Building Computational Models to Predict One-Year Mortality in ICU Patients with Acute Myocardial Infarction and Post Myocardial Infarction Syndrome.
Heart disease remains the leading cause of death in the United States. Compared with risk assessment guidelines that require manual calculation of scores, machine learning-based prediction for disease outcomes such as mortality can be utilized to save time and improve prediction accuracy. This study built and evaluated various machine learning models to predict one-year mortality in patients diagnosed with acute myocardial infarction or post myocardial infarction syndrome in the MIMIC-III database. The results of the best performing shallow prediction models were compared to a deep feedforward neural network (Deep FNN) with back propagation. We included a cohort of 5436 admissions. Six datasets were developed and compared. The models applying Logistic Model Trees (LMT) and Simple Logistic algorithms to the combined dataset resulted in the highest prediction accuracy at 85.12% and the highest AUC at .901. In addition, other factors were observed to have an impact on outcomes as well.


First-principles prediction of rate coefficients for free-radical cyclization reactions at selenium.
High-level ab initio calculations of the barriers, enthalpies, and rate coefficients for the intramolecular cyclization reactions of *CH(2)CH(2)CH(2)CH(2)SeR (R = Me, n-Bu, s-Bu, t-Bu, Bn, Bz, Ph(2)CH) and *CH(2)CH(2)CH(2)CH(2)CHCH(2) have been performed at the G3(MP2)-RAD level. The calculated rate coefficients show excellent agreement with experiment (to within a factor of 5 or better), although this might be due, in part, to a systematic cancelation of order-of-magnitude errors in the corresponding Arrhenius parameters. The intramolecular cyclizations at selenium were found to be energetically favorable processes that occur with synthetically accessible rate coefficients on the order of 10(4)-10(6) s(-1) at 294 K. These values are largely governed by the stabilization energy of the leaving radical, though with contributions from steric and polar effects.


Impact of liver fibrosis and clinical characteristics on dose-adjusted serum methadone concentrations.
There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements. We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations. We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016-2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis. When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5, the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: -2.16, 3.57; P: 0.631), even among those with advanced cirrhosis (-0.50; -4.59, 3.59; 0.810). Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.


Travel time and trajectory moments of conservative solutes in two-dimensional convergent flows.
We address advective transport of a solute traveling toward a single pumping well in a two-dimensional randomly heterogeneous aquifer. The two random variables of interest are the trajectory followed by an individual particle from the injection point to the well location and the particle travel time under steady-state conditions. Our main objective is to derive the predictors of trajectory and travel time and the associated uncertainty, in terms of their first two statistical moments (mean and variance). We consider a solute that undergoes mass transfer between a mobile and an immobile zone. Based on Lawrence et al. [Lawrence, A.E., Sánchez-Vila, X., Rubin, Y., 2002. Conditional moments of the breakthrough curves of kinetically sorbing solute in heterogeneous porous media using multirate mass transfer models for sorption and desorption. Water Resour. Res. 38 (11), 1248, doi:10.1029/2001WR001006.], travel time moments can be written in terms of those of a conservative solute times a deterministic quantity. Moreover, the moments of solute particles trajectory do not depend on mass transfer processes. The resulting mean and variance of travel time and trajectory for a conservative species can be written as functions of the first, second moments and cross-moments of trajectory and velocity components. The equations are developed from a consistent second order expansion in sigmaY (standard deviation of the natural logarithm of hydraulic conductivity). Our solution can be completely integrated with the moment equations of groundwater flow of Guadagnini and Neuman [Guadagnini, A., Neuman, S.P., 1999a. Nonlocal and localized analyses of conditional mean steady state flow in bounded, randomly non uniform domains 1. Theory and computational approach. Water Resour. Res. 35(10), 2999-3018.,Guadagnini, A., Neuman, S.P., 1999b. Nonlocal and localized analyses of conditional mean steady state flow in bounded, randomly non uniform domains 2. Computational examples. Water Resour. Res. 35(10), 3019-3039.], it is free of distributional assumptions regarding the log conductivity field, and formally includes conditioning. We present analytical expressions for the unconditional case by making use of the results of Riva et al. [Riva, M., Guadagnini, A., Neuman, S.P., Franzetti, S., 2001. Radial flow in a bounded randomly heterogeneous aquifer. Transport in Porous Media 45, 139-193.]. The quality of the solution is supported by numerical Monte Carlo simulations. Potential uses of this work include the determination of aquifer reclamation time by means of a single pumping well, and the demarcation of the region potentially affected by the presence of a contaminant in the proximity of a well, whenever the aquifer is very thin and Dupuit-Forchheimer assumption holds.


Engineered Zinc Oxide Nanoparticles; Biological Interactions at the Organ Level.
Zinc oxide nanoparticles (ZnO NPs) are one of the widely used nanoparticles with spectrum of application, in the areas like daily care products, sensors, antibacterial agents, and biomedical sector. With extensive application the risk of exposure at occupational and consumer level also increases. Huge amount of data are available on the biointeraction of ZnO NPs. Though the toxicity of ZnO NPs is attributed to particle dissolution inside the cellular compartments and their ability to generate the reactive oxygen species, the ambiguity prevails over the exact mechanism of toxicity. The in vivo studies on different animal models and humans suggest different level of toxicity in these organisms. However the synthetic route, physiochemical properties of the nanoparticle, mode of exposure and nature of the test system often influences these studies. Hence the study results vary and sometimes contradict on one another. The current review focuses on the interaction of ZnO NPs with different organ systems. It also points to the factors to be considered while undertaking such studies in order to ensure reliability of the results.


Hypothermic machine perfusion of liver grafts for transplantation: technical development in human discard and miniature swine models.
Cold storage (CS) is the standard preservation technique for liver transplantation (LTx). Hypothermic machine perfusion (HMP) is an alternative preservation technique that provides a continuous supply of substrates and removes waste products. HMP improves early graft function in kidney transplantation, especially for marginal organs: To our knowledge there have been no reports HMP in human LTx. The aim of this study was to develop a reproducible technique for liver HMP prior to initiating a clinical trial. For the discard protocol, between May 2001 and March 2002, 10 nontransplantable human livers were obtained. We designed a model of atraumatic, centrifugal HMP of the portal vein (PV) and hepatic artery (HA) via donor vascular conduit. Livers were perfused at 3 degrees C to 5 degrees C with Vasosol solution for 5 to 10 hours using a modified Medtronic Portable Bypass System. Perfusion variables (temp, flow, pressure) where recorded every 30 minutes. During the study, we also validated our techniques in an animal model. For the animal protocol; six swine were used as liver donors and randomized to 12 hours of CS in UW (n = 3) or 12 hours of HMP using Vasosol solution (n = 3). LTx was performed in six swine. Animals survived until postoperative day 5. For the discard protocol, mean HMP time was 6.7 +/- 1.8 hours. Target flow was 0.7 mL/g liver/min. PV and HA pressure ranged from 3 to 5 and 12 to 18 mm Hg, respectively. All grafts were maintained at 3 degrees C to 5 degrees C during HMP. For the animal protocol, all recipients had good liver function and survived to postoperative day 5. AST and TBili were similar between CS and HMP. Our method of liver HMP appears to be a safe and reliable method to preserve livers. A clinical trial is now underway to evaluate this technique in human LTx.


Nonfasting glucose, ischemic heart disease, and myocardial infarction: a Mendelian randomization study.
The purpose of this study was to test whether elevated nonfasting glucose levels associate with and cause ischemic heart disease (IHD) and myocardial infarction (MI). Elevated fasting plasma glucose levels associate with increased risk of IHD, but whether this is also true for nonfasting levels and whether this is a causal relationship is unknown. Using a Mendelian randomization approach, we studied 80,522 persons from Copenhagen, Denmark. Of those, IHD developed in 14,155, and MI developed in 6,257. Subjects were genotyped for variants in GCK (rs4607517), G6PC2 (rs560887), ADCY5 (rs11708067), DGKB (rs2191349), and ADRA2A (rs10885122) associated with elevated fasting glucose levels in genome-wide association studies. Risk of IHD and MI increased stepwise with increasing nonfasting glucose levels. The hazard ratio for IHD in subjects with nonfasting glucose levels ≥11 mmol/l (≥198 mg/dl) versus <5 mmol/l (<90 mg/dl) was 6.9 (95% confidence interval [CI]: 4.2 to 11.2) adjusted for age and sex, and 2.3 (95% CI: 1.3 to 4.2) adjusted multifactorially; corresponding values for MI were 9.2 (95% CI: 4.6 to 18.2) and 4.8 (95% CI: 2.1 to 11.2). Increasing number of glucose-increasing alleles was associated with increasing nonfasting glucose levels and with increased risk of IHD and MI. The estimated causal odds ratio for IHD and MI by instrumental variable analysis for a 1-mmol/l (18-mg/dl) increase in nonfasting glucose levels due to genotypes combined were 1.25 (95% CI: 1.03 to 1.52) and 1.69 (95% CI: 1.28 to 2.23), and the corresponding observed hazard ratio for IHD and MI by Cox regression was 1.18 (95% CI: 1.15 to 1.22) and 1.09 (95% CI: 1.07 to 1.11), respectively. Like common nonfasting glucose elevation, plasma glucose-increasing polymorphisms associate with increased risk of IHD and MI. These data are compatible with a causal association.


