Context-dependent interaction leads to emergent search behavior in social aggregates.
Locating the source of an advected chemical signal is a common challenge facing many living organisms. When the advecting medium is characterized by either high Reynolds number or high Peclet number, the task becomes highly nontrivial due to the generation of heterogeneous, dynamically changing filamental concentrations that do not decrease monotonically with distance to the source. Defining search strategies that are effective in these environments has important implications for the understanding of animal behavior and for the design of biologically inspired technology. Here we present a strategy that is able to solve this task without the higher intelligence required to assess spatial gradient direction, measure the diffusive properties of the flow field, or perform complex calculations. Instead, our method is based on the collective behavior of autonomous individuals following simple social interaction rules which are modified according to the local conditions they are experiencing. Through these context-dependent interactions, the group is able to locate the source of a chemical signal and in doing so displays an awareness of the environment not present at the individual level. This behavior illustrates an alternative pathway to the evolution of higher cognitive capacity via the emergent, group-level intelligence that can result from local interactions.


The fine structural localization of adenosine triphosphatase in the small intestine, kidney, and liver of the rat.
The distribution of the reaction product of a staining method for adenosine triphosphatase (ATPase) in rat small intestine, kidney, and liver was studied with electron microscopy. Several procedures were tried but the best results were obtained from tissue that had been quenched in liquid nitrogen, sectioned at 25 micro in a cryostat, fixed for 30 to 90 minutes at 4 degrees C in formalin-sucrose buffered to pH 7.2, incubated with substrate, and then osmicated and prepared for electron microscopy in the usual way. This procedure enabled the localization of mitochondrial ATPase to be studied. In tissue fixed in small blocks in osmium tetroxide for 3 minutes prior to incubation with substrate, good preservation was noted, and the reaction product for ATPase was localized on the cell membrane and nuclei. The reaction product was present in abundant amount in the nuclei, and particularly within nucleoli, of all tissues studied. Because the histochemical localization of nuclear enzymes poses numerous interpretative problems at the present time, the significance of this nuclear localization is uncertain. Cell (plasma) membranes were the site of localization, especially at areas where it has been proposed that active transport mechanisms may occur, namely, on the microvilli of intestinal epithelium, endothelial lining of capillaries, glomerular epithelial cell membranes, basal infoldings of the cell membrane of renal tubules, on the microvilli of bile canaliculi, and on the microvilli of proximal convoluted tubular epithelial cells. ATPase localization on the cristae mitochondriales was also demonstrated.


Robotic Versus Laparoscopic Colorectal Cancer Surgery in Elderly Patients: A Propensity Score Match Analysis.
Minimally invasive surgery in elderly patients with colorectal cancer remains controversial. The study aimed to compare the operative, postoperative, and oncologic outcomes of robotic (robotic colorectal resection surgery [RCRS]) versus laparoscopic colorectal resection surgery (LCRS) in elderly patients with colorectal cancer. Propensity score matching (PSM) was used to compare patients aged 70 years and more undergoing elective RCRS or LCRS for colorectal cancer between 2010 and 2017. Overall, 160 patients underwent elective curative LCRS (n = 102) or RCRS (n = 58) for colorectal cancer. Before PSM, the mean preoperative Charlson score and the tumor size were significantly lower in the robotic group. After matching, 43 RCRSs were compared with 43 LCRSs. The RCRS group showed longer operative times (300.6 versus 214.5 min, P = .03) compared with LCRS, but all other operative variables were comparable between the two groups. No differences were found for postoperative morbidity, mortality, time to flatus, return to regular diet, and length of hospital stay. R0 resection was obtained in 95.3% of procedures. The overall and disease-free survival rates at 1, 2, and 3 years were similar between RCRS and LCRS patients. The presence of more than one comorbidity before surgery was significantly associated with the incidence of postoperative complications. In patients aged 70 years or more, robotic colorectal surgery showed operative and oncologic outcomes similar to those obtained by laparoscopy, despite longer operative times. Randomized trials are awaited to reliably assess the clinical and oncological noninferiority and the costs/benefits ratio of robotic colorectal surgery in elderly populations.


Oreocharis wumengensis, a new species of Gesneriaceae from northeastern Yunnan, China.
A new species of Gesneriaceae, Oreocharis wumengensis Lei Cai & Z.L.Dao from Wumeng Mountain area, Yanjin County, Yunnan Province, China, is described. The new species is morphologically similar to O. panzhouensis Lei Cai, Y.Guo & F.Wen in the shape of corolla, number of stigma and stamens, but it can be easily distinguished from this species by the leaf shape and indumentum characters of leaf blade, calyx and stamens. Detailed descriptions with photographs of the plant and holotype, and comparisons with morphologically similar species, are also provided.


Acquisition and analysis of cardiovascular signals on smartphones: potential, pitfalls and perspectives: by the Task Force of the e-Cardiology Working Group of European Society of Cardiology.
Smartphones, mobile applications ('apps'), social media, analytics, and the cloud are profoundly changing the practice of medicine and the way health decisions are made. With the constant progress of technology, the measurement of vital signals becomes easier, cheaper, and practically a standard approach in clinical practice. The interest in measuring vital signals goes beyond medical professionals to the general public, patients, informal caregivers, and healthy individuals, who frequently lack any formal medical training. On smartphone platforms such as iOS and Android, a proliferation of health or medical 'apps' acquire and analyse a variety of vital signs through embedded sensors, interconnected devices or peripherals utilising on occasion analytics and social media. Smartphone vendors compete with traditional medical device manufacturers in the grey area between health care, wellness, and fitness, as US and EU regulatory bodies are setting and revising rules for these new technologies. On the other hand, in the absence of robust validation results, clinicians are hesitant to trust measurements by apps or recommend specific apps to their patients, partly also due to lack of a cost reimbursement policy. This review focuses on the acquisition and analysis on smartphones of three important vital signs in the cardiovascular and respiratory field as well as in rehabilitation i.e. heart or pulse rate, blood pressure, and blood oxygenation. The potential, pitfalls, and perspectives on mobile devices and smartphone apps for health management by patients and healthy individuals are discussed.


Nodal ring spin gapless semiconductor: New member of spintronic materials.
Spin gapless semiconductors (SGSs) and nodal ring states (NRSs) have aroused great scientific interest in recent years due to their unique electronic properties and high application potential in the field of spintronics and magnetoelectronics. Since their advent, all SGSs and NRSs have been predicted in independent materials. In this work, we proposed a novel type of material, nodal ring spin gapless semiconductor (NRSGS), which combines both states of the SGSs and NRSs. The synthesized material Mg2VO4 has been detailed with band structure analysis based on first principle calculations. Obtained results revealed that there are gapless crossings in the spin-up direction, which are from multiple topological nodal rings located exactly at the Fermi energy level. Mg2VO4 combines the advantages inherited from both NRSs and SGSs in terms of the innumerable gapless points along multiple nodal rings with all linear dispersions and direct contacts. In addition, Mg2VO4 also shows strong robustness against both the spin orbit coupling effect and strain conditions. For the first time, we propose the concept of an NRSGS, and the first such material candidate Mg2VO4 can immediately advance corresponding experimental measurements and even facilitate real applications.


Evaluation of a large glass-ceramic mirror blank.
A statistically designed study was performed to evaluate the homogeneity of selected properties of a large CER-VIT C-101 glass-ceramic mirror blank. A blank 1.9 m in diameter and 0.3 m thick weighing approximately 2180 kg was sampled to determine if the chemical composition, the density, the birefringence, and the linear coefficient of thermal expansion were dependent on the position within the blank. The blank had good homogeneity. The properties varied little throughout the blank, except for birefringence, which varied systematically with position.


Global burden of melioidosis in 2015: a systematic review and data synthesis.
Melioidosis is an infectious disease caused by the environmental bacterium Burkholderia pseudomallei. It is often fatal, with a high prevalence in tropical areas. Clinical presentation can vary from abscess formation to pneumonia and sepsis. We assessed the global burden of melioidosis, expressed in disability-adjusted life-years (DALYs), for 2015. We did a systematic review of the peer-reviewed literature for human melioidosis cases between Jan 1, 1990, and Dec 31, 2015. Quantitative data for cases of melioidosis were extracted, including mortality, age, sex, infectious and post-infectious sequelae, antibiotic treatment, and symptom duration. These data were combined with established disability weights and expert panel discussions to construct an incidence-based disease model. The disease model was integrated with established global incidence and mortality estimates to calculate global melioidosis DALYs. The study is registered with PROSPERO, number CRD42018106372. 2888 articles were screened, of which 475 eligible studies containing quantitative data were retained. Pneumonia, intra-abdominal abscess, and sepsis were the most common outcomes, with pneumonia occurring in 3633 (35·7%, 95% uncertainty interval [UI] 34·8-36·6) of 10 175 patients, intra-abdominal abscess in 1619 (18·3%, 17·5-19·1) of 8830 patients, and sepsis in 1526 (18·0%, 17·2-18·8) of 8469 patients. We estimate that in 2015, the global burden of melioidosis was 4·6 million DALYs (UI 3·2-6·6) or 84·3 per 100 000 people (57·5-120·0). Years of life lost accounted for 98·9% (UI 97·7-99·5) of the total DALYs, and years lived with disability accounted for 1·1% (0·5-2·3). Melioidosis causes a larger disease burden than many other tropical diseases that are recognised as neglected, and so it should be reconsidered as a major neglected tropical disease. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Research Grant 2018, AMC PhD Scholarship, The Netherlands Organisation for Scientific Research (NWO), H2020 Marie Skłodowska-Curie Innovative Training Network European Sepsis Academy.


