Facial disgust in response to touches, smells, and tastes.
Disgust serves to defend the body from the entry of toxins and disease. Central to this function is a strong relationship with the proximate senses of smell, taste, and touch. Theory suggests that distinct and reflexive facial movements should be evoked by gustatory and olfactory disgusts, serving to impede bodily entry. While this hypothesis has received some support from facial recognition studies, whether smell and taste disgusts actually produce distinct facial responses, is unknown. Moreover, there has been no assessment of the facial response evoked by contact with disgusting objects. To address these issues, this study compared facial responses to touch, smell, and taste disgusts. Sixty-four participants were asked to touch, smell, and taste disgust-evoking and neutral control stimuli, and rate them on disgust, on two occasions-first, while they were video recorded and second, with facial electromyography (EMG) applied (measuring levator labii and corrugator supercilii activity). Videos were coded for facial expressions by humans and for facial action units (FAUs) by machines. Self-report data confirmed the disgust stimuli as highly disgusting. Comparison of the overall pattern of FAUs evoked by touch, smell, and taste disgusts, indicated two distinct facial disgusts for the proximate senses-a chemosensory and a tactile-disgust face. The nose wrinkle and upper lip raise were central to all facial disgusts, indicating their centrality to the disgust face. Several facial disgusts appear to exist, each with different functional goals. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Quantification and Clustering of Inorganic Nanoparticles in Wastewater Treatment Plants across Switzerland.
Single particle Inductively Coupled Plasma Time-of-Flight Mass Spectrometry (sp-ICP-TOFMS), in combination with online microdroplet calibration, allows the determination of particle number concentrations (PNCs) and the masses of elements in individual particles. Because sp-ICP-TOFMS analyses of environmental samples produce rich datasets composed of both single-metal nanoparticles (smNPs) and many types of multimetal NPs (mmNPs), interpretation of these data is well suited to automated analysis schemes. Here, we present a data analysis approach that includes automatic particle detection and elemental mass determinations based on online microdroplet calibration, and unsupervised clustering analysis of mmNPs to identify unique classes of NPs based on their element compositions. To demonstrate the potential of our approach, we analyzed wastewater samples collected from the influent and effluent of five wastewater treatment plants (WWTPs) across Switzerland. We determined elemental masses in individual NPs, as well as PNCs, to estimate the NP removal efficiencies of the individual WWTPs. Through hierarchical clustering, we identified NP classes conserved across all WWTPs; the most abundant particle types were those rich in Ce-La, Fe-Al, Ti-Zr, and Zn-Cu. In addition, we found particle types that are unique to one or a few WWTPs, which could indicate point sources of anthropogenic NPs.


Asymmetric dihydroxylation of d-glucose derived alpha,beta-unsaturated ester: synthesis of azepane and nojirimycin analogues.
The asymmetric dihydroxylation of a d-glucose derived alpha,beta-unsaturated ester 3 afforded syn vicinal diols in good to high diastereoselectivity. The conversion of these vicinal diols to the corresponding cyclic sulfate, regio-, stereoselective nucleophilic ring opening by sodium azide, and LAH reduction afforded amino heptitols 7a,b that were converted to azepane 1c,d and nojirimycin analogues 2c,d.


Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta.
Transforming growth factor-beta (TGF-beta) arrests growth of epithelial cells by inducing the transcription of p15(Ink4B), a cyclin-dependent kinase inhibitor. In this study, we demonstrate that p15(Ink4B) induction was mediated by a TGF-beta-induced complex of Smad2, Smad3, Smad4 and Sp1. Mutations in the Sp1- or Smad-binding sequences decreased or abolished the TGF-beta responsiveness of the p15(Ink4B) promoter. Interference with, or deficiency in, Smad2, Smad3 or Smad4 functions also reduced or abolished the TGF-beta-dependent p15(Ink4B) induction, whereas the absence of Sp1 reduced the basal and TGF-beta-induced p15(Ink4B) transcription. In the nucleoprotein complex, Smad2 interacted through its C-domain with Sp1 and enhanced the DNA binding and transcriptional activity of Sp1. Smad3 interacted indirectly with Sp1 through its association with Smad2 and/or Smad4, and bound directly to the p15(Ink4B) promoter. Finally, Smad4 interacted through its N-domain with Sp1. Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15(Ink4B) gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-beta.


Effect of COVID-19 pandemic on the fracture demographics: Data from a tertiary care hospital in Turkey.
The purpose of this study was to evaluate the types and the frequency of fractures, both in the pediatric and adult population during the COVID-19 pandemic and to find out the differences in comparison to the non-pandemic period. Patients who were admitted to the hospital with a new fracture during pandemic period (March 16 to May 22, 2020) were evaluated. Control group consisted of patients with new fractures admitted to the hospital in the same date range in 2018 and 2019. The patients were divided into two groups as ≤16 years old (group 1) and >16 years old (group 2). The evaluation was based on the age and gender of the patients and localization of the fractures. Hospitalized and surgically treated patients were evaluated as well. A total of 1794, 1747, and 670 fractures were observed in 2018, 2019, and 2020, respectively. Mean age of the patients in group 1 was found to have decreased in the pandemic period (p<0.001). The most common fracture sites in the pediatric population were the distal forearm and distal arm, whereas hand, distal forearm, and foot were most common fracture sites in adults, in both pandemic and non-pandemic periods. The proportional increase in femoral and tibial shaft fractures in group 1, and toe, tibial shaft, and metacarpal fractures in group 2 was found to be statistically significantly (p<0.05). In group 1; 6.8%, 7.7%, and 14.6% of the fractures were treated surgically in 2018, 2019, and 2020, respectively (p<0.001). For group 2, these rates were 20.1%, 18.6%, and 18.1%, respectively (p=0.67). There were 48, 29, and 26 open fractures in 2018, 2019 and 2020, respectively (p=0.066). In pandemic period, duration of the hospital stay was significantly shorter for distal humerus and proximal femur fractures (p values= 0.001 and 0.017, respectively). We observed that the frequency of fractures decreased by approximately one-third during the pandemic period compared with that in the non-pandemic period. The mean age of the patients with a fracture in the pediatric group was found to have decreased also. Finger fractures in pediatric patients and metatarsal fractures in adult patients were found to have significantly decreased during the pandemic. Level III, Diagnostic study.


Long Timestep Molecular Dynamics on the Graphical Processing Unit.
Molecular dynamics (MD) simulations now play a key role in many areas of theoretical chemistry, biology, physics, and materials science. In many cases, such calculations are significantly limited by the massive amount of computer time needed to perform calculations of interest. Herein, we present Long Timestep Molecular Dynamics (LTMD), a method to significantly speed MD simulations. In particular, we discuss new methods to calculate the needed terms in LTMD as well as issues germane to a GPU implementation. The resulting code, implemented in the OpenMM MD library, can achieve a significant 6-fold speed increase, leading to MD simulations on the order of 5 μs/day using implicit solvent models.


Evolutionary and population genomics of the cavity causing bacteria Streptococcus mutans.
Streptococcus mutans is widely recognized as one of the key etiological agents of human dental caries. Despite its role in this important disease, our present knowledge of gene content variability across the species and its relationship to adaptation is minimal. Estimates of its demographic history are not available. In this study, we generated genome sequences of 57 S. mutans isolates, as well as representative strains of the most closely related species to S. mutans (S. ratti, S. macaccae, and S. criceti), to identify the overall structure and potential adaptive features of the dispensable and core components of the genome. We also performed population genetic analyses on the core genome of the species aimed at understanding the demographic history, and impact of selection shaping its genetic variation. The maximum gene content divergence among strains was approximately 23%, with the majority of strains diverging by 5-15%. The core genome consisted of 1,490 genes and the pan-genome approximately 3,296. Maximum likelihood analysis of the synonymous site frequency spectrum (SFS) suggested that the S. mutans population started expanding exponentially approximately 10,000 years ago (95% confidence interval [CI]: 3,268-14,344 years ago), coincidental with the onset of human agriculture. Analysis of the replacement SFS indicated that a majority of these substitutions are under strong negative selection, and the remainder evolved neutrally. A set of 14 genes was identified as being under positive selection, most of which were involved in either sugar metabolism or acid tolerance. Analysis of the core genome suggested that among 73 genes present in all isolates of S. mutans but absent in other species of the mutans taxonomic group, the majority can be associated with metabolic processes that could have contributed to the successful adaptation of S. mutans to its new niche, the human mouth, and with the dietary changes that accompanied the origin of agriculture.


[Comparative study of adverse events between a posterolateral and a direct lateral approach for uncemented primary hip arthroplasty in patients over 65 years of age with femoral neck fractures].
Femoral neck fractures represent an important chapter in the practice of Traumatology, due to their high incidence, mainly among patients over 65 years of age; they account for around 65% of surgeries in Traumatology. Early function of patients who sustained a femoral neck fracture is of the utmost importance, as survival decreases within the first 12 months. The purpose of this paper is to compare the intra- and postoperative course of patients who underwent primary hip surgery using Hardinge's direct lateral approach versus Moore's posterolateral approach. 79 patients over 65 years of age with femur fractures were selected and divided into 2 groups according to the approach used. Hardinge's direct lateral approach was used in 32 patients and Moore's posterolateral approach in 47 patients, from March 2011 to April 2013. Considering the variables studied, a statistically significant difference (p < 0.005) was seen in the number of blood units transfused to patients in whom Hardinge's direct lateral approach was used. We agree with the literature in that there is a significant difference in the intra- and post-operative course of patients with femur neck fractures managed using Hardinge's direct lateral approach. A statistically significant difference was seen in the number of blood units transfused per patient, something that in our setting represents better resource utilization.


