Laparoscopic appendectomy versus open appendectomy for suspected appendicitis during pregnancy: a systematic review and updated meta-analysis.
Recently, laparoscopic appendectomies (LAs) have been widely performed instead of open appendectomies (OAs) during pregnancy. However, concerns about the safety of LA during pregnancy remain. This systematic review and meta-analysis aimed to evaluate the current evidence relating to the safety of LA versus OA for suspected appendicitis during pregnancy. Comprehensive literature searches were conducted using the PubMed, EMBASE, and Cochrane Library databases to identify articles describing LA versus OA in pregnancy, without restrictions regarding the publication date. The primary endpoints were fetal loss and preterm delivery. After screening 801 studies, 22 comparative cohort studies were included in the analysis, which involved 4694 women, of whom 905 underwent LAs and 3789 underwent OAs. Fetal loss was significantly higher among those who underwent LAs compared with those who underwent OAs, and the pooled odds ratio (OR) was 1.72 (95% confidence interval [CI]: 1.22-2.42) without heterogeneity. The sensitivity analysis showed that the effect size was influenced by one of the studies, because its removal resulted in there being no significant difference between LA and OA with respect to the risk of fetal loss (OR 1.163, 95% CI: 0.68-1.99; P = 0.581). A significant difference was not evident between LA and OA with respect to preterm delivery (OR 0.76, 95% CI: 0.51-1.15), a result that did not change following the sensitivity analysis. The patients who underwent LA had shorter hospital stays (mean difference - 1.01, 95% CI: -1.61--0.41) and a lower wound infection risk (OR 0.40, 95% CI: 0.21-0.76) compared with those who underwent OA. It is not reasonable to conclude that LA in pregnant women might be associated with a greater risk of fetal loss. The difference between LA and OA with respect to preterm delivery was not significant.


The influence of dopaminergic striatal innervation on upper limb locomotor synergies.
To determine the role of striatal dopaminergic innervation on upper limb synergies during walking, we measured arm kinematics in 13 subjects with Parkinson disease. Patients were recruited according to several inclusion criteria to represent the best possible in vivo model of dopaminergic denervation. Of relevance, we included only subjects with normal spatio-temporal parameters of the stride and gait speed to avoid an impairment of upper limbs locomotor synergies as a consequence of gait impairment per se. Dopaminergic innervation of the striatum was measured by FP-CIT and SPECT. All patients showed a reduction of gait-associated arms movement. No linear correlation was found between arm ROM reduction and contralateral dopaminergic putaminal innervation loss. Still, a partition analysis revealed a 80% chance of reduced arm ROM when putaminal dopamine content loss was >47%. A significant correlation was described between the asymmetry indices of the swinging of the two arms and dopaminergic striatal innervation. When arm ROM was reduced, we found a positive correlation between upper-lower limb phase shift modulation (at different gait velocities) and striatal dopaminergic innervation. These findings are preliminary evidence that dopaminergic striatal tone plays a modulatory role in upper-limb locomotor synergies and upper-lower limb coupling while walking at different velocities.


Characterization of exochelins of the Mycobacterium bovis type strain and BCG substrains.
Pathogenic mycobacteria must acquire iron in the host in order to multiply and cause disease. To do so, they release abundant quantities of siderophores called exochelins, which have the capacity to scavenge iron from host iron-binding proteins and deliver it to the mycobacteria. In this study, we have characterized the exochelins of Mycobacterium bovis, the causative agent of bovine and occasionally of human tuberculosis, and the highly attenuated descendant of M. bovis, bacillus Calmette-Guérin (BCG), widely used as a vaccine against human tuberculosis. The M. bovis type strain, five substrains of M. bovis BCG (Copenhagen, Glaxo, Japanese, Pasteur, and Tice), and two strains of virulent Mycobacterium tuberculosis all produce the same set of exochelins, although the relative amounts of individual exochelins may differ. Among these mycobacteria, the total amount of exochelins produced is greatest in M. tuberculosis, intermediate in M. bovis, and smallest in M. bovis BCG.


It's about time: use of nonpharmacological interventions in the nursing home.
To provide a stronger evidence base for cultural change in the nursing home, this study elicited nursing, recreational therapy, and medical staff perceptions of barriers to the implementation of nonpharmacological interventions for the behavioral and psychological symptoms of dementia (BPSD). Thirty-five staff members (registered nurses, licensed practical nurses, nurses' aides, recreational therapists, activity personnel, and medical directors) from six nursing homes located in Pennsylvania and North Carolina participated in the qualitative study. A focus group methodology was used to capture discussions that were audio-recorded and transcribed verbatim. Data were analyzed using standard methods of content and thematic analysis. Four broad themes were identified: the changing landscape; resident behaviors; reaching out to the person with dementia; and the educational needs of staff. The concept of time emerged as a key barrier to the use of nonpharmacological interventions for BPSD. Successful use of nonpharmacological interventions requires the right staff with the right education at the right time. The Vulnerability Framework is a model that helped organize these findings into a meaningful perspective. To effect change in the nursing home, the findings indicate a need for: implementation of staffing patterns that allow staff the time to make a difference in the care of residents with BPSD; development of educational programs that promote staff understanding versus control; and design of research studies that answer questions about the influence of time on the selection of interventions for BPSD.


Challenges and Lessons Learned from Multi-Level Multi-Component Interventions to Prevent and Reduce Childhood Obesity.
Multi-level multi-component (MLMC) strategies have been recommended to prevent and reduce childhood obesity, but results of such trials have been mixed. The present work discusses lessons learned from three recently completed MLMC interventions to inform future research and policy addressing childhood obesity. B'more Healthy Communities for Kids (BHCK), Children's Healthy Living (CHL), and Health and Local Community (SoL) trials had distinct cultural contexts, global regions, and study designs, but intervened at multiple levels of the socioecological model with strategies that address multiple components of complex food and physical activity environments to prevent childhood obesity. We discuss four common themes: (i) How to engage with community partners and involve them in development of intervention and study design; (ii) build and maintain intervention intensity by creating mutual promotion and reinforcement of the intervention activities across the multiple levels and components; (iii) conduct process evaluation for monitoring, midcourse corrections, and to engage stakeholder groups; and (iv) sustaining MLMC interventions and its effect by developing enduring and systems focused collaborations. The paper expands on each of these themes with specific lessons learned and presents future directions for MLMC trials.


Evolving fuzzy neural networks for supervised/unsupervised online knowledge-based learning.
This paper introduces evolving fuzzy neural networks (EFuNNs) as a means for the implementation of the evolving connectionist systems (ECOS) paradigm that is aimed at building online, adaptive intelligent systems that have both their structure and functionality evolving in time. EFuNNs evolve their structure and parameter values through incremental, hybrid supervised/unsupervised, online learning. They can accommodate new input data, including new features, new classes, etc., through local element tuning. New connections and new neurons are created during the operation of the system. EFuNNs can learn spatial-temporal sequences in an adaptive way through one pass learning and automatically adapt their parameter values as they operate. Fuzzy or crisp rules can be inserted and extracted at any time of the EFuNN operation. The characteristics of EFuNNs are illustrated on several case study data sets for time series prediction and spoken word classification. Their performance is compared with traditional connectionist methods and systems. The applicability of EFuNNs as general purpose online learning machines, what concerns systems that learn from large databases, life-long learning systems, and online adaptive systems in different areas of engineering are discussed.


Autophagy prevents early proinflammatory responses and neutrophil recruitment during Mycobacterium tuberculosis infection without affecting pathogen burden in macrophages.
The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated. ATG5 is an essential autophagy protein that is required in innate immune cells to control neutrophil-dominated inflammation and promote survival during M. tuberculosis infection; however, the mechanistic basis for how ATG5 regulates neutrophil recruitment is unknown. To interrogate what innate immune cells require ATG5 to control neutrophil recruitment during M. tuberculosis infection, we used different mouse strains that conditionally delete Atg5 in specific cell types. We found that ATG5 is required in CD11c+ cells (lung macrophages and dendritic cells) to control the production of proinflammatory cytokines and chemokines during M. tuberculosis infection, which would otherwise promote neutrophil recruitment. This role for ATG5 is autophagy dependent, but independent of mitophagy, LC3-associated phagocytosis, and inflammasome activation, which are the most well-characterized ways that autophagy proteins regulate inflammation. In addition to the increased proinflammatory cytokine production from macrophages during M. tuberculosis infection, loss of ATG5 in innate immune cells also results in an early induction of TH17 responses. Despite prior published in vitro cell culture experiments supporting a role for autophagy in controlling M. tuberculosis replication in macrophages, the effects of autophagy on inflammatory responses occur without changes in M. tuberculosis burden in macrophages. These findings reveal new roles for autophagy proteins in lung resident macrophages and dendritic cells that are required to suppress inflammatory responses that are associated with poor control of M. tuberculosis infection.


Is reducing drinking always the answer to reducing consequences in first-year college students?
Pre-college drinking has been shown to be a predictor of risky drinking and harmful outcomes in college. By contrast, less is known about how pre-college alcohol consequences influence subsequent consequences during the freshman year. The present study examined pre-college drinking and consequences in relationship to consequences experienced during the freshman year to better understand alcohol-related problems in this population. Incoming freshmen (N = 340, 58% female) were randomly selected and completed measures of drinking quantity, alcohol-related consequences, and drinking style behaviors at pre-college baseline and at 10-month follow-up. Pre-college consequences demonstrated a unique relationship with consequences at 10-month follow-up controlling for both pre-college and freshman-year alcohol consumption. Furthermore, precollege consequences moderated the relationship between pre-college drinking and consequences at 10-month follow-up. For individuals who reported above-average pre-college consequences, no differences in 10-month follow-up consequences were observed across different levels of drinking. Finally, drinking style significantly mediated the relationship between the interaction between pre-college drinking and consequences and consequences at follow-up. The findings demonstrate the need to identify students who are at an increased risk of experiencing alcohol-related problems during their freshman year based on their history of consequences before college. Interventions aimed at these students may benefit from examining the usefulness of increasing protective behaviors as a method to reduce consequences in addition to reducing drinking quantity.


