 expression and cholesterol influx].
To investigate the effect of ciglitazone on CD36 expression and cholesterol influx in THP-1 macrophage. After exposure of the cultured THP-1 macrophage to ciglitazone for 24 h, [(3)H] labeled Cholesterol influx was determined by FJ-2107P typed liquid scintillator. CD36 mRNA and protein level were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting respectively. PPARγ agonist, ciglitazone, elevated CD36 in both protein and mRNA levels, and increased cholesterol influx in THP-1 macrophage. The levels of cholesterol influx were 20. 3%, 28. 6%, 37. 2%, 44. 3%, 48. 7% respectively. Our results indicated that ciglitazone may play an important role in cholesterol influx and modulating CD36 expression in THP-1 macrophage.


The antimicrobial effects of zinc oxide-calcium hydroxide mixture fillers: determining the ideal mixture ratio.
Although zinc oxide (ZO)-calcium hydroxide (CaOH) mixtures have been successful regarding their absorption rate compatibility with dissolving primary teeth, no study has been conducted on the appropriate mixture ratio to obtain effective antibacterial properties. In this study, we compared antibacterial activity of CaOH-ZO pastes using different mixture ratios sagainst Enterococcus faecalis as an important bacterium in root canal treatment failure. Seven types of pastes were prepared in our laboratory. The first group included one gram of ZO+eugenol, second group included one gram of CaOH+distilled water, third group included 0.5gram ZO+0.5gram CaOH+distilled water (1:1), forth group included 0.75gramCaOH+0.25gramZO+distilled water (3:1), the fifth group included 0.33gram of CaOH+0.66gram of ZO+distilled water (1:2), the sixth group included 0.75gram of ZO+0.25 CaOH+distilled water (3:1), the seventh group included 0.66 gram CaOH+0.33 gram ZO+distilled water (2:1), and the final group included one gram of gelatin+distilled water (as the control group). These pastes were compared regarding their antibacterial effects against Enterococcus faecalis using agar diffusion and microdilution methods. Except for the control group, all prepared pastes showed antibacterial properties. Order of minimum inhibitory concentration for pastes were as followed: CaOH-ZO (1:3)=CaOH-ZO (1:2)>CaOH-ZO (1:1)>CaOH-ZO (3:1)=CaOH-ZO (2:1)>CaOH=ZO-eugenol. Order of minimum bactericidal concentration, which shows a weaker bactericidal effect, according to type of paste, were as followed: CaOH-ZO (1:3)>CaOH-ZO mixture (1:2)>CaOH-ZO mixture (1:1)>CaOH-ZO mixture (3:1)=CaOH-ZO (2:1)>CaOH=ZO-eugenol. Only CaOH-ZO (1:3) and CaOH-ZO (1:2), showed significantly weaker MICs and MBCs (p < 0.001). Considering the limitations of an in-vitro study, in terms of anti-bacterial effects against Enterococcus faecalis, CaOH-ZO mixture (2:1) is equivalent to ZO-eugenol as the most commonly used material in polypectomy of primary teeth.


Research update of emergent gold nanoclusters: A reinforced approach towards evolution, synthesis mechanism and application.
Fluorescent biosensors and imaging devices have gained fervent consideration due to their prime functionality in biological. Among fluorescent nanomaterial (FNMs), the ultra-small gold nanoclusters (AuNCs) have gained promising attention with respect to extra-ordinary properties of bright fluorescence, economical synthesis, higher photostability, and biocompatibility, and deep tissue penetration. Therefore, the prior decades comprehended the revolutions in the field of real-time monitoring devices, nanotechnology-based biosensing, and bioimaging sensors. The present review primarily focuses on metal NCs (MNCs) and their advantages, a brief introduction of AuNCs along with history prospective and development, fundamental aspects regarding AuNCs quality and fluorescence, limitations and advantages of AuNCs, sensing mechanism, expected synthesis principle, and summarized the recent progress of AuNCs probe over the last 3 years (2019-2021) with their respective detection and bioimaging mechanism and synthesis principle. Moreover, the present work also serves as a novel stratagem for the preparation and potential applications of multifunctional AuNCs nano-systems responsiveness for various analytes detection and cell bioimaging with respective examples. At last, we described the challenges associated with the application of AuNCs based on recent signs of progress.


Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor.
Caffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase-1 (HO-1). Because HO-1 induction has been suggested to protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration. Neuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6-hydroxydopamine. CAPE protected dopaminergic neurons in slice cultures from IFN-γ/LPS-induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO-1 inhibitor, and by neutralizing antibody against brain-derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF-E2-related factor 2, attenuated increased expression of HO-1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS-injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up-regulated HO-1 and BDNF, and reduced the increase of activated microglia/macrophages. Neuroprotective effects of CAPE against LPS-induced injury was prevented by zinc protoporphyrin IX or anti-BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine-induced rotational behaviour also in 6-hydroxydopamine hemiparkinsonian mice. CAPE is a novel type of neuroprotective agent whose actions are mediated by both HO-1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders.


Malnutrition and susceptibility to enteroparasites: reinfection rates after mass chemotherapy.
The evidence that relates malnutrition to enteroparasite infections arises from studies that demonstrate the improvement of nutritional indicators after antiparasitism treatment. However, the role of malnutrition as an aggravating factor to the susceptibility to enteroparasite infections is still not fully understood. We investigated the correlation between malnutrition and enteroparasite infection after mass chemotherapy, in a poor city of São Paulo State, Brazil. The sample comprised 759 children between 1 and 10 years of age of whom 585 were followed up for a period of 1 year and periodically assessed for reinfection with enteroparasites. One year of follow-up after mass chemotherapy demonstrated that 38 of the undernourished children were reinfected with enteroparasites, as compared with 25 of the eutrophic children (P = 0.033). The survival multivariate analysis demonstrated that, after controlling for the potential confounding variables, maternal literacy and per capita income rate, malnutrition was associated with susceptibility to reinfection (P = 0.13). We demonstrate that, although maternal literacy and per capita income rate are indeed confounding variables, malnutrition contributes to an increase in the risk of enteroparasite infections.


[Pure calcium-sodium alginate dressing. Multicenter evaluation of chronic cutaneous lesions].
By means of a descriptive, non-comparative study of a series of clinical cases, the authors analyze the behavior of a dressing of pure calcic-sodium alginate with a stabilizing network in the treatment of pressure sores and profusely bleeding and/or infected vascular uclers. Based on the results of their studies, the authors confirm the effectiveness of this dressing under these conditions: no adverse reactions; the shrinking of the lesion in area or degree of severity; if there is tissue debridement accompanied by sloughing and necrotic tissue, the elimination of infection; ease of application and the reduction of the lesions; use as part of a non-daily cure treatment plan.


Propranolol-loaded electrospun nanofibrous wound dressing: From fabrication and characterization to preliminary wound healing evaluation.
The wound healing potential of beta-blocker drugs such as propranolol (PNL) has recently attracted attention. To date, incorporation of PNL into electrospun nanofibrous wound dressing mats has not been tested as a novel topical drug delivery system. Presently, electrospun nanofibrous mats loaded with PNL were fabricated, and their physicochemical properties and wound healing activities were evaluated. Polyvinyl alcohol solutions containing 0, 2% or 4% (wt/vol) PNL were electrospun into mats, and the physicochemical properties and PNL release were evaluated. In vitro biocompatibility of selected PNL-loaded mats was tested in human foreskin fibroblasts and wound healing capability was evaluated in mouse skin wounds. The 4% PNL mat had thin fibers (160 nm), convincing porosity (79.5%), and good hydrophilicity (swelling: 89.1%, water contact angle: 42.1°) with little degradability (14.2%). The release of PNL was not in bursts and was best explained by the Korsmeyer-Peppas equation (R2 = 0.96, n = 0.40), suggesting Fickian release. The viability of fibroblasts was 173% on day 5 of incubation with 4% PNL mats, indicating good mat biocompatibility. In vivo treatment for 14 days with 4% PNL mats resulted in wounds with a surface area of only 9% of the original wound area. These wounds had better histopathologic characteristics and were associated with less oxidative stress. The wound dressing fabricated with 4% PNL showed good potential for wound healing because of a favorable drug release profile from the nanofiber scaffold, and can be considered eligible for further clinical research.


PCR microfluidic devices for DNA amplification.
The miniaturization of biological and chemical analytical devices by micro-electro-mechanical-systems (MEMS) technology has posed a vital influence on such fields as medical diagnostics, microbial detection and other bio-analysis. Among many miniaturized analytical devices, the polymerase chain reaction (PCR) microchip/microdevices are studied extensively, and thus great progress has been made on aspects of on-chip micromachining (fabrication, bonding and sealing), choice of substrate materials, surface chemistry and architecture of reaction vessel, handling of necessary sample fluid, controlling of three or two-step temperature thermocycling, detection of amplified nucleic acid products, integration with other analytical functional units such as sample preparation, capillary electrophoresis (CE), DNA microarray hybridization, etc. However, little has been done on the review of above-mentioned facets of the PCR microchips/microdevices including the two formats of flow-through and stationary chamber in spite of several earlier reviews [Zorbas, H. Miniature continuous-flow polymerase chain reaction: a breakthrough? Angew Chem Int Ed 1999; 38 (8):1055-1058; Krishnan, M., Namasivayam, V., Lin, R., Pal, R., Burns, M.A. Microfabricated reaction and separation systems. Curr Opin Biotechnol 2001; 12:92-98; Schneegabeta, I., Köhler, J.M. Flow-through polymerase chain reactions in chip themocyclers. Rev Mol Biotechnol 2001; 82:101-121; deMello, A.J. DNA amplification: does 'small' really mean 'efficient'? Lab Chip 2001; 1: 24N-29N; Mariella, Jr. R. MEMS for bio-assays. Biomed Microdevices 2002; 4 (2):77-87; deMello AJ. Microfluidics: DNA amplification moves on. Nature 2003; 422:28-29; Kricka, L.J., Wilding, P. Microchip PCR. Anal BioAnal Chem 2003; 377:820-825]. In this review, we survey the advances of the above aspects among the PCR microfluidic devices in detail. Finally, we also illuminate the potential and practical applications of PCR microfluidics to some fields such as microbial detection and disease diagnosis, based on the DNA/RNA templates used in PCR microfluidics. It is noted, especially, that this review is to help a novice in the field of on-chip PCR amplification to more easily find the original papers, because this review covers almost all of the papers related to on-chip PCR microfluidics.