Genetic analysis of Bactrocera zonata (Diptera: Tephritidae) populations from India based on cox1 and nad1 gene sequences.
The peach fruit fly, Bactrocera zonata, is among the most serious and polyphagous insect pest of fruit crops in many parts of the world under genus Bactrocera. In the present study, the genetic structure, diversity and demographic history of B. zonata in India were inferred from mitochondrial cytochrome oxidase 1 (cox1) and NADH dehydrogenase 1 (nad1) sequences. The efficiency of DNA barcodes for identification of B. zonata was also tested. Genetic diversity indices [number of haplotypes (H), haplotype diversity (Hd), nucleotide diversity (π) and average number of nucleotide differences (k)] of B. zonata populations across India maintain high level of genetic diversity without isolation by distance among the geographic regions. Non-significant negative correlation between pairwise Fst and geographic distance suggests a high level of gene flow among studied populations of B. zonata. The possibility of sudden expansion of B. zonata revealed through mismatch distribution analysis as well as negative Tajima's D and Fu's Fs values further supported by star-like network of haplotypes. DNA barcoding analysis suggests that B. zonata specimens can be clearly differentiated from other species with 100% accuracy of identification. Therefore, cytochrome oxidase 1 (cox1) barcode sequences generated in the present study could be a valuable source for the rapid identification and global population genetic study of B. zonata.


Formation of nanostructured copper filaments in electrochemical deposition.
In this paper, we report in detail the studies of a different self-organized copper electrodeposition carried out in an ultrathin layer of CuSO4 electrolyte. On a macroscopic scale, the morphology of the electrodeposit is fingerlike. Microscopically, each fingering branch consists of long, straight copper filaments with periodic corrugated nanostructures. Branching rate of the electrodeposit is significantly decreased, compared with the patterns grown in conventional systems. Detailed information of the growth environment in the ultrathin electrodeposition system is provided, the formation mechanism of the periodic nanostructures on the deposit filaments is explored, and the origin of the significant descent of branching rate of the electrodeposit is discussed.


Quantification of β-region IgA monoclonal proteins - should we include immunochemical Hevylite® measurements? Point.
Accurate measurement of IgA monoclonal proteins presents a significant challenge to laboratory staff. IgA heavy/light chain (Hevylite, HLC) analysis is an alternative methodology for monoclonal protein assessment, giving an independent measure of IgAκ and IgAλ concentrations. Clonality is assessed by calculating the ratio of involved immunoglobulin to background uninvolved immunoglobulin concentrations (e.g. IgAκ/IgAλ in an IgAκ patient). Here we discuss the challenges faced by the laboratory in IgA monoclonal protein assessment, and compare the performance of Hevylite assays with electrophoresis and total IgA results. We present data which validates the use of Hevylite for response assessment: in most cases, Hevylite provides comparable response assignment to that provided by serum protein electrophoresis (SPE) and total IgA; in other cases Hevylite provides additional information, such as detection of residual disease or relapse.


Crohn's disease of the small bowel.
Crohn's disease is a perplexing panintestinal disease whose etiology is unknown. Symptoms and complications vary greatly from patient to patient. Despite the fact that no cure exists, thoughtful, well-planned therapy and appropriate timely intervention, where needed, can result in maintenance of a high quality of life for affected patients.


On the origin of flicker noise in carrier-envelope phase stabilization.
The origin of a 1/f noise contribution in the long-term carrier-envelope phase (CEP) measurements of mode-locked lasers is discussed. Using two different collinear interferometers for the out-of-loop characterization of feed-forward stabilized Ti:sapphire oscillators, we suppress a possible technical origin of 1/f noise to the extent possible. Both measurements indicate a lower limit of CEP frequency noise of 1 mHz/√Hz. Investigating several possible origins of this noise floor, we find a good agreement with a quantum noise mechanism that is directly induced by intracavity-amplified spontaneous emission (ASE). These findings enable direct access to ASE noise in short-pulse oscillators, which is very hard to characterize via repetition rate fluctuations. Finally, we discuss the possible consequences for frequency-comb-based timekeeping and frequency metrology, as well as for attosecond science.


Design of a fermentation process for agave fructooligosaccharides production using endo-inulinases produced in situ by Saccharomyces paradoxus.
Saccharomyces paradoxus, a native microorganism of the aguamiel, was used successfully for endoinulinase synthesis for agave fructooligasaccharide (FOS) production. We optimized the fermentation parameters to maximize the enzyme synthesis, and we performed enzyme kinetics studies to achieve agave fructans hydrolysis. The results showed that under constant operating conditions (pH 7.7, 40 °C, 175 rpm of agitation, and 0.005 VVM of aeration) results in the production of an enzymatic extract with 49.57 mg/L. This enzymatic extract, when mixed with an agave fructans solution containing 37.8 g/L, allowed us to obtain products with 18% more FOS content the original concentration. The mass spectrum plot shows that the hydrolyzed product contains FOS with a degree of polymerization from 5 to 9 hexose units. These results are promising because they show FOS production from agave and confirm that importance of using native strains in the design of directed fermentation processes.


A review of New World Malaxa (Hemiptera: Fulgoroidea: Delphacidae).
The New World species attributed to the genus Malaxa Melichar (Hemiptera: Fulgoroidea: Delphacidae) are reviewed with special reference to the type species Malaxa acutipennis from the Philippines. We provide an amended diagnosis for Malaxa acutipennis contrasted with the genus delineation presented for Chinese Malaxa, most recently by Hou et al. (2013). We find Malaxa to be an Old World genus and segregate New World species into two new genera, Lamaxa and Xalama, diagnosed most readily by proportions of the antennae and features of the terminalia. Both Lamaxa and Xalama are uncommonly encountered. Lamaxa is distributed widely through the Neotropics, whereas Xalama is heretofore known only from Bolivia and Peru.


Functional Modification of Electrospun Poly(ε-caprolactone) Vascular Grafts with the Fusion Protein VEGF-HGFI Enhanced Vascular Regeneration.
Synthetic artificial vascular grafts have exhibited low patency rate and severe neointimal hyperplasia in replacing small-caliber arteries (<6 mm) because of their failure to generate a functional endothelium. In this study, small-caliber (2.0 mm) electrospun poly(ε-caprolactone) (PCL) vascular grafts were modified with a fusion protein VEGF-HGFI which consists of the class I hydrophobin (HGFI) and vascular endothelial growth factor (VEGF), via hydrophobic interactions. Immunofluorescence staining with the anti-VEGF antibody showed that VEGF-HGFI formed a protein layer on the surface of fibers in the grafts. Scanning electron microscopy (SEM) and mechanical measurements showed that VEGF-HGFI modification had no effect on the structure and mechanical properties of PCL grafts. Blood compatibility tests demonstrated a lower level of fibrinogen (FGN) absorption, platelet activation, and aggregation on the VEGF-HGFI-modified PCL mats than that on the bare PCL mats. The hemolysis rate was comparable in both the modified and bare PCL mats. In vitro culture of human umbilical vein endothelial cells (HUVECs) demonstrated that VEGF-HGFI modification could remarkably enhance nitric oxide (NO) production, prostacyclin2 (PGI2) release, and the uptake of acetylated low-density lipoprotein (Ac-LDL) by HUVECs. The healing characteristics of the modified grafts were examined in the replacement of rat abdominal aorta for up to 1 month. Immunofluorescence staining revealed that endothelialization, vascularization, and smooth muscle cell (SMC) regeneration were markedly improved in the VEGF-HGFI-modified PCL grafts. These results suggest that modification with fusion protein VEGF-HGFI is an effective method to improve the regeneration capacity of synthetic vascular grafts.


Modified Aortic Uncrossing Procedure: A Novel Approach for Norwood Palliation of Complex Univentricular Congenital Heart Disease With a Circumflex Aorta.
The circumflex aorta is a rare type of true vascular ring anomaly. It consists of a retroesophageal right aortic arch, a left-sided descending thoracic aorta, and a left-sided ligamentum arteriosum. The "aortic uncrossing procedure" described by Planché and Lacour-Gayet is the procedure of choice for managing this aortic anomaly in patients with a biventricular heart. The presence of a circumflex aorta in a patient with heterotaxy syndrome and univentricular congenital heart disease requiring Norwood palliation is highly unusual. We report such a case and describe our approach to its surgical management.


Disembedding performance in children and adolescents with Asperger syndrome or high-functioning autism.
The aim of the present study was to assess the findings, reported in earlier studies, that individuals with autism spectrum disorders process visuo-spatial tasks faster than typically developing control persons. The participants in the present study were children and adolescents with Asperger syndrome (AS) or high-functioning autism (HFA) (N = 13), and a matched group of typically developing children and adolescents (N = 13). The results showed that the participants in the clinical group performed marginally less well than those in the control group on both the Block Design Test and the Embedded Figures Test, but the differences were not statistically significant. Thus, earlier findings suggesting that individuals with autism spectrum disorders solve non-social cognitive tasks faster than typically developing control persons were not replicated. The results are discussed with special reference to the hypothesis of weak central coherence.