Identification of structural properties associated with polychlorinated biphenyl dechlorination processes.
Polychlorinated biphenyl molecules can be biologically dechlorinated through sequential losses of a chlorine atom, following 840 pathways from higher chlorinated to lesser-chlorinated congeners and biphenyl. Previously, eight recurring sets of pathways, herein referred to as explicitly reported pathways in dechlorination processes, have been identified through qualitative analysis of shifts in congener masses in field and laboratory studies. Dechlorination process generalizations were qualitatively extrapolated based on limited attributes of the congeners dechlorinated in the explicitly reported pathways. They are valuable because they allow comparisons of dechlorination patterns across laboratory experiments and contaminated sites. However, due to analytical limitations and a paucity of studies, the explicitly reported pathways in dechlorination processes likely do not represent all of the pathways that could occur at contaminated sites. This work presents an alternative, quantitative, and replicable approach to the identification of candidate pathways for inclusion in dechlorination process generalizations through use of classification trees. This method considers 46 structural and property attributes of dechlorination pathways. Trees fit for pathway inclusion in each of the eight dechlorination processes with alternative assumptions are compared in terms of critical congener attributes. The classification trees correctly classify explicitly reported pathways into dechlorination processes at rates of 0.90 to 0.99. While many of the attributes used in the original generalizations were also selected as predictors by the classification trees, the extra attributes allow identification of additional dechlorination pathways that can be considered as candidates for monitoring in future studies.


Importance of psychiatric examination in predictive genetic testing for Huntington disease.
Huntington disease (HD) is an au-tosomal dominant hereditary neurodegenerative disease with multiplication of CAG triplet in the short arm of chromoso-me 4, manifested by motor symptoms, cognitive dysfunction progressing to dementia, and various types of neuropsychiat-ric disorders. The diagnosis of HD is confirmed by a gene-tic test, which may also be carried out presymptomatically. We studied differences in psychiatric examination and psychometric measures among the 52 people at risk of HD, who were recommended to postpone or to continue in the predictive protocol. In addition to the psychiatric examination, we administered the Eysenck Personality Questionnaire (EPQ-A), the Symptom Checklist 90 (SCL-90), and quality of life questionnaire (MANSA). People at risk of HD with the recommended test postponement showed lower rate of neuroticism and EPQ-A lie score, higher values on the phobia and the so-called 'positive symptom distress index' in SCL-90 and lower quality of life than people at risk of HD with the recommendation to continue. Our results indicate that the formalized testing does not bring significant information whereas the clinical psychiatric examination remains the main decisive factor in the recommendation to perform a predictive genetic test. The motivation of applicants is considered as the most important factor in the decision-making process.


Prognostic discrimination in "good-risk" chronic granulocytic leukemia.
The prognostic significance of disease features recorded at the time of diagnosis was examined among 813 patients with Philadelphia chromosome-positive, nonblastic chronic granulocytic leukemia (CGL) collected from six European and American series. The survival pattern for this population was typical of "good-risk" patients, and median survival was 47 mo. There were multiple interrelationships among different disease features, which led to highly significant correlations with survival for some that had no primary prognostic significance, such as hematocrit. Multivariable regression analysis indicated that spleen size and the percentage of circulating blasts were the most important prognostic indicators. These features, and age, behaved as continuous variables with progressively unfavorable import at higher values. The platelet count did not influence survival significantly at values below 700 X 10(9)/liter but was increasingly unfavorable above this level. Basophils plus eosinophils over 15%, more than 5% marrow blasts, and karyotypic abnormalities in addition to the Ph1 were also significant unfavorable signs. The Cox model, generated with four variables representing percent blasts, spleen size, platelet count, and age, provided a useful representation of risk status in this population, with good fit between predicted and observed survival over more than a twofold survival range. A hazard function derived from half of the patient population successfully segregated the remainder into three groups with significantly different survival patterns. We conclude that it should be possible to identify a lower risk group of patients with a 2-yr survival of 90%, subsequent risk averaging somewhat less than 20%/yr and median survival of 5 yr, an intermediate group, and a high-risk group with a 2-yr survival of 65%, followed by a death rate of about 35%/yr and median survival of 2.5 yr.


Intraoperative transit-time flow measurement and high-frequency ultrasound assessment in coronary artery bypass grafting.
We evaluated the influence of transit-time flow measurement with epicardial and epiaortic high-frequency ultrasound in patients undergoing coronary artery bypass grafting procedure. The Registry for Quality Assessment with Ultrasound Imaging and Transit-time Flow Measurement in Cardiac Bypass Surgery study is a multicenter, prospective study among 7 international centers performing coronary artery bypass grafting procedures. The primary end point was any change in the planned surgical procedure. Major secondary end points consisted of the rate and reason for surgical changes related to the aorta, in situ conduits, coronary targets, and completed grafts, and the rate of in-hospital mortality and major morbidity. Between April 2015 and December 2017, 1046 patients were enrolled. Of those, 1016 were included in the final analyses. Mean age was 65.9 years, 14.0% were women, and diabetes was present in 39.6%. Off-pump procedures were performed in 39.6% and bilateral internal thoracic arteries in 30.5%. The primary end point occurred in 25.2% of patients (n = 256) and in 77% (197 out of 256) this was based on transit-time flow measurement and/or high-frequency ultrasound. Surgical changes were related to the aorta in 9.9%, to in situ conduits in 2.7%, and the coronary targets in 22.6%. Graft revision occurred in 7.8%, including revisions of the proximal and/or distal anastomosis in 6.6%. In-hospital adverse event rates were 0.6% for mortality, 1.0% for cerebrovascular events, and 0.3% for myocardial infarction. Surgical changes related to the aorta, conduits, coronary targets, and anastomosis were made in 25% of patients. This was associated with low operative mortality and low major morbidity. Transit-time flow measurement and high-frequency ultrasound may improve the quality, safety, and efficacy of coronary artery bypass grafting procedures and should be considered as a routine procedural aspect.


Effects of combination treatment of intravesical resiniferatoxin instillation and hydrodistention in patients with refractory painful bladder syndrome/interstitial cystitis: a pilot study.
Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disabling disease of the urinary bladder, and its etiology and treatment are not yet established. Current medications used in the treatment of PBS/IC have shown limited efficacy. This prospective study investigated the efficacy of intravesical resiniferatoxin (RTX) in PBS/IC refractory to medical treatment. Patients with proven PBS/IC refractory to traditional medical treatment were enrolled. By randomized trial, a total of 18 consecutive patients were divided into two groups: treatment with hydrodistention and intravesical RTX (group 1) or treatment with hydrodistension only (group 2). We assessed bladder pain by use of a visual analogue pain scale, the maximal urine flow rate, post-void residual urine volume, and a voiding diary before and 3 months after treatment. The median age of the 18 patients was 55.8±6.9 years, and the median duration of symptoms before diagnosis was 3.6±1.6 years. Frequency, functional bladder capacity, and score on a 5-point pain scale were significantly improved at 3-month after treatment in both groups. Intravesical RTX instillation plus hydrodistention, compared with hydrodistention only, did not have a significant effect on the voiding symptoms or uroflowmetry of the patients but significantly improved scores on the pain scale. Intravesical RTX instillation plus hydrodistention was effective in relieving pain but was not effective in improving lower urinary tract symptoms. Further larger studies are needed to clarify the efficacy of combination treatment of intravesical RTX instillation and hydrodistention.


Amplitude-dependency of response of SI cortex to flutter stimulation.
It is established that increasing the amplitude of a flutter stimulus increases its perceived intensity. Although many studies have examined this phenomenon with regard to the responding afferent population, the way in which the intensity of a stimulus is coded in primary somatosensory cortex (SI) remains unclear. Optical intrinsic signal (OIS) imaging was used to study the evoked responses in SI of anesthetized squirrel monkeys by 25 Hz sinusoidal vertical skin displacement stimulation. Stimuli were 10 sec duration with a 50 sec inter-stimulus interval. Stimulus amplitude ranged from 50 to 400 microns and different amplitudes were interleaved. Control levels of activity were measured in the absence of stimulation, and used to compare with activation levels evoked by the different stimulus amplitudes. Stimulation of a discrete skin site on the forelimb evoked a prominent increase in absorbance within the forelimb representational region in cytoarchitectonic areas 3b and 1 of the contralateral hemisphere. An increase in stimulus amplitude led to a proportional increase in the magnitude of the absorbance increase in this region of areas 3b and 1 while surrounding cortex underwent a decrease in absorbance. Correlation maps revealed that as stimulus amplitude is increased, the spatial extent of the activated region in SI remains relatively constant, and the activity within this region increases progressively. Additionally, as stimulus amplitude is increased to suprathreshold levels, activity in the surround of the activated SI territory decreases, suggesting an increase in inhibition of neuronal activity within these regions. Increasing the amplitude of a flutter stimulus leads to a proportional increase in absorbance within the forelimb representational region of SI. This most likely reflects an increase in the firing rate of neurons in this region of SI. The relatively constant spatial extent of this stimulus-evoked increase in absorbance suggests that an increase in the amplitude of a 25 Hz skin stimulus does not evoke a larger area of SI neuronal activation due to an amplitude-dependent lateral inhibitory effect that spatially funnels the responding SI neuronal population.


Publication Trends in Drug Delivery and Magnetic Nanoparticles.
This bibliometric study investigated the public trends in the fields of nanoparticles which is limited to drug delivery and magnetic nanoparticles' literature published from 1980 to October 2017. The data were collected from the Web of Science Core Collections, and a network analysis of research outputs was carried out to analyse the research trends in the nanoparticles literature. Nanoparticles and its applications are progressing in recent years. The results show that documents in the field of nanoparticles in chemistry and material science have improved in citation rate, as the authors were researching in multidisciplinary zones. Top-cited documents are mainly focusing on drug delivery, magnetic nanoparticles and iron oxide nanoparticles which are also the top research keywords in all papers published. Top-cited papers are mostly published in Biomaterials journal which so far has published 12% of top-cited articles. Although research areas such as contrast agents, quantum dots, and nanocrystals are not considered as the top-ranked keywords in all documents, these keywords received noticeable citations. The trends of publications on drug delivery and magnetic nanoparticles give a general view on future research and identify potential opportunities and challenges.


