A growth model of saccular aneurysms based on hemodynamic and morphologic discriminant parameters for risk of rupture.
The aim of this study was to derive a model describing the evolution of bifurcation type cerebral aneurysms based on morphological and hemodynamic parameters. Idealized bifurcation models were constructed based on the two morphological parameters of aspect ratio (AR) and size ratio (SR). Aneurysm development was investigated according to the following four patterns: R1, increasing SR with constant AR; R2, increasing AR with constant SR; R3, increasing SR and increasing AR; R4, increasing AR with constant parent artery diameter. Relationships were obtained between energy loss (EL) and morphological parameters (EL-SR and EL-AR curves). The curves were validated by mapping the growth of a ruptured patient-specific bifurcation aneurysm at three stages of follow-up. EL increased in parallel with growth patterns R1 and R3, whereas growth pattern R2 showed a decrease in EL. No significant changes were observed in EL when the growth of the aneurysm was associated only with changes in aneurysm size and independent of changes in parent artery diameter and main flow (R4). Changes in parent artery diameter of bifurcation aneurysms resulted in significant variation in EL. Mapping the growth of a follow-up aneurysm onto the EL-AR curve demonstrated that aneurysms with increasing EL during the observation period are at higher risk of rupture than aneurysms with decreasing EL. Based on the proposed growth model, assessment of morphological (AR and SR) and hemodynamic (EL) parameters may provide quantifiable information on the risk of bifurcation aneurysm rupture during clinical patient follow-up.


Neutralizing Th2 inflammation in neonatal islets prevents β-cell failure in adult IUGR rats.
Intrauterine growth restriction (IUGR) leads to development of type 2 diabetes (T2D) in adulthood. The mechanisms underlying this phenomenon have not been fully elucidated. Inflammation is associated with T2D; however, it is unknown whether inflammation is causal or secondary to the altered metabolic state. Here we show that the mechanism by which IUGR leads to the development of T2D in adulthood is via transient recruitment of T-helper 2 (Th) lymphocytes and macrophages in fetal islets resulting in localized inflammation. Although this immune response is short-lived, it results in a permanent reduction in islet vascularity and impaired insulin secretion. Neutralizing interleukin-4 antibody therapy given only in the newborn period ameliorates inflammation and restores vascularity and β-cell function into adulthood, demonstrating a novel role for Th2 immune responses in the induction and progression of T2D. In the neonatal stage, inflammation and vascular changes are reversible and may define an important developmental window for therapeutic intervention to prevent adult-onset diabetes.


Partial response, nonresponse, and relapse with selective serotonin reuptake inhibitors in major depression: a survey of current "next-step" practices.
Many patients treated for major depression require more than one antidepressant trial to achieve or sustain response. However, the literature provides few treatment algorithms or effectiveness studies that empirically support "next-step" options available to clinicians. We conducted a survey of psychiatrists and other medical specialists who treat depression to ascertain what clinicians actually do when faced with patients who suboptimally respond to an adequate course of selective serotonin reuptake inhibitor (SSRI) therapy. Attendees at a psychopharmacology course (N = 801) were queried about their top choices for antidepressant-treatment nonresponders: a minimal responder after 4 weeks of adequate SSRI treatment, a partial responder after 8 weeks of adequate SSRI therapy, a nonresponder after 8 weeks of adequate SSRI therapy, and a relapser on long-term SSRI maintenance therapy. Choices included raising the dose, augmenting or combining with another agent, switching to a second SSRI. or switching to a non-SSRI agent. 432 (54%) of the surveys were returned. Raising the dose was the most frequently reported next-step strategy for a patient with minimal response after 4 weeks of adequate SSRI therapy, partial response after 8 weeks of adequate SSRI therapy, and relapse on long-term SSRI therapy. Switching to a non-SSRI agent was the most frequently chosen option for nonresponders to an adequate trial of SSRI therapy. Our findings suggest that clinicians select different next-step strategies when patients are nonresponders versus when patients are partial responders or relapsers.


Processivity of peptidoglycan synthesis provides a built-in mechanism for the robustness of straight-rod cell morphology.
The propagation of cell shape across generations is remarkably robust in most bacteria. Even when deformations are acquired, growing cells progressively recover their original shape once the deforming factors are eliminated. For instance, straight-rod-shaped bacteria grow curved when confined to circular microchambers, but straighten in a growth-dependent fashion when released. Bacterial cell shape is maintained by the peptidoglycan (PG) cell wall, a giant macromolecule of glycan strands that are synthesized by processive enzymes and cross-linked by peptide chains. Changes in cell geometry require modifying the PG and therefore depend directly on the molecular-scale properties of PG structure and synthesis. Using a mathematical model we quantify the straightening of curved Caulobacter crescentus cells after disruption of the cell-curving crescentin structure. We observe that cells straighten at a rate that is about half (57%) the cell growth rate. Next we show that in the absence of other effects there exists a mathematical relationship between the rate of cell straightening and the processivity of PG synthesis-the number of subunits incorporated before termination of synthesis. From the measured rate of cell straightening this relationship predicts processivity values that are in good agreement with our estimates from published data. Finally, we consider the possible role of three other mechanisms in cell straightening. We conclude that regardless of the involvement of other factors, intrinsic properties of PG processivity provide a robust mechanism for cell straightening that is hardwired to the cell wall synthesis machinery.


Contribution of Complementarity-Determining Region 3 of the T-Cell Receptor Vδ2 Chain to the Recognition of Aminobisphosphonates by Human γδ T-Cells.
Human gammadelta T-lymphocytes expressing Vgamma2Vdelta2 T-cell receptors (TCRs) can be stimulated by aminobisphosphonates and can kill certain tumor cells. Although germline-encoded lysine residues on the Jgamma1.2 segment have been demonstrated to be essential for the recognition of nonpeptide antigens by human gammadelta T-cells, the role of the junctional sequences of the TCR delta chain in the recognition of aminobisphosphonates by Vgamma2Vdelta2+ T-cells remains unknown. We examined the structure of complementarity-determining region 3 (CDR3) of Vdelta2 chains expressed by aminobisphosphonate-stimulated human gammadelta T-cells. CDR3 size-spectratyping analysis of Vdelta2 chains revealed that risedronate did not induce a CDR3 size distribution pattern of Vdelta2 cells that was distinct from that of Vdelta2 cells cultured without risedronate. The clonality of risedronate-expanded Vdelta2 T-cells was also determined by sequencing analysis, with the result that no particular consensus sequences were observed. However, most Vdelta2 T-cells freshly isolated from peripheral blood carried a distinctive junctional motif consisting of a hydrophobic amino acid residue (valine, leucine, or isoleucine [Val/Leu/Ile]) at conserved position 97, and this feature was not altered by risedronate stimulation. A significant proportion of Vdelta1 T-cells from the same individual had Leu at position 97, but Vdelta1 T-cells did not expand in response to risedronate. Moreover, Vdelta2 T-cells from the nonresponder against risedronate also carried a Val/Leu/Ile amino acid residue at position 97. These results suggest that the presence of a hydrophobic amino acid residue at position 97 in CDR3 of the TCR delta chain is not sufficient to account for the recognition of aminobisphosphonate by human gammadelta T-cells.


Human tumour xenografts.
The historical development, and more recent advances in the use of xenografts of human tumours as potential models for the study of human cancer are described and discussed. The practicality of the various systems available are critically reviewed, as well as their potential application in the field of experimental chemotherapy. Emphasis is given to the fact that over two decades of research effort has hardly produced any results of clinical relevance, often because workers have been too carried away with their technical achievements to appreciate the rules of experimental chemotherapy. The role of human tumour xenografts in the study of human cancer is appreciated, but the development of newer syngeneic, differentiated animal models may lessen their importance in the field of experimental chemotherapy.


[The experience of the physical examination of children in the administrative region].
The health conditions of children and the results of their active dynamic monitoring in the Lenigradskaya Oblast reflect the national trends in Russia. The typical characteristics of the region are discussed. The mass health examination, its results and retrospective analysis are presented. The major tendencies in children's health of the region during the last seven years are revealed.


Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America.
Guidelines for the diagnosis, prevention, and management of persons with catheter-associated urinary tract infection (CA-UTI), both symptomatic and asymptomatic, were prepared by an Expert Panel of the Infectious Diseases Society of America. The evidence-based guidelines encompass diagnostic criteria, strategies to reduce the risk of CA-UTIs, strategies that have not been found to reduce the incidence of urinary infections, and management strategies for patients with catheter-associated asymptomatic bacteriuria or symptomatic urinary tract infection. These guidelines are intended for use by physicians in all medical specialties who perform direct patient care, with an emphasis on the care of patients in hospitals and long-term care facilities.


Sensitivity modeling study for an ozone occurrence during the 1996 Paso Del Norte Ozone Campaign.
Surface ozone pollution has been a persistent environmental problem in the US and Europe as well as the developing countries. A key prerequisite to find effective alternatives to meeting an ozone air quality standard is to understand the importance of local anthropogenic emissions, the significance of biogenic emissions, and the contribution of long-range transport. In this study, an air quality modeling system that includes chemistry and transport, CMAQ, an emission processing model, SMOKE, and a mesoscale numerical meteorological model, WRF, has been applied to investigate an ozone event occurring during the period of the 1996 Paso del Norte Ozone Campaign. The results show that the modeling system exhibits the capability to simulate this high ozone occurrence by providing a comparable temporal variation of surface ozone concentration at one station and to capture the spatial evolution of the event. Several sensitivity tests were also conducted to identify the contributions to high surface ozone concentration from eight VOC subspecies, biogenic VOCs, anthropogenic VOCs and long-range transportation of ozone and its precursors. It is found that the reductions of ETH, ISOP, PAR, OLE and FORM help to mitigate the surface ozone concentration, and like anthropogenic VOCs, biogenic VOC plays a nonnegligible role in ozone formation. But for this case, long-range transport of ozone and its precursors appears to produce an insignificant contribution.


