Immune-related Genes to Dominate Neutrophil-lymphocyte Ratio (NLR) Associated With Survival of Cetuximab Treatment in Metastatic Colorectal Cancer.
Few clinical studies have investigated the association between neutrophil-lymphocyte ratio (NLR) and treatment with cetuximab-based chemotherapy in metastatic colorectal cancer (mCRC). The NLR may reflect immune cells modulating specific cytokine signals in the tumor microenvironment; however, which immune-related genes affect the NLR remain unclear. In 77 patients with KRAS exon2 wild-type mCRC from prospective trials of first-line chemotherapy with cetuximab, expression levels of 354 immune-related genes were measured in tissue samples obtained from all patients by the HTG EdgeSeq Oncology Biomarker Panel. The association between the NLR and clinical outcomes was evaluated using the Spearman rank correlation coefficient. In addition, 2-sample t tests were performed to investigate which genes among the top 100 genes associated with survival had significantly different expression levels between the NLR-low and NLR-high groups among all measured genes. NLR data were available for 71 patients. The NLR was associated with progression-free survival and overall survival (r = -0.24; P = .040 and r = -0.29; P = .010, respectively). When stratified by the median value of the NLR, the Kaplan-Meier curve of NLR-low versus NLR-high differed significantly for both progression-free survival (median, 11.8 vs. 9.1 months; P = .036) and overall survival (median, 42.8 vs. 26.7 months; P = .029). The 2-sample t test revealed that the expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR-low and NLR-high groups (t test P-value < .005; false discovery rate P-value < .15). NLR is significantly associated with survival in patients with mCRC treated with first-line chemotherapy with cetuximab. Genes encoding for activities on macrophages may affect the NLR.


Active immunotherapy for TNF-mediated inflammation using self-assembled peptide nanofibers.
Active immunotherapies raising antibody responses against autologous targets are receiving increasing interest as alternatives to the administration of manufactured antibodies. The challenge in such an approach is generating protective and adjustable levels of therapeutic antibodies while at the same time avoiding strong T cell responses that could lead to autoimmune reactions. Here we demonstrate the design of an active immunotherapy against TNF-mediated inflammation using short synthetic peptides that assemble into supramolecular peptide nanofibers. Immunization with these materials, without additional adjuvants, was able to break B cell tolerance and raise protective antibody responses against autologous TNF in mice. The strength of the anti-TNF antibody response could be tuned by adjusting the epitope content in the nanofibers, and the T-cell response was focused on exogenous and non-autoreactive T-cell epitopes. Immunization with unadjuvanted peptide nanofibers was therapeutic in a lethal model of acute inflammation induced by intraperitoneally delivered lipopolysaccharide, whereas formulations adjuvanted with CpG showed comparatively poorer protection that correlated with a more Th1-polarized response. Additionally, immunization with peptide nanofibers did not diminish the ability of mice to clear infections of Listeria monocytogenes. Collectively this work suggests that synthetic self-assembled peptides can be attractive platforms for active immunotherapies against autologous targets.


High seroprevalence of feline morbilliviruses in free-roaming domestic cats in Chile.
Feline morbillivirus infections have gained increased attention due to repeated reports of their association with urinary tract disease in cats. In the present study, 112 serum samples from free-roaming domestic cats in Chile were tested for antibodies against feline morbillivirus genotypes 1 and 2 (FeMV-1 and FeMV-2) using an indirect immunofluorescence assay. In total, 63% of the animals showed antibodies against one or both FeMV genotypes. Antibodies directed exclusively against FeMV-2 were significantly more prevalent in male cats. The correlation of sex and FeMV-2 infection might give insight into potential routes of transmission. We provide, for the first time, serological data on FeMV in Chile.


Prognosis of patients with systemic sclerosis-related interstitial lung disease on the lung transplant waiting list: a retrospective study.
Advanced systemic sclerosis-associated interstitial lung disease (SSc-ILD) can be treated with lung transplantation. There is limited data on lung transplantation outcomes in patients with SSc-ILD, in non-Western populations.We assessed survival data of patients with SSc-ILD, on the lung transplant (LT) waiting list, and evaluated post-transplant outcomes in patients from an Asian LT center. In this single-center retrospective study, 29 patients with SSc-ILD, registered for deceased LT at Kyoto University Hospital, between 2010 and 2022, were identified. We investigated post-transplant outcomes in recipients who underwent LT for SSc-ILD, between February 2002 and April 2022. Ten patients received deceased-donor LT (34%), two received living-donor LT (7%), seven died waiting for LT (24%), and ten survived on the waiting list (34%). Median duration from registration to deceased-donor LT was 28.9 months and that from registration to living-donor LT or death was 6.5 months. Analysis of 15 recipients showed improved forced vital capacity with a median of 55.1% at baseline, 65.8% at 6 months, and 80.3% at 12 months post-transplant. The 5-year survival rate for post-transplant patients with SSc-ILD was 86.2%. The higher post-transplant survival rate at our institute than previously reported suggests that lung transplantation is acceptable in Asian patients with SSc-ILD.


A 2021 Horizon Scan of Emerging Global Biological Conservation Issues.
We present the results from our 12th annual horizon scan of issues likely to impact biological conservation in the future. From a list of 97 topics, our global panel of 25 scientists and practitioners identified the top 15 issues that we believe society may urgently need to address. These issues are either novel in the biological conservation sector or represent a substantial positive or negative step-change in impact at global or regional level. Six issues, such as coral reef deoxygenation and changes in polar coastal productivity, affect marine or coastal ecosystems and seven relate to human and ecosystem-level responses to climate change. Identification of potential forthcoming issues for biological conservation may enable increased preparedness by researchers, practitioners, and decision-makers.


The contributing role of the intestinal microbiota in stressor-induced increases in susceptibility to enteric infection and systemic immunomodulation.
The body is colonized by highly complex and genetically diverse communities of microbes, the majority of which reside within the intestines in largely stable but dynamically interactive climax communities. These microbes, referred to as the microbiota, have many functions that enhance the health of the host, and it is now recognized that the microbiota influence both mucosal and systemic immunity. The studies outlined in this review demonstrate that the microbiota are also involved in stressor-induced immunomodulation. Exposure to different types of stressors, including both physical and psychological stressors, changes the composition of the intestinal microbiota. The altered profile increases susceptibility to an enteric pathogen, i.e., Citrobacter rodentium, upon oral challenge, but is also associated with stressor-induced increases in innate immune activity. Studies using germfree mice, as well as antibiotic-treated mice, provide further evidence that the microbiota contribute to stressor-induced immunomodulation; stressor-induced increases in splenic macrophage microbicidal activity fail to occur in mice with no, or reduced, intestinal microbiota. While the mechanisms by which microbiota can impact mucosal immunity have been studied, how the microbiota impact systemic immune responses is not clear. A mechanism is proposed in which stressor-induced degranulation of mucosal mast cells increases the permeability of the intestines. This increased permeability would allow intact bacteria and/or bacterial products (like peptidoglycan) to translocate from the lumen of the intestines to the interior of the body, where they directly, or indirectly, prime the innate immune system for enhanced reactivity to antigenic stimulation.


Sexually transmitted diseases and reproductive health in women.
The effect of sexually transmitted diseases (STDs) on the reproductive health of women, the reasons why women bear a disproportionate percent of STD morbidity and mortality, and the factors contributing to an increased risk for STDs and their complications in women are enumerated. Conclusions and recommendations from the 1997 Institute of Medicine report, The Hidden Epidemic: Confronting Sexually Transmitted Diseases, are categorized and addressed. The categories are education, population groups, and clinical practice. The contributions of midwives to implementing pertinent Institute of Medicine recommendations in basic and continuing education programs, individual practice, and in influencing policy are detailed. Factual information about STDs, risk assessment history, essential STD-related services, and treatment guidelines are provided in tables.


The Evolution of 'Ecological Release' into the 21st Century.
Ecological release, originally conceived as niche expansion following a reduction in interspecific competition, may prompt invasion success, morphological evolution, speciation, and other ecological and evolutionary outcomes. However, the concept has not been recently reviewed. Here, we trace the study of 'ecological release' from its inception through the present day and find that current definitions are broad and highly varied. Viewing this development as a potential impediment to clear communication and hypothesis testing, we suggest a consensus definition for ecological release: niche expansions and shifts when a constraining interspecific interaction is reduced or removed. In rationalizing this definition, we highlight the various ways ecological release can unfold and address its potential evolutionary consequences.


Effects of chronic nicotine administration on insulin, glucose, epinephrine, and norepinephrine.
There is an inverse relationship between nicotine administration and body weight. Previous research indicates that this relationship results partially from effects of nicotine on energy intake. The present research includes two animal studies designed to investigate the effects of chronic nicotine administration on biochemical responses that affect energy utilization. The results indicate that chronic nicotine administration is accompanied by significant decreases in circulating insulin levels. Nicotine increases levels of catecholamines, but this effect is short-lived. The effects of nicotine on insulin are consistent with the conclusion that nicotine administration increases energy utilization.


Effect of hypothalamic injections of 5,7-dihydroxytryptamine on elicitation of mouse-killing in rats.
An overall and marked serotonin (5-HT) depletion of the brain was found to facilitate initiation of mouse-killing behavior in the rat, whereas more selective 5-HT depletions within forebrain structures such as the septum, hippocampus, cingular cortex and amygdala, did not have such an effect. In order to further investigate the topography of the 5-HT pathways and terminals though to be involved in an inhibitory control over this behavior, localized lesions of the serotonergic system(s) were performed by means of bilateral 5,7-dihydroxytryptamine (5,7-DHT) injections (5 microgram/microliter) into the hypothalamus in naive rats. 5,7-DHT injections into the medial hypothalamus did not affect the initiation of mouse-killing behavior, whereas the reflexive startle responses to air puffs were increased. The animals' open-field behavior remained unchanged. Forebrain 5-HT content was reduced by 50% in this group. 5,7-DHT injections into the lateral hypothalamus increased the proportion of killers to 46% as compared to 10% in the control group, in spite of a reduced activity in the open-field and unchanged startle responses. Forebrain 5-HT content was reduced by 88%. As the lateral hypothalamus contains afferents from both the dorsal and the median raphe nuclei, it is likely that 5-HT terminals modulate some hypothalamic mechanism involved in the control of mouse-killing behavior.