Improved maximum a posteriori cortical segmentation by iterative relaxation of priors.
Thickness measurements of the cerebral cortex can aid diagnosis and provide valuable information about the temporal evolution of several diseases such as Alzheimer's, Huntington's, Schizophrenia, as well as normal ageing. The presence of deep sulci and 'collapsed gyri' (caused by the loss of tissue in patients with neurodegenerative diseases) complicates the tissue segmentation due to partial volume (PV) effects and limited resolution of MRI. We extend existing work to improve the segmentation and thickness estimation in a single framework. We model the PV effect using a maximum a posteriori approach with novel iterative modification of the prior information to enhance deep sulci and gyri delineation. We use a voxel based approach to estimate thickness using the Laplace equation within a Lagrangian-Eulerian framework leading to sub-voxel accuracy. Experiments performed on a new digital phantom and on clinical Alzheimer's disease MR images show improvements in both accuracy and robustness of the thickness measurements, as well as a reduction of errors in deep sulci and collapsed gyri.


Positioning of chemosensory proteins and FtsZ through the Rhodobacter sphaeroides cell cycle.
Bacterial chemotaxis depends on signalling through large protein complexes. Each cell must inherit a complex on division, suggesting some co-ordination with cell division. In Escherichia coli the membrane-spanning chemosensory complexes are polar and new static complexes form at pre-cytokinetic sites, ensuring positioning at the new pole after division and suggesting a role for the bacterial cytoskeleton. Rhodobacter sphaeroides has both membrane-associated and cytoplasmic, chromosome-associated chemosensory complexes. We followed the relative positions of the two chemosensory complexes, FtsZ and MreB in aerobic and in photoheterotrophic R. sphaeroides cells using fluorescence microscopy. FtsZ forms polar spots after cytokinesis, which redistribute to the midcell forming nodes from which FtsZ extends circumferentially to form the Z-ring. Membrane-associated chemosensory proteins form a number of dynamic unit-clusters with mature clusters containing about 1000 CheW(3) proteins. Individual clusters diffuse randomly within the membrane, accumulating at new poles after division but not colocalizing with either FtsZ or MreB. The cytoplasmic complex colocalizes with FtsZ at midcells in new-born cells. Before cytokinesis one complex moves to a daughter cell, followed by the second moving to the other cell. These data indicate that two homologous complexes use different mechanisms to ensure partitioning, and neither complex utilizes FtsZ or MreB for positioning.


Simultaneous high-resolution scanning Bragg contrast and ptychographic imaging of a single solar cell nanowire.
Simultaneous scanning Bragg contrast and small-angle ptychographic imaging of a single solar cell nanowire are demonstrated, using a nanofocused hard X-ray beam and two detectors. The 2.5 µm-long nanowire consists of a single-crystal InP core of 190 nm diameter, coated with amorphous SiO2 and polycrystalline indium tin oxide. The nanowire was selected and aligned in real space using the small-angle scattering of the 140 × 210 nm X-ray beam. The orientation of the nanowire, as observed in small-angle scattering, was used to find the correct rotation for the Bragg condition. After alignment in real space and rotation, high-resolution (50 nm step) raster scans were performed to simultaneously measure the distribution of small-angle scattering and Bragg diffraction in the nanowire. Ptychographic reconstruction of the coherent small-angle scattering was used to achieve sub-beam spatial resolution. The small-angle scattering images, which are sensitive to the shape and the electron density of all parts of the nanowire, showed a homogeneous profile along the nanowire axis except at the thicker head region. In contrast, the scanning Bragg diffraction microscopy, which probes only the single-crystal InP core, revealed bending and crystalline inhomogeneity. Both systematic and non-systematic real-space movement of the nanowire were observed as it was rotated, which would have been difficult to reveal only from the Bragg scattering. These results demonstrate the advantages of simultaneously collecting and analyzing the small-angle scattering in Bragg diffraction experiments.


Concentration effects of three common fish anesthetics on Pacific hagfish (Eptatretus stoutii).
The efficacy of three common fish anesthetics (clove oil, 2-phenoxyethanol, and tricaine methanesulfonate) was evaluated in the Pacific hagfish (Eptatretus stoutii). The overarching aim of our study was to identify the best anesthetic and concentration for the purposes of routine laboratory use of Pacific hagfish (i.e., short and consistent induction and recovery times and minimized stress and safety risk to hagfish). The objectives of our study were fourfold: (1) identify anesthetic stages of Pacific hagfish using clove oil anesthesia; (2) establish standardized anesthesia preparation procedures; (3) determine the optimal anesthetic and concentration for safely achieving stage V anesthesia; and (4) investigate the effects of repeatedly exposing Pacific hagfish to anesthesia. Experimental concentrations, ranging from 50 to 400 mg/L, of each anesthetic were tested on at least three Pacific hagfish individuals. We found the following: (1) Pacific hagfish exhibited similar stages of anesthesia to those described for bony fishes; (2) sufficient mixing of clove oil with seawater had a considerable effect on the consistency and timing of anesthetic induction; (3) concentration and anesthetic significantly impacted induction and recovery timing, whereas body mass had no impact on anesthetic trends; and (4) repeatedly exposing Pacific hagfish to optimal concentrations of clove oil or MS-222 had no effect on induction or recovery timing, whereas exposure number significantly impacted induction timing when using 2-PE. Due to consistent induction and recovery times, low risk of accidental overdose, and high safety margins for both handler and hagfish, we recommend 175 mg/L of clove oil as the ideal anesthetic and concentration for the routine laboratory use of Pacific hagfish.


Inflammation-induced recombinant protein expression in vivo using promoters from acute-phase protein genes.
We report that promoters for two murine acute-phase protein (APP) genes, complement factor 3 (C3) and serum amyloid A3 (SAA3), can increase recombinant protein expression in response to inflammatory stimuli in vivo. To deliver APP promoter-luciferase reporter gene constructs to the liver, where most endogenous APP synthesis occurs, we introduced them into a nonreplicating adenovirus vector and injected the purified viruses intravenously into mice. When compared with the low levels of basal luciferase expression observed prior to inflammatory challenge, markedly increased expression from the C3 promoter was detected in liver in response to both lipopolysaccharide (LPS) and turpentine, and lower-level inducible expression was also found in lung. In contrast, expression from the SAA3 promoter was found only in liver and was much more responsive to LPS than to turpentine. After LPS challenge, hepatic luciferase expression increased rapidly and in proportion to the LPS dose. Use of cytokine-inducible promoters in gene transfer vectors may make it possible to produce antiinflammatory proteins in vivo in direct relationship to the intensity and duration of an individual's inflammatory response. By providing endogenously controlled production of recombinant antiinflammatory proteins, this approach might limit the severity of the inflammatory response without interfering with the beneficial components of host defense and immunity.


Efficacy of upfront high-dose chemotherapy plus rituximab followed by autologous peripheral blood stem cell transplantation for untreated high-intermediate-, and high-risk diffuse large B-cell lymphoma: a multicenter prospective phase II study (JSCT-NHL04).
To evaluate the efficacy and feasibility of upfront high-dose chemotherapy (HDCT) and rituximab (R) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) in patients with newly diagnosed high-intermediate(HI)-, and high(H)-risk diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter prospective phase II trial. In 15-60-year-old patients with H- or HI-risk DLBCL, after three courses of (R-)CHOP14, high-dose etoposide was given prior to peripheral blood stem cell harvesting. After an additional three courses of (R-)CHOP14, auto-PBSCT was performed following HDCT. The primary endpoint of the study is progression-free survival (PFS) at 2 years after registration in eligible patients. The expected PFS and the threshold PFS were estimated to be 70 and 50 %, respectively. Among 40 eligible patients registered, 30 patients completed treatment. With a median observation period in surviving eligible patients of 63 months, the 2- and 4-year PFS after registration were 79.9 and 72.0 %, respectively. The 2- and 4-year overall survival (OS) were 92.5 and 84.6 %, respectively. In 30 patients who completed treatment, the 4-year PFS and OS after auto-PBSCT were 79.2 and 85.9 %, respectively. In conclusion, the results of our study suggest that upfront HDCT and auto-PBSCT combined with rituximab is highly effective as an initial treatment for HI-, and H-risk DLBCL.


The mitochondrial calcium uniporter underlies metabolic fuel preference in skeletal muscle.
The mitochondrial Ca2+ uniporter (MCU) complex mediates acute mitochondrial Ca2+ influx. In skeletal muscle, MCU links Ca2+ signaling to energy production by directly enhancing the activity of key metabolic enzymes in the mitochondria. Here, we examined the role of MCU in skeletal muscle development and metabolic function by generating mouse models for the targeted deletion of Mcu in embryonic, postnatal, and adult skeletal muscle. Loss of Mcu did not affect muscle growth and maturation or otherwise cause pathology. Skeletal muscle-specific deletion of Mcu in mice also did not affect myofiber intracellular Ca2+ handling, but it did inhibit acute mitochondrial Ca2+ influx and mitochondrial respiration stimulated by Ca2+, resulting in reduced acute exercise performance in mice. However, loss of Mcu also resulted in enhanced muscle performance under conditions of fatigue, with a preferential shift toward fatty acid metabolism, resulting in reduced body fat with aging. Together, these results demonstrate that MCU-mediated mitochondrial Ca2+ regulation underlies skeletal muscle fuel selection at baseline and under enhanced physiological demands, which affects total homeostatic metabolism.


Feasibility and preliminary outcomes of a school-based mindfulness intervention for urban youth.
Youth in underserved, urban communities are at risk for a range of negative outcomes related to stress, including social-emotional difficulties, behavior problems, and poor academic performance. Mindfulness-based approaches may improve adjustment among chronically stressed and disadvantaged youth by enhancing self-regulatory capacities. This paper reports findings from a pilot randomized controlled trial assessing the feasibility, acceptability, and preliminary outcomes of a school-based mindfulness and yoga intervention. Four urban public schools were randomized to an intervention or wait-list control condition (n=97 fourth and fifth graders, 60.8% female). It was hypothesized that the 12-week intervention would reduce involuntary stress responses and improve mental health outcomes and social adjustment. Stress responses, depressive symptoms, and peer relations were assessed at baseline and post-intervention. Findings suggest the intervention was attractive to students, teachers, and school administrators and that it had a positive impact on problematic responses to stress including rumination, intrusive thoughts, and emotional arousal.