Design and evaluation of locked nucleic acid-based splice-switching oligonucleotides in vitro.
Antisense-mediated modulation of pre-mRNA splicing is an attractive therapeutic strategy for genetic diseases. Currently, there are few examples of modulation of pre-mRNA splicing using locked nucleic acid (LNA) antisense oligonucleotides, and, in particular, no systematic study has addressed the optimal design of LNA-based splice-switching oligonucleotides (LNA SSOs). Here, we designed a series of LNA SSOs complementary to the human dystrophin exon 58 sequence and evaluated their ability to induce exon skipping in vitro using reverse transcription-polymerase chain reaction. We demonstrated that the number of LNAs in the SSO sequence and the melting temperature of the SSOs play important roles in inducing exon skipping and seem to be key factors for designing efficient LNA SSOs. LNA SSO length was an important determinant of activity: a 13-mer with six LNA modifications had the highest efficacy, and a 7-mer was the minimal length required to induce exon skipping. Evaluation of exon skipping activity using mismatched LNA/DNA mixmers revealed that 9-mer LNA SSO allowed a better mismatch discrimination. LNA SSOs also induced exon skipping of endogenous human dystrophin in primary human skeletal muscle cells. Taken together, our findings indicate that LNA SSOs are powerful tools for modulating pre-mRNA splicing.


Impact of treatment with direct-acting antivirals on anxiety and depression in chronic hepatitis C.
Treatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series. All patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures. One hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed. DAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.


Smoking-related general and cause-specific mortality in Estonia.
Tobacco smoking is known to be the single largest cause of premature death worldwide. The aim of present study was to analyse the effect of smoking on general and cause-specific mortality in the Estonian population. The data from 51,756 adults in the Estonian Genome Center of the University of Tartu was used. Information on dates and causes of death was retrieved from the National Causes of Death Registry. Smoking status, general survival, general mortality and cause-specific mortality were analysed using Kaplan-Meier estimator and Cox proportional hazards models. The study found that smoking reduces median survival in men by 11.4 years and in women by 5.8 years. Tobacco smoking produces a very specific pattern in the cause of deaths, significantly increasing the risks for different cancers and cardiovascular diseases as causes of death for men and women. This study also identified that external causes, such as alcohol intoxication and intentional self-harm, are more prevalent causes of death among smokers than non-smokers. Additionally, smoking cessation was found to reverse the increased risks for premature mortality. Tobacco smoking remains the major cause for losses of life inducing cancers and cardiovascular diseases. In addition to the common diseases, external causes also reduce substantially the years of life. External causes of death indicate that smoking has a long-term influence on the behaviour of smokers, provoking self-destructive behaviour. Our study supports the idea, that tobacco smoking generates complex harm to our health increasing mortality from both somatic and mental disorders.


Sex differences in the cardiovascular and renal actions of vasopressin in conscious rats.
The present study was carried out to investigate whether prostaglandins (PG) are involved in the mechanism that contributes to the sex difference in the antidiuretic and pressor actions of vasopressin. The experiments were performed in conscious male and nonestrous female rats. In hydrated rats, the graded infusion of vasopressin (10-1,000 pg.min 1.kg body wt-1) resulted in a dose-dependent antidiuresis: decreases in urine flow and free water clearance and an increase in urine osmolality. These responses were significantly greater in male than in nonestrous female rats. Pretreatment with a cyclooxygenase inhibitor, indomethacin (10 mg/kg body wt iv), significantly enhanced the antidiuretic response to vasopressin in both sexes. However, the magnitude of this enhancement was greater in female than in male rats. Thus indomethacin abolished the sex difference in the antidiuretic response to vasopressin. In a separate experiment in rats without water hydration and urine collection, infusion of pressor doses of vasopressin (1,000-6,000 pg.min-1.kg body wt-1) resulted in a greater increase in blood pressure in male than in nonestrous female rats. Treatment with indomethacin enhanced this response equivalently in both sexes and thus did not affect the sex difference in the pressor action of vasopressin. These data indicate that renal PG may mediate, at least in part, the sex difference in the antidiuretic action of vasopressin, whereas vascular PG seem not to play an important role in the sex difference in the pressor action of vasopressin.


Hormone-dependent differentiation of immature mouse mammary gland in vitro.
Explants from the mammary glands of 3-week-old mice can be induced to synthesize casein in vitro in the absence of lobuloalveolar development. Maximum biochemical differentiation requires the presence of insulin, hydrocortisone, and prolactin in the culture medium. In contrast to explants from adult mice, the mammary epithelium of immature animals undergoes DNA synthesis and mitosis in vitro in the absence of exogenous insulin; however, such proliferation does not lead to the formation of differentiated daughter cells. Insulin acts in at least two ways during the proliferative phases of the cell cycle of differentiating mammary epithelial cells.


Viscoelastic characteristics of contracted collagen gels populated with rat fibroblasts or cardiomyocytes.
The viscoelastic characteristics of contracted collagen gels populated with rat fibroblasts or cardiomyocytes were investigated by uniaxial tensile testing. Rat type I collagen-Dulbecco's modified Eagle's medium solution (each 2 ml in volume, 0.5 mg/ml collagen concentration) containing 2.0 million rat fibroblasts or cardiomyocytes were cast in a circular shape. After gelation and culture for 10 days the contracted gels were first stretched to a tensile strain of approximately 0.20 at 4.6 × 10(-3)/s strain rate, and then the strain was kept unchanged for 3 min. The tensile stress in the gels was recorded. The results were regressed against the equations of the Kelvin viscoelastic model. It was found that the two elastic coefficients in the model were 6.5 ± 1.7 and 10.2 ± 3.2 kPa, respectively, for gels with cardiomyocytes and 5.1 ± 1.6 and 4.5 ± 0.9 kPa for those with fibroblasts; the values for gels with cardiomyocytes were significantly higher than those for gels with fibroblasts. The viscous coefficient was 169.6 ± 60.7 kPa s for the cardiomyocytes and 143.6 ± 44.7 kPa s for the fibroblasts. The relaxation time constant for gels with cardiomyocytes was 19.6 ± 10.6 s, significantly smaller than for gels with fibroblasts (36.4 ± 13.3 s). This study is the first to obtain viscoelastic data for living cell-contracted collagen gels. These data show that the viscous effect has a vital effect on the mechanical behavior of the gels and cannot be neglected in the culture and function of artificial substitutes based on contracted collagen gels. Furthermore, the data may imply that viscous coefficient of the gels might be closely related to collagen density rather than to cross linking among collagen fibrils.


Application of heat shock protein assay and proteome assay to water from wastewater treatment plant.
In this study we applied bioassay using Chinese hamster ovary (CHO) cells with a heat shock protein (HSP) 47 promoter to the effluent of the wastewater treatment plants in Sapporo and we observed the statistically significant HSP production. This implied the effluent contained some organic matter which can stress the CHO cells. To investigate the possible causes of the toxicity of the effluent, we applied the assay to the rejected water from the sludge treatment plant, the mixtures of sewage and rejected water. The evolution of HSP production during the aerobic decay process and thickening process of sludge was also examined. These assay results showed that dissolved microbial products generated and/or released from activated sludge during its decay process in the aeration tank and during thickening and dewatering process in the sludge treatment train contributed to develop HSP production. The proteomics analysis was also applied to the effluent and detected the production of elongation factor 1beta. This result implies that the effluent from wastewater treatment plants may cause changes in cell proteins involved in allergic reaction.


[Communication and interaction in psychosomatic education: use of standardized patients].
An amendment to the German medical curriculum in April 2002 will place communication and social skills at the centre of medical training. In addition to providing cognitive knowledge, psychosomatic courses offer the opportunity to integrate affective learning, with a focus on communication and interaction processes. In winter term 2001/2002 a training with standardised patients was implemented and evaluated as part of the psychosomatic internship of the Department of General Internal and Psychosomatic Medicine at the Medical Hospital of the University of Heidelberg. Quantitative and qualitative results showed that training with standardised patients is well accepted and that acceptance is independent of student gender, career choice, or interests. These training units are easy to integrate into psychosomatic practical courses. The results discussed here will focus on the role and importance of various elements of medical training.


Integrated counseling and HIV testing centers of Delhi: An evaluation.
HIV counseling and testing services are a key entry point in prevention of HIV infection, treatment, and care of people with HIV. Evaluation of counseling, testing, and referral services help to increase the effectiveness, efficiency, and quality of services delivered by providers by improving any deficiencies in availability, accessibility, and acceptability of testing and counseling services. The objective of this study was to evaluate the integrated counseling and testing centers (ICTC) in New Delhi. The evaluation study was conducted among ICTCs during 2014-2015. Twenty ICTCs of New Delhi were selected on the basis of population proportion to the size of clients catered. The study tool was pretested structured tool for evaluating HIV voluntary counseling and testing (VCT). The evaluation tool consists of an assessment of components including the availability of infrastructure, laboratory services, referral services, and staff availability. Counseling sessions were also observed for assessing content and quality. Means and proportions were calculated. Twelve (60%) ICTCs had dedicated counseling rooms ensuring privacy for the clients. Waiting space was reported to be adequate in 16 (80%) ICTCs. Space within counseling room was observed to be adequate in 8 (40%) ICTCs. Counselors of both sexes were present in 12 (60%) ICTCs. Both external and internal quality assurance was observed in all ICTCs. Standard operating procedures were followed in 15 (75%) ICTCs. On observation of the counseling sessions, it was found that 67.4% of male counselors and 67.2% of female counselors addressed all the issues of content of counseling. ICTCs lack waiting area and adequate space in counseling room and required staff personnel. Records maintenance and laboratory quality control maintained by ICTCs were found to be adequate. The counseling rooms lack privacy that may compromise the confidentiality of clients. Few components of counseling need improvement.