Burden of cardiovascular risk factors, subclinical atherosclerosis, and incident cardiovascular events across dimensions of religiosity: The multi-ethnic study of atherosclerosis.
Religious involvement has been associated with improved health practices and outcomes; however, no ethnically diverse community-based study has examined differences in cardiac risk factors, subclinical cardiovascular disease, and cardiovascular disease (CVD) events across levels of religiosity. We included 5474 white, black, Hispanic, and Chinese participants who attended examination 2 of the National Heart, Lung, and Blood Institute's Multi-Ethnic Study of Atherosclerosis (MESA). We compared cross-sectional differences in cardiac risk factors and subclinical CVD and longitudinal CVD event rates across self-reported levels of religious participation, prayer/meditation, and spirituality. Multivariable-adjusted regression models were fitted to assess associations of measures of religiosity with risk factors, subclinical CVD, and CVD events. MESA participants (52.4% female; mean age, 63) with greater levels of religious participation were more likely to be female and black. After adjustment for demographic covariates, participants who attended services daily, compared with never, were significantly more likely to be obese (adjusted odds ratio 1.57, 95% confidence interval [CI] 1.12 to 1.72) but less likely to smoke (adjusted odds ratio 0.39, 95% CI 0.26 to 0.58). Results were similar for those with frequent prayer/meditation or high levels of spirituality. There were no consistent patterns of association observed between measures of religiosity and presence/extent of subclinical CVD at baseline or incident CVD events during longitudinal follow-up in the course of 4 years. Our results do not confirm those of previous studies associating greater religiosity with overall better health risks and status, at least with regard to CVD. There was no reduction in risk for CVD events associated with greater religiosity.


Concordance of SNP- and allele-based typing workflows in the context of a large-scale international Salmonella Enteritidis outbreak investigation.
A large European multi-country Salmonella enterica serovar Enteritidis outbreak associated with Polish eggs was characterized by whole-genome sequencing (WGS)-based analysis, with various European institutes using different analysis workflows to identify isolates potentially related to the outbreak. The objective of our study was to compare the output of six of these different typing workflows (distance matrices of either SNP-based or allele-based workflows) in terms of cluster detection and concordance. To this end, we analysed a set of 180 isolates coming from confirmed and probable outbreak cases, which were representative of the genetic variation within the outbreak, supplemented with 22 unrelated contemporaneous S. enterica serovar Enteritidis isolates. Since the definition of a cluster cut-off based on genetic distance requires prior knowledge on the evolutionary processes that govern the bacterial populations in question, we used a variety of hierarchical clustering methods (single, average and complete) and selected the optimal number of clusters based on the consensus of the silhouette, Dunn2, and McClain-Rao internal validation indices. External validation was done by calculating the concordance with the WGS-based case definition (SNP-address) for this outbreak using the Fowlkes-Mallows index. Our analysis indicates that with complete-linkage hierarchical clustering combined with the optimal number of clusters, as defined by three internal validity indices, the six different allele- and SNP-based typing workflows generate clusters with similar compositions. Furthermore, we show that even in the absence of coordinated typing procedures, but by using an unsupervised machine learning methodology for cluster delineation, the various workflows that are currently in use by six European public-health authorities can identify concordant clusters of genetically related S. enterica serovar Enteritidis isolates; thus, providing public-health researchers with comparable tools for detection of infectious-disease outbreaks.


Hyperglycemia Enhances Cancer Immune Evasion by Inducing Alternative Macrophage Polarization through Increased O-GlcNAcylation.
Diabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in patients with cancer. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression, and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAM). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype supporting tumor progression. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared with nondiabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in patients with cancer.


State-Of-The-Art and Recent Advances in Quantification for Therapeutic Follow-Up in Oncology Using PET.
(18)F-fluoro-2-deoxyglucose ((18)F-FDG) positron emission tomography (PET) is an important tool in oncology. Its use has greatly progressed from initial diagnosis to staging and patient monitoring. The information derived from (18)F-FDG-PET allowed the development of a wide range of PET quantitative analysis techniques ranging from simple semi-quantitative methods like the standardized uptake value (SUV) to "high order metrics" that require a segmentation step and additional image processing. In this review, these methods are discussed, focusing particularly on the available methodologies that can be used in clinical trials as well as their current applications in international consensus for PET interpretation in lymphoma and solid tumors.


Technology-Based Interventions to Reduce Sugar-Sweetened Beverages among Adolescents: A Scoping Review.
This scoping review investigates the effectiveness of technology-based interventions in reducing sugar-sweetened beverage (SSB) consumption among adolescents. The rise in SSB consumption among young individuals has become a global public health concern due to its association with obesity, diabetes, and various other health problems. The purpose of this scoping review is to map out and examine the various technology-based interventions used in reducing sugar-sweetened beverages among children and adolescents. A systematic search of three databases using the PRISMA guideline was followed, and 474 articles were retrieved. Seven articles met the inclusion criteria and the critical appraisal using the critical appraisal skill program (CASP). The seven articles underwent both descriptive and thematic analysis. Four technology-based interventions were identified from the selected articles, which include smartphone apps, online or web-based tools, text messages, and social marketing strategies. Our findings suggest that these interventions hold promise in improving adolescents' eating patterns and health outcomes associated with SSB intake, highlighting their potential as useful strategies in resolving this urgent public health concern.


Serial neuroimaging in infants with abusive head trauma: timing abusive injuries.
The appearance and evolution of neuroimaging abnormalities following abusive head trauma (AHT) is important for establishing the time frame over which these injuries might have occurred. From a legal perspective this frames the timing of the abuse and therefore identifies and excludes potential perpetrators. A previous pilot study involving 33 infants with AHT helped to refine the timing of these injuries but was limited by its small sample size. In the present study, the authors analyzed a larger group of 210 cases involving infants with AHT to chronicle the first appearance and evolution of radiological (CT, MRI) abnormalities. All children younger than 24 months admitted to the Penn State Hershey Medical Center with AHT over a 10-year period were identified from a medical record review; the time of injury was determined through an evaluation of the clinical records. All imaging studies were analyzed, and the appearance and evolution of abnormalities were chronicled on serial neuroimaging studies obtained in the days and weeks after injury. One hundred five infants with specific injury dates and available imaging studies were identified; a subset of 43 children additionally had documented times of injury. In infants with homogeneously hyperdense subdural hematomas (SDHs) on initial CT scans, the first hypodense component appeared within the SDH between 0.3 and 16 days after injury, and the last hyperdense subdural component disappeared between 2 and 40 days after injury. In infants with mixed-density SDHs on initial scans, the last hyperdense component disappeared between 1 and 181 days. Parenchymal hypodensities appeared on CT scans performed as early as 1.2 hours, and all were visible within 27 hours after the injury. Rebleeding into SDHs was documented in 17 cases (16%) and was always asymptomatic. Magnetic resonance imaging of the brain was performed in 49 infants. Among those with SDH, 5 patterns were observed. Patterns I and II reflected homogeneous SDH; Pattern I (T1 hyperintensity and T2/FLAIR hypointensity, "early subacute") more commonly appeared on scans performed earlier after injury compared with Pattern II (T1 hyperintensity and T2/FLAIR hyperintensity, "late subacute"), although there was considerable overlap. Patterns III and IV reflected heterogeneous SDH; Pattern III contained relatively equal mixtures having different intensities, whereas Pattern IV had fluid that was predominantly T1 hypointense and T2/FLAIR hyperintense. Again, Pattern III more commonly appeared on scans performed earlier after injury compared with Pattern IV, although there was significant overlap. These data extend the preliminary data reported by Dias and colleagues and provide a framework upon which injuries in AHT can be timed as well as the limitations on such timing estimates.


Anti-inflammatory effect of Taraxacum officinale leaves on lipopolysaccharide-induced inflammatory responses in RAW 264.7 cells.
To investigate the efficacy and the mechanism of the anti-inflammatory effect of Taraxacum officinale leaves (TOLs), the effect of a methanol extract and its fractions recovered from TOLs on lipopolysaccharide (LPS)-induced responses was studied in the mouse macrophage cell line, RAW 264.7. Cells were pretreated with various concentrations of the methanol extract and its fractions and subsequently incubated with LPS (1 microg/mL). The levels of nitric oxide (NO), prostaglandin (PG) E(2), and pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined using enzyme-linked immunosorbent assays. Expressions of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and activation of mitogen-activated protein (MAP) kinases were analyzed using western blotting. The methanol extract and its fractions inhibited LPS-induced production of NO, pro-inflammatory cytokines, and PGE(2) in a dose-dependent manner. The chloroform fraction significantly suppressed production of NO, PGE(2), and two pro-inflammatory cytokines (TNF-alpha and IL-1beta) in a dose-dependent manner with 50% inhibitory concentration values of 66.51, 90.96, 114.76, and 171.06 microg/mL, respectively. The ethyl acetate fraction also inhibited production of the inflammatory molecules. The chloroform and ethyl acetate fractions reduced LPS-induced expressions of iNOS and COX-2 and activation of MAP kinases in a dose-dependent manner. Among the fractions of the methanol extract, the chloroform and ethyl acetate fractions exhibited the most effective anti-inflammatory activities. These results show that the anti-inflammatory effects of TOLs are probably due to down-regulation of NO, PGE(2), and pro-inflammatory cytokines and reduced expressions of iNOS and COX-2 via inactivation of the MAP kinase signal pathway.