Autophagy is increased in postmortem brains of persons with HIV-1-associated encephalitis.
Autophagy is critical to maintaining cell homeostasis and is implicated in neurodegenerative diseases. This research examined the role of autophagy in human immunodeficiency virus type 1 (HIV-1)-associated encephalitis, the pathologic hallmark of neuroAIDS. The frontal cortex from 32 HIV-infected persons (12 without evidence HIV-1 encephalitis or clinical signs of central nervous system impairment and 20 with histopathological findings of HIV-1 encephalitis) and 8 persons without HIV infection and any neuropathology were examined postmortem. Green fluorescent protein-labeled (GFP) light chain 3 (LC3)-expressing neuroblastoma SK-N-SH cells treated with gp120 from CXCR4 and CCR5 viruses were also examined. Autophagic markers were assessed by means of Western blot analysis, transmission electron microscopy (TEM), and confocal microscopy. Autophagic proteins Beclin 1, Autophagy-related gene (Atg)-5, Atg-7, and LC3-II were significantly increased in brains with HIV-1 encephalitis (P < .05). These findings were confirmed by TEM and immunostaining of brain tissue. Additionally, levels of autophagic proteins and autophagosomes were increased in neuronal cells treated with both CXCR4- or CCR5-tropic HIV-1 gp120. No increase in the level of autophagy was observed in the brains of HIV-infected persons without HIV-1 encephalitis compared with the level in brains of HIV-uninfected persons. Postmortem brains with HIV-1 encephalitis exhibit increased markers of autophagy compared with brains from HIV-infected persons without HIV-1 encephalitis or HIV-uninfected control brains, which suggests that dysregulation of autophagy may be important in the pathogenesis of neuroAIDS.


Structural Characterization of the Full-Length Anti-CD20 Antibody Rituximab.
Rituximab, a murine-human chimera, is the first monoclonal antibody (mAb) developed as a therapeutic agent to target CD20 protein. Its Fab domain and its interaction with CD20 have been extensively studied and high-resolution atomic models obtained by X-ray diffraction or cryo-electron microscopy are available. However, the structure of the full-length antibody is still missing as the inherent protein flexibility hampers the formation of well-diffracting crystals and the reconstruction of 3D microscope images. The global structure of rituximab from its dilute solution is here elucidated by small-angle X-ray scattering (SAXS). The limited data resolution achievable by this technique has been compensated by intensive computational modelling that led to develop a new and effective procedure to characterize the average mAb conformation as well as that of the single domains. SAXS data indicated that rituximab adopts an asymmetric average conformation in solution, with a radius of gyration and a maximum linear dimension of 52 Å and 197 Å, respectively. The asymmetry is mainly due to an uneven arrangement of the two Fab units with respect to the central stem (the Fc domain) and reflects in a different conformation of the individual units. As a result, the Fab elbow angle, which is a crucial determinant for antigen recognition and binding, was found to be larger (169°) in the more distant Fab unit than that in the less distant one (143°). The whole flexibility of the antibody has been found to strongly depend on the relative inter-domain orientations, with one of the Fab arms playing a major role. The average structure and the amount of flexibility has been studied in the presence of different buffers and additives, and monitored at increasing temperature, up to the complete unfolding of the antibody. Overall, the structural characterization of rituximab can help in designing next-generation anti-CD20 antibodies and finding more efficient routes for rituximab production at industrial level.


Genome-wide fitness analyses of the foodborne pathogen Campylobacter jejuni in in vitro and in vivo models.
Campylobacter is the most common cause of foodborne bacterial illness worldwide. Faecal contamination of meat, especially chicken, during processing represents a key route of transmission to humans. There is a lack of insight into the mechanisms driving C. jejuni growth and survival within hosts and the environment. Here, we report a detailed analysis of C. jejuni fitness across models reflecting stages in its life cycle. Transposon (Tn) gene-inactivation libraries were generated in three C. jejuni strains and the impact on fitness during chicken colonisation, survival in houseflies and under nutrient-rich and -poor conditions at 4 °C and infection of human gut epithelial cells was assessed by Tn-insertion site sequencing (Tn-seq). A total of 331 homologous gene clusters were essential for fitness during in vitro growth in three C. jejuni strains, revealing that a large part of its genome is dedicated to growth. We report novel C. jejuni factors essential throughout its life cycle. Importantly, we identified genes that fulfil important roles across multiple conditions. Our comprehensive screens showed which flagella elements are essential for growth and which are vital to the interaction with host organisms. Future efforts should focus on how to exploit this knowledge to effectively control infections caused by C. jejuni.


Sample Complexity Bounds for Differentially Private Learning.
This work studies the problem of privacy-preserving classification - namely, learning a classifier from sensitive data while preserving the privacy of individuals in the training set. In particular, the learning algorithm is required in this problem to guarantee differential privacy, a very strong notion of privacy that has gained significant attention in recent years. A natural question to ask is: what is the sample requirement of a learning algorithm that guarantees a certain level of privacy and accuracy? We address this question in the context of learning with infinite hypothesis classes when the data is drawn from a continuous distribution. We first show that even for very simple hypothesis classes, any algorithm that uses a finite number of examples and guarantees differential privacy must fail to return an accurate classifier for at least some unlabeled data distributions. This result is unlike the case with either finite hypothesis classes or discrete data domains, in which distribution-free private learning is possible, as previously shown by Kasiviswanathan et al. (2008). We then consider two approaches to differentially private learning that get around this lower bound. The first approach is to use prior knowledge about the unlabeled data distribution in the form of a reference distribution chosen independently of the sensitive data. Given such a reference , we provide an upper bound on the sample requirement that depends (among other things) on a measure of closeness between and the unlabeled data distribution. Our upper bound applies to the non-realizable as well as the realizable case. The second approach is to relax the privacy requirement, by requiring only label-privacy - namely, that the only labels (and not the unlabeled parts of the examples) be considered sensitive information. An upper bound on the sample requirement of learning with label privacy was shown by Chaudhuri et al. (2006); in this work, we show a lower bound.


Deconstructing heterostyly: the evolutionary role of incompatibility system, pollinators, and floral architecture.
Darwin's early work on heterostyly and related style polymorphisms (the presence of two or three style morphs within a population) generated much interest to understand how precise interactions between ecological and genetic mechanisms influence the evolution of floral diversity. Here we tested three key hypotheses proposed to explain the evolution of heterostyly: (i) the presence of self-incompatibility; (ii) the role of pollinators in promoting dissasortative mating; and (iii) floral architecture, which restricts pollinators' movements and ensures more exact pollen deposition on their bodies. We combined data from experiments, field observations, and published studies to test whether evolution of style polymorphism in Narcissus is driven by the incompatibility system, pollinator guilds, or floral architecture, within a phylogenetic framework. Neither differences in pollinator environment nor the presence of genetic self-incompatibility were correlated with presence of style polymorphism. However, our results indicate that the evolution of style polymorphism was driven by the presence of a narrow and long floral tube.


Stage 0 sporulation gene A as a molecular marker to study diversity of endospore-forming Firmicutes.
In this study, we developed and validated a culture-independent method for diversity surveys to specifically detect endospore-forming Firmicutes. The global transcription regulator of sporulation (spo0A) was identified as a gene marker for endospore-forming Firmicutes. To enable phylogenetic classification, we designed a set of primers amplifying a 602 bp fragment of spo0A that we evaluated in pure cultures and environmental samples. The amplification was positive for 35 strains from 11 genera, yet negative for strains from Alicyclobacillus and Sulfobacillus. We also evaluated various DNA extraction methods because endospores often result in reduced yields. Our results demonstrate that procedures utilizing increased physical force improve DNA extraction. An optimized DNA extraction method on biomass pre-extracted from the environmental sample source (indirect DNA extraction) followed by amplification with the aforementioned primers for spo0A was then tested in sediments from two different sources. Specifically, we validated our culture-independent diversity survey methodology on a set of 8338 environmental spo0A sequences obtained from the sediments of Lakes Geneva (Switzerland) and Baikal (Russia). The phylogenetic affiliation of the environmental sequences revealed a substantial number of new clades within endospore-formers. This novel culture-independent approach provides a significant experimental improvement that enables exploration of the diversity of endospore-forming Firmicutes.


PCSK9 inhibitors.
The discovery of proprotein convertase subtilisin kexin 9 (PCSK9) has considerably changed the therapeutic options in the field of lipid management. PCSK9 reduces LDL receptor recycling, leading to a decrease of low-density lipoprotein cholesterol (LDL-C) receptors on the surface of hepatocytes and a subsequent increase of circulating LDL-C levels. In observational studies, the loss-of-function mutations of PCSK9 have been associated with a reduction of LDL-C levels and cardiovascular disease (CVD) events. In contrast, humans with high levels of PCSK9 have higher level of plasma LDL-C and significantly enhanced CVD risk during their lifetime, gain-of-function mutations on PCSK9 are, for instance, causatively associated with familial hypercholesterolaemia (FH). Inhibition of PCSK9 is therefore a promising therapeutic option for the lowering of LDL-C levels. The clinical development of human monoclonal antibodies against PCSK9 has progressed, with promising results reported from phase 2 clinical studies in patients with FH or intolerant to statin with LDL-C levels not on target levels. Phase I studies demonstrated safety and efficacy. In phase II, a 60%-70% reduction in LDL-C was observed, especially when subcutaneous injections were performed regularly every two weeks. No significant side effects were observed, with the exception of injection site reactions. Three large phase III programmes with the new anti PCSK9 antibodies are currently underway in patients with acute coronary syndrome (ACS) and LDL-C inadequately controlled by standard treatments. The main objective of these studies is to evaluate the effect of PCSK9 inhibition on the occurrence of CVD events in patients with ACS.