The Family of Single-Case Experimental Designs.
Single-case experimental designs (SCEDs) represent a family of research designs that use experimental methods to study the effects of treatments on outcomes. The fundamental unit of analysis is the single case-which can be an individual, clinic, or community-ideally with replications of effects within and/or between cases. These designs are flexible and cost-effective and can be used for treatment development, translational research, personalized interventions, and the study of rare diseases and disorders. This article provides a broad overview of the family of single-case experimental designs with corresponding examples, including reversal designs, multiple baseline designs, combined multiple baseline/reversal designs, and integration of single-case designs to identify optimal treatments for individuals into larger randomized controlled trials (RCTs). Personalized N-of-1 trials can be considered a subcategory of SCEDs that overlaps with reversal designs. Relevant issues for each type of design-including comparisons of treatments, design issues such as randomization and blinding, standards for designs, and statistical approaches to complement visual inspection of single-case experimental designs-are also discussed.


One-dimensional transport equation models for sound energy propagation in long spaces: simulations and experiments.
In this paper, the accuracy and efficiency of the previously discussed one-dimensional transport equation models [Y. Jing et al., J. Acoust. Soc. Am. 127, 2312-2322 (2010)] are examined both numerically and experimentally. The finite element method is employed to solve the equations. Artificial diffusion is applied in the numerical implementation to suppress oscillations of the solution. The transport equation models are then compared with the ray-tracing based method for different scenarios. In general, they are in good agreement, and the transport equation models are substantially less time consuming. In addition, the two-group model is found to yield more accurate results than the one-group model for the tested cases. Lastly, acoustic experimental results obtained from a 1:10 long room scale-model are used to verify the transport equation models. The results suggest that the transport equation models are able to accurately model the sound field in a long space.


Comparison of perioperative outcomes of robotic versus laparoscopic partial nephrectomy for complex renal tumors (RENAL nephrometry score of 7 or higher).
To compare the perioperative outcomes of laparoscopic partial nephrectomy (LPN) and robotic partial nephrectomy (RPN) for moderately or highly complex tumors (RENAL nephrometry score ≥ 7). A retrospective analysis was performed for 127 consecutive patients who underwent either LPN (n=38) or RPN (n=89) between 2007 and 2013. Perioperative outcomes were compared. There were no significant differences between the two groups with respect to patient gender, laterality, RENAL nephrometry score, or body mass index. The RPN group had a slightly higher RENAL nephrometry score (7.8 vs. 7.5, p=0.061) and larger tumor size (3.0 cm vs. 2.5 cm, p=0.044) but had a lower Charlson comorbidity index (3.7 vs. 4.4, p=0.017) than did the LPN group. There were no significant differences with respect to warm ischemia time, estimated blood loss, intraoperative complications, or operative time. Only one patient who underwent LPN had a positive surgical margin. There were statistically significant differences in surgical marginal width between the LPN and RPN groups (0.6 cm vs. 0.4 cm, p=0.001). No significant differences in postoperative complications were found between the two groups. Owing to potential baseline differences between the two groups, we performed a propensity-based matching analysis, in which differences in surgical margin width between the LPN and RPN groups remained statistically significant (0.6 cm vs. 0.4 cm, p=0.029). RPN provides perioperative outcomes comparable to those of LPN and has the advantage of healthy parenchymal preservation for complex renal tumors (RENAL score ≥ 7).


Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regulation.
Regulation of liver cell proliferation is a key event to control organ size during development and liver regeneration. Methionine adenosyltransferase (MAT) 2A is expressed in proliferating liver, whereas MAT1A is the form expressed in adult quiescent hepatocytes. Here we show that, in H35 hepatoma cells, growth factors such as hepatocyte growth factor (HGF) and insulin up-regulated MAT2A expression. HGF actions were time- and dose-response dependent and required transcriptional activity. Mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-phosphate kinase (PI 3-K) pathways were required for both HGF-induced cell proliferation and MAT2A up-regulation. Furthermore, in H35 cells treated with HGF, the inhibition of these pathways was associated with the switch from the expression of fetal liver MAT2A to the adult liver MAT1A isoform. Fetal liver hepatocytes exhibited an identical response pattern. Treatment of H35 hepatoma cells with MAT2A antisense oligonucleotides decreased cell proliferation induced by HGF; this decrease correlated with the decay in MAT2A messenger RNA (mRNA) levels. Finally, growth inhibitors such as transforming growth factor (TGF) beta blocked HGF-induced MAT2A up-regulation while increasing MAT1A mRNA levels in H35 cells. In conclusion, our results show that MAT2A expression not only correlates with liver cell proliferation but is required for this process.


Plagiodera versicolora feeding induces systemic and sexually differential defense responses in poplars.
Dioecious plants have evolved effective defense strategies to deal with various biotic and abiotic stresses. However, little is known regarding sexual differences in their defense against herbivores. In this study, we investigated the mechanism of systemic defense responses in male and female Populus cathayana attacked by Plagiodera versicolora Laicharting. The results revealed that P. cathayana exhibits sexually differential responses to a defoliator. The percentage of damaged leaf area was greater in males than in females. Furthermore, the observed saccharide changes imply that males and females exhibit different response times to defoliators. The contents of flavonoids and anthocyanins were significantly increased in both sexes but were higher in females. Specifically, the jasmonic acid (JA) pathway plays an important role. Expression of pest-related genes further revealed that hormones induce changes in downstream genes and metabolites, and upregulation of JA ZIM-domain (JAZ) and CORONATINE INSENSITIVE 1 (COI1) was more significant in females. In the undamaged adjacent leaves, metabolite and gene changes displayed similar patterns to the damaged local leaves, but levels of JA, JAZ1, and COI1 were higher in females. Therefore, our data confirmed that plants initiate the JA pathway to defend against herbivores, that there is systematic signal transduction, and that this ability is stronger in females than in males. This study provides new insights into the resistance of dioecious plants to herbivory and adds a new theoretical basis for the systemic signal transduction of plants in response to biotic stress.


Replication pattern of the pericentromeric region of chromosome 10q and expression of the RET protooncogene.
Regulation of the RET gene is highly specific during embryo development and is strictly tissue-specific. Control of transcription depends on mechanisms influenced by epigenetic processes, in particular, histone acetylation at regions flanking the 5' end of the gene. Since the RET gene is mapped in the pericentromeric region of the human chromosome 10, the implication of epigenetic processes is even more striking and worth to be investigated in an extended chromosomal tract. One experimental approach to study the chromatin status in relationship with gene transcription is to assess the replication timing, which we did by using fluorescent in situ hybridization in cells expressing or not expressing the RET gene. By using probes spanning a 700-kb genomic region from the RET locus toward the centromere, we found a relationship between RET expression and early replication. Different patterns were observed between cells naturally expressing RET and cells induced to expression of RET by treatment with sodium butyrate, an inhibitor of histone deacetylases. Three-dimensional analysis of the nuclear localization of fluorescent signals by confocal microscopy showed difference of localization between the RET probe and a probe for a housekeeping gene, G3PDH, located at 12p13.3, in cells that do not express RET, in accordance with previous data for other genes and chromosomal regions. However, RET-expressing cells showed a localization of signals which was not consistent with that expected for expressed genes.


Two fatal cases of child abuse in which neighbors were unaware of the victims' disappearance for a long period.
We describe two fatal cases of child abuse in which neighbors were unaware of the victims' disappearance for 1.5 months and 1 year, respectively. Recently, there have been fatal child abuse cases in which neighbors have been aware of the signs of the abuse but not notified the Child Care Authorities. Lack of concern about child welfare in the community is the greatest obstacle to protecting children at risk of abuse. The most effective means of preventing child abuse is to educate the community about how to recognize the signs of abuse and to inform the authorities. We emphasize that the community has an obligation to protect children against crime, including child abuse. The roles of the Social Services in preventing child abuse have been extended. Forensic pathologists are required to play a key role in child abuse prevention, and in Japan their activity should be extended to the administrative field.


Plasma xanthine oxidase, superoxide dismutase and glutathione peroxidase activities and uric acid levels in severe and mild pre-eclampsia.
The aim of the present study was to measure plasma uric acid (UA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and xanthine oxidase (XO) activities and to evaluate the relationship between these parameters and the severity of pre-eclampsia. Twenty-five pre-eclamptic, 15 healthy pregnant and 15 non-pregnant women were enrolled in this study. Increased mean plasma XO activity was found to be higher in both pre-eclampsia groups than in the healthy pregnant group. Plasma UA levels were the highest in the severe pre-eclampsia group among the study groups. SOD and GSH-Px activities were significantly lower in both pre-eclampsia groups than in the healthy pregnant group (p < 0.005 and p < 0.001, respectively). Increased XO and decreased SOD and GSH-Px activities may contribute to the pathophysiological mechanisms of pre-eclampsia and increased UA may serve a protective role responding to superoxide radicals arising from increased XO activity or other sources in pre-eclampsia.