Thermal unfolding of proteins studied by coupled reversed-phase HPLC-electrospray ionization mass spectrometry techniques based on isotope exchange effects.
In this study, a deuterium exchange procedure has been employed to evaluate the thermal stability of globular proteins under conditions that replicate their interactive behavior in reversed-phase high performance chromatographic (RP-HPLC) systems. In particular, this investigation has permitted the conformational stability of two proteins, hen egg white lysozyme (HEWL) and horse heart myoglobin (HMYO) to be examined under different temperature and low-pH solvent regimes. The results confirm that this experimental approach provides an efficient strategy to explore fundamental conformational features of polypeptides or proteins in their folded and partial unfolded states under these interactive conditions. In particular, this analytical procedure permits insight to be readily gained into the processes that occur when polypeptides and globular proteins interact with lipophilic liquid/ solid interfaces in the presence of water-organic solvent mixtures at different temperatures.


Comparative analysis of armadillo family proteins in the regulation of a431 epithelial cell junction assembly, adhesion and migration.
p0071 is an armadillo family protein related to both the adherens junction protein p120ctn and to the desmosomal proteins plakophilins 1-3. p0071 assembles into both adherens junctions and desmosomes, suggesting that this protein may regulate the balance between adherens junction and desmosome formation. Furthermore, this subfamily of proteins may also regulate cell functions directly influenced by intercellular junctions, including the strength of cell adhesion and the ability of cells to migrate. These possibilities were tested by expressing exogenous p0071 in A431 epithelial cells and monitoring the effects on adhesive junction assembly in comparison to other closely related armadillo family proteins. In this model system, p0071 specifically enhanced adherens junction assembly but dramatically compromised desmosome assembly, resulting in keratin filament retraction from regions of cell-cell contact. Protein interaction studies revealed that p0071 bound to the first 160 amino-terminal residues of desmoplakin and also interacted directly with plakoglobin, suggesting that p0071 may regulate desmosome assembly by controlling plakoglobin availability. Using an in vitro assay to measure the strength of cell-cell contacts, both plakophilin-1 and p120ctn were found to increase the strength of adhesion. Interestingly, p0071 expression caused no overall changes in adhesive strength, but dramatically inhibited the ability of A431 cells to close an in vitro wound. These results suggest that p120ctn/plakophilin family proteins interact with intercellular junction binding partners to differentially modulate the adhesive and migratory behavior of epithelial cells.


SNPexp - A web tool for calculating and visualizing correlation between HapMap genotypes and gene expression levels.
Expression levels for 47294 transcripts in lymphoblastoid cell lines from all 270 HapMap phase II individuals, and genotypes (both HapMap phase II and III) of 3.96 million single nucleotide polymorphisms (SNPs) in the same individuals are publicly available. We aimed to generate a user-friendly web based tool for visualization of the correlation between SNP genotypes within a specified genomic region and a gene of interest, which is also well-known as an expression quantitative trait locus (eQTL) analysis. SNPexp is implemented as a server-side script, and publicly available on this website: http://tinyurl.com/snpexp. Correlation between genotype and transcript expression levels are calculated by performing linear regression and the Wald test as implemented in PLINK and visualized using the UCSC Genome Browser. Validation of SNPexp using previously published eQTLs yielded comparable results. SNPexp provides a convenient and platform-independent way to calculate and visualize the correlation between HapMap genotypes within a specified genetic region anywhere in the genome and gene expression levels. This allows for investigation of both cis and trans effects. The web interface and utilization of publicly available and widely used software resources makes it an attractive supplement to more advanced bioinformatic tools. For the advanced user the program can be used on a local computer on custom datasets.


Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease.
A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-syn particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used a model of spreading of α-syn induced by striatal injection of α-syn preformed fibrils into the mouse striatum to address this question. We performed quantitative analysis for α-syn inclusions, neurodegeneration, and microgliosis in different brain regions, and generated gene expression profiles of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-syn inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. Using longitudinal gene expression profiling, we observed early gene expression changes, linked to neuroinflammation, that preceded neurodegeneration, indicating an active role of microglia in this process. Altered gene pathways overlapped with those typical of PD. Our observations indicate that α-syn inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that microglia, activated by diffusible, oligomeric α-syn, may play a key role in this process. Our findings uncover new features of α-syn induced pathologies, in particular microgliosis, and point to the necessity for a broader view of the process of α-syn spreading.


Experimental growing of wild pea in Israel and its bearing on Near Eastern plant domestication.
The wild progenitors of the Near Eastern legumes have low germination rates mediated by hardseededness. Hence it was argued that cultivation of these wild legumes would probably result in no yield gain. Based on the meagre natural yield of wild lentil and its poor germination, it was suggested that wild Near Eastern grain legumes were unlikely to have been adopted for cultivation unless freely germinating types were available for the incipient farmers. Unlike wild cereals, data from experimental cultivation of wild legumes are lacking. Replicated nurseries of wild pea (Pisum elatius, P. humile and P. fulvum) were sown during 2007-2010 in the Mediterranean district of Israel. To assess the effect of hardseededness on the yield potential, seeds of the wild species were either subjected to scarification (to ensure germination) or left intact, and compared with domesticated controls. Sowing intact wild pea seeds mostly resulted in net yield loss due to poor establishment caused by wild-type low germination rates, while ensuring crop establishment by scarification resulted in net, although modest, yield gain, despite considerable losses due to pod dehiscence. Harvest efficiency of the wild pea plots was significantly higher (2-5 kg seeds h(-1)) compared with foraging efficiency in wild pea populations (ranging from a few grams to 0·6 kg h(-1)). Germination and yield data from 'cultivation' of wild pea suggest that Near Eastern legumes are unlikely to have been domesticated via a protracted process. Put differently, the agronomic implications of the hardseededness of wild legumes are incompatible with a millennia-long scenario of unconscious selection processes leading to 'full' domestication. This is because net yield loss in cultivation attempts is most likely to have resulted in abandonment of the respective species within a short time frame, rather than perpetual unprofitable cultivation for several centuries or millennia.


Health-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER (Placement of AoRTic TraNscathetER Valve) Trial (Cohort A).
This study sought to compare health status and quality-of-life outcomes for patients with severe aortic stenosis (AS) and high surgical risk treated with either transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (AVR). For high-risk patients with severe AS, TAVR has been shown to result in similar 12-month survival but differing adverse events compared with AVR. We evaluated the health status of 628 patients with severe, symptomatic AS at high risk of surgical complications who were randomized to either TAVR or AVR in the PARTNER Trial. Health status was assessed at baseline and 1, 6, and 12 months using the Kansas City Cardiomyopathy Questionnaire, the Short Form-12, and the EuroQol-5D. The primary outcome, the Kansas City Cardiomyopathy Questionnaire summary score, improved more rapidly with TAVR, but was similar for the 2 groups at 6 and 12 months. However, there was a significant interaction between the benefit of TAVR and access site (transapical vs. transfemoral). Patients eligible for transfemoral TAVR demonstrated significant health status benefits with TAVR versus AVR at 1 month (difference, 9.9 points; 95% confidence interval: 4.9 to 14.9; p < 0.001), whereas patients treated via the TA approach demonstrated no benefits with TAVR compared with AVR at any time point. Results for Kansas City Cardiomyopathy Questionnaire subscales and generic measures demonstrated similar patterns. In high-risk patients with severe AS, health status improved substantially between baseline and 1 year after either TAVR or AVR. TAVR via the transfemoral, but not the transapical route, was associated with a short-term advantage compared with surgery. (Placement of AoRTic TraNscathetER Valve [PARTNER] trial; NCT00530894).


Growth monitoring in children.
Growth monitoring is widely accepted and strongly supported by health professionals, and is a standard component of community paediatric services throughout the world. We sought to evaluate research evidence of its impact. This requires definition, consideration of the setting, and discussion of the intended effects of this activity. In this review, we define growth monitoring as the regular recording of a child's weight, coupled with some specified remedial actions if the weight is abnormal in some way. Although the causes of growth faltering and the responses to it may be region specific, the process is the same, and we consider here growth monitoring in both the deprived and richer populations of the world. Growth monitoring consists of routine measurements to detect abnormal growth, combined with some action when this is detected. As primary care workers worldwide invest time in this activity, we sought evidence of its benefits and harms. The review objectives are to evaluate the effects of routine growth monitoring on: 1. The child, in relation to preventing death, illness or malnutrition; and referrals for medical care, medical specialist assessment or professional social support follow-up. 2. The mother, in relation to nutritional knowledge, anxiety or reassurance about the child's health, and satisfaction with services. Cochrane Controlled Trials Register; MEDLINE; EMBASE; CINAHL; World Health Organization and World Bank publications; specialists in this area; citations in existing reviews and identified studies. Randomised or quasi-randomised trials comparing routine growth monitoring (regular monitoring of growth, plotting on a chart, combined with referral or intervention when growth is abnormal) with no growth monitoring. Trial quality was assessed, and data abstracted by both reviewers. Two studies included, both conducted in developing countries. In one, the nutritional status at 30 months in 500 children showed no difference between those allocated to growth monitoring and those not. The other study examined whether counselling improved mothers' knowledge of the growth chart, and reported better test scores at four months. Given the level of investment in growth monitoring worldwide, it is surprising there is so little research evaluating its potential benefits and harms.