Scaling up of a high average power dye laser amplifier and its new pumping designs.
Scaling up of a high average power dye laser amplifier is discussed. Differences in the characteristics between a high average power dye laser amplifier with transverse pumping and longitudinal pumping are presented by a simple theory and simulations. The simulation results for dye laser amplifiers of 10-kW average output power show that longitudinal pumping is as efficient as transverse pumping with the potential of orders of magnitude lower dye flow rate. New pumping designs are also proposed for a dye laser amplifier aimed to achieve high gain with high efficiency to reduce the number of amplifier stages. Simulation results suggest that the new designs, in comparison with a conventional amplifier, can produce several orders of magnitude higher gain without decreasing the conversion efficiency.


Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial.
Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. ClinicalTrials.gov Identifier: NCT02314819.


Quasiperiodic behavior in the electrodeposition of Cu/Sn multilayers: extraction of activation energies and wavelet analysis.
Living systems are one of the many examples in which self-organizing systems yield more intricate structures than those that can be achieved using a "step-by-step" approach. This phenomenon can be observed in electrochemical organic synthesis, oscillating metal deposition and in chemical clocks. There is a plenitude of temporal instabilities during self-organization, from ordinary period-one oscillations, going through quasiperiodicity, to the onset of chaos. Here, we describe the emergence of quasiperiodic behavior during the oscillatory electro-deposition of Cu/Sn. The time-series were characterized using a continuous wavelet transform in order to extract the oscillation frequency of the process with changes in temperature, and to calculate the apparent activation energies. Two different energy ranges are presented, and these are attributed to an activation barrier (∼50 kJ mol-1) which is closely related to a fast time-scale of the feedback loops responsible for the current oscillations and a diffusional process (∼20 kJ mol-1), connected to the slow modulations of the oscillation amplitude, giving rise to quasiperiodic dynamics. This kinetic information might provide information on the self-organized synthesis of Cu/Sn metallic multilayers which are kept far from the thermodynamic equilibrium. As self-organization in chemical systems is rapidly developing into a powerful strategy for designing new functional materials, the availability of kinetic parameters is of major interest in rational design.


Nonconsumptive effects of a generalist ungulate herbivore drive decline of unpalatable forest herbs.
High herbivore pressure is expected to benefit unpalatable species that co-occur with palatable browsed species. However, for five unpalatable understory species we found no evidence of benefit from deer browse. Detailed studies of one species in natural populations, Arisaema triphyllum, revealed surprising changes in its population structure and demography: deer browse level on a palatable species significantly correlates with reduced plant size and seed rain and male-biased sex ratios of co-occurring Arisaema populations. Analyses of individual size in five unpalatable forest plant species in long-term experimental paired deer exclosure/deer access plots corroborate the natural site results; all five species were smaller in deer access plots. Analyses of abiotic variables in natural and experimental sites suggest one potential mechanism for indirect effects of deer. Deer-mediated soil quality declines included increased soil penetration resistance and decreased leaf litter depth, which are known to hinder plant growth. Our results are likely applicable to other unpalatable forest species and have clear consequences for understory biodiversity. Unpalatable plant species in forests experiencing high deer numbers may be in decline along with their palatable neighbors. Our study implicates deer overabundance in the cascade of forest species decline and the urgency of this conservation issue in North America.


Association of human ubiquitin-conjugating enzyme CDC34 with the mitotic spindle in anaphase.
Present in organisms ranging from yeast to man, homologues of the Saccharomyces cerevisiae ubiquitin-conjugating enzyme CDC34 have been shown to play important roles in the regulation of cell cycle progression and checkpoint function. Here we analyze the expression and intracellular localization of endogenous CDC34 during mammalian cell cycle progression. We find that CDC34 protein is constitutively expressed during all stages of the cell cycle. Immunofluorescence experiments reveal that during interphase, endogenous CDC34 is localized to distinct speckles in both the nucleus and the cytoplasm. The presence of CDC34 in these compartments has also been established by biochemical fractionation experiments. Interestingly, nuclear localization depends on the presence of specific carboxy-terminal CDC34 sequences that have previously been shown to be required for CDC34's cell cycle function in Saccharomyces cerevisiae. Finally, we find that in anaphase and not during early stages of mitosis, CDC34 colocalizes with (beta)-tubulin at the mitotic spindle, implying that it may contribute to spindle function at later stages of mitosis. Taken together, these results support a model in which CDC34 ubiquitin-conjugating enzyme functions in the regulation of nuclear and cytoplasmic activities as well as in the process of chromosome segregation at the onset of anaphase in mammalian cells.


A Coaxial Dual-element Focused Ultrasound Probe for Guidance of Epidural Catheterization: An Experimental Study.
Ultrasound guidance for epidural block has improved clinical blind-trial problems but the design of present ultrasonic probes poses operating difficulty of ultrasound-guided catheterization, increasing the failure rate. The purpose of this study was to develop a novel ultrasonic probe to avoid needle contact with vertebral bone during epidural catheterization. The probe has a central circular passage for needle insertion. Two focused annular transducers are deployed around the passage for on-axis guidance. A 17-gauge insulated Tuohy needle containing the self-developed fiber-optic-modified stylet was inserted into the back of the anesthetized pig, in the lumbar region under the guidance of our ultrasonic probe. The inner transducer of the probe detected the shallow echo signals of the peak-peak amplitude of 2.8 V over L3 at the depth of 2.4 cm, and the amplitude was decreased to 0.8 V directly over the L3 to L4 interspace. The outer transducer could detect the echoes from the deeper bone at the depth of 4.5 cm, which did not appear for the inner transducer. The operator tilted the probe slightly in left-right and cranial-caudal directions until the echoes at the depth of 4.5 cm disappeared, and the epidural needle was inserted through the central passage of the probe. The needle was advanced and stopped when the epidural space was identified by optical technique. The needle passed without bone contact. Designs of the hollow probe for needle pass and dual transducers with different focal lengths for detection of shallow and deep vertebrae may benefit operation, bone/nonbone identification, and cost.


Improving chronic disease management with mobile health platform.
In modern society, aging and chronic disease is becoming common phenomenon due to the increasing numbers of elderly patients. To best treat this growing segment of the population, medical care should be based on constant vital sign monitoring. In this study, we propose a mobile vital sign measurement and data collection system for chronic disease management.. And we implemented a middle ware using Multi-Agent platform in SOS (Self-Organizing System) platform that transmits patient clinical data for services. We also implemented a HL7 messaging interface for interoperability of clinical data exchange. We propose health services on a self-organized software platform.


The Multiplicity of Cellular Infection Changes Depending on the Route of Cell Infection in a Plant Virus.
The multiplicity of cellular infection (MOI) is the number of virus genomes of a given virus species that infect individual cells. This parameter chiefly impacts the severity of within-host population bottlenecks as well as the intensity of genetic exchange, competition, and complementation among viral genotypes. Only a few formal estimations of the MOI currently are available, and most theoretical reports have considered this parameter as constant within the infected host. Nevertheless, the colonization of a multicellular host is a complex process during which the MOI may dramatically change in different organs and at different stages of the infection. We have used both qualitative and quantitative approaches to analyze the MOI during the colonization of turnip plants by Turnip mosaic virus. Remarkably, different MOIs were observed at two phases of the systemic infection of a leaf. The MOI was very low in primary infections from virus circulating within the vasculature, generally leading to primary foci founded by a single genome. Each lineage then moved from cell to cell at a very high MOI. Despite this elevated MOI during cell-to-cell progression, coinfection of cells by lineages originating in different primary foci is severely limited by the rapid onset of a mechanism inhibiting secondary infection. Thus, our results unveil an intriguing colonization pattern where individual viral genomes initiate distinct lineages within a leaf. Kin genomes then massively coinfect cells, but coinfection by two distinct lineages is strictly limited. The MOI is the size of the viral population colonizing cells and defines major phenomena in virus evolution, like the intensity of genetic exchange and the size of within-host population bottlenecks. However, few studies have quantified the MOI, and most consider this parameter as constant during infection. Our results reveal that the MOI can depend largely on the route of cell infection in a systemically infected leaf. The MOI is usually one genome per cell when cells are infected from virus particles moving long distances in the vasculature, whereas it is much higher during subsequent cell-to-cell movement in mesophyll. However, a fast-acting superinfection exclusion prevents cell coinfection by merging populations originating from different primary foci within a leaf. This complex colonization pattern results in a situation where within-cell interactions are occurring almost exclusively among kin and explains the common but uncharacterized phenomenon of genotype spatial segregation in infected plants.


Technical Note: Effects of rotating gantry on magnetic field and eddy currents in 0.35 T MRI-guided radiotherapy (MR-IGRT) system.
The purpose of this study was to identify the cause of severe image artifacts that occurred during gantry rotation in a 0.35 T MRI-Linac by comparing measurements of eddy currents, center frequency, and field inhomogeneities made with the gantry in motion and stationary. Gradient and B0 eddy currents were calculated from the free induction decays (FIDs) resulting from selective excitation at a temporal resolution of 200 ms/measurement. B0 eddy currents were also calculated from FIDs acquired with nonselective excitation at a temporal resolution of 100 ms/measurement. Center frequencies and B0 inhomogeneities were measured by acquiring FIDs with a repetition time (TR) of 290 ms. Cartesian and radial 2D true fast imaging with steady-state precession (TrueFISP) pulse sequences used in real-time MRI-guided radiation therapy (MR-IGRT) were acquired. To assess artifact severity, the normalized root mean square error (nRMSE) was calculated between a reference MRI (static gantry) and MRIs acquired during gantry rotation for each serial acquisition. Image artifacts were qualitatively graded as nominal, minor, or severe. Measurements were conducted while the gantry was rotated through its entire range for both clockwise and counterclockwise. Measurements during gantry rotation were compared to measurements with a stationary gantry (every 30°). Severe image artifacts were observed 22-35% of the time while the gantry was rotating. Short time constant eddy currents were not affected by gantry rotation. The peak to peak center frequency and FWHM rose by factors of 13.2-14.5 and 1.1-1.6, respectively, for the rotating versus stationary gantry. The magnitude of the center frequency offset and field inhomogeneities depended on the direction of the gantry rotation. Image artifacts during gantry rotation were primarily caused by center frequency variations and field inhomogeneities. Therefore, dynamic B0 compensation techniques should be able to reduce artifacts during gantry rotation.