Antigen peptide transporters are upregulated in squamous cell carcinoma of the oral tongue and show sex-specific associations with survival.
Transporter associated with antigen processing 1 (TAP1) and TAP2 serve pivotal roles in adaptive immunity. Tumor cells often show reduced antigen presentation on their surface as one mechanism to escape immune recognition. Whether downregulation of TAPs is a common mechanism of tumor immune evasion in squamous cell carcinoma of the oral tongue (SCCOT) is unclear. In the present study, samples from 78 patients with SCCOT and 17 patients with benign hyperplastic tongue lesions were analyzed for TAP1 and TAP2 expression by immunohistochemistry. The percentage of positive cells and staining intensity were scored. Associations with clinicopathological variables and survival outcome were also investigated. The results demonstrated that TAP1 and TAP2 levels were highly associated with each other in individual samples and were upregulated in SCCOT compared with benign lesions (P<0.001). The proportion of TAP1- or TAP2-positive tumor cells was >80% in all but two of the tumors, whereas 25.6 and 23.0% of the tumors showed weak intensity of TAP1 and TAP2, respectively. There were no significant associations with clinicopathological variables or survival outcomes between TAP-intermediate/strong and TAP-weak tumors. However, in patients <70 years old and with early stage SCCOT, male patients had better outcomes than female patients (log-rank P<0.05), and the best outcome was observed in male patients with intermediate/strong TAP expression. In conclusion, loss of TAP was not a frequent event in SCCOT and stronger TAP expression in male patients was associated with improved survival, providing further evidence for sex-specific immune modulation in cancer.


Variation in antibiotic use in neonatal intensive care units in the Netherlands.
To examine the variation in quantity and classes of antibiotics used in all 10 tertiary care neonatal intensive care units (NICUs) in the Netherlands during 2005. We collected data from all tertiary care NICUs in the Netherlands on clinical and demographic characteristics and the type and quantity of systemic antibiotic use [expressed as defined daily doses (DDD)/100 admissions] in 2005. Antibiotics were ranked by volume of DDDs, and those antibiotics which accounted for 90% of the total volume of use [drug utilization (DU) 90%] were noted. Antibiotic consumption ranged from 130 to 360 DDD/100 admissions. In total, 9-24 different antibiotics were used, of which 3-10 were in the DU90% segment. By comparing antibiotic use in Dutch NICUs we found a considerable variation in the number of different antibiotics used and in the total amount of antibiotic use. Further exploration of the opportunities to reach consensus in antibiotic policy, and to increase attention to antibiotic stewardship, is recommended.


Molecular Networking Reveals the Chemical Diversity of Selaginellin Derivatives, Natural Phosphodiesterase-4 Inhibitors from Selaginella tamariscina.
Selaginellins are unique pigments found in the genus Selaginella, the largest genus of Lycopodiophyta. Recent studies reported that some selaginellin analogues have potent phosphodiesterase-4 (PDE4) inhibitory activity. In this study, the chemical diversity of natural selaginellin derivatives was revealed by an MS/MS molecular networking-based dereplication of the Selaginella tamariscina extract. It led to the prioritization of chromatographic peaks predicted as previously unknown selaginellin derivatives. Targeted isolation of these compounds afforded two unusual selaginellin analogues with a 1H,3H-dibenzo[de,h]isochromene skeleton, namely, selariscins A (1) and B (2), along with eight new diarylfluorene derivatives, selaginpulvilins M-T (3-10), and five known analogues, 11-15. The absolute configurations of 1, 2, and 8-10 were elucidated by spectroscopic data analyses including computational electronic circular dichroism data. Compounds 1 and 3-10 showed PDE4 inhibitory activity with IC50 values in the range of 2.8-33.8 μM, and their binding modes are suggested by a molecular docking study.


[Reconstruction technics for ruptured rotator cuff].
The principal signs for the diagnosis of a ruptured rotator sheath are a painful arch and painful, restricted movement of the shoulder joint. The diagnosis is confirmed by arthrography. Surgical reconstruction is indicated only if prior conservative treatment has been unsuccessful. A variety of approaches to the rotator sheath are advocated. Of these, the posterior-superior incision described by Debeyre et al. is particularly worthy of consideration. This approach is especially suitable for more extensive ruptures. It is described here with modifications, including the various fixation methods used for rupture of the rotator sheaths in the authors' own patients. The results obtained by the authors are classified and compared with opinions expressed in the literature. It is emphasized that the procedure described is particularly suitable for reconstruction of ruptured rotator sheaths.


Sex steroids and bone.
The adult skeleton is periodically remodeled by temporary anatomic structures that comprise juxtaposed osteoclast and osteoblast teams and replace old bone with new. Estrogens and androgens slow the rate of bone remodeling and protect against bone loss. Conversely, loss of estrogen leads to increased rate of remodeling and tilts the balance between bone resorption and formation in favor of the former. Studies from our group during the last 10 years have elucidated that estrogens and androgens decrease the number of remodeling cycles by attenuating the birth rate of osteoclasts and osteoblasts from their respective progenitors. These effects result, in part, from the transcriptional regulation of genes responsible for osteoclastogenesis and mesenchymal cell replication and/or differentiation and are exerted through interactions of the ligand-activated receptors with other transcription factors. However, increased remodeling alone cannot explain why loss of sex steroids tilts the balance of resorption and formation in favor of the former. Estrogens and androgens also exert effects on the lifespan of mature bone cells: pro-apoptotic effects on osteoclasts but anti-apoptotic effects on osteoblasts and osteocytes. These latter effects stem from a heretofore unexpected function of the classical "nuclear" sex steroid receptors outside the nucleus and result from activation of a Src/Shc/extracellular signal-regulated kinase signal transduction pathway probably within preassembled scaffolds called caveolae. Strikingly, estrogen receptor (ER) alpha or beta or the androgen receptor can transmit anti-apoptotic signals with similar efficiency, irrespective of whether the ligand is an estrogen or an androgen. More importantly, these nongenotropic, sex-nonspecific actions are mediated by the ligand-binding domain of the receptor and can be functionally dissociated from transcriptional activity with synthetic ligands. Taken together, these lines of evidence strongly suggest that, in sex steroid deficiency, loss of transcriptional effects may be responsible for the increased osteoclastogenesis and osteoblastogenesis and thereby the increased rate of bone remodeling. Loss of nongenotropic anti-apoptotic effects on mature osteoblasts and osteocytes, in combination with an opposite effect on the lifespan of mature osteoclasts, may be responsible for the imbalance between formation and resorption and the progressive loss of bone mass and strength. Elucidation of the dual function of sex steroid receptors has important pathophysiologic and pharmacologic implications. Specifically, synthetic ligands of the ER that can evoke the nongenotropic but not the genotropic signal may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are antiresorptive agents. The same ligands may also circumvent the side effects associated with conventional hormone replacement therapy.


Effect and comparison of sodium butyrate and trichostatin A on the proliferation/differentiation of K562.
In order to explore the molecular mechanisms of sodium butyrate and trichostatin A on K562 cell proliferation/differentiation, K562 cells were grown in the absence or presence of sodium butyrate or trichostatin A. The percentage of viable cells was determined by trypan blue exclusion. Differentiation was determined by nitro-blue tetrazolium (NBT) reduction and cell surface adhesion molecules analyzed by FACS. Cell cycle distribution was studied after DNA staining by propidium iodide. Cell cycle regulatory proteins were detected by Western blot and reverse transcription-polymerase chain reaction. The results showed that sodium butyrate blocked cells mainly at the G0/G1 phase of the cell cycle, whereas trichostatin A arrested the cells at G2 phase. Sodium butyrate could down-regulate the mRNA expression of cyclin D1, but not affect its protein expression; down-regulate the protein expression of cyclin D3, but not affect its mRNA expression. Trichostatin A showed similar effects on cyclin D1 and D3 as sodium butyrate. Both sodium butyrate and trichostatin A could stimulate p21 expression of K562 cells at mRNA and protein levels. It may be concluded that sodium butyrate and trichostatin A could promote the proliferation/differentiation of the K562 cells, which might be contributed to the induced expression of cyclin D3 and p21 proteins.


Photodissociation dynamics of the iodide-uracil (I(-)U) complex.
Photofragment action spectroscopy and femtosecond time-resolved photoelectron imaging are utilized to probe the dissociation channels in iodide-uracil (I(-) ⋅ U) binary clusters upon photoexcitation. The photofragment action spectra show strong I(-) and weak [U-H](-) ion signal upon photoexcitation. The action spectra show two bands for I(-) and [U-H](-) production peaking around 4.0 and 4.8 eV. Time-resolved experiments measured the rate of I(-) production resulting from excitation of the two bands. At 4.03 eV and 4.72 eV, the photoelectron signal from I(-) exhibits rise times of 86 ± 7 ps and 36 ± 3 ps, respectively. Electronic structure calculations indicate that the lower energy band, which encompasses the vertical detachment energy (4.11 eV) of I(-)U, corresponds to excitation of a dipole-bound state of the complex, while the higher energy band is primarily a π-π(∗) excitation on the uracil moiety. Although the nature of the two excited states is very different, the long lifetimes for I(-) production suggest that this channel results from internal conversion to the I(-) ⋅ U ground state followed by evaporation of I(-). This hypothesis was tested by comparing the dissociation rates to Rice-Ramsperger-Kassel-Marcus calculations.


An ab initio calculation of the vibronic energy levels of the X (2)Pi and 1 (2)Delta electronic states of C(2)P.
In the present study, the results of an ab initio calculation of the vibronic energy levels in the X (2)Pi and 1 (2)Delta electronic states of C(2)P are reported. This work is motivated by recent measurements carried out by [Sunahori et al. J. Chem. Phys. 128, 244311 (2008)]. The vertical electronic spectrum, excitation energies, bending potential curves, and spin-orbit constants for the title molecule are computed by means of the state-average complete active space self-consistent field and multireference configuration interaction approach. Vibronic energy levels of the X (2)Pi and 1 (2)Delta states are calculated with the help of a simple, effectively one-dimensional model. The results of the present study strongly support the analysis of experimental data by Sunahori et al. and offer reliable predictions for experimental searches for heretofore unobserved electronic states.