Actions of the new antimuscarinic compound Lu 25-109 on isolated human and pig detrusor.
The aim of this study was to evaluate the effects of a novel antimuscarinic agent, Lu 25-109, a partial M1 receptor agonist, and M2/M3 receptor antagonist in human and pig detrusor to establish its affinity for muscarinic receptors in human detrusor and parotid gland and to compare the results with those obtained with oxybutynin. Effects on the detrusor were determined as regards the ability to inhibit carbachol-induced contractions and contractions induced by electrical field stimulation (EFS). Radioligand binding studies were performed to assess the ability to displace quinuclidinyl benzilate (3H-QNB) from muscarinic receptors in the detrusor and parotid gland. Lu 25-109 produced a concentration-dependent rightward shift of the concentration-response curves for carbachol in both human and pig detrusor, the pK(b) values being 6.2+/-0.1 (n=6) and 5.8+/-0.3 (n=6). Corresponding values for oxybutynin were 7.9+/-0.1 (n=7) and 7.8+/-0.1 (n=6). Contractions induced by EFS in human detrusor were almost completely inhibited by 100 micromol/L Lu 25-109 (84+/-4%; n=4). In contrast, EFS-induced contractions in pig detrusor were less sensitive to Lu 25-109, resulting in a final inhibition of 32+/-6% (n=9) with the highest concentration used (100 micromol/L). This difference in effect between human and pig detrusor was not observed with oxybutynin. Radioligand binding experiments demonstrated a small difference in affinity for Lu 25-109 in the parotid gland compared with the bladder, the pKi values being 6.2+/-0.1 versus 6.5+/-0.1 (n=4). Corresponding values for oxybutynin were 8.5+/-0.1 versus 8.2+/-0.1 (n=4). The results show that Lu 25-109 competitively and effectively antagonizes carbachol-induced contractions and contractions induced by EFS in human detrusor muscle. Even if Lu 25-109 were less potent than oxybutynin, it has an effect profile that makes it of interest to test its ability to counteract bladder overactivity in humans.


Influence of nuclear data on uranium enrichment results obtained by XKalpha spectral region analysis.
During the recent international uranium exercise organized by the ESARDA NDA Working Group, several participants determined the uranium enrichment of samples using methods based on analysis of the XKalpha region of the uranium spectrum. For these methods, no calibration with known enrichment standards is required but accurate knowledge of nuclear data is needed. Despite this requirement, it appeared that during the exercise, four different sets of nuclear data were used by the participants. In view of this fact, it was decided to introduce these nuclear data sets into some computer codes in order to check their effects on the enrichment results. Two participants agreed to cooperate, and the main results of this test are presented here. It can be seen that three nuclear data sets, although different, give satisfactory results with no significant bias. Nevertheless, a more accurate characterization of X- and gamma-ray emission from 235U, 235U and their daughters appears necessary.


Marine bacterial sources of bioactive compounds.
Thousands of novel compounds have been isolated from various marine bacteria and tested for pharmacological properties, many of which are commercially available. Many more are being tested as potential bioactive compound at the preclinical and clinical stages. The growing interest in marine-derived antiviral compounds, along with the development of new technology in marine cultures and extraction, will significantly expedite the current exploration of the marine environment for compounds with significant pharmacological applications, which will continue to be a promising strategy and new trend for modern medicine. Marine actinomycetes and cyanobacteria are a prolific but underexploited source for the discovery of novel secondary metabolites.


Hierarchical star formation in the Magellanic Clouds with the VMC survey.
The VISTA Magellanic Clouds Survey (VMC) is a near-infrared survey of the Magellanic system. The VMC data has been exploited to detect and study statistically correlated young groups of stars - also known as "young stellar structures" - in the Large and Small Magellanic Clouds (LMC and SMC). We showcase the ~ 3000 recently detected young stellar structures in the LMC and their similarity to the fractal interstellar medium. We discuss how their properties indicate their formation mechanisms and that there are no preferred scales of star formation in the LMC.


Seasonal variability of airborne mold concentrations as related to dust in a coastal urban area in the Eastern Mediterranean.
Recent studies have demonstrated that the amount of specific airborne mold types and their concentrations increase during dust events. This study investigates the seasonal variation of airborne mold concentrations before, during, and after the dust transport in an eastern Mediterranean coastal area, Izmir city, Turkey. A total of 136 airborne mold samples were collected between September 2020 and May 2021. Two different culture media, namely Potato Dextrose Agar (PDA) and Malt-Extract Agar (MEA), were used for enumeration and genus-based identification of the airborne mold. In addition to culture media, the influences of air temperature, relative humidity, and particulate matter equal to or less than 10 µm (PM10) were also investigated seasonally. The HYSPLIT trajectory model and web-based simulation results were mainly used to determine dusty days. The mean total mold concentrations (TMC) on dusty days (543 Colony Forming Unit (CFU)/m3 on PDA and 668 CFU/m3 on MEA) were approximately 2-2.5 times higher than those on non-dusty days (288 CFU/m3 on PDA and 254 CFU/m3 on MEA) for both culture media. TMC levels showed seasonal variations (p < 0.001), indicating that meteorological parameters influenced mold concentrations and compositions. Some mold genera, including Cladosporium sp., Chrysosporium sp., Aspergillus sp., Bipolaris sp., Alternaria sp., and yeast, were found higher during dusty days than non-dusty days. Thus, dust event impacts levels and types of airborne molds and has implications for regions where long-range dust transport widely occurs.


Protein kinase activity and ribosome phosphorylation in ethionine-treated rats.
The regulation of protein synthesis at the level of the ribosome was investigated using the model system of ethionine-induced inhibition of protein synthesis. The phosphorylation of ribosomal protein S6 was examined in vivo during ethionine intoxication and during the adenine-induced reversal of ethionine intoxication. The extent of phosphorylation of S6 correlated well with protein synthetic activity observed after ethionine, and ethionine followed by adenine treatments. No clear correlation was observed in the ethionine system between cyclic adenosine 3':5'-monophosphate concentration or the activity of ribosomal protein kinase and the phosphorylation of ribosomal protein S6. A role for a cyclic adenosine 3':5'-monophosphate-dependent ribosomal phosphoprotein phosphatase is postulated.


Management of Mental Health in Cystic Fibrosis.
This article is intended for use among all cystic fibrosis care team members. It covers common mental health concerns and their unique presentations in persons with cystic fibrosis (pwCF) in areas such as depression, anxiety, trauma, behavioral disorders emerging in childhood, sleep, problematic eating patterns, and the impact of substance use. Furthermore, the authors address ways to manage these mental health symptoms through risk assessment, psychological interventions, and/or psychotropic medications. Quick reference tables are provided for evidence-based psychological interventions and medications often used for mental health conditions in pwCF.


The association between admission for poisoning with paracetamol or other weak analgesics and subsequent admission for psychiatric disorder: a Danish nationwide case-control study.
Many cases of paracetamol poisoning are with suicidal intent, but the association between paracetamol poisoning and subsequent psychiatric disorder is unknown. To examine the association between poisoning with paracetamol or other weak analgesics and subsequent psychiatric disorder. The study was set in a nested case-control design and based on nationwide Danish registers. We identified all patients diagnosed with schizophrenia, affective disorder or eating disorder in 1994-1998 and matched population controls. We estimated the relative risk of these psychiatric disorders after admission for paracetamol or nonparacetamol poisoning, adjusting for income, employment and marital status. We included 12,603 cases with psychiatric disorder, and 1.2% had a diagnosis of poisoning compared with 0.2% of the 252,060 matched population controls. Compared with those with no diagnoses of weak analgesic poisoning, the risk of schizophrenia increased 3.9-fold after paracetamol poisoning, and 2.0-fold after nonparacetamol poisoning. The risk of affective disorder increased 12.2-fold after paracetamol poisoning and 2.6-fold after nonparacetamol poisoning. The risk of eating disorder increased 5.0-fold after paracetamol poisoning, and 2.2-fold after nonparacetamol poisoning. The risk of a diagnosis of psychiatric disorder was very high immediately after poisoning and remained increased for more than 10 years. Paracetamol poisoning is a strong risk marker for psychiatric disorder, particularly affective disorders.


Chiasmal syndrome caused by pituitary-sellar disproportion.
A patient with pituitary-sellar disproportion, a perichiasmal visual field defect, and no clinically demonstrable endocrinopathy is presented. Radiographic and pathologic studies suggested that the pituitary-sellar disproportion was secondary to sellar hypoplasia, a previously unrecognized cause of the chiasmal syndrome. It remains to be seen whether hormonal manipulation aimed at suppression of gonadotropin- and/or prolactin-secreting cells might obviate the need for exploration in patients similar to ours.


Pre-procambial cells are niches for pluripotent and totipotent stem-like cells for organogenesis and somatic embryogenesis in the peach palm: a histological study.
The direct induction of adventitious buds and somatic embryos from explants is a morphogenetic process that is under the influence of exogenous plant growth regulators and its interactions with endogenous phytohormones. We performed an in vitro histological analysis in peach palm (Bactris gasipaes Kunth) shoot apexes and determined that the positioning of competent cells and their interaction with neighboring cells, under the influence of combinations of exogenously applied growth regulators (NAA/BAP and NAA/TDZ), allows the pre-procambial cells (PPCs) to act in different morphogenic pathways to establish niche competent cells. It is likely that there has been a habituation phenomenon during the regeneration and development of the microplants. This includes promoting the tillering of primary or secondary buds due to culturing in the absence of NAA/BAP or NAA/TDZ after a period in the presence of these growth regulators. Histological analyses determined that the adventitious roots were derived from the dedifferentiation of the parenchymal cells located in the basal region of the adventitious buds, with the establishment of rooting pole, due to an auxin gradient. Furthermore, histological and histochemical analyses allowed us to characterize how the PPCs provide niches for multipotent, pluripotent and totipotent stem-like cells for vascular differentiation, organogenesis and somatic embryogenesis in the peach palm. The histological and histochemical analyses also allowed us to detect the unicellular or multicellular origin of somatic embryogenesis. Therefore, our results indicate that the use of growth regulators in microplants can lead to habituation and to different morphogenic pathways leading to potential niche establishment, depending on the positioning of the competent cells and their interaction with neighboring cells. Our results indicate that the use of growth regulators in microplants can lead to habituation and to different morphogenic pathways leading to potential niche establishment, depending on the positioning of the competent cells and their interaction with neighboring cells.


