Cumulative operative experience is decreasing during general surgery residency: a worrisome trend for surgical trainees?
The aim of this study was to quantify the changes over time in general surgical residents' operative experience as surgeon, first assistant, and teaching assistant. The introduction of work hour restrictions in July 2003 raised concern that residents' operative experience might decline. Early studies evaluating the mean number of operations performed as surgeon reported no major change. The experiences of residents as first assistant and teaching assistant have not been closely examined. The Accreditation Council for Graduate Medical Education Resident Statistics Summary reports from academic year 1992 to 1993 through the present were reviewed. The mean number of cases reported as total surgeon, surgeon chief, and surgeon junior for academic year 2001 to 2002 through 2005 to 2006 were analyzed for total major operations. The median number of cases reported as total surgeon, first assistant, and teaching assistant for academic year 1992 to 1993 through 2005 to 2006 were analyzed for total major operations. Since the implementation of the 80-hour work duty restrictions, the number of total major operations reported by residents as surgeon decreased from 930 to 909 (2.3% decrease, p < 0.0001), surgeon chief operations decreased from 252 to 231 (8.3% decrease, p <0.0001), and surgeon junior operations remained essentially unchanged, from 677 to 678. From academic year 1992 to 1993 through 2005 to 2006, the median number of first assistant and teaching assistant cases declined from 231 to 49 (79% decrease) and from 67 to 23 (66% decrease), respectively. Since duty hour restrictions were introduced, there have been small but notable declines in the number of total surgeon and surgeon chief operative cases reported by graduating residents. Over a longer time period, operative cases reported by graduating residents in the roles of first assistant and teaching assistant declined dramatically. Although some of these declines were gradual, recent declines may have been accelerated by the 80-hour duty hour restrictions. These trends must be considered as we plan the education of present and future surgical residents.


Phylogenetic analysis of Leuconostoc and Lactobacillus species isolated from sugarcane processing streams.
High levels of gums such as dextran, produced by Leuconostoc and Lactobacillus spp., have a severe impact on factory throughput and sugar quality. This study aimed to determine the phylogenetic relationships between gum-producing Leuconostoc and Lactobacillus bacteria which were isolated from various locations in a sugarcane processing factory at times when low- and high-dextran raw sugar, respectively, were produced. Phylogenetic analysis of 16S rRNA gene sequences grouped 81 isolates with the type strains of Leuconostoc mesenteroides (subspp. mesenteroides, dextranicum, and cremoris), Leuconostoc pseudomesenteroides, Leuconostoc lactis, and Leuconostoc citreum, respectively. Forty-three isolates clustered with the type strain of Lactobacillus fermentum. The phylogenetic relatedness of the isolates was determined by sequencing and analysis of the housekeeping genes rpoA and dnaA for Leuconostoc spp. and the pheS and tuf genes for the Lactobacillus spp. The rpoA gene proved discriminatory for the phylogenetic resolution of all of the isolated Leuconostoc spp. and the dnaA housekeeping gene was shown to be effective for isolates clustering with the type strains of Leuc. mesenteroides and Leuc. citreum. None of the loci examined permitted differentiation at the subspecies level of Leuc. mesenteroides. Single-locus analysis, as well as the concatenation of the pheS and tuf housekeeping gene sequences, yielded identical phylogenies for the Lactobacillus isolates corresponding to L. fermentum.


The Role of Delocalization and Excess Energy in the Quantum Efficiency of Organic Solar Cells and the Validity of Optical Reciprocity Relations.
The photon energy dependence of long-range charge separation is studied for two prototypical polymer:fullerene systems. The internal quantum efficiency (IQE) of PCDTBT:PC61BM is experimentally shown to be independent of the excitation energy. In contrast, for TQ1:PC71BM the IQE is strongly energy-dependent for excitation energies close to charge transfer (CT) electroluminescence peak maximum while it becomes energy-independent at higher excitation energies. Kinetic Monte Carlo simulations reproduce the experimental IQE and reveal that the photon energy-dependence of the IQE is governed by charge delocalization. Efficient long-range separation at excitation energies corresponding to the CT electroluminescence peak maximum or lower requires an initial separation of the hole-electron pair by ∼4-5 nm, whereas delocalization is less important for charge separation at higher photon energies. Our modeling results suggest that a phenomenological reciprocity between CT electroluminescence and external quantum efficiency does not necessarily prove that commonly employed reciprocity relations between these spectra are valid from a fundamental perspective.


Deconvolution by thresholding in mirror wavelet bases.
The deconvolution of signals is studied with thresholding estimators that decompose signals in an orthonormal basis and threshold the resulting coefficients. A general criterion is established to choose the orthonormal basis in order to minimize the estimation risk. Wavelet bases are highly sub-optimal to restore signals and images blurred by a low-pass filter whose transfer function vanishes at high frequencies. A new orthonormal basis called mirror wavelet basis is constructed to minimize the risk for such deconvolutions. An application to the restoration of satellite images is shown.


Synergetic plasmonic effect of Al and Au nanoparticles for efficiency enhancement of air processed organic photovoltaic devices.
Enhancement in the efficiency of air processed bulk heterojunction photovoltaic devices is demonstrated via the addition of highly stable uncapped gold (Au) and aluminum (Al) nanoparticles (NPs) into the photoactive layer. An enhancement in conversion efficiency by 15% is observed, which can be attributed to Localised Surface Plasmon Resonance effects at the small diameter Au NPs and to efficient scattering by the large diameter Al NPs.


Apoptosis induction by the photosensitizer verteporfin: identification of mitochondrial adenine nucleotide translocator as a critical target.
We report that the photosensitizer verteporfin kills lymphoma cells by an apoptotic process involving a dissipation of the mitochondrial inner transmembrane potential (deltapsim). Light-activated verteporfin-induced apoptosis was abolished by transfection with Bcl-2, a procedure reported to inhibit the mitochondrial permeability transition pore complex (PTPC). Verteporfin triggered the deltapsim loss in isolated mitochondria in vitro, and this effect was suppressed by bongrekic acid and cyclosporin A. Verteporfin plus light also permeabilized proteoliposomes containing the semipurified PTPC or the purified PTPC component adenine nucleotide translocator (ANT), yet had no effect on protein-free control liposomes. Verteporfin phototoxicity on ANT proteoliposomes was mediated by reactive oxygen species and was prevented by recombinant Bcl-2 or the adenine nucleotides ATP and ADP. In conclusion, verteporfin belongs to a class of clinically used chemotherapeutic agents acting on PTPC and ANT.


Carbon dioxide hydrate and floods on Mars.
Ground ice on Mars probably consists largely of carbon dioxide hydrate, CO(2) . 6H(2)O. This hydrate dissociates upon release of pressure at temperatures between 0 degrees and 10 degrees C. The heat capacity of the ground would be sufficient to produce up to 4 percent (by volume) of water at a rate equal to that at which it can be drained away. Catastrophic dissociation of carbon dioxide hydrate during some past epoch when the near surface temperature was in this range would have produced chaotic terrain and flood channels.


Economic impact of pelviscopic surgery.
Pelviscopic surgery has been reported to reduce costs and recovery time for patients undergoing a variety of procedures, including oophorectomy, salpingo-oophorectomy, treatment of endometriosis, and removal of adhesions, ovarian cysts and tumors. Pelviscopic surgery was performed on 21 patients undergoing oophorectomy, salpingo-oophorectomy and ovarian resection. There were no complications, and all patients had a rapid return to normal activity. The economic impact of pelviscopic surgery was compared with that of conventional surgery for patients whose records were matched by diagnosis and procedure. An average reduction of 49% in overall hospital costs was observed with pelviscopic surgery.


Costs of surgical ablation of atrial fibrillation in Ontario, Canada from 2006 to 2017.
International guidelines currently recommend concomitant surgical ablation of atrial fibrillation (AF) in patients with AF undergoing cardiac surgery. However, a systematic review and meta-analysis of 23 randomized controlled trials (RCTs) showed no significant difference in mortality or stroke in patients who underwent surgical AF ablation compared with those who did not (moderate-quality evidence). We estimated the Ontario-wide costs of surgical AF ablation between 2006 and 2017 using data from a systematic review and meta-analysis of RCTs, estimates of case volumes from Ontario Health Insurance Plan fee codes, the ongoing left atrial appendage occlusion study III trial (NCT01561651), institutional costs from large academic centers in Ontario, as well as professional fees based on the Ontario fee schedule. Device costs were obtained from Canadian industry data with expert input. We estimated the average extra cost of surgical AF ablation at $4,287 CAD (95% CI $4,113-4,619) per patient. Procedural costs (equipment costs and physician remuneration) comprise 82.2% of this, while smaller portions relate to the increased need for pacemaker (3.9%) and additional hospital length of stay (13.9%). Approximately 2,391 patients underwent surgical AF ablation between 2006 and 2017, corresponding to an estimated $10.2 million in incremental cost during that time span. Ontario taxpayers spend significant financial resources on surgical ablation of AF, a procedure lacking high-quality evidence demonstrating benefit in reducing mortality or stroke. Further large prospective studies examining clinically important outcomes are needed to justify its routine use in patient care and to guide allocation of healthcare funds.


Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5.
Chromosome 7q22 has been the focus of many cytogenetic and molecular studies aimed at delineating regions commonly deleted in myeloid leukemias and myelodysplastic syndromes. We have compared a gene-dense, GC-rich sub-region of 7q22 with the orthologous region on mouse chromosome 5. A physical map of 640 kb of genomic DNA from mouse chromosome 5 was derived from a series of overlapping bacterial artificial chromosomes. A 296 kb segment from the physical map, spanning ACHE: to Tfr2, was compared with 267 kb of human sequence. We identified a conserved linkage of 12 genes including an open reading frame flanked by ACHE: and Asr2, a novel cation-chloride cotransporter interacting protein Cip1, Ephb4, Zan and Perq1. While some of these genes have been previously described, in each case we present new data derived from our comparative sequence analysis. Adjacent unfinished sequence data from the mouse contains an orthologous block of 10 additional genes including three novel cDNA sequences that we subsequently mapped to human 7q22. Methods for displaying comparative genomic information, including unfinished sequence data, are becoming increasingly important. We supplement our printed comparative analysis with a new, Web-based program called Laj (local alignments with java). Laj provides interactive access to archived pairwise sequence alignments via the WWW. It displays synchronized views of a dot-plot, a percent identity plot, a nucleotide-level local alignment and a variety of relevant annotations. Our mouse-human comparison can be viewed at http://web.uvic.ca/~bioweb/laj.html. Laj is available at http://bio.cse.psu.edu/, along with online documentation and additional examples of annotated genomic regions.


Total Healing of a Partial Rupture of the Supraspinatus Tendon Using Barbotage Technique Associated with Platelet-Rich Plasma: A Randomized, Controlled, and Double-Blind Clinical Trial.
The prevalence of partial rotator cuff tears (PRCTs) is high in the general population. Our hypothesis is that barbotage, when associated with platelet-rich plasma (PRP), is an effective method for healing these tears. The aim of this study was to compare the effects of barbotage with or without PRP on the healing of partial supraspinatus tendon tears (PSTTs). This study assessed the Western Ontario Rotator Cuff Index score and ultrasound (US) images at 6 weeks and 6 months after treatment. Patients in both groups showed clinical improvement, with no significant difference in scores at 6 weeks. However, at 6 months, the PRP group exhibited significant improvement (p = 0.019). Both groups experienced a reduction in ST tear size, but the PRP group demonstrated a significant enhancement at 6 weeks and 6 months. In conclusion, the US-guided barbotage technique, whether associated with PRP or saline solution, proved to be an effective treatment for clinical improvement and reduction in the size of PSTT. Better clinical improvement results were observed with PRP at 6 months. The combination of PRP with barbotage was superior in reducing the size of the ST tear at both 6 weeks and 6 months, resulting in complete healing in 79.3% of the tears.


Sustained visual-spatial attention produces costs and benefits in response time and evoked neural activity.
This study investigated the simple reaction time (RT) and event-related potential (ERP) correlates of biasing attention towards a location in the visual field. RTs and ERPs were recorded to stimuli flashed randomly and with equal probability to the left and right visual hemifields in the three blocked, covert attention conditions: (i) attention divided equally to left and right hemifield locations; (ii) attention biased towards the left location; or (iii) attention biased towards the right location. Attention was biased towards left or right by instructions to the subjects, and responses were required to all stimuli. Relative to the divided attention condition, RTs were significantly faster for targets occurring where more attention was allocated (benefits), and slower to targets where less attention was allocated (costs). The early P1 (100-140 msec) component over the lateral occipital scalp regions showed attentional benefits. There were no amplitude modulations of the occipital N1 (125-180 msec) component with attention. Between 200 and 500 msec latency, a late positive deflection (LPD) showed both attentional costs and benefits. The behavioral findings show that when sufficiently induced to bias attention, human observers demonstrate RT benefits as well as costs. The corresponding P1 benefits suggest that the RT benefits of spatial attention may arise as the result of modulations of visual information processing in the extrastriate visual cortex.


Contribution of Particulate Nitrate Photolysis to Heterogeneous Sulfate Formation for Winter Haze in China.
Nitrate and sulfate are two key components of airborne particulate matter (PM). While multiple formation mechanisms have been proposed for sulfate, current air quality models commonly underestimate its concentrations and mass fractions during northern China winter haze events. On the other hand, current models usually overestimate the mass fractions of nitrate. Very recently, laboratory studies have proposed that nitrous acid (N(III)) produced by particulate nitrate photolysis can oxidize sulfur dioxide to produce sulfate. Here, for the first time, we parameterize this heterogeneous mechanism into the state-of-the-art Community Multi-scale Air Quality (CMAQ) model and quantify its contributions to sulfate formation. We find that the significance of this mechanism mainly depends on the enhancement effects (by 1-3 orders of magnitude as suggested by the available experimental studies) of nitrate photolysis rate constant ( J NO 3 - ) in aerosol liquid water compared to that in the gas phase. Comparisons between model simulations and in-situ observations in Beijing suggest that this pathway can explain about 15% (assuming an enhancement factor (EF) of 10) to 65% (assuming EF = 100) of the model-observation gaps in sulfate concentrations during winter haze. Our study strongly calls for future research on reducing the uncertainty in EF.


Industrially Scalable Piezoresistive Smart-Textile Sensor for Flexible Electronics Application.
Industrially scalable pressure-sensitive smart textile sensors have been developed using graphite-polyurethane (G-PU) composite materials by the plasma-assisted dip-pad-dry-cure method. The advantage of this technique is that it is easy, simple, and suitable for high-volume production with industrially available machinery. The sandwich structure sensor has been constructed with the pressure-sensitive textile semiconductor and embroidery electrodes for manufacturing a single sensor and sensor matrix, which can detect touch, pressure, movement, etc., and send information wirelessly (via smartphone) to the user in real-time. The sensibility, hysteresis behavior, repeatability, and stability against washing, martindale abrasion, etc. of the piezoresistive polyester (PES) textile sensor have been optimized by the plasma-assisted semiconductive coating. The smart textile sensor built into this work provides flexibility, breathability, and wearability and can be easily integrated into wearable items allowing for object detection by scanning their weight, movement, interactive floor mate, and seat sensor mate for dynamic posture detection and sensor hand glove to translate finger movement into sign language (e.g., text or audio able). All necessary electronics and software associated with the relevant application have been developed to demonstrate the effectiveness of the products in a real-world demonstration, which encourages the widespread use of smart textile piezoresistive sensors for a variety of applications in flexible electronics sectors.


Risk Factors of Congenital Hypothyroidism in Israel.
Congenital hypothyroidism (CH) is the most common preventable cause of mental retardation and delayed growth in children. Several prenatal and environmental factors might be associated with the disease. To determine the prevalence and risk factors of permanent CH and transient congenital hypothyroidism (TCH) in Israel. We conducted a retrospective analysis of the Israeli national newborn screening program database from 2011 to 2015. Chi-square and logistic regression were used to assess the association of the demographic and gestational factors with the CH and TCH. Of the 889,033 live births screened between 2011 and 2015, 860 were diagnosed with CH (9.76 per 10,000 live births) and 298 with TCH (3.35 per 10,000 live births). In multivariate analyses, CH was positively associated with female sex, gestational ages < 38 or > 39 weeks, birth weight < 3000 grams, and winter birth. A decreased risk of TCH was detected in Arabs and neonates from high socioeconomic areas. An increased risk was independently associated with gestational ages < 38 weeks, low birth weight, and winter birth. Several demographic, gestational, and geographical factors are associated with the development of CH and TCH. Future studies are needed to further investigate the pathogenesis in Israel.


Compared to CPAP extubation to non-invasive ventilation is associated with higher risk of bronchopulmonary dysplasia in extremely low birth weight infants.
While non-invasive ventilation (NIV) has been associated with improved extubation rates, its impact on bronchopulmonary dysplasia (BPD) remains unclear. In this retrospective, chart review study of infants admitted to the Cleveland Clinic, we aimed to compare the incidence of BPD among extremely low birth weight (ELBW) infants extubated to continuous positive pressure (CPAP) versus those extubated to NIV via RAM cannula or biphasic CPAP. Data collected included demographics, ventilatory modes, extubation data, and presence of complications. Infants extubated to either CPAP or NIV were compared using Wilcoxon rank- sum and Chi-square tests, and data were corrected using logistic regression models. Data are presented as medians. A total of 120 infants were included, of whom 62% were extubated to NIV. The incidence of BPD was significantly lower in the CPAP group vs NIV (57% vs. 78%, p = 0.011). Infants in the CPAP group were heavier (birth weight (BWT) of 833 vs 724 grams, p = 0.005), more mature (gestation age (GA) 27 vs 25 weeks, p < 0.001) and were extubated significantly earlier (2 vs 8 days, p < 0.001). After adjusting for BWT and GA, NIV continued to be significantly associated with higher incidence of BPD among those extubated on the first day of life (odds ratio 5.9; 95% CI: 1.2-29.1, p = 0.029). This study concludes that, as compared to CPAP, early use of NIV is associated with higher risk of BPD in ELBW infants. Further investigation using prospective studies is recommended to validate these findings.


Beyond antiviral: Interferon induced by bacteria maintains tolerance in the gut.
Type I interferons are best known for their antiviral role. Here, Ayala et al. (https://doi.org/10.1084/jem.20230063) reveal that commensal bacteria elicit tonic type I interferons to prime dendritic cells and induce regulatory T cells that maintain a tolerogenic intestinal milieu.