Rubella epidemiology in the Central African Republic, 2015-2016 and molecular characterization of virus strains from 2008-2016.
Rubella cases in the Central African Republic (CAF) are currently identified during measles surveillance. This study aimed to investigate rubella epidemiology between 2015 and 2016 and to provide baseline genotype data for monitoring future rubella control efforts. 831 measles IgM negative or equivocal sera from 2015/2016 were tested for rubella IgM antibodies and 350 rubella IgM positive sera collected between 2008 and 2016 were selected for PCR and sequencing. 411 of the 831 sera (49.5%) were rubella IgM positive and most cases (n=391, 95.1%) occurred between January and April. Most patients were between 5 and 9 years old (50.2%) and more than half of the rubella cases (56.7%) originated from the capital Bangui. Genotype information was obtained for 37 of the 350 selected rubella IgM-positive specimens, with the majority of the patients originating from Bangui (n=24, 64.9%) and sequences covering all years except 2009. Phylogenetic analysis identified genotypes 1E (n=12), 1G (n=5) and 2B (n=20), with 2B being detected from 2014 onwards. Our study confirmed the important role of rubella as a rash and fever disease in CAF and provided comprehensive data on rubella epidemiology and the first information on rubella genotypes in the country.


Aerobic and breathing exercises improve dyspnea, exercise capacity and quality of life in idiopathic pulmonary fibrosis patients: systematic review and meta-analysis.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea and limited exercise capacity. This systematic review aimed to synthesize evidence of exercise interventions during pulmonary rehabilitation that aim to improve exercise capacity, dyspnea, and health-related quality of life (HRQL) in IPF patients. Searches were performed in MEDLINE, Embase, CENTRAL, SPORTDiscus, PubMed and PEDro from inception to January 2019 using search terms for: (I) participants: 'IPF or interstitial lung disease'; (II) interventions: 'aerobic training or resistance training or respiratory muscle training'; and (III) outcomes: 'exercise capacity or dyspnea or health-related quality of life'. Two reviewers independently screened titles, abstracts and full texts to identify eligible studies. Methodological quality of studies was assessed using the Downs and Black checklist and meta-analyses were performed. Of 1,677 articles identified, 14 were included (four randomized controlled trials and 10 prospective pre-post design studies) that examined 362 patients receiving training and 95 control subjects. Exercise capacity was measured with the 6-minute walk distance, peak oxygen consumption, peak work rate, or endurance time for constant work rate cycling, which increased after exercise [aerobic exercise; aerobic and breathing exercises; aerobic and inspiratory muscle training (IMT) exercises] compared to the control groups. Dyspnea scores improved after aerobic and breathing exercises. HRQL also improved after aerobic exercise training alone or combined with breathing exercises. Aerobic training alone or combined with IMT or breathing exercises improved exercise capacity. Breathing exercises appears to complement exercise training towards improved dyspnea and HRQL in patients with IPF.


[Intoxication syndrome in acute pancreatitis].
Surgical treatment of 342 patients with an acute pancreatitis (AP), aged from 18 to 86 years, was conducted. Pathomorphism of the disease was analyzed, the elaborated classification and principles of complex treatment of intoxicational syndrome includes the affect toward the primary focus, the homeostasis correction and desintoxicational therapy conduction.


Guillan-Barré Syndrome after First Vaccination Dose against COVID-19: Case Report.
A number of neurological complications have been reported after the administration of flu vaccine, including Guillain-Barré syndrome (GBS), especially after vaccination against swine flu. Only facial nerve neuropathy has thus far been reported after vaccination against COVID-19. More recently, there was a case of an elderly woman with GBS. In our report, we describe a case of a 42-year-old, previously almost healthy male who developed sensory symptoms 14 days after the first dose of Pfizer vaccine. One week later, the patient developed right facial nerve palsy and lower limb weakness and was no longer able to walk. Albuminocytological dissociation was detected in the cerebrospinal fluid, and there were inflammatory radicular changes in MRI scans of the lumbosacral spine. EMG indicated significant demyelinating polyradiculoneuritis and no antibodies against gangliosides were demonstrated. A 5-day course of immunoglobulins at a dose of 2 g/kg lead to a significant improvement and the patient was soon able to walk. In conclusion, we report a case of Guillan-Barré syndrome after COVID-19 vaccine in a young patient with a rapid diagnosis and prompt administration of immunoglobulins.


Outcome of microscopic incomplete resection (R1) of colorectal liver metastases in the era of neoadjuvant chemotherapy.
Data from patients with colorectal liver metastases (CRLM) who received neoadjuvant chemotherapy before resection were reviewed and evaluated to see whether neoadjuvant chemotherapy influences the predictive outcome of R1 resections (margin is 0 mm) in patients with CRLM. Between January 2000 and December 2008, all consecutive patients undergoing liver resection for CRLM were analyzed. Patients were divided into those who did and did not receive neoadjuvant chemotherapy. The outcome after R0 (tumor-free margin >0 mm) and R1 (tumor-free margin 0 mm) resection was compared. A total of 264 were eligible for analysis. Median follow-up was 34 months. Patients without chemotherapy showed a significant difference in median disease-free survival (DFS) after R0 or R1 resection: 17 [95% confidence interval (CI) 10-24] months versus 8 (95% CI 4-12) months (P < 0.001), whereas in patients with neoadjuvant chemotherapy the difference in DFS between R0 and R1 resection was not significant: 18 (95% CI 10-26) months versus 9 (95% CI 0-20) months (P = 0.303). Patients without chemotherapy showed a significant difference in median overall survival (OS) after R0 or R1 resection: 53 (95% CI 40-66) months versus 30 (95% CI 13-47) months (P < 0.001). In patients with neoadjuvant chemotherapy, the median OS showed no significant difference: 65 (95% CI 39-92) months for the R0 group versus the R1 group, in whom the median OS was not reached (P = 0.645). In patients treated with neoadjuvant chemotherapy, R1 resection was of no predictive value for DFS and OS.


Identification of cervical radiculopathies: optimizing the electromyographic screen.
To determine the optimal electromyography screening examination of the upper limb that ensures detection of those cervical radiculopathies, which can be electrodiagnostically confirmed, yet minimizes the number of muscles studied. A prospective multicenter study was conducted from May 1996 to September 1997 at five institutions. Patients who were referred to participating electrodiagnostic laboratories with suspected cervical radiculopathy were recruited. A standard set of muscles were examined by needle electromyography. Patients with electrodiagnostically confirmed cervical radiculopathies, based on electromyography findings, were selected for analysis. Muscle screens were tested against this group to determine whether the screen identified the patients with radiculopathy. There were 101 patients with cervical radiculopathies representing all cervical root levels. When paraspinal muscles were one of the screening muscles, five muscle screens identified 90% to 98% of radiculopathies, six muscle screens identified 94% to 99%, and seven muscle screens identified 96% to 100%. When paraspinal muscles were not part of the screen, eight distal limb muscles recognized 92% to 95% of radiculopathies. This study demonstrated that six muscle screens including paraspinal muscles yielded consistently high identification rates. Studying additional muscles led to marginal increases in identification.


Quantification of furan and 5 alkylfurans with complete separation of 2-ethylfuran and 2,5-dimethylfuran isomers in cereals, coffee and Infant products by GC-MS.
Alkylfurans have been found concurrently to furan in thermally processed food and might add to the overall exposure, thereby increase the health concern. The analytical methods developed for these compounds are based on gas chromatography separation coupled to mass spectrometry. Two of those alkylfurans, 2,5-dimethylfuran and 2-ethylfuran, are isomers, for which accurate quantification require either complete chromatographic separation or tandem mass spectrometry (MS/MS) selectivity. A new chromatographic method is reported using the Supelco Equity-1 column, demonstrating complete baseline separation of these two isomers, with a shorter runtime when using single mass spectrometry. Full validation was performed successfully for furan, 2- and 3-methylfuran, 2-ethylfuran, 2,5-dimethylfuran and 2-pentylfuran on different food matrices with recovery rates in the range of 80-110 %, repeatability below 14%, intermediate reproducibility below 22% as well as expanded uncertainty under 50%.


Health risks during travel: a population-based study amongst the Hong Kong Chinese.
Between June 1998 and October 1998, a cross-sectional survey was carried out in Hong Kong on 369 Chinese residents who had travelled to mainland China or elsewhere overseas in the previous 12 months. The aim was to collect data on which intervention strategies to minimise travel-related illness among the public might be based. In interviews by telephone, information on travel-related health problems, factors related to such problems, and barriers in the acquisition of travel-health advice was gathered using a structured, pre-tested questionnaire. Most of the subjects had travelled to countries in the Asia-Pacific region, with mainland China as the most popular destination (44%), followed by Thailand (14%). Overall, 16% of the respondents had developed health (mainly alimentary and respiratory) problems during or after their travel, 8% had received pre-travel health advice but 59% reported taking some form of precaution against travel-related illness. Although only 12% had lost at least a day of work or travel because of their travel-related health problems, 40% perceived themselves at risk of future travel-related illness, and 68% said they were willing to pay for the prevention of travel-health problems. Younger travellers and those who perceived relatively few health risks in future travel were relatively more likely to have developed health problems. There appears to be a clear need to develop appropriate health-promotion strategies to reduce travel-health risks among the residents of Hong Kong and the rest of the Asia-Pacific region.


Opportunities and threats to contact lens practice: A global survey perspective.
To understand the views of contact lens (CL) practitioners across the globe regarding what they perceive as opportunities and threats in CL practice. A self-administered anonymised questionnaire, constructed in English and translated in six more languages, was distributed through reputed international professional bodies and academic institutions worldwide. The questionnaire included items on demographic characteristics, type of practice, and questions designed to explore practitioners' perspective on the future of their CL practice over the next five years. A total of 2408 valid responses were analysed. Multifocal CLs for presbyopia, CLs for myopia control, use of daily disposable (DD) CLs for occasional wear, and biocompatible materials to improve comfort were identified as promising areas of opportunities by practitioners (all 8/10). Respondents from North America, and Europe valued DDCLs for occasional wear moderately more favourable (Median: 9/10 for all) as compared to colleagues in Asia (Median: 8/10, p < 0.001), South America (Median: 8/10, p < 0.01), and Africa (Median: 8/10p < 0.01). Multifocal CLs for presbyopia was perceived as a better opportunity by practitioners in North America and Europe (Median: 9/10 for both), as well as in Australasia (Median: 8/10), in comparison to Asia, Africa, and Middle East (for all Median: 6/10, p < 0.001). Practitioners expressed concerns about the availability of CLs and CL prescriptions online without direct professional involvement (both 9/10). Overall, the most appealing opportunities for CL practice growth were identified in occasional use of DD CLs, biocompatible materials to reduce CL discomfort, multifocal CLs for presbyopia correction and management of myopia control with CLs. Lack of regulation in CL sales, especially online, seemed to be a constant threat. The insights from this study can be used to design targeted strategies to enhance CL practice across the globe and in specific geographical areas.