Cascaded multiple recycling amplifications for aptamer-based ultrasensitive fluorescence detection of protein biomarkers.
Highly sensitive detection of molecular biomarkers plays a significant role in diagnosing various types of diseases at the early stage. We demonstrated in this paper an ultrasensitive aptamer-based fluorescence method for detecting mucin 1 (MUC1) in human serum via a cascaded multiple recycling signal amplification strategy. The MUC1 target molecules present in the samples cause structure switching of the hairpin aptamer probes, which initiates three cascaded recycling cycles for the cleavage of the fluorescently quenched signal probes to recover significant fluorescence for highly sensitive detection of MUC1. The developed method has a linear range from 100 fM to 1 nM for MUC1 detection. Besides, owing to the substantial signal amplification by the integrated and cascaded recycling cycles, a low detection limit of 35 fM is achieved with high selectivity. Moreover, the monitoring of trace MUC1 in human serum can also be realized with such a method, indicating its great potential for highly sensitive detection of different disease biomarkers.


Analysis of spatial variation of street landscape greening and influencing factors: an example from Fuzhou city, China.
Urban street greening is an important part of urban green infrastructure, and Green View Index (GVI) is widely used to assess urban street quality and ecosystem service value as an important indicator to quantify the perception of green street landscape from a pedestrian perspective. However, the distribution of street greenery is imbalanced. Therefore, to explore the differences in street greening levels within urban cities, we crawled streetscape data using the Internet to assess the spatial distribution patterns of urban street GVI using deep learning and spatial autocorrelation, and combined 11 surrounding environmental features with multi-source geographic data to further analyze the key factors influencing the spatial variation of block GVI using ordinary least squares, geographically weighted regression (GWR) models, and multi-scale geographically weighted regression (MGWR) models. The results show that the mean value of GVI in Fuzhou city is low (23.08%), with large differences among neighborhoods and a significant spatial autocorrelation. Among the regression models, MGWR has the best fit with an R2 of 0.702, where the variables of NDVI, house price, accessibility of water bodies and parks, and the proportion of built-up land have a greater impact on GVI, and the factors do not have the same spatial effect size. The results can provide a scientific basis for promoting green visual equity in different blocks.


Effect of fat- and sucrose-containing foods on the size of eating episodes and energy intake in lean dietary restrained and unrestrained females: potential for causing overconsumption.
This study compared the action of high fat and high sucrose foods on snack size (satiation) and post snack satiety, in dietary unrestrained (UR) and restrained (R) lean females. 2 x 2 within-subjects design, each subject received each of four conditions in a counter-balanced order. The Human Appetite Research Unit. 10 R and 10 UR lean young female students. Subjects consumed a low (1678 kJ) or high (2971 kJ) energy lunch, followed 2 hours later by an ad libitum snack consisting of a selection of high fat, low sucrose or high sucrose, low fat foods. Visual analogue rating scales recording subjective feelings of appetite were completed periodically. Energy intake at the snack was related to level of hunger (P < 0.01) and snack macronutrient composition (P < 0.001). Subjects consumed more energy when offered high fat snack foods, and more following a low energy lunch. Total group energy intake of the high fat snack selection following the low and high energy lunch was 4.39 and 3.63 MJ respectively, energy intake of the high sucrose snack selection following the low and high energy lunch was 3.03 and 2.81 MJ respectively. Post snack satiety was similar. Mean test day energy intake (including standard breakfast, fixed lunch, test snack and rest of day intake) was least when a low energy lunch was followed by an ad libitum snack of high sucrose foods. Some differences were seen between R and UR. R consumed more energy at the high fat snack following a low energy lunch, but not a high energy lunch. UR consumed more of the high fat snack following both lunch types. R consumed less energy (excluding alcoholic drinks) over the test day than UR (P < 0.05), and also less on the day following the study day (P < 0.05). R generally rated themselves as lower on measures of appetite, and rated the high fat snacks as more pleasant. These results indicate the energy intake of an eating episode is related to hunger level and macronutrient composition of foods consumed. High fat foods give rise to higher current energy intake than high sucrose foods, and kilojoule for kilojoule are less effective in suppressing subsequent food intake.


Substrate and cofactor requirements for RNA editing of chloroplast transcripts in Arabidopsis in vitro.
None of the macromolecular components of the chloroplast RNA editing apparatus has yet been identified. In order to facilitate biochemical purification and characterization of the chloroplast RNA editing apparatus, we have identified conditions suitable for production of chloroplast extracts from the model plant Arabidopsis that are capable of editing exogenous substrates produced by in vitro transcription. A simple poisoned primer extension assay readily quantified editing extent of mutated and wild-type substrates. Maximum editing efficiency typically varied from 10 to 40% with different chloroplast preparations. Substrates carrying as little as 47 nt surrounding the psbE editing site were as efficiently edited as longer substrates. Editing activity was stimulated when either ATP, CTP, or dCTP was provided to the extract, an unusual observation also recently seen with plant mitochondrial editing extracts. Editing was sensitive to a zinc chelator, also a characteristic of the mammalian APOBEC editing enzyme, which is a zinc-dependent cytidine deaminase.


Engineering of 3D self-directed quantum dot ordering in multilayer InGaAs/GaAs nanostructures by means of flux gas composition.
Lateral ordering of InGaAs quantum dots on the GaAs (001) surface has been achieved in earlier reports, resembling an anisotropic pattern. In this work, we present a method of breaking the anisotropy of ordered quantum dots (QDs) by changing the growth environment. We show experimentally that using As(2) molecules instead of As(4) as a background flux is efficient in controlling the diffusion of distant Ga adatoms to make it possible to produce isotropic ordering of InGaAs QDs over GaAs (001). The control of the lateral ordering of QDs under As(2) flux has enabled us to improve their optical properties. Our results are consistent with reported experimental and theoretical data for structure and diffusion on the GaAs surface.


GC-MS analysis of ring and side chain regioisomers of ethoxyphenethylamines.
Mass spectral differentiation of 3,4-methylenedioxymethamphetamine (3,4-MDMA), a controlled drug, and its 2,3-regioisomer from the ring substituted ethoxyphenethylamines is possible after formation of the perfluoroacyl derivatives, pentafluoropropionamides (PFPA), and heptafluorobutyrylamides (HFBA). The ring substituted ethoxyphenethylamines constitute a unique set of compounds having an isobaric relationship with 3,4-MDMA. These isomeric forms of the 2-, 3-, and 4-ethoxy phenethylamines have mass spectra essentially equivalent to 3,4-MDMA; all have molecular weight of 193 and major fragment ions in their electron ionization mass spectra at m/z 58 and 135/136. All the side chain regioisomers of 2-ethoxy phenethylamine having equivalent mass spectra to 3,4-MDMA are synthesized and compared via gas chromatography-mass spectrometry to 2,3- and 3,4-methylenedioxymethamphetamine. The mass spectra for the perfluoroacyl derivatives of the primary and secondary amine regioisomers are significantly individualized, and the side chain regioisomers yield unique hydrocarbon fragment ions at m/z 148, 162, and 176. Additionally, the substituted ethoxymethamphetamines are distinguished from the methylenedioxymethamphet-amines via the presence of the m/z 107 ion. Gas chromatographic separation on relatively non-polar stationary phases successfully resolves these derivatives.


Characterization of the serum from a patient with insulin resistance and hypoglycemia. Evidence for multiple populations of insulin receptor antibodies with different receptor binding and insulin-mimicking activities.
The serum from a patient with lupus nephritis, insulin resistance, and hypoglycemia was studied. This serum both inhibits the binding of 125I-insulin to its receptor and has insulin-like activity on fat cells (see refs. 1 and 2). The IgG fraction from this patient's serum one-half maximally inhibited 125I-insulin binding to IM-9 cells at 1 microM, but did not markedly inhibit 125I-monoclonal antibody binding even at concentrations as high as 4 microM. The IgG was then subjected to affinity chromatography on a protein A-Sepharose column. Four protein peaks were eluted from this column by a step pH gradient from 5.5 to 2.3. Three of the four peaks inhibited 125I-insulin binding to its receptors, but none was more potent than the unfractionated IgG itself. One IgG peak, however, was able to inhibit 125I-monoclonal antibody binding at tenfold lower concentrations than the unfractionated IgG. When the ability of the four IgG fractions to stimulate 2-deoxy[3H]-D-glucose transport in rat adipocytes was studied, two fractions showed stimulatory activity. Compared with unfractionated IgG, one had a weak ability to inhibit 125I-insulin binding, but tenfold more potency to mimic insulin action. The other had a strong ability to inhibit 125I-insulin binding but less potency to mimic insulin action. These studies indicate, therefore, that the serum contains multiple populations of antibodies to the insulin receptor, or portions of the plasma membrane adjacent to the receptor, which have different biologic effects.