Interoceptive awareness and its relationship to hippocampal dependent processes.
Many neuropsychological and animal lesion studies point to the hippocampus as being critical for mediating interoceptive awareness, while neuroimaging studies have been used to argue for the importance of the insula and anterior cingulate cortex. Here, using healthy young adults - as with the neuroimaging data - we tested for an association between performance on a hippocampal dependent learning and memory (HDLM) measure (logical memory percent retention) and interoceptive awareness assessed on three tasks - heart rate tracking, water loading and the Multidimensional Assessment of Interoceptive Awareness questionnaire (MAIA). After controlling for other relevant potentially confounding variables, we found significant associations between both the water loading and MAIA measures (which were both correlated) and HDLM performance. These findings imply that hippocampal dependent processes are involved in interoceptive awareness in healthy young adults. More tentatively, they suggest that medial temporal lobe structures may mediate interoceptive tasks that involve ingestion and/or integration of past and current state-based information.


Epiglottitis and Haemophilus influenzae immunization: the Pittsburgh experience--a five-year review.
Current trends in the clinical presentation and management of children with epiglottitis at Children's Hospital of Pittsburgh were reviewed for the years 1988 to 1993. The medical records of all patients diagnosed as having epiglottitis between July 1988 and June 1993 at the Children's Hospital of Pittsburgh were reviewed. An additional telephone survey was conducted among the primary care physicians of those patients to collect information regarding administration of Haemophilus influenzae type b (HIB) vaccines. During the study period 28 children (age range, 11 months to 11 years, 10 months) were admitted with the diagnosis of epiglottitis. Cases declined remarkably in 1991. Fever, sore throat, and stridor were the usual symptoms. HIB was the most common cause of epiglottitis accounting for 21 cases. Candida albicans was recovered from the surface culture of the epiglottis in two patients. At least 11 children experienced vaccine failure: nine with polysaccharide vaccine and two with the conjugate vaccine for HIB. Cases of epiglottitis have declined dramatically since licensure of HIB conjugate vaccines for use in early infancy. At least 52% of the reported cases represent vaccine failures with the purified polysaccharide vaccine.


Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses.
The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T-cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP-76 protein in thymocytes. Here, we show that following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR-generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T-cell-mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects.


Tips and nodes are complementary not competing approaches to the calibration of molecular clocks.
Molecular clock methodology provides the best means of establishing evolutionary timescales, the accuracy and precision of which remain reliant on calibration, traditionally based on fossil constraints on clade (node) ages. Tip calibration has been developed to obviate undesirable aspects of node calibration, including the need for maximum age constraints that are invariably very difficult to justify. Instead, tip calibration incorporates fossil species as dated tips alongside living relatives, potentially improving the accuracy and precision of divergence time estimates. We demonstrate that tip calibration yields node calibrations that violate fossil evidence, contributing to unjustifiably young and ancient age estimates, less precise and (presumably) accurate than conventional node calibration. However, we go on to show that node and tip calibrations are complementary, producing meaningful age estimates, with node minima enforcing realistic ages and fossil tips interacting with node calibrations to objectively define maximum age constraints on clade ages. Together, tip and node calibrations may yield evolutionary timescales that are better justified, more precise and accurate than either calibration strategy can achieve alone.


Ambulatory gas usage in patients with chronic obstructive pulmonary disease and exertional hypoxemia.
Nonblinded observational studies have described the use of exertional supplemental oxygen in heterogeneous study populations. This report characterizes ambulatory gas usage among patients with chronic obstructive pulmonary disease (COPD) and exertional hypoxemia. Patients with COPD and exertional hypoxemia were included in blinded N-of-1 randomized controlled trials consisting of 3 pairs (oxygen and placebo) of 2-week treatment periods. Patient-reported and objective equipment measurements of cylinder and concentrator usage were collected. Patients (N = 26) self-reported using gas for a median of 1.3 hours per day; measured equipment usage was 1.2 hours per day. Median concentrator use (0.8 hour per day) was significantly greater than cylinder use (0.5 hours per day) (P = .02). Patients may underestimate use by as much 1.9 hours per day or overestimate it by as much as 2.4 hours per day. The correlation coefficient between the magnitude of gas usage and the difference between the 2 estimates was 0.63 (P = .0006). As duration of gas use increased, the discrepancy between patient-reported usage and equipment gas usage increased. Below 2 hours per day, differences between patient-reported and equipment measurements were small. Patients with COPD and exertional hypoxemia used little more than an hour of ambulatory oxygen daily, mostly from concentrators. Individual self-reported values are reasonably accurate under 2 hours per day but inaccurate for more prolonged use.


Koopman-based Impulsive Model Predictive Control of BCG Immunotherapy.
Bacillus of Calmette and Guerin (BCG) is the most effective immunologic treatment for non-muscle-invasive bladder cancer by stimulating the immune response of patients. The therapeutic performance of BCG treatment is limited by the dosing scheme, which is difficult to design due to nonlinear dynamics and constraints in the pharmacodynamic model. Here we present a computational method that combines linearization, impulsive control, and constrained optimization to design optimal drug dosing. We do so by first adopting Koopman theory to map the nonlinear pharmacodynamic model into linear space. Then we use model predictive control to design drug dosing schemes based on the transformed linear model with impulsive drug instillation, constrained by drug concentration. With this pipeline, we find that the Koopman-based linear system has almost identical dynamic behaviors to the original model based on numerical simulations. Also, the designed drug doses stay within the constraints and cancerous cell proliferation is effectively suppressed by driving the uninfected tumor cell population to a descending reference trajectory. Robustness tests are performed to show the proposed controller is robust to a certain level of model uncertainty. The method is expected to be generalized to the design of other model-based drug dosing schemes because of its optimality, impulsivity, and linearity.


[Functional condition of pancreas after stomach resection according to Roux].
Available are the results of surgical treatment of 90 patients with stenotic gastroduodenal ulcer in Burdenko Surgical Faculty Hospital of Sechenov Moscow Medical Academy between 1984 and 1985. 30 patients (study group) underwent stomach Roux-type resection. Truncal vagotomy with a stomach Bilroth-I resection was made in 20 control patients, after 20 control patients had a truncal vagotomy with pyloroplasty according to Heineke-Mikulicz, and 20 patients had selective proximal vagotomy with gastroduodenostomy by Joboulay (the third control group). Exocrine function of the pancreas was assessed by serum concentration of immunoreactive trypsin, endocrine function by fasting blood sugar, oral glucose tolerance and serum concentration of immunoreactive insulin. The authors came to the conclusion that exocrine function of the pancreas was equally damaged in patients with a Roux stomach resection, stem vagotomy with a stomach Bilroth-I resection and a stem vagotomy with pyloroplasty Heineke-Mikulicz. After selective proximal vagotomy a level of immunoreactive trypsin was normal. After a Roux stomach resection relative incompetence of basophil cells of the pancreas and long increase of insulin in the blood were observed but without influence on the glucose curve. The changes of glucose curve and level of immunoreactive insulin were similar in the control groups.


Which peer teaching methods do medical students prefer?
The beneficial effects of peer teaching in medical education have been well-described in the literature. However, it is unclear whether students prefer to be taught by peers in small or large group settings. This study's aim was to identify differences in medical students' preferences and perceptions of small-group versus large-group peer teaching. Questionnaires were administered to medical students in Year 3 and Year 4 (first 2 years of clinical training) at one institution in the United Kingdom to identify their experiences and perceptions of small-and large-group peer teaching. For this study, small-group peer teaching was defined as a tutorial, or similar, taught by peer tutor to a group of 5 students or less. Large-group peer teaching was defined as a lecture, or similar, taught by peer tutors to a group of more than 20 students. Seventy-three students (81% response rate) completed the questionnaires (54% males; median age of 23). Nearly 55% of respondents reported prior exposure to small-group peer teaching but a larger proportion of respondents (86%) had previously attended large-group peer teaching. Of all valid responses, 49% did not have a preference of peer teaching method while 47% preferred small-group peer teaching. The majority of Year 3 students preferred small-group peer teaching to no preference (62.5% vs 37.5%, Fisher's exact test; P = 0.035) whereas most Year 4 students did not report a particular preference. Likert-scale responses showed that the majority of students held negative perceptions about large-group peer teaching, in comparison with small-group peer teaching, with respect to (1) interactivity, (2) a comfortable environment to ask questions, and (3) feedback received. Most respondents in this study did not report a preference for small-versus large-group settings when taught by peers. More Year 3 respondents were likely to prefer small-group peer teaching as opposed to Year 4 respondents.


Pulmonary embolism causes endomyocarditis in the human heart.
Pulmonary embolism (PE) is a significant cause of morbidity and mortality. In a recent study in patients with PE, an increased level of macrophages was found in the right ventricle. To evaluate the presence of inflammatory cells, myocytolysis and intracavitary thrombi in the left and right ventricle of patients who died because of PE as a putative new source of heart failure. 22 patients with PE were studied. For comparison, eight controls and 11 patients who died of chronic pulmonary hypertension (PHT) were used. Slides of the left and right ventricle were stained with antibodies, identifying neutrophilic granulocytes, lymphocytes and macrophages, which were subsequently quantified. Myocytolysis was visualised using complement staining. Thrombi were identified by conventional staining. Compared with controls, in patients with PE a significant increase in extravascular localisation of all three inflammatory cells was found both in the right and left ventricle, coinciding with myocytolysis, indicative for myocarditis. No increase in inflammatory cells was found in patients with PHT. Endocardial cellular infiltration was also found, partly coinciding with the presence of ventricular thrombi. In patients with PE, endomyocarditis and intracavitary thrombi in the left and right ventricle were found. These abnormalities may be an additional new explanation for the observed cardiac enzyme release and functional abnormalities of the heart in these patients and may contribute to the morbidity and mortality of the disease.


