Comparative transcriptional survey between laser-microdissected cells from laminar abscission zone and petiolar cortical tissue during ethylene-promoted abscission in citrus leaves.
Abscission is the cell separation process by which plants are able to shed organs. It has a great impact on the yield of most crop plants. At the same time, the process itself also constitutes an excellent model to study cell separation processes, since it occurs in concrete areas known as abscission zones (AZs) which are composed of a specific cell type. However, molecular approaches are generally hampered by the limited area and cell number constituting the AZ. Therefore, detailed studies at the resolution of cell type are of great relevance in order to accurately describe the process and to identify potential candidate genes for biotechnological applications. Efficient protocols for the isolation of specific citrus cell types, namely laminar abscission zone (LAZ) and petiolar cortical (Pet) cells based on laser capture microdissection (LCM) and for RNA microextraction and amplification have been developed. A comparative transcriptome analysis between LAZ and Pet from citrus leaf explants subjected to an in-vitro 24 h ethylene treatment was performed utilising microarray hybridization and analysis. Our analyses of gene functional classes differentially represented in ethylene-treated LAZ revealed an activation program dominated by the expression of genes associated with protein synthesis, protein fate, cell type differentiation, development and transcription. The extensive repertoire of genes associated with cell wall biosynthesis and metabolism strongly suggests that LAZ layers activate both catabolic and anabolic wall modification pathways during the abscission program. In addition, over-representation of particular members of different transcription factor families suggests important roles for these genes in the differentiation of the effective cell separation layer within the many layers contained in the citrus LAZ. Preferential expression of stress-related and defensive genes in Pet reveals that this tissue is likely to be reprogrammed to prevent pathogen attacks and general abiotic stresses after organ shedding. The LCM-based data generated in this survey represent the most accurate description of the main biological processes and genes involved in organ abscission in citrus. This study provides novel molecular insight into ethylene-promoted leaf abscission and identifies new putative target genes for characterization and manipulation of organ abscission in citrus.


Telomere associations in interphase nuclei: possible role in maintenance of interphase chromosome topology.
The relative sizes of individual telomeres in cultured human cells under conditions of cell cycling, replicative quiescence, cell transformation and immortalization were determined using quantitative fluorescence in situ hybridization (Q-FISH) with a telomere-specific peptide nucleic acid (PNA) probe. Results obtained from analysis of telomere length profiles (TLPs), which display the distribution of relative telomere lengths for individual cells, confirmed telomere length heterogeneity at the single cell level and proportional shortening of telomere length during replicative aging of virus-transformed cells. TLPs also revealed that some telomeric ends of chromosomes are so closely juxtaposed within interphase nuclei that their fluorescent signals appear as a single spot. These telomeric associations (TAs) were far more prevalent in interphase nuclei of noncycling normal and virus-transformed cells than in their cycling counterparts. The number of interphase TAs per nucleus observed in late-passage E6/E7-transformed cells did not increase during progression to crisis, suggesting that telomere shortening does not increase the frequency of interphase TAs. Furthermore, interphase TAs were rarely observed in rapidly cycling, telomerase-positive, immortalized cells that exhibit somewhat shortened, but stabilized, telomere length through the activity of telomerase. Our overall results suggest that the number of interphase TAs is dependent more on whether or not cells are cycling than on telomere length, with TAs being most prominent in the nuclei of replicatively quiescent cells in which nonrandom (even preferred) chromosome spatial arrangements have been observed. We propose that interphase TAs may play a role in the generation and/or maintenance of nuclear architecture and chromosome positional stability in interphase nuclei, especially in cells with a prolonged G(1)/G(0) phase and possibly in terminally differentiated cells.


Autologous bone marrow transplantation for hematologic cancer.
In summary, autologous BMT is emerging as a way to deliver myeloablative therapy to patients with hematologic cancer ineligible for allogeneic BMT. Moreover, there are likely circumstances in which autologous is preferable to allogeneic BMT--most notably in Hodgkin's disease, but likely also in the older adult acute leukemia patient. Work is clearly required to produce upgraded conditioning regimens, and to define the need for and utility of marrow purification procedures. However, these pressing needs should not obscure the benefits of the current use of autologous BMT techniques for selected patients--nor prevent the realization that improved patient selection is the most immediate method to improve current results.


CD4+ cytolytic T cell clone confers protection against murine malaria.
A CD4+ T cell clone (A1.6) was derived from spleen cells of mice immunized with irradiated sporozoites. This T cell clone recognizes an antigen that is shared by sporozoites and blood forms of Plasmodium berghei and differs from the circumsporozoite protein. Clone A1.6 displays cytotoxic activity, produces IFN-gamma and IL-2 in vitro, and recognizes the plasmodial antigen in the context of the class II I-Ed molecule. Passive transfer of this CD4+ clone into naive mice resulted in a high degree of protection against sporozoite challenge.


Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial.
To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26). Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45). These results remained after further adjustment for treatment strategy. Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12-63% risk gradient from patients carrying none compared with all predictors. Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off. In a secondary exploratory analysis using cut-off >1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses. The other parameters also remained significant using this lower cut-off. In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA. NCT00764725.


Clinical Features of a Chinese Sample with Self-Reported Symptoms of Pathological Dissociation.
People with pathological dissociation should receive proper clinical attention and timely support. Recent studies have shown that pathological dissociation is common in the Chinese context. However, little is known about the clinical features of Chinese people with pathological dissociation. This paper reports the first data regarding trauma histories, mental health symptoms, clinical diagnoses, service usages, stigma and psychosocial needs in a convenience sample of Chinese people who screened positive for pathological dissociation on a self-report measure (N = 72). This sample was characterized by a history of trauma and high levels of trauma-related symptoms and depression. Medication treatments were the most common interventions for them; many participants did not receive psychotherapy. We found no clinical differences between participants who had and had not received psychotherapy for post-traumatic/dissociative symptoms. This implies that many participants did not have the chance of receiving specific psychotherapy even though their trauma histories and clinical symptoms were as severe as those who were receiving specific psychotherapy. Stigma and unmet psychosocial needs were common in this sample and should receive more attention in the field. Implications for research and practice are highlighted. More dissociation-informed services are required for Chinese-speaking populations.


Dissociated functional significance of decision-related activity in the primate dorsal stream.
During decision making, neurons in multiple brain regions exhibit responses that are correlated with decisions. However, it remains uncertain whether or not various forms of decision-related activity are causally related to decision making. Here we address this question by recording and reversibly inactivating the lateral intraparietal (LIP) and middle temporal (MT) areas of rhesus macaques performing a motion direction discrimination task. Neurons in area LIP exhibited firing rate patterns that directly resembled the evidence accumulation process posited to govern decision making, with strong correlations between their response fluctuations and the animal's choices. Neurons in area MT, in contrast, exhibited weak correlations between their response fluctuations and choices, and had firing rate patterns consistent with their sensory role in motion encoding. The behavioural impact of pharmacological inactivation of each area was inversely related to their degree of decision-related activity: while inactivation of neurons in MT profoundly impaired psychophysical performance, inactivation in LIP had no measurable impact on decision-making performance, despite having silenced the very clusters that exhibited strong decision-related activity. Although LIP inactivation did not impair psychophysical behaviour, it did influence spatial selection and oculomotor metrics in a free-choice control task. The absence of an effect on perceptual decision making was stable over trials and sessions and was robust to changes in stimulus type and task geometry, arguing against several forms of compensation. Thus, decision-related signals in LIP do not appear to be critical for computing perceptual decisions, and may instead reflect secondary processes. Our findings highlight a dissociation between decision correlation and causation, showing that strong neuron-decision correlations do not necessarily offer direct access to the neural computations underlying decisions.


Global micronutrient deficiencies in childhood and impact on growth and survival: challenges and opportunities.
Despite numerous advances and improvements in child health, malnutrition still remains as one of the main public health challenges of the 21st century, particularly in developing countries. It undermines the survival, growth and development of children, and is associated with almost 35% of all deaths in children under the age of 5 years worldwide. An estimated 178 million children are stunted globally, and an additional 19 million children have severe acute malnutrition (wasting). These conditions are very often associated with concomitant micronutrient deficiencies, and among these, vitamin A, iron, zinc and iodine deficiencies are the most prevalent in childhood. Vitamin A and zinc deficiency is associated with an estimated 1 million child deaths and 9% of global childhood disability-adjusted life years. Recent data on the timing of growth retardation and stunting in infants suggest that the onset is commensurate with inappropriate complementary feeding and potentially compounded by maternal undernutrition and intrauterine growth retardation, and that the first 24 months represent a critical window of opportunity for intervention. Given the wide prevalence of multiple micronutrient deficiencies in malnourished children in developing countries, the challenge is to implement intervention strategies that combine appropriate infant and young child feeding with micronutrient interventions at scale. Emerging data from community intervention trials now provide evidence that this is both tangible and can lead to alleviation of childhood undernutrition. Some of these recent findings will be discussed.


Controlled defunctionalisation of biobased organic acids.
The production of chemicals from biomass is of large interest to the sustainable chemistry community. While the main focus in the literature is on compounds that can be directly obtained from carbohydrates via fermentation and on the conversion of lignocellulosic biomass, the production of chemicals via the controlled defunctionalisation of highly functional biobased compounds is largely undervalued. This feature article intends to highlight the recent progress in heterogeneous chemocatalytic defunctionalisation of the widely available citric and amino acids, focusing on the different chemical routes available and identifying the most promising defunctionalisation strategies based on atom economy and functionality index.