A comprehensive comparison of cell seeding methods using highly porous melt electrowriting scaffolds.
Cell seeding is challenging in the case of additively manufactured 3-dimensional scaffolds, as the open macroscopic pore network impedes the retention of the seeding solution. The present study aimed at comparing several seeding conditions (no fetal bovine serum, 10% or 100% serum) and methods (Static seeding in Tissue Culture Treated plate (CT), Static seeding of the MES in non-Culture Treated plate (nCT), Seeding in nCT plate placed on an orbital shaker at 20 rpm (nCTR), Static seeding of the MES previously incubated with 100% FBS for 1 h to allow for protein adsorption (FBS)) commonly utilised in tissue engineering using highly porous melt electrowritten scaffolds, assessing their seeding efficacy, cell distribution homogeneity and reproducibility. Firstly, we demonstrated that the incubation in 100% serum was superior to the 10% serum pre-incubation and that 1 h only was sufficient to obtain enhanced cell attachment. We further compared this technique to the other methods and demonstrated significant and beneficial impact of the 100% serum pre-incubation, which resulted in enhanced efficacy, homogeneous cell distribution and high reproducibility, leading to accelerated colonisation/maturation of the tissue engineered constructs. We further showed the superior performance of this method using 3D-printed scaffolds also made of different polymers, demonstrating its capacity for up-scaling. Therefore, the pre-incubation of the scaffold in 100% serum is a simple yet highly effective method for enhancing cell adhesion and ensuring seeding reproducibility. This is crucial for tissue engineering applications, especially when cell availability is scarce, and for product standardisation from a translational perspective.


Surface charges associated with fenestrated brain capillaries. I. In vitro labeling of anionic sites.
Ferritin derivatives with different pI values and the basic dye ruthenium red have been used as cationic probes to localize anionic sites associated with fenestrated brain capillaries. Cationic ferritin was found in the endothelial basement membrane and the basement membrane of the perivascular cellular linings in amounts far exceeding those observed with anionic derivatives, the degree being greater for the more cationized ferritin molecules. Labeling of the luminal endothelial front with cationic ferritin was only achieved when a serum- or albumin-free medium was applied. Furthermore, the striated collagen fibers were coated with cationic ferritin molecules in a highly ordered fashion. Ruthenium red localized to the same sites. The findings suggest the existence of a perivascular charge filter around fenestrated capillaries of the brain. Some physiological roles of this filter are discussed, as related to its possible function in regulating homeostasis of cerebrospinal fluid.


Cellular cytotoxicity to membrane-associated insulin in an autologous system.
A method is described for the measurement of T-cell cytotoxicity to purified preparations of insulin, their high molecular weight fractions and C-peptide derivatives. The technique assesses cellular cytotoxicity to membrane associated insulin in an autologous system. Peripheral blood lymphocytes from 19 type 1 diabetic patients were stimulated in vitro for 6 days with the pharmaceutical preparation(s) used therapeutically. At the end of this period, they were set up in a 4-h cytotoxicity assay against 51Cr labelled PHA blast transformed lymphocytes in the presence of therapeutic insulin, monocomponent insulin, B-component or C-peptide. The results presented here demonstrate cytotoxicity to insulin B-component in diabetic patients who have received pork insulin for 2-6 years. The possible reasons for this finding are discussed.


Computer Simulation Modeling for Recreation Management: A Study on Carriage Road Use in Acadia National Park, Maine, USA.
/ The number of visits to outdoor recreation areas has increased dramatically in the last three decades, leading managers and researchers to wonder if there is a limit to the amount of use a resource such as a park can accommodate. One of the difficulties in addressing this carrying capacity-related question has been the complex nature of visitor travel patterns on often extensive networks of roads and trails. Systematic direct observation is often impractical and anecdotal information is usually inadequate. This study explores the utility of computer simulation as a tool for describing visitor travel by building a dynamic model of visitor travel on the carriage roads of Acadia National Park, Maine, USA. The simulation model uses empirical inputs such as travel routes and travel speeds to generate simulated recreation days on the carriage roads. Data on persons-per-viewscape (PPV) conditions were then gathered from multiple model runs and incorporated into the National Park Service's visitor experience and resource protection (VERP) planning process. Results show that PPV conditions under present-day use levels do not violate proposed standards of quality. Results also show likely PPV conditions under scenarios of increasing use and in different areas within the carriage road system. Goodness-of-fit validity tests indicate the model is an accurate representation of the actual system. The findings of this study suggest that computer simulation is useful for estimating current carrying capacity conditions, predicting future conditions, and guiding related research. KEY WORDS: Computer simulation modeling; Carrying capacity; Recreation management; Acadia National Park


Arf6-driven endocytic recycling of CD147 determines HCC malignant phenotypes.
Adhesion molecules distributed on the cell-surface depends upon their dynamic trafficking that plays an important role during cancer progression. ADP-ribosylation factor 6 (Arf6) is a master regulator of membrane trafficking. CD147, a tumor-related adhesive protein, can promote the invasion of liver cancer. However, the role of Arf6 in CD147 trafficking and its contribution to liver cancer progression remain unclear. Stable liver cancer cell lines with Arf6 silencing and over-expression were established. Confocal imaging, flow cytometry, biotinylation and endomembrane isolation were used to detect CD147 uptake and recycling. GST-pull down, gelatin zymography, immunofluorescence, cell adhesion, aggregation and tight junction formation, Transwell migration, and invasion assays were used to examine the cellular phenotypes. GEPIA bioinformatics, patient's specimens and electronic records collection, and immunohistochemistry were performed to obtain the clinical relevance for Arf6-CD147 signaling. We found that the endocytic recycling of CD147 in liver cancer cells was controlled by Arf6 through concurrent Rab5 and Rab22 activation. Disruption of Arf6-mediated CD147 trafficking reduced the cell-matrix and cell-cell adhesion, weakened cell aggregation and junction stability, attenuated MMPs secretion and cytoskeleton reorganization, impaired HGF-stimulated Rac1 activation, and markedly decreased the migration and invasion of liver cancer cells. Moreover, high-expression of the Arf6-CD147 signaling components in HCC (hepatocellular carcinoma) was closely correlated with poor clinical outcome of patients. Our results revealed that Arf6-mediated CD147 endocytic recycling is required for the malignant phenotypes of liver cancer. The Arf6-driven signaling machinery provides excellent biomarkers or therapeutic targets for the prevention of liver cancer.


Microcystin-LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase.
Microcystin-LR (MC-LR) is a cyanobacteria-derived heptapeptide that has been commonly characterized as a hepatotoxin. Although the liver is a primary organ in glucose homeostasis, the effect of MC-LR on glucose metabolism remains unclear. In this study, the human liver cell line HL7702 and ICR mice were exposed to various concentrations of MC-LR for 24 h, and the proteins involved in insulin signaling were investigated. The results showed that MC-LR treatment induced the hyperphosphorylation of insulin receptor substrate 1 (IRS1) at several serine sites, S307, S323, S636/639, and S1101 in HL7702 cells, and S302, S318, S632/635, and S1097 in mice livers. In addition, the activation of S6K1 was demonstrated to play an important role in MC-LR-induced IRS1 hyperphosphorylation at several serine sites. Decreased levels of total IRS1 were observed in the mice livers, but there was no significant change in HL7702 cells. MC-LR also induced glycogen synthase (GS) hyperphosphorylation at S641 (inactivating GS) both in vitro and in vivo, even glycogen synthase kinase 3, a well-known GS kinase, was inactivated after MC-LR treatment. Moreover, MC-LR could block insulin-induced GS activation. In addition, glucose transport in liver cells was not impacted by MC-LR either with or without insulin stimulation. Our study implies that MC-LR can interfere with the actions of IRS1 and GS in insulin signaling and may have a toxic effect on glucose metabolism in the liver.


Reprogrammable Graphene-based Metasurface Mirror with Adaptive Focal Point for THz Imaging.
Recent emergence of metasurfaces has enabled the development of ultra-thin flat optical components through different wavefront shaping techniques at various wavelengths. However, due to the non-adaptive nature of conventional metasurfaces, the focal point of the resulting optics needs to be fixed at the design stage, thus severely limiting its reconfigurability and applicability. In this paper, we aim to overcome such constraint by presenting a flat reflective component that can be reprogrammed to focus terahertz waves at a desired point in the near-field region. To this end, we first propose a graphene-based unit cell with phase reconfigurability, and then employ the coding metasurface approach to draw the phase profile required to set the focus on the target point. Our results show that the proposed component can operate close to the diffraction limit with high focusing range and low focusing error. We also demonstrate that, through appropriate automation, the reprogrammability of the metamirror could be leveraged to develop compact terahertz scanning and imaging systems, as well as novel reconfigurable components for terahertz wireless communications.


Relative Age Within School Grade, Including Delayed and Accelerated School Start: Associations With Midlife Psychiatric Disorders, Suicide, and Alcohol- and Drug-Related Mortality.
Within a school grade, children who are young for grade are at increased risk of psychiatric diagnoses, but the long-term implications remain understudied, and associations with students who delay or accelerate entry underexplored. We used Norwegian birth cohort records (birth years: 1967-1976, n = 626,928) linked to records in midlife. On-time school entry was socially patterned; among those born in December, 23.0% of children in the lowest socioeconomic position (SEP) delayed school entry, compared with 12.2% among the highest SEP. Among those who started school on time, there was no evidence for long-term associations between birth month and psychiatric/behavioral disorders or mortality. Controlling for SEP and other confounders, delayed school entry was associated with increased risk of psychiatric disorders and mortality. Children with delayed school entry were 1.31 times more likely to die by suicide (95% confidence interval: 1.07, 1.61) by midlife, and 1.96 times more likely to die from drug-related death (95% confidence interval: 1.59, 2.40) by midlife than those born late in the year who started school on time. Associations with delayed school entry are likely due to selection, and results thus underscore that long-term health risks can be tracked early in life, including through school entry timing, and are highly socially patterned.