Stem cells and the dental pulp: potential roles in dentine regeneration and repair.
The dentine-pulp complex displays exquisite regenerative potential in response to injury. The postnatal dental pulp contains a variety of potential progenitor/stem cells, which may participate in dental regeneration. A population of multipotent mesenchymal progenitor cells known as dental pulp stem cells with high proliferative potential for self-renewal has been described and may be important to the regenerative capacity of the tissue. The nature of the progenitor/stem cell populations in the pulp is of importance in understanding their potentialities and development of isolation or recruitment strategies, and allowing exploitation of their use in regeneration and tissue engineering. Various strategies will be required to ensure not only effective isolation of these cells, but also controlled signalling of their differentiation and regulation of secretory behaviour. Characterization of these cells and determination of their potentialities in terms of specificity of regenerative response will form the foundation for development of new clinical treatment modalities, whether involving directed recruitment of the cells and seeding of stem cells at sites of injury for regeneration or use of the stem cells with appropriate scaffolds for tissue engineering solutions. Such approaches will provide an innovative and novel biologically based new generation of clinical treatments for dental disease.


Specific insertions of zinc finger domains into Gag-Pol yield engineered retroviral vectors with selective integration properties.
Retroviral vectors offer benefits of efficient delivery and stable gene expression; however, their clinical use raises the concerns of insertional mutagenesis and potential oncogenesis due to genomic integration preferences in transcriptional start sites (TSS). We have shifted the integration preferences of retroviral vectors by generating a library of viral variants with a DNA-binding domain inserted at random positions throughout murine leukemia virus Gag-Pol, then selecting for variants that are viable and exhibit altered integration properties. We found seven permissive zinc finger domain (ZFD) insertion sites throughout Gag-Pol, including within p12, reverse transcriptase, and integrase. Comprehensive genome integration analysis showed that several ZFD insertions yielded retroviral vector variants with shifted integration patterns that did not favor TSS. Furthermore, integration site analysis revealed selective integration for numerous mutants. For example, two retroviral variants with a given ZFD at appropriate positions in Gag-Pol strikingly integrated primarily into four common sites out of 3.1 x 10(9) possible human genome locations (P = 4.6 x 10(-29)). Our findings demonstrate that insertion of DNA-binding motifs into multiple locations in Gag-Pol can make considerable progress toward engineering safer retroviral vectors that integrate into a significantly narrowed pool of sites on human genome and overcome the preference for TSS.


Does wastewater treatment plant upgrading with activated carbon result in an improvement of fish health?
In the present study, the efficiency of a wastewater treatment plant (WWTP) upgraded with a powdered activated carbon unit for the reduction of micropollutants and the related advantages for fish health have been analyzed by means of different biomarkers, i.e. histopathological investigations, analyses of glycogen content and stress proteins, as well as by chemical analyses in different matrices. Comparative analyses were conducted prior and subsequent to the installation of the additional purification unit. Chemical analyses revealed a significant reduction of several pharmaceuticals, including diclofenac, carbamazepine and metoprolol, in samples of effluent and surface water downstream of the WWTP after its upgrade. In addition, diminished concentrations of diclofenac and PFOS were detected in tissues of analyzed fish. Histopathological investigations of fish liver, gills, and kidney revealed improved tissue integrity in fish after improved wastewater treatment. In parallel, biochemical measurements of glycogen revealed increased energy resources in fish liver and, furthermore, hsp70 levels in livers of exposed rainbow trout and in kidneys of exposed brown trout were lower after than before the WWTP upgrade. In summary, additional treatment with powdered activated carbon led to a reduction of potentially hazardous chemicals in the effluent and the adjacent river and, consequently, to an improvement of fish health in the receiving water course.


Determination of optical parameters of human breast tissue from spatially resolved fluorescence: a diffusion theory model.
We report the measurement of optical transport parameters of pathologically characterized malignant tissues, normal tissues, and different types of benign tumors of the human breast in the visible wavelength region. A spatially resolved steady-state diffuse fluorescence reflectance technique was used to estimate the values for the reduced-scattering coefficient (mu(s)') and the absorption coefficient (mu(a)) of human breast tissues at three wavelengths (530, 550, and 590 nm). Different breast tissues could be well differentiated from one another, and different benign tumors could also be distinguished by their measured transport parameters. A diffusion theory model was developed to describe fluorescence light energy distribution, especially its spatial variation in a turbid and multiply scattering medium such as human tissue. The validity of the model was checked with a Monte Carlo simulation and also with different tissue phantoms prepared with polystyrene microspheres as scatterers, riboflavin as fluorophores, and methylene blue as absorbers.


Simultaneous quantification of multiple bacterial metabolites using surface-enhanced Raman scattering.
Given the commercial importance of the compounds produced by genetically modified organisms, there is a need for screening methods which facilitate the evaluation of newly developed strains, especially during the phase of proof-of-concept development. We report a time-efficient analysis method for the screening of bacterial strains, which enables the detection of two structurally similar secondary bacterial metabolites. By combining liquid-liquid extraction and surface-enhanced Raman scattering we were able to quantify p-coumaric acid and cinnamic acid, produced by genetically modified E. coli from tyrosine and phenylalanine, respectively. With the simple sample pre-treatment method, and by applying a partial least squares data analysis method, we simultaneously detected the analytes from four E. coli strains cultured in the presence or absence of tyrosine and phenylalanine.


Isolation, characterization and structure-elicitor activity relationships of hibernalin and its two oxidized forms from Phytophthora hibernalis Carne 1925.
Three alpha-elicitins, named hibernalin1, hibernalin2 and hibernalin3 (hib1, hib2 and hib3, respectively), were isolated by reverse phase-low-pressure liquid chromatography from culture filtrates of Phytophthora hibernalis Carne 1925, the causal agent of citrus lemon brown rot. Hib1 proved to be identical to syringicin previously isolated from culture filtrates of Phytophthora syringae. Hib2 and hib3 shared the same primary structure with hib1, but contained, at position 50, Met sulphoxide or sulphone, respectively. By SDS-PAGE, the three proteins showed the same electrophoretic mobility, corresponding to about 10 kDa. Exact M(r) values were obtained by MALDI-TOF-MS (10,194.82 for hib1, 10,209.33 for hib2 and 10,223.80 for hib3), while by ESI-MS an M(r) value of 10,194.90 was found for hib1 and no results for hib2 and hib3. The hibernalin forms showed a high propensity to self-association, after exposure to acetonitrile. Hib1 showed to be active in both the hypersensitivity response and electrolytes leakage assays; the sample containing hib1 and hib2 was only weakly active in the first assay and inactive in the second assay, while the sample containing all three hibernalin forms proved to be inactive in both tests. It is proposed that the different activities of the three hibernalin samples could be very likely attributed to both Met50 oxidation and aggregation.


Hydrogen-bond-assisted activation of allylic alcohols for palladium-catalyzed coupling reactions.
We report direct activation of allylic alcohols using a hydrogen-bond-assisted palladium catalyst and use this for alkylation and amination reactions. The novel catalyst comprises a palladium complex based on a functionalized monodentate phosphoramidite ligand in combination with urea additives and affords linear alkylated and aminated allylic products selectively. Detailed kinetic analysis show that oxidative addition of the allyl alcohol is the rate-determining step, which is facilitated by hydrogen bonds between the alcohol, the ligand functional group, and the additional urea additive.


Modeling equine race surface vertical mechanical behaviors in a musculoskeletal modeling environment.
Race surfaces have been associated with the incidence of racehorse musculoskeletal injury, the leading cause of racehorse attrition. Optimal race surface mechanical behaviors that minimize injury risk are unknown. Computational models are an economical method to determine optimal mechanical behaviors. Previously developed equine musculoskeletal models utilized ground reaction floor models designed to simulate a stiff, smooth floor appropriate for a human gait laboratory. Our objective was to develop a computational race surface model (two force-displacement functions, one linear and one nonlinear) that reproduced experimental race surface mechanical behaviors for incorporation in equine musculoskeletal models. Soil impact tests were simulated in a musculoskeletal modeling environment and compared to experimental force and displacement data collected during initial and repeat impacts at two racetracks with differing race surfaces - (i) dirt and (ii) synthetic. Best-fit model coefficients (7 total) were compared between surface types and initial and repeat impacts using a mixed model ANCOVA. Model simulation results closely matched empirical force, displacement and velocity data (Mean R(2)=0.930-0.997). Many model coefficients were statistically different between surface types and impacts. Principal component analysis of model coefficients showed systematic differences based on surface type and impact. In the future, the race surface model may be used in conjunction with previously developed the equine musculoskeletal models to understand the effects of race surface mechanical behaviors on limb dynamics, and determine race surface mechanical behaviors that reduce the incidence of racehorse musculoskeletal injury through modulation of limb dynamics.


Short communication: repeatability of measures of rectal temperature in dairy cows.
Although taking body temperature by rectal thermometer is the method most commonly used to identify sick cows in the postpartum period, no data on the repeatability of this measure are available. The overall objective of this study was to evaluate variability of rectal temperatures in dairy cows considering different factors (intra- and interinvestigator repeatability, different thermometers, penetration depth into the rectum, and defecation). High coefficients of correlation (r=0.98) and small differences between values of rectal temperatures (observer A=39.3+/-1.0 degrees C and observer B=39.4+/-1.0 degrees C) provide evidence that rectal temperature was a repeatable measure in dairy cows. Testing was carried out using 4 different digital thermometers: GLA M750 (GLA Agricultural Electronics, San Luis Obispo, CA), MTI8101 (SES Scala Electronics, Stahnsdorf, Germany), MT1831 (Microlife AG, Widnau, Switzerland) and Domotherm TH1 (Uebe Medical GmbH, Wertheim, Germany). Thermometers were inserted into the rectum to a certain depth (GLA M750 and MTI8101=11.5cm; MT1831=8.4cm; Domotherm TH1=7.7cm) and a measure was finished when a visual or acoustic signal was emitted by the thermometer. The measures could be influenced by the procedure itself (up to 0.5 degrees C), type of thermometer (up to 0.3 degrees C), and the penetration depth (11.5cm or 6.0cm in one of the experiments) into the rectum (up to 0.4 degrees C difference between a penetration depth of 11.5cm and 6.0cm in one of the experiments). Differences in rectal temperature before and after defecation were minor (<0.1 degrees C). These results indicate that some care is required in generalizing rectal measures of body temperature.