Clinical Tests of Ultra-Low Vision Used to Evaluate Rudimentary Visual Perceptions Enabled by the BrainPort Vision Device.
We evaluated whether existing ultra-low vision tests are suitable for measuring outcomes using sensory substitution. The BrainPort is a vision assist device coupling a live video feed with an electrotactile tongue display, allowing a user to gain information about their surroundings. We enrolled 30 adult subjects (age range 22-74) divided into two groups. Our blind group included 24 subjects (n = 16 males and n = 8 females, average age 50) with light perception or worse vision. Our control group consisted of six subjects (n = 3 males, n = 3 females, average age 43) with healthy ocular status. All subjects performed 11 computer-based psychophysical tests from three programs: Basic Assessment of Light Motion, Basic Assessment of Grating Acuity, and the Freiburg Vision Test as well as a modified Tangent Screen. Assessments were performed at baseline and again using the BrainPort after 15 hours of training. Most tests could be used with the BrainPort. Mean success scores increased for all of our tests except contrast sensitivity. Increases were statistically significant for tests of light perception (8.27 ± 3.95 SE), time resolution (61.4% ± 3.14 SE), light localization (44.57% ± 3.58 SE), grating orientation (70.27% ± 4.64 SE), and white Tumbling E on a black background (2.49 logMAR ± 0.39 SE). Motion tests were limited by BrainPort resolution. Tactile-based sensory substitution devices are amenable to psychophysical assessments of vision, even though traditional visual pathways are circumvented. This study is one of many that will need to be undertaken to achieve a common outcomes infrastructure for the field of artificial vision.


Mie resonances and Bragg-like multiple scattering in opacity of two-dimensional photonic crystals.
The lowest (main) and high-order Mie resonances and the Bragg-like multiple scattering of electromagnetic (EM) waves are determined as three mechanisms of formation and frequency position of two opaque bands, with narrow peaks in one of the bands in the transmission spectra of 2D photonic crystals composed of dielectric cylinders arranged parallel to the EM wave's electric vector in the square lattice. The main Mie resonance in a single cylinder defines the frequency position of the main gap whose formation results from the Bragg-like scattering. An additional gap with narrow transmission peaks opens in the spectrum of a cylinder layer and becomes pronounced with the number of layers. It is argued that higher-order Mie resonances are responsible for the transmission peaks within the additional band of a perfect crystal. It is shown that 2D photonic crystals with a filling factor ranging from 3% to 20% at a fixed crystal period may be a good zero approximation to study wave transmission through a localizing 2D dense random medium slab.


On the efficiency of the orthogonal least squares training method for radial basis function networks.
The efficiency of the orthogonal least squares (OLS) method for training approximation networks is examined using the criterion of energy compaction. We show that the selection of basis vectors produced by the procedure is not the most compact when the approximation is performed using a nonorthogonal basis. Hence, the algorithm does not produce the smallest possible networks for a given approximation error. Specific examples are given using the Gaussian radial basis functions type of approximation networks.


Gate control of the electron spin-diffusion length in semiconductor quantum wells.
The spin diffusion length is a key parameter to describe the transport properties of spin polarized electrons in solids. Electrical spin injection in semiconductor structures, a major issue in spintronics, critically depends on this spin diffusion length. Gate control of the spin diffusion length could be of great importance for the operation of devices based on the electric field manipulation and transport of electron spin. Here we demonstrate that the spin diffusion length in a GaAs quantum well can be electrically controlled. Through the measurement of the spin diffusion coefficient by spin grating spectroscopy and of the spin relaxation time by time-resolved optical orientation experiments, we show that the diffusion length can be increased by more than 200% with an applied gate voltage of 5 V. These experiments allow at the same time the direct simultaneous measurements of both the Rashba and Dresselhaus spin-orbit splittings.


Autoimmune cytopenias and thrombotic thrombocytopenic purpura.
The autoimmune cytopenias are a group of disorders resulting primarily from autoantibody-mediated destruction of blood cells, with variable clinical sequelae depending on the severity and lineage affected. Disease presentation ranges from an asymptomatic finding on a routine full blood count to an acutely unwell patient suffering the clinical consequences of severe anaemia, neutropenia or thrombocytopenia. The cytopenia may be primary or secondary to underlying infectious, immune or malignant processes. Thrombotic thrombocytopenic purpura (TTP) is a distinct, rare but potentially life-threatening entity that classically but not invariably presents with a pentad of acute onset haemolytic anaemia, thrombocytopenia, neurological symptoms, renal impairment and fevers. Autoimmune cytopenias have formed a recognised diagnostic entity for over 150 years yet continue to present a challenge in medical practice due to heterogeneity in clinical presentation and triggering factors, an incomplete understanding of underlying pathophysiology and a lack of evidence-based therapeutic approaches.


First Report of Collar and Root Rot of Physic Nut (Jatropha curcas) Caused by Neoscytalidium dimidiatum in Brazil.
Physic nut (Jatropha curcas L.; Euphorbiaeae) has become important in Brazil due to its potential as a feedstock for biodiesel production. In October 2010, during routine monitoring of fields in the state of Piauí, several plants were observed with symptoms of collar and root rot. Initially, plants appeared withered and chlorotic, and later became defoliated. Roots and collars of affected plants also appeared rotten with black fungal structures directly observed. Symptomatic tissue fragments of 5 mm diameter were washed with 70% ethanol, 1% sodium hypochlorite, and sterilized water, before being placed in petri dishes containing potato dextrose agar (PDA) and incubated at 25°C. Pure cultures were then obtained by single-spore isolation. The fungus isolated was grown on plates containing 2% water agar overlaid with sterilized corn straw or pine twigs and incubated at 25°C under a photoperiod of 12 h for 4 weeks to induce the formation of fruiting bodies. Thirty measurements of all of the relevant morphological characters were made using a light microscope for the identification of the species. On PDA, isolates initially appeared white and became dark after 7 days. The aerial mycelia formed chains of zero- to one-septate arthroconidia, oblong to globose, initially hyaline that became brown and with a thick wall with age. The dimensions of arthroconidia were 4 to 12 × 2.5 to 8 μm. The formation of pycnidia was observed on the plates with corn straw and pines twigs. These were dark, with a globose base up to 250 μm and a neck up to 810 μm. Conidiogenous cells were holoblastic, lageniform to ampulliform, hyaline, and 6 to 10 × 1.5 to 2.5 μm. Conidia were hyaline, ellipsoid to nearly fusiform, and 8 to 12 × 4 to 5 μm. Septate and dark conidia were not observed. DNA was extracted from one isolate following Wizard Genomic DNA Purification Kit procedures and amplified using primers ITS1 and ITS4. Products were directly sequencing by Macrogen, Korea. The 856-bp sequence obtained was deposited in GenBank (Accession No. JQ927342). The sequence was 99% similar to Neoscytalidium dimidiatum (Penz.) Crous & Slippers, further supporting the identification by morphology. Pathogenicity tests were conducted by using 6 mm disks removed from the outer bark of the collar region of healthy plants using a sterile cork borer, and 6-mm diameter plugs were placed in each wound. Five plants were inoculated with the isolate and five plants inoculated with an isolate-free agar plug. Below these, pieces of moistened cotton were placed and covered with Parafilm. After 60 days, all inoculated plants reproduced the symptoms observed in the field, and the pathogen was successfully reisolated. All non-inoculated plants remained healthy. The genus Neoscytalidium includes species having Scytalidium-like synanamorphs in the aerial mycelia and Fusicoccum-like conidia in the pycnidia (1). Currently, this species is reported to cause diseases in fig, mango, and orange (2,3). To our knowledge, this is the first report of collar and rot root caused by N. dimidiatum in J. curcas and of this fungus in Brazil. It seems likely the disease exists in areas beyond Piauí and could cause important losses for biodiesel production. References: (1) P. W. Crous et al. Stud. Mycol. 55:235, 2006. (2) G. Polizzi et al. Plant Dis. 93:1215, 2009. (3) J. D. Ray et al. Austral. Plant Dis. Notes 5:48, 2010.


Clinical characteristics of Mycobacterium tuberculosis infection among rheumatoid arthritis patients.
To evaluate the clinical characteristics of Mycobacterium tuberculosis infection in rheumatoid arthritis (RA) patients, we examined the clinical manifestations and radiography/computed tomography (CT) findings in RA patients with tuberculosis (RA+/TB+). A total of 1121 tuberculosis patients were admitted to our hospital from 1995 to 2003, with the RA patients among them comprising 1.8% (20 cases; 9 men and 11 women). This is approximately three times as high as the prevalence of RA in the entire population in Japan. In addition, the RA+/TB+ patients were older and had a longer history of RA than the 140 outpatients in our RA clinic who did not have tuberculosis (RA+/TB-). Half of the RA+/TB+ patients had no symptoms (e.g., cough, sputum, pyrexia), and their tuberculosis was detected accidentally by radiography/CT. The positive rates of the bacilli in the smear and culture of the sputum from the RA+/TB+ patients were lower than those from 143 patients randomly selected from among 1091 tuberculosis patients without any collagen disease including RA (RA-/TB+). The RA+/TB+ patients had a higher incidence of extrapulmonary tuberculosis (30%), including four cases (20%) of miliary tuberculosis, an incidence seven times higher than among the general population of tuberculosis patients. Among 14 cases of pulmonary tuberculosis patients with RA, bilateral lesions and non-cavitary lesions were found in 71.4% and 64.3%, respectively, which tended to be a higher incidence than in the RA-/TB+ patients. The mortality rate and sputum conversion time of the RA+/TB+ patients were no different from those of the RA-/TB+ patients. The prevalence of tuberculosis in RA patients is expected to increase after introduction of anti-cytokine therapy in Japan, and careful observation should be done to avoid this complication in RA patients.