[Anterolateral thigh flaps for reconstruction of traumatological and oncological defects].
The anterolateral thigh flap (ALT) has become one of the most preferred options for soft tissue defect reconstruction in Asia with an increasing popularity in Europe. The article presents the authors' experience using the ALT flap for various indications in the upper and lower extremities. Between January 2005 and March 2007, 60 free ALT flaps were operated for reconstruction of various soft tissue defects. The causes of soft tissue defects included trauma (13), infection (26), and sarcoma resection (21). We operated on 39 male and 19 female patients with an average age of 50.9 years (range: 16-84 years). The flap survival rate was 95.0% percent (57 of 60 flaps); 5% of the flaps died. The donor site was closed primarily in all cases. Donor site complications were minimal. The average operative time was 282 min (69-544 min). Flap-related major complications occurred in 35.0% of patients including reexploration of the anastomoses and partial flap necrosis. Minor complications, e.g., wound infection, hematoma, and swelling were seen in 23 cases. Our experience indicates that the free ALT flap is a reliable method for soft tissue defect reconstruction. The use of the ALT offers many advantages such as a long and large caliber vascular pedicle, a large skin island as well as minimal donor site morbidity. The surgery can simultaneously performed by two teams with the patient in a supine position.


Evaluate the role of biochar during the organic waste composting process: A critical review.
Composting is very robust and efficient for the biodegradation of organic waste; however secondary pollutants, namely greenhouse gases (GHGs) and odorous emissions, are environmental concerns during this process. Biochar addition to compost has attracted the interest of scientists with a lot of publication in recent years because it has addressed this matter and enhanced the quality of compost mixture. This review aims to evaluate the role of biochar during organic waste composting and identify the gaps of knowledge in this field. Moreover, the research direction to fill knowledge gaps was proposed and highlighted. Results demonstrated the commonly referenced conditions during composting mixed biochar should be reached such as pH (6.5-7.5), moisture (50-60%), initial C/N ratio (20-25:1), biochar doses (1-20% w/w), improved oxygen content availability, enhanced the performance and humification, accelerating organic matter decomposition through faster microbial growth. Biochar significantly decreased GHGs and odorous emissions by adding a 5-10% dosage range due to its larger surface area and porosity. On the other hand, with high exchange capacity and interaction with organic matters, biochar enhanced the composting performance humification (e.g., formation humic and fulvic acid). Biochar could extend the thermophilic phase of composting, reduce the pH value, NH3 emission, and prevent nitrogen losses through positive effects to nitrifying bacteria. The surfaces of the biochar particles are partly attributed to the presence of functional groups such as Si-O-Si, OH, COOH, CO, C-O, N for high cation exchange capacity and adsorption. Adding biochars could decrease NH3 emissions in the highest range up to 98%, the removal efficiency of CH4 emissions has been reported with a wide range greater than 80%. Biochar could absorb volatile organic compounds (VOCs) more than 50% in the experiment based on distribution mechanisms and surface adsorption and efficient reduction in metal bioaccessibilities for Pb, Ni, Cu, Zn, As, Cr and Cd. By applicating biochar improved the compost maturity by promoting enzymatic activity and germination index (>80%). However, physico-chemical properties of biochar such as particle size, pore size, pore volume should be clarified and its influence on the composting process evaluated in further studies.


Electrochemical synthesis of reduced graphene sheet-AuPd alloy nanoparticle composites for enzymatic biosensing.
A simple, fast, green and controllable approach was developed for electrochemical synthesis of a novel nanocomposite of electrochemically reduced graphene oxide (ERGO) and gold-palladium (1:1) bimetallic nanoparticles (AuPdNPs), without the aid of any reducing reagent. The electrochemical reduction efficiently removed oxygen-containing groups in ERGO, which was then modified with homogeneously dispersed AuPdNPs in a good size distribution. ERGO-AuPdNPs nanocomposite showed excellent biocompatibility, enhanced electron transfer kinetics and large electroactive surface area, and were highly sensitive and stable towards oxygen reduction. A biosensor was constructed by immobilizing glucose oxidase as a model enzyme on the nanocomposites for glucose detection through oxygen consumption during the enzymatic reaction. The biosensor had a detection limit of 6.9μM, a linear range up to 3.5mM and a sensitivity of 266.6μAmM(-1)cm(-2). It exhibited acceptable reproducibility and good accuracy with negligible interferences from common oxidizable interfering species. These characteristics make ERGO-AuPdNPs nanocomposite highly suitable for oxidase-based biosensing.


Conditional power calculations as an aid in the decision whether to continue a clinical trial.
It is shown how stochastically curtailed testing can be included in the process of deciding whether to continue a clinical trial in which survival times or times to some other event in two treatment arms are compared. A model with constant intensities is used. One examines the power function of the test which would be computed if the trial were prolonged, conditional on the course of the trial up to the time of decision.


Complete Genome of African Swine Fever Virus Genotype II in Central Italy.
We report here the whole-genome sequence of the African swine fever virus (ASFV) genotype II, strain 20355/RM/2022_Italy, identified in a wild boar in the city of Rome (Lazio region, Italy) in April 2022.


Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas.
The Wnt signaling pathway is an important cellular mechanism for regulating differentiation processes as well as cell cycle events, and different inhibitors of this pathway, for example, PRI-724, are showing promising results in clinical trials for treatment of advanced pancreatic adenocarcinoma or ovarian cancer. Growing evidence suggests that Wnt signaling may also be crucial for tumorigenesis and progression of soft tissue sarcomas (STS), a malignant neoplasm with few therapeutic options at an advanced state. Our study with several STS cell lines and primary cultures shows that inhibition of Wnt/β-catenin signaling with PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates. TCF/β-catenin-mediated transcriptional activity is decreased in treated cells, leading to downregulation of its target genes CCND1 and CDC25A. The latter was critical because its downregulation via siRNA was able to mimic the effect of PRI-724 on cell cycle arrest and cell death induction. An evaluation of NCBI/GenBank data confirmed that CDC25A mRNA is elevated in STS patients. Importantly, PRI-724 in combination with standard STS chemotherapeutics doxorubicin or trabectedin enhanced their antitumoral effect in a synergistic manner according to isobolographic analysis, suggesting that Wnt inhibition through PRI-724 could be a beneficial combination regime in patients with advanced STS.


Psychiatric Medication, African Americans and the Paradox of Mistrust.
To examine race differences in how generalized mistrust, mistrust in physicians, and mistrust in psychiatric medication shape the willingness to utilize psychiatric medication. Data was used from two waves (1998 and 2006) of the U.S. General Social Survey a representative sample of non-institutionalized Americans. We analyzed data for 343 African American and 1,920 white adults, ages 18-89. The data included measures of the respondents' willingness to utilize psychiatric medication as well as measures of generalized mistrust, mistrust in physicians, and mistrust in psychiatric medication. We employed ordinary least squares regression to test whether these three forms of mistrust reduce the black-white gap in psychiatric drug usage and whether race moderates the association between any type of mistrust and the willingness to endorse psychiatric medication utilization. Mistrust in physicians and psychiatric medication is related to less willingness to utilize psychiatric medicines for both African Americans and whites; however, paradoxically, these forms of mistrust decrease psychiatric drug usage more steeply for whites. The pattern of findings in this study suggests that trust or low levels of mistrust, rather than high levels of mistrust, actually maintains the black-white difference in the use of psychiatric medication.


Host plant predictability and the feeding patterns of monophagous, oligophagous, and polyphagous insect herbivores.
Host plant preferences for 34 insect herbivore species are reported. Most polyphagous herbivores feeding on annuals, herbaceous perennials, and woody perennials show distinct preferences for the least abundant plant species among their various host plants. In addition, some populations of widely distributed polyphagous species are much more specialized in their diet than host plant lists alone would suggest. The high level of polyphagy on annuals and herbaceous perennials is suggested to be strongly influenced by the unpredictability of the host plant that is, in turn, controlled by environmental variability. Oligophagous herbivores preferred the least abundant woody perennials on the study sites. Ten of the 22 monophagous herbivores preferred the rarest of all the plant species on the same sites.


Acceptability of dementia screening in primary care patients.
To determine the acceptability of dementia screening in two populations of older adults in different primary care settings. Cross-sectional study of consecutive patients presenting for primary care appointments in the Duke University Health System (n = 152) or Durham VA Medical Center (n = 193) were evaluated face to face using the Dementia Screening and Perceived Harms (SAPH) questionnaire. Overall, 81% of primary care patients indicated that they would want to be screened to determine if they are developing dementia. After exposure to possible risks and benefits of screening, 86% of patients indicated they would like to be screened. The SAPH was easy to use and contained five relevant and cohesive domains. The items most associated with a desire for dementia screening were male gender, acceptance of other types of screening, and a belief that a treatment for dementia exists. Primary care patients in two different health care systems indicated they would like to be screened for dementia. The SAPH was easy to use and contains cohesive domains.


Measurement of incident position of hypervelocity particles on piezoelectric lead zirconate titanate detector.
A cosmic dust detector for use onboard a satellite is currently being developed by using piezoelectric lead zirconate titanate (PZT). The characteristics of the PZT detector have been studied by bombarding it with hypervelocity iron (Fe) particles supplied by a Van de Graaff accelerator. One central electrode and four peripheral electrodes were placed on the front surface of the PZT detector to measure the impact positions of the incident Fe particles. It was demonstrated that the point of impact on the PZT detector could be identified by using information on the time at which the first peak of the output signal obtained from each electrode appeared.