Fetal rhythm-based language discrimination: a biomagnetometry study.
Using fetal biomagnetometry, this study measured changes in fetal heart rate to assess discrimination of two rhythmically different languages (English and Japanese). Two-minute passages in English and Japanese were read by the same female bilingual speaker. Twenty-four mother-fetus pairs (mean gestational age=35.5 weeks) participated. Fetal magnetocardiography was recorded while the participants were presented first with passage 1, a passage in English, and then, following an 18 min interval, with passage 2, either a different passage in English (English-English condition: N=12) or in Japanese (English-Japanese condition: N=12). The fetal magnetocardiogram was reconstructed following independent components analysis decomposition. The mean interbeat intervals were calculated for a 30 s baseline interval directly preceding each passage and for the first 30 s of each passage. We then subtracted the mean interbeat interval of the 30 s baseline interval from that of the first 30 s interval, yielding an interbeat interval change value for each passage. A significant interaction between condition and passage indicated that the English-Japanese condition elicited a more robust interbeat interval change for passage 2 (novelty phase) than for passage 1 (familiarity phase), reflecting a faster heart rate during passage 2, whereas the English-English condition did not. This effect indicates that fetuses are sensitive to the change in language from English to Japanese. These findings provide the first evidence for fetal language discrimination as assessed by fetal biomagnetometry and support the hypothesis that rhythm constitutes a prenatally available building block in language acquisition.


Specific capture of uranyl protein targets by metal affinity chromatography.
To improve general understanding of biochemical mechanisms in the field of uranium toxicology, the identification of protein targets needs to be intensified. Immobilized metal affinity chromatography (IMAC) has been widely developed as a powerful tool for capturing metal binding proteins from biological extracts. However uranyl cations (UO2(2+)) have particular physico-chemical characteristics which prevent them from being immobilized on classical metal chelating supports. We report here on the first development of an immobilized uranyl affinity chromatography method, based on the cation-exchange properties of aminophosphonate groups for uranyl binding. The cation distribution coefficient and loading capacity on the support were determined. Then the stability of the uranyl-bonded phase under our chromatographic conditions was optimized to promote affinity mechanisms. The successful enrichment of uranyl binding proteins from human serum was then proven using proteomic and mass spectral analysis.


Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.
Ten percent of North American patients with non-small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.


Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens.
Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens. Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit. A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%). The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.


The Boston keratoprosthesis.
The Boston keratoprosthesis (BKPro) is often the only hope for visual rehabilitation in severe corneal disease. Since Food and Drug Administration approval of the device in 1992, there have been a series of advances in its design, surgical techniques, and postoperative care, which have widened its applicability and decreased associated complications. The purpose of this review is to highlight the indications, management, outcomes, and advances in the BKPro literature. With more surgeons reporting long-term data, it is evident that modifications to the device and perioperative care have led to higher rates of device retention and improved visual outcomes. Recent data also suggest that BKPro may be superior to traditional corneal transplant in the setting of a previously failed graft. There may be advantages to implantation of the device earlier in the course of some diseases without an increased risk of postoperative complications. Devices to reliably measure intraocular pressure and imaging modalities to provide improved visualization of intraocular structures have the potential to further improve outcomes. The current indications for implantation of the BKPro have broadened. Initially considered a surgery of last resort, the clinical indications for use of the BKPro continue to grow. Early detection and management of postoperative complications can mitigate vision loss and improve outcomes.


Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations.
It has become increasingly clear that the cells within the tumor microenvironment play a critical role in cancer growth and metastasis. Studies in experimental models suggest that carcinoma-associated fibroblasts (CAF) differ from normal fibroblasts and are capable of promoting cancer progression through a variety of mechanisms. At present, a definitive view is lacking on whether genomic abnormalities are present and whether they might underlie the observed phenotypic differences. This study reports the molecular analysis of the largest series of breast CAFs reported to date, with an array comparative genomic hybridization-based DNA copy number analysis of cultured CAFs derived from 25 freshly resected human breast cancers. We found DNA copy number changes consisting of the whole arm of chromosomes 6p and 9p plus interstitial 4q loss in only one sample. No abnormalities were observed in non-tumor-associated fibroblast counterparts. Karyotyping of the same CAF revealed further chromosomal abnormalities, which included clonal loss of chromosomes, chromosomal duplications, and less frequent chromosomal rearrangements. These abnormalities were not associated with alterations in the global gene expression profile of this particular CAF, relative to its non-tumor-associated fibroblast counterpart. Moreover, this particular patient's CAF also displayed the only p53 mutation in the cohort, the first time such a mutation has been reported in freshly cultured human CAFs. These findings argue that the procancerous effects of CAFs are unlikely to be due to DNA copy number-type genomic abnormalities in the CAFs themselves. As such, breast CAFs should be mainly regarded as genomically stable cellular constituents that exist within complex cancer microenvironments.


[An analysis of the results of a program for the prevention of sickle-cell anemia in Camagüey Province, 1986].
This paper deals with results of the programme for the prevention of anemia due to sickle cells carried out in Camagüey Province, during 1986. The programme is based on the statistical study of all pregnant women searched during 1986 (12,154), to verify those carriers (heterozygous) of hemoglobin AS and AC, as well as risk couples and to be able to analyze incidence by health area during the period comprised from March 1st. to June 30, 1986, at the Maternal Hospital and "Manuel Ascunce Domenech" Provincial Hospital, Camagüey. A data collecting model looking upon particular and familial aspects of the pregnant woman, such as origin, race, number of clinical history and gestational age, within others, was filled by them. There is 2.13% (259) pregnant women carriers of this pathology in the province. Ten risk couples were detected, but without presenting consanguinity. The concept that this disease prevails in black people is sustained. It is considered that there is need of a publishing work on this theme among patients and of preparing scientifically the nursing personnel in charge of pregnant women.


A tele-medicine service over satellite network.
The main objective of paper is to describe a proposed tele-medicine pilot is for establishing a telemedicine network in a Private Healthcare Organization, to be developed in the frame of the ESA project, HOSTHOST - HELLAS SAT Offering in Satellite Communications, ESA sponsored project: " Satcom Network Systems and Services". The HOST program focuses on the development of the Hellas Sat commercial offering in end-to-end satellite telecommunication services for supporting the delivery of bidirectional (broadband) applications in Greece, the Balkans, SE Europe, and the Middle East. To this effect a satellite broadband network will be implemented and operated 5 remote sites, three of them acting as trainers and the rest two as trainees The pilot system will allow real time exchanges of medical records to aid tele-diagnosis, coordination of medical and administrative processes, tele-assistance using videoconferencing; distant medical equipment or medical records (images and examinations, allergies, medical history, etc) monitoring and real time tele-diagnosis by specialized medical doctors on remote sites.


A quantitative cell migration assay for murine enteric neural progenitors.
Neural crest cells (NCC) are a transient and multipotent cell population that originates from the dorsal neural tube and migrates extensively throughout the developing vertebrate embryo. In addition to providing peripheral glia and neurons, NCC generate melanocytes as well as most of the cranio-facial skeleton. NCC migration and differentiation is controlled by a combination of their axial origin along the neural tube and their exposure to regionally distinct extracellular cues. Such contribution of extracellular ligands is especially evident during the formation of the enteric nervous system (ENS), a complex interconnected network of neural ganglia that locally controls (among other things) gut muscle movement and intestinal motility. Most of the ENS is derived from a small initial pool of NCC that undertake a long journey in order to colonize - in a rostral to caudal fashion - the entire length of the prospective gut. Among several signaling pathways known to influence enteric NCC colonization, GDNF/RET signaling is recognized as the most important. Indeed, spatiotemporally controlled secretion of the RET ligand GDNF by the gut mesenchyme is chiefly responsible for the attraction and guidance of RET-expressing enteric NCC to and within the embryonic gut. Here, we describe an ex vivo cell migration assay, making use of a transgenic mouse line possessing fluorescently labeled NCC, which allows precise quantification of enteric NCC migration potential in the presence of various growth factors, including GDNF.


Kinesin-2 from C. reinhardtii Is an Atypically Fast and Auto-inhibited Motor that Is Activated by Heterotrimerization for Intraflagellar Transport.
Construction and function of virtually all cilia require the universally conserved process of intraflagellar transport (IFT) [1, 2]. During the atypically fast IFT in the green alga C. reinhardtii, on average, 10 kinesin-2 motors "line up" in a tight assembly on the trains [3], provoking the question of how these motors coordinate their action to ensure smooth and fast transport along the flagellum without standing in each other's way. Here, we show that the heterodimeric FLA8/10 kinesin-2 alone is responsible for the atypically fast IFT in C. reinhardtii. Notably, in single-molecule studies, FLA8/10 moved at speeds matching those of in vivo IFT [4] but additionally displayed a slow velocity distribution, indicative of auto-inhibition. Addition of the KAP subunit to generate the heterotrimeric FLA8/10/KAP relieved this inhibition, thus providing a mechanistic rationale for heterotrimerization with the KAP subunit fully activating FLA8/10 for IFT in vivo. Finally, we linked fast FLA8/10 and slow KLP11/20 kinesin-2 from C. reinhardtii and C. elegans through a DNA tether to understand the molecular underpinnings of motor coordination during IFT in vivo. For motor pairs from both species, the co-transport velocities very nearly matched the single-molecule velocities, and both complexes spent roughly 80% of the time with only one of the two motors attached to the microtubule. Thus, irrespective of phylogeny and kinetic properties, kinesin-2 motors work mostly alone without sacrificing efficiency. Our findings thus offer a simple mechanism for how efficient IFT is achieved across diverse organisms despite being carried out by motors with different properties.


Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2-Substituted-Alkynyl-1-Sulfonyl Fluoride (SASF) Hubs.
Diversity Oriented Clicking (DOC) is a unified click-approach for the modular synthesis of lead-like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving "diversity with ease", by combining classic C-C π-bond click chemistry with recent developments in connective SuFEx-technologies. We showcase 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs) as a new class of connective hub in concert with a diverse selection of click-cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click-library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3- and 1,5-dipoles; while reaction with cyclic dienes yields several three-dimensional bicyclic Diels-Alder adducts. Growing the library to 278 discrete compounds through late-stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well-plates-demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.


On the impact of physiological noise in spinal cord functional MRI.
Functional magnetic resonance imaging (fMRI) techniques are widely exploited for the study of brain activation. In recent years, similar approaches have been attempted for the study of spinal cord function; however, obtaining good functional images of spinal cord still represents a technical and scientific challenge. Some of the main limiting factors can be classified under the broad category of "physiological noise," and are related to 1) the cerebrospinal fluid (CSF) flux in the subarachnoid space surrounding the spinal cord; 2) the cord motion itself; and 3) the small area of the cord, which makes it critical to have a high image resolution. In addition, the different magnetic susceptibility properties of tissues surrounding the spinal cord reduce the local homogeneity of the static magnetic field, causing image distortion, reduction of the effective resolution, and signal loss, all effects that are modulated by motion. For these reasons, a number of methods have been developed for the purpose of denoising spinal cord fMRI time series. In this work, after a short introduction on the relevant features of the spinal cord anatomy, we review the main sources of physiological noise in spinal cord fMRI and discuss the main approaches useful for its mitigation.


Bench surgical training with lyophilized esophageal segments.
To present lyophilized esophageal segments that can be used to learn surgical skills. Four esophagus were harvested from four non-esophagus related research dogs at the moment of euthanasia. Each esophagus was trimmed in 3 cm long segments. They were lyophilized and stored during 30 days. The day programmed for surgical skills practice, they were rehydrated. Sixteen segments have been used. After rehydrating, all the segments kept their normal anatomic shape and structural integrity. One incision was made on every esophageal segment and sutured with running stitches of 3-0 polyglactin 910. There were no complications, such as tissue tears, nor esophageal hardening. The lyophilized esophagus is a high fidelity, practical, reproducible, portable, low-cost bench model. It allows general surgery apprentices to learn how to handle an esophagus, as well as to perfect their surgical and suture abilities before applying them on real patient's esophagus.


The relative merit of ruminal undegradable protein from soybean meal or soluble fiber from beet pulp to improve nitrogen utilization in dairy cows.
Early lactating dairy cows were used to determine whether the replacement of solvent-extracted soybean meal [SSBM; a source of rumen-degradable protein (RDP)] with expeller soybean meal (ESBM; a source of rumen-undegradable protein), or the replacement of high-moisture shelled corn (HMSC) with beet pulp (a source of soluble fiber) would be effective in improving efficiency of N usage for milk production. The study was designed as a replicated 4 x 4 Latin square with 21-d periods. Eight multiparous Holstein cows were fed, ad libitum, the following diets, which were based on alfalfa silage and HMSC, and formulated to be isocaloric: 1) basal diet without a protein supplement (negative control diet: NC); 2) NC supplemented with solvent-extracted SBM (diet SSBM); 3) NC supplemented with expeller SBM (diet ESBM); 4) SSBM in which unmolassed dried beet pulp replaced half of the HMSC (diet SSBMBP). Compared with diet NC, protein supplementation increased intake of organic matter and dry matter. Milk and milk protein yields were lower with NC but this diet resulted in the greatest efficiency of N usage for milk production (30% milk N/N intake). Supplementation with ESBM, a proven source of RUP, increased plasma concentrations of histidine and branched-chain amino acids, and reduced milk urea N concentration, but failed to improve the yields of milk or milk protein. Milk fat yield tended to decrease with RUP supplementation. Replacing part of HMSC with soluble fiber from beet pulp (SSBMBP) tended to decrease milk production compared with SSBM; the effect was due to a reduction in dry matter intake. There were no differences among diets SSBM, ESBM, or SSBMBP in urinary excretion of purine derivatives. Neither substitution of ESBM for SSBM nor partial replacement of HMSC with beet pulp altered the efficiency of N usage for milk production or manure N excretion.


Seated T'ai Chi in Older Taiwanese People Using Wheelchairs: A Randomized Controlled Trial Investigating Mood States and Self-Efficacy.
There is growing interest in t'ai chi, but little research has addressed whether t'ai chi is effective in older people using wheelchairs for mobilization. The aim of this study was to compare the effects of seated t'ai chi exercise and usual standard activities on mood states and self-efficacy in older people living in a long-term care facility and using wheelchairs for mobilization. Randomized controlled trial (trial registration no. ACTRN12613000029796). One long-term-care facility in Taiwan. Sixty participants were randomly assigned by a computer-generated random sequence to a t'ai chi group (n = 30) or a usual exercise and entertainment activities group (n = 30). Seated t'ai chi exercise for 40 minutes three times a week for 26 weeks was provided. Mood states (Profile of Mood States Short Form [POMS-SF]) and self-efficacy (Self-Efficacy for Exercise [SEE]). At week 26, participants in the t'ai chi group reported significantly lower mood states on the fatigue-inertia dimension of the POMS-SF (mean score ± standard deviation, 3.56 ± 3.71) than did the control group (mean score, 7.16 ± 6.36) (F [1, 58] = 7.15; p < 0.05). The t'ai chi group recorded significantly higher SEE levels (mean, 35.66 ± 36.83) than did those in the control group (mean, 15.30 ± 26.43) (F [1, 58] = 6.05; p < 0.05). The findings highlight the importance of t'ai chi for a reduction in the fatigue-inertia mood state and an increase in self-efficacy for older people using wheelchairs.


Loss of the endothelin signal pathway in C6 rat glioma cells persistently infected with measles virus.
Endothelin 1 causes a strong Ca2+ signal in C6 rat glioma cells as measured by fura-2 fluorescence. This endothelin 1-induced Ca2+ signal was not observed when the cells were persistently infected with a measles virus strain of subacute sclerosing panencephalitis (SSPE, strain Lec). Binding of 125I-labeled endothelin 1 to the C6/SSPE cells was less than 5% of the binding to the C6 control cells, suggesting that the impairment in signal transduction was due to a loss of binding sites for endothelin 1. Treatment of the C6/SSPE cells with measles antiserum resulted in the loss of expression of viral proteins located in the membrane as well as inside the cells (antigenic modulation), but it restored neither the endothelin 1-induced Ca2+ rise nor the 125I-endothelin 1 binding. Cocultivation of uninfected C6 cells with C6/SSPE cells (9:1 ratio) resulting in contact-mediated transmission of measles virus showed that the 125I-endothelin 1 binding activity was gradually lost as a consequence of persistent virus infection.


Mechanoregulatory Cholesterol Oxidase-Functionalized Nanoscale Metal-Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells.
Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD-functionalized nanoscale metal-organic framework, Hf-TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf-TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase-1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf-TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf-TBP, Hf-TBP/COD improves anti-tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple-negative breast cancer model and a colon cancer model, respectively.


The cost of tachyarrhythmia management.
Health economy measures in the United States demand that physicians develop more cost effective approaches to the management of patients who have tachyarrhythmias. Accordingly, the hospital records of 47 patients admitted for electrophysiologic evaluations were reviewed. The average length hospital stay for patients who had ventricular tachycardia was 32 days (range: 7-75) and the average cost of hospitalization was $41,988 (range: $6,299-131,259) per patient. Hospitalization costs were significantly less for 14 patients who had supraventricular tachycardia and for 10 patients who were evaluated for syncope of uncertain etiology. The cost of hospitalization correlated significantly with the length of hospital stay (r = 0.98). Therefore, new approaches to managing critical arrhythmias are needed; these include outpatient surveillance and intervention systems, use of potentially curative therapies; e.g. resection or ablation application of electrical devices capable of detecting and terminating lethal arrhythmias.


Osmotic effects on amino acid oxidation in skate liver mitochondria.
The mechanism responsible for the osmotic sensitivity of sarcosine oxidation by liver mitochondria from the little skate, Raja erinacea Mitchill, is examined. Assay medium tonicity, rather than a solute effect (urea or trimethylamine oxide), is probably responsible for the inverse relationship between osmolarity and the rate of oxidation of sarcosine by these mitochondria. Sarcosine oxidation proceeds through the flavin-linked sarcosine oxidase with the resultant glycine catabolized in the NAD-linked glycine cleavage system. The tonicity-sensitive component of the sarcosine oxidative pathway is not the glycine cleavage system. Sarcosine oxidation in the presence of rotenone is sensitive to medium tonicity. Oxidation of serine, which is also catabolized through the glycine cleavage system, is not as sensitive to tonicity as is sarcosine oxidation. Mitochondrial volume changes also appear to affect the transport of glycine. Although sarcosine does not appear to share the glycine transporter, it is possible that sarcosine transport is similarly sensitive to medium tonicity. The effects of osmolarity on the oxidation of dimethylglycine appear to support this hypothesis. Tonicity effects on sarcosine oxidase cannot yet be eliminated.