The bandwidth of consolidation into visual short-term memory (VSTM) depends on the visual feature.
We investigated the nature of the bandwidth limit in the consolidation of visual information into visual short-term memory. In the first two experiments, we examined whether previous results showing differential consolidation bandwidth for color and orientation resulted from methodological differences by testing the consolidation of color information with methods used in prior orientation experiments. We briefly presented two color patches with masks, either sequentially or simultaneously, followed by a location cue indicating the target. Participants identified the target color via button-press (Experiment 1) or by clicking a location on a color wheel (Experiment 2). Although these methods have previously demonstrated that two orientations are consolidated in a strictly serial fashion, here we found equivalent performance in the sequential and simultaneous conditions, suggesting that two colors can be consolidated in parallel. To investigate whether this difference resulted from different consolidation mechanisms or a common mechanism with different features consuming different amounts of bandwidth, Experiment 3 presented a color patch and an oriented grating either sequentially or simultaneously. We found a lower performance in the simultaneous than the sequential condition, with orientation showing a larger impairment than color. These results suggest that consolidation of both features share common mechanisms. However, it seems that color requires less information to be encoded than orientation. As a result two colors can be consolidated in parallel without exceeding the bandwidth limit, whereas two orientations or an orientation and a color exceed the bandwidth and appear to be consolidated serially.


Low environmentally relevant levels of bioactive xenobiotics and associated degradation products cause cryptic perturbations of metabolism and molecular stress responses in Arabidopsis thaliana.
Anthropic changes and chemical pollution confront wild plant communities with xenobiotic combinations of bioactive molecules, degradation products, and adjuvants that constitute chemical challenges potentially affecting plant growth and fitness. Such complex challenges involving residual contamination and mixtures of pollutants are difficult to assess. The model plant Arabidopsis thaliana was confronted by combinations consisting of the herbicide glyphosate, the fungicide tebuconazole, the glyphosate degradation product aminomethylphosphonic acid (AMPA), and the atrazine degradation product hydroxyatrazine, which had been detected and quantified in soils of field margins in an agriculturally intensive region. Integrative analysis of physiological, metabolic, and gene expression responses was carried out in dose-response experiments and in comparative experiments of varying pesticide combinations. Field margin contamination levels had significant effects on plant growth and metabolism despite low levels of individual components and the presence of pesticide degradation products. Biochemical and molecular analysis demonstrated that these less toxic degradation products, AMPA and hydroxyatrazine, by themselves elicited significant plant responses, thus indicating underlying mechanisms of perception and transduction into metabolic and gene expression changes. These mechanisms may explain observed interactions, whether positive or negative, between the effects of pesticide products (AMPA and hydroxyatrazine) and the effects of bioactive xenobiotics (glyphosate and tebuconazole). Finally, the metabolic and molecular perturbations induced by low levels of xenobiotics and associated degradation products were shown to affect processes (carbon balance, hormone balance, antioxidant defence, and detoxification) that are likely to determine environmental stress sensitivity.


Advanced diagnostic endoscopy in the lower gastrointestinal tract: A review of JGES core sessions.
At each of the 89th to the 92nd congresses of the Japan Gastroenterological Endoscopy Society, a series of featured discussion sessions concerning advanced diagnostic endoscopy in the lower gastrointestinal tract were presented. In total, 45 lectures were presented in this subject area. It was shown that, in recent years, several convenient and less invasive colonoscopic modalities have been developed. This review article summarizes these core sessions and the efficacy of the techniques discussed.


Successful ABO-incompatible living-donor renal transplant without splenectomy for renal coloboma syndrome: a case report.
To our knowledge, this is the first report of an ABO-incompatible living-donor renal transplant without a splenectomy performed in a patient with renal coloboma syndrome, a rare disorder caused by PAX2 gene mutations, and that presents with renal and optic nerve hypodysplasia and disorders of the central nervous system. Many patients with renal coloboma syndrome develop end-stage renal disease requiring renal replacement therapy. Few reports of a well-defined course of renal transplant for coloboma syndrome have been published. We treated a 22-year-old man who had end-stage renal disease from renal coloboma syndrome. We performed an ABO-incompatible living-donor renal transplant with a kidney donated by his father. Two years after the transplant, the patient has good preserved renal function, and his compliance with the immunosuppressive regimen was good.


Increased concentrations of fructose 2,6-bisphosphate contribute to the Warburg effect in phosphatase and tensin homolog (PTEN)-deficient cells.
Unlike normal differentiated cells, tumor cells metabolize glucose via glycolysis under aerobic conditions, a hallmark of cancer known as the Warburg effect. Cells lacking the commonly mutated tumor suppressor PTEN exhibit a glycolytic phenotype reminiscent of the Warburg effect. This has been traditionally attributed to the hyperactivation of PI3K/Akt signaling that results from PTEN loss. Here, we propose a novel mechanism whereby the loss of PTEN negatively affects the activity of the E3 ligase APC/C-Cdh1, resulting in the stabilization of the enzyme PFKFB3 and increased synthesis of its product fructose 2,6-bisphosphate (F2,6P2). We discovered that when compared with wild-type cells, PTEN knock-out mouse embryonic fibroblasts (PTEN KO MEF) have 2-3-fold higher concentrations of F2,6P2, the most potent allosteric activator of the glycolytic enzyme phosphofructokinase-1 (PFK-1). Reintroduction of either wild-type or phosphatase mutant PTEN in the PTEN KO cells effectively lowers F2,6P2 to the wild-type levels and reduces their lactate production. PTEN KO cells were found to have high protein levels of PFKFB3, which directly contribute to the increased concentrations of F2,6P2. PTEN enhances interaction between PFKFB3 and Cdh1, and overexpression of Cdh1 down-regulates the PFKFB3 protein level in wild-type, but not in PTEN-deficient cells. Importantly, we found that the degradation of endogenous PFKFB3 in PTEN KO cells occurs at a slower rate than in wild-type cells. Our results suggest an important role for F2,6P2 in the metabolic reprogramming of PTEN-deficient cells that has important consequences for cell proliferation.


Cultural Transmission, Evolution, and Revolution in Vocal Displays: Insights From Bird and Whale Song.
Culture, defined as shared behavior or information within a community acquired through some form of social learning from conspecifics, is now suggested to act as a second inheritance system. Cultural processes are important in a wide variety of vertebrate species. Birdsong provides a classic example of cultural processes: cultural transmission, where changes in a shared song are learned from surrounding conspecifics, and cultural evolution, where the patterns of songs change through time. This form of cultural transmission of information has features that are different in speed and form from genetic transmission. More recently, culture, vocal traditions, and an extreme form of song evolution have been documented in cetaceans. Humpback whale song "revolutions," where the single population-wide shared song type is rapidly replaced by a new, novel song type introduced from a neighboring population, represents an extraordinary example of ocean basin-wide cultural transmission rivaled in its geographic extent only by humans. In this review, we examine the cultural evolutions and revolutions present in some birdsong and whale song, respectively. By taking a comparative approach to these cultural processes, we review the existing evidence to understand the similarities and differences for their patterns of expression and the underlying drivers, including anthropogenic influences, which may shape them. Finally, we encourage future studies to explore the role of innovation vs. production errors in song evolution, the fitness information present in song, and how human-induced changes in population sizes, trajectories, and migratory connections facilitating cultural transmission may be driving song revolutions.


Advances in spinal cord regeneration.
Spinal cord injury continues to be a major cause of morbidity, particularly among young people involved in vehicle-related trauma, falls, and sports injuries. Although research advances are still a long way from clinical treatments, recent studies on animals have indicated new possibilities for recovery of function. In this review, these new findings on the use of neurotrophic factors, antibodies to inhibitory molecules, electrical stimulation, and transplantation of peripheral nerves and olfactory glial cells, and their success in achieving functional recovery after adult spinal cord lesions are discussed.


Neuropsychological and behavioral aspects of Noonan syndrome.
The current paper introduces concise neuropsychological assessment as an essential tool for studying the contribution of cognition and behavior in the expression of genetic syndromes, like Noonan syndrome (NS). Cognitive and behavioral findings in NS show intelligence scores across a wide range, with a mildly lowered average level. Language and motor development are often delayed, but no longer dysfunctional in adulthood. Continuing mild problems in selective and sustained attention are noted, as well as suboptimal organization skills and compromised abilities to structure complex information. These problems seem to culminate in learning difficulties, requiring attention for special needs in education. It seems that a complex of psychosocial immaturity, alexithymia and amenable traits is typical of NS patients. Consequently, psychopathology or psychological problems in leading a self-serving life may often remain underreported. This is why the authors advocate the integration of the domain of social cognition and personality in NS assessment.