Proteomic and Transcriptomic Approaches for Studying Bone Regeneration in Health and Systemically Compromised Conditions.
Bone regeneration is a complex biological process, where the molecular mechanisms are only partially understood. In an ageing population, where the prevalence of chronic diseases with an impact on bone metabolism is increasing, it becomes crucial to identify new strategies that would improve regenerative outcomes also in medically compromised patients. In this context, omics are demonstrating a great potential, as they offer new insights on the molecular mechanisms regulating physiologic/pathologic bone healing and, at the same time, allow the identification of new diagnostic and therapeutic targets. This review provides an overview on the current evidence on the use of transcriptomic and proteomic approaches in bone regeneration research, particularly in relation to type 1 diabetes and osteoporosis, and discusses future scenarios and potential benefits and limitations on the integration of multi-omics. It is suggested that future research will leverage the synergy of omics with statistical modeling and bioinformatics to prompt the understanding of the biology underpinning bone formation in health and medically compromised conditions. With an eye toward personalized medicine, new strategies combining the mining of large datasets and bioinformatic data with a detailed characterization of relevant phenotypes will need to be pursued to further the understanding of disease mechanisms.


Culturally Informed Australian Aboriginal and Torres Strait Islander Evaluations: A Scoping Review.
Rigorous and effective evaluations inform policy and service delivery and create evidence of program impacts and outcomes for the communities they are designed to support. Genuine engagement of communities is a key feature of effective evaluation, building trust and enhancing relevancy for communities and providing meaningful outcomes and culturally relevant findings. This applies to Indigenous peoples' leadership and perspectives when undertaking evaluations on programs that involve Indigenous communities. This systematic scoping review sought to explore the characteristics of culturally informed evaluations and the extent of their application in Australia, including the use of specific evaluation tools and types of community engagement. Academic and grey literature were searched between 2003 and 2023, with 57 studies meeting the inclusion criteria. Over time, there was an increase in the number of culturally informed evaluations undertaken, predominantly in the health and wellbeing sector. Around a quarter used a tool specifically developed for Indigenous evaluations. Half of the publications included Indigenous authorship; however, most studies lacked detail on how evaluations engaged with communities. This review highlights the need for further development of evaluation tools and standardised reporting to allow for shared learnings and improvement in culturally safe evaluation practices for Aboriginal and Torres Strait Islander communities.


Innovation in maternal-fetal therapy: a position statement from the North American Fetal Therapy Network.
For conscientious practitioners, innovative medical therapy often occupies an uncomfortable space between formal research and established clinical practice. Newer and more rapid methods of information dissemination increase the risk of advertising unproven therapies. These and other concerns should not stifle medical progress and innovation but require guidelines and boundaries. The problem is not unique to fetal therapy, but rarely do other fields consider the well-being of two individuals at the same time. Herein, the North American Fetal Therapy Network offers expanded guidelines and suggestions regarding medical innovation that are particular to maternal-fetal therapy.


Training of familiar face recognition and visual scan paths for faces in a child with congenital prosopagnosia.
In the current report we describe a successful training study aimed at improving recognition of a set of familiar face photographs in K., a 4-year-old girl with congenital prosopagnosia (CP). A detailed assessment of K.'s face-processing skills showed a deficit in structural encoding, most pronounced in the processing of facial features within the face. In addition, eye movement recordings revealed that K.'s scan paths for faces were characterized by a large percentage of fixations directed to areas outside the internal core features (i.e., eyes, nose, and mouth), in particular by poor attendance to the eye region. Following multiple baseline assessments, training focused on teaching K. to reliably recognize a set of familiar face photographs by directing visual attention to specific characteristics of the internal features of each face. The training significantly improved K.'s ability to recognize the target faces, with her performance being flawless immediately after training as well as at a follow-up assessment 1 month later. In addition, eye movement recordings following training showed a significant change in K.'s scan paths, with a significant increase in the percentage of fixations directed to the internal features, particularly the eye region. Encouragingly, not only was the change in scan paths observed for the set of familiar trained faces, but it generalized to a set of faces that was not presented during training. In addition to documenting significant training effects, our study raises the intriguing question of whether abnormal scan paths for faces may be a common factor underlying face recognition impairments in childhood CP, an issue that has not been explored so far.


Genome physical mapping from large-insert clones by fingerprint analysis with capillary electrophoresis: a robust physical map of Penicillium chrysogenum.
Physical mapping with large-insert clones is becoming an active area of genomics research, and capillary electrophoresis (CE) promises to revolutionize the physical mapping technology. Here, we demonstrate the utility of the CE technology for genome physical mapping with large-insert clones by constructing a robust, binary bacterial artificial chromosome (BIBAC)-based physical map of Penicillium chrysogenum. We fingerprinted 23.1x coverage BIBAC clones with five restriction enzymes and the SNaPshot kit containing four fluorescent-ddNTPs using the CE technology, and explored various strategies to construct quality physical maps. It was shown that the fingerprints labeled with one or two colors, resulting in 40-70 bands per clone, were assembled into much better quality maps than those labeled with three or four colors. The selection of fingerprinting enzymes was crucial to quality map construction. From the dataset labeled with ddTTP-dROX, we assembled a physical map for P.chrysogenum, with 2-3 contigs per chromosome and anchored the map to its chromosomes. This map represents the first physical map constructed using the CE technology, thus providing not only a platform for genomic studies of the penicillin-producing species, but also strategies for efficient use of the CE technology for genome physical mapping of plants, animals and microbes.


Colonic transit time, sphincter EMG, and rectoanal videomanometry in multiple system atrophy.
Both constipation and fecal incontinence are prominent lower gastrointestinal tract (LGIT) dysfunctions that occur frequently in multiple system atrophy (MSA). We investigated the mechanism of constipation and fecal incontinence in MSA. Colonic transit time (CTT), sphincter electromyography (EMG), and rectoanal videomanometry were performed in 15 patients with MSA (10 men, 5 women; mean age, 63.5 years; mean duration of disease, 3 years; decreased bowel frequency [< 3 times a week] in 9; difficulty in expulsion in 11; fecal incontinence in 3) and 10 age-matched healthy control subjects (7 men and 3 women; mean age, 62 years; decreased bowel frequency in 2; mild difficulty in expulsion in 2; fecal incontinence in none). Compared to the control subjects, MSA patients had significantly prolonged CTT in the rectosigmoid segment and total colon. Sphincter EMG showed neurogenic motor unit potentials in none of control subjects but in 93% of MSA patients. At the resting state, MSA patients showed a lower anal squeeze pressure (external sphincter weakness) and a smaller increase in abdominal pressure on coughing. During rectal filling, MSA patients showed smaller amplitude in phasic rectal contraction, which was accompanied by an increase in anal pressure that normally decreased, together with leaking in 3 patients. During defecation, most MSA patients could not defecate completely and had larger postdefecation residuals. MSA patients had weak abdominal strain, smaller rectal contraction on defecation, and larger anal contraction on defecation (paradoxical sphincter contraction on defecation), although these differences were not statistically significant. These findings in MSA patients were similar to those in Parkinson's disease patients in our previous study, except for the sphincter denervation and weakness in MSA. Constipation in MSA most probably results from slow colonic transit, decreased phasic rectal contraction, and weak abdominal strain, and fecal incontinence results from weak anal sphincter due to denervation. The responsible sites for these dysfunctions seem to be both central and peripheral nervous systems that regulate the LGIT.


All-optical UWB generation and modulation using SOA-XPM effect and DWDM-based multi-channel frequency discrimination.
An all-optical UWB pulses generation and modulation scheme using cross phase modulation (XPM) effect of semiconductor optical amplifier (SOA) and DWDM-based multi-channel frequency discrimination is proposed and demonstrated, which has potential application in multiuser UWB-Over-Fiber communication systems. When a Gaussian pulse light and a wavelength-tunable CW probe light are together injected into the SOA, the probe light out from the SOA will have a temporal chirp due to SOA-XPM effect. When the chirped probe light is tuned to the slopes of single DWDM channel transmittance curve, the optical phase modulation to intensity modulation conversion is achieved at DWDM that serves as a multi-channel frequency discriminator, the inverted polarity Gaussian monocycle and doublet pulse is detected by a photodetector, respectively. If the probe lights are simultaneously aimed to different slopes of several DWDM channels, multi-channel or binary-phase-coded UWB signal generation can be acquired. Using proposed scheme, pulse amplitude modulation (PAM), pulse polarity modulation (PPM) and pulse shape modulation (PSM) to UWB pulses also can be conveniently realized.


Impact of Transcatheter Edge-to-Edge Mitral Valve Repair on Atrial Functional Mitral Regurgitation from the GIOTTO Registry.
Atrial functional mitral regurgitation (aFMR) has a peculiar pathophysiology that may have distinctive outcomes. We investigated the impact of transcatheter edge-to-edge repair in aFMR compared with other FMR etiologies. The GIOTTO (GIse registry Of Transcatheter treatment of MR) is a multicenter, prospective study enrolling patients with symptomatic MR treated with MitraClip up to 2020. We categorized patients with FMR as aFMR, ischemic FMR (iFMR), and nonischemic ventricular FMR (niFMR). The clinical end points were defined according to the Mitral Valve Academic Research Consortium. Of 1,153 patients, 6% had aFMR, 47% iFMR, and 47% niFMR. Patients with aFMR were older, mostly women, and had a higher atrial fibrillation rate. They had better left ventricular ejection fraction and smaller left ventricular volumes, with no difference in mitral effective regurgitant orifice area. The acute device and procedural success rates were similar among the groups. At the longest available follow-up (median 478 days, interquartile range 91 to 741 days), the rate of MR ≥2+ was similar among the groups. Patients with aFMR had a lower rate of cardiovascular death and heart failure than patients with iFMR (hazard ratio [HR] 0.43, p = 0.02) and niFMR (HR 0.45, p = 0.03). The aFMR etiology remained independently associated with the composite outcome, together with postprocedural MR ≤1+ (HR 0.63, p <0.01) and peripheral arteriopathy (HR 1.82, p = 0.003). The results of this GIOTTO subanalysis suggested that aFMR is less prevalent and associated with better outcomes compared with other causes of FMR treated by transcatheter edge-to-edge repair. Postprocedural MR >1+, peripheral vasculopathy, non-aFMR were independent predictors of worse outcomes.