Heterotrimeric type I collagen C-telopeptide conformation as docked to its helix receptor.
The amino (N-telo) and carboxyl (C-telo) telopeptides of type I collagen play crucial roles, in vivo and in vitro, in the assembly of collagen fibrils, regulating the axial alignment of the molecules within a fibril, azimuthal orientations of neighboring molecules, and cross-link formation. High-resolution structures of the telopeptides are not available from X-ray diffraction studies, but computational methods permitted prediction of the N-telo structure within a fibril. Here, using a suite of molecular modeling software, the more complex heterotrimeric C-telo of human type I collagen has been built from the correct sequences and energy minimized and the energy minimum confirmed by molecular dynamics. The receptor triple helix was modeled on the basis of the Protein Data Bank coordinates of a collagen-like sequence. Docking of the heterotrimeric C-telopeptide to its receptor showed that hydrophobic interactions involving the short alpha2 C-telopeptide are crucial determinants of its azimuthal orientation within the docked structure. A docked C-telo can interact with only one neighboring helix. The two alpha1(I) C-telo chains in the alpha1(Alpha)-alpha2-alpha1(B) chain stagger do not have identical docked conformations, and one of the alpha1(I) C-telo chains appears to be favored for formation of a cross-link between its K(16C) and a helix K87. Prior studies showed that a docked N-telopeptide can interact with two adjacent collagen monomers, forming a tightly packed region. A recent X-ray analysis showed the N- and C-telo regions pack differently, with the C-telo region being less densely packed than N-telo regions. This difference between N- and C-telopeptide docked structures demonstrates how unique and specific packing can occur in the fibril at each boundary of the type I collagen gap region.


Regulation of nitrate reductase in Neurospora crassa: regulation of transcription and translation.
A technique employing cycloheximide and actinomycin D has been used for the separation of transcription and translation during the induction of nitrate reductase in Neurospora crassa. Nitrate reductase is found to be synthesized in low efficiency when nitrate is not provided during both transcription and translation. Nitrate reductase synthesis is enhanced by nitrate. Nitrate is found to induce nitrate reductase by enhancing the increase of the capacity to synthesize nitrate reductase, and ammonia is found to repress nitrate reductase, by inhibiting the induced increase of the capacity to make the enzyme, or by making it unstable in vivo, or both. The effect of ammonia is partially reversed by nitrate. The addition of ammonium tartrate or the removal of nitrate during translation of the induced capacity to synthesize nitrate reductase is found to result in the inactivation of nitrate reductase in vivo. A low level of nitrate in the medium is found to be sufficient for enhancing the induced increase of the capacity to synthesize nitrate reductase, but a higher level of nitrate is required to stabilize the enzyme after its formation. The induced capacity to synthesize nitrate reductase is relatively stable in the presence or absence of nitrate, but not in the presence of ammonia.


Synopsis of the 6th Walker's Cay Colloquium on Cancer Vaccines and Immunotherapy.
The 6th annual Cancer Vaccines and Immunotherapy Colloquium at Walker's Cay was held under the auspices of the Albert B. Sabin Vaccine Institute on March 10-13, 2004. The Colloquium consisted of a select group of 34 scientists representing academia, biotechnology and pharmaceutical industry. The main goal of this gathering was to promote in a peaceful and comfortable environment exchanges between basic and clinical science. The secondary benefit was to inspire novel bench to bedside ventures and at the same time provide feed back about promising and/or disappointing clinical results that could help re-frame some scientific question or guide the design of future trials. Several topics were covered that included tumor antigen discovery and validation, platforms for vaccine development, tolerance, immune suppression and tumor escape mechanisms, adoptive T cell therapy and dendritic cell-based therapies, clinical trials and assessment of response. Here we report salient points raised by speakers or by the audience during animated discussion that followed each individual presentation.


Xenograft and Transgenic Mouse Models of Epithelial Ovarian Cancer and Non Invasive Imaging Modalities to Monitor Ovarian Tumor Growth In situ -Applications in Evaluating Novel Therapeutic Agents.
Epithelial ovarian cancer (EOC) is the most commonly fatal gynecologic malignancy in developed countries. Most EOC patients are diagnosed at advanced stage when disease has spread beyond the ovary. While many patients initially respond to surgery and chemotherapy, the long term prognosis is generally unfavorable, with recurrence and development of drug resistant disease. There is a critical need to identify new therapeutic agents that prolong disease-free intervals and effectively manage recurrent disease. Murine models of ovarian carcinoma are excellent models to study tumor biology in the search for new treatments for EOC. Described in this unit are methods for establishing xenograft or allograft models of EOC using ovarian carcinoma cell lines, in vivo imaging strategies for detection and quantification of EOC in transgenic and in xenograft/allograft models, and procedures for necropsy and pathological evaluation of experimental animals.


Peripheral immunity and risk of incident brain disorders: a prospective cohort study of 161,968 participants.
Whether peripheral immunity prospectively influences brain health remains controversial. This study aims to investigate the longitudinal associations between peripheral immunity markers with incident brain disorders. A total of 161,968 eligible participants from the UK Biobank were included. We investigated the linear and non-linear effects of peripheral immunity markers including differential leukocytes counts, their derived ratios and C-reactive protein (CRP) on the risk of dementia, Parkinson's disease (PD), stroke, schizophrenia, bipolar affective disorder (BPAD), major depressive disorder (MDD) and anxiety, using Cox proportional hazard models and restricted cubic spline models. Linear regression models were used to explore potential mechanisms driven by brain structures. During a median follow-up of 9.66 years, 16,241 participants developed brain disorders. Individuals with elevated innate immunity markers including neutrophils, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) had an increased risk of brain disorders. Among these markers, neutrophils exhibited the most significant correlation with risk of dementia (hazard ratio 1.08, 95% confidence interval 1.04-1.12), stroke (HR 1.06, 95% CI 1.03-1.09), MDD (HR 1.13, 95% CI 1.10-1.16) and anxiety (HR 1.07, 95% CI 1.04-1.10). Subgroup analysis revealed age-specific and sex-specific associations between innate immunity markers with risk of dementia and MDD. Neuroimaging analysis highlighted the associations between peripheral immunity markers and alterations in multiple cortical, subcortical regions and white matter tracts, typically implicated in dementia and psychiatric disorders. These findings support the hypothesis that neuroinflammation is important to the etiology of various brain disorders, offering new insights into their potential therapeutic approaches.


[Electron microscopy study of the midgut of ticks after experimental infection with Karshi virus].
The guts of H. asiaticum and H. anatolicum ticks infected with Karshi virus and incubated at 22 degrees and 37 degrees C were studied. Virus particles with morphological features of flaviviruses were found 5 days after infection in the cells of the gut of ticks incubated at 22 degrees C and within 24 hours postinfection in the gut cells of the ticks incubated at 37 degrees C. The possible effect of temperature on the rate of development and spread of the infectious process in the gut wall of the midgut of ticks of both species is discussed.


Perfluoroalkyl substances in the blood of wild rats and mice from 47 prefectures in Japan: use of samples from nationwide specimen bank.
Numerous studies have reported on the global distribution, persistence, fate, and toxicity of perfluoroalkyl and polyfluoroalkyl substances (PFASs). However, studies on PFASs in terrestrial mammals are scarce. Rats can be good sentinels of human exposure to toxicants because of their habitat, which is in close proximity to humans. Furthermore, exposure data measured for rats can be directly applied for risk assessment because many toxicological studies use rodent models. In this study, a nationwide survey of PFASs in the blood of wild rats as well as surface water samples collected from rats' habitats from 47 prefectures in Japan was conducted. In addition to known PFASs, combustion ion chromatography technique was used for analysis of total fluorine concentrations in the blood of rats. In total, 216 blood samples representing three species of wild rats (house rat, Norway rats, and field mice) were analyzed for 23 PFASs. Perfluorooctanesulfonate (PFOS; concentration range <0.05-148 ng/mL), perfluorooctane sulfonamide (PFOSA; <0.1-157), perfluorododecanoate (<0.05-5.8), perfluoroundecanoate (PFUnDA; <0.05-51), perfluorodecanoate (PFDA; <0.05-9.7), perfluorononanoate (PFNA; <0.05-249), and perfluorooctanoate (PFOA) (<0.05-60) were detected >80 % of the blood samples. Concentrations of several PFASs in rat blood were similar to those reported for humans. PFSAs (mainly PFOS) accounted for 45 % of total PFASs, whereas perfluoroalkyl carboxylates (PFCAs), especially PFUnDA and PFNA, accounted for 20 and 10 % of total PFASs, respectively. In water samples, PFCAs were the predominant compounds with PFOA and PFNA found in >90 % of the samples. There were strong correlations (p < 0.001 to p < 0.05) between human population density and levels of PFOS, PFNA, PFOA, and PFOSA in wild rat blood.


Differential expression and activity of melanogenesis-related proteins during induced hair growth in mice.
In C57 Bl-6 mice, melanogenesis is strictly coupled to the growth phase of the hair cycle (anagen). To further study this phenomenon of concerted developmental and pigmentary activity, we followed the sequence of tyrosinase (key enzyme of melanogenesis) expression and activity and the presence of the melanosomal protein gp 75 during the development of traumatically induced anagen follicles (days 0 = telogen, and days 1-12, after anagen induction studied). In addition to performing Northern and Western blots for tyrosinase, tyrosine hydroxylase activity (THA) and dopa oxidase activity (DOA) were measured. On day 0, DOA was undetectable, and THA was very low. On days 1 and 2, both activities were undetectable; starting from day 3, they increased rapidly, reaching a plateau on days 8 and 12. DO-positive proteins had apparent molecular weights (MW) of 66-68 kD (days 3-12), 72-74 kD (days 5-12), and 130 kD (days 8 and 12). Western blotting emphasized proteins of MW 66-68 kD (tyrosinase), and 73-75 kD (gp 75); tyrosinase was undetectable on day 0, but already present on days 1 and 2; it increased by day 5 and had reached a plateau on days 8 and 12; gp 75 was undetectable on days 0-2; it was present on day 3, increased by day 5, and reached a plateau on days 8 and 12. Northern blot analysis revealed high levels of tyrosinase mRNA on days 5 and 8, low levels on days 1-3, and none on day 0. These data suggest a highly regulated, time frame-restricted, differential pattern of tyrosinase transcription, translation, and enzyme activity during the different stages of the developing murine anagen follicle, possibly as a result of complex interactions between follicular melanocytes and their environment.