Surgical treatment of acute aortic dissection in a patient with SLE and prior antiphospholipid syndrome on therapy for over 30 years: a case report.
In patients with systemic lupus erythematosus (SLE), lengthy treatment and long-term steroid use are the main risk factors for developing aortic aneurysms or aortic dissections. In patients with cardiac tamponade, hemodynamic collapse may lead to acute renal and hepatic failure. We report the successful treatment of a 55-year-old woman with SLE since the age of 21. She suddenly felt chest pain approximately 2 weeks before developing fever and vomiting and was admitted to our hospital. Initially, she had severe liver dysfunction and was admitted to the hepatology department, where treatment for fulminant hepatitis was initiated. However, computed tomography (CT) showed an acute aortic dissection (DeBakey type II) and severe bloody pericardial effusion. Therefore, we performed emergency pericardial drainage. Plasma exchange therapy was initiated as emergency aortic surgery was deemed impossible due to impaired liver function tests and coagulation. Ten days later, the patient developed peritonitis due to small bowel perforation, and laparotomy was performed for abscess drainage and perforation closure. She had received steroid pulse therapy at the age of 21. At 40 years of age, she developed deep vein thrombosis due to antiphospholipid antibodies and was prescribed prednisolone. She was ambulatory at 3 months after the onset of acute aortic dissection, and CT revealed a rapidly enlarging true aneurysm in the distal arch. We performed elective aortic surgery. Although there were no antiphospholipid antibodies, surgery could have led to a devastating antiphospholipid syndrome. Therefore, we decided to treat the patient with triple therapy. Methylprednisolone was intravenously administered intraoperatively and at 1 day postoperatively. The patient was discharged without complications after returning to her usual oral prednisolone regimen. The patient described herein had a systemic circulatory failure due to cardiac tamponade, accompanied by liver failure. This condition is a significant cause of death in patients with aortic dissection-associated SLE and is extremely dangerous. However, multi-specialty intervention helped the patient recover, and she has been attending the outpatient clinic. Aortic surgery requiring hypothermia in SLE patients with antiphospholipid syndrome and a history of thrombocytopenia or thrombosis requires a multi-disciplinary treatment team, including cardiac surgeons and medical experts.


Association of trainee involvement in an acute pain service with postoperative opioid use in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
Several hospitals have implemented a multidisciplinary Acute Pain Service (APS) to execute surgery-specific opioid sparing analgesic pathways. Implementation of an anesthesia attending-only APS has been associated with decreased postoperative opioid consumption, time to ambulation, and time to solid food intake for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. In this study, we evaluated the impact of introducing an APS trainee on postoperative opioid consumption in patients undergoing hyperthermic intraperitoneal chemotherapy during POD 0-3. We performed a retrospective propensity-matched cohort study where we compared opioid consumption and hospital length of stay among two historical cohorts: attending-only APS service versus service involving a regional anesthesia fellow. In the matched cohorts, the median postoperative day (POD) 0-3 opioid use [25%, 75% quartile] for the single attending and trainee involvement cohort were 38.5 mg morphine equivalents (MEQ) [14.1 mg, 106.3 mg] and 50.4 mg MEQ [28.4 mg, 91.2 mg], respectively. The median difference was -9.8 mg MEQ (95% CI -30.7-16.5 mg; P = 0.43). There was no difference in hospital length of stay between both cohorts (P = 0.67). We found that the addition of a regional anesthesia fellow to the APS team was not associated with statistically significant differences in total opioid consumption or hospital length of stay in this surgical population. The addition of trainees to the infrastructure, with vigilant supervision, is not associated with change in outcomes.


Masking disrupts recovery of location information.
In two experiments, we tested subjects' ability to localize a letter in a character string with identification controlled by varying the delay of a mask, dimming the display, or deleting some of the dots used to define the letters on the cathode-ray screen. The first experiment involved two tasks. In the first task, subjects indicated whether or not a letter named verbally had been present in an eight-letter target string. In the second task, they localized a letter named verbally in the target string; the target string was presented by using display parameters shown in the first task to hold character identification between 70% and 75% correct. In the second experiment, we tallied errors in a partial-report bar-probe study after equating performance across the manipulations of display quality. Masking disrupted subjects' ability to recover location information more than either a manipulation of stimulus luminance or a manipulation of its visual form.


In vivo anticlastogenic effects of L-ascorbic acid in mice.
The effects of l-ascorbic acid on the frequency of micronuclei induced by model mutagens, cyclophosphamide (CP), mitomycin-C (MMC) and bleomycin (BLM) hydrochloride were tested using mouse bone marrow. Three doses of ascorbic acid (AsA) viz., 10, 30 and 60 mg/kg b.w. were tested for anticlastogenic effects. The doses of positive mutagens used were, CP-50 mg/kg, MMC-4 mg/kg and BLM-20 mg/kg b.w. Bone marrow sampling was done at 24 h after the treatment. AsA was found to be effective in reducing MN frequency induced by CP and BLM. With MMC only, the highest dose showed a slight inhibitory effect.


Whole-brain death and integration: realigning the ontological concept with clinical diagnostic tests.
For decades, physicians, philosophers, theologians, lawyers, and the public considered brain death a settled issue. However, a series of recent cases in which individuals were declared brain dead yet physiologically maintained for prolonged periods of time has challenged the status quo. This signals a need for deeper reflection and reexamination of the underlying philosophical, scientific, and clinical issues at stake in defining death. In this paper, I consider four levels of philosophical inquiry regarding death: the ontological basis, actual states of affairs, epistemological standards, and clinical criteria for brain death. I outline several candidates for the states of affairs that may constitute death, arguing that we should strive for a single, unified ontological definition of death as a loss of integrated functioning as a unified organism, while acknowledging that two states of affairs (cardiopulmonary death and whole-brain death) may satisfy this concept. I argue that the clinical criteria for determining whole-brain death should be bolstered to meet the epistemic demand of sufficient certainty in defining death by adding indicators of cerebro-somatic dis-integration to the traditional triad of loss of consciousness, loss of brainstem function, and absence of confounding explanations.


Photoaffinity labeling of uncoupler binding sites on mitochondrial membrane.
3H 2-azido-4-nitrophenol, a photoactive uncoupler, has been synthesized, and its uncoupling action on oxidative phosphorylation and its binding to the mitochondrial membrane have been studied. The uncoupler bound covalently to the mitochondrial membrane on photoirradiation was 3-4 times that bound reversibly in the absence of light. When irradiation was carried out in the presence of serum albumin, covalent binding was significantly depressed. The pattern of loss of ATP-Pi exchange activity with increasing amounts of the uncoupler suggests that serum albumin prevents the binding of the uncoupler to the functional sites as well. Polyacrylamide gel electrophoresis of photoaffinity labeled submitochondrial particles in the presence of sodium dodecyl sulfate revealed that a 9000 dalton peptide bound high levels of uncoupler. Other proteins in the molecular weight range of 20,000-40,000 and 55,000 were also labeled. Photolysis in the presence of serum albumin or ATP decreased the covalent binding of the uncoupler to all the proteins, but particularly to the 20,000 dalton component. Soluble ATPase and the mitochondrial proteolipid purified from labeled mitochondria showed the presence of label.


Low night temperature effect on photosynthate translocation of two C4 grasses.
Translocation of assimilates in plants of Echinochloa crus-galli, from Quebec and Mississippi, and of Eleusine indica from Mississippi was monitored, before and after night chilling, using radioactive tracing with the short-life isotope 11C. Plants were grown at 28°/22°C (day/night temperatures) under either 350 or 675 μl·l-1 CO2. Low night temperature reduced translocation mainly by increasing the turn-over times of the export pool. E. crus-galli plants from Mississippi were the most susceptible to chilling; translocation being completely inhibited by exposure for one night to 7°C at 350 μl·l-1 CO2. Overall, plants from Quebec were the most tolerant to chilling-stress. For plants of all three populations, growth under CO2 enrichment resulted in higher 11C activity in the leaf phloem. High CO2 concentrations also seemed to buffer the transport system against chilling injuries.


The differential diagnosis of anxiety. Psychiatric and medical disorders.
This article has reviewed clinical and demographic features of the primary anxiety disorders and other psychiatric and medical disorders that often are associated with anxiety symptoms, highlighting differential diagnosis. In summary, phobic disorders (exogenous anxiety) are characterized by anxiety reliably elicited by specific environmental stimuli; the stimuli involved determine which type of phobia is diagnosed. In contrast, panic attacks and generalized anxiety (endogenous anxiety) involve symptoms of anxiety not associated only with specific eliciting stimuli. Panic disorder is differentiated from generalized anxiety disorder by the presence of discrete attacks; both disorders usually have some level of persistent anxiety. Obsessive-compulsive disorder is characterized by recurrent unwanted but irresistible thoughts and the ritualized repetitive acts resulting from these obsessions, in the absence of preexisting psychosis or depression. Finally, posttraumatic stress disorder involves various anxiety (and other) symptoms as a direct result of an obvious stressor. Depressive symptoms are frequently associated with anxiety. It is sometimes impossible to determine which is the primary disorder. Overlap of syndromes probably also occurs with other primary psychiatric disorders, especially somatoform disorders, adjustment disorder with anxious mood, and several personality disorders. Finally, primary anxiety can be confused with several medical syndromes, especially when the medical disorder has not been recognized. Nevertheless, research with patients with pheochromocytoma suggests that medical causes of anxiety may be qualitatively different from primary anxiety disorders, especially the psychic anxiety component. Attention to the clinical and demographic features listed in Table 4, as well as the use of newly-developed structured diagnostic interviews should usually lead to a correct diagnosis, as illustrated by the following examples. The onset of a fear of public speaking in mid-adolescence suggests an uncomplicated social phobia, whereas the onset in the mid-twenties of several social and other situational anxieties in a person with a previous history of panic attacks would be strongly suggestive of the panic-agoraphobia syndrome. The new onset of generalized anxiety symptoms and depression in a 45-year-old patient who has had a previous significant depression would suggest that this person's anxiety is part of, and secondary to, the affective disorder and not a primary anxiety disorder.(ABSTRACT TRUNCATED AT 400 WORDS)


Post-traumatic stress disorder among people exposed to the Ventotene street disaster in Rome.
To test five hypotheses on Post-traumatic stress disorder (PTSD): 1) Is PTSD the most prevalent disorder after trauma? 2) Is the proximity to the disaster related to the risk of PTSD? 3) Is PTSD associated with child mourning or separation, previous stress, or familiarity for psychiatric disorders? 4) Does the exposition to trauma increase substance abuse or somatization? 5) Can episodic trauma cause long-lasting psychiatric morbidity? Clinical assessment of subjects exposed to an explosion in a building caused by a gas-leak. Best estimate clinical diagnoses were made according to DSM-IV-TR criteria. The Zung Depression Rating Scale, the Zung Anxiety Rating Scale, and the Clinician Administered Post Traumatic Stress Disorder Scale were used in the clinical assessment. Statistical analysis was performed by means of t-test with Bonferroni's correction on continuous variables and chi2 or Fisher test on categorical variables. PTSD was the most prevalent disorder after trauma, diagnosed in 32 (36.8%) subjects. The subjects who had not seen dead or injured people were more likely to receive no psychiatric diagnosis. Civil status, parenthood, death of relatives in the disaster, personal injuries, history of child mourning or separation, of previous stress, as well as familiarity for any psychiatric disorder or substance use disorder were not related with the rate of ascertained psychiatric diagnoses. Nearly two years after trauma, most of patients who had suffered PTSD still met PTSD criteria. The 1st and the 5th hypotheses were corroborated, the 3rd and the 4th hypotheses were not confirmed. The 2nd hypothesis was partially confirmed.