Potentiation of specific association of insulin with HepG2 cells by phorbol esters.
The effects of tumour-promoting phorbol esters on the receptor-mediated endocytosis of insulin were investigated in the human hepatoma cell line HepG2. Treatment of these cells with the biologically active phorbol 12-O-tetradecanoylphorbol 13-acetate (TPA), but not with the non-tumour-promoting analogue 4 alpha-phorbol 12,13-didecanoate, resulted in dramatic morphological changes, which were accompanied by a 1.5-2.5-fold increase in specific 125I-insulin association with the cells at 37 degrees C. This increase in insulin binding was not observed when the binding reaction was performed at 4 degrees C. The potentiation of 125I-insulin association with TPA-treated cells at 37 degrees C could be completely accounted for by an increase in the intracellular pool of internalized insulin; there was no concomitant increase in cell-surface insulin binding. Dissociation studies showed that the enhanced internalization of insulin by cells after treatment with TPA resulted from a decrease in the rate of intracellular processing of the insulin after receptor-mediated endocytosis. The phorbol-ester-induced enhancement of internalized insulin in HepG2 cells was additive with the potentiation of endocytosed insulin induced by both the lysosomotropic reagent chloroquine and the ionophore monensin; this indicates that TPA affects the intracellular processing of the insulin receptor at a point other than those disrupted by either of these two reagents. The potentiation of insulin receptor internalization by tumour-promoting phorbol esters could be completely mimicked by treatment with phospholipase C, but not with phospholipase A, and partially mimicked by treatment with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol. By these criteria, the effects of phorbol esters on the insulin receptor in HepG2 cells appear to be mediated through protein kinase C. These results support the concept that the activation of protein kinase C by treatment with phorbol esters causes a perturbation of the insulin-receptor-mediated endocytotic pathway in HepG2 cells, reflected in a long-term decreased rate of dissociation of internalized insulin by the phorbol-ester-treated cells.


Automated reconstruction of multiple objects with individual movement based on PSP.
Many methods have been proposed to reconstruct the moving object based on phase shifting profilometry. Quality reconstruction results can be achieved when a single moving object or multiple objects with same movement are measured. However, errors will be introduced when multiple objects with individual movements are reconstructed. This paper proposes an automated method to track and reconstruct the multiple objects with individual movement. First, the objects are identified automatically and their bounding boxes are obtained. Second, with the identified objects' images before movement, the objects are tracked by the KCF algorithm in the successive fringe pattern after movement. Third, the SIFT method is applied on the tracked object images and the objects' movement is described individually by the rotation matrix and translation vector. Finally, the multiple objects are reconstructed based on the different movement information. Experiments are presented to verify the effectiveness.


The histone demethylase lysine-specific demethylase-1-mediated epigenetic silence of KLF2 contributes to gastric cancer cell proliferation, migration, and invasion.
Gastric cancer is one of the most common malignancies and leading causes of cancer-related death worldwide. An increasing number of evidence has revealed that gastric tumorigenesis is a multistage pathological state, and epigenetic alterations are considered to play critical roles in the etiology of gastric cancer. Lysine-specific demethylase-1, a histone demethylase, has been linked to malignancy in several human cancers and considered to epigenetically regulate many tumor suppressor genes during tumorigenesis and cancer progression. However, its role and underlying targets in gastric cancer are still unclear. In this study, we detected the lysine-specific demethylase-1 expression level in gastric cancer tissues and cell lines and investigated the function and mechanism of lysine-specific demethylase-1 in the gastric cancer. The in vitro analysis shows that knockdown of lysine-specific demethylase-1 significantly inhibits gastric cancer cell proliferation, migration, and invasion and induces cell cycle G1 phase arrest and cell apoptosis. In vivo assays determine that lysine-specific demethylase-1 downregulation represses gastric cancer cell tumorigenesis. Mechanistic investigation reveals that tumor suppressor KLF2 is a key downstream target of lysine-specific demethylase-1 in gastric cancer. These findings indicate that lysine-specific demethylase-1 is an important oncogene in gastric cancer, and lysine-specific demethylase-1-mediated epigenetic repression of KLF2 plays a critical role in gastric cancer development and progression, which supports lysine-specific demethylase-1 as a potential therapeutic target in this disease.


Accurate numerical simulation of electrodiffusion and water movement in brain tissue.
Mathematical modelling of ionic electrodiffusion and water movement is emerging as a powerful avenue of investigation to provide a new physiological insight into brain homeostasis. However, in order to provide solid answers and resolve controversies, the accuracy of the predictions is essential. Ionic electrodiffusion models typically comprise non-trivial systems of non-linear and highly coupled partial and ordinary differential equations that govern phenomena on disparate time scales. Here, we study numerical challenges related to approximating these systems. We consider a homogenized model for electrodiffusion and osmosis in brain tissue and present and evaluate different associated finite element-based splitting schemes in terms of their numerical properties, including accuracy, convergence and computational efficiency for both idealized scenarios and for the physiologically relevant setting of cortical spreading depression (CSD). We find that the schemes display optimal convergence rates in space for problems with smooth manufactured solutions. However, the physiological CSD setting is challenging: we find that the accurate computation of CSD wave characteristics (wave speed and wave width) requires a very fine spatial and fine temporal resolution.


A novel role of Rho-kinase in the regulation of ligand-induced phosphorylated EGFR endocytosis via the early/late endocytic pathway in human fibrosarcoma cells.
The small GTPase RhoA and its downstream effectors, the Rho-associated kinase (Rho-kinase) family, are known to regulate cell morphology, motility, and tumor progression via the regulation of actin cytoskeleton rearrangement. In the present study, we evaluated the role of Rho-kinase in the intracellular endocytic trafficking of ligand-induced phosphorylated epidermal growth factor receptor (pEGFR). We investigated the time course of the internalization fate of EGF-induced pEGFR via the early/late endocytic pathway in human fibrosarcoma cell line HT1080 cells using Y-27632, a selective Rho-kinase inhibitor. We found, using confocal immunofluorescence microscopy and Western blot analysis, a large accumulation of pEGFR in the nuclei of HT1080 cells. In contrast, we observed decreased amounts of the pEGFR-positive staining in the nuclei along with an accumulation of cytosolic pEGFR staining when the cells were incubated for 15-30 min in the presence of Y-27632, implying that an aberrant endocytic trafficking mechanism of pEGFR occurs in HT1080 cells whereby pEGFR might be selectively translocated into the nucleus. Moreover, we demonstrated that after 15-min of stimulation with Texas Red-EGF, increasing numbers of pEGFR-positive staining that had colocalized with Texas Red-EGF-positive punctate staining were seen in the cytoplasm of HT1080 cells but after 30-min of stimulation, most of this staining had disappeared from the cytoplasm and a large accumulation of pEGFR-positive staining appeared in the nucleus. Thus, nuclear accumulation of pEGFR appears to occur in an EGF-dependent manner. In contrast, such nuclear pEGFR-positive staining was not seen in the Y-27632-treated cells. Furthermore, silencing of RhoA or Rho-kinases I/II by sequence specific siRNAs considerably inhibited the EGF-dependent nuclear accumulation of pEGFR. Collectively, these results provide the first evidence that Rho-kinase signaling pathway plays a suppressive role in the intracellular vesicle trafficking of pEGFR via the endocytic pathway and that an increased Rho-kinase activity leads to the attenuation of the normal endocytic vesicular traffic of pEGFR via the early/late endocytic pathway, instead causing pEGFR to be trafficked out of the endocytic vesicles into the nucleus.


The Induction of Heme Oxygenase 1 Decreases Painful Diabetic Neuropathy and Enhances the Antinociceptive Effects of Morphine in Diabetic Mice.
Painful diabetic neuropathy is a common complication of diabetes mellitus which is poorly controlled by conventional analgesics. This study investigates if treatment with an heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the allodynia and hyperalgesia induced by diabetes and enhanced the antinociceptive effects of morphine. In a diabetic mice model induced by the injection of streptozotocin (STZ), we evaluated the antiallodynic and antihyperalgesic effects produced by the intraperitoneal administration of 5 and 10 mg/kg of CoPP at several days after its administration. The antinociceptive actions produced by the systemic administration of morphine alone or combined with CoPP were also evaluated. In addition, the effects of CoPP treatment on the expression of HO-1, the microglial activation marker (CD11b/c), the inducible nitric oxide synthase (NOS2) and μ-opioid receptors (MOR), were also assessed. Our results showed that the administration of 10 mg/kg of CoPP during 5 consecutive days completely blocked the mechanical and thermal hypersensitivity induced by diabetes. These effects are accompanied by the increased spinal cord, dorsal root ganglia and sciatic nerve protein levels of HO-1. In addition, the STZ-induced activation of microglia and overexpression of NOS2 in the spinal cord were inhibited by CoPP treatment. Furthermore, the antinociceptive effects of morphine were enhanced by CoPP treatment and reversed by the administration of an HO-1 inhibitor, tin protoporphyrin IX (SnPP). The spinal cord expression of MOR was also increased by CoPP treatment in diabetic mice. In conclusion, our data provide the first evidence that the induction of HO-1 attenuated STZ-induced painful diabetic neuropathy and enhanced the antinociceptive effects of morphine via inhibition of microglia activation and NOS2 overexpression as well as by increasing the spinal cord levels of MOR. This study proposes the administration of CoPP alone or combined with morphine as an interesting therapeutic approach for the treatment of painful diabetic neuropathy.