Culture, Sex, and Group-Bias in Trait and State Empathy.
Empathy is sharing and understanding others' emotions. Recently, researchers identified a culture-sex interaction effect in empathy. This phenomenon has been largely ignored by previous researchers. In this study, the culture-sex interaction effect was explored with a cohort of 129 participants (61 Australian Caucasians and 68 Chinese Hans) using both self-report questionnaires (i.e., Empathy Quotient and Interpersonal Reactivity Index) and computer-based empathy tasks. In line with the previous findings, the culture-sex interaction effect was observed for both trait empathy (i.e., the generalized characteristics of empathy, as examined by the self-report questionnaires) and state empathy (i.e., the on-spot reaction of empathy for a specific stimulus, as evaluated by the computer-based tasks). Moreover, in terms of state empathy, the culture-sex interaction effect further interacted with stimulus traits (i.e., stimulus ethnicity, stimulus sex, or stimulus emotion) and resulted in three- and four-way interactions. Follow-up analyses of these higher-order interactions suggested that the phenomena of ethnic group bias and sex group favor in empathy varied among the four culture-sex participant groups (i.e., Australian female, Australian male, Chinese female, and Chinese male). The current findings highlighted the dynamic nature of empathy (i.e., its sensitivity toward both participant traits and stimulus features). Furthermore, the newly identified interaction effects in empathy deserve more investigation and need to be verified with other Western and Asian populations.


Clostridium difficile infection: molecular pathogenesis and novel therapeutics.
The Gram-positive anaerobic bacterium Clostridium difficile produces toxins A and B, which can cause a spectrum of diseases from pseudomembranous colitis to C. difficile-associated diarrhea. A limited number of C. difficile strains also produce a binary toxin that exhibits ADP ribosyltransferase activity. Here, the structure and the mechanism of action of these toxins as well as their role in disease are reviewed. Nosocomial C. difficile infection is often contracted in hospital when patients treated with antibiotics suffer a disturbance in normal gut microflora. C. difficile spores can persist on dry, inanimate surface for months. Metronidazole and oral vancomycin are clinically used for treatment of C. difficile infection but clinical failure and concern about promotion of resistance are motivating the search for novel non-antibiotic therapeutics. Methods for controlling both toxins and spores, replacing gut microflora by probiotics or fecal transplant, and killing bacteria in the anaerobic gut by photodynamic therapy are discussed.


Fluorescent microspheres for one-photon and two-photon imaging of mesenchymal stem cells.
Stem cell-mediated therapy has emerged as a novel regenerative treatment for tissue repair in the last decade. However, noninvasive monitoring of stem cells remains a grand challenge for stem cell-based regenerative medicine for the complete understanding of the function and the behaviors of cells. Herein, acridine orange, a fluorescent dye was encapsulated into polymer nanospheres based on double emulsions. The fluorescent nanospheres with a diameter of around 200 nm were incubated with human mesenchymal stem cells (hMSCs) to produce nanosphere-endocytosed hMSCs. The fluorescent imaging of hMSCs can be directly and clearly captured using confocal microscopy in the one-photon and two-photon modes. The results indicated that the hMSCs adhered and spread well on the surface of the scaffolds with a high population and good distribution. Meanwhile, polystyrene microspheres were stained with dye complexes by using a gradual solvent evaporation method. The as-prepared fluorescent beads exhibited bright and multiple colors and a broad emission spectrum ranging from 500 to 800 nm, which was further used to quantitatively evaluate the one-photon and two-photon fluorescent signals of the hMSCs. Our study offers the possibility of direct monitoring of stem cells with high resolution, and encourages future quantitative clinical assessment in imaging-guided cell therapies.


Biodegradation of the herbicide glyphosate by filamentous fungi in platform shaker and batch bioreactor.
The biodegradation conducted by microorganisms on herbicide glyphosate (N-phosphonomethylglycine) was investigated. Five strains of filamentous fungi belonging to the Fusarium genre were grown on Czapeck medium without phosphorous and supplemented with the addition of glyphosate. The assays were conducted to determine the ability of use as a phosphorous source, the inhibition caused by presence of herbicide, and the biodegradation in shaker and bioreactor by Fusarium strains. It was observed that the herbicide did not show any negative effect on microrganisms by quantity of the biomass. Among the strains tested, no inhibition was noted by the addition of glyphosate even at a high concentration. All strains studied were able to biodegrade it and use the herbicide as a phosphorous source. The formation of consortium was not better than the strains tested in pure culture. The biodegradation in the bioreactor was better than in the shaker. However, there wasn't any influence on biodegradation rate by changing the amount of oxygen in the system.


Population Pharmacokinetics and Exposure-Response Analyses of Eslicarbazepine Acetate Efficacy and Safety in Monotherapy of Partial-Onset Seizures.
Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). ESL pharmacokinetics (PK) and exposure-response analyses were supported by 2 phase 3 conversion to ESL (1200, 1600 mg) monotherapy studies. The PK model development included 10 phase 1-2 studies (ESL 600-1200 mg daily). Seizure diaries were completed daily; subjects exited if seizures worsened. Exposure-response models were developed for time to study exit, probability of seizure freedom, time to first occurrence of dizziness, headache, and nausea; serum sodium levels were explored. A 1-compartment model with first-order absorption/elimination described ESL PK. Clearance and distribution volume were significantly related to body weight and sex. Higher eslicarbazepine minimum concentration (Cmin ) and use of 1 baseline AED were associated with significantly lower risk of study exit, whereas eslicarbazepine Cmin was a significant predictor of seizure freedom during the last 4 weeks of monotherapy. Eslicarbazepine exposure and the time to first occurrence of adverse events were not related. A shallow negative relationship described the relationship between change from baseline in serum sodium level and eslicarbazepine exposure. Eslicarbazepine apparent clearance and distribution volume estimates were similar to those reported for ESL adjunctive therapy. Dose adjustment based on body weight was not required. The time to study exit and probability of seizure freedom during the last 4 weeks of monotherapy were weakly related to eslicarbazepine exposure. Because the first occurrence of adverse events or hyponatremia were also not significantly related to eslicarbazepine exposure, dose adjustment using plasma eslicarbazepine concentrations is not supported.


Threat of Sexual Disqualification: The Consequences of Erectile Dysfunction and Other Sexual Changes for Gay and Bisexual Men With Prostate Cancer.
Gay and bisexual (GB) men with prostate cancer (PCa) have been described as an "invisible diversity" in PCa research due to their lack of visibility, and absence of identification of their needs. This study examined the meaning and consequences of erectile dysfunction (ED) and other sexual changes in 124 GB men with PCa and 21 male partners, through an on-line survey. A sub-sample of 46 men with PCa and seven partners also took part in a one-to-one interview. ED was reported by 72 % of survey respondents, associated with reports of emotional distress, negative impact on gay identities, and feelings of sexual disqualification. Other sexual concerns included loss of libido, climacturia, loss of sensitivity or pain during anal sex, non-ejaculatory orgasms, and reduced penis size. Many of these changes have particular significance in the context of gay sex and gay identities, and can result in feelings of exclusion from a sexual community central to GB men's lives. However, a number of men were reconciled to sexual changes, did not experience a challenge to identity, and engaged in sexual re-negotiation. The nature of GB relationships, wherein many men are single, engage in casual sex, or have concurrent partners, influenced experiences of distress, identity, and renegotiation. It is concluded that researchers and clinicians need to be aware of the meaning and consequences of sexual changes for GB men when designing studies to examine the impact of PCa on men's sexuality, advising GB men of the sexual consequences of PCa, and providing information and support to ameliorate sexual changes.


Association of left ventricular global area strain derived from resting 3D speckle-tracking echocardiography and exercise capacity in individuals undergoing treadmill exercise test.
Background: Left ventricular (LV) global area strain (GAS) is a novel index derived from resting 3D speckle-tracking echocardiography (STE), and its clinical significance has rarely been studied. We examined the association of LV GAS and exercise capacity in a health check-up population. Methods: We recruited 94 symptom-free participants (52.2 ± 11.7 years, 62.8% male) without substantial structural heart disease or coronary heart diseases who were undergoing a routine health examination. All participants underwent resting echocardiography and symptom-limited treadmill exercise test according to the Bruce protocol. Four strain parameters were obtained from the analysis, namely 3D GAS (GAS3d), global longitudinal strain, global circumferential strain, and global radial strain. Results: After multivariate analysis for factors of exercise time, we observed a significant association in LV GAS3d (P < 0.001). We divided participants into preserved and impaired exercise capacity groups according to the cutoff value of 8 metabolic equivalent of tasks. LV GAS3d (OR 1.24, 95% CI 1.10-1.39, P < 0.001) was an independent predictor of impaired exercise capacity and the optimal cut-off value was -19.96% at a sensitivity of 77.8% and at a specificity of 92.1%. LV GAS3d could improve the discriminatory power of exercise capacity in individuals with early mitral filling velocity to average mitral annulus velocity ratio (E/e') ≥ 8. Conclusions: LV GAS3d was significantly associated with exercise time and exhibited incremental predictive value on E/e' for exercise capacity in participants undergoing treadmill exercise test.


Long-Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure-Associated Liver Disease [Formula: see text].
Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF-associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long-term PN and FOLE therapy due to chronic IF. A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. Of 215 patients with IFALD treated from 2004-2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight-for age and length-for-age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. Children with IFALD who required long-term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.


Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy.
Many eukaryotic cell-surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). There are at least 26 genes involved in biosynthesis and remodeling of GPI anchors. Hypomorphic coding mutations in seven of these genes have been reported to cause decreased expression of GPI anchored proteins (GPI-APs) on the cell surface and to cause autosomal-recessive forms of intellectual disability (ARID). We performed homozygosity mapping and exome sequencing in a family with encephalopathy and non-specific ARID and identified a homozygous 3 bp deletion (p.Leu197del) in the GPI remodeling gene PGAP1. PGAP1 was not described in association with a human phenotype before. PGAP1 is a deacylase that removes an acyl-chain from the inositol of GPI anchors in the endoplasmic reticulum immediately after attachment of GPI to proteins. In silico prediction and molecular modeling strongly suggested a pathogenic effect of the identified deletion. The expression levels of GPI-APs on B lymphoblastoid cells derived from an affected person were normal. However, when those cells were incubated with phosphatidylinositol-specific phospholipase C (PI-PLC), GPI-APs were cleaved and released from B lymphoblastoid cells from healthy individuals whereas GPI-APs on the cells from the affected person were totally resistant. Transfection with wild type PGAP1 cDNA restored the PI-PLC sensitivity. These results indicate that GPI-APs were expressed with abnormal GPI structure due to a null mutation in the remodeling gene PGAP1. Our results add PGAP1 to the growing list of GPI abnormalities and indicate that not only the cell surface expression levels of GPI-APs but also the fine structure of GPI-anchors is important for the normal neurological development.


The dentate adult human mandible: an anatomic basis for surgical decision making.
Mandibular resection for oral cancer assumes two major forms; segmental mandibulectomy for invasion and rim mandibulectomy for margins, the extent of removal being governed by the need to ensure oncologic safety. The purpose of our study was to establish basic principles for optimal resection design in various clinical situations. Thirty-six cadaveric, adult, dentate human mandibles were examined in detail and sectioned at six points each to study the cross- sectional anatomy at these sites. The majority of bones (32 of 36) revealed a conspicuous medullary core with a thin cortical rim 2 to 4 mm in thickness. The inferior alveolar nerve was found to course consistently within the anterior segment of the ramus and to dip significantly within the body (median height at molar area 7 mm). Accordingly, rim resections cannot include the entire medullary core and nerve as currently defined, whereas segmental resections can spare the posterior segment of the ramus in appropriate cases.


Audit and feedback versus alternative strategies: effects on professional practice and health care outcomes.
Audit and feedback has been identified as having the potential to change the practice of health care professionals. To assess the effects of audit and feedback compared with other interventions in changing health professional practice and to assess whether the effectiveness of audit and feedback can be improved by modifying how it is done. We searched MEDLINE up to June 1997, the Research and Development Resource Base in Continuing Medical Education, and reference lists of related systematic reviews and articles. Randomised trials of audit and feedback (defined as any summary of clinical performance of health care over a specified period of time) compared with other interventions. The participants were health care providers responsible for patient care. Two reviewers independently extracted data and assessed study quality. Twelve studies were included involving more than 2194 physicians. Seven trials with direct comparisons were included. The targeted behaviours were the management of low haemoglobin, the delivery of preventive care services (two studies), the management of high cholesterol, the performance of cervical smears, and the ordering of diagnostic tests (two studies). From the results of four trials, there is little evidence of a measurable effect of adding a complementary intervention such as a local consensus process to audit and feedback compared to audit and feedback alone. Two of three trials that compared audit and feedback to reminders reported that reminders were more effective in improving the delivery of some preventive services. It is not possible to recommend a complementary intervention to enhance the effectiveness of audit and feedback. Reminders might be more effective than audit and feedback to improve the delivery of some preventive services but the results are not striking. Few trials have investigated the effect of varying different characteristics of the audit and feedback process. Consideration should be given to testing the effects of modifying important characteristics such as the content, source, timing, recipient and format.


A hypothesis on the pathogenesis of pterygiums.
All true pterygiums are attracted to a specific site at the corneoscleral junction along the 3 to 9 o'clock meridian. The pathogenesis of a pinguecula-pterygium is postulated to be due to a noninfected inflammation at the junction of the conjunctival blood vessels and Bowman's membrane where the autolytic process of inflammation results in a protein degradation amino acid mixture which has the ability of attracting conjunctival blood vessels on the cornea. This amino acid mix is hypothesized to contain a pterygium angiogenesis factor.


Association of a Multimodal Intervention With Decreased Opioid Prescribing After Neck Dissection for Malignant Thyroid Disease With Short Hospital Stay.
Prescribing practices for opioid medication after thyroid surgery have been well-studied and established; however, the need for pain management with opioid medication following lateral neck dissection for malignant thyroid disease with a short hospital stay has not been established. To evaluate a multimodal opioid reduction intervention and its association with a decrease in prescribing of opioid medication at hospital discharge for patients after a lateral neck dissection for thyroid cancer. This was a retrospective cohort study of patients treated from 2011 to 2021 by a tertiary academic institution that performs a high volume of thyroid cancer surgeries annually. We evaluated the electronic health records of 417 patients who had undergone lateral neck dissection for malignant thyroid disease from June 1, 2011, to June 30, 2021, and had a short hospital stay (≤3 days). Patients with longer stays (>3 days) or additional surgical procedures were excluded. Group 1 comprised patients who underwent a neck dissection before the intervention; and group 2, those who underwent the procedure after implementation of the intervention. A multimodal intervention composed of 3 components to reduce opioid prescribing at hospital discharge home after neck dissection for malignant thyroid disease with a short hospital stay. The primary outcome was the quantity of opioid medication prescribed in the postoperative period, measured as oral morphine milliequivalents (MME). The eta-squared effect size (η2ES) metric was used to determine the association of the intervention with a reduction in the MME quantities of opioid medication administered to inpatients and prescribed at discharge. An estimated need for opioids was established for the average patient undergoing lateral neck dissection for thyroid cancer based on the upper range of prescribing after intervention. The data were analyzed from January to March 2022. The total study population was 417 patients: group 1 with 171 patients (mean [SD] age , 47.1 [15.6] years; 104 [61%] women; 144 [84%] non-Hispanic White) and group 2 with 246 patients (mean [SD] age , 46.2 [17.4] years; 146 [60%] women; 206 [83.7%] non-Hispanic White). The median MME prescribed at discharge for group 1 per patient was 225 MME compared with 0 MME for group 2, a large effect-size difference. There was a moderate association between the dose amount administered to an inpatient and the prescription dose they received at discharge (r, 0.33). Multiple linear regression analysis of sex, age, race and ethnicity, extent of surgery, and opioid reduction intervention showed that the intervention had a large clinically meaningful association with decreasing opioid prescriptions and dosage amounts at discharge (η2ES, 0.26; 95% CI, 0.19-0.33). The findings of this retrospective cohort study suggest that patients undergoing lateral neck dissections for thyroid cancer with short hospitalization needed very small amounts, if any, postoperative opioid medication for pain management. Adequate postoperative pain control was achieved using nonopioid interventions. Implementing an intervention to decrease the quantity of unnecessarily prescribed opioid medications during hospital discharge may help to reduce the risk of opioid addiction and overdose in patients after surgery.


Association between pro-inflammatory diet and liver cancer risk: a systematic review and meta-analysis.
This systematic review aimed to investigate the association between dietary inflammatory potential and liver cancer to provide evidence regarding scientific dietary health education. Systematic review and meta-analysis. A comprehensive literature review was conducted to identify case-control or cohort studies that involved dietary inflammation index (DII)/empirical dietary inflammation pattern (EDIP) and liver cancer in PubMed, EMBASE, Cochrane, and Web of Science databases. Using a combination of DII/EDIP and liver cancer as the search terms, the associations between DII/EDIP and liver cancer were then assessed. Three case-control studies and two cohort studies were brought into the meta-analysis, with 225 713 enrolled participants. Meta-analysis of categorical variables showed that DII/EDIP in the highest category increased the risk of liver cancer compared to DII/EDIP in the lowest category (relative risk (RR) = 2·35; 95 % CI 1·77, 3·13; P = 0·000) and with low heterogeneity across studies (I2 = 40·8 %, P = 0·119). Meta-analysis of continuous variables showed that significant positive association between liver cancer and DII/EDIP scores (RR = 1·24; 95 % CI 1·09, 1·40; P = 0·001), and no heterogeneity (I² = 0·0 %, P = 0·471). Stratified according to the study design, there was a significant positive association between liver cancer and DII/EDIP scores in both cohort studies (RR = 2·16; 95 % CI 1·51, 3·07; P = 0·000) and case-control studies (RR = 2·75; 95 % CI 1·71, 4·41; P = 0·000). The higher the DII/EDIP score, the higher the risk of liver cancer. This finding may have prominent implications for the general population.


Peripheral infiltration of remdesivir in 3 patients with COVID-19: Case series and discussion.
The coronavirus disease 2019 (COVID-19) pandemic resulted in accelerated market access to remdesivir worldwide. Therefore, data about complications experienced during use of the drug are limited. This is the first published case series (1 case report exists) to describe remdesivir infiltration in 3 patients with COVID-19. In the first case, a 91-year-old woman experienced remdesivir infiltration resulting in edema, hematoma at the area of infiltration; on palpation, the affected area felt cooler than the surrounding areas. Swelling was still present after 6 weeks. In the second case, remdesivir infiltration occurred in a 72-year-old male, resulting in edema, hematoma, and pain at the area of infiltration. The hematoma lasted for 7 days. The third case concerned a 67-year-old woman, in whom remdesivir infiltration led to edema and a small hematoma. The hematoma regressed to a negligible size within 3 days. However, a week after infiltration, redness had reappeared. In 2 cases, the patient was immediately treated with hyaluronidase injections, but no specific treatments were provided in the other case. Based on the product information provided by remdesivir's manufacturer, we believe symptoms and signs observed in the 3 cases may have resulted from the low pH (~4) of the nonbuffered remdesivir solution, although the patients were not formally assessed for caustic injury. Previous experience with other noncytotoxic medications suggests that infusion-specific factors (eg, volume of leaked fluid) and patient-specific factors (eg, advanced age) may have a role in the outcome of remdesivir infiltration. The possibility of symptoms caused by cyclodextrins in the formulation or by intrinsic toxicity of remdesivir warrants exploration.