Therapeutic effect of a Gag-nuclease fusion protein against retroviral infection in vivo.
Recently, remarkable progress has been made in developing effective combination drug therapies that can control but not cure retroviral replication. Even when effective, these drug regimens are toxic, they require demanding administration schedules, and resistant viruses can emerge. Thus the need for new gene-based therapies continues. In one such approach, capsid-targeted viral inactivation (CTVI), nucleases fused to viral coat proteins are expressed in infected cells and become incorporated during virion assembly. CTVI can eliminate infectious murine retrovirus titer in tissue culture. Here we describe transgenic mice expressing fusions of the Moloney murine leukemia virus (Mo-MuLV) Gag protein to staphylococcal nuclease. This work tests the protective effect and demonstrates in vivo proof-of-principle of CTVI in transgenic mice expressing endogenous proviral copies of Mo-MuLV. The antiviral protein-expressing mice are phenotypically normal, attesting to the lack of toxicity of the fusion protein. The Mo-MuLV infection was much less virulent in transgenic littermates than in nontransgenic littermates. Gag-nuclease expression reduced infectious titers in blood up to 10-fold, decreased splenomegaly and leukemic infiltration, and increased life spans up to 2.5-fold in transgenic relative to nontransgenic infected animals. These results suggest that gene therapies based on similar fusion proteins, designed to attack human immunodeficiency virus or other retroviruses, could provide substantial therapeutic benefits.


Infection of rats with human T-cell leukemia virus type-I: susceptibility of inbred strains, antibody response and provirus location.
The susceptibilities of different strains of inbred rats to infection with the human T-cell leukemia virus (HTLV-I) after inoculation of human HTLV-I producer cell lines were compared. The Fisher F344 and Brown Norway strains developed the highest antibody response to HTLV-I, while the Lewis and BB strains were low responders. Antibodies against the HTLV-I gag proteins, and env gp21 but not env gp46, were detected in Western blots with sera from HTLV-I-infected Fischer F344 and Brown Norway rats. These sera were inactive in an in vitro syncytium-formation inhibition test. The HTLV-I provirus was detected by polymerase chain reaction in all Fischer F344, and some Lewis and Brown Norway rats, but not in the BB, which lack CD8+ T lymphocytes. The most frequent locations of the HTLV-I provirus in the Fischer F344, Lewis and Brown Norway rats at 12 weeks after infection were the peripheral blood mononuclear cells (PBMC) and spinal cord. In a second experiment in Brown Norway rats, the provirus was again detected in the PBMC of rats at 12 weeks, but not at 22 weeks, and among the other organs tested at 22 weeks the sympathetic nerve ganglia were positive. It is concluded that HTLV-I infection occurs in adult rats, but is suppressed with time.


Low-Dose Pesticide Mixture Induces Senescence in Normal Mesenchymal Stem Cells (MSC) and Promotes Tumorigenic Phenotype in Premalignant MSC.
Humans are chronically exposed to multiple environmental pollutants such as pesticides with no significant evidence about the safety of such poly-exposures. We exposed mesenchymal stem cells (MSC) to very low doses of mixture of seven pesticides frequently detected in food samples for 21 days in vitro. We observed a permanent phenotype modification with a specific induction of an oxidative stress-related senescence. Pesticide mixture also induced a shift in MSC differentiation towards adipogenesis but did not initiate a tumorigenic transformation. In modified MSC in which a premalignant phenotype was induced, the exposure to pesticide mixture promoted tumorigenic phenotype both in vitro and in vivo after cell implantation, in all nude mice. Our results suggest that a common combination of pesticides can induce a premature ageing of adult MSC, and as such could accelerate age-related diseases. Exposure to pesticide mixture may also promote the tumorigenic transformation in a predisposed stromal environment. Abstract Video Link: https://youtu.be/mfSVPTol-Gk Stem Cells 2017;35:800-811.


Delirium in elderly inpatients admitted to clinical wards Prevalence and investigation of clinical conditions in a Brazilian sample.
In Brazil there is scarce data about the occurrence of delirium among hospitalized elderly patients. This study aimed to evaluate the prevalence of delirium among elderly patients hospitalized in clinical wards. This cross-sectional study examined a sample of elderly inpatients admitted to three clinical wards of a general hospital between July 2011 and May 2012. The presence of delirium was detected by applying the Confusion Assessment Method (CAM). Dementia diagnosis was conducted in two steps: screening and diagnosis (Cambridge Examination, CAMDEX, was applied during hospitalization at a second timepoint). Other medical diagnoses and medications in use were extracted from medical records. A sample of 173 elderly inpatients was examined; mean age 71.2 years (SD: 7.8; 60-92 years); 64.2% male. Thirty-one patients were diagnosed with delirium; prevalence of 17.9% (95% CI: 12.2-23.6). Delirium was directly associated with Urinary Tract Infection, Renal Failure and Dementia (p<0.05). The principal findings of this study were a high prevalence of delirium and the identification of associated factors, helping to guide preventive approaches and clinical management for at-risk patients in a Brazilian sample.


Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: The EnvIMS study.
Low vitamin D levels have been associated with an increased risk of multiple sclerosis (MS), although it remains unknown whether this relationship varies by age. The objective of this paper is to investigate the association between vitamin D3 supplementation through cod liver oil at different postnatal ages and MS risk. In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis (EnvIMS), a total of 953 MS patients with maximum disease duration of 10 years and 1717 controls reported their cod liver oil use from childhood to adulthood. Self-reported supplement use at ages 13-18 was associated with a reduced risk of MS (OR 0.67, 95% CI 0.52-0.86), whereas supplementation during childhood was not found to alter MS risk (OR 1.01, 95% CI 0.81-1.26), each compared to non-use during the respective period. An inverse association was found between MS risk and the dose of cod liver oil during adolescence, suggesting a dose-response relationship (p trend = 0.001) with the strongest effect for an estimated vitamin D3 intake of 600-800 IU/d (OR 0.46, 95% CI 0.31-0.70). These findings not only support the hypothesis relating to low vitamin D as a risk factor for MS, but further point to adolescence as an important susceptibility period for adult-onset MS.


Characterization of the adenovirus proteinase: development and use of a specific peptide assay.
An assay system has been developed for the adenovirus endoproteinase which utilizes the synthetic peptide MSGGAFSW, derived from the cleavage site of the adenovirus type 2 (Ad2) protein pVI. MSGGAFSW was shown to be cleaved at the G-A bond when incubated with a source of Ad2 proteinase. Digestions were readily monitored by either fast protein liquid chromatography or thin layer electrophoresis, enabling the rapid production of quantitative data. Comparison of the peptide assay with a previously described [35S]methionine assay system showed it to be faster, cleaner and less prone to extreme conditions of pH and ionic strength. The effect on adenovirus proteinase activity of a number of inhibitors was assessed using both the [35S]methionine and peptide assays. Identical inhibitor profiles were obtained and these suggested that the adenovirus enzyme is a cysteine proteinase. The 23K gene product, thought to be the proteinase, contains cysteine and histidine residues at positions 122 and 54, respectively, that could constitute part of the active site of a cysteine proteinase. These amino acids and their surrounding residues are conserved in all serotypes examined and appear to bear some resemblance to those in the putative active sites of the 3C proteinases in picornaviruses.


Tandem mass spectrometry defines the stoichiometry and quaternary structural arrangement of tryptophan molecules in the multiprotein complex TRAP.
We have used tandem mass spectrometry to examine the stoichiometry and binding sites of trp molecules in various assemblies of the protein complex TRAP. The results show that TRAP forms oligomers containing 11 and 12 subunits. MS/MS experiments show that up to 11 trp molecules bind to the 12-mer but that during gas-phase dissociation 5 then 6 trp molecules are released reflecting the different gas-phase stabilities of the partially ligated forms. At high trp concentrations, the protein assembles to form a double ring structure. Tandem mass spectrometry reveals that it is composed of 24 subunits with up to 22 molecules of trp. Dissociation of the complex reveals the same dissociation pathway as for the single ring structure, allowing us to propose a model for the assembly of the TRAP 24-mer based on the different environments of trp molecules. More generally, these results demonstrate the power of tandem mass spectrometry for defining the stoichiometry and quaternary structural arrangement of subunits and ligands within a 46-component multiprotein multiligand complex.


A systematic review of randomised controlled trials evaluating the use of patient-reported outcome measures (PROMs).
Patient-reported outcome measures (PROMs) could play an important role in identifying patients' needs and goals in clinical encounters, improving communication and decision-making with clinicians, while making care more patient-centred. Comprehensive evidence that PROMS are an effective intervention is lacking in single randomised controlled trials (RCTs). A systematic search was performed using controlled vocabulary related to the terms: clinical care setting and patient-reported outcome. English language studies were included if they were a RCT with a PROM as an intervention in a patient population. Included studies were analysed and their methodologic quality was appraised using the Cochrane Risk of Bias tool. The protocol was registered with PROSPERO (CRD42016034182). Of 4302 articles initially identified, 115 underwent full-text review resulting in 22 studies reporting on 25 comparisons. The majority of included studies were conducted in USA (11), among cancer patients (11), with adult participants only (20). Statistically significant and robust improvements were reported in the pre-specified outcomes of the process of care (2) and health care (3). Additionally, five, eight and three statistically significant but possibly non-robust findings were reported in the process of care, health and patient satisfaction outcomes, respectively. Overall, studies that compared PROM to standard care either reported a positive effect or were not powered to find pre-specified differences. There is justification for the use of a PROM as part of standard care, but further adequately powered studies on their use in different contexts are necessary for a more comprehensive evidence base.