Effect of anaesthesia and surgery on the number of and mitogen-induced transformation of T- and B-lymphocytes.
Lymphocyte responses are affected by anaesthesia and surgery. 52 patients were studied to ascertain the affect on lymphocytic responses of thiopentone +N2O +O2, combined, diethyl ether +N2O +O2, and local anaesthesia in connection with surgery. The variables followed were: the leucocyte and differential count, the T- and B-lymphocyte count, and lymphocyte transformation by phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), and purified protein derivative of tuberculin (PPD) in cultures using separated lymphocytes and whole blood. Thiopentone +N2O +O2 anaesthesia together with uterine curettage caused a decrease in the total lymphocyte and T-lymphocyte counts. The Con A response of separated lymphocytes decreased, but the response to other mitogens increased. Combined anaesthesia with thiopentone +N2O +O2 + analgesic + muscle relaxant together with surgery decreased the total lymphocyte and T-lymphocyte counts. The separated lymphocytic and whole blood cultures revealed throughout a decrease in the mitogen and PPD responses. Diethyl ether +N2O +O2 and local anaesthesia, both together with surgery, produced no statistically significant changes in the total lymphocyte or in the T- and B-lymphocyte counts. The mitogen and PPD responses in these groups showed throughout a fall in lymphocyte transformation. Neither patient's age, sex, nor the duration of the anaesthesia or operation affected the magnitude of the changes. The increase in the leucocyte count and in the percentage of neutrophils and the decrease in the percentage of eosinophils and lymphocytes and in the mitogen- and PPD-induced lymphocytic responses increased with the severity of the operative trauma. A new finding was the correlation observed between the changes in the leucocyte and differential counts and the decrease of lymphocytic responses in whole blood culture. The findings in this study indicate that operative trauma determine the decrease in lymphocytic responses associated with anaesthesia and surgery.


Validity and Reliability of the Rear Foot Elevated Split Squat 5 Repetition Maximum to Determine Unilateral Leg Strength Symmetry.
Helme, M, Bishop, C, Emmonds, S, and Low, C. Validity and reliability of the rear foot elevated split squat 5 repetition maximum to determine unilateral leg strength symmetry. J Strength Cond Res 33(12): 3269-3275, 2019-The purpose of this study was to examine the validity and reliability of the rear foot elevated split squat (RFESS) 5 repetition maximum (5RM) test as a field method for measuring unilateral leg strength symmetry. As a validated method of testing symmetry, the RFESS 5RM may be used by strength and conditioning coaches and sports medicine staff to measure the presence of imbalances with minimal equipment and time. Twenty-six subjects (age = 23.8 ± 4.6 years, mass = 88.1 ± 10.7 kg, and height = 1.79 ± 0.1 m) with a minimum 2 years of strength and conditioning experience were recruited. After a familiarization session, subjects performed an incremental 5RM protocol on both legs, on 2 occasions where 3D motion and force data were collected. Moderate reliability of bar load symmetry was found between test and retest conditions correlation (intraclass coefficient = 0.73, 0.33-0.91) with no proportional bias between sessions. Validation of the exercise was analyzed using a correlation between asymmetries in mean set vertical ground reaction forces (vGRF) of the lead foot during the concentric phase, with bar load. When all maximal trials, from both test conditions, were analyzed, a most likely large positive correlation (0.57, 0.30-0.76) was found for mean set concentric lead foot vGRF. When a threshold level of load symmetry (96.54-103.46%) was applied, a most likely large positive correlation (r = 0.59, 0.14-0.84) between symmetry in lead foot vGRF was found in subjects who exceeded this limit. Conversely, analysis of subjects within the threshold produced unclear correlations. Findings of this study suggest the RFESS is a valid and reliable measure of unilateral leg strength symmetry. Practitioners are recommended to use this exercise to investigate the strength symmetry of athletes, but are guided to note that a threshold level of symmetry (96.54-103.46%) may be required to have been exceeded to indicate a true difference in vGRF production.


Elevated ovarian follicular apoptosis and heat shock protein-70 expression in white sucker exposed to bleached kraft pulp mill effluent.
Exposure of feral fish populations to bleached kraft pulp mill effluent (BKME) results in a variety of negative impacts on reproductive fitness including reduced ovarian development, reduced egg size, decreased fecundity with age, delayed sexual maturation, and alterations in reproductive endocrine homeostasis at multiple sites along the pituitary-gonadal axis. The present study provides evidence of elevated apoptotic DNA fragmentation and increased expression of the 70-kDa heat shock protein (HSP70) in ovarian follicular cells from prespawning white sucker (Catostomus commersoni) exposed to BKME. Apoptosis is the molecular mechanism responsible for ovarian follicular atresia which is involved in various stages of vertebrate ovarian development such as follicular recruitment, growth, differentiation, and regression. In mammals, induction of HSP70 is associated with inhibition of hormone-sensitive steroidogenesis and mediation of luteal regression. The 3'-end labeling of isolated ovarian follicular cell DNA revealed a 10-fold increase in the extent of apoptosis in BKME-exposed white sucker in comparison to follicles collected from a nearby reference site. Western blotting for ovarian follicular HSP70 levels showed increased expression of this protein in fish exposed to BKME. The elevated ovarian cell apoptosis and increased HSP70 expression in BKME-exposed fish were associated with reduced ovary size, decreased plasma testosterone, and increased plasma 17 beta-estradiol concentrations, but not induction of hepatic ethoxyresorufin O-deethylase activity. It is not known whether increased ovarian HSP70 expression in BKME-exposed fish is related to elevated apoptosis or represents a general response to environmental stress. Since apoptosis is regulated by several hormonal factors and conserved gene products, these data suggest that certain components of BKME increase ovarian cell apoptosis in fish via stimulation of cell death signaling. However, it is unclear whether BKME stimulates ovarian cell apoptosis directly or if this response occurs secondarily as a result of altered reproductive endocrine homeostasis.


Diagnosis and surgical treatment of pathologic nipple discharge using ultrasound-guided wire localization of focal ductal dilatation.
Nipple discharge is the third breast complaint after pain and lumps. The modern high-resolution ultrasound techniques are becoming more sensitive for the visualization of intraductal changes especially focal ductal dilatation (FDD), hypothesized as a radiographic manifestation of the lesion itself and that ultrasound-guided wire localization of this finding would enable identification and excision of the causative lesion. The aim of this study was to evaluate the safety, feasibility, efficiency and outcome of ultrasound-guided wire localization of FDD as possible cause of pathological nipple discharge (PND). The present study was conducted on 56 patients with PND presented to Surgical Oncology Unit at General Surgery Department, Tanta University Hospital from January 2018 to January 2019. The patients subjected to ultrasound-guided wire localization of FDD on the day of surgery, the involved duct was cannulated with a lacrimal duct probe, the targeted tissue was excised, and the specimen was sent for histopathological examination. The patients' age ranged between 26 and 71 years with a mean age of 48 years. The bloody nipple discharge was the commonest presenting symptom in 44 out of 56 patients (78.5%). The duct dilatation on study ultrasound ranged from 2.1 to 3.7 mm with a mean of 2.6 mm. Preoperative ultrasound-guided wire localization of the site of FDD was successfully performed in all cases. Papilloma alone founded in 40 out of 56 patients (71.4%), papilloma + ductal carcinoma in situ (DCIS) in six patients (10.7%), papilloma + invasive ductal carcinoma in six patients (10.7%), DCIS in two patients (3.6%) and duct ectasia in two patients (3.6%). Ultrasound-guided wire localization of FDD is an easy and safe technique for evaluation, precise localization, and targeted excision of the underlying lesions of PND.


Analysis of deep brain stimulation electrode characteristics for neural recording.
Closed-loop deep brain stimulation (DBS) systems have the potential to optimize treatment of movement disorders by enabling automatic adjustment of stimulation parameters based on a feedback signal. Evoked compound action potentials (ECAPs) and local field potentials (LFPs) recorded from the DBS electrode may serve as suitable closed-loop control signals. The objective of this study was to understand better the factors that influence ECAP and LFP recording, including the physical presence of the electrode, the geometrical dimensions of the electrode, and changes in the composition of the peri-electrode space across recording conditions. Coupled volume conductor-neuron models were used to calculate single-unit activity as well as ECAP responses and LFP activity from a population of model thalamic neurons. Comparing ECAPs and LFPs measured with and without the presence of the highly conductive recording contacts, we found that the presence of these contacts had a negligible effect on the magnitude of single-unit recordings, ECAPs (7% RMS difference between waveforms), and LFPs (5% change in signal magnitude). Spatial averaging across the contact surface decreased the ECAP magnitude in a phase-dependent manner (74% RMS difference), resulting from a differential effect of the contact on the contribution from nearby or distant elements, and decreased the LFP magnitude (25% change). Reductions in the electrode diameter or recording contact length increased signal energy and increased spatial sensitivity of single neuron recordings. Moreover, smaller diameter electrodes (500 µm) were more selective for recording from local cells over passing axons, with the opposite true for larger diameters (1500 µm). Changes in electrode dimensions had phase-dependent effects on ECAP characteristics, and generally had small effects on the LFP magnitude. ECAP signal energy and LFP magnitude decreased with tighter contact spacing (100 µm), compared to the original dimensions (1500 µm), with the opposite effect on the ECAP at longer contact-to-contact distances (2000 µm). Finally, acute edema reduced the single neuron and population ECAP signal energy, as well as LFP magnitude, and glial encapsulation had the opposite effect, after accounting for loss of cells in the peri-electrode space. This study determined recording conditions and electrode designs that influence ECAP and LFP recording fidelity.