Probing interactions between the U2 small nuclear ribonucleoprotein and the DEAD-box protein, Prp5.
Pre-mRNA binding to the yeast U2 small nuclear ribonucleoprotein (snRNP) during prespliceosome formation requires ATP hydrolysis, the highly conserved UACUAAC box of the branch point region of the pre-mRNA, and several factors. Here we analyzed the binding of a radiolabeled 2'-O-methyl oligonucleotide complementary to U2 small nuclear RNA to study interactions between the UACUAAC box, U2 snRNP, and Prp5p, a DEAD box protein necessary for prespliceosome formation. Binding of the 2'-O-methyl oligonucleotide to the U2 snRNP in yeast cell extract was assayed by gel electrophoresis. Binding was rapid, enhanced by ATP, and dependent on the integrity and conformation of the U2 snRNP. It was also stimulated by Prp5p that was found to associate physically with U2 snRNP. In vitro heat inactivation of the temperature-sensitive prp5-1 mutant extract decreased oligonucleotide binding to U2 and the ATP enhancement of binding by 3-fold. Furthermore, the temperature-sensitive prp5-1 mutation maps to the ATP-binding motif I within the helicase-like domain. Thus the catalytic activity of Prp5p likely promotes a conformational change in the U2 snRNP.


2014 White Paper on recent issues in bioanalysis: a full immersion in bioanalysis (Part 1--small molecules by LCMS).
The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years' editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies' input) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the upcoming issues of Bioanalysis.


The regulatory subunits of PI3Kγ control distinct neutrophil responses.
Neutrophils, which migrate toward inflamed sites and kill pathogens by producing reactive oxygen species (ROS), are important in the defense against bacterial and fungal pathogens, but their inappropriate regulation causes various chronic inflammatory diseases. Phosphoinositide 3-kinase γ (PI3Kγ) functions downstream of proinflammatory G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) in neutrophils and is a therapeutic target. In neutrophils, PI3Kγ consists of a p110γ catalytic subunit, which is activated by the guanosine triphosphatase Ras, and either a p84 or p101 regulatory subunit. Loss or inhibition of p110γ or expression of a Ras-insensitive variant p110γ (p110γ(DASAA/DASAA)) impairs PIP3 production, Akt phosphorylation, migration, and ROS formation in response to GPCR activation. The p101 subunit binds to, and mediates PI3Kγ activation by, G protein βγ subunits, and p101(-/-) neutrophils have a similar phenotype to that of p110γ(-/-) neutrophils, except that ROS responses are normal. We found that p84(-/-) neutrophils displayed reduced GPCR-stimulated PIP3 and Akt signaling, which was indistinguishable from that of p101(-/-) neutrophils. However, p84(-/-) neutrophils produced less ROS and exhibited normal migration in response to GPCR stimulation. These data suggest that p84-containing PI3Kγ controls GPCR-dependent ROS production. Thus, the PI3Kγ regulatory subunits enable PI3Kγ to mediate distinct neutrophil responses, which may occur by targeting PIP3 signaling into spatially distinct domains.


Laparoscopic total pancreatectomy: Case report and literature review.
Laparoscopic total pancreatectomy is a complicated surgical procedure and rarely been reported. This study was conducted to investigate the safety and feasibility of laparoscopic total pancreatectomy. Three patients underwent laparoscopic total pancreatectomy between May 2014 and August 2015. We reviewed their general demographic data, perioperative details, and short-term outcomes. General morbidity was assessed using Clavien-Dindo classification and delayed gastric emptying (DGE) was evaluated by International Study Group of Pancreatic Surgery (ISGPS) definition. The indications for laparoscopic total pancreatectomy were intraductal papillary mucinous neoplasm (IPMN) (n = 2) and pancreatic neuroendocrine tumor (PNET) (n = 1). All patients underwent laparoscopic pylorus and spleen-preserving total pancreatectomy, the mean operative time was 490 minutes (range 450-540 minutes), the mean estimated blood loss was 266 mL (range 100-400 minutes); 2 patients suffered from postoperative complication. All the patients recovered uneventfully with conservative treatment and discharged with a mean hospital stay 18 days (range 8-24 days). The short-term (from 108 to 600 days) follow up demonstrated 3 patients had normal and consistent glycated hemoglobin (HbA1c) level with acceptable quality of life. Laparoscopic total pancreatectomy is feasible and safe in selected patients and pylorus and spleen preserving technique should be considered. Further prospective randomized studies are needed to obtain a comprehensive understanding the role of laparoscopic technique in total pancreatectomy.


Nanotechnology: is there a need for ethical principles?
Nanotechnology (NT) is concerned with materials and systems whose structures and components exhibit novel physical, chemical and biological properties due to their nanoscale size. This new scientific discipline is fast becoming a major driver of the future direction of health care and is likely to have a significant impact on society, medicine and nursing. This article demonstrates that ethical reflections lie at the heart of nursing. In contextualizing the ethics of NT, this article questions the conclusion reached by others that ethical reflections on NT lag behind its scientific developments. Instead it proposes that the ethical issues raised by NT are similar to those relating to biotechnology, considered by ethicists since the 1970s. Consequently, this article argues that a foundation of ethical reflections already exists that can be transferred to NT. Finally, this article asserts the need for nurses to be proactively involved in interdisciplinary discussions likely to extend the current ethical reflections of autonomy, non-maleficence, beneficence and justice to NT.


Synthesis, characterization, and bioavailability of mannosylated shell cross-linked nanoparticles.
Saccharide-functionalized shell cross-linked (SCK) polymer micelles designed as polyvalent nanoscaffolds for selective interactions with receptors on Gram negative bacteria were constructed from mixed micelles composed of poly(acrylic acid-b-methyl acrylate) and mannosylated poly(acrylic acid-b-methyl acrylate). The mannose unit was conjugated to the hydrophilic chain terminus of the amphiphilic diblock copolymer precursor, from which the SCK nanoparticles were derived, by the growth of the diblock copolymer from a mannoside functionalized atom transfer radical polymerization (ATRP) initiator. Mixed micelle formation between the amphiphilic diblock copolymer and mannosylated amphiphilic diblock copolymer was followed by condensation-based cross-linking between the acrylic acid residues present in the periphery of the polymer micelles to afford SCK nanoparticles. SCKs presenting variable numbers of mannose functionalities were prepared from mixed micelles of controlled stoichiometric ratios of mannosylated and nonmannosylated diblock copolymers. The polymer micelles and SCKs were characterized by dynamic light scattering (DLS), electrophoretic light scattering, atomic force microscopy (AFM), transmission electron microscopy (TEM), and analytical ultracentrifugation (AU). Surface availability and bioactivity of the mannose units were evaluated by interactions of the nanostructures with the model lectin Concanavalin A via DLS studies, with red blood cells (rabbit) via agglutination inhibition assays and with bacterial cells (E. coli) via TEM imaging.


HIV Infection Is Associated with Impaired Striatal Function during Inhibition with Normal Cortical Functioning on Functional MRI.
The aim of the present study was to investigate the effect of HIV infection on cortical and subcortical regions of the frontal-striatal system involved in the inhibition of voluntary movement. Functional MRI (fMRI) studies suggest that human immunodeficiency virus (HIV) infection is associated with frontostriatal dysfunction. While frontostriatal systems play a key role in behavioral inhibition, there are to our knowledge no fMRI studies investigating the potential impact of HIV on systems involved during the inhibition of voluntary movement. A total of 17 combined antiretroviral therapy (cART) naïve HIV+ participants as well as 18 age, gender, ethnic, education matched healthy controls performed a modified version of the stop-signal paradigm. This paradigm assessed behavior as well as functional brain activity associated with motor execution, reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing before stopping). HIV+ participants showed significantly slower responses during motor execution compared to healthy controls, whereas they had normal proactive response slowing. Putamen hypoactivation was evident in the HIV+ participants based on successful stopping, indicating subcortical dysfunction during reactive inhibition. HIV+ participants showed normal cortical functioning during proactive inhibition. Our data provide evidence that HIV infection is associated with subcortical dysfunction during reactive inhibition, accompanied by relatively normal higher cortical functioning during proactive inhibition. This suggests that HIV infection may primarily involve basic striatal-mediated control processes in cART naïve participants.