Minimum clinically important difference in pain, disability, and quality of life after neural decompression and fusion for same-level recurrent lumbar stenosis: understanding clinical versus statistical significance.
Spine surgery outcome studies rely on patient-reported outcome (PRO) measurements to assess treatment effect, but the extent of improvement in the numerical scores of these questionnaires lacks a direct clinical meaning. Because of this, the concept of a minimum clinically important difference (MCID) has been used to measure the critical threshold needed to achieve clinically relevant treatment effectiveness. As utilization of spinal fusion has increased over the past decade, so has the incidence of same-level recurrent stenosis following index lumbar fusion, which commonly requires revision decompression and fusion. The MCID remains uninvestigated for any PROs in the setting of revision lumbar surgery for this pathology. In 53 consecutive patients undergoing revision surgery for same-level recurrent lumbar stenosis-associated back and leg pain, PRO measures of back and leg pain were assessed preoperatively and 2 years postoperatively, using the visual analog scale for back pain (VAS-BP) and leg pain (VAS-LP), Oswestry Disability Index (ODI), Physical and Mental Component Summary categories of the 12-Item Short Form Health Survey (SF-12 PCS and MCS) for quality of life, Zung Depression Scale (ZDS), and EuroQol-5D health survey (EQ-5D). Four established anchor-based MCID calculation methods were used to calculate MCID (average change; minimum detectable change; change difference; and receiver operating characteristic curve analysis) for 2 separate anchors (health transition index of the SF-36 and the satisfaction index). All patients were available for 2-year PRO assessment. Two years after surgery, a significant improvement was observed for all PROs assessed. The 4 MCID calculation methods generated a range of MCID values for each of the PROs (VAS-BP 2.2-6.0, VAS-LP 3.9-7.5, ODI 8.2-19.9, SF-12 PCS 2.5-12.1, SF-12 MCS 7.0-15.9, ZDS 3.0-18.6, and EQ-5D 0.29-0.52). Each patient answered synchronously for the 2 anchors, suggesting both of these anchors are equally appropriate and valid for this patient population. The same-level recurrent stenosis surgery-specific MCID is highly variable based on calculation technique. The "minimum detectable change" approach is the most appropriate method for calculation of MCIDs in this population because it was the only method to reliably provide a threshold above the 95% confidence interval of the unimproved cohort (greater than the measurement error). Based on this method, the MCID thresholds following neural decompression and fusion for symptomatic same-level recurrent stenosis are 2.2 points for VAS-BP, 5.0 points for VAS-LP, 8.2 points for ODI, 2.5 points for SF-12 PCS, 10.1 points for SF-12 MCS, 4.9 points for ZDS, and 0.39 QALYs for EQ-5D.


GAL11 (SPT13), a transcriptional regulator of diverse yeast genes, affects the phosphorylation state of GAL4, a highly specific transcriptional activator.
The GAL4 protein of Saccharomyces cerevisiae is a DNA-binding transcriptional activator that is highly specific for the GAL genes. In vivo levels of GAL gene transcription are closely correlated with the phosphorylation state of GAL4. In vivo levels of GAL gene transcription are also affected by the activity of the GAL11 (SPT13) protein, a protein that has been implicated as a global auxiliary transcriptional factor. Here we examine the influence of GAL11 (SPT13) on the phosphorylation state of GAL4. Cells bearing a gal11 deletion mutation are defective in the production or maintenance of GAL4III, a phosphorylated form of GAL4 that is associated with higher levels of GAL gene transcription. In addition, the gal11 deletion cells are reduced in total GAL4 protein. However, the fivefold-reduced expression of the GAL1 gene observed in gal11 deletion cells cannot be due solely to reduced levels of total GAL4 protein, since gal11 deletion cells amplified for GAL4 production are still markedly reduced in GAL4 protein-dependent transcription. Thus, these data demonstrate that the GAL11 protein augments GAL4 protein-dependent transcription in a manner that is tightly coupled to the formation or maintenance of a phosphorylated form of GAL4.


Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes.
Nitric oxide (NO), synthesized by the inducible isoform of nitric oxide synthase (iNOS), has been proposed as a mediator of immune-induced beta-cell destruction in type 1 diabetes. To evaluate the role of iNOS for beta-cell dysfunction and death, we investigated the sensitivity of beta-cells from mice genetically deficient in this enzyme (iNOS-/-, background C57BL/6x129SvEv, H-2b) both to interleukin (IL)-1beta-induced beta-cell dysfunction in vitro and to multiple low-dose streptozotocin (MLDS)-induced diabetes in vivo. Exposure of islets isolated from C57BL/6 mice to IL-1beta for 24 h in vitro resulted in an induction of iNOS mRNA expression, an increase in nitrite formation, and a decrease in insulin release and proinsulin biosynthesis as compared with untreated C57BL/6 islets. IL-1beta failed to induce iNOS mRNA expression and increase nitrite formation by islets isolated from iNOS knockout mice (iNOS-/-), and no impairment in islet function was observed. The iNOS-/- mice showed a reduced incidence of hyperglycemia after treatment with MLDS as compared with wild-type C57BL/6 (H-2b) and 129 SvEv (H-2b) mice. On day 21 after the first streptozotocin (STZ) injection, 75% of the C57BL/6 mice and 100% of the 129SvEv mice had blood glucose levels >11 mmol/l, whereas the corresponding number for iNOS-/- mice was only 23%. This protection was not due to a delay in the onset of hyperglycemia, since no increase in number of hyperglycemic iNOS-/- mice was observed when the animals were followed up to 42 days. Moreover, islets isolated from iNOS-/- mice were susceptible to the in vitro deleterious effects of STZ. In conclusion, the present study provides evidence that iNOS may contribute to beta-cell damage after exposure to IL-1beta in vitro and treatment with MLDS in vivo.


Cadherin-11 promotes the metastasis of prostate cancer cells to bone.
Bone is the most common site of metastases from prostate cancer. The mechanism by which prostate cancer cells metastasize to bone is not fully understood, but interactions between prostate cancer cells and bone cells are thought to initiate the colonization of metastatic cells at that site. Here, we show that cadherin-11 (also known as osteoblast-cadherin) was highly expressed in prostate cancer cell line derived from bone metastases and had strong homophilic binding to recombinant cadherin-11 in vitro. Down-regulation of cadherin-11 in bone metastasis-derived PC3 cells with cadherin-11-specific short hairpin RNA (PC3-shCad-11) significantly decreased the adhesion of those cells to cadherin-11 in vitro. In a mouse model of metastasis, intracardiac injection of PC3 cells led to metastasis of those cells to bone. However, the incidence of PC3 metastasis to bone in this model was reduced greatly when the expression of cadherin-11 by those cells was silenced. The clinical relevance of cadherin-11 in prostate cancer metastases was further studied by examining the expression of cadherin-11 in human prostate cancer specimens. Cadherin-11 was not expressed by normal prostate epithelial cells but was detected in prostate cancer, with its expression increasing from primary to metastatic disease in lymph nodes and especially bone. Cadherin-11 expression was not detected in metastatic lesions that occur in other organs. Collectively, these findings suggest that cadherin-11 is involved in the metastasis of prostate cancer cells to bone.


The ontogeny of antigen-specific T cells.
Although the fetal lamb is unable to form circulating antiovalbumin antibodies until about 120 days of gestation, ovalbumin-specific helper T cells can be stimulated to function at an earlier age. This would suggest that the critical event responsible for the precise sequential maturation of immunologic competence to different antigens at different developmental stages is not the first appearance of specific receptors on immunocytes. Alternative explanations of this phenomenon are discussed.


A quality improvement initiative to reduce central line-associated bloodstream infections in a neonatal intensive care unit.
To reduce the rate of late-onset sepsis in a neonatal intensive care unit (NICU) by decreasing the rate of central line-associated bloodstream infection (CLABSI). We conducted a quasi-experimental study of an educational intervention designed to improve the quality of clinical practice in an NICU. Participants included all NICU patients with a central venous catheter (CVC). Data were collected during the period from July 1, 2005, to June 30, 2007, to document existing CLABSI rates and CVC-related practices. A multidisciplinary quality improvement committee was established to review these and published data and to create guidelines for CVC placement and management. Educational efforts were conducted to implement these practices. Postintervention CLABSI rates were collected during the period from January 1, 2008, through March 31, 2009, and compared with preintervention data and with benchmark data from the National Healthcare Safety Network (NHSN). The rate of CLABSI in the NICU decreased from 8.40 to 1.28 cases per 1,000 central line-days (adjusted rate ratio, 0.19 [95% confidence interval, 0.08-0.45]). This rate was lower than the NHSN benchmark rate for level III NICUs. The overall rate of late-onset sepsis was reduced from 5.84 to 1.42 cases per 1,000 patient-days (rate difference, -4.42 cases per 1,000 patient-days [95% confidence interval, -5.55 to -3.30 cases per 1,000 patient-days]). It is possible to reduce the rate of CLABSI, and therefore the rate of late-onset sepsis, by establishing and adhering to evidence-based guidelines. Sustainability depends on continued data surveillance, knowledge of medical and nursing literature, and timely feedback to the staff. The techniques established are applicable to other populations and areas of inpatient care.


Nrf2 rs6721961 and Oxidative Stress in Preeclampsia: Association with the Risk of Preeclampsia and Early-Onset Preeclampsia.
Preeclampsia as a multifactor hypertensive disorder of pregnancy is associated with enhanced placental oxidative stress. The Keap1-Nrf2 pathway protects cells against oxidative stress. We examined the possible association between the Nrf2 variants in relation to oxidative stress parameters with the risk of preeclampsia. We studied 150 preeclampsia women and 150 women with a normal pregnancy to find the frequency of Nrf2 rs6721961 genotypes using the PCR-RFLP method. Also, an association between the Nrf2 genotypes with the levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) was analyzed. Significantly lower TAC and higher MDA levels were found in preeclampsia patients compared to controls (P<0.0001). For the first time, we report an association between the Nrf2 rs6721961 polymorphism and preeclampsia risk. The present study indicated that the GT genotype and the T allele of the Nrf2 rs6721961 increased the risk of preeclampsia by 2.81 and 2.39 times, respectively. Also, the Nrf2 TT genotype was associated with a 3.9-fold increased risk of early-onset preeclampsia. We detected a positive association between the levels of body mass index, MDA, and the Nrf2 polymorphism with the risk of preeclampsia and a negative correlation between the level of TAC with the preeclampsia risk. Also, an association between the rs6721961 TT genotype with higher serum MDA levels was found. Our study suggests oxidative stress is involved in the pathogenesis of preeclampsia and the Nrf2 rs6721961 polymorphism through alteration in the levels of oxidative stress parameters might increase the risk of preeclampsia and early-onset preeclampsia.