Magnitude of surgical site infection and determinant factors among postoperative patients, A cross sectional study.
Surgical site infections (SSIs) are infections that occur within 30 days of surgery or within 1 year in patients with implants at or around the surgical site. They are among the dangerous complications of surgical procedures that expose patients to higher costs and increase the risk of death because of severe morbidity and associated longer hospital stays. This study aimed to determine the extent and determinants of surgical site infections in surgically treated cases during the study period. A hospital-based cross-sectional study was conducted among surgically treated patients at Dilla University Referral Hospital in the surgical department. The calculated sample size was 408, calculated using the single population proportion formula, and the required information was collected from the medical records of the study participants using checklists. Bivariate logistic regression was performed to identify candidate variables, and all candidate variables with a P-value < of 0.25 were included in multivariable logistic regression. Variables with a P-value < 0.05 were considered statically significant, and the strength of association was measured by odds ratio (OR) with 95% confidence intervals (CIs). As our finding showed magnitude of surgical site infections was 19.3%. The factors which had significant association with surgical wound infections were blood transfusion (AOR = 0.16 (0.04-0.73), hemoglobin level < 7 g/dl (AOR = 10.40 (3.39-32.49), shock (AOR = 19.09 (4.69-77.51), previous surgery (AOR = 11.53(3.73-35.61), hospitalization 7-14 days (AOR = 5.51(1.52-19.91) and hospitalization >14 days (AOR = 8.18(1.84-36.75). The percentage of surgical site infections was high. Shock, low haemoglobin level, blood transfusion, previous surgery, and longer length of hospital stay were significantly related to surgical site infections.


Risk factors of lymph node metastasis in 734 early gastric carcinoma radical resections in a Chinese population.
To investigate the risk factors of lymph node metastasis (LNM) in early gastric carcinoma (EGC) in a Chinese population. The data were analyzed to determine risk factors of LNM. The patients' characteristics, the tumor's location, gross features, histological type, differentiation, invasive depth, lymphovascular invasion (LVI), perineural invasion and the numbers of lymph nodes retrieved and involved were statistically analyzed. A total of 734 patients with EGC were finally enrolled in the study, and LNM was present in 14.2% (104/734) of them. By univariate analysis, significant risk factors for LNM included depressed or excavated gross patterns, size ≥1.0 cm, SM2, moderate/poor differentiation, histological type of hepatoid or micropapillary adenocarcinoma, LVI, perineural invasion and tumor necrosis. By multivariate analysis, independent risk factors for LNM were size ≥3.0 cm (odds ratio [OR] 4.9), SM2 (OR 2.4), moderate (OR 3.6) and poor (OR 5.0) differentiation, LVI (OR 3.1) and tumor necrosis (OR 1.7). Early gastric cardiac carcinoma (OR 0.3) had a significantly lower risk than non-cardiac carcinoma. No LNM was identified in 67 EGC of <1.0 cm in size and without poor differentiation, in 142 intramucosal EGC cases of smaller than 2.0 cm and without poor differentiation, in 129 cases of well-differentiated EGC without deep SM2 submucosal invasion, or in 54 intramucosal EGC located in the gastric cardia. Independent risk factors for LNM in EGC include tumor size ≥3.0 cm, SM2 invasion, moderate/poor differentiation, LVI and tumor necrosis. Early cardiac carcinoma had a significantly lower risk of LNM than non-cardiac EGC.


Prenatal diagnosis of Bardet Biedl Syndrome: A case report.
The Bardet-Biedl Syndrome (BBS), also called Laurence-Moon-Bardet-Biedl syndrome is a rare ciliopathic autosomal recessive genetic defect. BBS phenotype develops over the years and diagnosis is usually made in late childhood or early adulthood. Prenatal diagnosis is rare in absence of family history or consanguinity. The major features of this syndrome are cone-rod dystrophy, obesity, polydactyly, learning disabilities, hypogonadism in males, renal anomalies, nystagmus, speech disorders, developmental delay and ataxia. At least 20 BBS genes have been identified and all are involved in primary cilia functioning. Genetic diagnosis includes multigene sequencing technologies. Clinical management includes symptomatic treatment. In our case report, we present a case of a baby born to parents of Bengali Asian ancestry with high clinical suspicion of BBS based on fetal magnetic resonance imaging findings done during antepartum surveillance.


Tracking errors related to cardiac cycle: a new approach.
One-dimensional manual tracking was investigated in relation to cardiac activity. The task of the subjects was, by means of a joy-stick, to maintain a spotlight between two vertical lines moving horizontally across an oscilloscope screen. Error incidence was time-locked with respect to the cardiac cycle. Error rate was higher for faster (2-s trial periods) than for slower (3-s trial periods) target movement. Using linear-ramp and sinusoidal movements, it was demonstrated that error incidence is associated with positive and negative cardiac acceleration.


Perioperative antibiotic use in vagus nerve stimulator implantation: a clinical series.
Preoperative antibiosis contributes up to one third of total antibiotic use in major hospitals. Choice of antibiotic is not uniformly standardized, and polypharmacy regimens may be used without knowing the effect on rates of surgical site infection, nonsurgical infections, or antibiotic resistance. Careful examination of trends in surgical prophylaxis is warranted. In this study, we aimed to examine our institution's experience with vagus nerve stimulator (VNS) implantation, focusing on association between perioperative antibiotic practices and postoperative infectious outcomes. We conducted a single-center case-control study using a retrospective chart review of 50 consecutively operated patients undergoing VNS implantation over 24 months by two experienced surgeons at our institution from April 2014 to March 2016. In each surgery, the technical procedure, operating room, and surgical team were the same, while surgeon's preference in antibiotic prophylaxis differed. Group 1 received a single dose of intravenous (IV) cefazolin (n = 26), and Group 2 received IV cefazolin, paired with one or both of gentamicin/vancomycin, in addition to a 10-day outpatient oral course of clindamycin (n = 24). Patient demographics, perioperative details, and minimum 3-month follow-up for infection and healthcare utilization were recorded. Student t tests were computed for significance. Group 1 patients on average were older than group 2 patients (10.2, 7.1 years, p = 0.01), and length of surgery was longer (115.5, 91.9 min, p = 0.007). There were no differences in number of surgeons gowned (p = 0.11), presence of tracheostomy (p = 0.43) or gastrostomy (p = 0.20) tube, nonsurgical infections (p = 0.32), and number of postoperative emergency department (ED) visits (p = 0.22) or readmissions (p = 0.23). Neither group had VNS infections in the follow-up period. Single preoperative dosing of one antibiotic appropriately chosen to cover typical skin flora conferred equal benefit to perioperative prophylactic polypharmacy in this study. There were no differences in postoperative infection events or ED visits/readmissions. Restraint with preoperative antibiosis shows equipoise in postoperative infection and overall resource utilization.


Simultaneous multislice imaging (SIMUSIM) for improved cardiac imaging.
In conventional ECG gated multislice imaging of the heart, slice position and phase in the heart cycle are not independent parameters. This drawback is removed by simultaneous imaging of multiple slices. This paper describes a technique which is based on simultaneous excitation of several slices by multifrequency selective rf pulses. In comparison to conventional cardiac multislice imaging an improved quality of heart images is obtained, because more acquisitions are attributed to the MR signal of the slices. The gain in signal-to-noise ratio per measurement time increases with the square root of the number of slices investigated simultaneously. This is demonstrated using phantom experiments and cardiac images.


Evaluation of the prescription and use of antibiotics in Brazilian children.
Inappropriate use of antibiotics leads to increased levels of bacterial resistance making it difficult to treat upper respiratory tract infections. The appropriate use of these drugs has a fundamental role in controlling resistance and in success of treatment of childhood infections. Therefore, the aim of this study was to assess the prescription and use of antibiotics for Brazilian children. The use of antibiotics in 160 children was monitored in two Primary Health Centers by questionnaires administered to parents and caregivers that assessed the social, demographic and clinical conditions of the children. Furthermore, the antibiotic use pattern was ascertained in these children and compared to the recommendations of the Brazilian and international guidelines. The use of these drugs had an inverse relationship with children breast-fed to six months of age, showing that breast-fed children had a tendency to use less of these drugs. There was great variability in the amoxicillin doses used for upper respiratory infections ranging from 8.2 to 91.9mg/kg/day. The doses used in most treatments were far below the doses recommended in the Brazilian and international guidelines (50% and 97%, respectively). Although there are guidelines for the use of these medications, compliance is still very low, leading to under dosage and therapeutic failures. It is essential for pediatricians to be aware of and comply with the guidelines, avoid personal decisions and take measures based on strong clinical evidence. The proper use of these medications, in addition to greater therapeutic success, decreases the possibility of the appearance of resistant microorganisms.


The delivery of Ask-Advise-Connect for smoking cessation in Dutch general practice during the COVID-19 pandemic: results of a pre-post implementation study.
The Ask-Advise-Connect approach can help primary care providers to increase the number of smokers that attempt to quit smoking and enrol into cessation counselling. The approach has not yet been implemented in general practice in the Netherlands. The aim of this study was to investigate the influence of a comprehensive implementation strategy on the delivery of Ask-Advise-Connect for smoking cessation within Dutch general practice during the COVID-19 pandemic. A pre-post study was conducted between late 2020 and early 2022, and included 106 Dutch primary care providers (GPs, practice nurses and doctor's assistants). Participation lasted nine months: during the first three months participants delivered smoking cessation care as usual (pre-intervention); the implementation strategy came into effect after three months and participants were followed up for another six months (post-intervention). The implementation strategy consisted of two meetings in which participants were educated about Ask-Advise-Connect, made agreements on the implementation of Ask-Advise-Connect and reflected on these agreements. Participants also received online educational materials and a desk card as reminder. The changes in the proportions of 'Ask' and 'Advise' over time were modelled using linear mixed effects models. A descriptive analysis was conducted with regard to referrals to cessation counselling. Participants provided consultations to 29,112 patients (both smokers and non-smokers). Results of the linear mixed effects model show that the proportion of patients that were asked about smoking ('Ask') significantly decreased in the first three months (pre-intervention), but slightly increased again after the implementation strategy came into effect (post-intervention). No significant change over time was found with regard to the proportion of patients advised to quit smoking ('Advise'). Descriptive statistics suggested that more participants proactively (vs. passively) referred patients to cessation counselling post-intervention ('Connect'). The findings indicate that a comprehensive implementation strategy can support primary care providers in offering smoking cessation care to patients, even under stressful COVID-19 conditions. Additional implementation efforts are needed to increase the proportion of patients that receive a quit advice and proactive referral.