The Effects of Mobile Phone Radiofrequency Radiation on Cochlear Stria Marginal Cells in Sprague-Dawley Rats.
To investigate the possible mechanisms for biological effects of 1,800 MHz mobile radiofrequency radiation (RFR), the radiation-specific absorption rate was applied at 2 and 4 W/kg, and the exposure mode was 5 min on and 10 min off (conversation mode). Exposure time was 24 h short-term exposure. Following exposure, to detect cell DNA damage, cell apoptosis, and reactive oxygen species (ROS) generation, the Comet assay test, flow cytometry, DAPI (4',6-diamidino-2-phenylindole dihydrochloride) staining, and a fluorescent probe were used, respectively. Our experiments revealed that mobile phone RFR did not cause DNA damage in marginal cells, and the rate of cell apoptosis did not increase (P > 0.05). However, the production of ROS in the 4 W/kg exposure group was greater than that in the control group (P < 0.05). In conclusion, these results suggest that mobile phone energy was insufficient to cause cell DNA damage and cell apoptosis following short-term exposure, but the cumulative effect of mobile phone radiation still requires further confirmation. Activation of the ROS system plays a significant role in the biological effects of RFR. Bioelectromagnetics. © 2020 The Authors. Bioelectromagnetics published by Wiley Periodicals, Inc.


Determination of the distribution of shallow-water seagrass and drift algae communities with acoustic seafloor discrimination.
The spatial distribution of seagrass and algae communities can be difficult to determine in large, shallow lagoon systems where high turbidity prevents the use of optical methods like aerial photography or satellite imagery. Further complications can arise when algae are not permanently attached to the substratum and drift with tides and currents. A study using acoustic seafloor discrimination was conducted in the Indian River Lagoon (Florida, USA) to determine the extent of drift algae and seagrass. Acoustic surveys using the QTC View V system based on 50 and 200 kHz transducers were conducted near Sebastian Inlet. Results indicate that areas of seagrass can be identified, and are mixed with a high abundance of drift algae. Nearest-neighbor extrapolation was used to fill in spaces between survey lines and thus obtain spatially cohesive maps. These maps were then ground-truthed using data from towed video and compared using confusion matrices, The maps showed a high level of agreement (60%) with the actual distribution of algae, however some confusion existed between bare sand and algae as well as seagrass.


Comparison of IPAQ-SF and Two Other Physical Activity Questionnaires with Accelerometer in Adolescent Boys.
Self-report measures of physical activity (PA) are easy to use and popular but their reliability is often questioned. Therefore, the general aim of the present study was to investigate the association of PA questionnaires with accelerometer derived PA, in a sample of adolescent boys. In total, 191 pubertal boys (mean age 14.0 years) completed three self-report questionnaires and wore an accelerometer (ActiGraph GT1M) for 7 consecutive days. The PA questionnaires were: International Physical Activity Questionnaire-Short Form (IPAQ-SF), Tartu Physical Activity Questionnaire (TPAQ), and the Inactivity subscale from Domain-Specific Impulsivity (DSI) scale. All three questionnaires were significantly correlated with accelerometer derived MVPA: the correlations were 0.31 for the IPAQ-SF MVPA, 0.34 for the TPAQ MVPA and -0.29 for the DSI Inactivity scale. Nevertheless, none of the questionnaires can be used as a reliable individual-level estimate of MVPA in male adolescents. The boys underreported their MVPA in IPAQ-SF as compared to accelerometer-derived MVPA (respective averages 43 and 56 minutes); underreporting was more marked in active boys with average daily MVPA at least 60 minutes, and was not significant in less active boys. Conversely, MVPA index from TPAQ overestimated the MVPA in less active boys but underestimated it in more active boys. The sedentary time reported in IPAQ-SF was an underestimate as compared to accelerometer-derived sedentary time (averages 519 and 545 minutes, respectively).


Longitudinal Walking Analysis in Hemiparetic Patients Using Wearable Motion Sensors: Is There Convergence Between Body Sides?
Background: Longitudinal movement parameter analysis of hemiparetic patients over several months could reveal potential recovery trends and help clinicians adapting therapy strategies to maximize recovery outcome. Wearable sensors offer potential for day-long movement recordings in realistic rehabilitation settings including activities of daily living, e.g., walking. The measurement of walking-related movement parameters of affected and non-affected body sides are of interest to determine mobility and investigate recovery trends. Methods: By comparing movement of both body sides, recovery trends across the rehabilitation duration were investigated. We derived and validated selected walking segments from free-living, day-long movement by using rules that do not require data-based training or data annotations. Automatic stride segmentation using peak detection was applied to walking segments. Movement parameters during walking were extracted, including stride count, stride duration, cadence, and sway. Finally, linear regression models over each movement parameter were derived to forecast the moment of convergence between body sides. Convergence points were expressed as duration and investigated in a patient observation study. Results: Convergence was analyzed in walking-related movement parameters in an outpatient study including totally 102 full-day recordings of inertial movement data from 11 hemiparetic patients. The recordings were performed over several months in a day-care centre. Validation of the walking extraction method from sensor data yielded sensitivities up to 80 % and specificity above 94 % on average. Comparison of automatically and manually derived movement parameters showed average relative errors below 6 % between affected and non-affected body sides. Movement parameter variability within and across patients was observed and confirmed by case reports, reflecting individual patient behavior. Conclusion: Convergence points were proposed as intuitive metric, which could facilitate training personalization for patients according to their individual needs. Our continuous movement parameter extraction and analysis, was feasible for realistic, day-long recordings without annotations. Visualizations of movement parameter trends and convergence points indicated that individual habits and patient therapies were reflected in walking and mobility. Context information of clinical case reports supported trend and convergence interpretation. Inconsistent convergence point estimation suggested individually varying deficiencies. Long-term recovery monitoring using convergence points could support patient-specific training strategies in future remote rehabilitation.


The influence of the antiandrogen 2-hydroxyflutamide on the androgen receptor expression in the porcine ovarian follicles - an in vitro study.
Androgens are one of the most important agents influencing ovarian follicles growth and development. The biological action of androgens is primarily exerted through transcriptional regulation by the androgen receptor (AR), a member of the steroid hormone receptor superfamily. The purpose of this study was to test the role of androgen receptor agonist testosterone (T) or antagonist 2-hydroxyflutamide (2-Hf) and in combination on AR expression in cultured porcine granulosa cells (GC) or whole follicles. Granulosa cells isolated from mature pig follicles were cultured for 48 h. During the last 12 and 24 h of culture, they were incubated in the presence of T (10(-7) m/ml), 2-Hf (1.7 × 10(-4) m) or both T and 2-Hf (T + 2-Hf, at the same concentrations as when added separately). To better imitate in vivo conditions, whole follicles (6-8 mm in diameter) isolated from porcine ovaries have been incubated (for 12 and 24 h) in an organ culture system with the addition of the same factors. Thereafter, cells or sections obtained from cultured follicles were processed for AR detection by immunocytochemistry or immunohistochemistry. Moreover, expression of AR mRNA and protein was determined by real-time PCR and Western blot analysis. It was shown that the addition of 2-Hf in the presence of T had a positive effect on AR mRNA and protein expression in porcine GC and ovarian follicles. Moreover, the addition of 2-Hf influenced AR distribution in GC cultures which is seen as change of its localization from nuclear to perinuclear. Our results suggest that androgens acting through AR could be involved in the control of AR expression in porcine GC in vitro and in vivo.


Transient pharmacologic lowering of Aβ production prior to deposition results in sustained reduction of amyloid plaque pathology.
Alzheimer's disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting Aβ that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of Aβ in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain Aβ with a γ-secretase inhibitor (GSI ) for 1-3 months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M. These data show that reducing Aβ production in a 2-3M windows both initiated and discontinued before detectable Aβ deposition has the most significant impact on Aβ loads up to 11M after treatment discontinuation. In contrast, initiation of treatment for 3M windows from 7-10M or 12-15M shows progressively decreasing efficacy. These data have major implications for clinical testing of therapeutics aimed at lowering Aβ production, indicating that; i) these therapies may have little efficacy unless tested as prophylactics or in the earliest preclinical stage of AD where there is no or minimal Aβ accumulation and ii) lowering Aβ production transiently during a critical pre-deposition window potentially provides long-lasting efficacy after discontinuation of the treatment.


Metformin as a geroprotector: experimental and clinical evidence.
Apart from being a safe, effective and globally affordable glucose-lowering agent for the treatment of diabetes, metformin has earned much credit in recent years as a potential anti-aging formula. It has been shown to significantly increase lifespan and delay the onset of age-associated decline in several experimental models. The current review summarizes advances in clinical research on the potential role of metformin in the field of geroprotection, highlighting findings from pre-clinical studies on known and putative mechanisms behind its beneficial properties. A growing body of evidence from clinical trials demonstrates that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, cancer, chronic inflammation, and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain cancer types. Moreover, due to the ability of metformin to induce autophagy by activation of AMPK, it is regarded as a potential hormesis-inducing agent with healthspan-promoting and pro-longevity properties. Long-term intake of metformin is associated with low risk of adverse events; however, well-designed clinical trials are still warranted to enable potential use of this therapeutic agent as a geroprotector.


Intraoperative complications during VATS lobectomies from conversion to minimally-invasive "trouble-shooting".
The aim of this study was to explore intraoperative complications during video-assisted thoracoscopic surgery (VATS) lobectomy. Vascular and bronchial injuries, after a robust learning curve, can be sometimes successfully managed by VATS. During a VATS lobectomy, it is necessary: to be prepared in potentially dangerous situations; to think about strategies to handle intraoperative complications and to share these strategies with your own staff. Herein we present some videos showing cases where vascular injuries led to conversion and others where a minimally-invasive trouble shooting of intraoperative complications was achieved.