Rising incidence of clinically evident Barrett's oesophagus in The Netherlands: a nation-wide registry of pathology reports.
The incidence of oesophageal adenocarcinoma has increased steadily over the past few decades, but little information is available on trends in the incidence of its presumed precursor, Barrett's oesophagus (BO). The nation-wide registry of pathology reports (PALGA) was used to investigate time trends in the incidence of BO in The Netherlands. Standardized morbidity ratios (SMRs) were calculated to examine the magnitude of the changes. The study comprised 105,283 patients with a first-time biopsy taken from the oesophagus. Of these patients, 33,365 had BO, 6168 squamous cell carcinoma and 9854 had adenocarcinoma of the oesophagus, diagnosed between 1992 and 2003. The age-adjusted incidence of BO increased among men by 41% (95% confidence interval (CI) 38-44%). Among women, the increase was 23% (CI 19-26%) in 1996-99, followed by a slight decline in 2000-03. The increase was most notable among younger patients (<60 years), whereas the incidence remained stable among men and decreased among women aged 75 or older. Although the number of oesophageal biopsies increased by 21% among men and by 6% among women, the proportion of biopsies with a diagnosis of BO increased to a larger extent, by 33% (CI 30-36%) for men and by 25% (CI 22-29%) for women. The incidence of adenocarcinoma of the oesophagus increased by 28% for men and by 22% for women. Our findings show a significant increase in the incidence of clinically evident BO. Although changes in endoscopic practice may partly explain these findings, a true increase in the incidence of BO seems likely.


Comparison of carbohydrate content between grain-containing and grain-free dry cat diets and between reported and calculated carbohydrate values.
Objectives The aim of this study was to compare the carbohydrate content of grain-containing and grain-free dry cat diets and compare major protein and carbohydrate sources of these diets. Methods This was a cross-sectional study of 77 randomly selected dry cat diets (42 grain-containing, 35 grain-free). Reported carbohydrate values were compared between grain-containing and grain-free cat diets. A subset of 25% of diets from each category (grain-containing and grain-free) was analyzed and nitrogen-free extract was calculated as an estimate of carbohydrate content. These calculated values were compared with reported values from the manufacturer. Animal- and plant-sourced ingredients were also compared between grain-containing and grain-free diets. Results Mean reported carbohydrate content of the grain-free diets (n = 35) was lower than the grain-containing diets (n = 41; 64 ± 16 vs 86 ± 22 g/1000 kcal; P <0.001). Reported carbohydrate values were higher than analyzed nitrogen-free extract (n = 20; 79 ± 30 vs 73 ± 27 g/1000 kcal; P = 0.024). Poultry ( P = 0.009) and soy (P = 0.007) were less common in grain-free diets than in diets containing grain. The alternative carbohydrate sources of chickpeas, lentils, peas, potato, sweet potato and cassava/tapioca were more common ( P <0.05) in grain-free diets than in diets containing grain. Conclusions and relevance This sample of grain-free diets had lower mean reported carbohydrate content than grain-containing diets, but there was considerable overlap between groups and individual diets' carbohydrate/nitrogen-free extract content varied widely.


Evaluation of a fatigue model using data from published napping studies.
The authors have previously published the development and empirical validation of a work-related fatigue model. However, published work has not involved data from napping studies. The aim of this paper is to determine how closely the model predicts changes in subjective and objective measures from data published from napping studies. The regression results between the model outputs and logical reasoning, multiple sleep latency test scores, self-rated alertness, profile of mood state fatigue, visual vigilance and reaction time were all strong to very strong (R2 = 0.4-0.9). Only digit symbol substitution revealed moderate (R2 = 0.1-0.2) regression values. The outputs of the model reflect changes due to naps of varying duration and timing measured at varying periods following a nap. Together with the outputs from previous investigations, these results further support the potential use of the fatigue model in operational settings. This appears to be true in settings that utilise napping as well as those that do not.


Synthesis and biochemical evaluation of novel and potent inhibitors of the enzyme oestrone sulphatase (ES).
In an effort to investigate the structural requirements for the inhibition of the enzyme oestrone sulphatase (ES), we have previously undertaken extensive structure-activity relationship studies. Using the data from molecular modelling and structure-activity relationship determination studies, we have designed a number of compounds based upon 4-sulphamated phenyl ketones. Here, we report the results of our study into a series of these compounds as potential inhibitors of ES. The results of the study show that these compounds are potent inhibitors the possessing greater inhibitory activity than 4-methylcoumarin-7-O-sulphamate derivative (COUMATE) (a potent non-steroidal inhibitor), but are weaker than oestrone-3-sulphamate (EMATE) and the recently reported 667- and 669-COUMATE, however, they provide good lead compounds in the search for potent inhibitors of ES. Furthermore, the compounds are observed to be irreversible inhibitors. From the consideration of the structure-activity relationship of these novel compounds, we have attempted to rationalise the significance of the log P factor in the inhibition of ES and suggest that a log P requirement of approximately 3.5 aids the inhibition through the rapid expulsion of the carbon backbone from the active site. We also propose that the same factor is responsible for the hydrolysis of oestrone sulphate reaction, appearing to be an irreversible process.


Association between Work and Chronic Obstructive Pulmonary Disease (COPD).
To support occupational physicians in their assessment and notification of occupational diseases, diagnostic registration guidelines are developed with information about associations between work-related risk factors and diseases. The objective of this review of systematic reviews is to examine whether work-related risk factors are associated with chronic pulmonary obstructive disease (COPD). We searched the electronic database of Medline for systematic reviews published between 1 January 2009 and 20 June 2017. Reviews were included when COPD was assessed by data on lung function and when work-related exposures to vapors, dusts, gases, or fumes (VDGF) were described. One author selected studies and extracted data; two authors assessed study quality using A MeaSurement Tool to Assess systematic Reviews (AMSTAR). In all eight systematic reviews included, various exposures to vapors, dusts, gases, and fumes (VGDF) at work are associated with COPD. Two-thirds of the included studies are cross-sectional and show a high heterogeneity in population, setting, and mostly self-reported-exposures. Two high-quality reviews (AMSTAR score ≥ 9) including meta-analyses show associations and excess risk of COPD for work-related general exposure to VDGF with a summary odds ratio of 1.4 (95% confidence interval (CI) 1.19⁻1.73) and to inorganic dust with a mean difference in predicted forced expiratory volume in one second (FEV₁) of -5.7% (95% CI: -8.62% to -2.71%). Exposure to VGDF at work is associated with a small but increased risk of COPD. More detailed workplace measurements of specific VGDF are warranted to gain an insight into dose⁻response relationships.


Wear-resistant and antismudge superoleophobic coating on polyethylene terephthalate substrate using SiO2 nanoparticles.
It is of interest to create superoleophobic surfaces that exhibit high oil contact angle, low contact angle hysteresis, high wear resistance, antismudge properties, and optical transparency for industrial applications. In the superoleophobic surfaces developed to date, the mechanical durability data is lacking. By dip-coating polyethylene terephthalate substrate with hydrophobic SiO2 nanoparticles and methylphenyl silicone resin, followed by O2 plasma treatment and vapor deposition of 1H,1H,2H,2H-perfluorooctyltrichlorosilane, a durable superoleophobic surface was fabricated. The degree of superoleophobicity was found to be dependent on the particle-to-binder ratio. The coatings were found to exhibit wear resistance on microscale and macroscale, antismudge properties, and transparency.


Usual Course of Treatment and Predictors of Treatment Utilization for Patients With Posttraumatic Stress Disorder.
Posttraumatic stress disorder (PTSD) is a debilitating psychiatric illness that frequently remains undiagnosed and untreated. While extensive research has been conducted among veterans, little research has evaluated course of treatment for PTSD in a general hospital setting. We utilized data from the Partners HealthCare Research Patient Data Registry to evaluate mental health treatment utilization, including psychotherapy and pharmacotherapy, by patients with recently diagnosed primary PTSD following DSM-IV criteria between January 1, 2002, and June 30, 2011. We additionally evaluated predictors of treatment utilization 6 months postdiagnosis. Among 2,475 patients with recently diagnosed primary PTSD, approximately half (55.7%) had any therapy visit and 10% had at least 12 therapy visits in the 6 months following diagnosis. Approximately half (47.0%) received a psychiatric prescription, with 29.3% receiving a selective serotonin reuptake inhibitor (SSRI), 11.8% receiving an atypical antipsychotic, and 24.4% receiving a benzodiazepine. Latinos were 25% (95% CL = 1.09, 1.43) more likely to have an SSRI prescription, 35% (95% CL = 1.05, 1.75) more likely to have an atypical antipsychotic prescription, and 28% (95% CL = 1.19, 1.38) more likely to receive any psychotherapy. Women were 49% (95% CL = 0.42, 0.63) less likely to have an atypical antipsychotic prescription. Patients with Medicare were 23% (95% CL = 0.67, 0.88) less likely to have any psychotherapy, and patients with Medicaid were 35% (95% CL = 0.46, 0.92) less likely to have 12 or more therapy visits. Many patients with a primary diagnosis of PTSD do not receive psychotherapy, and psychiatric prescriptions, including atypical antipsychotics and benzodiazepines, are common. Future research is needed to determine the quality of care received and explore subpopulation-specific barriers limiting access to care.