The responses to surface wettability gradients induced by chitosan nanofilms on microtextured titanium mediated by specific integrin receptors.
Microtexture and chemistry of implant surfaces are important variables for modulating cellular responses. Surface chemistry and wettability are connected directly. While each of these surface properties can influence cell response, it is difficult to decouple their specific contributions. To address this problem, the aims of this study were to develop a surface wettability gradient with a specific chemistry without altering micron scale roughness and to investigate the role of surface wettability on osteoblast response. Microtextured sandblasted/acid-etched (SLA, Sa = 3.1 μm) titanium disks were treated with oxygen plasma to increase reactive oxygen density on the surface. At 0, 2, 6, 10, and 24 h after removing them from the plasma, the surfaces were coated with chitosan for 30 min, rinsed and dried. Modified SLA surfaces are denoted as SLA/h in air prior to coating. Surface characterization demonstrated that this process yielded differing wettability (SLA0 < SLA2 < SLA10 < SLA24) without modifying the micron scale features of the surface. Cell number was reduced in a wettability-dependent manner, except for the most water-wettable surface, SLA24. There was no difference in alkaline phosphatase activity with differing wettability. Increased wettability yielded increased osteocalcin and osteoprotegerin production, except on the SLA24 surfaces. mRNA for integrins α1, α2, α5, β1, and β3 was sensitive to surface wettability. However, surface wettability did not affect mRNA levels for integrin α3. Silencing β1 increased cell number with reduced osteocalcin and osteoprotegerin in a wettability-dependent manner. Surface wettability as a primary regulator enhanced osteoblast differentiation, but integrin expression and silencing β1 results indicate that surface wettability regulates osteoblast through differential integrin expression profiles than microtexture does. The results may indicate that both microtexture and wettability with a specific chemistry have important regulatory effects on osseointegration. Each property had different effects, which were mediated by different integrin receptors.


Transmission of chlamydiae by the housefly.
The ability of the housefly to carry viable Chlamydia trachomatis and to transmit a chlamydial ocular infection was studied under laboratory conditions. After feeding flies (Musca domestica) on suspensions of egg yolk sac infected with C. trachomatis serotypes A or B (responsible for hyperendemic trachoma) the agents were reisolated from flies' intestines for up to 6 hours and from their legs and/or proboscises for up to 2 hours. It was found that the viability of chlamydiae is dependent on the protective effect of yolk concentration in the original inoculum. Results of experiments with guinea-pig inclusion conjunctivitis as an animal model show that under laboratory conditions flies can readily transmit this chlamydial ocular infection from one animal to another. These results suggest that under field conditions flies can play an important role in the transmission of trachoma, particularly in areas with favourable conditions such as a large reservoir of infection among children with severe trachoma, copious eye discharge caused by trachoma and associated bacterial infections, a large fly population, and close proximity of children in large family groups.


Proteasome inhibitors: complex tools for a complex enzyme.
As the dominant protease dedicated to protein turnover, the proteasome shapes the cellular protein repertoire. Our knowledge of proteasome regulation and activity has improved considerably over the past decade. Novel inhibitors, in particular, have helped to advance our understanding of proteasome biology. They range from small peptide-based structures that can be modified to vary target specificity, to large macromolecular inhibitors that include proteins. While these reagents have played an important role in establishing our current knowledge of the proteasome's catalytic mechanism, many questions remain. Rapid advances in the synthesis and identification of new classes of proteasome inhibitors over the last 10 years serve as a positive indicator that many of these questions will soon be resolved. The future lies in designing compounds that can function as drugs to target processes involved in disease progression. It may only be a short while before the products of such research have safe application in a practical setting. Structural and combinatorial chemistry approaches are powerful techniques that will bring us closer to these goals.


Prediction of Tumor Control in 90Y Radioembolization by Logit Models with PET/CT-Based Dose Metrics.
The aim of this work was to develop models for tumor control probability (TCP) in radioembolization with 90Y PET/CT-derived radiobiologic dose metrics. Methods: Patients with primary liver cancer or liver metastases who underwent radioembolization with glass microspheres were imaged with 90Y PET/CT for voxel-level dosimetry to determine lesion absorbed dose (AD) metrics, biological effective dose (BED) metrics, equivalent uniform dose, and equivalent uniform BED for 28 treatments (89 lesions). The lesion dose-shrinkage correlation was assessed on the basis of RECIST and, when available, modified RECIST (mRECIST) at first follow-up. For a subset with mRECIST, logit regression TCP models were fit via maximum likelihood to relate lesion-level binary response to the dose metrics. As an exploratory analysis, the nontumoral liver dose-toxicity relationship was also evaluated. Results: Lesion dose-shrinkage analysis showed that there were no significant differences between model parameters for primary and metastatic subgroups and that correlation coefficients were superior with mRECIST. Therefore, subsequent TCP analysis was performed for the combined group using mRECIST only. The overall lesion-level mRECIST response rate was 57%. The AD and BED metrics yielding 50% TCP were 292 and 441 Gy, respectively. All dose metrics considered for TCP modeling, including mean AD, were significantly associated with the probability of response, with high areas under the curve (0.87-0.90, P < 0.0001) and high sensitivity (>0.75) and specificity (>0.83) calculated using a threshold corresponding to 50% TCP. Because nonuniform AD deposition by microspheres cannot be determined by PET at a microscopic scale, radiosensitivity values extracted here by fitting models to clinical response data were substantially lower than reported for in vitro cell cultures or for external-beam radiotherapy clinical studies. There was no correlation between nontumoral liver AD and toxicity measures. Conclusion: Despite the heterogeneous patient cohort, logistic regression TCP models showed a strong association between various dose metrics and the probability of response. The performance of mean AD was comparable to that of radiobiologic dose metrics that involve more complex calculations. These results demonstrate the importance of considering TCP in treatment planning for radioembolization.


Motor cortical representation of speed and direction during reaching.
The motor cortical substrate associated with reaching was studied as monkeys moved their hands from a central position to one of eight targets spaced around a circle. Single-cell activity patterns were recorded in the proximal arm area of motor cortex during the task. In addition to the well-studied average directional selectivity ("preferred direction") of single-cell activity, we also found the time-varying speed of movement to be represented in the cortical activity. A single equation relating motor cortical discharge rate to these two parameters was developed. This equation, which has both independent (speed only) and interactive (speed and direction) components, described a large portion of the time-varying motor cortical activity during the task. Electromyographic activity from a number of upper arm muscles was recorded during this task. Muscle activity was also found to be directionally tuned; however, the distributions of preferred directions were found to be significantly different from cortical activity. In addition, the effect of speed on cortical and muscle activity was also found to be significantly different.


Difference of interferon-α and interferon-β on melanoma growth and lymph node metastasis in mice.
Interferon (IFN)-α and IFN-β are type I IFNs which are known to exert an antitumor effect on malignant melanoma. The aim of this study was to evaluate and compare the efficacy of IFN-α2b and IFN-β1a on primary tumor growth and lymph node metastasis, and to examine the mechanisms of lymph node metastasis. The efficacy of IFN-α2b and IFN-β1a was evaluated using a human melanoma xenograft model. We further examined the effect of IFNs on lymphangiogenic growth factors in human melanoma cells. IFN-β1a showed a stronger antiproliferative and proapoptotic effect, whereas IFN-α2b inhibited tumor growth and lymph node metastasis through inhibition of lymphangiogenesis. Both IFN-α2b and IFN-β1a were effective in inhibiting lymph node metastasis compared with the control. Microvessel density decreased in tumors treated with IFN-α2b and IFN-β1a compared with the control, without statistical significance. Lymphatic vessel density decreased significantly only in tumors treated with IFN-α2b (P<0.05). Both IFN-α2b and IFN-β1a decreased in-vitro and in-vivo vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 protein expression and secretory VEGF-C level in vitro. IFN-α2b showed an earlier and sustained effect in decreasing VEGF-C and VEGF receptor-3 protein expression and a superior effect in decreasing the secretory VEGF-C level compared with IFN-β1a. Our investigation shows that both IFN-α2b and IFN-β1a exerted different antitumor and antimetastatic effects in human melanoma xenograft. Moreover, the present findings indicate that inhibition of lymphangiogenesis is another possible antimetastatic action mechanism of IFN-α2b.


Recruitment and blocking properties of the CardioFit stimulation lead.
The CardioFit vagal stimulation system has been developed as a proposed therapy for congestive heart failure (CHF). CardioFit is to be implanted in several hundred CHF patients enrolled in the INOVATE-HF clinical trial, an FDA approved study. The CardioFit stimulation lead (CSL), which is a cuff electrode that delivers stimulation pulses to the right cervical vagus, was designed to recruit efferent cardiac vagal fibers while minimizing unwanted recruitment of other fibers. This paper presents the CSL and measurements of its recruiting and blocking properties when placed on isolated porcine vagus nerves maintained at an elevated temperature in oxygenated artificial cerebrospinal fluid. Using charge balanced quasi-trapezoidal pulses driven through the CSL, we show in eight out of nine nerves a 63% ± 13% (mean ± SD) unidirectional attenuation of the A-fiber compound action potential attained at a current of 3.0 ± 0.8 mA. The threshold for the activation of A- and B-fibers was found to be 0.3 ± 0.17 mA and 2.5 ± 1.1 mA, respectively. The results presented here should help to guide the optimal parameters used in the upcoming deployment of the CardioFit system.