Cultural repertoires and food-related household technology within colonia households under conditions of material hardship.
BSTRACT: Mexican-origin women in the U.S. living in colonias (new-destination Mexican-immigrant communities) along the Texas-Mexico border suffer from a high incidence of food insecurity and diet-related chronic disease. Understanding environmental factors that influence food-related behaviors among this population will be important to improving the well-being of colonia households. This article focuses on cultural repertoires that enable food choice and the everyday uses of technology in food-related practice by Mexican-immigrant women in colonia households under conditions of material hardship. Findings are presented within a conceptual framework informed by concepts drawn from sociological accounts of technology, food choice, culture, and material hardship. Field notes were provided by teams of promotora-researchers (indigenous community health workers) and public-health professionals trained as participant observers. They conducted observations on three separate occasions (two half-days during the week and one weekend day) within eight family residences located in colonias near the towns of Alton and San Carlos, Texas. English observations were coded inductively and early observations stressed the importance of technology and material hardship in food-related behavior. These observations were further explored and coded using the qualitative data package Atlas.ti. Technology included kitchen implements used in standard and adapted configurations and household infrastructure. Residents employed tools across a range of food-related activities identified as forms of food acquisition, storage, preparation, serving, feeding and eating, cleaning, and waste processing. Material hardships included the quality, quantity, acceptability, and uncertainty dimensions of food insecurity, and insufficient consumption of housing, clothing and medical care. Cultural repertoires for coping with material hardship included reliance on inexpensive staple foods and dishes, and conventional and innovative technological practices. These repertoires expressed the creative agency of women colonia residents. Food-related practices were constrained by climate, animal and insect pests, women's gender roles, limitations in neighborhood and household infrastructure, and economic and material resources. This research points to the importance of socioeconomic and structural factors such as gender roles, economic poverty and material hardship as constraints on food choice and food-related behavior. In turn, it emphasizes the innovative practices employed by women residents of colonias to prepare meals under these constraints.


Effective nationwide school-based participatory extramural program on adolescent body mass index, health knowledge and behaviors.
Adolescent obesity is a major public health concern. Open to all high school students regardless of weight status, HealthCorps is a nationwide program offering a comprehensive high school-based participatory educational program to indirectly address obesity. We tested a hypothesis that the HealthCorps program would decrease BMI z-scores among overweight or obese students, and reduce obesity rates, and evaluated its effects on health knowledge and behaviors. HealthCorps aimed to improve student knowledge and behaviors regarding nutrition quality, physical activity, sleep, breakfast intake, and mental resilience. Participating students received through HealthCorps coordinators weekly or bi-weekly classroom lessons either for a semester or a year in addition to various during- and after-school health-promoting activities and mentorship. Self-reported height and weight were collected along with questionnaires assessing knowledge and behaviors during 2013-2014 academic year among 14 HealthCorps-participating New York City high schools. This quasi experimental two-arm pre-post trial included 611 HealthCorps and 221 comparison arm students for the analytic sample. Sex-specific analyses stratified by weight status were adjusted for age and Hispanic ethnicity with clustering effects of schools and students taken into account. HealthCorps female overweight/obese and obese student had a significant decrease in BMI z-scores (post-pre delta BMI z-score = -0.16 (95%CI = (-0.26, -0.05), p = 0.004 for the former; and = -0.23 (-0.44, -0.03), p = 0.028, for the latter) whereas comparison female counterparts did not. The HealthCorps students, but not the comparison students, had a significant increase for all knowledge domains except for the breakfast realm, and reported a greater number of significant behavior changes including fruit and vegetable intake and physical activities. The HealthCorps program was associated with reduced BMI z-score in overweight/obese and obese female adolescents, with enhanced health knowledge and behavior for both sexes. With its wide reach, this may be a promising program to help combat adolescent obesity in schools. This study is registered as a clinical trial at the ClinicalTrials.gov registry with trial number NCT02277496 on September 10, 2014 (Retrospectively registered).


Mangiferin inhibits lipopolysaccharide-induced epithelial-mesenchymal transition (EMT) and enhances the expression of tumor suppressor gene PER1 in non-small cell lung cancer cells.
Non-small cell lung cancer (NSCLC) is often complicated by pulmonary infection, which affects treatment and prognosis. Bacterial lipopolysaccharide (LPS) is an effective stimulator of inflammatory cytokine production, and previous studies have reported that LPS promotes tumor invasion and metastasis. Mangiferin is a plant-derived C-glucosylxanthone with many biological activities, such as antioxidation and anti-inflammation. This research mainly explored the mechanism of its antitumor activities on LPS-induced A549, NCI-H460, and NCI-H520 NSCLC cells. We determined that mangiferin exhibits growth inhibiting activity against LPS-induced NSCLC cells through the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. In addition, mangiferin reversed the LPS-induced downregulation of E-cadherin (epithelial marker); conversely, it significantly inhibited the expression of raised vimentin (mesenchymal markers). Moreover, the ability of NSCLC cells to migrate, as evidenced by the wound healing and transwell migration assays, and the expression of CXCR4 increased by LPS were significantly repressed by mangiferin. In addition, mangiferin markedly mediated protein levels of PER1 and NLRP3 in LPS-induced NSCLC cells and reduced the secretion of IL-1β. These results indicate that mangiferin is not only a remarkable anti-inflammatory compound but also an antitumor agent; thus, it has the potential for being developed into anti-inflammatory and antitumor drugs in the future.


Urinary KIM-1, but not urinary cystatin C, should be corrected for urinary creatinine.
The interest for tubular damage markers such as urinary cystatin C (U-CystC) and kidney injury molecule-1 (U-KIM-1) grows, especially for the diagnosis of acute kidney injury. The trend to measure proteins in spot urine samples instead of 24-h urine collections calls for adjustment of urine dilution with urinary creatinine (UCr). However, it is not known whether UCr adjustment provides a more true value of basal U-CystC and U-KIM-1 levels than absolute values. This study examines the rationale for UCr correction for U-CystC and U-KIM-1 by exploring the linear relations between U-CystC and U-KIM-1 and UCr, respectively, and the biological day to day variation of absolute concentrations and UCr adjusted values of the two biomarkers. Both U-CystC and U-KIM-1 concentrations correlated positively with UCr (R=0.37, P<0.001 and R=0.62, P<0.001, respectively) in 378 participants in a community cohort, which indicated a rationale for adjustment with UCr. However, U-CystC/Cr ratio associated negatively with UCr (R=- 0.31, P<0.001), which could indicate a certain amount of 'over-adjustment'. Morning urine collected for 10 consecutive days from 13 healthy volunteers showed a biological day to day variation of 82% for U-CystC, 75% for U-cystC/Cr ratio, 70% for U-KIM-1 and 46% for U-KIM-1/Cr ratio. This study supports the use of U-KIM-1/Cr ratio in clinical population studies. Data supporting the use of U-CysC/U-Cr ratio were less convincing and the possible confounding of UCr has to be acknowledged in clinical settings.


Resting-state functional connectivity emerges from structurally and dynamically shaped slow linear fluctuations.
Brain fluctuations at rest are not random but are structured in spatial patterns of correlated activity across different brain areas. The question of how resting-state functional connectivity (FC) emerges from the brain's anatomical connections has motivated several experimental and computational studies to understand structure-function relationships. However, the mechanistic origin of resting state is obscured by large-scale models' complexity, and a close structure-function relation is still an open problem. Thus, a realistic but simple enough description of relevant brain dynamics is needed. Here, we derived a dynamic mean field model that consistently summarizes the realistic dynamics of a detailed spiking and conductance-based synaptic large-scale network, in which connectivity is constrained by diffusion imaging data from human subjects. The dynamic mean field approximates the ensemble dynamics, whose temporal evolution is dominated by the longest time scale of the system. With this reduction, we demonstrated that FC emerges as structured linear fluctuations around a stable low firing activity state close to destabilization. Moreover, the model can be further and crucially simplified into a set of motion equations for statistical moments, providing a direct analytical link between anatomical structure, neural network dynamics, and FC. Our study suggests that FC arises from noise propagation and dynamical slowing down of fluctuations in an anatomically constrained dynamical system. Altogether, the reduction from spiking models to statistical moments presented here provides a new framework to explicitly understand the building up of FC through neuronal dynamics underpinned by anatomical connections and to drive hypotheses in task-evoked studies and for clinical applications.


Oxidative changes and apoptosis induced by 1800-MHz electromagnetic radiation in NIH/3T3 cells.
To investigate the potential adverse effects of mobile phone radiation, we studied reactive oxygen species (ROS), DNA damage and apoptosis in mouse embryonic fibroblasts (NIH/3T3) after intermittent exposure (5 min on/10 min off, for various durations from 0.5 to 8 h) to an 1800-MHz GSM-talk mode electromagnetic radiation (EMR) at an average specific absorption rate of 2 W/kg. A 2',7'-dichlorofluorescin diacetate fluorescence probe was used to detect intracellular ROS levels, immunofluorescence was used to detect γH2AX foci as a marker for DNA damage, and flow cytometry was used to measure apoptosis. Our results showed a significant increase in intracellular ROS levels after EMR exposure and it reached the highest level at an exposure time of 1 h (p < 0.05) followed by a slight decrease when the exposure continued for as long as 8 h. No significant effect on the number of γH2AX was detected after EMR exposure. The percentage of late-apoptotic cells in the EMR-exposed group was significantly higher than that in the sham-exposed groups (p < 0.05). These results indicate that an 1800-MHz EMR enhances ROS formation and promotes apoptosis in NIH/3T3 cells.