VO(2peak), myocardial hypertrophy, and myocardial blood flow in endurance-trained men.
Endurance training induces cardiovascular and metabolic adaptations, leading to enhanced endurance capacity and exercise performance. Previous human studies have shown contradictory results in functional myocardial vascular adaptations to exercise training, and we hypothesized that this may be related to different degrees of hypertrophy in the trained heart. We studied the interrelationships between peak aerobic power (V˙O2peak), myocardial blood flow (MBF) at rest and during adenosine-induced vasodilation, and parameters of myocardial hypertrophy in endurance-trained (ET, n = 31) and untrained (n = 17) subjects. MBF and myocardial hypertrophy were studied using positron emission tomography and echocardiography, respectively. Both V˙O2peak (P < 0.001) and left ventricular (LV) mass index (P < 0.001) were higher in the ET group. Basal MBF was similar between the groups. MBF during adenosine was significantly lower in the ET group (2.88 ± 1.01 vs 3.64 ± 1.11 mL·g·min, P < 0.05) but not when the difference in LV mass was taken into account. V˙O2peak correlated negatively with adenosine-stimulated MBF, but when LV mass was taken into account as a partial correlate, this correlation disappeared. The present results show that increased LV mass in ET subjects explains the reduced hyperemic myocardial perfusion in this subject population and suggests that excessive LV hypertrophy has negative effect on cardiac blood flow capacity.


Inhomogeneous phase shifting: an algorithm for nonconstant phase displacements.
In this work, we have developed a different algorithm than the classical one on phase-shifting interferometry. These algorithms typically use constant or homogeneous phase displacements and they can be quite accurate and insensitive to detuning, taking appropriate weight factors in the formula to recover the wrapped phase. However, these algorithms have not been considered with variable or inhomogeneous displacements. We have generalized these formulas and obtained some expressions for an implementation with variable displacements and ways to get partially insensitive algorithms with respect to these arbitrary error shifts.


Matrix proteases, green tea, and St. John's wort: biomedical research catches up with folk medicine.
Some proteases involved in extracellular matrix degradation are instrumental not only in overcoming tissue barriers to allow normal extravasation of hematic cells, but also in facilitating pathological processes such as inflammation, angiogenesis and tumor invasion. The possibility of blocking these enzymes has led to the development of synthetic inhibitors, though clinical trials have been disappointing owing to considerable side effects. However, long before enzymes were first isolated, these same pathologies were being treated in plant-based folk remedies, and today science is screening them for their reputed beneficial effects. We present studies of 2 vegetable components as protease inhibitors. The first, (-)epigallocatechin-3-gallate - from green tea, has proved a good weapon for inhibiting gelatinases MMP-2 and MMP-9, but an even better inhibitor of leukocyte elastase (LE) activity; in vivo it blocks inflammation, angiogenesis and tumor invasion. The second, hyperforin - from Hypericum sp, inhibits LE-triggered activation of MMP-9, PMN chemotaxis and chemoinvasion, PMN-triggered angiogenesis, and inflammation-triggered pulmonary fibrosis; it also represses tumor-cell expression of MMP-2, thereby restraining invasion and metastasis. Modern research clearly vindicates epidemiological and historical evidence of the beneficial effects of two long-used allies from the plant kingdom, going a step beyond by shedding light on mechanistic keys.


Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion.
Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (>650) hexanucleotide GGCCTG repeat expansion in the first intron of the NOP56 gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36. The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members. Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected. SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms.


Burden and challenges of heart failure in patients with chronic kidney disease. A call to action.
Patients with the dual burden of chronic kidney disease (CKD) and chronic congestive heart failure (HF) experience unacceptably high rates of symptom load, hospitalization, and mortality. Currently, concerted efforts to identify, prevent and treat HF in CKD patients are lacking at the institutional level, with emphasis still being placed on individual specialty views on this topic. The authors of this review paper endorse the need for a dedicated cardiorenal interdisciplinary team that includes nephrologists and renal nurses and jointly manages appropriate clinical interventions across the inpatient and outpatient settings. There is a critical need for guidelines and best clinical practice models from major cardiology and nephrology professional societies, as well as for research funding in both specialties to focus on the needs of future therapies for HF in CKD patients. The implementation of cross-specialty educational programs across all levels in cardiology and nephrology will help train future specialists and nurses who have the ability to diagnose, treat, and prevent HF in CKD patients in a precise, clinically effective, and cost-favorable manner.


Sex-specific enhancement of palatability-driven feeding in adolescent rats.
It has been hypothesized that brain development during adolescence perturbs reward processing in a way that may ultimately contribute to the risky decision making associated with this stage of life, particularly in young males. To investigate potential reward dysfunction during adolescence, Experiment 1 examined palatable fluid intake in rats as a function of age and sex. During a series of twice-weekly test sessions, non-food-deprived rats were given the opportunity to voluntarily consume a highly palatable sweetened condensed milk (SCM) solution. We found that adolescent male, but not female, rats exhibited a pronounced, transient increase in SCM intake (normalized by body weight) that was centered around puberty. Additionally, adult females consumed more SCM than adult males and adolescent females. Using a well-established analytical framework to parse the influences of reward palatability and satiety on the temporal structure of feeding behavior, we found that palatability-driven intake at the outset of the meal was significantly elevated in adolescent males, relative to the other groups. Furthermore, although we found that there were some group differences in the onset of satiety, they were unlikely to contribute to differences in intake. Experiment 2 confirmed that adolescent male rats exhibit elevated palatable fluid consumption, relative to adult males, even when a non-caloric saccharin solution was used as the taste stimulus, demonstrating that these results were unlikely to be related to age-related differences in metabolic need. These findings suggest that elevated palatable food intake during adolescence is sex specific and driven by a fundamental change in reward processing. As adolescent risk taking has been hypothesized as a potential result of hypersensitivity to and overvaluation of appetitive stimuli, individual differences in reward palatability may factor into individual differences in adolescent risky decision making.


METATRYP v 2.0: Metaproteomic Least Common Ancestor Analysis for Taxonomic Inference Using Specialized Sequence Assemblies-Standalone Software and Web Servers for Marine Microorganisms and Coronaviruses.
We present METATRYP version 2 software that identifies shared peptides across the predicted proteomes of organisms within environmental metaproteomics studies to enable accurate taxonomic attribution of peptides during protein inference. Improvements include ingestion of complex sequence assembly data categories (metagenomic and metatranscriptomic assemblies, single cell amplified genomes, and metagenome assembled genomes), prediction of the least common ancestor (LCA) for a peptide shared across multiple organisms, increased performance through updates to the backend architecture, and development of a web portal (https://metatryp.whoi.edu). Major expansion of the marine METATRYP database with predicted proteomes from environmental sequencing confirms a low occurrence of shared tryptic peptides among disparate marine microorganisms, implying tractability for targeted metaproteomics. METATRYP was designed to facilitate ocean metaproteomics and has been integrated into the Ocean Protein Portal (https://oceanproteinportal.org); however, it can be readily applied to other domains. We describe the rapid deployment of a coronavirus-specific web portal (https://metatryp-coronavirus.whoi.edu/) to aid in use of proteomics on coronavirus research during the ongoing pandemic. A coronavirus-focused METATRYP database identified potential SARS-CoV-2 peptide biomarkers and indicated very few shared tryptic peptides between SARS-CoV-2 and other disparate taxa analyzed, sharing <1% peptides with taxa outside of the betacoronavirus group, establishing that taxonomic specificity is achievable using tryptic peptide-based proteomic diagnostic approaches.


Cost and cost-effectiveness of the 'Stand and Move at Work' multicomponent intervention to reduce workplace sedentary time and cardiometabolic risk.
Few studies have reported the cost and cost-effectiveness of workplace interventions to reduce sedentary time. The purpose of this study was to complete an economic evaluation of a multilevel intervention to reduce sitting time and increase light-intensity physical activity (LPA) among employees. We conducted a retrospective within-trial cost and cost-effectiveness analysis (CEA) to compare a 12-month multilevel intervention with (STAND+) and without (MOVE+) a sit-stand workstation, across 24 worksites (N=630 employee participants) enrolled in a cluster randomized clinical trial. We estimated the intervention costs using activity-based costing strategy. The intervention costs were further expressed as per person and per worksite. CEA was conducted using an incremental cost-effectiveness ratio (ICER) metric, expressed as costs for additional unit of sitting time (minute/day), LPA (minutes/day), cardiometabolic risk score, and quality-adjusted life years (QALY) increased/decreased at 12 months. We assessed the cost analysis and CEA from the organizational (ie, employer) perspective with a one-year time horizon. Total intervention costs were $134 and $72 per person, and $3939 and $1650 per worksite for the STAND+ (N worksites = 12; N employees = 354) and MOVE+ (N worksites = 12; N employees = 276) interventions, respectively. The ICER was $1 (95% CI $0.8-1.4) for each additional minute reduction of workplace sitting time (standardized to 8-hour workday); and $4656 per QALY gained at 12 months. There was a modest and non-significant change of loss of work productivity improvement (-0.03 hours, 95% CI -4.16-4.09 hours), which was associated with a $0.34 return for every $1 invested. The multi-level intervention with sit-stand workstations has the potential to be widely implemented to reduce workplace sitting time. Future research into work productivity outcomes in terms of cost-benefits for employers is warranted.


Federated queries of clinical data repositories: the sum of the parts does not equal the whole.
In 2008 we developed a shared health research information network (SHRINE), which for the first time enabled research queries across the full patient populations of four Boston hospitals. It uses a federated architecture, where each hospital returns only the aggregate count of the number of patients who match a query. This allows hospitals to retain control over their local databases and comply with federal and state privacy laws. However, because patients may receive care from multiple hospitals, the result of a federated query might differ from what the result would be if the query were run against a single central repository. This paper describes the situations when this happens and presents a technique for correcting these errors. We use a one-time process of identifying which patients have data in multiple repositories by comparing one-way hash values of patient demographics. This enables us to partition the local databases such that all patients within a given partition have data at the same subset of hospitals. Federated queries are then run separately on each partition independently, and the combined results are presented to the user. Using theoretical bounds and simulated hospital networks, we demonstrate that once the partitions are made, SHRINE can produce more precise estimates of the number of patients matching a query. Uncertainty in the overlap of patient populations across hospitals limits the effectiveness of SHRINE and other federated query tools. Our technique reduces this uncertainty while retaining an aggregate federated architecture.