Perception of silent and motionless prey on vegetation by echolocation in the gleaning bat Micronycteris microtis.
Gleaning insectivorous bats that forage by using echolocation within dense forest vegetation face the sensorial challenge of acoustic masking effects. Active perception of silent and motionless prey in acoustically cluttered environments by echolocation alone has thus been regarded impossible. The gleaning insectivorous bat Micronycteris microtis however, forages in dense understory vegetation and preys on insects, including dragonflies, which rest silent and motionless on vegetation. From behavioural experiments, we show that M. microtis uses echolocation as the sole sensorial modality for successful prey perception within a complex acoustic environment. All individuals performed a stereotypical three-dimensional hovering flight in front of prey items, while continuously emitting short, multi-harmonic, broadband echolocation calls. We observed a high precision in target localization which suggests that M. microtis perceives a detailed acoustic image of the prey based on shape, surface structure and material. Our experiments provide, to our knowledge, the first evidence that a gleaning bat uses echolocation alone for successful detection, classification and precise localization of silent and motionless prey in acoustic clutter. Overall, we conclude that the three-dimensional hovering flight of M. microtis in combination with a frequent emission of short, high-frequency echolocation calls is the key for active prey perception in acoustically highly cluttered environments.


De subitaneis mortibus. XXVII. Histological abnormalities in the sinus node, atrioventricular node and His bundle associated with coarctation of the aorta.
A twenty-year-old carpenter died suddenly and unexpectedly nine years after surgical treatment of coarctation of the aorta. Both before and after surgery he had paroxysmal atrial fibrillation, T wave inversions in the ECG and persisting cardiac hypertrophy. At postmortem examination there was focal fibromuscular dysplasia narrowing the sinus node artery, but other small coronary arteries were normal and there was no focal fibrosis of the ventricular myocardium. Within the sinus node there were several small glomera surrounding branches of the sinus node artery. Pericardial fibrosis was present over much of the heart, including margins of the sinus node. The central fibrous body was thickened, particularly on the left, and the His bundle was smaller than normal in cross section. The His bundle appeared displaced toward the right. The artioventricular (A-V) node was split into an upper and lower half tenuously connected through the central fibrous body which divided it. In its lower half the A-V node was directly continuous with ordinary myocardial cells of the interventricular septum. Possible developmental relationships between these unusual anatomical findings in the conduction system and coarctation of the aorta are discussed. How these findings might relate to the known electrophysiological disturbances and some causes for his sudden death are considered.


Costs and Charges for Pediatric Tonsillectomy in New York State.
Objective In this study, we aimed to determine the correlation between costs/charges related to admissions for pediatric tonsillectomy in New York State (NYS) and variables including discharge year, All Patient Refined (APR) severity of illness, length of hospital stay, payment typology, location, race, and institutional factors during 2009-2017. Methods Data were extracted from the Statewide Planning and Research Cooperative System (SPARCS) Hospital Inpatient Discharges database developed by the NYS Department of Health. Statistical analysis was employed to determine multiple linear regression coefficients with the costs and charges set as the dependent variable. Results Costs increased by an estimated $230.73 (p<.001) each year, and charges increased by an estimated $1,231.41 (p<.001) annually. For each categorical increase in severity of illness, costs increased by $1,019.21 (p<.001), and charges increased by $3,088.41 (p<.001). For each day spent in the hospital, costs increased by $3,539.23 (p<.001), and charges increased by $8,908.01 (p<.001). Unspecified managed care had the highest mean costs and charges (p<.001). Bronx County had the highest costs, and Queens County had the highest charges. Queens County demonstrated the largest gap between costs and charges. Conclusion This study revealed that the costs and charges related to admissions for elective tonsillectomy had risen from 2009 to 2017, and these changes were not accounted for by inflation alone. We found that the costs and charges for inpatient pediatric tonsillectomy were significantly correlated with discharge year, APR severity of illness, length of hospital stay, location of the hospital, and primary payer.


[Colorectal cancer. Progress and unsolved problems].
This review deals with colorectal carcinoma, the most frequent malignant tumor in western countries aside from skin cancer. Epidemiologic data confirm the crucial role of nutrition in the pathogenesis of these tumors. The pathology and natural history of colorectal cancers are reviewed. Screening programs have yielded encouraging first results. In recent years surgery of rectal cancer has been improved by the introduction of a new stapling device permitting more sphincter-saving operations. Pre- and postoperative radiotherapy as an adjuvant to surgery are important elements in the primary management of rectal carcinoma. Radiotherapy is often effective in palliating pain, bleeding, and mucous discharge. Chemotherapy of colorectal cancer is still unsatisfactory. The prospects for adjuvant chemotherapy are discussed. The often dismal outlook for patients with colorectal cancer will be more promising if etiological factors can be eliminated, early diagnosis improved and chemotherapy ameliorated.


VV116 as a potential treatment for COVID-19.
VV116 is a chemically-modified version of the antiviral remdesivir with oral bioavailability and potent activity against SARS-CoV-2. The optimal treatment of standard-risk outpatients who develop mild-to-moderate COVID-19 is controversial. While several therapeutic are currently recommended, including nirmatrelvir-ritonavir (Paxlovid), molnupiravir, and remdesivir, these treatments have substantial drawbacks, including drug-drug interactions and questionable efficacy in vaccinated adults. Novel therapeutic options are urgently needed. On 28 December 2022, a phase 3, observer-blinded, randomized trial was published evaluating 771 symptomatic adults with mild-to-moderate COVID-19 with a high risk of progression to severe disease. Participants were assigned to receive a 5-day course of either Paxlovid)\, which is recommended by the World Health Organization for treating mild-to-moderate COVID-19, or VV116 and the primary end point was the time to sustained clinical recovery through day 28. Among study subjects, VV116 was found to be noninferior to Paxlovid with respect to the time to sustained clinical recovery and with fewer safety concerns. This manuscript examines what is known about VV116 and explores how this novel treatment option may be used in the future to address the ongoing SARS-CoV-2 pandemic.


Obstruction of an ileal urinary conduit in an incarcerated right inguinal hernia.
We present the case of a 72-year-old man with a history of anuria from his ileal conduit 15 months following its formation. That conduit had become incarcerated in a right-sided ingunial hernia. The patient presented with anuria and an acute kidney injury. A clincal diagnosis of an incarcerated hernia was made, and he was taken to theatre for reduction and repair of the hernia. On removal of the conduit from the hernial sac, it began to drain immediately. He made a full recovery, with normalisation of his renal function.


Efficiency of the conditioned eyelid response.
A method for estimating directly the efficiency of the conditioned eyelid response is capable of reflecting marked chaniges in response efficiency during acquisition of the conditioned response. conditioned response.


Anthocyanin characterization of pilot plant water extracts of Delonix regia flowers.
Following the development of new applications of pilot plant scale extraction and formulation processes for natural active bioproducts obtained from various underutilized tropical plants and herbs, we have manufactured water-extracts from Delonix regia flowers, grown in Ivory Coast. These extracts, which contain polyphenols, are traditionally home made and used as healthy bioproducts. They are reddish-coloured due to the presence of anthocyanins. The three major anthocyanins in these extracts have been characterized. The molecular structures were confirmed by LC-SM analysis. Amongst them, two are described for the first time in Delonix regia.


Three diterpenoids (excoecarins V1-V3) and a flavanone glycoside from the fresh stem of Excoecaria agallocha.
Three new diterpenoids, excoecarins V1-V3 (1-3) and a new flavanone glycoside (7) were isolated from the fresh stem of Excoecaria agallocha L. Their structures were elucidated as: 2alpha,3alpha,18-trihydroxy-3beta,20-epoxybeyer-15-ene (1), ent-2,3-secokaur-16-en-2,3-dioic acid (2), ent-3,4-seco-16alpha-hydroxyatis-4(19)-en-3-oic acid (3), and 3,5,7,3',5'-pentahydroxy-2R,3R-flavanonol 3-O-alpha-L-rhamnopyranoside (7) on the basis of spectroscopic data, chemical evidence, and/or X-ray analysis.


Glomerulonephritis, Th1 and Th2: what's new?
Glomerulonephritis (GN), the major worldwide cause of chronic renal disease and renal failure, shows a wide spectrum of histological patterns, severity of injury and clinical outcomes that may be related to the nature of the nephritogenic immune response. In the majority of cases, there is evidence of a central role for cognate immunity in the initiation of human GN and contributions of both humoral and cellular effector mechanisms have been demonstrated in both humans and in animal models. T helper cell subsets are known to activate different immune effector mechanisms which influence disease outcomes in infectious and autoimmune diseases and evidence is now accumulating that Th1 and Th2 subsets direct diverging effector pathways that lead to different patterns and severity of glomerular injury in GN. Th1-predominant responses appear to be associated strongly with proliferative and crescentic forms of GN that result in severe renal injury, while Th2 responses are associated with membranous patterns of injury. The challenge remains to understand fully the relevance of T helper cell subset responses to the spectrum of human GN and to apply this new knowledge to the development of more potent and selective therapeutic strategies.