Modeling the overdetection of screen-identified cancers in population-based cancer screening with the Coxian phase-type Markov process.
Modeling overdetection resulting from screening often uses the conventional competing risk model. This model assigns screen-detected cases dying from other causes as overdetection modeled by a one-jump process, which may not be true for the censored overdetected cases. To relax this restrictive assumption, accommodate a finite Markov process for overdetection, and dispense with long-term follow-up until death, we propose a generalized Coxian phase-type Markov process to distinguish the progressive latent multistate pathway from the nonprogressive (overdetected) latent multistate pathway. Various new likelihood functions were developed to estimate the transition parameters with the available data accrued at the time of diagnosis. The proportion of overdetected cancers by the cured model was further estimated by using parameters with and without distinguishing between the two latent pathways. While perturbation analyses were conducted by changing their parameters to assess their effects on overdetection, the results, including of asymptotic analyses, were very robust for an overdetection rate higher than 20% but not for low overdetection rates. These two scenarios were demonstrated by applying the Coxian phase-type model to prostate cancer and breast cancer screening, yielding a substantial proportion of overdetected prostate cancer (60%) attributed to the prostate specific antigen test and a small fraction of overdetected breast cancer (3%) detected by mammography. This kind of variation in overdetection elucidated by the Coxian phase-type Markov process provides new insights into the quantitative mechanisms producing overdetection, which is informative for evaluating the benefits and risks of various types of population-based cancer screening programs.


Connexin-dependent transcellular transcriptomic networks in mouse brain.
Microarray experiments have generally focused on magnitude of gene expression changes in pathological conditions, thereby using the method as a high throughput screen to identify candidate marker genes and/or to validate phenotypic differences. We have used novel strategies to extract additional information from array studies, including expression variability and coordination, from which organizational principles of transcriptomes are emerging. We have reported that the expression level, variability and coordination of numerous genes are regulated in brains of connexin43 null (Gja1(-/-)) mouse with respect to wildtype. Moreover, expression coordination with Gja1 in wildtype largely predicted the expression regulation in Gja1(-/-) tissues. We now report a remarkable overlap between regulations in Gja1(-/-) and connexin32 null (Gjb1(-/-)) brains, and that both differ markedly from those in connexin36 null (Gja9(-/-)) brain. Since in brain these three connexins are expressed in different cell types (Cx43 in astrocytes, ependymal and vascular cells, Gjb1 in oligodendrocytes, and Cx36 in neurons and microglia), and because astrocytes and oligodendrocytes (and possibly neurons and microglia) may form syncytia coupled by gap junction channels, these observations suggest the existence of distinct connexin-dependent panglial and neuronal transcriptomic networks. Such networks, where linkage partners are rearranged and strengths modified in brains of knockouts, may explain downstream and parallel "ripples" of phenotypic change resulting from single gene manipulations as illustrated by alterations in transcription factor networks resulting from deletion of Gja1 or Gjb1. The transcription factors also formed network hubs with genes from other functional categories, thus allowing regulation of one functional pathway through manipulation of another.


Critical appraisal of tubular putative eumetazoans from the Ediacaran Weng'an Doushantuo biota.
Molecular clock analyses estimate that crown-group animals began diversifying hundreds of millions of years before the start of the Cambrian period. However, the fossil record has not yielded unequivocal evidence for animals during this interval. Some of the most promising candidates for Precambrian animals occur in the Weng'an biota of South China, including a suite of tubular fossils assigned to Sinocyclocyclicus, Ramitubus, Crassitubus and Quadratitubus, that have been interpreted as soft-bodied eumetazoans comparable to tabulate corals. Here, we present new insights into the anatomy, original composition and phylogenetic affinities of these taxa based on data from synchrotron radiation X-ray tomographic microscopy, ptychographic nanotomography, scanning electron microscopy and electron probe microanalysis. The patterns of deformation observed suggest that the cross walls of Sinocyclocyclicus and Quadratitubus were more rigid than those of Ramitubus and Crassitubus. Ramitubus and Crassitubus specimens preserve enigmatic cellular clusters at terminal positions in the tubes. Specimens of Sinocyclocyclicus and Ramitubus have biological features that might be cellular tissue or subcellular structures filling the spaces between the cross walls. These observations are incompatible with a cnidarian interpretation, in which the spaces between cross walls are abandoned parts of the former living positions of the polyp. The affinity of the Weng'an tubular fossils may lie within the algae.


High-fidelity replication of Dammann gratings using soft lithography.
We report the experimental results of using the soft lithography method for replication of Dammann gratings. By using an elastomeric stamp, uniform grating structures were transferred to the UV-curable polymer. To evaluate the quality of the replication, diffraction images and light intensity were measured. Compared with the master devices, the replicas of Dammann gratings show a slight deviation in both surface relief profile and optical performance. Experimental results demonstrated that high-fidelity replication of Dammann gratings is realized by using soft lithography with low cost and high throughput.


Rothmund-Thomson syndrome.
Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose and congenital radial ray defects), and/or subtle (visible only by radiographic analysis). Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients), whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma (including dyskeratosis congenita, Kindler syndrome and Poikiloderma with Neutropaenia), other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, Werner syndrome and Ataxia-telangiectasia) and the allelic disorders, RAPADILINO syndrome and Baller-Gerold syndrome, which also share some clinical features. A few mutations recur in all three RECQL4 diseases. Genetic counselling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTSII. Patients should be managed by a multidisciplinary team and offered long term follow-up. Treatment includes the use of pulsed dye laser photocoagulation to improve the telangiectatic component of the rash, surgical removal of the cataracts and standard treatment for individuals who develop cancer. Although some clinical signs suggest precocious aging, life expectancy is not impaired in RTS patients if they do not develop cancer. Outcomes in patients with osteosarcoma are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. The sensitivity of RTS cells to genotoxic agents exploiting cells with a known RECQL4 status is being elucidated and is aimed at optimizing the chemotherapeutic regimen for osteosarcoma.


Recombinant Factor VIIa Use for Endoscopic Retrograde Cholangiopancreatography With Sphincterotomy in a Patient With Choledocholithiasis and Unusual Coagulopathy.
Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure that combines the use of endoscopy and fluoroscopy to diagnose and treat pancreaticobiliary disorders. The risks of ERCP include pancreatitis, infection, bleeding and perforation. Bleeding during ERCP typically develops after sphincterotomy, hence patients should be screened and tested for coagulopathy before undergoing ERCP. Coagulopathy is a major risk factor for ERCP-related bleeding. Inherited factor VII (FVII) deficiency is a rare autosomal recessive hemorrhagic disorder that can lead to significant coagulopathy and severe bleeding if not appropriately recognized and treated preoperatively. Clinically, the disease ranges between an asymptomatic state to lethal hemorrhage and the degree of FVII deficiency does not correlate with the severity of bleeding. The use of FVII replacement therapy has been reported to prevent bleeding during surgery. We present the first report of a patient with a rare cause of coagulopathy due to inherited FVII deficiency who successfully underwent ERCP with sphincterotomy without bleeding where we used recombinant factor VIIa before and after the procedure.


Understanding light intensity thresholds for catastrophic optical damage in LiNbO3.
The appearance of light intensity thresholds for catastrophic optical damage in LiNbO3 is satisfactorily explained by using a photorefractive model based on the Fe(2+)?Fe(3+) and NbLi(4+)?NbLi(5+) defect pairs. Model simulations of the photorefractive amplification gain as a function of the light intensity present sharp threshold behavior. A similar behavior is shown by the saturating refractive index change. In agreement with experiments, predicted thresholds appear shifted towards higher intensities (up to a 10(4) factor) when the Nb(Li) concentration is decreased or the temperature is increased. The model also explains very recent data on the threshold enhancement with the Fe(2+)/Fe(3+) ratio in optical waveguides.


Long-read sequence and assembly of segmental duplications.
We have developed a computational method based on polyploid phasing of long sequence reads to resolve collapsed regions of segmental duplications within genome assemblies. Segmental Duplication Assembler (SDA; https://github.com/mvollger/SDA ) constructs graphs in which paralogous sequence variants define the nodes and long-read sequences provide attraction and repulsion edges, enabling the partition and assembly of long reads corresponding to distinct paralogs. We apply it to single-molecule, real-time sequence data from three human genomes and recover 33-79 megabase pairs (Mb) of duplications in which approximately half of the loci are diverged (<99.8%) compared to the reference genome. We show that the corresponding sequence is highly accurate (>99.9%) and that the diverged sequence corresponds to copy-number-variable paralogs that are absent from the human reference genome. Our method can be applied to other complex genomes to resolve the last gene-rich gaps, improve duplicate gene annotation, and better understand copy-number-variant genetic diversity at the base-pair level.