Accuracy of a 3-Dimensionally Printed Navigational Template for Localizing Small Pulmonary Nodules: A Noninferiority Randomized Clinical Trial.
Localization of small lung nodules are challenging because of the difficulty of nodule recognition during video-assisted thoracoscopic surgery. Using 3-dimensional (3-D) printing technology, a navigational template was recently created to assist percutaneous lung nodule localization; however, the efficacy and safety of this template have not yet been evaluated. To assess the noninferiority of the efficacy and safety of a 3-D-printed navigational template guide for localizing small peripheral lung nodules. This noninferiority randomized clinical trial conducted between October 2016 and October 2017 at Shanghai Pulmonary Hospital, Shanghai, China, compared the safety and precision of lung nodule localization using a template-guided approach vs the conventional computed tomography (CT)-guided approach. In total, 213 surgical candidates with small peripheral lung nodules (<2 cm) were recruited to undergo either CT- or template-guided lung nodule localization. An intention-to-treat analysis was conducted. Percutaneous lung nodule localization. The primary outcome was the accuracy of lung nodule localization (localizer deviation), and secondary outcomes were procedural duration, radiation dosage, and complication rate. Of the 200 patients randomized at a ratio of 1:1 to the template- and CT-guided groups, most were women (147 vs 53), body mass index ranged from 15.4 to 37.3, the mean (SD) nodule size was 9.7 (2.9) mm, and the mean distance between the outer edge of target nodule and the pleura was 7.8 (range, 0.0-43.9) mm. In total, 190 patients underwent either CT- or template-guided lung nodule localization and subsequent surgery. Among these patients, localizer deviation did not significantly differ between the template- and CT-guided groups (mean [SD], 8.7 [6.9] vs 9.6 [5.8] mm; P = .36). The mean (SD) procedural durations were 7.4 (3.2) minutes for the template-guided group and 9.5 (3.6) minutes for the CT-guided group (P < .001). The mean (SD) radiation dose was 229 (65) mGy × cm in the template-guided group and 313 (84) mGy × cm in CT-guided group (P < .001). The use of the 3-D-printed navigational template for localization of small peripheral lung nodules showed efficacy and safety that were not substantially worse than those for the CT-guided approach while significantly simplifying the localization procedure and decreasing patient radiation exposure. ClinicalTrials.gov identifier: NCT02952261.


SMAC Mimetic Plus Triple-Combination Bispecific HIVxCD3 Retargeting Molecules in SHIV.C.CH505-Infected, Antiretroviral Therapy-Suppressed Rhesus Macaques.
The "shock-and-kill" human immunodeficiency virus type 1 (HIV-1) cure strategy involves latency reversal followed by immune-mediated clearance of infected cells. We have previously shown that activation of the noncanonical NF-κB pathway using an inhibitor of apoptosis (IAP), AZD5582, reverses HIV/simian immunodeficiency virus (SIV) latency. Here, we combined AZD5582 with bispecific HIVxCD3 DART molecules to determine the impact of this approach on persistence. Rhesus macaques (RMs) (n = 13) were infected with simian/human immunodeficiency virus SHIV.C.CH505.375H.dCT, and triple antiretroviral therapy (ART) was initiated after 16 weeks. After 42 weeks of ART, 8 RMs received a cocktail of 3 HIVxCD3 DART molecules having human A32, 7B2, or PGT145 anti-HIV-1 envelope (Env) specificities paired with a human anti-CD3 specificity that is rhesus cross-reactive. The remaining 5 ART-suppressed RMs served as controls. For 10 weeks, a DART molecule cocktail was administered weekly (each molecule at 1 mg/kg of body weight), followed 2 days later by AZD5582 (0.1 mg/kg). DART molecule serum concentrations were well above those considered adequate for redirected killing activity against Env-expressing target cells but began to decline after 3 to 6 weekly doses, coincident with the development of antidrug antibodies (ADAs) against each of the DART molecules. The combination of AZD5582 and the DART molecule cocktail did not increase on-ART viremia or cell-associated SHIV RNA in CD4+ T cells and did not reduce the viral reservoir size in animals on ART. The lack of latency reversal in the model used in this study may be related to low pre-ART viral loads (median, <105 copies/ml) and low preintervention reservoir sizes (median, <102 SHIV DNA copies/million blood CD4+ T cells). Future studies to assess the efficacy of Env-targeting DART molecules or other clearance agents to reduce viral reservoirs after latency reversal may be more suited to models that better minimize immunogenicity and have a greater viral burden.IMPORTANCE The most significant barrier to an HIV-1 cure is the existence of the latently infected viral reservoir that gives rise to rebound viremia upon cessation of ART. Here, we tested a novel combination approach of latency reversal with AZD5582 and clearance with bispecific HIVxCD3 DART molecules in SHIV.C.CH505-infected, ART-suppressed rhesus macaques. We demonstrate that the DART molecules were not capable of clearing infected cells in vivo, attributed to the lack of quantifiable latency reversal in this model with low levels of persistent SHIV DNA prior to intervention as well as DART molecule immunogenicity.


Gambling among European professional athletes. Prevalence and associated factors.
In Europe, the prevalence of gambling disorders in the general population ranges from 0.15 to 6.6%. Professional athletes are known for having risk factors for addictive behaviors, such as young age or sensation seeking, though no study has yet tried to evaluate the prevalence of gambling and gambling disorders among this specific population. The goals of this study were to estimate the prevalence of gambling, problematic or not, among European professional athletes and to explore the factors that are associated with gambling practice and gambling problems in professional athletes. A self-completion questionnaire was specifically designed for this study. The questionnaires were distributed by European Union athletes to professional ice hockey, rugby, handball, basketball, football, indoor football, volleyball, and cricket teams in Spain, France, Greece, Ireland, Italy, Sweden, and the United Kingdom. Socio-demographic variables (age, sex, education, marital and parental status, sport, country of birth, and country of practice), variables linked to gambling (gambling habits, screening of gambling problems with the Lie/Bet questionnaire, and gambling related cognitions), and impulsive behavior data (urgency, premeditation, perseverance, and sensation seeking [UPPS]-Short Form questionnaire) were gathered. There were 1,236 questionnaires filled out. The percentage of professional athletes that had gambled at least once during the previous year was 56.6%. The prevalence of problem gambling, current or past, was 8.2%. A certain number of variables were associated with the gambling status. In particular, betting on one's own team (OR = 4.1, CI95% [1.5-11.5]), betting online (OR = 2.9, CI95% [1.6-5.4]), gambling regularly (OR = 4.0, CI95% [2.1-7.6]), and having a high positive urgency score (OR = 1.5, CI95% [1.3-1.7]) were associated with gambling problems, current or past, among professional athletes. Professional athletes are particularly exposed to both gambling and problem gambling.


The triple-A supply chain.
Building a strong supply chain is essential for business success. But when it comes to improving their supply chains, few companies take the right approach. Many businesses work to make their chains faster or more cost-effective, assuming that those steps are the keys to competitive advantage. To the contrary: Supply chains that focus on speed and costs tend to deteriorate over time. The author has spent 15 years studying more than 60 companies to gain insight into this and other supply chain dilemmas. His conclusion: Only companies that build supply chains that are agile, adaptable, and aligned get ahead of their rivals. All three components are essential; without any one of them, supply chains break down. Great companies create supply chains that respond to abrupt changes in markets. Agility is critical because in most industries, both demand and supply fluctuate rapidly and widely. Supply chains typically cope by playing speed against costs, but agile ones respond both quickly and cost-efficiently. Great companies also adapt their supply networks when markets or strategies change. The best supply chains allow managers to identify structural shifts early by recording the latest data, filtering out noise, and tracking key patterns. Finally, great companies align the interests of the partners in their supply chains with their own. That's important because every firm is concerned solely with its own interests. If its goals are out of alignment with those of other partners in the supply chain, performance will suffer. When companies hear about the triple-A supply chain, they assume that building one will require increased technology and investment. But most firms already have the infrastructure in place to create one. A fresh attitude alone can go a long way toward making it happen.


Heterogeneous and Combined Heterogeneous/Homogeneous Combustion Modeling of SOFC Off-Gases.
The heterogeneous (catalytic) and the hetero-/homogeneous (catalytic and gas-phase) combustion processes of solid oxide fuel cell (SOFC) off-gases with compositions typical of a high cell utilization rate are investigated with high-fidelity 2D simulations in a platinum-coated planar channel using detailed hetero-/homogeneous chemistry. The pressures are 1-8 bar; the reactant streams have volumetric H2 and CO contents 0.7-1.5 and 5.3-9.7%, respectively; H2O and CO2 dilutions are ∼40 and ∼50%, respectively; and the global fuel/air equivalence ratio is 0.90. Water inhibits chemically the catalytic oxidation of H2, as it leads to high H(s) surface coverage that favors the recombinative desorption of H(s) to H2. On the other hand, H2O promotes chemically the catalytic oxidation of CO by creating high OH(s) coverage that in turn accelerates the CO consumption. Strong flames are established at the highest H2 content cases and for pressures p ≥ 3 bar. For all cases with vigorous homogeneous combustion, the catalytic and gas-phase reaction pathways coexist and compete with each other for the consumption of H2 and CO. The large H2O content leads to gas-phase production of H2 via the reaction H2O + H = H2 + OH. However, the gas-phase produced H2 is subsequently consumed by the catalytic pathway, such that nearly complete H2 conversion is attained at the reactor outlet. Gaseous chemistry does not affect the reactor lengths required for complete H2 conversion but substantially reduces the corresponding lengths for CO conversion. The H2 emissions decrease with increasing pressure and are in the range 8-110 ppmv, while the CO emissions increase with rising pressure and span the range 0.3-52 ppmv, thus leading to corrected CO emissions (at 15% O2) of less than 15 ppmv. Finally, the peak wall temperatures are largely acceptable in terms of catalyst thermal stability.