Terbinafine induces the PMNL priming effect and enhances in vitro PMNL fungicidal activity against Candida albicans blastospores.
Terbinafine, a new antifungal drug of the allylamine category, has been shown not to interfere with some polymorphonuclear leucocyte (PMNL) functions such as chemotaxis and chemiluminescence. The aim of the present study was to elucidate the effects of terbinafine on PMNL respiratory burst activation and killing of Candida albicans blastospores by PMNLs at the biochemical and ultrastructural level by means of scanning electron microscopy (SEM). Terbinafine is shown to enhance the respiratory burst and superoxide anion release in human PMNLs stimulated by phorbol esters or chemotactic peptides, and to have a priming effect on PMNL functions. Moreover, in our experiments we found that terbinafine does not interfere with PMNL killing of C. albicans blastospores but, in fact, at the concentration found in tissues after oral administration, slightly increases it. As PMNLs play a key role in the early stages of fungal infections we suggest that in vivo terbinafine induces priming of PMNLs, and that this effect is related to enhanced candidacidal activity independent of direct drug damage to fungal particles.


Detection of yellow fever virus in serum by enzyme immunoassay.
Yellow fever (YF) virus is present in patient's blood during the acute phase of illness. Virus isolation and identification provide a potential method of early diagnosis, but available techniques are slow and require specialized materials and equipment. An alternative approach is direct detection of YF antigen in serum by means of an enzyme-linked immunosorbent assay (ELISA). An antigen-capture ELISA was developed, which used anti-YF antibodies, immobilized on a solid phase (polystyrene plates), to capture YF virus from serum samples. After addition of the virus-containing sample, anti-YF detecting antibody conjugated to alkaline phosphatase was added to detect viral antigen. Trials with various capture and detecting antibodies in systems employing purified YF 17D virus, led to the selection of: 1) two capture antibodies (pooled human serum containing high titer YF IgM antibodies and a type-specific YF monoclonal antibody), and 2) a detecting antibody conjugate consisting of monoclonal antibody broadly cross-reactive with all flaviviruses, purified by affinity chromatography, and conjugated to alkaline phosphatase. The limit of sensitivity in tests against purified YF 17D virus diluted in buffer or normal human serum was 10(3.0) - 10(3.6) PFU/0.05 ml or 0.007-0.029 microgram viral protein/0.05 ml. Sera obtained at intervals from rhesus and cynomolgus monkeys after infection with a wild YF virus strain were tested. The limit of sensitivity of the assay applied to viremic monkey serum was similar (approximately 3.5 log10PFU/0.05 ml).(ABSTRACT TRUNCATED AT 250 WORDS)


Selective decontamination of the gastrointestinal tract in patients undergoing esophageal resection.
Selective decontamination of the digestive tract (SDD) to eliminate gram-negative bacteria is still not widely accepted, although it reduces the incidence of nosocomial infections. In a previous retrospective study, a clear benefit to perioperative morbidity, and a reduction in nosocomial infections were found in patients who underwent an esophageal anastomosis. Thus, SDD was applied routinely for esophageal anastomoses. We report the outcome of a cohort of 81 patients who underwent this treatment. From 2002, patients who underwent an esophageal anastomosis (esophagojejunostomy) were prospectively recorded. Perioperatively, patients received polymyxin, tobramycin, vancomycin and nystatin by mouth four times a day. Outcome was compared to a control group that was treated before 2002 (68 patients without SDD and 53 patients with SDD). Postoperative morbidity and mortality were assessed. Between 2002 and 2007, 81 patients who underwent an esophageal anastomosis received SDD. Compared to a retrospective control group, patients with SDD had significantly less pneumonia (OR 0.06 (0.01-0.46), p < 0.001) and lower morbidity (OR 0.16 (0.05-0.49), p < 0.001). Furthermore, fewer anastomotic insufficiencies and complications were found. Similar results were found in the analysis of the patients treated before 2002. SDD significantly reduces perioperative morbidity and mortality in patients who undergo a distal esophageal anastomosis compared to a historical control group. In patients with an anastomotic leakage, there was a strong tendency of SDD to reduce postoperative mortality.


LAMB3 Promotes Intestinal Inflammation Through SERPINA3 and Is Directly Transcriptionally Regulated by P65 in Inflammatory Bowel Disease.
Various extracellular matrix (ECM) reshaping events are involved in inflammatory bowel disease (IBD). LAMB3 is a vital subunit of laminin-332, an important ECM component. Data on the biological function of LAMB3 in intestinal inflammation are lacking. Our aim is to discuss the effect of LAMB3 in IBD. LAMB3 expression was assessed in cultured intestinal epithelial cells, inflamed mucosal tissues of patients and mouse colitis models. RNA sequencing, quantitative real-time polymerase chain reaction and Western blotting were used to detect the LAMB3 expression distribution and potential downstream target genes. Dual-luciferase assays and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to determine whether P65 could transcriptionally activate LAMB3 under tumor necrosis factor α stimulation. LAMB3 expression was increased in inflammatory states in intestinal epithelial cells and colonoids and was associated with adverse clinical outcomes in Crohn's disease. Knockdown of LAMB3 inhibited the expression of proinflammatory cytokines. Mechanistically, LAMB3 expression was directly transcriptionally activated by P65 and was inhibited by nuclear factor kappa B inhibitors under tumor necrosis factor α stimulation. Furthermore, RNA sequencing and replenishment experiments revealed that LAMB3 upregulated SERPINA3 to promote intestinal inflammation via the integrin α3β1/FAK pathway. We propose that LAMB3 could serve as a potential therapeutic target of IBD and a predictor of intestinal stenosis of Crohn's disease. Our findings demonstrate the important role of ECM in the progression of IBD and offer an experimental basis for the treatment and prognosis of IBD.


Association of anxious and depressive symptoms with medication nonadherence in patients with stable coronary artery disease.
Depression and anxiety lead to increased morbidity and mortality in patients with coronary artery disease (CAD). Medication nonadherence is one possible pathway contributing to adverse outcome, but it is unknown how either depression or anxiety itself influences adherence compared to combined depressive-anxious comorbidity. The aim of the study was to evaluate the influence of simultaneous depressive and anxious symptoms on medication adherence in patients with stable CAD. Between 02/2009 and 06/2010 we examined the association between current depressive and anxious symptoms with medication nonadherence in a cross-sectional study of 606 inpatients with stable CAD. Symptoms were assessed by using the Hospital Anxiety and Depression Scale. Morisky Medical Adherence Scale measured medication adherence. Depressive and anxious symptoms were weakly and independently associated with medication nonadherence (r=0.28, p<0.01 and r=0.27, p<0.01 respectively). Compared to non-depressed, patients with depressive symptoms had an up to 3.6-fold odds, those with anxious symptoms an up to 3.2-fold odds of nonadherence. The presence of combined anxiety and depressive symptoms was also weakly correlated with adherence (r=0.30, p<0.01). The risk for nonadherence in patients suffering from both anxiety and depression was up to 4.4 times higher compared to patients without symptoms. Apart from depressive symptoms, anxiety is a second important and independent marker for nonadherence in patients with coronary artery disease. The negative effect of anxiety on medication adherence increases in case of comorbid depressive symptoms. Future studies addressing medication adherence should focus more on anxious-depressive comorbidity than on singular depressive or anxious symptoms.


Differences in selection drive olfactory receptor genes in different directions in dogs and wolf.
The olfactory receptor (OR) gene family is the largest gene family found in mammalian genomes. It is known to evolve through a birth-and-death process. Here, we characterized the sequences of 16 segregating OR pseudogenes in the samples of the wolf and the Chinese village dog (CVD) and compared them with the sequences from dogs of different breeds. Our results show that the segregating OR pseudogenes in breed dogs are under strong purifying selection, while evolving neutrally in the CVD, and show a more complicated pattern in the wolf. In the wolf, we found a trend to remove deleterious polymorphisms and accumulate nondeleterious polymorphisms. On the basis of protein structure of the ORs, we found that the distribution of different types of polymorphisms (synonymous, nonsynonymous, tolerated, and untolerated) varied greatly between the wolf and the breed dogs. In summary, our results suggest that different forms of selection have acted on the segregating OR pseudogenes in the CVD since domestication, breed dogs after breed formation, and ancestral wolf population, which has driven the evolution of these genes in different directions.


Indicator-dilution dispersion models and cardiac output computing methods.
The general theory of indicator-dilution methods provides a basis for computing improved cardiac output estimates. Interpretation is via indicator-dispersion modeling with Brownian motion of drifting particles. Detected curves indicate the distribution of passage times from the injection site: the local density random walk (LDRW) function of a Wiener process. Fitting the LDRW to 70 dye curves by nonlinear regression for examples, I show how all possible undistorted curves can, in principle, be simulated. I show via semilogarithmic plots that conventional exponential decay constructs systematically underestimate cardiac output by up to 8%. To help reconcile the predictions of LDRW-fitted dilution curves and contemporary practice, I show how curve-shape asymmetry (skewness) dramatically affects the enclosed areas. Mean transit times may overestimate blood volumes by 15-100% in very skewed thermodilution curves if the dispersion effects are overlooked. Triangle constructions, which accounted for hundreds of experimental findings, also have theoretical explanations. Curve-fitting methods reduce the extrapolation biases inherent in many computers and in any respiration-induced artifacts. Compatibility of cardiac output predictions from various dilution methods and modules becomes feasible.