Squamous cell and basal cell carcinoma of the skin in relation to radiation therapy and potential modification of risk by sun exposure.
Epidemiologic studies consistently find enhanced risk of basal cell carcinoma of the skin among individuals exposed to ionizing radiation, but it is unclear whether the radiation effect occurs for squamous cell carcinoma. It is also not known whether subgroups of individuals are at greater risk, eg, those with radiation sensitivity or high ultraviolet radiation exposure. We analyzed data from a case-control study of keratinocyte cancers in New Hampshire. Incident cases diagnosed in 1993-1995 and 1997-2000 were identified through a state-wide skin cancer surveillance system, and controls were identified through the Department of Transportation and Center for Medicare and Medicaid Service Files (n = 1121 basal cell carcinoma cases, 854 squamous cell carcinoma cases, and 1049 controls). We found an association between history of radiation treatment and basal cell carcinoma. The association was especially strong for basal cell carcinomas arising within the radiation treatment field (odds ratio = 2.6; 95% confidence interval = 1.5-4.3), and among those treated with radiation therapy before age 20 (3.4; 1.8-6.4), those whose basal cell carcinomas occurred 40 or more years after radiation treatment (3.2; 1.8-5.8), and those treated with radiation for acne (11; 2.7-49). Similar age and time patterns of risk were observed for squamous cell carcinoma, although generally with smaller odds ratios. For basal cell carcinoma, early exposure to radiation treatment was a risk factor largely among those without a history of severe sunburns, whereas for squamous cell carcinoma, radiation treatment was a risk factor primarily among those with a sun-sensitive skin type (ie, a tendency to sunburn). Radiation treatment, particularly if experienced before age 20, seems to increase the long-term risk of both basal and squamous cell carcinomas of the skin. These risks may differ by sun exposure or host response to sunlight exposure.


DFLAT: functional annotation for human development.
Recent increases in genomic studies of the developing human fetus and neonate have led to a need for widespread characterization of the functional roles of genes at different developmental stages. The Gene Ontology (GO), a valuable and widely-used resource for characterizing gene function, offers perhaps the most suitable functional annotation system for this purpose. However, due in part to the difficulty of studying molecular genetic effects in humans, even the current collection of comprehensive GO annotations for human genes and gene products often lacks adequate developmental context for scientists wishing to study gene function in the human fetus. The Developmental FunctionaL Annotation at Tufts (DFLAT) project aims to improve the quality of analyses of fetal gene expression and regulation by curating human fetal gene functions using both manual and semi-automated GO procedures. Eligible annotations are then contributed to the GO database and included in GO releases of human data. DFLAT has produced a considerable body of functional annotation that we demonstrate provides valuable information about developmental genomics. A collection of gene sets (genes implicated in the same function or biological process), made by combining existing GO annotations with the 13,344 new DFLAT annotations, is available for use in novel analyses. Gene set analyses of expression in several data sets, including amniotic fluid RNA from fetuses with trisomies 21 and 18, umbilical cord blood, and blood from newborns with bronchopulmonary dysplasia, were conducted both with and without the DFLAT annotation. Functional analysis of expression data using the DFLAT annotation increases the number of implicated gene sets, reflecting the DFLAT's improved representation of current knowledge. Blinded literature review supports the validity of newly significant findings obtained with the DFLAT annotations. Newly implicated significant gene sets also suggest specific hypotheses for future research. Overall, the DFLAT project contributes new functional annotation and gene sets likely to enhance our ability to interpret genomic studies of human fetal and neonatal development.


Telepsychiatry Today.
The use of video-based telepsychiatry is increasing in response to consumer demand for convenient, inexpensive, and readily accessible services; improved financial reimbursement; and a robust body of evidence-based literature. Telepsychiatry leads to high patient and provider satisfaction ratings, and outcomes equivalent to in-person care, while younger generations often prefer telepsychiatry over face-to-face encounters. The evidence base for telepsychiatry is especially strong with respect to the treatment of post-traumatic stress disorder (PTSD), depression, and ADHD, while its use in underserved ethnic groups is well described in the American Indian, Hispanic, and Asian populations. Despite this, telepsychiatry barriers still persist. These include personal bias-especially in leadership-and insufficient training; the challenging business environment and legislative processes; and inconsistent reimbursement, licensing, and prescription policies. Technology is now less of a barrier, and it is clear that telepsychiatry overall is flourishing and changing the way that providers are working and patients are being treated.


B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity.
Clinical studies indicate that anti-CD20 B-cell depletion may be an effective multiple sclerosis (MS) therapy. We investigated mechanisms of anti-CD20-mediated immune modulation using 2 paradigms of experimental autoimmune encephalomyelitis (EAE). Murine EAE was induced by recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35-55, which does not require B cells. In EAE induced by rMOG, B cells became activated and, when serving as antigen-presenting cells (APCs), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B-cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less central nervous system (CNS) inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in MOG p35-55-induced EAE, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naive B cells. In this setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B-cell depletion reduced the frequency of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), and increased the proinflammatory polarizing capacity of remaining myeloid APCs. Our study highlights distinct roles for B cells in CNS autoimmunity. Clinical benefit from anti-CD20 treatment may relate to inhibition of proinflammatory B cell APC function. In certain clinical settings, however, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable. Differences in immune responses to MOG protein and peptide may be important considerations when choosing an EAE model for testing novel B cell-targeting agents for MS.


Small Heat Shock Protein αB-Crystallin Controls Shape and Adhesion of Glioma and Myoblast Cells in the Absence of Stress.
Cell shape and adhesion and their proper controls are fundamental for all biological systems. Mesenchymal cells migrate at an average rate of 6 to 60 μm/hr, depending on the extracellular matrix environment and cell signaling. Myotubes, fully differentiated muscle cells, are specialized for power-generation and therefore lose motility. Cell spreading and stabilities of focal adhesion are regulated by the critical protein vinculin from immature myoblast to mature costamere of differentiated myotubes where myofibril Z-band linked to sarcolemma. The Z-band is constituted from microtubules, intermediate filaments, cell adhesion molecules and other adapter proteins that communicate with the outer environment. Mesenchymal cells, including myoblast cells, convert actomyosin contraction forces to tension through mechano-responsive adhesion assembly complexes as Z-band equivalents. There is growing evidence that microtubule dynamics are involved in the generation of contractile forces; however, the roles of microtubules in cell adhesion dynamics are not well determined. Here, we show for the first time that αB-crystallin, a molecular chaperon for tubulin/microtubules, is involved in cell shape determination. Moreover, knockdown of this molecule caused myoblasts and glioma cells to lose their ability for adhesion as they tended to behave like migratory cells. Surprisingly, αB-crystallin knockdown in both C6 glial cells and L6 myoblast permitted cells to migrate more rapidly (2.7 times faster for C6 and 1.3 times faster for L6 cells) than dermal fibroblast. On the other hand, overexpression of αB-crystallin in cells led to an immortal phenotype because of persistent adhesion. Position of matured focal adhesion as visualized by vinculin immuno-staining, stress fiber direction, length, and density were clearly αB-crystallin dependent. These results indicate that the small HSP αB-crystallin has important roles for cell adhesion, and thus microtubule dynamics are necessary for persistent adhesion.


Metal particle manipulation by laser irradiation in borosilicate glass.
We propose a new technique of manipulating a metal particle in borosilicate glass. A metal particle that is heated by laser illumination heats the surrounding glass by radiation and conduction. A softened glass enabled metal particle migration. A 1-µm-thick platinum film was deposited on the back surface of a glass plate and irradiated with a green CW laser beam through the glass. As a result, the platinum film was melted and implanted into the glass as a particle. Platinum particles with diameters of 3 to 50 μm migrated at speeds up to 10 mm/s. In addition to platinum particles, nickel and austenitic stainless steel (SUS304) particles can be implanted.


Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study.
Despite clearly defined histologic criteria, the prediction of tumor behavior for patients with gastrointestinal stromal tumors (GIST) still poses a challenge to pathologists. Therefore, searching for alternative markers that allow for better prognostic evaluation is an important task. To determine the practicability of immunohistochemical staining for p16 in clinical cases, we examined p16 protein expression in a group of 284 GISTs, a subset of which had long-term follow-up (median, 45 months; range, 1-204 months). P16 protein expression was ascertained on tissue microarrays as well as on standard sections. Survival analyses were carried out in 157 patients. P16 loss was found in 50% of GISTs, there being no correlation with age, sex, histologic subtype, signs of necrosis, or metastases. Patients having p16-negative tumors had a worse prognosis than those with p16-positive tumors (P = 0.012) with a 2.3-fold relative increased risk of dying of disease. P16 loss identified a subgroup of gastric tumors with a worse prognosis (P = 0.03). The multivariate configural frequency analysis identified two "antitypes," whose observed frequency was found to be significantly lower than the expected frequency [i.e., marker combinations: p16 positive, no metastases, and death of disease and p16 loss, metastases, and still alive]. The "type" whose observed frequency was significantly higher than the expected frequency consisted of the following marker pattern: p16 loss, necrosis, and death of disease (P < 0.001). In the multivariate Cox regression analysis, p16 loss, necrosis, and metastases each had independent prognostic value. P16 loss is a common molecular abnormality in GISTs and might be used in routine diagnosis to identify patients with high-risk tumors.