Balancing between deaf and hearing worlds: reflections of mainstreamed college students on relationships and social interaction.
This qualitative study of the social aspects of mainstreaming from the perspective of deaf college students indicates that for some students, social adjustment to college is complicated by experiences of separation and alienation from both deaf and hearing peers. Data were collected through open-ended interviews with deaf students who had little or no previous experience with or exposure to deaf culture or language before their arrival at a mainstream college environment. Feelings of isolation, loneliness, and resentment were most intense during orientation and first year, when alienation from the deaf student community appeared to be caused by lack of sign language skills, unfamiliarity with norms and values of deaf culture, and perceived hostility from deaf peers. Simultaneous experiences of separation from hearing peers appeared to be caused by physical barriers inherent in the classroom, residence hall, and cafeteria environments, as well as by discrimination from hearing peers, who tended to stereotype deaf students. Findings suggest that those involved in the administration and delivery of postsecondary programs for the deaf should investigate the experiences of students who arrive on campus without knowledge of sign language or familiarity with deaf culture and evaluate currently existing programs and services designed to meet these students' needs.


[Carpal tunnel syndrome--surgical and anesthesiology considerations].
Carpal tunnel syndrome presents the most common peripheral nerve entrapment, and section of carpal transverse ligament is the most common procedure in peripheral nerve surgery. Favourable outcomes depend on several factors including correct diagnosis, careful patient selection, precise operative technique and appropriate postoperative care. The goal of this paper is to establish the most common causes of failed surgery analysing primary and secondary outcomes, and to give the possibility for better results in the future. Analysis was based on 250 operated patients. Primary outcome and secondary outcome 3 months after surgery was estimated. Total rate of complications was 8% with persistent complaints in 7 (35%) patients and recurrent symptoms in 13 (65%) patients.


Types of intra-muscular opioids for maternal pain relief in labour.
Pethidine is the most widely used intra-muscular opioid for the relief of labour pain. However concerns have been raised about its effectiveness and the possibility of depressing respiration in newborns. The objective of this review was to assess the effects of different opioids (and different doses of the same opioid) administered intra-muscularly in labour. We searched the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register (Cochrane Library, issue 4, 1997) and reference lists of articles. Randomised trials comparing the effects of different currently used opioids (and different doses of the same opioid) administered intramuscularly in labour for women who request systemic analgesia. Two reviewers assessed trial quality and extracted data. Analysis was based on the groups as randomly allocated. Sixteen trials were included. There were problems with methodological quality of some of the trials, and lack of consistency in the way various outcomes were reported. There was no evidence of a difference between pethidine and tramadol in terms of pain relief, interval to delivery, or instrumental or operative delivery. There appeared to be more adverse effects such as nausea and vomiting and drowsiness with pethidine. Maternal pain relief seemed almost identical between the meptazinol and pethidine groups, whether assessed as maternal satisfaction with pain relief, visual analogue scales, or use of other pain relief, but meptazinol gave rise to slightly more side effects. Maternal satisfaction with pain relief appeared similar for pentazocine and pethidine, with more frequent nausea and vomiting with pethidine. There is not enough evidence to evaluate the comparative efficacy and safety of the various opioids used for analgesia in labour.


cDNA microarray profiles of canine mammary tumour cell lines reveal deregulated pathways pertaining to their phenotype.
Mammary cancer is the most common type of cancer in female dogs with a lifetime risk of over 24% when dogs are not spayed. The elucidation of the complete canine genome opens new areas for development of cancer therapies. These should be tested first by in vitro models such as cell lines. However, to date, no canine mammary cell lines have been characterized by expression profiling. In this study, canine mammary tumour cell lines with histologically distinct primary tumours of origin were characterized using a newly developed canine cDNA microarray. Comparisons of gene expression profiles showed enrichment for distinct biological pathways and were related to biological properties of the cell lines such as growth rate and in vitro tumourigenicity. Additionally, gene expression profiles of cell lines also showed correspondence to their tumour of origin. Major differences were found in Wnt, cell cycle, cytokine/Rho-GTPase, alternative complement and integrin signalling pathways. Because these pathways show an overlap at the molecular level with those found in human breast cancer, the expression profiling of spontaneous canine mammary cancer may also function as a biological sieve to identify conserved gene expression or pathway profiles of evolutionary significance that are involved in tumourigenesis. These results are the basis for further characterization of canine mammary carcinomas and development of new therapies directed towards specific pathways. In addition these cell lines can be used to further investigate identified deregulated pathways and characterize until now unannotated genes.


Physiotherapy in Patients with Stress Urinary Incontinence: A Systematic Review and Meta-analysis.
Physiotherapy is the most commonly used treatment for stress urinary incontinence including pelvic floor muscle training, biofeedback, and electrical stimulation. This systematic review evaluated the effects of physiotherapy in patients with stress urinary incontinence compared with no treatment, placebo, sham, surgery, or other inactive control treatments. MEDLINE (via PubMed), The Cochrane Library (CENTRAL), Embase, Scopus, Web of Science, PEDro, and Trip Database were explored using applicable vocabularies for all English and Persian language investigations released from inception to January 2021. On one side, trials including physiotherapy of pelvic floor muscle training, biofeedback, and electrical stimulation and on the other, either no treatment, placebo, sham, surgery, or other inactive control treatments were included. Studies were assessed for appropriateness and methodological excellence. Two authors extracted data. Disagreements were resolved by a third opinion. Data were processed as described in the Joanna Briggs Institute Handbook. Twenty-nine trials with 2601 participants were found, but only 16 were included because of data heterogeneity. The results showed that physiotherapy interventions are better than no treatment in terms of urine leakage, but no difference was found for urinary incontinence severity. Also, physiotherapy showed favorable results over comparison groups for International Consultation on Incontinence Questionnaire, pad test, pelvic floor muscle function, and improvement outcomes. This systematic review supports the widespread use of pelvic physiotherapy as the first-line treatment for adult patients with stress urinary incontinence.


Concreteness of positive, negative, and neutral repetitive thinking about the future.
Consistent with assertions that the adaptiveness of repetitive thinking is influenced by both its valence and style, Stöber (e.g., Stöber & Borkovec, 2002) has argued that worry is characterized by a reduced concreteness of thought content and that the resulting abstractness contributes to its inhibition of some aspects of anxious responding. However, extant research does not provide a direct test of Stöber's reduced concreteness theory of worry. We sought to test Stöber's theory and to examine the adaptiveness of repetitive worrisome thinking by randomly assigning 108 participants to engage in five consecutive periods of repetitive thinking about positively, negatively, or neutrally valenced potential future events. Results based on coding of thought data indicated that (a) repetitive thinking became increasingly less concrete as periods progressed; (b) contrary to Stöber's theory, both negative and positive repetitive future thinking were more concrete than neutral repetitive future thinking (and did not differ from each other); and (c) abstractness of thought during negative repetitive future thinking was associated with reduced reports of imagery-based activity. Results based on self-reported affect indicated that negatively valenced repetitive future thinking was uniquely associated with initial decreases in anxious affect, followed by increased anxious affect that coincided with increased imagery-based activity. This suggests that worry is associated with a sequential mitigation of anxious meaning followed by a strengthening of anxious meaning over time. Theoretical and clinical implications of these findings are discussed.


Effects of body weight control on changes in blood pressure: three-year follow-up study in young Japanese individuals.
Numerous epidemiological studies have shown a close relationship between obesity and hypertension. However, there have been few reports on the relationship between changes in the body weight and blood pressure of lean to normal-weight young subjects. The purpose of this study was to investigate the effects of body weight control on blood pressure in lean to obese young Japanese individuals in a 3-year follow-up study. University students (3,558 males and 1,418 females, aged 18.6+/-0.8 in 1994) were classified into 4 groups according to the baseline body mass index (BMI), and were followed up for 3 years. Among male students, changes in body weight were significantly correlated with changes in blood pressure during the 3 years in all 4 BMI groups, and the correlation coefficient was larger in the group with higher baseline BMI. Positive correlations between changes in body weight and changes in heart rate were noted only in the obese and mildly-obese groups. Also in female students, positive correlations were observed between changes in body weight and changes in blood pressure in lean to obese groups. However, no correlations between changes in body weight and changes in heart rate were noted in any of the female groups. To summarize, close correlations were observed between changes in body weight and those in blood pressure during the 3 years in both male and female university students. These findings suggest the importance of body weight control not only in obese but also in normal to mildly-obese young subjects in reducing or preventing an increase in blood pressure. There could be, however, a gender difference in the effects of body weight change on heart rate.


Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway.
Adaptation of cardiomyocytes to chronic hypoxia in cyanotic patients remains unclear. Mitochondrial biogenesis is enhanced in myocardium from cyanotic patients, which is possibly an adaptive response. Erythropoietin (EPO) in blood and its receptor (EPOR) on cardiomyocytes are upregulated by chronic hypoxia, suggesting that EPO-EPOR interaction is increased, which is inferred to positively regulate mitochondrial biogenesis through protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signalling pathway. H9c2 cardiomyocytes were exposed to hypoxia (1% O(2)) for 1 week and treated with different doses of recombinant human erythropoietin (rhEPO). Mitochondrial number, mitochondrial DNA (mtDNA) copy number and peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1α) mRNA expression increased in a dose-dependent manner induced by rhEPO. Akt and eNOS were significantly phosphorylated by rhEPO. Both blocking Akt with Wortmannin and silencing eNOS expression with shRNA plasmid decreased the mtDNA copy number and PGC-1α mRNA expression induced by rhEPO. Blocking Akt was associated with the decreased phosphorylation of Akt and eNOS. RNA interference led to a reduction in the total and phosphorylated proteins of eNOS. Thus EPO enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia, at least partly through Akt/eNOS signalling, which might be an adaptive mechanism of cardiomyocytes associated with the increased EPO-EPOR interaction in patients with cyanotic congenital heart disease (CCHD).


Activity of indenoisoquinolines against African trypanosomes.
African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.