MSMExplorer: visualizing Markov state models for biomolecule folding simulations.
Markov state models (MSMs) for the study of biomolecule folding simulations have emerged as a powerful tool for computational study of folding dynamics. MSMExplorer is a visualization application purpose-built to visualize these MSMs with an aim to increase the efficacy and reach of MSM science. MSMExplorer is available for download from https://simtk.org/home/msmexplorer. The source code is made available under the GNU Lesser General Public License at https://github.com/SimTk/msmexplorer.


Randomized Controlled Trial of Shared Care for Patients With Cancer Involving General Practitioners and Cancer Specialists.
We aimed to determine whether a shared care model (SCM) during chemotherapy treatment improved emotional well-being, empowerment, and prevalence of symptoms for people being treated for cancer. People receiving chemotherapy for hematologic, breast, ovarian, or colorectal malignancies at two cancer centers were randomly assigned to receive SCM or standard care. The SCM involved a patient-held record, a project coordinator, routine contact between the patient and general practitioner/primary care physician, and primary care physician education. Participants completed the Hospital Anxiety and Depression Scale, the Mini-Mental Adjustment to Cancer, and an empowerment questionnaire before, in the middle of, and on completion of chemotherapy. The presence and severity of adverse effects of chemotherapy were recorded by patients in a symptom diary. Ninety-seven eligible participants were randomly allocated, less than half the intended recruitment. There were no significant differences between the groups for empowerment, symptom prevalence, or Mini-Mental Adjustment to Cancer scores. The proportion with clinical anxiety (Hospital Anxiety and Depression Scale anxiety score of ≥ 11) decreased over time in both groups (P = .013) but decreased more in the intervention group (P = .002). Depression was unchanged over time. Our study was limited by low recruitment and predominance of patients with breast cancer, and was underpowered for the main analyses. Results should therefore be interpreted with caution. Little benefit was seen for SCM in the majority of domains including empowerment, symptom prevalence, and psychological adjustment to cancer. The SCM showed efficacy in clinically anxious patients. Such interventions may be better implemented by using a targeted approach to identify at-need subgroups.


Capsular serotyping of Pasteurella multocida from various animal hosts - a comparison of phenotypic and genotypic methods.
One hundred and fourteen strains of Pasteurella multocida were isolated from different domestic animals species (cattle, buffalo, sheep, goat, pig, rabbit, dog, cat), avian species (chicken, duck, turkey) and wild animals (deer, tiger, orang utan, marmoset). The serogroups of P. multocida were determined by both conventional capsular serotyping and a multiplex PCR assay targeting specific capsular genes. Based on the conventional serotyping method, the 114 strains of P. multocida were subtyped into 55 species-specific (untypeable strains) P. multocida, 15 serogroup A, 23 serogroup B and 21 serogroup D. Based on the multiplex PCR assay on the specific capsular genes associated with each serogroup, the 114 strains were further divided to 22 species-specific P. multocida (KMT1 - 460 bp), 53 serogroup A (A - 1,044 bp), 33 serogroup B (B - 760 bp) and 6 serogroup D (D - 657 bp). No serogroup E (511 bp) or F (851 bp) was detected among the Malaysian P. multocida. PCR-based typing was more discriminative and could further subtype the previously untypeable strains. Overall, there was a significant and positive correlation between both methods in serogrouping P. multocida (r = 0.7935; p<0.4893). Various serogroups of P. multocida were present among the livestock with 75% of the strains belonging to serogroups A or B. PCR serotyping was therefore a highly species-specific, sensitive and robust method for detection and differentiation of P. multocida serogroups compared to conventional serotyping. To the best of our knowledge, this is the first report from Malaysia of the application of a PCR to rapidly define the species-specific P. multocida and its serogroups as an important zoonotic pathogen in Malaysia.


Optimal spectral inversion of atmospheric radiometric measurements in the near-UV to near-IR range: A case study.
WWe present a general analysis of the error budget in the spectral inversion of atmospheric radiometric measurements. By focussing on the case of an occultation experiment, we simplify the problem through a reduced number of absorbers in a linearized formalism. However, our analysis is quite general and applies to many other situations. For a spectrometer having an infinite spectral resolution, we discuss the origin of systematic and random errors. In particular, the difficult case of aerosols is investigated and several inversion techniques are compared. We underline the importance of carefully simulating the spectral inversion as a function of the target constituent to be retrieved, and the required accuracy level.


[Ischemic hepatitis in congestive heart failure after an episode of hypotension].
Ischemic hepatitis can occur as an acute episode in advanced congestive heart failure (CHF). The mechanism is massive necrosis of the central lobules resulting from acute hypoxia when low cardiac output further reduces oxygen supply, aggravating underlying congestion due to poor venous outflow. We describe a 70-year-old woman with congestive heart failure for 7 years who was admitted with jaundice, vomiting, abdominal pain and oliguria after an episode of hypotension. The diagnosis of ischemic hepatitis was established by a documented episode of severe hypotension, followed by elevation of serum transaminases, a rise in serum bilirubin and LDH levels, prolonged prothrombin time and acute renal failure. Other causes of acute hepatitis, such as a virus or drugs were excluded, and improved liver and renal function followed hemodynamic stabilization. We conclude that ischemic hepatitis should be considered whenever acute hepatitis follows a recent episode of systemic hypotension, especially in the context of concomitant CHF.


Employment and attendance in day care centres for people with mild intellectual disabilities - do age, gender, functional level or hospital admissions matter?
Workforce inclusion is an important political goal in many countries. However, nearly 70% of Norwegians registered with mild intellectual disabilities (IDs) are not registered employed or attending in day care centres. This study investigates the association between age, gender, functional level and hospital admissions with employment or attendance in public financed, community-based day care centres for adults with mild IDs in Norway. This study is based on data from a linkage of the national population-based registries from 2013 to 2015: Statistics Norway (SSB), the Norwegian Information System for the Nursing and Care Sector (IPLOS) and the Norwegian Patient Registry (NPR). The sample consisted of 2370 adults registered with a mild ID, receiving disability pension in Norway, aged 18-67 years. Binary and multinomial logistic analyses, adjusted for age, gender, functional level and hospital admissions, were performed. In 2015, 45.7% and 19.6% of the samples aged 20-31 and 52-63 years, respectively, were registered as employed or in day care centres. Participation in day care is a public service registered in IPLOS, which requires registration of functional level, while attendance in employment support is registered in SSB, where functional level is not registered. Compared with people registered with a high functional level, the probability of being employed or in day care centres was lower for people without registration of functional level. People with hospital admissions were less likely to be employed, especially if they had both psychiatric and somatic hospital admissions. People were less likely to attend day care and open employment only if they had a combination of both types of hospital admissions. Attendance in day care centres was less likely for men than women. Older people with mild ID, without registered functional level (meaning not receiving public community-based services) and with a history of hospital admissions were significantly less likely to be employed or participate in day care centres. The clear association between not being employed or attending day care centres and not having one's functional level registered implies there is a need for increased focus on how to enhance work participation among people with mild IDs who are not within the system of receiving public services.


Accuracy of funduscopy to identify true edema versus pseudoedema of the optic disc.
Differential diagnosis between acute optic disc edema (ODE) and optic disc pseudoedema (PODE) may be a clinical challenge even for well-trained ophthalmologists. Funduscopy remains the first-line investigation. The aim of this study was to assess the accuracy, sensitivity, and specificity of funduscopy in differentiating ODE from PODE. This was an observational, cross-sectional, two-center study of subjects referred for presumed acute ODE. During funduscopy, each observer completed a form concerning the presence/absence of the 10 conventional signs of ODE. Seventy-four patients with ODE and 48 subjects with PODE were included in the analysis. Accuracy, sensitivity, and specificity from all possible combinations of signs were calculated by support vector machine (SVM) analysis. As a single sign, the swelling of the peripapillary retinal nerve fiber layer had the highest accuracy (0.92; 95% confidence interval [CI], 0.82-0.97). Little variation was observed when more than fours signs were present. The best four-sign combinations were SWELLING, HEMORRHAGES, papilla ELEVATION, and CONGESTION of peripapillary vessels (accuracy, 0.93; 95% CI, 0.83-0.98; sensitivity, 0.95; specificity, 0.89). The presence of retinal or choroidal folds appeared to be a pathognomonic sign of true ODE (100% sensitivity) but had a low rate of presentation (23%). The presence of at least four ophthalmoscopic signs (with the sign "swelling" included) gives the highest accuracy. Furthermore, peripapillary retinal folds seem to be related exclusively to ODE because they were never observed in our PODE group. These data may be useful for clinicians when evaluating patients referred for presumed optic disc edema in the acute phase.


Phase response characteristics of model neurons determine which patterns are expressed in a ring circuit model of gait generation.
In order to assess the relative contributions to pattern-generation of the intrinsic properties of individual neurons and of their connectivity, we examined a ring circuit composed of four complex physiologically based oscillators. This circuit produced patterns that correspond to several quadrupedal gaits, including the walk, the bound, and the gallop. An analysis using the phase response curve (PRC) of an uncoupled oscillator accurately predicted all modes exhibited by this circuit and their phasic relationships--with the caveat that in certain parameter ranges, bistability in the individual oscillators added nongait patterns that were not amenable to PRC analysis, but further enriched the pattern-generating repertoire of the circuit. The key insights in the PRC analysis were that in a gait pattern, since all oscillators are entrained at the same frequency, the phase advance or delay caused by the action of each oscillator on its postsynaptic oscillator must be the same, and the sum of the normalized phase differences around the ring must equal to an integer. As suggested by several previous studies, our analysis showed that the capacity to exhibit a large number of patterns is inherent in the ring circuit configuration. In addition, our analysis revealed that the shape of the PRC for the individual oscillators determines which of the theoretically possible modes can be generated using these oscillators as circuit elements. PRCs that have a complex shape enable a circuit to produce a wider variety of patterns, and since complex neurons tend to have complex PRCs, enriching the repertoire of patterns exhibited by a circuit may be the function of some intrinsic neuronal complexity. Our analysis showed that gait transitions, or more generally, pattern transitions, in a ring circuit do not require rewiring the circuit or any changes in the strength of the connections. Instead, transitions can be achieved by using a control parameter, such as stimulus intensity, to sculpt the PRC so that it has the appropriate shape for the desired pattern(s). A transition can then be achieved simply by changing the value of the control parameter so that the first pattern either ceases to exist or loses stability, while a second pattern either comes into existence or gains stability. Our analysis illustrates the predictive value of PRCs in circuit analysis and can be extended to provide a design method for pattern-generating circuits.