[Comparison of maternal self-esteem, postpartal depression, and family function in mothers of normal and of low birth-weight infants].
The study investigates the degree of maternal self-esteem, postpartal depression, and family function in mothers of normal and of low birth-weight infants. A retrospective cohort design was applied to compare the variables of interest between a group of 73 mothers with normal birth weight infants and a group of 45 mothers with low birth-weight infants, using the maternal self-report inventory(MSRV), Edinburgh Postnatal Depression Scale(EPDS) and Family APGAR(FAPGAR). The total mean score was 82.57 for MSRV, 8.45 for EPDS, and 6.83 for FAPGAR with no differences between two groups. A positive correlation was found between MSRV and FAPGAR, while a negative correlations between MSRV and EPDS, and FAPGAR and EPDS. Regardless of the direction of the relationship, the degrees of the correlations were stronger in low birth-weight mothers group than in normal group. No differences in MSRV, EPDS and FAPGAR between the normal and the low birth-weight group considered as beneficial effects of the follow-up management which low birth-weight group was engaged in. This suggested the early intervention(follow-up) for the family with risk factor(low birth-weight) could reduce negative outcomes such as the impaired maternal self-esteem and family function, and the occurrence of postpartal depression, retrospectively.


Endovascular Recanalization of Non-acute Symptomatic Middle Cerebral Artery Total Occlusion and Its Short-Term Outcomes.
Background and Purpose: The optimal treatment for patients with non-acute symptomatic middle cerebral artery (MCA) total occlusion and a high risk of recurrent ischemic stroke despite medical management is not well-established. We aimed to assess the feasibility, safety, and short-term outcomes of angioplasty and stenting for these patients. Methods: Data of 22 patients with non-acute symptomatic MCA total occlusion who have failed medical management and undergone endovascular recanalization were retrospectively collected in our prospective database. All occlusive lesions were predilated with conventional balloons, followed by paclitaxel-coated coronary balloon inflation or not, and then a remedial stenting was performed or not, depending on the discretion of the operator. The rate of successful recanalization, perioperative outcomes, and short-term outcomes, such as restenosis and stroke recurrence, was analyzed. Results: Successful recanalization was achieved in 95.5% of patients, with 14 patients undergoing balloon angioplasty and 7 patients undergoing remedial stenting. Seven patients developed perioperative complications, including one patient with persistent neurological deficit. Over a median clinical follow-up duration of 5.0 months, only one patient had recurrent ischemic symptoms attributed to the cessation of antiplatelet treatment owing to postoperative intracranial hemorrhage. The proportion of patients who achieved favorable clinical outcome (modified ranking scale score of 0-2) was 85.7%. Post-procedural repeat vascular imaging was performed at 4.5 ± 1.84 months, with nine and one patient undergoing cerebral angiography and magnetic resonance angiography, respectively. One (10%) artery presented with asymptomatic reocclusion. Conclusions: Angioplasty and stenting may be feasible for the patients with non-acute symptomatic atherosclerotic MCA total occlusive disease who have failed medical management.


The Pathology of Cetacean Morbillivirus Infection and Comorbidities in Guiana Dolphins During an Unusual Mortality Event (Brazil, 2017-2018).
Cetacean morbillivirus (CeMV; Paramyxoviridae) is the most significant pathogen of cetaceans worldwide. The novel "multi-host" Guiana dolphin (Sotalia guianensis; GD)-CeMV strain is reported in South American waters and infects Guiana dolphins and southern right whales (Eubalaena australis). This study aimed to describe the pathologic findings, GD-CeMV viral antigen distribution and detection by RT-PCR (reverse transcriptase polymerase chain reaction), and infectious comorbidities in 29 Guiana dolphins that succumbed during an unusual mass-mortality event in Rio de Janeiro state, Brazil, between November 2017 and March 2018. The main gross findings were lack of ingesta, pulmonary edema, ascites, icterus, hepatic lipidosis, multicentric lymphadenomegaly, as well as pneumonia, polyserositis, and multiorgan vasculitis caused by Halocercus brasiliensis. Microscopically, the primary lesions were bronchointerstitial pneumonia and multicentric lymphoid depletion. The severity and extent of the lesions paralleled the distribution and intensity of morbilliviral antigen. For the first time in cetaceans, morbilliviral antigen was detected in salivary gland, optic nerve, heart, diaphragm, parietal and visceral epithelium of glomeruli, vulva, and thyroid gland. Viral antigen within circulating leukocytes suggested this as a mechanism of dissemination within the host. Comorbidities included disseminated toxoplasmosis, mycosis, ciliated protozoosis, and bacterial disease including brucellosis. These results provide strong evidence for GD-CeMV as the main cause of this unusual mass-mortality event.


Update on the neuropathogenesis of delirium.
Delirium has been considered a syndrome of generalized dysfunction of higher cortical functions due to its breadth of symptoms and associated diffuse slowing on electroencephalogram. Advances in neuropsychiatry have revealed differences between brain regions, including the hemispheres, which may underlie the constellation of symptoms among different psychiatric disorders. For example, different neural pathways are involved in major depression and obsessive-compulsive disorder, including lateralization to one or the other hemisphere. In this article the author proposes that delirium, too, involves particular neural pathways and that lateralization to the right may be relevant. Structural and functional neuroimaging reports and recent neuropsychological studies support this lateralization. Prefrontal cortices, anterior and right thalamus, and right basilar mesial temporoparietal cortex may play a significant role in subserving delirium symptoms and may be the 'final common pathway' for delirium from a variety of etiologies. The final common pathway may be responsible for certain 'core symptoms' (disorientation, cognitive deficits, sleep-wake cycle disturbance, disorganized thinking, and language abnormalities), while other symptoms (delusions, hallucinations, illusions, and affective lability) may occur depending on the etiology causing delirium. An imbalance in the cholinergic and dopaminergic neurotransmitter systems is most commonly implicated in causing delirium, and could both account for delirium symptoms and be consistent with the neuroanatomical pathways being implicated.


Effect of S5P alpha-helix charge mutants on inactivation of hERG K+ channels.
The ether-à-go-go (EAG) family of voltage-gated K(+) channels contains three subfamilies, EAG, ether-à-go-go related (ERG) and ether-à-go-go like (ELK). The human ether-à-go-go related gene (hERG) K(+) channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K(+) channel is predicted to be different from that of other members of the voltage-gated K(+) channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K(+) channels (43 amino acids compared to 14-23 amino acids). Further, the S5P linker contains an amphipathic alpha-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1-S6 of hERG but with the S5P alpha-helical region of either hEAG or rELK2, and one consisting of the S1-S6 of rELK2 but with the S5P alpha-helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the alpha-helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P alpha-helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P alpha -helix. We suggest that inactivation of hERG involves the interaction of this face of the S5P alpha-helix with a charged residue on the remainder of the outer pore domain of the channel.


Modulation of hepatic mRNA translation activity and specific expression of arylsulfotransferase IV during acetylaminofluorene-induced rat hepatocarcinogenesis.
Enzymatic sulfation of N-hydroxylated arylamines by mammalian hepatic cytosol sulfotransferases (AST; EC 126.96.36.199) is an important metabolic step which generates ultimate carcinogens. The metabolic activity of AST IV, the putative isozymic form of AST primarily responsible for catalyzing N-hydroxy-2-acetylaminofluorene sulfation, is modulated during 2-acetylaminofluorene (AAF)-induced rat hepatocarcinogenesis. To characterize the molecular mechanisms regulating the differential expression of AST IV, we have assessed polyadenylated mRNA derived from the livers of Sprague-Dawley rats undergoing different stages of AAF hepatocarcinogenesis for general in vitro translation capacity and specific expression of AST IV and albumin. Following 1 and 3 cycles of a cyclical feeding regimen (3 weeks 0.05% AAF, then 1 week basal diet), the mRNA capacity for translation was lowered and the expression of AST IV and albumin was down-regulated about 2-fold each but recovered to normal levels when treated rats were subsequently placed on basal diet for 3 continuous weeks. Cytosolic albumin levels were determined by Western blot analysis to be lowered about 1.5-2-fold. In contrast, however, mRNA from rats on basal diets for 3 weeks subsequent to cycle 5 of the feeding regimen recovered only about 50% of the capacity for AST IV expression, although overall translation capacity and albumin expression returned to normal levels. This pattern of reversible expression, followed by irreversible expression of AST IV at early and late stages of AAF hepatocarcinogenesis, respectively, provides the first evidence correlating the modulation of hepatic mRNA capacity for AST IV expression with differential cytosolic AST IV activity in the AAF hepatocarcinogenesis model. The results further suggest that during early stages in hepatocarcinogenesis modulation of mRNA protein synthesis functions may be a critical factor in AAF-mediated lowering of AST IV expression, while other persistent genetic lesions are likely playing a more significant role at the late stages of the carcinogenic process leading to neoplastic transformation of initiated hepatocytes.