Targeting gut microbiota: a potential promising therapy for diabetic kidney disease.
Conventional studies reveal a contributory role of gut microbiota in the process of diabetes mellitus (DM) and end-stage renal disease (ESRD). However, the mechanism through which gut microbiota influence diabetic kidney disease (DKD) is ignored. In the present article, we reviewed the changes in gut microbiota of patients with DM, DKD as well as ESRD, and how this may contribute to the progression of DKD. Although further studies are needed to either selectively change the composition of the gut microbiota or to pharmacologically control the metabolites of microbiota, the gut microbiota represents a new potential therapeutic target for DKD.


Synergistic antitumor efficacy of antibacterial helvolic acid from Cordyceps taii and cyclophosphamide in a tumor mouse model.
The antibacterial agent helvolic acid, which was isolated from the active antitumor fraction of Cordyceps taii, showed potent cytotoxicity against different human cancer cells. In the present study, the in vivo antitumor effect of helvolic acid was investigated in murine sarcoma S180 tumor-bearing mice. Doses of 10 and 20 mg/kg/day helvolic acid did not exert significant antitumor activity. Interestingly, co-administration of 10 mg/kg/day helvolic acid and 20 mg/kg/day cyclophosphamide (CTX) - a well-known chemotherapy drug - showed promising antitumor activity with a growth inhibitory rate of 70.90%, which was much higher than that of CTX alone (19.5%). Furthermore, the combination markedly prolonged the survival of tumor-bearing mice. In addition, helvolic acid enhanced the immune organ index. The protein expression levels of β-catenin, cyclin D1, and proliferating cell nuclear antigen were significantly suppressed in mice treated with 20 mg/kg/day helvolic acid and in those receiving combination therapy. Taken together, these results indicated that helvolic acid in combination with CTX showed potent in vivo synergistic antitumor efficacy, and its mechanism of action may involve the Wnt/ β-catenin signaling pathway.


Obesity Is Not a Predictor of Complications in Upper Extremity Surgery.
Obesity is an often-cited cause of surgical morbidity. As a result, many institutions have required screening prior to "clearing" obese individuals for surgery. However, it remains unclear whether such testing is warranted for obese patients prior to upper extremity procedures. This study reviews surgical outcomes to determine if obesity does predict operative morbidity following upper extremity surgery. The National Surgical Quality Improvement Program was queried for 18 Current Procedural Terminology codes, representing upper extremity fracture and arthroplasty procedures. Patients' body mass index (BMI) and medical histories were examined as predictors for postoperative complications. Both individual and combined incidences of complications were compared between patients stratified as normal-weight (BMI < 30); obese (BMI 30-40); and morbidly obese (BMI> 40). A total of 8,477 patients were identified over the 5-year study period; 5,303 had a BMI <30, 2,565 a BMI of 30 to 40 and 585 a BMI >40. With the exception of postoperative blood transfusions, there were no significant increases in the incidence rates of any complication event as a function of BMI class. The overall incidence of complications was 2.70 % for BMI <30; 2.74 % for BMI 30 to 40; and 1.54 % for BMI >40. Obesity is not a reliable predictor of complications following upper extremity surgery. Thus, requiring preoperative screening for obese patients may constitute an unnecessary burden on medical resources. Further study is needed to identify specific demographics that might serve as more accurate predictors of poor outcomes in obese patients undergoing surgery of the upper extremity.


Distinct Metabolic Flow in Response to Temperature in Thermotolerant Kluyveromyces marxianus.
The intrinsic mechanism of the thermotolerance of Kluyveromyces marxianus was investigated by comparison of its physiological and metabolic properties at high and low temperatures. After glucose consumption, the conversion of ethanol to acetic acid became gradually prominent only at a high temperature (45°C) and eventually caused a decline in viability, which was prevented by exogenous glutathione. Distinct levels of reactive oxygen species (ROS), glutathione, and NADPH suggest a greater accumulation of ROS and enhanced ROS-scavenging activity at a high temperature. Fusion and fission forms of mitochondria were dominantly observed at 30°C and 45°C, respectively. Consistent results were obtained by temperature upshift experiments, including transcriptomic and enzymatic analyses, suggesting a change of metabolic flow from glycolysis to the pentose phosphate pathway. The results of this study suggest that K. marxianus survives at a high temperature by scavenging ROS via metabolic change for a period until a critical concentration of acetate is reached. IMPORTANCE Kluyveromyces marxianus, a thermotolerant yeast, can grow well at temperatures over 45°C, unlike Kluyveromyces lactis, which belongs to the same genus, or Saccharomyces cerevisiae, which is a closely related yeast. K. marxianus may thus bear an intrinsic mechanism to survive at high temperatures. This study revealed the thermotolerant mechanism of the yeast, including ROS scavenging with NADPH, which is generated by changes in metabolic flow.


Thioredoxin/Glutaredoxin System of Chlorella: CHLORELLA ADENOSINE 5'-PHOSPHOSULFATE SULFOTRANSFERASE CANNOT USE THIOREDOXIN OR GLUTAREDOXIN AS COFACTORS.
Using the thioredoxin/glutaredoxin-dependent adenosine 3'-phosphate 5'-phosphosulfate reductase coupled assay system, the Chlorella thioredoxin/glutaredoxin system has been partially purified and characterized. A NADPH-thioredoxin reductase and two thioredoxin/glutaredoxin activities, designated as Chlorella thioredoxin/glutaredoxin protein I and II (CPI and CPII), were found in crude extracts of Chlorella. Similar to their counterparts from Escherichia coli, both CPI and CPII are heat-stable low molecular proteins of approximately 14,000. While CPI (but not CPII) is a substrate for its homologous NADPH-thioredoxin reductase as well as for E. coli NADPH-thioredoxin reductase, CPII is better than CPI as a substrate for reduction by the glutathione system. Based on these properties, CPI and CPII may be classified as Chlorella thioredoxin and Chlorella glutaredoxin, respectively. The Chlorella NADPH-thioredoxin reductase (M(r) = 72,000, with two 36,000-dalton subunits) resembles E. coli-thioredoxin reductase in size. Besides Chlorella thioredoxin, the Chlorella thioredoxin reductase will also use E. coli thioredoxin, but not glutaredoxin, as a substrate. Although a thioredoxin-like protein has been implicated in higher plant light-dependent sulfate reaction, neither Chlorella thioredoxin nor glutaredoxin can stimulate the thiol-dependent adenosine 5'-phosphosulfate-sulfotransferase reaction. Furthermore, Chlorella thioredoxin and glutaredoxin, in conjunction with an appropriate reductase system, cannot replace the thiol requirement of Chlorella adenosine 5'-phosphosulfate-sulfotransferase. The exact physiological roles and subcellular localization of the Chlorella thioredoxin and glutaredoxin systems remain to be determined.


Anatomical evidence for somatotopic maps in the zona incerta of rats.
We explore the patterns of connectivity between the zona incerta (ZI) and major centres of the somatosensory system in rats. Injections of cholera toxin subunit B (CTb) or biotinylated dextran (BD) were made into different somatosensory centres (Par1, FL and HL cortex; principal and spinal trigeminal nuclei; cervical, thoracic and lumbar spinal cord) of rats. Double injections of different coloured fluorescent dextrans (fluororuby and dextran-fluorescein) or BD and CTb (revealed with different chromogens) were also made into adjacent cortical regions (Par1 and FL). After injections into each of these somatosensory centres, a distinctive labelling pattern becomes apparent. Labelled terminals from centres representing the head (Par1, trigeminal nuclei) are found in the medial ZI, while labelled terminals from forelimb (FL, cervical spinal cord), trunk (thoracic cord) and hindlimb (HL, lumbar cord) centres are found in progressively more lateral areas of the nucleus. In general, rich terminal labelling is seen in the ZI after injections into the head and forelimb centres, while very poor labelling is seen after injections into the trunk and hindlimb centres. Our double injections show that adjacent but distinct cortical areas (Par1 and FL) occupy mainly separate territories in the ZI, but with some overlap. After each injection, from the cortex to the spinal cord, only a few labelled cells are seen. Our results indicate anatomical evidence for a somatotopic map within the ZI, with a preferential representation of the head and upper limbs. We suggest that the ZI may function to influence arousal states and orientating movements in relation to particularly active somatosensory inputs.


Effects of different resuscitation fluids on acute lung injury in a rat model of uncontrolled hemorrhagic shock and infection.
To investigate the effects of different resuscitation fluids on acute lung injury in a rat model of uncontrolled hemorrhagic shock (HS) followed by mimicked infection. Sixty Sprague-Dawley rats were randomly assigned to one of the five groups (n = 12 per group) to receive the following treatments: (1) control group (group C), surgery, no hemorrhage, and no resuscitation; (2) no fluid resuscitation group; (3) lactated Ringer's solution group; (4) 7.5% hypertonic saline (HTS) group; and (5) hydroxyethyl starch group (group HES). All experimental groups were subjected to three phases: phase I entailed massive hemorrhage with a mean arterial pressure of 35 mm Hg to 40 mm Hg for 60 minutes by tail amputation and followed by mimicked infection by intratracheal administration of lipopolysaccharide 2 mg/kg. The animals in each group were then partially resuscitated with the fluid assigned to the group. Phase II of 60 minutes commenced at tail ligation, involved hemostasis, and return of all the blood initially shed. Phase III was an observation phase with no any further treatment and lasted for 3.5 hours. The survival rate at the end of the phase III was recorded. After phase III, arterial blood gases were recorded. The wet to dry lung weight ratio, pulmonary microvascular permeability, the expression of transforming growth factor (TGF)-beta1, and Smad2 were determined. The lung histology was also assessed. HES and HTS solutions were more effective than no fluid resuscitation and lactated Ringer's solution in reducing the detrimental effects of HS and infection on the lungs, as seen by the significantly lower pulmonary microvascular permeability and wet to dry lung weight ratio, the improved arterial blood gases and lower levels of TGF-beta1and Smad2 expression in lung tissues. These beneficial effects were most pronounced in the group HES. This study demonstrated that resuscitation with HTS and especially with HES could reduce lung tissue damage and pulmonary edema after severe uncontrolled HS. The TGF-beta1/Smad2 signaling pathway might play a key role in regulation of pulmonary permeability and formation of pulmonary edema in a rat model of uncontrolled HS and infection.