[Analysis of the structure and specific features of maternal and infant mortality according to the data of Forensic Medical Examination Bureau and Pathologic Anatomy Bureau for 2002-2006].
The present analysis of maternal and infant (under 1 year of age) mortality is based on the data for the period from 2002 to 2006 that have come to the address of the All-Russia scientific and practical conference "Topical issues of forensic medical examination of the human corpse" (5-6 June 2008, Sankt-Peterburg). The materials were collected using a standard questionnaire form distributed among regional forensic-medical examination bureaus an pathologic anatomy departments. The questionnaire comprised over 50 questions. The study revealed a steady tendency toward a decrease in maternal and infant mortality in the Russian Federation as a whole and in its different regions. The study included analysis of similarities and differences in the mortality rates reported by forensic-medical examination bureaus and pathologic anatomy departments of the country and in the technical approaches practiced by them.


Correlation between health-related quality of life in veterans with chronic spinal cord injury and their caregiving spouses.
Recently, investigations have indicated that caring of a chronically ill family member strongly influences the health status and the quality of life (QOL) of the caregiving family members. The purpose of this study was to examine the relationship between health-related QOL of veterans with chronic spinal cord injury and their caregiving spouses. We designed a cross-sectional study including two groups; veterans with chronic spinal cord injury and their caregiving wives who were living in the city of Mashhad, Iran. The patients with spinal cord injury were veterans from the Iran-Iraq war (1980-1988). All the participants filled out the short form 36 (SF-36) health survey questionnaire. A Pearson correlation coefficient was calculated for the scales of the two groups. The mean age and standard deviation of veterans and their spouses were 48.5 ± 5.9 and 44.8 ± 7.2, respectively and their number of children ranged between 0-6. Our data analysis showed that there was a significant difference between the two groups in some domains of the SF-36, including PF, MH, PCS, MCS, BP and GH (P < 0.05), but there was no significant difference in RP, VT, SF and RE between the two groups. The results indicate that a decrease in health status level of veterans, physically and mentally, can affect the health-related QOL of their caregiving spouses.


Health and health-related quality of life among treatment-seeking overweight and obese adults: associations with internalized weight bias.
Weight bias is widespread and has numerous harmful consequences. The internalization of weight bias has been associated with significant psychological impairment. Other forms of discrimination, such as racial and anti-gay bias, have been shown to be associated with physical health impairment. However, research has not yet examined whether internalized weight bias is associated with physical as well as psychological impairment in health-related quality of life. Participants included 120 treatment-seeking overweight and obese adults (mean body mass index = 35.09; mean age = 48.31; 68% female; 59% mixed or Asian ethnicity). Participants were administered measures of internalized weight bias and physical and mental health-related quality of life, and they were assessed for the presence of chronic medical conditions, use of prescription and non-prescription medications, and current exercise. Internalized weight bias was significantly correlated with health impairment in both physical (r = -.25) and mental (r = -.48) domains. In multivariate analyses controlling for body mass index, age, and other physical health indicators, internalized weight bias significantly and independently predicted impairment in both physical (β = -.31) and mental (β = -.47) health. Internalized weight bias was associated with greater impairment in both the physical and mental domains of health-related quality of life. Internalized weight bias also contributed significantly to the variance in physical and mental health impairment over and above the contributions of BMI, age, and medical comorbidity. Consistent with the association between prejudice and physical health in other minority groups, these findings suggest a link between the effects of internalized weight-based discrimination and physical health. Research is needed on strategies to prevent weight bias and its internalization on both a societal and individual level.


Pre-miRNA-149 G-quadruplex as a molecular agent to capture nucleolin.
One of the most significant challenges in capturing and detecting biomarkers is the choice of an appropriate biomolecular receptor. Recently, RNA G-quadruplexes emerged as plausible receptors due to their ability to recognize with high-affinity proteins. Herein, we have unveiled and characterized the capability of the precursor microRNA 149 to form a G-quadruplex structure and determined the role that some ligands may have in its folding and binding capacity to nucleolin. The G-quadruplex formation was induced by K+ ions and stabilized by ligands, as demonstrated by nuclear magnetic resonance and circular dichroism experiments. Surface plasmon resonance measurements showed a binding affinity of precursor microRNA 149 towards ligands in the micromolar range (10-5-10-6 M) and a strong binding affinity to nucleolin RNA-binding domains 1 and 2 (8.38 × 10-10 M). Even in the presence of the ligand PhenDC3, the binding remains almost identical and in the same order of magnitude (4.46 × 10-10 M). The molecular interactions of the RNA G-quadruplex motif found in precursor miRNA 149 (5'-GGGAGGGAGGGACGGG- 3') and nucleolin RNA-binding domains 1 and 2 were explored by means of molecular docking and molecular dynamics studies. The results showed that RNA G-quadruplex binds to a cavity between domains 1 and 2 of the protein. Then, complex formation was also evaluated through polyacrylamide gel electrophoresis. The results suggest that precursor microRNA 149/ligands and precursor microRNA 149/nucleolin RNA-binding domains 1 and 2 form stable molecular complexes. The in vitro co-localization of precursor microRNA 149 and nucleolin in PC3 cells was demonstrated using confocal microscopy. Finally, a rapid and straightforward microfluidic strategy was employed to check the ability of precursor microRNA 149 to capture nucleolin RNA-binding domains 1 and 2. The results revealed that precursor microRNA 149 can capture nucleolin RNA-binding domains 1 and 2 labeled with Fluorescein 5-isothiocyanate in a concentration-dependent manner, but PhenDC3 complexation seems to decrease the ability of precursor microRNA 149 to capture the protein. Overall, our results proved the formation of the G-quadruplex structure in the precursor microRNA 149 and the ability to recognize and detect nucleolin. This proof-of-concept study could open up a new framework for developing new strategies to design improved molecular receptors for capture and detection of nucleolin in complex biological samples.


The Detection of Malingering: A New Tool to Identify Made-Up Depression.
Major depression is a high-prevalence mental disease with major socio-economic impact, for both the direct and the indirect costs. Major depression symptoms can be faked or exaggerated in order to obtain economic compensation from insurance companies. Critically, depression is potentially easily malingered, as the symptoms that characterize this psychiatric disorder are not difficult to emulate. Although some tools to assess malingering of psychiatric conditions are already available, they are principally based on self-reporting and are thus easily faked. In this paper, we propose a new method to automatically detect the simulation of depression, which is based on the analysis of mouse movements while the patient is engaged in a double-choice computerized task, responding to simple and complex questions about depressive symptoms. This tool clearly has a key advantage over the other tools: the kinematic movement is not consciously controllable by the subjects, and thus it is almost impossible to deceive. Two groups of subjects were recruited for the study. The first one, which was used to train different machine-learning algorithms, comprises 60 subjects (20 depressed patients and 40 healthy volunteers); the second one, which was used to test the machine-learning models, comprises 27 subjects (9 depressed patients and 18 healthy volunteers). In both groups, the healthy volunteers were randomly assigned to the liars and truth-tellers group. Machine-learning models were trained on mouse dynamics features, which were collected during the subject response, and on the number of symptoms reported by participants. Statistical results demonstrated that individuals that malingered depression reported a higher number of depressive and non-depressive symptoms than depressed participants, whereas individuals suffering from depression took more time to perform the mouse-based tasks compared to both truth-tellers and liars. Machine-learning models reached a classification accuracy up to 96% in distinguishing liars from depressed patients and truth-tellers. Despite this, the data are not conclusive, as the accuracy of the algorithm has not been compared with the accuracy of the clinicians; this study presents a possible useful method that is worth further investigation.


Thrombotic and Embolic Complications Associated With Atrial Arrhythmia After Fontan Operation: Role of Prophylactic Therapy.
There are limited data about the risk of thrombotic and embolic complication (TEC) in adults with atrial arrhythmia after Fontan operation. This study sought to determine the risk of TEC in this population and the role of anticoagulation therapy in TEC prevention. This was a retrospective review of adults with atrial arrhythmia after Fontan operation who were evaluated at the Mayo Clinic between 1994 to 2014. TEC was classified into 2 groups: systemic TEC, defined as intracardiac thrombus, ischemic stroke, or systemic arterial embolus; and nonsystemic TEC, defined as Fontan conduit/right atrial thrombus or pulmonary embolus. Patients were divided into 3 groups: anticoagulation, antiplatelet, and no therapy cohorts. We followed 278 patients, mean age 31 ± 9 years, for 88 ± 14 months (1,464 patient-years). Patient groups included antiplatelet (n = 181), anticoagulation (n = 91), and no therapy (n = 6). There were 97 TEC in 81 patients (29%); 32 were systemic, yielding an event rate of 2.1 systemic TEC per 100 patient-years, and 65 were nonsystemic TEC, yielding an event rate of 4.4 nonsystemic TEC per 100 patient-years. Prevalence of TEC was 18% and 55% at 5 and 10 years, respectively. Atriopulmonary connection was a risk factor for TEC (hazard ratio: 2.31; 95% confidence interval: 1.61 to 4.64), and TEC were associated with higher risk of death and hospitalization (p < 0.0001). Anticoagulation was protective against TEC and resulted in a reduction of TEC risk by 2.5 TEC per 100 patient-years. Anticoagulation was also associated with lower risk of death and hospitalization (p = 0.02). Bleeding complications occurred in 21 (7%) patients and were similar in all groups. Anticoagulation was associated with lower TEC rate and lower risk of death and hospitalization, without a significant increase in bleeding risk. Perhaps anticoagulation should be the preferred preventive strategy.