The case for randomized controlled trials to assess the impact of clinical information systems.
There is a persistent view of a significant minority in the medical informatics community that the randomized controlled trial (RCT) has a limited role to play in evaluating clinical information systems. A common reason voiced by skeptics is that these systems are fundamentally different from drug interventions, so the RCT is irrelevant. There is an urgent need to promote the use of RCTs, given the shift to evidence-based policy and the need to demonstrate cost-effectiveness of these systems. The authors suggest returning to first principles and argue that what is required is clarity about how to match methods to evaluation questions. The authors address common concerns about RCTs, and the extent to which they are fallacious, and also discuss the challenges of conducting RCTs in informatics and alternative study designs when randomized trials are infeasible. While neither a perfect nor universal evaluation method, RCTs form an important part of an evaluator's toolkit.


Antimicrobial activity of organic acids against Campylobacter spp. and development of combinations-A synergistic effect?
Contaminated poultry meat is considered to be the main source of human infection with Campylobacter spp., a pathogen that asymptomatically colonizes broiler chickens during fattening and contaminates carcasses during slaughter. To prevent or reduce the colonization of broiler flocks with Campylobacter spp., applying different organic acids, especially in combinations, via feed or drinking water seems to be a promising approach. However, only very few combinations of organic acids have been tested for their antibacterial efficacy against Campylobacter spp. Therefore, the in vitro susceptibility of 30 Campylobacter spp. isolates (20 C. jejuni and ten C. coli) to ten organic acids and ten combinations was determined. The testing of minimum inhibitory concentration (MIC) values was performed at pH 6.0 and 7.3 by using the broth microdilution method and included the following organic acids: Caprylic acid, sorbic acid, caproic acid, benzoic acid, ascorbic acid, propionic acid, acetic acid, formic acid, fumaric acid and tartaric acid and combinations thereof. The lowest MIC values were seen for caprylic acid (MIC range at pH 7.3: 0.5-2 mmol/L) and sorbic acid (MIC range at pH 7.3: 1-4 mmol/L). One to two dilution steps lower MIC values were determined at the lower pH value of 6.0. Furthermore, ten combinations consisting of three to five organic acids were developed. In addition to the tested antibacterial activity, other criteria were included such as approval as feed additives, reported synergistic effects and chemical properties. For nine of ten combinations, the MIC90 values of the organic acids decreased 1.25- to 241.5-fold compared to the MIC90 values for the individual substances. Furthermore, nine of ten combinations exhibited synergistic activities against two or more of the tested C. jejuni and C. coli isolates. A combination of caprylic acid, sorbic acid and caproic acid exhibited synergistic activities against the largest number of Campylobacter spp. isolates (six C. jejuni and four C. coli) with fractional inhibitory concentration (FIC) indices (∑FIC) ranging from 0.33 to 1.42. This study shows in vitro synergistic activities of different organic acids in combinations against the major Campylobacter species and could therefore be a promising basis for reducing Campylobacter spp. in vivo.


Orientation selectivity of motion-boundary responses in human visual cortex.
Motion boundaries (local changes in visual motion direction) arise naturally when objects move relative to an observer. In human visual cortex, neuroimaging studies have identified a region (the kinetic occipital area [KO]) that responds more strongly to motion-boundary stimuli than to transparent-motion stimuli. However, some functional magnetic resonance imaging (fMRI) studies suggest that KO may encompass multiple visual areas and single-unit studies in macaque visual cortex have identified neurons selective for motion-boundary orientation in areas V2, V3, and V4, implying that motion-boundary selectivity may not be restricted to a single area. It is not known whether fMRI responses to motion boundaries are selective for motion-boundary orientation, as would be expected if these responses reflected the population activity of motion-boundary-selective neurons. We used an event-related fMRI adaptation protocol to measure orientation-selective responses to motion boundaries in human visual cortex. On each trial, we measured the response to a probe stimulus presented after an adapter stimulus (a vertical or horizontal motion-boundary grating). The probe stimulus was either a motion-boundary grating oriented parallel or orthogonal to the adapter stimulus or a transparent-motion stimulus. Orientation-selective adaptation for motion boundaries--smaller responses for trials in which test and adapter stimuli were parallel to each other--was observed in multiple extrastriate visual areas. The strongest adaptation, relative to the unadapted responses, was found in V3A, V3B, LO1, LO2, and V7. Most of the visual areas that exhibited orientation-selective adaptation in our data also showed response preference for motion boundaries over transparent motion, indicating that most of the human visual areas previously shown to respond to motion boundaries are also selective for motion-boundary orientation. These results suggest that neurons selective for motion-boundary orientation are distributed across multiple human visual cortical areas and argue against the existence of a single region or area specialized for motion-boundary processing.


Dauer pheromone and G-protein signaling modulate the coordination of intraflagellar transport kinesin motor proteins in C. elegans.
Cilia length and function are dynamically regulated by modulation of intraflagellar transport (IFT). The cilia of C. elegans amphid channel neurons provide an excellent model to study this process, since they use two different kinesins for anterograde transport: kinesin-II and OSM-3 kinesin together in the cilia middle segments, but only OSM-3 in the distal segments. To address whether sensory signaling modulates the coordination of the kinesins, we studied IFT protein motility in gpa-3 mutant animals, since dominant active mutation of this sensory Galpha protein GPA-3QL) affects cilia length. In addition, we examined animals exposed to dauer pheromone, since dauer formation, which involves gpa-3, induces changes in cilia morphology. Live imaging of fluorescently tagged IFT proteins showed that in gpa-3 mutants and in larvae exposed to dauer pheromone, kinesin-II speed is decreased and OSM-3 speed is increased, whereas structural IFT proteins move at an intermediate speed. These results indicate that mutation of gpa-3 and exposure to dauer pheromone partially uncouple the two kinesins. We propose a model in which GPA-3-regulated docking of kinesin-II and/or OSM-3 determines entry of IFT particles into the cilia subdomains, allowing structural and functional plasticity of cilia in response to environmental cues.


Functionally-focused algorithmic analysis of high resolution microarray-CGH genomic landscapes demonstrates comparable genomic copy number aberrations in MSI and MSS sporadic colorectal cancer.
Array-based comparative genomic hybridization (aCGH) emerged as a powerful technology for studying copy number variations at higher resolution in many cancers including colorectal cancer. However, the lack of standardized systematic protocols including bioinformatic algorithms to obtain and analyze genomic data resulted in significant variation in the reported copy number aberration (CNA) data. Here, we present genomic aCGH data obtained using highly stringent and functionally relevant statistical algorithms from 116 well-defined microsatellites instable (MSI) and microsatellite stable (MSS) colorectal cancers. We utilized aCGH to characterize genomic CNAs in 116 well-defined sets of colorectal cancer (CRC) cases. We further applied the significance testing for aberrant copy number (STAC) and Genomic Identification of Significant Targets in Cancer (GISTIC) algorithms to identify functionally relevant (nonrandom) chromosomal aberrations in the analyzed colorectal cancer samples. Our results produced high resolution genomic landscapes of both, MSI and MSS sporadic CRC. We found that CNAs in MSI and MSS CRCs are heterogeneous in nature but may be divided into 3 distinct genomic patterns. Moreover, we show that although CNAs in MSI and MSS CRCs differ with respect to their size, number and chromosomal distribution, the functional copy number aberrations obtained from MSI and MSS CRCs were in fact comparable but not identical. These unifying CNAs were verified by MLPA tumor-loss gene panel, which spans 15 different chromosomal locations and contains 50 probes for at least 20 tumor suppressor genes. Consistently, deletion/amplification in these frequently cancer altered genes were identical in MSS and MSI CRCs. Our results suggest that MSI and MSS copy number aberrations driving CRC may be functionally comparable.


Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury.
Although periventricular white matter injury (PWMI) is the leading cause of chronic neurological disability and cerebral palsy in survivors of premature birth, the cellular-molecular mechanisms by which ischemia-reperfusion contributes to the pathogenesis of PWMI are not well defined. To define pathophysiologic relationships among ischemia, acute cerebral white matter damage, and vulnerable target populations, we used a global cerebral ischemia-reperfusion model in the instrumented 0.65 gestation fetal sheep. We developed a novel method to make repeated measurements of cerebral blood flow using fluorescently labeled microspheres to resolve the spatial heterogeneity of flow in situ in three-dimensional space. Basal flow in the periventricular white matter (PVWM) was significantly lower than in the cerebral cortex. During global cerebral ischemia induced by carotid occlusion, flow to all regions was reduced by nearly 90%. Ischemia of 30 or 37 min duration generated selective graded injury to frontal and parietal PVWM, two regions of predilection for human PWMI. Injury was proportional to the duration of ischemia and increased markedly with 45 min of ischemia to extensively damage cortical and subcortical gray matter. Surprisingly, the distribution of PVWM damage was not uniform and not explained by heterogeneity in the degree of white matter ischemia. Rather, the extent of white matter damage coincided with the presence of a susceptible population of late oligodendrocyte progenitors. These data support that although ischemia is necessary to generate PWMI, the presence of susceptible populations of oligodendrocyte progenitors underlies regional predilection to injury.