Immunoelectron microscopic study of gamma-aminobutyric acid inputs to identified thalamocortical projection neurons in the anterior thalamus of the rat.
We have carried out a semi-quantitative ultrastructural study to determine the characteristics and distribution of gamma-aminobutyric acid (GABA)-containing constituents of the anterodorsal (AD) and anteroventral (AV) thalamic nuclei in adult rats. We used a polyclonal antibody to GABA and a postembedding immunogold detection method in animals in which the cortical projection neurons of these nuclei had been labelled by retrograde transport of cholera toxin/horseradish peroxidase (HRP) injected into the retrosplenial granular cortex. Two types of GABA-immunopositive structures were identified, with gold particle densities 4-40 times higher than the highest densities over blood-vessel lumens and areas of empty resin: (1) an apparently homogeneous population of axon terminals with Gray type-2 (symmetric) synaptic contacts corresponding to F-axon terminals; and (2) small-medium sized myelinated axons scattered individually or in small groups within the neuropil which may be their parent axons. These axons and terminals may originate from the ipsilateral thalamic reticular nucleus; others may arise from the basal forebrain or brainstem. The GABA-immunopositive terminals comprised approximately 16% of all axon terminal profiles in AD and 12% in AV, a significant difference. However, because the immunoreactive axon terminals in AD were significantly larger than those in AV (1.09+/-0.47 microm2 vs 0.90+/-0.43 microm2) and would therefore be encountered more frequently, it is not possible to conclude that the GABAergic innervation of AD is heavier than that of AV. The GABA-positive terminals established synaptic contacts with cell bodies and dendrites of all sizes (some of which were HRP-labelled) with the following frequency distribution (AD/AV, no significant difference): somata 5%/7%; large dendrites (> or = 1.5 microm) 14%/9%; medium dendrites (1.00-1.49 microm) 35%/45% and small dendrites (< 1 microm) 46%/40%. Despite evidence from previous studies, we found no evidence in this study for the presence of GABAergic interneurons or for GABA-containing projection neurons in AD or AV.


Machine learning-based detection of soil salinity in an arid desert region, Northwest China: A comparison between Landsat-8 OLI and Sentinel-2 MSI.
Accurate assessment of soil salinization is considered as one of the most important steps in combating global climate change, especially in arid and semi-arid regions. Multi-spectral remote sensing (RS) data including Landsat series provides the potential for frequent surveys for soil salinization at various scales and resolutions. Additionally, the recently launched Sentinel-2 satellite constellation has temporal revisiting frequency of 5 days, which has been proven to be an ideal approach to assess soil salinity. Yet, studies on detailed comparison in soil salinity tracking between Landsat-8 OLI and Sentinel-2 MSI remain limited. For this purpose, we collected a total of 64 topsoil samples in an arid desert region, the Ebinur Lake Wetland National Nature Reserve (ELWNNR) to compare the monitoring accuracy between Landsat-8 OLI and Sentinel-2 MSI. In this study, the Cubist model was trained using RS-derived covariates (spectral bands, Tasseled Cap transformation-derived wetness (TCW), and satellite salinity indices) and laboratory measured electrical conductivity of 1:5 soil:water extract (EC). The results showed that the measured soil salinity had a significant correlation with surface soil moisture (Pearson's r = 0.75). The introduction of TCW generated satisfactory estimating performance. Compared with OLI dataset, the combination of MSI dataset and Cubist model yielded overall better model performance and accuracy measures (R2 = 0.912, RMSE = 6.462 dS m-1, NRMSE = 9.226%, RPD = 3.400 and RPIQ = 6.824, respectively). The differences between Landsat-8 OLI and Sentinel-2 MSI were distinguishable. In conclusion, MSI image with finer spatial resolution performed better than OLI. Combining RS data sets and their derived TCW within a Cubist framework yielded accurate regional salinity map. The increased temporal revisiting frequency and spectral resolution of MSI data are expected to be positive enhancements to the acquisition of high-quality soil salinity information of desert soils.


Preterm labor: stimulation of arachidonic acid metabolism in human amnion cells by bacterial products.
There is a strong association between preterm labor and infection. Some potentially pathogenic bacteria have phospholipase activity, and it has been suggested that release of phospholipase from these organisms may increase prostaglandin E2 synthesis in amnion cells and hence initiate preterm labor. In this study we established monolayer amnion cell cultures from tissue collected at elective cesarean section at term before labor. Cells were prelabeled with tritiated arachidonic acid and then further incubated after addition of 2%, 5%, or 10% (vol/vol) filtered medium in which either group B beta-hemolytic streptococcus, Streptococcus viridans, Escherichia coli, Bacteroides fragilis, or Lactobacillus had been growing. Tritiated arachidonic acid and its metabolites released by the amnion cells in these or control incubates were extracted from culture medium and separated by high-performance liquid chromatography. Addition of conditioned medium from each of the organisms with the exception of Lactobacillus caused an increase in overall arachidonic acid metabolism. There was an increase in the ratio of cyclooxygenase to lipoxgenase metabolism and in prostaglandin E2 production in particular when compared to controls. The profile of arachidonic acid metabolism in amnion cells following addition of filtered bacterial medium resembled that obtained from amnion cells cultured following spontaneous labor. We suggest that abnormal bacterial colonization of the genital tract may lead to an increase in arachidonic acid metabolism in amnion cells with an increase in prostaglandin E2 production and the consequent initiation of preterm labor.


[Expression and its significance of aquaporin 5 in nasal polyps with or without allergic rhinitis].
To confirm the expression and distribution of aquaporin 5 (AQP5) in nasal polyps. AQP5 were studied in 20 samples nasal polyp without AR (Group NAR) and 16 samples with AR (Group AR) with immunochemistric staging and its integrated light intensity and its grey step. (1) Hematoxylin and eosin staining showed that there was obvious inflammation reaction, a large quantity of glands hyperplasia and acidophils soaked in nasal polyps, especially those with allergic rhinitis. (2) Immunofluorescence technique showed that the distribution of AQP5 in the two groups was in accordance with that in nasal polyps on the whole. AQP5 expressed mainly in the membrane and cytoplasm of the epithelium of the glands, ducts and cilia. (3) The statistical analysis of the immunohistochemical staining showed that the integrated light intensity of AQP5 in Group AR (0.1675+/-0.006536) was obviously higher than that in the Group NARs nasal polyps (0.09343+/-0.001816). There was statistical significance between the two groups (t = -12.00, P<0.01). (4) The statistical analysis of the immunohistochemical staining showed that the grey step of AQP5 in Group AR (175.6+/-2.471) was obviously lower than that in the Group NAR's nasal polyps (206.2+/-0.9649). There was statistical significance between the two groups (t=12.46, P<0.01). AQP5 is expressed in nasal polyp. Combined with the research before, it was conferred that the hypersecretion of glands and its character has a relationship with the high expression of AQP5 in nasal polyps, and nasal polyp with different symptom has different mechanism.


Risk of Recurrent Pancreatitis and Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis.
Patients with a first episode of acute pancreatitis can develop recurrent or chronic pancreatitis (CP). However, little is known about the incidence or risk factors for these events. We performed a cross-sectional study of 669 patients with a first episode of acute pancreatitis admitted to 15 Dutch hospitals from December 2003 through March 2007. We collected information on disease course, outpatient visits, and hospital readmissions, as well as results from imaging, laboratory, and histology studies. Standardized follow-up questionnaires were sent to all available patients to collect information on hospitalizations and interventions for pancreatic disease, abdominal pain, steatorrhea, diabetes mellitus, medications, and alcohol and tobacco use. Patients were followed up for a median time period of 57 months. Primary end points were recurrent pancreatitis and CP. Risk factors were evaluated using regression analysis. The cumulative risk was assessed using Kaplan-Meier analysis. Recurrent pancreatitis developed in 117 patients (17%), and CP occurred in 51 patients (7.6%). Recurrent pancreatitis developed in 12% of patients with biliary disease, 24% of patients with alcoholic etiology, and 25% of patients with disease of idiopathic or other etiologies; CP occurred in 3%, 16%, and 10% of these patients, respectively. Etiology, smoking, and necrotizing pancreatitis were independent risk factors for recurrent pancreatitis and CP. Acute Physiology and Chronic Health Evaluation II scores at admission also were associated independently with recurrent pancreatitis. The cumulative risk for recurrent pancreatitis over 5 years was highest among smokers at 40% (compared with 13% for nonsmokers). For alcohol abusers and current smokers, the cumulative risks for CP were similar-approximately 18%. In contrast, the cumulative risk of CP increased to 30% in patients who smoked and abused alcohol. Based on a retrospective analysis of patients admitted to Dutch hospitals, a first episode of acute pancreatitis leads to recurrent pancreatitis in 17% of patients, and almost 8% of patients progress to CP within 5 years. Progression was associated independently with alcoholic etiology, smoking, and a history of pancreatic necrosis. Smoking is the predominant risk factor for recurrent disease, whereas the combination of alcohol abuse and smoking produces the highest cumulative risk for chronic pancreatitis.


The key role of meteorites in the formation of relevant prebiotic molecules in a formamide/water environment.
We show that carbonaceous chondrite meteorites actively and selectively catalyze the formation of relevant prebiotic molecules from formamide in aqueous media. Specific catalytic behaviours are observed, depending on the origin and composition of the chondrites and on the type of water present in the system (activity: thermal > seawater > pure). We report the one-pot synthesis of all the natural nucleobases, of aminoacids and of eight carboxylic acids (forming, from pyruvic acid to citric acid, a continuous series encompassing a large part of the extant Krebs cycle). These data shape a general prebiotic scenario consisting of carbonaceous meteorites acting as catalysts and of a volcanic-like environment providing heat, thermal waters and formamide. This scenario also applies to the other solar system locations that experienced rich delivery of carbonaceous materials, and whose physical-chemical conditions could have allowed chemical evolution.


Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.
Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.