Sleep-related breathing disorders in patients who are critically ill.
This descriptive study describes the frequency and severity of sleep-related breathing disorders in men who are hemodynamically stable who have an acute cardiovascular illness and are hospitalized in a critical care unit. Sixty-four males, aged 55-79 years, with an acute cardiovascular illness, stable hemodynamics, and no ongoing chest pain or history of sleep apnea were studied for 1 night in the critical care unit using polysomnography. Forty-seven percent of the sample had an apnea-hypopnea index > or = 5, with events of both obstructive and central etiologies, including Cheyne-Stokes respiration. Oxygen desaturation to < or = 90% occurred in 61% of the sample. There were no episodes of chest pain, ventricular tachycardia, or heart block associated with apneic or hypopneic events; however, dysrhythmias, including sinus bradycardia, supraventricular tachycardia, and premature ventricular beats, were associated with apneic and hypopneic events.


Evaluation of AR-H067637, the active metabolite of the new direct thrombin inhibitor AZD0837, in models of venous and arterial thrombosis and bleeding in anaesthetised rats.
AZD0837, currently in clinical development, is a once-daily oral anticoagulant that is bioconverted to AR-H067637, a selective, reversible direct thrombin inhibitor (DTI). When developing a new DTI, the antithrombotic effects are commonly investigated in in vivo animal models; this report shows the effect of AR-H067637 in venous and arterial thrombosis and bleeding models in anaesthetised rats. Thrombus formation was induced by topical application of ferric chloride to the carotid artery or to the caval vein with partial stasis. Cutaneous incision bleeding time and muscle transection blood loss were assessed, with or without acetylsalicylic acid (ASA). Activated partial thromboplastin time (APTT), ecarin coagulation time (ECT) and thrombin coagulation time (TCT) were used as plasma biomarkers of anticoagulant effect. Dalteparin was used as a reference compound. AR-H067637, given by continuous infusion, displayed a dose-dependent antithrombotic effect, with 50% inhibition (IC50) of thrombus size in venous and arterial thrombosis models obtained at plasma concentrations of 0.13 μM and 0.55 μM, respectively, without increased bleeding. Dose-dependent increased bleeding and blood loss were seen at plasma concentrations ≥1 μM AR-H067637. At the highest AR-H067637 plasma concentration tested, bleeding time and blood loss increased two and four times the vehicle group. Addition of ASA moderately potentiated bleeding time and blood loss. APTT, ECT and TCT were dose-dependently prolonged. These studies demonstrate that the DTI AR-H067637 inhibits thrombus formation in rat venous and arterial thrombosis models with no or minor increases in bleeding.


Regional variations in bone mineral density as assessed with dual-energy photon absorptiometry and dual x-ray absorptiometry.
Total-body, lumbar spine, and hip bone mineral density (BMD) scans were obtained in postmenopausal women to examine regional variations in mineralization of trabecular bone. One hundred ninety-nine patients were studied with dual-energy photon absorptiometry (DPA) and/or dual x-ray absorptiometry (DXA). Comparison of BMD at the different sites showed statistically significant correlations (P < .001) among all the sites; however, variations between sites were observed in many patients. Total-body measurements were within normal limits as defined by the system software in 90% of patients with substantial bone mineral loss in the spine or hip. Lumbar spine measurements calculated from the total-body scan differed from the direct measurements by an average of 10% (DPA) and 12% (DXA). These results suggest that site-specific measurements are required to assess regional osteopenia. While total-body scans may be precise and offer the advantage of total-body composition determination, BMD values derived from total-body scans cannot currently replace direct measurements.


A comparison of multiple testing procedures for the gold standard non-inferiority trial.
For the three-arm parallel-group design, several procedures have been proposed in the literature to control for the multiple type I error when all groups are to be statistically compared. Mere statements regarding the rejection of the null hypotheses are not satisfactory, but instead confidence intervals are more desirable. For this purpose, the procedure by Koch and Röhmel (2004) is modified and the theoretical reasoning behind it is given. However, one combination of effects occurs where control of the multiple type I error cannot be guaranteed. This pathologic case is discussed theoretically and further investigated in a simulation study.


Expanding public-private collaborations to enhance cancer drug development: a report of the Institute of Medicine's workshop series, "Implementing a National Cancer Clinical Trials System for the 21st Century".
Since their inception in the 1950s, the National Cancer Institute-funded cancer cooperative groups have been important contributors to cancer clinical and translational research. In 2010, a committee appointed by the Institute of Medicine (IOM) of the National Academy of Sciences completed a consensus review on the status of the U.S. publicly funded cancer clinical trials system. This report identified a need to reinvigorate the cooperative groups and provided recommendations for improving their effectiveness. Follow-up workshops to monitor progress were conducted by the IOM's National Cancer Policy Forum and the American Society of Clinical Oncology (ASCO) in 2011 and 2013. One of the key recommendations of the IOM report was a call for greater collaboration among stakeholders in cancer research. In particular, more active engagement and better alignment of incentives among the cooperative groups, the National Cancer Institute, the U.S. Food and Drug Administration, and the biopharmaceutical industry were identified as essential to achieving the promise of oncology drug development. This review, based on presentations and discussion during the IOM-ASCO workshops, outlines the progress and remaining challenges of these collaborations.


Mitochondrial Copy Number and D-Loop Variants in Pompe Patients.
Pompe disease is a rare neuromuscular genetic disorder and is classified into two forms of early and late-onset. Over the past two decades, mitochondrial abnor- malities have been recognized as an important contributor to an array of neuromuscular diseases. We therefore aimed to compare mitochondrial copy number and mitochondrial displacement-loop sequence variation in infantile and adult Pompe patients. In this retrospective study, the mitochondrial D-loop sequence was analyzed by polymerase chain reaction (PCR) and direct sequencing to detect pos- sible variation in 28 Pompe patients (17 infants and 11 adults). Results were compared with 100 healthy controls and sequences of all individuals were compared with the Cam- bridge reference sequence. Real-time PCR was used to quantify mitochondrial DNA copy number. Among 59 variants identified, 37(62.71%) were present in the infant group, 14(23.333%) in the adult group and 8(13.333%) in both groups. Mitochondrial copy number in infant patients was lower than adults (P<0.05). A significant frequency differ- ence was seen between the two groups for 12 single nucleotide polymorphism (SNP). A novel insertion (317-318 ins CCC) was observed in patients and six SNPs were iden- tified as neutral variants in controls. There was an inverse association between mito- chondrial copy number and D-loop variant number (r=0.54). The 317-318 ins CCC was detected as a new mitochondrial variant in Pompe patients.


Effectiveness of serotonin-receptor antagonist antiemetic therapy over successive courses of carboplatin-based chemotherapy.
There are extremely limited data available in the general oncology or gynecologic cancer literature to document the effectiveness of antiemetic therapy over multiple courses of cytotoxic chemotherapy. To examine this highly clinically relevant issue, we analyzed the complete treatment course of patients with gynecologic cancers receiving carboplatin-based chemotherapy regimens who had participated in one of four institutional serotonin-receptor antagonist antiemetic trials, which had specifically evaluated the benefits of such therapy during only the first treatment course. Medical records were reviewed to examine the development of emesis during subsequent chemotherapy treatment cycles. The 91 patients included in this analysis received a median of 6 courses (range 1-18) of carboplatin (initial AUC dose 4, 5, and 6 in 29, 29, and 32 patients, respectively). All received ondansetron or granisetron plus dexamethasone with every treatment course. Complete control of emesis (no acute or delayed nausea or vomiting) was experienced by 56 (62%) patients during every cycle. Conversely, 20% of women noted one or more episodes of nausea without vomiting and 19% developed at least one incidence of vomiting. In no case was emesis considered to be severe (grade 3), and no patient required either discontinuation of carboplatin or a dose reduction due to the development of emesis. In the large majority of patients, serotonin-receptor antagonist antiemetic therapy, administered in combination with dexamethasone, is highly effective over multiple courses in preventing significant carboplatin-induced nausea and vomiting.