Human pregnane X receptor genotype of the donor but not of the recipient is a risk factor for delayed graft function after renal transplantation.
Delayed graft function (DGF) is an important complication in renal transplantation, contributing significantly to decrease in long-term allograft survival. In addition to donor- and recipient-related risk factors such as immunosuppression, altered renal excretion of xenobiotics by membrane transporters may influence DGF. Using DNA samples from recipients and donors, we assessed the impact on DGF of genetic variants in P-glycoprotein (ABCB1), multidrug resistance protein 2 (ABCC2), and the nuclear pregnane X receptor (PXR/NR1I2), which regulates the transcription of enzymes and transporters. In our local cohort of renal transplant recipients (n = 178), DGF occurred in 27.5%. The PXR 8055TT genotype of the donor only (not of the recipient) was significantly associated with an increased risk for DGF. This finding emerged from univariate as well as multivariate logistic regression analysis including 16 nongenetic factors and held true after correction for multiple testing. Our findings provide the first evidence that PXR may be associated with risk of DGF, independent of previously identified risk factors.


Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.
The rapid onset of massive, systemic viral replication during primary HIV or simian immunodeficiency virus (SIV) infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that vaccines designed to maintain differentiated effector memory T cell (TEM cell) responses at viral entry sites might improve efficacy by impairing viral replication at its earliest stage, and we have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM cell responses. RhCMV vectors expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, regardless of preexisting RhCMV immunity, and primed and maintained robust, SIV-specific CD4+ and CD8+ TEM cell responses (characterized by coordinate tumor necrosis factor, interferon-gamma and macrophage inflammatory protein-1beta expression, cytotoxic degranulation and accumulation at extralymphoid sites) in the absence of neutralizing antibodies. Compared to control rhesus macaques, these vaccinated rhesus macaques showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated limiting-dose intrarectal challenge, including four macaques who controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development--vaccines capable of generating and maintaining HIV-specific TEM cells might decrease the incidence of HIV acquisition after sexual exposure.


Transduction of M+- and SOR+-markers in group A streptococci.
Phagolysates obtained in passage of the virulent phage CA1 on M+ SOR+-cultures of streptococcus, serotype 22, offered a possibility of transduction of the M22+-sign to M-SOR--strains of serotype T12. Transductants were selected in direct bactericidal test with subsequent determination of their type in the indirect bactericidal test with homo- and heterologous immune sera. The UV-lysates of the lysogenic M+ SOR+-cultures of serotypes 4, 22, and 49 offered a possibility of transducing both signs conjointly. In this case transductants were selected by the SOR-phenotype in the dishes with serum agar. All the transductants retained the T-serotype of the recipient's strain and segregated M-- and SOR--clones with high frequency. There were for the first time obtained in streptococcus of group A proofs of transduction of M+- and SOR+-signs pointing to their determination by different, but closely conjoint genes. Conditions of the marker transduction, selection and study of transductant were chosen, they opened new possibilities for genetic analysis of the virulence of streptococcus, group A.


Imaging of the porta hepatis: spectrum of disease.
A wide array of pathologic conditions can arise within the porta hepatis, which encompasses the portal triad (the main portal vein, common hepatic artery, and common bile ducts), lymphatics, nerves, and connective tissue. Major vascular diseases of the portal triad include thrombosis, stenosis, and aneurysm. Portal vein thrombosis can complicate liver cirrhosis and hepatocellular carcinoma and has important therapeutic implications. Hepatic artery thrombosis and stenosis require immediate attention to reduce graft loss in liver transplant recipients. Congenital (eg, choledochal cyst) and acquired (benign and malignant) diseases of the biliary system can manifest as mass lesions in the porta hepatis. Lymphadenopathy can arise from neoplastic and nonneoplastic entities. Uncommon causes of mass lesions arise from nerves (eg, neurofibroma, neurofibrosarcoma) and connective tissue (sarcomas) and are rare. The hepatoduodenal ligament is a peritoneal reflection at the porta hepatis and is an important route for the spread of pancreatic and gastrointestinal cancers. Imaging plays a major role in diagnosis and enables appropriate management. Ultrasonography accurately demonstrates anatomic variations and pathologic conditions and is the initial modality of choice for detection of vascular and biliary lesions. Multidetector computed tomography and magnetic resonance imaging allow characterization and differentiation of various masses in the porta hepatis. Imaging-guided interventions, including embolization and stent placement, also play a key role in disease management.


Acute viral hepatitis superimposed on alcoholic liver cirrhosis: clinical and histopathologic features.
Of 20 patients with alcoholic liver cirrhosis and a superimposed episode of acute viral hepatitis, 12 developed hepatic encephalopathy or ascites or both. Four died of hepatic failure. Seventeen patients had received blood transfusions within 6 months before the acute hepatitic episode. Two patients were HBsAg-positive; the other 18 were presumptively diagnosed as having non-A, non-B hepatitis. However, hepatitis A virus infection was excluded in only three of the 18 patients. Histologic examination performed in 13 cases disclosed necrotizing inflammatory activity, which is commonly observed in acute viral hepatitis. The distinctive histologic feature was a meager regenerating activity. We conclude that patients with alcoholic cirrhosis complicated by acute viral hepatitis frequently develop hepatic failure and have a high fatality rate (20% in our series).


Threshold photoelectron spectroscopy and dissociative photoionization of benzonitrile.
The threshold photoionization and dissociative ionization of benzonitrile (C6H5CN) were studied using double imaging photoelectron photoion coincidence (i2PEPICO) spectroscopy at the Vacuum Ultraviolet (VUV) beamline of the Swiss Light Source (SLS). The threshold photoelectron spectrum was recorded from 9.6 to 12.7 eV and Franck-Condon simulations of ionization into the ionic ground state, X̃+, as well as the B̃+ and C̃+ states were performed to assign the observed vibronic structures. The adiabatic ionization energies of the X̃+, B̃+ and C̃+ states are determined to be (9.72 ± 0.02), (11.85 ± 0.03) and, tentatively, (12.07 ± 0.04) eV, respectively. Threshold ionization mass spectra were recorded from 13.75 to 19.75 eV and the breakdown diagram was constructed by plotting the fractional abundances of the parent ion and ionic dissociation products as a function of photon energy. The seven lowest energy dissociative photoionization channels of benzonitrile were found to yield CN˙ + c-C6H5+, HCN + C6H4˙+, C2H4 + HC5N˙+, HC3N + C4H4˙+, H2C3N˙ + C4H3+, CH2CHCN + C4H2˙+ and H2C4N˙ + c-C3H3+. HCN loss from the benzonitrile cation is the dominant dissociation channel from the dissociation onset of up to 18.1 eV and CH2CHCN loss becomes dominant from 18.1 eV and up. We present extensive potential energy surface calculations on the C6H5CN˙+ surface to rationalize the detected products. The breakdown diagram and time-of-flight mass spectra are fitted using a Rice-Ramsperger-Kassel-Marcus statistical model. Anchoring the fit to the CBS-QB3 result (3.42 eV) for the barrier to HCN loss, we obtained experimental dissociation barriers for the products of 4.30 eV (CN loss), 5.53 eV (C2H4 loss), 4.33 eV (HC3N loss), 5.15 eV (H2C3N loss), 4.93 eV (CH2CHCN loss) and 4.41 eV (H2C4N loss). We compare our work to studies of the electron-induced dissociative ionization of benzonitrile and isoelectronic phenylacetylene (C8H6), as well as the VUV-induced dissociation of protonated benzonitrile (C6H5CNH+). Also, we discuss the potential role of barrierless association reactions found for some of the identified fragments as a source of benzonitrile(˙+) in interstellar chemistry and in Titan's atmosphere.


The Path to Advanced Practice Licensure for Clinical Nurse Specialists in Washington State.
The aim of this study was to provide a review of the history and process to obtaining advanced practice licensure for clinical nurse specialists in Washington State. Before 2016, Washington State licensed certified nurse practitioners, certified nurse midwives, and certified nurse anesthetists under the designation of an advanced registered nurse practitioner; however, the state did not recognize clinical nurse specialists as advanced practice nurses. The work to drive the rule change began in 2007. The Washington Affiliate of the National Association of Clinical Nurse Specialists used the Power Elite Theory to guide advocacy activities, building coalitions and support for the desired rule changes. On January 8, 2016, the Washington State Nursing Care Quality Assurance Commission voted to amend the state's advanced practice rules, including clinical nurse specialists in the designation of an advanced practice nurse. Since the rule revision, clinical nurse specialists in Washington State have been granted advanced registered nurse practitioner licenses. Driving changes in state regulatory rules requires diligent advocacy, partnership, and a deep understanding of the state's rule-making processes. To be successful in changing rules, clinical nurse specialists must build strong partnerships with key influencers and understand the steps in practice required to make the desired changes.


A Fluorogenic Assay To Monitor Rho-Dependent Termination of Transcription.
Transcription termination mediated by the ring-shaped, ATP-dependent Rho motor is a multipurpose regulatory mechanism specific to bacteria and constitutes an interesting target for the development of new antibiotics. Although Rho-dependent termination can punctuate gene expression or contribute to the protection of the genome at hundreds of sites within a given bacterium, its exact perimeter and site- or species-specific features remain insufficiently characterized. New advanced approaches are required to explore thoroughly the diversity of Rho-dependent terminators and the complexity of associated mechanisms. Current in vitro analyses of Rho-dependent termination rely on radiolabeling, gel electrophoresis, and phosphorimaging of transcription reaction products and are thus hazardous, inconvenient, and low-throughput. To address these limitations, we have developed the first in vitro assay using a fluorescence detection modality to study Rho-dependent transcription termination. This powerful experimental tool accurately estimates terminator strengths in a matter of minutes and is optimized for a microplate reader format allowing multiplexed characterization of putative terminator sequences and mechanisms or high-throughput screening of new drugs targeting Rho-dependent termination.