[Metabolic syndrome and rheumatic diseases].
To characterize prevalence and features of rheumatic diseases in patients with metabolic syndrome, metabolic disturbances in patients with rheumatic diseases (RD), to ascertain their most frequent variants and characteristics. After examination of 1291 therapeutic patients 19 to 79 years of age for metabolic syndrome (MS), those with MS were screened for RD. In parallel, 1212 RD patients were studied for associated pathology: arterial hypertension, coronary heart disease, obesity, dyslipidemia, hyperuricemia and other components of MS. A separate electronic matrix was created for each of the two groups. Statistics were obtained using standard programs Statistica 6.0 and MS Excel 2000 for Windows XP 2000. MS was detected in 317 (24.6%) patients seeking medical advice (mean age 54.11 +/- 0.59 years). MS was complete in 272 (85.8%) patients, 287 (90.5%) had arthralgia, 131 (41.3%)--episodes of painful joints swelling in the presence of family history. RD were detected in 295 (93.1%) MS patients. Osteoarthrosis, osteochondrosis and systemic osteoporosis occurred most often. Various metabolic disorders occurred in all the examinees with RD. The disorders were most pronounced in patients with gout and osteoarthrosis. MS patients comprise a group of a high risk for RD, especially gout and osteoarthrosis.


Polyelectrolyte complexes between (cross-linked) N-carboxyethylchitosan and (quaternized) poly[2-(dimethylamino)ethyl methacrylate]: preparation, characterization, and antibacterial properties.
Novel polyelectrolyte complexes (PECs) between N-carboxyethylchitosan (CECh) and well-defined (quaternized) poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) have been obtained. The modification of chitosan into CECh allows the preparation of PECs in a pH range in which chitosan cannot form complexes. The CECh/PDMAEMA complex is formed in a narrow pH range around 7. The quaternization of the tertiary amino groups of PDMAEMA enables complex formation with CECh both in neutral and in alkaline medium. Cross-linked CECh is also capable of forming complexes with (quaternized) PDMAEMA. The antibacterial activity of (cross-linked) CECh, (quaternized) PDMAEMA, and their complexes against Escherichia coli has been evaluated. In contrast to (quaternized) PDMAEMA, (cross-linked) CECh exhibits no antibacterial activity. The complex formation between cross-linked CECh and (quaternized) PDMAEMA results in a loss of the inherent antibacterial activity of the latter in neutral medium. In acidic medium, the complexes exhibit strong antibacterial activity due to complex disintegration and release of (quaternized) PDMAEMA.


Cutting edge: attrition of Plasmodium-specific memory CD8 T cells results in decreased protection that is rescued by booster immunization.
Sterile protection against infection with Plasmodium sporozoites requires high numbers of memory CD8 T cells. However, infections with unrelated pathogens, as may occur in areas endemic to malaria, can dramatically decrease pre-existing memory CD8 T cells. It remains unknown whether unrelated infections will compromise numbers of Plasmodium-specific memory CD8 T cells and thus limit the duration of antimalarial immunity generated by subunit vaccination. We show that P. berghei circumsporozoite-specific memory CD8 T cells underwent significant attrition in numbers in mice subjected to unrelated infections. Attrition was associated with preferential loss of effector memory CD8 T cells and reduced immunity to P. berghei sporozoite challenge. However, and of relevance to deployment of Plasmodium vaccines in areas endemic to malaria, attrition of memory CD8 T cells was reversed by booster immunization, which restored protection. These data suggest that regular booster immunizations may be required to sustain protective vaccine-induced Plasmodium-specific memory CD8 T cells in the face of attrition caused by unrelated infections.


Treatment-induced remission in rheumatoid arthritis patients is characterized by a reduction in macrophage content of synovial biopsies.
To document the change in synovial membrane macrophage and T-lymphocyte content in rheumatoid arthritis (RA) patients who achieve remission induced by disease-modifying anti-rheumatic drugs (DMARDs). Arthroscopic synovial biopsies were taken from four to seven sites around a knee joint in 13 patients with RA before and at regular intervals after commencing treatment with a DMARD. The cellular content of synovial membrane biopsies taken at regular intervals for a period of up to 3 yr after commencing treatment was quantitated by routine histopathology and immunohistochemical labelling with anti-macrophage (CD68) and anti-T lymphocyte (UCHL-1) antibodies. Synovial biopsies were quantitated with a validated semiquantitative scoring system and video image analysis. Nine patients obtained clinical remission, as defined by American College of Rheumatology (ACR) criteria. The changes that occurred in the synovial biopsies included a reduction in lining layer thickness, reduced vascularity and cellular infiltrate. The most significant reduction in cellular infiltrate was in the lining layer macrophages, with less dramatic change in the subintimal macrophage infiltrate. Although there was a reduction in CD45 Ro-positive T lymphocytes in the synovial membranes of patients who attained ACR-defined disease remission, it was less significant than the reduction in macrophage content of the synovial membranes and tended to plateau at a reduced level of T-cell infiltration. Remission in RA patients is characterized by a predominant reduction in macrophage content of the synovial membrane, suggesting that current DMARDs may target this cell and its inflammatory mediators.


Laparoscopic gastric wedge resection for Dieulafoy's disease following preoperative endoscopic localization with India ink and endoscopic clips.
Dieulafoy's lesion is a vascular malformation, usually of the stomach but occasionally of the small or large bowel. It is an uncommon, but clinically significant, source of upper gastrointestinal hemorrhage. Three cases have been reported in the literature of laparoscopic gastric wedge resection of these lesions by using intraoperative endoscopic localization. We present the only reported case of preoperative endoscopic localization of a Dieulafoy's lesion with India ink and an endoscopic clip before laparoscopic resection. We present an 82-year-old female patient who presented to the emergency department with 3 episodes of hematemesis. Esophagogastroduodenoscopy revealed an actively bleeding Dieulafoy's lesion in the fundus of the stomach along the greater curvature, which was controlled endoscopically. However, the patient had a recurrent episode of bleeding. Repeat endoscopy was performed and the lesion was tagged with 2 endoscopic clips and marked with India ink. A laparoscopic wedge resection was performed after the India ink was identified in the fundus. The patient did well postoperatively. Preoperative localization of a Dieulafoy's lesion with India ink and endoscopic clips before laparoscopic wedge resection is a feasible procedure. Therefore, no need exists for intraoperative endoscopy to aid in the localization, as previously reported.


A novel role for thrombopoietin in regulating osteoclast development in humans and mice.
Emerging data suggest that megakaryocytes (MKs) play a significant role in skeletal homeostasis. Indeed, osteosclerosis observed in several MK-related disorders may be a result of increased numbers of MKs. In support of this idea, we have previously demonstrated that MKs increase osteoblast (OB) proliferation by a direct cell-cell contact mechanism and that MKs also inhibit osteoclast (OC) formation. As MKs and OCs are derived from the same hematopoietic precursor, in these osteoclastogenesis studies we examined the role of the main MK growth factor, thrombopoietin (TPO) on OC formation and bone resorption. Here we show that TPO directly increases OC formation and differentiation in vitro. Specifically, we demonstrate the TPO receptor (c-mpl or CD110) is expressed on cells of the OC lineage, c-mpl is required for TPO to enhance OC formation in vitro, and TPO activates the mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappaB signaling pathways, but does not activate the PI3K/AKT pathway. Further, we found TPO enhances OC resorption in CD14+CD110+ human OC progenitors derived from peripheral blood mononuclear cells, and further separating OC progenitors based on CD110 expression enriches for mature OC development. The regulation of OCs by TPO highlights a novel therapeutic target for bone loss diseases and may be important to consider in the numerous hematologic disorders associated with alterations in TPO/c-mpl signaling as well as in patients suffering from bone disorders.


Microparticle surface modifications targeting dendritic cells for non-activating applications.
Microparticulate systems for delivery of therapeutics to DCs for immunotherapy have gained attention recently. However, reports addressing the optimization of DC-targeting microparticle delivery systems are limited, particularly for cases where the goal is to deliver payload to DCs in a non-activating fashion. Here, we investigate targeting DCs using poly (d lactide-co-glycolide) microparticles (MPs) in a non-stimulatory manner and assess efficacy in vitro and in vivo. We modified MPs by surface immobilizing DC receptor targeting molecules - antibodies (anti-CD11c, anti-DEC-205) or peptides (P-D2, RGD), where anti-CD11c antibody, P-D2 and RGD peptides target integrins and anti-DEC-205 antibody targets the c-type lectin receptor DEC-205. Our results demonstrate the modified MPs are neither toxic nor activating, and DC uptake of MPs in vitro is improved by the anti-DEC-205 antibody, the anti-CD11c antibody and the P-D2 peptide modifications. The P-D2 peptide MP modification significantly improved DC antigen presentation in vitro both at immediate and delayed time points. Notably, MP functionalization with P-D2 peptide and anti-CD11c antibody increased the rate and extent of MP translocation in vivo by DCs and MΦs, with the P-D2 peptide modified MPs demonstrating the highest translocation. This work informs the design of non-activating polymeric microparticulate applications such as vaccines for autoimmune diseases.


[Studies of relationship between the melanocortin-3 receptor gene and body weight in chicken for high and low weight lines' intercross].
Genetic studies in mice have demonstrated a complementary role for the melanocortin-3 receptor (MC3R) and MC4R in the control of energy balance. Knockout of the MC3R in mice revealed an exclusively metabolic syndrome and increased fat mass. In the present study, we found a total of 5 novel single nucleotide polymorphisms (SNPs) of the MC3R gene in the chickens of high weight (HW) and low weight (LW) lines from divergently selected for high or low body weight at 8 weeks of age in White Plymouth Rock. Only one of the 5 SNPs led to amino acid substitution (Leu-->Arg) in HW and LW lines animals: a T/G substitution at nucleotide (nt) position 452 of coding sequence. Three of the 5 SNPs distinguished the birds from HW and LW lines: an A/G substitution at nt position 549 in LW line, an A/G substitution at nt position 882 in HW line, and a C/T substitution at nt position 894 in LW line, respectively. Another SNP was presented only in one of two HW line animals: a C/T substitution at nt position 564. Of the 5 SNPs, only A/G polymorphism at nt position 549 is located within a Dde I restriction enzyme recognition site. We designed a PCR-RFLP test based on the enzyme Dde I and screened the chickens for HW and LW lines' intercross. Analysis of variance revealed a significant influence of the MC3R genotype on body weight in the chickens for both sex and abdominal fat mass in male chickens. The result suggests that the MC3R as a candidate gene can explain significant difference for body weight in the intercross chickens.