Biomedical aspects of pyridoxal 5'-phosphate availability.
The biologically active form of vitamin B6, pyridoxal 5'-phosphate (PLP), is a cofactor in over 160 enzyme activities involved in a number of metabolic pathways, including neurotransmitter synthesis and degradation. In humans, PLP is recycled from food and from degraded PLP-dependent enzymes in a salvage pathway requiring the action of pyridoxal kinase, pyridoxine 5'-phosphate oxidase and phosphatases. Once pyridoxal 5'-phosphate is made, it is targeted to the dozens different apoenzymes that need it as a cofactor. The regulation of the salvage pathway and the mechanism of addition of PLP to the apoenzymes are poorly understood and represent a very challenging research field. Severe neurological disorders, such as convulsions and epileptic encephalopathy, result from a reduced availability of pyridoxal 5'-phosphate in the cell, due to inborn errors in the enzymes of the salvage pathway or other metabolisms and to interactions of drugs with PLP or pyridoxal kinase. Multifactorial neurological pathologies, such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and epilepsy have also been correlated to inadequate intracellular levels of PLP.


Addition of Benzyl Halides to Aldehydes and Imines Using Photoactivated TDAE: Access to 3,4-Dihydroisocoumarins, 1,2-Diarylethanols, and 1,2-Diarylcarbamates under Metal-Free Conditions.
We describe herein the intermolecular addition reaction of benzyl halides to aldehydes and imines using photoactivated tetrakis(dimethylamino)ethylene (TDAE) as superphotoreductant. 3,4-Dihydroisocoumarins, 1,2-diarylethanols, and 1,2-diarylcarbamates were obtained with good functional group tolerance using simple, mild, and metal-free conditions.


Macrolevel stressors, terrorism, and mental health outcomes: broadening the stress paradigm.
We examined the extent to which the stress paradigm linking psychosocial stressors to mental health status has focused disproportionate attention on microlevel social stressors to the detriment of macrolevel stressors. Also, we assessed the effects of the terrorist attacks of September 11, 2001, on subsequent mental health among participants in a Midwestern cohort study. Respondents in a 6-wave longitudinal mail survey completed questionnaires before September 11, 2001, and again in 2003 and 2005. Regression analyses focused on measures of negative terrorism-related beliefs and fears, as well as psychological distress and deleterious alcohol use outcomes measured both before and after September 11. Negative terrorism-related beliefs and fears assessed in 2003 predicted distress and drinking outcomes in 2005 after control for sociodemographic characteristics and pre-September 11 distress and drinking. The events of September 11 continue to negatively affect the mental health of the American population. Our results support the utility of according greater attention to the effects of such macrolevel social stressors in population studies embracing the stress paradigm.


Suppression of pulmonary P4502b and induction of hepatic, intestinal and kidney P4501a-1 and 1a-2 in the Ah-responsive and non-responsive mouse by Aroclor 1254.
1. Investigations in our laboratory have demonstrated a rapid suppression of the P4502b isoform in mouse lung, concomitant with significant induction of this enzyme in liver from these same animals. The current study was designed to determine whether the suppression by polychlorinated biphenyls of pulmonary P4502b required the presence of a functional Ah receptor, and additionally to delineate the time course of the induction responses to Aroclor 1254 in the liver, kidney, and intestine of the AH-responsive and non-responsive mouse. 2. P450s were quantified by specific enzyme assay and immunoblot in liver (1a-1, 1a-2, 2b), lung (1a-1, 1a-2), kidney (1a-1, 1a-2, 2b) and small intestine (1a-1, 2b) of C57 and DBA animals at varying times (48 h-12 weeks) following a single intraperitoneal dose of Aroclor 1254 (250 mg/kg). 3. The suppression of constitutive P4502b in the lung by Aroclor was observed in both strains, but was more prominent over a longer time course in the non-responsive animals. P4502b enzyme activity was increased in the liver and intestine of both strains of mouse; however, there was a significantly greater response to Aroclor in the C57 animals. These data indicate that the AH receptor does not participate in the suppression of pulmonary P4502b, and suggests that the regulation of inducible P4502b in liver and intestine is quantitatively different between these two strains of mouse. 4. P4501a was predictably induced in all tissues examined from the C57 animal, but was largely unaffected by PCBs in the DBA strain. P4501a-2, which is also regulated by the Ah receptor, was highly induced in the liver of the responsive strain, and also increased approximately two-fold in the liver of the non-responsive animals. Kidney P4501a-2 was also modestly increased by Aroclor, only in the responsive mouse.


Examining the activity-distribution model of visual attention with exogenous cues and targets.
LaBerge and his co-workers (e.g., LaBerge & Brown, 1986, 1989; LaBerge, Carlson, Williams, & Bunney, 1997) used an experimental method consisting of three rapid successive displays, each requiring a difficult letter discrimination, to show that visual attention is best accounted for with an activity-distribution model rather than a moving-spotlight model. The present study sought to further this line of investigation by inserting exogenous cues and targets, often used in studies that have found support for the moving-spotlight model, into the basic method used by LeBerge and colleagues. The results from three experiments were consistent with the activity-distribution model and not with the moving-spotlight model.


Studies on RNase T1 mutants affecting enzyme catalysis.
Using an Escherichia coli overproducing strain secreting Aspergillus oryzae RNase T1, we have constructed and characterized mutants where amino acid residues in the catalytic center have been substituted. The mutants are His40----Thr, Glu58----Asp, Glu58----Gln, His92----Ala and His92----Phe. His92----Ala and His92----Phe mutants are inactive. On the basis of their kcat/Km values, the mutants Glu58----Asp and Glu58----Gln show 10% and 7% residual activity, relative to wild-type RNase T1, whereas the His40----Thr mutant shows 2% activity. The effect of amino acid substitutions on the enzymatic activity of RNase T1 lends further support for a mechanism where Glu58 (possibly activated by His40 and His92 act as general base and acid respectively; this is discussed in terms of the known three-dimensional structure of the enzyme.


A roadmap for the conservation of freshwater mussels in Europe.
Europe has a long history of human pressure on freshwater ecosystems. As pressure continues to grow and new threats emerge, there is an urgent need for conservation of freshwater biodiversity and its ecosystem services. However, whilst some taxonomic groups, mainly vertebrates, have received a disproportionate amount of attention and funds, other groups remain largely off the public and scientific radar. Freshwater mussels (Bivalvia, Unionida) are an alarming example of this conservation bias and here we point out six conceptual areas that need immediate and long-term attention: knowledge, threats, socioeconomics, conservation, governance and education. The proposed roadmap aims to advance research, policy and education by identifying the most pressing priorities for the short- and long-term conservation of freshwater mussels across Europe.


Routes to chaos and multiple time scale dynamics in broadband bandpass nonlinear delay electro-optic oscillators.
The response of a nonlinear optical oscillator subject to a delayed broadband bandpass filtering feedback is studied experimentally, numerically, and analytically. The oscillator loop is characterized by a high cutoff frequency with a response time tau approximately 10 ps and by a low cutoff frequency with a response time theta approximately 1 micros. Moreover, the optoelectronic feedback also consists of a significant delay tauD of the order of 100 ns. Depending on two key physical parameters, the loop gain beta and the nonlinearity operating point Phi, a large variety of multiple time scale regimes are reported, including slow or fast periodic oscillations with different waveforms, regular or chaotic breathers, slow time envelope dynamics, complex and irregular self-pulsing, and fully developed chaos. Many of these regimes are exhibiting new features that are absent in the classical first-order scalar nonlinear delay differential equations (DDEs), which differ in the modeling by the low cutoff only. Nearly all kinds of solutions are recovered numerically by a new class of integro-DDE (iDDE) that take into account both the high and low cutoff frequencies of the feedback loop. For moderate feedback gain, asymptotic solutions are determined analytically by taking advantage of the relative values of the time constants tau, theta, and tauD. We confirm the experimental observation of two distinct routes to oscillatory instabilities depending on the value of Phi. One route is reminiscent of the square wave oscillations of the classical first-order DDE, but the other route is quite different and allows richer wave forms. For higher feedback gain, these two distinct regimes merge leading to complex nonperiodic regimes that still need to be explored analytically and numerically. Finally, we investigate the theoretical limits of our iDDE model by experimentally exploring phenomena at extreme physical parameter setting, namely, high-frequency locking at strong feedback gain or pulse packages for very large delays. The large variety of oscillatory regimes of our broadband bandpass delay electro-optic oscillator is attractive for applications requiring rich optical pulse sources with different frequencies and/or wave forms (chaos-based communications, random number generation, chaos computing, and generation of stable multiple GHz frequency oscillations).


Hypersensitive-like response to the pore-former peptaibol alamethicin in Arabidopsis thaliana.
In Arabidopsis thaliana cell cultures, the peptaibol alamethicin induced a form of active cell death that was associated with cell shrinkage and DNA fragmentation. The transfer of mature A. thaliana plants from a peptide-free medium to a medium containing a moderate concentration of alamethicin caused the development of lesions in leaves after a few days. These lesions were characterized by cell death, deposition of callose, production of autofluorescent phenolic compounds, and transcription of defense genes, just like in the hypersensitive response to a pathogen attack. The induction of defense-like responses in Arabidopsis by other membrane-disrupting peptides was also evaluated. The peptides selected for comparison included the natural antimicrobial melittin and the peptaibol ampullosporin A, as well as synthetic analogues of the peptaibols cervinin and trichogin. The response amplitude in A. thaliana increased with the peptaibol's ability to permeabilize biological membranes through a pore-forming mechanism and was strongly associated with their content in the helicogenic α-aminoisobutyric acid residue.


Beta-phenyl cysteine: a leucine aminopeptidase inhibitor.
Beta-phenyl cysteine: a leucine aminopeptidase inhibitor. The kinetic parameters of the inhibition of the leucine aminopeptidase by beta-phenyl cysteine are reported in this communication.