Establishment of vertebrate left-right asymmetry.
The generation of morphological, such as left-right, asymmetry during development is an integral part of the establishment of a body plan. Until recently, the molecular basis of left-right asymmetry was a mystery, but studies indicate that Nodal and the Lefty proteins, transforming growth factor-beta-related molecules, have a central role in generating asymmetric signals. Although the initial mechanism of symmetry breaking remains unknown, developmental biologists are beginning to analyse the pathway that leads to left-right asymmetry establishment and maintenance.


PD-1 Inhibitors: Safety of Use and Management of Immune-Mediated Adverse Reactions in Patients With Head and Neck Cancer.
Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with programmed cell death protein 1 (PD-1) inhibitors has been associated with risk of developing immune-mediated adverse reactions (IMARs). This review provides nurses with an overview of the safety of PD-1 inhibitors approved by the U.S. Food and Drug Administration for recurrent or metastatic SCCHN following platinum chemotherapy, as well as recommendations for assisting with the diagnosis and management of IMARs. PubMed® searches were conducted to identify relevant articles to support this review. Algorithms from drug manufacturers for IMAR management were also reviewed. Before treatment with PD-1 inhibitors, nurses should map patients' baseline profiles, which play a key role in aiding the healthcare team in the timely diagnosis and treatment of IMARs. Nurses should educate patients and caregivers on identifying signs and symptoms of IMARs and their progression. Within the interprofessional healthcare team, nurses play an important role in ensuring efficient management of IMARs to minimize withholding or discontinuation of PD-1 immunotherapy.


Pre- vs. postoperative initiation of thromboprophylaxis in liver surgery.
Thromboprophylaxis protocols in liver surgery vary greatly worldwide. Due to limited research, there is no consensus whether the administration of thromboprophylaxis should be initiated pre- or postoperatively. Patients undergoing liver resection in Helsinki University Hospital between 2014 and 2017 were reviewed retrospectively. Initiation of thromboprophylaxis was changed in the institution in the beginning of 2016 from postoperative to preoperative. Patients were classified into two groups for analyses: thromboprophylaxis initiated preoperatively (Preop-group) or postoperatively (Postop-group). The incidences of VTE and haemorrhage within 30 days of surgery were compared between these groups. Patients with permanent anticoagulation were excluded. A total of 512 patients were included to the study (Preop, n = 253, Postop, n = 259). The incidence of VTE was significantly lower in the Preop-group compared to the Postop-group (3 (1.2%) vs. 25 (9.7%), P = <.0001), mainly due to a lower incidence of pulmonary embolisms in the Preop-group (3 (1.2%) vs. 24 (9.3%), P < .0001). The rates of posthepatectomy haemorrhage within 30 days of surgery were similar (Preop 38 (15.0%) vs. Postop 36 (13.9%), p = .719). Initiating thromboprophylaxis preoperatively may reduce the incidence of postoperative VTE without affecting the incidence of posthepatectomy haemorrhage in patients undergoing liver resection.


Photoautotrophic cultivation of mixed microalgae consortia using various organic waste streams towards remediation and resource recovery.
In this study, mixed microalgae consortia was cultivated using digestate (D), animal manure (AM) and textile wastewater (TW) as growth medium providing mainly N (nitrogen) and P (phosphorous) sources without any extra nutrient addition. The corresponding total nitrogen (TN) and total phosphorous (TP, PO3-P) concentrations were noted as 323 and 21 for AM, 481 and 31 for TW and 747 and 55mg/L for D, respectively. After a cultivation period of 13days, P were completely removed (100%), however, N was still remain and attained the removal rate of 70.1, 72.3 and 16.7% for TW, AM and D, respectively. The peak growth rate and biomass production of 0.419d-1 and 0.4g/L (in terms of volatile solids, VS) was achieved using TW as growth medium.


Severe atrophic gastritis with Helicobacter pylori infection and gastric cancer.
BACKGROUND: We conducted a case-control study to evaluate whether patients with severe gastric atrophy (indicated by serum pepsinogen concentration) have a high risk of gastric cancer.METHODS: At the time of diagnosis of gastric cancer, sera from 301 patients (cases) and 602 sex- and age-matched cancer-free individuals (controls) were tested for the presence of anti- Helicobacter pylori IgG antibody (HM-CAP enzyme-linked immunoassay [ELISA] kit; Kyowa Medix, Tokyo, Japan) and serum pepsinogen (PG) levels (PG I and II Riabead Kits; Dainabot, Tokyo, Japan). We defined positivity for pepsinogen a pepsinogen I concentration of less than 70 ng/mL and a PG I/II ratio of less than 3.0. We categorized the subjects according to serum pepsinogen levels and anti- Helicobacter pylori IgG antibody, creating four categories.RESULTS: Of the 301 cancer cases, 177 had positive serum pepsinogen levels, and 172 were positive for anti- Helicobacter pylori IgG antibody. The category in which subjects had positive serum pepsinogen levels and were negative for anti- Helicobacter pylori IgG antibody had the highest proportion (76.9%) of individuals with gastric cancer and the highest odds ratio (4.20) of the four categories. The odds ratios were 2.55 (95% confidence interval; 1.92-3.88) for positive serum pepsinogen levels and 0.93 (95% confidence interval; 0.63-1.27) for positive anti- Helicobacter pylori IgG antibody.CONCLUSION: These results suggest that patients with positive serum pepsinogen levels who are negative for IgG antibody to Helicobacter pylori, constitute a high-risk group for gastric cancer. Helicobacter pylori infection is associated with the development of gastric cancer by providing a suitable environment i.e., severe gastric atrophy, for carcinogenesis of the gastric mucosa.


The effect of secretin on bile flow and bile acid and bilirubin excretion following relief of prolonged bile duct obstruction in the rat.
Bile flow was re-established in rats whose bile ducts had been obstructed for 5, 10, 15 and 28 days (Groups I, II, III and IV, n = 5). The effect of i.v. secretin on bile flow in control rats, whose bile ducts had been cannulated, was minimal, but in cholestatic rats there was an immediate response which was related to the duration of the obstruction and the degree of bile duct proliferation. In 40 min the mean excess bile flow production amounted to 76, 258, 320 and 432 microliters/100 g body wt. in Groups I, II, III and IV, respectively. Choleresis was prolonged in the Group IV rats that had developed cirrhosis. Synthetic secretin had a minimal effect on bile acid and bilirubin excretion. It is postulated that the proliferating bile ductules are the site of secretin choleresis, although the possibility that reduced inactivation of the hormone plays a role cannot be excluded.


A scoping review of evidence-based interventions available to parents of maltreated children ages 0-5 involved with child welfare services.
Parents referred to child welfare services for child maltreatment often struggle against chronic risk factors including violence, substance abuse, mental health concerns, and poverty, which impinge upon their ability to be sensitive caregivers. The first line of intervention within the child welfare context is to modify parenting behavior. This scoping review comprehensively surveyed all available literature to map the extent and range of research activity around the types of interventions available within a child welfare context to parents of infants and toddlers (0-5 years of age), to identify the facilitators and/or barriers to the uptake of interventions, and to check that interventions match the risk factors faced by parents. This scoping review engaged in stringent screening of studies based upon inclusion/exclusion criteria. Sixty-five articles involving forty-two interventions met inclusion criteria. Interventions generally aimed to improve parenting practices, the relationship between parent and child, and/or attachment security, along with reducing child abuse and/or neglect. A notable finding of this scoping review is that at present, interventions for parents of children ages 0-5 involved with the child welfare system are most frequently measured via case study and quasi-experimental designs, with randomized control trials making up 26.2% of included study designs.


Deceased-donor split-liver transplantation in adult recipients: is the learning curve over?
Infants have the highest wait-list mortality of all liver transplantation candidates. Deceased-donor split-liver transplantation, a technique that provides both an adult and pediatric graft, might be the best way to decrease this disproportionate mortality. Yet concern for an increased risk to adult split recipients has discouraged its widespread adoption. We aimed to determine the current risk of graft failure in adult recipients after split-liver transplantation. United Network for Organ Sharing data from 62,190 first-time adult recipients of deceased-donor liver transplants (1995-2010) were analyzed (889 split grafts). Bivariate risk factors (p < 0.2) were included in Cox proportional hazards models of the effect of transplant type on graft failure. Split-liver recipients had an overall hazard ratio of graft failure of 1.26 (p < 0.001) compared with whole-liver recipients. The split-liver hazard ratio was 1.45 (p < 0.001) in the pre-Model for End-Stage Liver Disease era (1995-2002) and 1.10 (p = 0.28) in the Model for End-Stage Liver Disease era (2002-2010). Interaction analyses suggested an increased risk of split-graft failure in status 1 recipients and those given an exception for hepatocellular carcinoma. Excluding higher-risk recipients, split and whole grafts had similar outcomes (hazard ratio = 0.94; p = 0.59). The risk of graft failure is now similar between split and whole-liver recipients in the vast majority of cases, which demonstrates that the expansion of split-liver allocation might be possible without increasing the overall risk of long-term graft failure in adult recipients. Additional prospective analysis should examine if selection bias might account for the possible increase in risk for recipients with hepatocellular carcinoma or designated status 1.