Amnesia produced by electroconvulsive shock or cycloheximide: conditions for recovery.
Retrograde amnesia for a passive avoidance response was produced in rats by electroconvulsive shock and in mice by cycloheximide, an inhibitor of protein synthesis. One day after training the memory could be restored if a "reminder" of the original foot shock was given after the retention test on which the amnesia was demonstrated. Memory did not return if the reminder was given without the prior retention test or if the reminder and the test were separated by 23 hours.


Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs.
The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results, we designed a randomized phase III trial to investigate the FLASH effect in cat patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-radiotherapy was studied on mini pigs by using large field irradiation. Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to two arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10 × 4.8 Gy (90% isodose); arm 2 used 1 × 30 Gy (90% isodose) FLASH. Mini pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH. In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis, which occurred 9 to 15 months after radiotherapy in 3 of 7 cats treated with FLASH-radiotherapy (43%), as compared with 0 of 9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded, but severe late skin necrosis occurred in a volume-dependent manner (7-9 months), which later resolved. The reported outcomes point to the caveats of translating single-high-dose FLASH-radiotherapy and emphasizes the need for caution and further investigations. See related commentary by Maity and Koumenis, p. 3636.


Combination dolutegravir-abacavir-lamivudine in the management of HIV/AIDS: clinical utility and patient considerations.
The current standard of care for human immunodeficiency virus (HIV) treatment is a three-drug regimen containing a nonnucleoside reverse transcriptase inhibitor, a protease inhibitor, or an integrase strand transfer inhibitor (INSTI) plus two nucleoside/tide reverse transcriptase inhibitors. Given their potency, safety, and distinctive mechanism of action, INSTIs represent an important advance in HIV type 1 (HIV-1) therapy. Dolutegravir (DTG) is a new-generation INSTI recently approved for the treatment of HIV-1-infected adult patients, with distinct advantages compared with other available antiretroviral agents. In well-designed, large clinical trials, DTG-containing regimens have demonstrated either noninferiority or superiority to current first-line agents such as raltegravir-, darunavir/ritonavir-, and efavirenz-containing regimens. The favorable safety profile, low potential for drug interactions, minimal impact on lipids, good tolerability, and high resistance barrier of DTG makes this compound one of the preferred choices for HIV therapy in multiple clinical scenarios, including treatment-naïve and treatment-experienced patients. DTG is the only antiretroviral drug not yet associated with de novo emergence of resistance mutations in treatment-naïve individuals. However, data from in vitro studies and clinical trial suggest the possibility of cross-resistance between first- and second-generation INSTIs. Even though these profiles are infrequent at the moment, they need to be monitored in all current patients treated with INSTIs. With its potent activity, good tolerability, simplicity of dosing, and minimal drug interaction profile, DTG will likely play a major role in the management of patients with HIV-1 infection. On the basis of clinical trial data, current guidelines endorse DTG in combination with nucleoside/tide reverse transcriptase inhibitors as one of the recommended regimens in antiretroviral therapy-naïve patients. Most of the favorable clinical experiences from clinical trials are based on the combination of DTG with abacavir/lamivudine, and DTG is planned to be coformulated with abacavir/lamivudine. This will provide a further advantage, given that single tablet regimens are associated with higher adherence rates as well as improvement in quality of life and enhanced patient preference.


Discrete electrostatic charge transfer by the electrophoresis of a charged droplet in a dielectric liquid.
We have experimentally investigated the electrostatic charging of a water droplet on an electrified electrode surface to explain the detailed inductive charging processes and use them for the detection of droplet position in a lab-on-a-chip system. The periodic bouncing motion of a droplet between two planar electrodes has been examined by using a high-resolution electrometer and an image analysis method. We have found that this charging process consists of three steps. The first step is inductive charge accumulation on the opposite electrode by the charge of a droplet. This induction process occurs while the droplet approaches the electrode, and it produces an induction current signal at the electrometer. The second step is the discharging of the droplet by the accumulated induced charge at the moment of contact. For this second step, there is no charge-transfer detection at the electrometer. The third step is the charging of the neutralized droplet to a certain charged state while the droplet is in contact with the electrode. The charge transfer of the third step is detected as the pulse-type signal of an electrometer. The second and third steps occur simultaneously and rapidly. We have found that the induction current by the movement of a charged droplet can be accurately used to measure the charge of the droplet and can also be used to monitor the position of a droplet under actuation. The implications of the current findings for understanding and measuring the charging process are discussed.


Effectiveness of a multi-facetted blended eHealth intervention during intake supporting patients and clinicians in Shared Decision Making: A cluster randomised controlled trial in a specialist mental health outpatient setting.
To investigate the effectiveness of a multi-facetted blended eHealth intervention, called SDM-Digital Intake (SDM-DI), in which patients and clinicians are supported in Shared Decision Making during the intake process. The study is a two-arm matched-paired cluster Randomised Controlled Trial in a specialist mental health outpatient setting with two conditions: SDM-DI and Intake As Usual (IAU). Four intake teams were allocated to each arm. All patients who followed an intake, were asked to participate if they were capable to complete questionnaires. Decisional Conflict (DC), referring to patients' engagement and satisfaction with clinical decisions, was the primary outcome. Secondary outcomes were patient participation, applying Shared Decision Making (SDM), working alliance, treatment adherence and symptom severity. Effects were measured at two weeks (T1) and two months (T2) after intake. Multilevel regression and intention-to-treat analyses were used. Additionally, the influence of subgroups and intervention adherence on DC were explored. At T1, 200 patients participated (47% intervention, 53% control), and at T2 175 patients (47% intervention, 53% control). At T1 and T2, no differences were found between conditions on DC. Subgroup analyses showed that effects of SDM-DI on DC were not modified by primary diagnoses mood, anxiety and personality disorders. Compared to IAU, at T2, patients reported positive effects of SDM-DI on SDM (β 7.553, p = 0.038, 95%CI:0.403-14.703, d = 0.32) and reduction of symptoms (β -7.276, p = 0.0497, 95%CI:-14.544--0.008, d = -0.43). No effects were found on patient participation, working alliance and treatment adherence. Exploratory analyses demonstrated that if SDM was applied well, patients reported less DC (β = -0.457, p = 0.000, 95%CI:-0.518--0.396, d = -1.31), which was associated with better treatment outcomes. Although, this trial fails to demonstrate that SDM-DI by itself is sufficient to reduce DC, the results are encouraging for further efforts in improving and implementing the SDM intervention.


Three phenotypes of anti-N-methyl-D-aspartate receptor antibody encephalitis in children: prevalence of symptoms and prognosis.
Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is becoming an increasingly recognized cause of encephalopathy in individuals previously presumed to have viral encephalitis. Various manifestations of this disease include altered mental status, behavioral changes, seizures, and movement disorders. We have noted three distinct subtypes of this disease which appear to have differential responses to immunotherapies and differences in prognosis. We report eight patients observed at our children's hospital from 2009 through 2013 who appear to clearly fall into one of our three clinical categories. To find comparable articles reflecting this classification, we then performed a MEDLINE search of all articles involving the subject heading "anti-NMDA receptor encephalitis" or just the keyword phrase "NMDA encephalitis," and we found 162 articles to review. Twenty-two articles were eliminated due to basic science, and we were able to review 105 of the remaining articles, most of which were case reports or case series, although a few were larger reviews. For the sake of our review, we defined type 1 or "classic" anti-NMDA receptor antibody encephalitis as having a duration of <60 days and being characterized predominantly by a catatonic or stuporous state, type 2 or psychiatric-predominant anti-NMDA receptor antibody encephalitis as having no noteworthy catatonic or stuporous state in addition to the presence of predominantly behavioral and psychiatric symptoms, and type 3 or catatonia-predominant anti-NMDA receptor antibody encephalitis as having a duration of ≥60 days in a predominantly catatonic or stuporous state. We note that the poorest responders, even to aggressive immunotherapies, are the patients with catatonia-persistent type anti-NMDA receptor antibody encephalitis, which has, as its hallmark, prolonged periods of severe encephalopathy. Patients with predominantly psychiatric symptoms, which we call the psychiatric-predominant anti-NMDA receptor antibody encephalitis, have had excellent responses to plasma exchange or other immunotherapies and appear to have the least residual deficits at follow-up. Patients with fairly equal representations of periods of altered mental status, behavioral problems, and movement disorders appear to have an intermediate prognosis and likely require early aggressive immunotherapy. In our series, we discuss representative examples of these clinical subtypes and their associated outcomes, and we suggest that tracking these subtypes in future cases of anti-NMDA receptor antibody encephalitis might lead to better understanding and better risk stratification with regard to immunotherapy decisions.