Nucleotide exchange factor for the yeast Hsp70 molecular chaperone Ssa1p.
We report on the identification of Fes1p (yBR101cp) as a cytosolic homologue of Sls1p, an endoplasmic reticulum (ER) protein previously shown to act as a nucleotide exchange factor for yeast BiP (M. Kabani, J.-M. Beckerich, and C. Gaillardin, Mol. Cell. Biol. 20:6923-6934, 2000). We found that Fes1p associates preferentially to the ADP-bound form of the cytosolic Hsp70 molecular chaperone Ssa1p and promotes nucleotide release. Fes1p activity was shown to be compartment and species specific since Sls1p and Escherichia coli GrpE could not substitute for Fes1p. Surprisingly, whereas Sls1p stimulated the ATPase activity of BiP in cooperation with luminal J proteins, Fes1p was shown to inhibit the Ydj1p-mediated activation of Ssa1p ATPase activity in steady-state and single-turnover assays. Disruption of FES1 in several wild-type backgrounds conferred a strong thermosensitive phenotype but partially rescued ydj1-151 thermosensitivity. The Delta fes1 strain was proficient for posttranslational protein translocation, as well as for the ER-associated degradation of two substrates. However, the Delta fes1 mutant showed increased cycloheximide sensitivity and a general translational defect, suggesting that Fes1p acts during protein translation, a process in which Ssa1p and Ydj1p are known to be involved. In support of this hypothesis, Fes1p was found to be associated with ribosomes.


Interaction of Escherichia coli and soil particles in runoff.
A laboratory-scale model system was developed to investigate the transport mechanisms involved in the horizontal movement of bacteria in overland flow across saturated soils. A suspension of Escherichia coli and bromide tracer was added to the model system, and the bromide concentration and number of attached and unattached E. coli cells in the overland flow were measured over time. Analysis of the breakthrough curves indicated that the E. coli and bromide were transported together, presumably by the same mechanism. This implied that the E. coli was transported by advection with the flowing water. Overland-flow transport of E. coli could be significantly reduced if the cells were preattached to large soil particles (> 45 microm). However, when unattached cells were inoculated into the system, the E. coli appeared to attach predominantly to small particles (< 2 microm) and hence remained unattenuated during transport. These results imply that in runoff generated by saturation-excess conditions, bacteria are rapidly transported across the surface and have little opportunity to interact with the soil matrix.


Facile Transferring of Wafer-Scale Ultrathin Alumina Membranes onto Substrates for Nanostructure Patterning.
Ordered nanostructure arrays have attracted intensive attention because of their various applications. However, it is still a great challenge to achieve ordered nanostructure patterning over a large area (such as wafer-scale) by a technique that allows high throughput, large pattern area and low equipment costs. Here, through a unique design of the fabrication and transferring processes, we achieve a facile transferring of wafer-scale ultrathin alumina membranes (UTAMs) onto substrates without any twisting, folding, cracking and contamination. The most important in our method is fixing the UTAM onto the wafer-scale substrate before removing the backside Al and alumina barrier layer. It is also demonstrated that the thickness and surface smoothing of UTAMs play crucial roles in this transferring process. By using these perfectly transferred UTAMs as masks, various nanostructure patterning including nanoparticle, nanopore (nanomesh) and nanowire arrays are fabricated on wafer-scale substrates with tunable and uniform dimension. Because there are no requirements for UTAMs, substrates and materials to be deposited, the method presented here shall provide a cost-effective platform for the fabrication of ordered nanostructures on large substrates for various applications in nanotechnology.


Acquired chronic hepatocerebral degeneration due to cirrhosis from non-alcoholic steatohepatitis.
Acquired chronic hepatocerebral degeneration, acquired hepatolenticular degeneration or pseudo-Wilson is an infrequent disorder with a hepatic origin. Cases in the literature are scarce and it is frequently confused with hepatic encephalopathy and Wilson s disease. The aim of this essay is to report a patient suffering from this disorder due to cirrhosis from non-alcoholic steatohepatitis. We present a 54-year-old man diagnosed from cirrhosis grade B9 of the Child Pugh classification. He progressively developed a picture with bradylalia, mild postural and action tremor and spatial and temporal disorientation. Further studies demonstrated an increase of the values of hepatic transaminases and a hyperintensity in the basal nuclei in the cerebral magnetic resonance imaging. Clinical and radiological data established the diagnosis of hepatocerebral degeneration. Acquired chronic hepatocerebral degeneration is a disorder rarely reported in the literature that it is usually confused with other diseases. We alert about the need of having this diagnosis into account with patients developing neurological symptoms after hepatic disease.


Role of intrinsic airway neurons in ozone-induced airway hyperresponsiveness in ferret trachea.
Exposure to ozone (O(3)) enhances airway responsiveness, which is mediated partly by the release of substance P (SP) from airway neurons. In this study, the role of intrinsic airway neurons in O(3)-induced airway responses was examined. Ferrets were exposed to 2 ppm O(3) or air for 1 h. Reactivity of isolated tracheal smooth muscle to cholinergic agonists was significantly increased after O(3) exposure, as were contractions to electrical field stimulation at 10 Hz. Pretreatment with CP-99994, a neurokinin type 1 receptor antagonist, partially abolished the O(3)-induced reactivity to cholinergic agonists and electrical field stimulation. The O(3)-enhanced airway responses were present in tracheal segments cultured for 24 h, a procedure shown to deplete sensory nerves while maintaining viability of intrinsic airway neurons, and all the enhanced smooth muscle responses were also diminished by CP-99994. Immunocytochemistry showed that the percentage of SP-containing neurons in longitudinal trunk and the percentage of neurons innervated by SP-positive nerve fibers in superficial muscular plexus were significantly increased at 1 h after exposure to O(3). These results suggest that enhanced SP levels in airway ganglia contribute to O(3)-induced airway hyperresponsiveness.


Bladder Urothelial Carcinoma with Peritoneal Involvement: Benefit of Continuous Maintenance Chemotherapy.
We investigated bladder urothelial carcinoma with peritoneal involvement. Inclusion criteria were: pathology-confirmed urothelial carcinoma; peritoneal spread identified on computed tomographic (CT) scans performed initially or after either cystectomy or concomitant chemoradiotherapy (CCRT), and absence of visceral metastases; and chemotherapy administered after peritoneal spread was diagnosed. Forty-seven cases included initial modes of therapy with chemotherapy in 24 patients (51%), cystectomy in 17 (36%), and CCRT in six (13%), only given as a result of under-staging. After local therapy, these patients received a continuous maintenance chemotherapy regimen of 5-fluorouracil, leucovorin, cisplatin, and gemcitabine. The overall response rate was 85%, and the side-effects were mild and tolerated. The median survival time was 28 months. The survival time of cases initially treated only with chemotherapy was not statistically different to that of those with local disease. Bladder urothelial carcinomas with peritoneal involvement can benefit from continuous maintenance chemotherapy.


Uptake and Metabolism of Carbohydrates by Bradyrhizobium japonicum Bacteroids.
Bradyrhizobium japonicum bacteroids were isolated anaerobically and were supplied with (14)C-labeled trehalose, sucrose, UDP-glucose, glucose, or fructose under low O(2) (2% in the gas phase). Uptake and conversion of (14)C to CO(2) were measured at intervals up to 90 minutes. Of the five compounds studied, UDP-glucose was most rapidly absorbed but it was very slowly metabolized. Trehalose was the sugar most rapidly converted to CO(2), and fructose was respired at a rate at least double that of glucose. Sucrose and glucose were converted to CO(2) at a very low but measurable rate (<0.1 nanomoles per milligram protein per hour). Carbon Number 1 of glucose appeared in CO(2) at a rate 30 times greater than the conversion of carbon Number 6 to CO(2), indicating high activity of the pentose phosphate pathway. Enzymes of the Entner-Doudoroff pathway were not detected in bacteroids, but very low activities of sucrose synthase and phosphofructokinase were demonstrated. Although metabolism of sugars by B. japonicum bacteroids was clearly demonstrated, the rate of sugar uptake was only 1/30 to 1/50 the rate of succinate uptake. The overall results support the view that, although bacteroids metabolize sugars, the rates are very low and are inadequate to support nitrogenase.


Hsa_circ_0060450 Negatively Regulates Type I Interferon-Induced Inflammation by Serving as miR-199a-5p Sponge in Type 1 Diabetes Mellitus.
Circular RNAs (circRNAs) constitute a class of covalently circular non-coding RNA molecules formed by 5' and 3' end back-splicing. The rapid development of bioinformatics and large-scale sequencing has led to the identification of functional circRNAs. Despite an overall upward trend, studies focusing on the roles of circRNAs in immune diseases remain relatively scarce. In the present study, we obtained a differential circRNA expression profile based on microarray analysis of peripheral blood mononuclear cells (PBMCs) in children with type 1 diabetes mellitus (T1DM). We characterized one differentially expressed circRNA back-spliced from the MYB Proto-Oncogene Like 2 (MYBL2) gene in patients with T1DM, termed as hsa_circ_0060450. Subsequent assays revealed that hsa_circ_0060450 can serve as the sponge of miR-199a-5p, release its target gene, Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the tyrosine-protein phosphatase non-receptor type 11 gene (PTPN11), and further suppress the JAK-STAT signaling pathway triggered by type I interferon (IFN-I) to inhibit macrophage-mediated inflammation, which indicates the important roles of circRNAs in T1DM and represents a promising therapeutic molecule in the treatment of T1DM.