Enzymatic cleavage of pro-opiomelanocortin by anterior pituitary granules. Evidence for a chymotryptic-like enzyme.
This paper presents the results obtained when pig anterior pituitary granule lysates are incubated with rat pro-opiomelanocortin (POMC). The resultant peptides were analyzed by 3 systems of high-performance liquid chromatography. This approach, when coupled with microsequence analysis of the conversion products, allowed the unambiguous identification of a major chymotryptic-like activity (pH optimum around 8) associated with the granule lysates with a specificity directed towards selective Tyr-X and Phe-X bonds within the POMC molecule. Furthermore, these results also demonstrate that although the detected enzyme activity gives rise to products 'resembling' those expected, the characterization of the 'elusive' maturation enzyme responsible for the cleavage at pairs of basic residues remain to be critically evaluated.


Bacillus amyloliquefaciens modulate sugar metabolism to mitigate arsenic toxicity in Oryza sativa L. var Saryu-52.
In the current study, plant growth-promoting rhizobacterium Bacillus amyloliquefaciens SN13 (SN13) was evaluated for arsenic (As) toxicity amelioration potential under arsenate (AsV) and arsenite (AsIII) stress exposed to rice (Oryza sativa var Saryu-52) plants for 15 days. The PGPR-mediated alleviation of As toxicity was demonstrated by modulated measures such as proline, total soluble sugar, malondialdehyde content, enzymatic status, relative water content, and electrolytic leakage in treated rice seedlings under arsenic-stressed conditions as compared to the respective control. SN13 inoculation not only improved the agronomic traits but also modulated the micronutrient concentrations (Fe, Mo, Zn, Cu, and Co). The desirable results were obtained due to a significant decrease in the AsIII and AsV accumulation in the shoot (47 and 10 mg kg-1 dw), and the root (62 and 26 mg kg-1 dw) in B. amyloliquefaciens inoculated seedlings as compared to their uninoculated root (98 and 43 mg kg-1 dw) and shoot (57 and 12 mg kg-1 dw), respectively. Further, metabolome (GC-MS) analysis was performed to decipher the underlying PGPR-induced mechanisms under arsenic stress. A total of 67 distinct metabolites were identified, which influence the metabolic and physiological factors to modulate the As stress. The expression analysis of metabolism- and stress-responsive genes further proclaimed the involvement of SN13 through modulating the carbohydrate metabolism in rice seedlings, to enable improved growth and As stress tolerance.


Studies of the thermodynamics and nature of interaction between serum albumin and penicillins.
The possibility of a calorimetric determination of the number of homogeneous independent binding sites on the protein molecule surface is presented, together with the possibility of the determination of interaction heat and association constants for the binding of small molecules to one such site. Thermodynamic characteristics of interaction of 10 penicillins and methyl orange with primary and secondary binding sites of bovine serum albumin have been obtained using this technique. The data show that hydrogen bonds between the component parts of the complexes studied are absent. The main contribution to free energy change at forming these complexes is made by hydrophobic interactions. Electrostatic forces are also of some importance, their contribution into the complex formation is more significant in the case of quinacillin and carbenicillin which have an additional charged carboxyl group.


Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma.
In recent decades, global pharmaceutical companies have suffered from an R&D innovation gap between the increased cost of a new drug's development and the decreased number of approvals. Drug repositioning offers another opportunity to fill the gap because the approved drugs have a known safety profile for human use, allowing for a reduction of the overall cost of drug development by eliminating rigorous safety assessment. In this study, we compared the transcriptional profile of LC28-0126, an investigational drug for acute myocardial infarction (MI) at clinical trial, obtained from healthy male subjects with molecular activity profiles in the Connectivity Map. We identified dyphilline, an FDA-approved drug for bronchial asthma, as a top ranked connection with LC28-0126. Subsequently, we demonstrated that LC28-0126 effectively ameliorates the pathophysiology of neutrophilic bronchial asthma in OVALPS-OVA mice accompanied with a reduction of inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), inhibition of the release of proinflammatory cytokines, relief of airway hyperactivity, and improvement of histopathological changes in the lung. Taken together, we suggest that LC28-0126 could be a potential therapeutic for bronchial asthma. In addition, this study demonstrated the potential general utility of computational drug repositioning using clinical profiles of the investigational drug.


Generating high repetition rate X-ray attosecond pulses in a diffraction limited storage ring.
To steer and track electron motion in atoms, molecules, and nanostructures, light pulses with attosecond duration and high repetition rate are required. In this paper, we use the angular dispersion-induced microbunching scheme and a few-cycle laser within a straight section (a few meters) of a diffraction-limited storage ring to generate a coherent high-flux attosecond pulse in the water window region. Simulation results based on the Southern Advanced Photon Source indicate that the proposed method can generate a chirp-free Fourier transform limited pulse with a minimum duration of 50 as, a maximum repetition rate of a few MHz, and a maximum average flux of about [Formula: see text] photons/s/1%Bw.


Critical heart disease in the neonate: presentation and outcome at a tertiary care center.
To define the modes of presentation, incidence of major organ dysfunction, predictors of hospital mortality, and adverse outcomes in neonates with critical heart disease admitted to a tertiary care center. Retrospective chart review. A tertiary care pediatric cardiac intensive care unit and neonatal intensive care unit. The medical records for all neonates (< or = 30 days of age) with heart disease admitted to the cardiac intensive care unit or neonatal intensive care unit between October 1, 2002, and September 30, 2003, were reviewed. None. A total of 190 neonates met inclusion criteria during this 1-yr period, of which 146 (77%) had at least one surgical procedure. Single ventricle heart disease was present in 42%. The most common mode of presentation was following a prenatal diagnosis (53%), followed by diagnosis in the newborn nursery (38%) and diagnosis after newborn hospital discharge (8%). The most common presenting findings in the newborn nursery were isolated murmur (38%) or cyanosis (32%), while circulatory collapse (38%) was the most common presentation after discharge. For the entire study cohort, 13% had a known genetic syndrome, 23% had a major noncardiac congenital anomaly, and 16% weighed < 2.5 kg. The hospital mortality for the entire cohort was 7.4%. Risk factors associated with an increased risk of hospital mortality included younger age at admission, higher number of cardiopulmonary bypass runs, and need for postoperative cardiopulmonary resuscitation. Total hospital length of stay was > 1 month in 17% of neonates. In patients with complex congenital heart disease, including nearly half with single ventricle heart disease, neonatal hospital mortality was 7%. These patients have a high frequency of multiple congenital anomalies, genetic syndromes, low birth weight, and prolonged length of stay.


In vitro and in situ evaluation of herb-drug interactions during intestinal metabolism and absorption of baicalein.
Baicalein (B), a bioactive flavone isolated from the root of a traditional Chinese medicinal herb Scutellaria baicalensis Georgi, was found to undergo extensive intestinal Phase II metabolism during its absorption process. Compounds sharing the same metabolic pathways with B or being inhibitors of enzymes UGT and SULT are expected to interfere with the metabolism of B leading to alteration of the absorption of B. The present study aims to identify potential intestinal absorption and metabolism interactions between B and four selected compounds, namely acetaminophen (APAP), (-)-epicatechin (EC), piperine (PIP) and curcumin (CUR) using in vitro and in situ models. Three in vitro and one in situ methods were employed to investigate the effect of selected compounds on the metabolism and absorption on B. Incubation studies using rat intestinal s9 and Caco-2 cell lysate were used to study the effect of selected compounds on glucuronidation and sulfation of B. Sigmoidal dose-response curves were plotted and IC(50) values were estimated. Apical to basolateral absorption study using Caco-2 cell monolayer model was also employed to study the effect of selected compounds on absorption of B. The most potent inhibitor identified was selected to further investigate its potential herb-drug interaction with B using in situ rat intestinal perfusion model. LC/MS/MS was used for the analysis of B and its metabolites in collected samples. It was found that all the four selected compounds could produce a dose-dependent inhibition on the glucuronidation and sulfation of B. Moreover, the presence of CUR and high-dose EC demonstrated a subsequent increase in the absorption of B. In general, the order of potency on glucuronidation inhibition is: CUR>PIP>EC>APAP; while the potency order on sulfation inhibition is: CUR>EC>PIP>APAP. CUR was selected to further study its in vivo effect on B using in situ rat intestinal perfusion model. It was found that CUR could significantly increase the absorption of B via the inhibition on formation of its metabolites. Our findings indicated that the intestinal metabolism of B could be inhibited by all the selected compounds with CUR being the most potent inhibitor, which could result in subsequent increase of absorption of B. The current study had significant implications for further investigation on the in vivo evaluations of the herb-drug and herb-herb interactions between B and selected compounds, especially CUR.


Guideline-based standardized care is associated with substantially lower mortality in medicare patients with acute myocardial infarction: the American College of Cardiology's Guidelines Applied in Practice (GAP) Projects in Michigan.
We sought to assess the impact of the American College of Cardiology's Guidelines Applied in Practice (GAP) project for acute myocardial infarction (AMI) care, encompassing 33 acute-care hospitals in southeastern Michigan, on rates of mortality in Medicare patients treated in Michigan. The GAP project increases the use of evidence-based therapies in patients with AMI. It is unknown whether GAP also can reduce the rate of mortality in patients with AMI. Using a before (n = 1,368) and after GAP implementation (n = 1,489) cohort study, 2,857 Medicare patients with AMI were studied to assess the influence of the GAP program on mortality. Multivariate models tested the independent impact of GAP after controlling for other conditions on in-hospital, 30-day, and one-year mortality. Average patient age was 76 years, 48% were women, and 16% represented non-white minorities. The rate of mortality decreased after GAP for each interval studied: hospital, 10.4% versus 13.6%; 30-day, 16.7% versus 21.6%; and one-year, 33.2% versus 38.3%; all p < 0.02. After multivariate adjustment, GAP correlated with a 21% to 26% reduction in mortality, particularly at 30 days (odds ratio of GAP to baseline 0.74; 95% confidence interval [CI] 0.59 to 0.94; p = 0.012) and one year (odds ratio 0.78; 95% CI 0.64 to 0.95; p = 0.013), particularly in the patients for whom a standard discharge tool was used (1-year mortality, odds ratio 0.53; 95% CI 0.36 to 0.76; p = 0.0006). Embedding AMI guidelines into practice was associated with improved 30-day and one-year mortality. This benefit is most marked when patients are cared for using standardized, evidence-based clinical care tools.