Autografting of Renal Progenitor Cells Ameliorates Kidney Damage in Experimental Model of Pyelonephritis.
Current therapies for pyelonephritic renal damage have severe limitations; stem cells may offer an exciting potential in regenerating nephrology. We aimed to investigate the feasibility of direct intrarenal injection of autologous renal progenitor cells (RPCs; originated from epithelial cells in Bowman's capsule) in chronic pyelonephritis rat model. Twenty-seven rats were divided into three groups. The control group (GI, n = 3) underwent sham subcapsular injection of isotonic saline. Pyelonephritis was induced in the right kidney of the remaining 24 rats and isotonic saline (GII, n = 12) or labeled autologous RPCs, obtained from a biopsy of left kidney (GIII, n = 12), were injected into the subcapsular space 6 weeks later. At 7, 14, 28, and 60 days, dimercaptosuccinic acid scan was performed in three animals of each group at every interval and subsequently renal sections were obtained for the evaluation of tubular and glomerular regeneration and proliferation. Cell transplantation resulted in the reduction of tubular and glomerular atrophy after 2 weeks. The transplanted cells were observed in the reconstructed region of the kidneys as evidenced by the presence of fluorescently labeled cells both in tubules and glomeruli. We also observed significant decrease in interstitial fibrosis in the fourth week and there were higher amount of Ki-67-positive cells in GIII. Notably, the right renal tissue integrity was significantly improved in this group and revealed normal cortical function on day 60. Transplanting RPCs showed the potential for partial augmentation of kidney structure and function in pyelonephritis. Cellular repair was seen predominantly in the proximal tubule, the major site of injury in pyelonephritis. Our findings may pave the way toward the future regeneration of renal scarring of pyelonephritis in children.


The thriving of older people assessment scale: Psychometric evaluation and short-form development.
To evaluate the psychometric properties and performance of the 32-item Thriving of Older People Assessment Scale (TOPAS) and to explore reduction into a short-form. The 32-item TOPAS has been used in studies of place-related well-being as a positive measure in long-term care to assess nursing home resident thriving; however, item redundancy has not previously been explored. Cross-sectional study. Staff members completed the 32-item TOPAS as proxy raters for a random sample of Swedish nursing home residents (N = 4,831) between November 2013 - September 2014. Reliability analysis, exploratory factor analysis and item response theory-based analysis were undertaken. Items were systematically identified for reduction using statistical and theoretical analysis. Correlation testing, means comparison and model fit evaluation confirmed scale equivalence. Psychometric properties of the 32-item TOPAS were satisfactory and several items were identified for scale reduction. The proposed short-form TOPAS exhibited a high level of internal consistency (α = 0.90) and strong correlation (r = 0.98) to the original scale, while also retaining diversity among items in terms of factor structure and item difficulties. The 32-item and short-form TOPAS' indicated sound validity and reliability to measure resident thriving in the nursing home context. There is a lack of positive life-world measures for use in nursing homes. The short-form TOPAS indicated sound validity and reliability to measure resident thriving, providing a feasible measure with enhanced functionality for use in aged care research, assessments and care planning for health-promoting purposes in nursing homes.


The acute effect of alcohol on decision making in social drinkers.
Many studies have reported the long-term adverse effects of alcohol on executive cognitive function in chronic alcohol abusers, yet little research has investigated the acute effects of alcohol in social drinkers. Studies on acute effects report alcohol-induced deficits on tasks that require executive cognitive processes, with alcohol acting to increase preservative errors and reduce planning. The present investigation examines the acute effects of a moderate dose of alcohol on a decision-making task that involves participants making a forced choice between two simultaneously presented binary-outcome gambles. Alcohol (0.6 g/kg) or placebo was administered to 32 social drinkers. Participants completed the task, making a total of 80 decisions about gambles that varied in the magnitude of expected gains, losses and the probability with which these outcomes were delivered. Participants also chose between gambles probing identified non-normative biases in human decision making, namely, risk aversion for choosing between gains and risk seeking for choosing between losses. All participants picked the experimental gamble more frequently when the probability of winning was high vs low, when the gains were large vs small and when the losses were small vs large; the alcohol group had an impaired ability to factor in the magnitude of gains and the likelihood of winning when the losses were large. Deliberation time did not differ between the groups. These data suggest that alcohol given acutely impairs risky decision making. In particular, alcohol impairs one's ability to alter responding in light of changing prospective rewards in order to make favourable decisions.


Components of gating charge movement and S4 voltage-sensor exposure during activation of hERG channels.
The human ether-á-go-go-related gene (hERG) K(+) channel encodes the pore-forming α subunit of the rapid delayed rectifier current, IKr, and has unique activation gating kinetics, in that the α subunit of the channel activates and deactivates very slowly, which focuses the role of IKr current to a critical period during action potential repolarization in the heart. Despite its physiological importance, fundamental mechanistic properties of hERG channel activation gating remain unclear, including how voltage-sensor movement rate limits pore opening. Here, we study this directly by recording voltage-sensor domain currents in mammalian cells for the first time and measuring the rates of voltage-sensor modification by [2-(trimethylammonium)ethyl] methanethiosulfonate chloride (MTSET). Gating currents recorded from hERG channels expressed in mammalian tsA201 cells using low resistance pipettes show two charge systems, defined as Q(1) and Q(2), with V(1/2)'s of -55.7 (equivalent charge, z = 1.60) and -54.2 mV (z = 1.30), respectively, with the Q(2) charge system carrying approximately two thirds of the overall gating charge. The time constants for charge movement at 0 mV were 2.5 and 36.2 ms for Q(1) and Q(2), decreasing to 4.3 ms for Q(2) at +60 mV, an order of magnitude faster than the time constants of ionic current appearance at these potentials. The voltage and time dependence of Q2 movement closely correlated with the rate of MTSET modification of I521C in the outermost region of the S4 segment, which had a V(1/2) of -64 mV and time constants of 36 ± 8.5 ms and 11.6 ± 6.3 ms at 0 and +60 mV, respectively. Modeling of Q(1) and Q(2) charge systems showed that a minimal scheme of three transitions is sufficient to account for the experimental findings. These data point to activation steps further downstream of voltage-sensor movement that provide the major delays to pore opening in hERG channels.


Successful twin pregnancy after renal transplant maintained on cyclosporine A immunosuppression.
Cyclosporine A has recently been reported to be an effective immunosuppressant agent for use in renal allograft recipients. Questions have been raised regarding its effects during pregnancy, in light of an increased life span and return of fertility in renal transplant patients. A preterm delivery is reported in a cadaveric renal allograft recipient chronically immunosuppressed with cyclosporine A and methylprednisolone. Dizygotic twins were delivered at 35 weeks' gestation, weighing 2452 and 2386 g. Maternal cyclosporine A levels were determined weekly by whole blood radioimmunoassay, with little increase in requirement found before delivery. No indication of maternal renal compromise was apparent, as evidenced by stable weekly creatinine clearance studies. Cyclosporine A, at the doses used, was passed transplacentally, with cord blood values of 34 and 57% of the maternal cyclosporine A level found at delivery. No adverse effects were noted at birth in the average for gestational age neonates, nor at nine-month follow-up evaluation. Given careful monitoring, cyclosporine A may be an effective immunosuppressant agent for use in pregnancies complicated by renal transplantation.


Developing and user-testing Decision boxes to facilitate shared decision making in primary care--a study protocol.
Applying evidence is one of the most challenging steps of evidence-based clinical practice. Healthcare professionals have difficulty interpreting evidence and translating it to patients. Decision boxes are summaries of the most important benefits and harms of diagnostic, therapeutic, and preventive health interventions provided to healthcare professionals before they meet the patient. Our hypothesis is that Decision boxes will prepare clinicians to help patients make informed value-based decisions. By acting as primers, the boxes will enhance the application of evidence-based practices and increase shared decision making during the clinical encounter. The objectives of this study are to provide a framework for developing Decision boxes and testing their value to users. We will begin by developing Decision box prototypes for 10 clinical conditions or topics based on a review of the research on risk communication. We will present two prototypes to purposeful samples of 16 family physicians distributed in two focus groups, and 32 patients distributed in four focus groups. We will use the User Experience Model framework to explore users' perceptions of the content and format of each prototype. All discussions will be transcribed, and two researchers will independently perform a hybrid deductive/inductive thematic qualitative analysis of the data. The coding scheme will be developed a priori from the User Experience Model's seven themes (valuable, usable, credible, useful, desirable, accessible and findable), and will include new themes suggested by the data (inductive analysis). Key findings will be triangulated using additional publications on the design of tools to improve risk communication. All 10 Decision boxes will be modified in light of our findings. This study will produce a robust framework for developing and testing Decision boxes that will serve healthcare professionals and patients alike. It is the first step in the development and implementation of a new tool that should facilitate decision making in clinical practice.


Blood flow and metabolism in locally advanced breast cancer: relationship to response to therapy.
Locally advanced breast cancer (LABC) is commonly treated with neoadjuvant chemotherapy followed by definitive surgery. The factors influencing the response of LABC to presurgical chemotherapy are incompletely understood. To characterize in vivo tumor biology in patients with LABC, we measured pretherapy blood flow and glucose metabolism in LABC, compared measurements with clinical and pathologic parameters, and examined blood flow and response to subsequent neoadjuvant chemotherapy. Thirty-seven patients with newly diagnosed LABC underwent (18)F-FDG and (15)O-water PET imaging. Thirty-one of these patients underwent neoadjuvant chemotherapy, and response was evaluated by serial measurements of tumor size and pathologic examination after definitive surgery after chemotherapy. Tumor metabolism was estimated from graphic analysis of dynamic (18)F-FDG studies and was expressed as the metabolic rate of (18)F-FDG (MRFDG). Blood flow was estimated from dynamic images after bolus (15)O-water injection using a 1-compartment model. Tumor blood flow and metabolism were compared with clinical and pathologic parameters and with response to chemotherapy. Both blood flow and metabolism were significantly higher in tumor than in normal breast. Tumor blood flow and metabolism were correlated but highly variable. There were weak associations of metabolism with patient age and tumor grade and of blood flow with estrogen receptor status. There was a statistically significant trend for patients with a high MRFDG to have a poorer response to therapy (P = 0.001). Response was not significantly correlated with any other parameters. A low ratio of MRFDG to blood flow was the best predictor of macroscopic complete response (CR) (P = 0.02 vs. non-CR). Preliminary analysis of patient follow-up showed the ratio of MRFDG to blood flow to also be predictive of disease-free survival. Despite uniformly large tumor size, blood flow and metabolism in LABC are highly variable. High glucose metabolism predicts a poor response to neoadjuvant chemotherapy, and low MRFDG relative to blood flow is a predictor of CR. Further work is needed to elucidate the biologic mechanisms underlying these findings.