Direct intramolecular carbon(sp2)-nitrogen(sp2) reductive elimination from gold(iii).
The reactivity of bidentate AuIII-Cl species, [(C^N)AuCl2], with a bisphosphine or carbon donor ligands results in reductive elimination. Combined experimental and computational investigations lead to the first evidence of a direct intramolecular C(sp2)-N(sp2) bond formation from a monomeric [(C^N)AuCl2] gold(iii) complex. We show that bidentate ligated Au(iii) systems bypass transmetallation to form C(sp2)-N(sp2) species and NHC-Au-Cl. Mechanistic investigations of the reported transformation reveal a ligand-induced reductive elimination via a key AuIII intermediate. Kinetic studies of the reaction support a second-order rate process.


[Irreversible airflow limitation in asthmatics].
To evaluate irreversible airflow limitation in asthmatics, we studied 168 patients admitted to our hospital with acute exacerbation of asthma. All patients were given intravenous methylprednisolone for at least 7 days to maximum 14 days and the best of PEF (% of predicted) was evaluated. In all subjects, the best of PEF showed significant correlations with both the patients' age (r = -0.411, p < 0.0001) and the duration of asthma (r = -0.494, p < 0.0001). A significant correlations between the best of PEF and the duration of asthma were also observed in both patients over 60 years old (r = -0.157, p < 0.0001) and non-smokers (r = -0.568, p < 0.0001). We conclude that asthma may develop irreversible airflow limitation in itself and the degree of impairment of lung function correlated with the duration of the disease.


Correlating Dietary Pattern and Bladder Cancer Risk Using Principal Component and Reduced Rank Regression Analyses.
We investigated the association between dietary patterns (DPs) and bladder cancer (BC) using principal component analysis (PCA) and reduced rank regression (RRR). This case-control study comprised 102 BC patients and 197 controls aged ≥ 45 years. Dietary intakes were assessed using a food-frequency questionnaire. The response variables for RRR were nitrite and trans-fatty acid consumption. The following DPs were retained using PCA: "high fat and high carbohydrate", "healthy", and "ready-to-eat". The first pattern was positively (OR = 5.78, 95% CI: 3.14, 10.6) and the healthy was negatively (OR = 0.60, 95%CI: 0.42, 0.86) associated with BC risk in the fully adjusted model. The first RRR pattern, "high trans-fatty acids and high nitrite", was positively correlated with trans-fatty acids and nitrite. A higher score on this pattern was associated with a more likely to have BC (OR = 1.83, 95% CI: 1.23, 2.71). The second one, "high trans-fatty acids and low nitrite", was positively correlated with trans-fatty acids but negatively correlated with nitrite. More adherence to this pattern increased BC risk (OR = 1.75, 95% CI: 1.23, 2.50). We identified DPs positively linked to BC. Furthermore, a diet rich in vegetables, fruits, nuts, seafood, and olive oil was inversely associated with BC.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2047739 .


Role of astroglia and insulin-like growth factor-I in gonadal hormone-dependent synaptic plasticity.
Gonadal hormones exert a critical influence over the architecture of specific brain areas affecting the formation of neuronal contacts. Cellular mechanisms mediating gonadal hormone actions on synapses have been studied extensively in the rat arcuate nucleus, a hypothalamic center involved in the feed-back regulation of gonadotropins. Gonadal steroids exert organizational and activational effects on arcuate nucleus synaptic connectivity. Perinatal testosterone induces a sexual dimorphic pattern of synaptic contacts. Furthermore, during the preovulatory and ovulatory phases of the estrous cycle there is a transient disconnection of inhibitory synaptic inputs to the somas of arcuate neurons. This synaptic remodeling is induced by estradiol, blocked by progesterone, and begins with the onset of puberty in females. Astroglia appear to play a significant role in the organizational and the activational hormone effects on neuronal connectivity by regulating the amount of neuronal membrane available for the formation of synaptic contacts and by releasing soluble factors, such as insulin-like growth factor I (IGF-I), which promote the differentiation of neural processes. Recent evidence indicates that gonadal steroids and IGF-I may interact in their trophic effects on the neuroendocrine hypothalamus. Estradiol and IGF-I promote the survival and morphological differentiation of rat hypothalamic neurons in primary cultures. The effect of estradiol depends on IGF-I, while the effects of both estradiol and IGF-I depend on estrogen receptors. Furthermore, estrogen activation of astroglia in hypothalamic tissue fragments depends on IGF-I receptors. These findings indicate that IGF-I may mediate some of the developmental and activational effects of gonadal steroids on the brain and suggest that IGF-I may activate the estrogen receptor to induce its neurotrophic effects on hypothalamic cells. In addition, IGF-I levels in the neuroendocrine hypothalamus are regulated by gonadal steroids. IGF-I levels in tanycytes, a specific astroglia cell type present in the arcuate nucleus and median eminence, increase at puberty, are affected by neonatal androgen levels, show sex differences, and fluctuate in accordance to the natural variations in plasma levels of ovarian steroids that are associated with the estrous cycle. These changes appear to be mediated by hormonal regulation of IGF-I uptake from blood or cerebrospinal fluid by tanycytes. These results suggest that tanycytes may be involved in the regulation of neuroendocrine events in adult rats by regulating the availability of IGF-I to hypothalamic neurons. In summary, IGF-I and different forms of neuron-astroglia communication are involved in the effects of estradiol on synaptic plasticity in the hypothalamic arcuate nucleus.


[Study on spatial site selection assessment of urban medical waste treatment facility].
Based on the principle of regional differentiation and gravity model, this paper proposes a GIS-based urban medical waste treatment facility spatial site selection assessment method. And the method is implemented by use of the third generation GIS database model, Geodatabase. Taking a city in Pearl River Delta as a case, based on its 46 basic units, two scenarios for medical waste central treatment are designed and analyzed by means of scenario analysis (SA) and then the better scenario is recommended. The assessment result of traditional cost model shows the same conclusion. Further spatial analysis shows that the distribution of medical waste quantity and density are both related to the better scenario spatially.


Repression of transcriptional enhancer factor-1 and activator protein-1-dependent enhancer activity by vascular actin single-stranded DNA binding factor 2.
Transcriptional repression of the murine vascular smooth muscle alpha-actin gene in fibroblasts results from the interaction of two sequence-specific single-stranded DNA binding activities (VACssBF1 and VACssBF2) with opposite strands of an essential transcriptional enhancer factor-1 (TEF-1) element (Sun, S., Stoflet, E. S., Cogan, J. G., Strauch, A. R., and Getz, M. J. (1995) Mol. Cell. Biol. 15, 2429-2436). Here, we identify a sequence element located within a protein-coding exon of the gene that bears structural similarity with the TEF-1 enhancer. This includes a 30-base pair region of purine-pyrimidine asymmetry encompassing a perfect 6-base pair GGAATG TEF-1 recognition motif. Unlike the enhancer, however, the exon sequence exhibits no TEF-1 binding activity nor does the pyrimidine-rich strand bind VACssBF1. However, VACssBF2 interacts equally well with the purine-rich strand of both the enhancer and the exon sequence. To test the ability of VACssBF2 to independently repress transcription, the exon sequence was placed upstream of a deletionally activated promoter containing an intact TEF-1 binding site. The exon sequence repressed promoter activity, whereas a mutant deficient in VACssBF2 binding did not. Moreover, VACssBF2 similarly repressed activator protein-1-dependent transcription of a heterologous tissue factor promoter. These results suggest that VACssBF2 possesses an intrinsic ability to disrupt enhancer function independently of the enhancer-binding proteins involved.


Radiological features of mucocele of the appendix.
The clinical features of mucocele of the appendix are nonspecific, and a correct preoperative diagnosis based on abdominal pain, a palpable mass in the right lower quadrant, and conventional radiography is rare. The diagnosis of appendiceal mucocele has become easier with the utilisation of the recent imaging techniques ultrasonography and computed tomography. Six patients with mucocele of the appendix are presented, and the characteristic radiological features and differential diagnosis are discussed.


Diagnosis and treatment of deep pulmonary laceration with intrathoracic hemorrhage from blunt trauma.
Blunt chest trauma resulting in massive hemothorax requires immediate attention. We investigated the diagnostic and prognostic utility of various clinical factors in patients with deep pulmonary laceration caused by blunt chest trauma with a view toward interventional treatment. We reviewed 42 patients with deep pulmonary laceration resulting from blunt chest trauma who were treated between 1988 and 2008. Various clinical factors were compared between survivors and nonsurvivors. Of the 42 patients, 29 (69%) survived. Median (25th, 75th percentile) systolic blood pressure at arrival was 102 (76, 121) mm Hg for survivors and 70 (60, 90) mm Hg for nonsurvivors (p = 0.015). The median heart rate at arrival was 107 (98, 120) beats/min for survivors and 130 (120, 140) beats/min for nonsurvivors (p = 0.014). Respiratory rate, Glasgow Coma Scale score, and arterial blood gas values did not affect prognosis. Blood loss through the chest tube at insertion was 500 (400, 700) mL for survivors and 700 (500, 1000) mL for nonsurvivors (p = 0.147) and within 2 hours of arrival was 850 (590, 1100) mm Hg and 1600 (1400, 2000) mL, respectively (p < 0.001). Blood loss during thoracotomy was 1170 (600, 1790) mL and 3500 (2000, 6690), respectively (p < 0.001). In patients with deep pulmonary laceration, hemorrhagic shock with systolic blood pressure less than 80 mm Hg and heart rate more than 120 beats/min leads to a poor prognosis. Emergency thoracotomy and pulmonary lobectomy should be performed before the intrathoracic hemorrhage reaches 1200 mL.