The σB signalling activation pathway in the enteropathogen Clostridioides difficile.
Clostridium difficile is the main cause of antibiotic-associated diarrhoea. Inside the gut, C. difficile must adapt to the stresses it copes with, by inducing protection, detoxification and repair systems that belong to the general stress response involving σB . Following stresses, σB activation requires a PP2C phosphatase to dephosphorylate the anti-anti-sigma factor RsbV that allows its interaction with the anti-sigma factor RsbW and the release of σB . In this work, we studied the signalling pathway responsible for the activation of σB in C. difficile. Contrary to other firmicutes, the expression of sigB in C. difficile is constitutive and not autoregulated. We confirmed the partner switching mechanism that involved RsbV, RsbW and σB . We also showed that CD2685, renamed RsbZ, and its phosphatase activity are required for RsbV dephosphorylation triggering σB activation. While CD0007 and CD0008, whose genes belong to the sigB operon, are not involved in σB activity, depletion of the essential iron-sulphur flavoprotein, CD2684, whose gene forms an operon with rsbZ, prevents σB activation. Finally, we observed that σB is heterogeneously active in a subpopulation of C. difficile cells from the exponential phase, likely leading to a 'bet-hedging' strategy allowing a better chance for the cells to survive adverse conditions.


Significance of early aminotransferase elevation after liver transplantation.
We retrospectively reviewed 213 consecutive patients who received their first liver allograft between January 1 and December 31, 1993, in order to study the impact of ischemia/preservation/reperfusion injury (IPRI) on patient and graft outcome. The extent of IPRI was assessed by the peak value of aspartate aminotransferase (ASTmax) observed within the first 72 hr after transplant. For the purpose of univariate analysis, categorical classification of recipients was done based upon ASTmax as follows: group 1, ASTmax<600 U/L (n=46); group 2, ASTmax=600-2000 U/L (n=97); group 3, ASTmax>2000-5000 U/L (n=50), and group 4, ASTmax>5000 U/L (n=17). For multivariate analysis, stepwise Cox regression was performed with age, ASTmax, and United Network for Organ Sharing (UNOS) status as covariates. Groups were comparable with respect to age, UNOS status at the time of transplantation, and diagnostic case mix. Median follow-up was 644 days. The overall incidence of primary graft nonfunction (PNF) was 7.6%. PNF incidence was significantly correlated with the severity of IPRI (0%, 4%, 10%, and 41% for groups 1 to 4, respectively, P < 0.0001), but this impact was confined to the respective rates of retransplantation as early patient survival was unaffected. The 1-year survival of patients whose initial grafts manifested extreme IPRI (group 4) was significantly inferior to recipients in the three other groups (77%, 71%, 73%, and 52% for groups 1 to 4, respectively, P=0.03). This increased mortality was confined to patients who never achieved discharge from their initial hospitalization, with no significant differences between groups being detected in the survival of those patients who were discharged (84%, 80%, 85%, and 81% for groups 1 to 4, respectively, P=NS). Although overall 1-year graft survival was strongly correlated with the extent of IPRI (77%, 67%, 62%, and 41% for groups 1 to 4, respectively, P=0.001), this correlation was abolished when survival of grafts not lost to PNF was examined at 1 and 2 years. Stepwise Cox regression analysis confirmed the independent association between ASTmax and patient and graft survival. The long-term quality of allograft function as well as the incidence of chronic rejection and biliary complications were unrelated to the extent of IPRI. We conclude that: (1) patient survival is influenced by IPRI only when it is extreme (ASTmax>5000 U/L), provided parameters of graft function are used in conjunction with aminotransferase values to assess the need for prompt retransplantation; (2) short-term graft survival is proportional to the extent of IPRI, but grafts that are not lost to PNF have equivalent 1- and 2-year survival irrespective of the magnitude of IPRI; (3) 40% of grafts with extreme IPRI are lost to PNF, but the same proportion also provide long-term function; and (4) for surviving grafts, long-term biochemical function as well as the incidence of biliary complications and of chronic rejection are unrelated to the extent of IPRI.


New Insights into the Pathogenesis of Preeclampsia - The Role of Nrf2 Activators and their Potential Therapeutic Impact.
Preeclampsia (PE), characterized by proteinuric hypertension and occurring in 2-3 % of all pregnancies, is one of the leading causes of maternal, fetal and neonatal morbidity and mortality. The etiology of PE still remains unclear and current treatments for this devastating disorder are still limited to symptomatic therapies. Placental oxidative stress may be a key intermediate step in the pathogenesis of PE; it has been related to excessive secretion of multiple antiangiogenic factors, mainly soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). The nuclear factor-erythroid 2-like 2 (Nrf2) pathway is one of the most important systems that enhance cellular protection against oxidative stress. Nrf2 serves as a master transcriptional regulator of the basal and inducible expression of a multitude of genes encoding detoxification enzymes and antioxidative proteins. Evidence for a link between Nrf2 and restoring the balance between pro- and antiangiogenic factors mainly through its downstream target protein heme oxygenase-1 (HO-1) has lately been discussed. HO-1 metabolizes heme to biliverdin, iron and carbon monoxide (CO). CO enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle and promotes its relaxation and hence vasodilatation. In addition, HO-1 has been shown in vitro to inhibit the production of sFlt-1. A recent animal study demonstrated that the induction of HO-1 in a mouse model of PE attenuates the induced hypertension in pregnant mice. This provides compelling evidence for the protective role of Nrf2/HO-1 in pregnancy and identifies this pathway as a target to treat women with PE. We summarize the recent findings on the involvement of Nrf2 in the pathogenesis of PE, and provide an overview of the possible beneficial effects of Nrf2 inducers in PE.


Direct Visualization of Single-Nucleotide Variation in mtDNA Using a CRISPR/Cas9-Mediated Proximity Ligation Assay.
The accumulation of mitochondrial DNA (mtDNA) mutations in cells is strongly related to aging-associated diseases. Imaging of single-nucleotide variation (SNV) in mtDNA is crucial for understanding the heteroplasmy of mtDNAs that harbor pathogenic changes. Herein, we designed a CRISPR/Cas9-mediated proximity ligation assay (CasPLA) for direct visualization of the ND4 and ND5 genes in the mtDNAs of single cells. Taking advantage of the high specificity of CRISPR/Cas9, CasPLA can be used to image SNV in the ND4 gene at single-molecule resolution. Using CasPLA, we observed a mtDNA-transferring process between different cells through a tunneling nanotube, which may account for the spreading of mtDNA heteroplasmy. Moreover, we demonstrated that CasPLA strategy can be applied for imaging of single copy genomic loci ( KRAS gene) in the nuclear genome. Our results establish CasPLA as a tool to study SNV in situ in single cells for basic research and genetic diagnosis.


Modulation of cardiovascular reflexes by arginine vasopressin.
Arginine vasopressin (AVP), a potent vasoconstrictor, does not raise arterial pressure in normal humans or neurally intact animals, even during infusions that achieve pathophysiological plasma concentrations. It has been proposed that this is because AVP facilitates the baroreflex control of the circulation. We performed a series of investigations to test this hypothesis, and to determine sites at which AVP might act to augment the baroreflex. In anesthetized rabbits, vasopressin (36 pmol.kg-1.min-1) increased discharge from both medullated and nonmedullated single fibres from aortic baroreceptor nerves during elevations in aortic arch pressure. Similarly, vasopressin (36 pmol.kg-1.min-1) increased the response of left ventricular mechanoreceptor single fibre discharge to elevations of left ventricular end-diastolic pressure. These observations suggest that sensitization of high and low pressure baroreceptors is one mechanism by which vasopressin may facilitate baroreflexes. In a further series of experiments in sinoaortic denervated anesthetized rabbits, vasopressin (18 pmol.kg-1.min-1) facilitated vagally mediated reflex inhibition of renal sympathetic nerve activity during volume expansion. In humans, AVP (0.37 pmol.kg-1.min-1) raised plasma AVP to an antidiuretic level (22 +/- 4 fmol/mL), but did not change blood pressure or the baroreflex control of heart rate or forearm vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)


Change, conflict, and coping.
Managing in a health care organization requires the ability to cope with a constantly changing environment in which the manager is often caught in a situation of conflict. Developing a broader perspective on the problem and reframing one's thought process allows more opportunity to deal with the issues through logical rather than crisis management.


Bacterial landscape of human skin: seeing the forest for the trees.
Skin harbours large communities of colonizing bacteria. The same bacterial species can exist in different physiological states: viable, dormant, non-viable. Each physiological state can have a different impact on skin health and disease. Various analytical methodologies target different physiological states of bacteria, and this must be borne in mind while interpreting microbiological tests and drawing conclusions about possible cause-effect relationships.


Engagement and education: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement.
Engagement and education of ICU clinicians in disaster preparedness is fragmented by time constraints and institutional barriers and frequently occurs during a disaster. We reviewed the existing literature from 2007 to April 2013 and expert opinions about clinician engagement and education for critical care during a pandemic or disaster and offer suggestions for integrating ICU clinicians into planning and response. The suggestions in this article are important for all of those involved in a pandemic or large-scale disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. A systematic literature review was performed and suggestions formulated according to the American College of Chest Physicians (CHEST) Consensus Statement development methodology. We assessed articles, documents, reports, and gray literature reported since 2007. Following expert-informed sorting and review of the literature, key priority areas and questions were developed. No studies of sufficient quality were identified upon which to make evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. Twenty-three suggestions were formulated based on literature-informed consensus opinion. These suggestions are grouped according to the following thematic elements: (1) situational awareness, (2) clinician roles and responsibilities, (3) education, and (4) community engagement. Together, these four elements are considered to form the basis for effective ICU clinician engagement for mass critical care. The optimal engagement of the ICU clinical team in caring for large numbers of critically ill patients due to a pandemic or disaster will require a departure from the routine independent systems operating in hospitals. An effective response will require robust information systems; coordination among clinicians, hospitals, and governmental organizations; pre-event engagement of relevant stakeholders; and standardized core competencies for the education and training of critical care clinicians.