Diagnosis of gastroesophageal reflux disease in general practice: a Belgian national survey.
The aim of the present study was to analyze the results of a prospective national survey conducted in Belgium to investigate discrepancies between general practitioners' attitudes and the available guidelines on the management of new patients with symptoms of gastroesophageal reflux disease (GERD). A total of 641 general practitioners (GPs) were asked to complete a questionnaire on each consultation by a patient with suspected GERD. The study population included 2234 patients (mean age +/- SD: 47.37 +/- 16.23 years; 52 % aged 45 or older) consulting for the first time for GERD symptoms, without previous endoscopy. Symptoms were classified as mild, moderate, or severe in 39.5 %, 48.0 %, and 11.3 % respectively, and as typical, atypical, or "alarm" in 87.5 %, 16.8 %, and 10.5 % respectively. Upper gastrointestinal endoscopy was requested by GPs in 24.7 % of patients (553 of 2234; including 186 cases that were not justified according to the guidelines), while it should have been requested in 56.6 % (1266 of 2234) if the GPs had respected the national guidelines. Only 28.4 % of the 1171 patients aged 45 or older and 52.6 % of the 95 patients under 45 presenting with alarm symptoms had an endoscopy requested at the first visit. A stepwise multiple logistic regression analysis showed that anemia and symptom severity were the two main factors prompting the GPs to request endoscopy for these patients. There are major discrepancies between GP practice and national or international guidelines for GERD diagnosis. GPs clearly underused endoscopy in patients with alarm symptoms of GERD and in older patients with a new onset of GERD symptoms. GPs are more strongly influenced by the severity of symptoms than by the type of symptoms.


Effects of Diaspirin Crosslinked Hemoglobin (DCLHb) on microcirculation and local tissue pO2 of striated skin muscle following resuscitation from hemorrhagic shock.
The hemoglobin based oxygen carrier (HBOC) Diaspirin Crosslinked Hemoglobin (DCLHb) has been developed to substitute not only the blood volume, but also to restore the oxygen-carrying properties of blood during hemorrhagic shock. However, it has been suggested that HBOCs may enhance the formation of free oxygen radicals through the release of free iron ions via the Haber-Weiss reaction. The aim of this study was to investigate the effects of DCLHb on the microcirculation, leukocyte-endothelial cell interaction and local tissue oxygenation in striated skin muscle of Syrian golden hamsters during and after resuscitation from hemorrhagic shock. In particular we focused on the local tissue oxygenation after resuscitation with DCLHb (hemoglobin content 10 g%) compared to resuscitation using autologous blood diluted to a hemoglobin content of 10 g%. Hemorrhagic shock was induced for 45 minutes by bleeding the animals at a rate of 33 ml/kg BW maintaining a mean arterial pressure of 30 +/- 5 mmHg. Animals were resuscitated either with 33 ml/kg BW 6% Dextran-60.000 or with 10 g% DCLHb. The control group received shed blood diluted with Ringers to a hemoglobin content of 10 g%. Intravital microscopy was used for investigation of the microcirculatory parameters and a multiwire platinum surface electrode for measurement of local tissue pO2 in striated skin muscle in the dorsal skinfold chamber of Syrian golden hamsters. Resuscitation from hemorrhagic shock with 10 g% AUB revealed significant increase of leukocytes rolling in postcapillary venules at 30 to 120 minutes after resuscitation compared to baseline values. DCLHb turned out to reduce the number of firmly adherent leukocytes after resuscitation compared to 10 g% AUB. Microvascular permeability as an indicator for functional endothelial integrity revealed no significant differences between the groups. DCLHb and 10 g% AUB led to a significant increase in local tissue oxygenation after resuscitation from hemorrhagic shock. However, 10 g% AUB turned out to be most effective to restore the local tissue pO2 compared to Dx-60. Our findings indicate that DCLHb restores microvascular perfusion after critical hemorrhagic shock as efficient as Dx-60 and 10 g% AUB. The absence of enhanced leukocyte-endothelium interaction after resuscitation with DCLHb implies that this HBOC does not exacerbate formation of oxygen free radicals during reperfusion. DCLHb effectively increases local tissue pO2 after resuscitation from hemorrhagic shock; however, not as effectively as 10 g% AUB.


A new measure of centrality for brain networks.
Recent developments in network theory have allowed for the study of the structure and function of the human brain in terms of a network of interconnected components. Among the many nodes that form a network, some play a crucial role and are said to be central within the network structure. Central nodes may be identified via centrality metrics, with degree, betweenness, and eigenvector centrality being three of the most popular measures. Degree identifies the most connected nodes, whereas betweenness centrality identifies those located on the most traveled paths. Eigenvector centrality considers nodes connected to other high degree nodes as highly central. In the work presented here, we propose a new centrality metric called leverage centrality that considers the extent of connectivity of a node relative to the connectivity of its neighbors. The leverage centrality of a node in a network is determined by the extent to which its immediate neighbors rely on that node for information. Although similar in concept, there are essential differences between eigenvector and leverage centrality that are discussed in this manuscript. Degree, betweenness, eigenvector, and leverage centrality were compared using functional brain networks generated from healthy volunteers. Functional cartography was also used to identify neighborhood hubs (nodes with high degree within a network neighborhood). Provincial hubs provide structure within the local community, and connector hubs mediate connections between multiple communities. Leverage proved to yield information that was not captured by degree, betweenness, or eigenvector centrality and was more accurate at identifying neighborhood hubs. We propose that this metric may be able to identify critical nodes that are highly influential within the network.


Discovery and pharmacological characterization of a new class of prolyl-tRNA synthetase inhibitor for anti-fibrosis therapy.
Scleroderma has clinical characteristics including skin and other tissue fibrosis, but there is an unmet need for anti-fibrotic therapy. Halofuginone (HF) is a well-known anti-fibrosis agent in preclinical and clinical studies which exerts its effect via inhibition of TGF-β/Smad3 signaling pathway. Recently, prolyl-tRNA synthetase (PRS) was elucidated as a target protein for HF that binds to the proline binding site of the catalytic domain of PRS. Here, we characterized a new class of PRS inhibitor (T-3833261) that is carefully designed in a way that binds to the ATP site of the catalytic domain and does not disrupt binding of proline. The anti-fibrotic activity and the mechanism of action for T-3833261 on TGF-β-induced fibrotic assay were compared with those of HF in primary human skin fibroblast. We evaluated in vivo effect of topical application of T-3833261 and HF on TGF-β-induced fibrotic genes expression in mice. We found that T-3833261 suppressed TGF-β-induced α-smooth muscle actin (α-SMA) and type I collagen α1 (COL1A1) expression through the Smad3 axis in a similar fashion to HF. In vivo topical application of T-3833261 reduced the increase of fibrotic genes expression such as α-Sma, Col1a1 and Col1a2 by TGF-β intradermal injection to the ear of a mouse. We revealed that T-3833261 is more effective than HF under the conditions of high proline concentration, as reported in fibrotic tissues. These results suggest the potential of ATP competitive PRS inhibitors for the treatment of fibrotic diseases such as scleroderma.


Application of local policy to prevent alcohol problems: experiences from a community trial.
Alcohol policy conventionally has been established at the national or regional, state and provincial levels. Alcohol policy at any level is not actually limited to the regulation and control of alcohol production, wholesale distribution, and retail sales. There are a number of alternatives for setting alcohol policies within a local community. Building upon existing national and state/provincial laws, policy makers at the community level can set priorities for allocating resources and enforcing laws related to drinking and driving, underage alcohol sales, alcohol serving practices of bars and restaurants and geographical density of alcohol outlets in the community. This paper concludes from the Community Trials Project that policies established at the local level can reduce alcohol problems.


Phenotypic analysis of retinal leukocyte infiltration during combined cyclosporin A and nasal antigen administration of retinal antigens: delay and inhibition of macrophage and granulocyte infiltration.
Nasal antigen administration successfully suppresses a model of organ-specific autoimmune disease, experimental autoimmune uveoretinitis (EAU), when administered prior to immunisation. We have previously shown that nasal antigen therapy for active disease or in primed, sensitised animals does not reliably or consistently suppress histological disease. However, when nasal antigen administration is combined with cyclosporin A (CsA) therapy, rod outer segment destruction (target organ) is reduced despite the presence of clinical and histological leukocytic infiltration of the eye. In this study, two colour flow cytometric phenotypic analysis of retinal and choroidal leukocytic infiltration of animals treated with either CsA alone, combined therapy with CsA and inhalational tolerance therapy with retinal antigens or sham treated controls was performed. There was no clinical difference between the two treated groups. Flow cytometric phenotypic analysis was performed in all groups at both maximal clinical disease and during resolution of clinical signs. Although the cell number within the infiltrate was reduced in combined treated group, CD4+ IL-2R+ T cells were still present in large numbers, in contrast to the markedly reduced numbers of ED7+ (macrophages/granulocytes) cells infiltrating during height of disease. In the CsA-nasal antigen treated group, when clinical inflammation had subsided, an increase in both macrophages and granulocyte numbers in the chorioretina was observed. The cell numbers were always less than CsA-only treated animals. Despite the late cellular influx of monocytes/macrophages, rod outer segment (ROS) integrity as determined histologically, was maintained. Nasal antigen administration of retinal antigens in CsA-only treated animals (combined therapy group) protects against target organ damage without inhibiting activated T cell traffic to the eye. These results suggest that recruitment of macrophages to the target tissue is central to autoimmune target organ damage, the mechanisms of which are discussed.