Unusual case of acute neck pain: acute calcific longus colli tendinitis.
Acute calcific longus colli tendinitis (ACLCT), a very rare cause of severe neck pain, dysphagia and odynophagia, is often mistaken for other common causes of neck pain. However, prompt recognition of this uncommon presentation is important to prevent unnecessary medical and surgical intervention. A 46-year-old Caucasian man presented with a 1-day history of severe neck pain, headache and odynophagia. The patient was afebrile with stable vital signs, however, the laboratory data showed mildly elevated C reactive protein and erythrocyte sedimentation rate. The physical examination was remarkable for markedly reduced cervical range of motion. MRI revealed the pathognomonic findings of paravertebral oedema and calcification. The definitive diagnosis of ACLCT was made and the patient was successfully managed with a short course of oral steroid, benzodiazepine and aural acupuncture, with complete resolution of the condition within a week.


Assessment and classification of choroidal vasculitis in posterior uveitis using indocyanine green angiography.
By allowing one to detect fluorescence beyond the retinal pigment epithelium, indocyanine green angiography (ICGA) has made it possible to analyse the choroidal vessels. Our aim was to characterize choroidal vasculitis in posterior uveitis using ICGA. Charts of active posterior uveitis patients with a specific diagnosis seen in the different centers participating in the study who had undergone dual fluorescein and ICG angiography were reviewed. The type of inflammatory involvement of the choroidal circulation at entry and the treatment response on follow-up angiograms were analysed. A total of 129 patients were analysed. Choroidal vasculitis could be subdivided into two main patterns: (1) primary inflammatory choriocapillaropathy and (2) stromal inflammatory vasculopathy. The first pattern consisted of hypofluorescent areas up to the late phase of angiography characteristic for choriocapillaris non-perfusion and included entities such as multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multifocal choroiditis (MC), ampiginous choroidopathy and serpiginous choroidopathy. The second pattern consisted of fuzzy indistinct appearance of vessels in the intermediate angiographic phase and diffuse choroidal hyperfluorescence in the late phase indicating inflammatory vasculopathy of larger choroidal vessels. This pattern was found in all cases of active Vogt-Koyanagi-Harada disease, ocular sarcoidosis and tuberculosis and birdshot chorioretinopathy. In Behçet's uveitis of recent onset, choriocapillaris perfusion delay and fuzzy choroidal vessels without diffuse late choroidal hyperfluorescence was found. In posterior scleritis, enlargement of vorticous veins was an additionnal ICGA sign. Stromal inflammatory vasculopathy always responded to anti-inflammatory therapy. A third group of patients with severe retinal or choroidal inflammation presented with associated secondary inflammatory choriocapillaropathy angiographically identical to the primary involvement. ICGA allowed the hitherto impossible characterization of inflammatory involvement of the choroidal vessels, showing either predominant inflammation of the choriocapillaris or predominant inflammation of the stromal choroidal vessels with or without secondary choriocapillaritis. ICGA will be indispensable for the correct evaluation and follow-up of posterior inflammation with suspected choroidal involvement.


Total synthesis and stereochemical assignment of bipolamide A acetate.
Asymmetric total synthesis of an acetate analogue of the endophytic unstable secondary metabolite bipolamide A has been achieved for the first time adopting a convergent approach. The key feature of this synthesis includes Evans's asymmetric ethylation, Wittig olefination, Takai olefination, stereoselective Grignard addition and intermolecular Heck coupling. This eventually developed a synthetic route of the rarely found branched amine bearing an acyloin moiety. Our synthesis finally established unambiguously the stereochemistry of the unassigned C-8 center of the naturally occurring unstable bipolamide A.


Impervious Surfaces Alter Soil Bacterial Communities in Urban Areas: A Case Study in Beijing, China.
The rapid expansion of urbanization has caused land cover change, especially the increasing area of impervious surfaces. Such alterations have significant effects on the soil ecosystem by impeding the exchange of gasses, water, and materials between soil and the atmosphere. It is unclear whether impervious surfaces have any effects on soil bacterial diversity and community composition. In the present study, we conducted an investigation of bacterial communities across five typical land cover types, including impervious surfaces (concrete), permeable pavement (bricks with round holes), shrub coverage (Buxus megistophylla Levl.), lawns (Festuca elata Keng ex E. Alexeev), and roadside trees (Sophora japonica Linn.) in Beijing, to explore the response of bacteria to impervious surfaces. The soil bacterial communities were addressed by high-throughput sequencing of the bacterial 16S rRNA gene. We found that Proteobacteria, Actinobacteria, Acidobacteria, Bacteroidetes, Chloroflexi, and Firmicutes were the predominant phyla in urban soils. Soil from impervious surfaces presented a lower bacterial diversity, and differed greatly from other types of land cover. Soil bacterial diversity was predominantly affected by Zn, dissolved organic carbon (DOC), and soil moisture content (SMC). The composition of the bacterial community was similar under shrub coverage, roadside trees, and lawns, but different from beneath impervious surfaces and permeable pavement. Variance partitioning analysis showed that edaphic properties contributed to 12% of the bacterial community variation, heavy metal pollution explained 3.6% of the variation, and interaction between the two explained 33% of the variance. Together, our data indicate that impervious surfaces induced changes in bacterial community composition and decrease of bacterial diversity. Interactions between edaphic properties and heavy metals were here found to change the composition of the bacterial community and diversity across areas with different types of land cover, and soil properties play a more important role than heavy metals.


"Do my qPCR calculation", a web tool.
In order to automatically process qPCR raw data, we present the tool "Do my qPCR calculation". We offer a website to automatically calculate the data normalization and represent the different samples graphically in an Excel file. This tool is also available on Github for installation and local use with or without web interface.


Mechanistic Insights into the Metal-Dependent Activation of ZnII-Dependent Metallochaperones.
Members of the COG0523 subfamily of candidate GTPase metallochaperones function in bacterial transition-metal homeostasis, but the nature of the cognate metal, mechanism of metal transfer, and identification of target protein(s) for metal delivery remain open questions. Here, we explore the multifunctionality of members of the subfamily linked to delivering ZnII to apoprotein targets under conditions of host-imposed transition-metal depletion. We examine two zinc-uptake repressor (Zur)-regulated COG0523 family members, each from a major human pathogen, Acinetobacter baumannii (AbZigA) and Staphylococcus aureus (SaZigA), in an effort to develop a model for ZnII metallochaperone activity. ZnII chelator competition experiments reveal one high-affinity (KZn1 ≈ 1010-1011 M-1) metal-binding site in each GTPase, while AbZigA and SaZigA are characterized by an additional one and two (lower-affinity) metal-binding sites, respectively. CoII titrations reveal that both metallochaperones have similar electronic absorption characteristics that indicate the presence of two tetrahedral metal coordination sites. High-affinity metal binding at the CXCC motif activates the GTPase activity of both enzymes, with ZnII more effective than CoII. Both GTPases bind the product, GDP, more tightly in the apoprotein than the ZnII-bound state and exhibit what is best described as a "locked" conformation around the GTP substrate. Negative thermodynamic linkage is observed between nucleotide binding and metal binding, leading to a new mechanistic model for COG0523-catalyzed metal delivery.


Expression of TNF-related apoptosis-inducing ligand in human hepatocellular carcinoma.
TNF-related apoptosis-inducing ligand (TRAIL), as well as Fas ligand, plays a pivotal role in lymphocyte cytotoxicity and the maintenance of immunological homeostasis in various tissues, but its physiological role in immune evasion of cancer cells remains unknown. We have previously shown strong resistance to TRAIL-induced cytotoxicity in human hepatocellular carcinomas (HCCs). The current study investigates the expression of TRAIL in HCCs. We found that three HCC cells, HepG2, Hep3B and Huh7 cells, constitutively express TRAIL mRNA and protein, as detected by reverse transcriptase PCR and Western blotting. Four of 10 human HCC tissues demonstrated positive staining for TRAIL, whereas non-tumor tissues showed little detectable staining. TRAIL expression on tumor cells was detected by flow cytometry and was dramatically induced after the addition of doxorubicin, a chemotherapeutic agent, or cytokine stimulation with TNF-alpha, IL-1beta or IL-18. This expression was induced principally via the NF-kappaB activation pathway, since IkappaB transfection significantly reduced TRAIL expression. In addition, the expressed TRAIL was functional. The TRAIL on HCC cells induced apoptosis in Jurkat cells that are sensitive to TRAIL-mediated apoptosis, and this process was specifically inhibited by recombinant TRAIL-receptors:Fc which binds to TRAIL. In conclusion, TRAIL expressed on the surface of HCC cells by cytokines or cytostatic drugs might contribute to an alternative mechanism that enables tumors to evade immune surveillance by inducing apoptosis of activated human lymphocytes.


Colorectal stenting in England: a cross-sectional study of practice.
UK and European guidelines recommend consideration of a self-expandable metallic stent (SEMS) as an alternative to emergency surgery in left-sided colonic obstruction. However, there is no clear consensus on stenting owing to concern for complications and long-term outcomes. Our study is the first to explore SEMS provision across England. All colorectal surgery department leads in England were contacted in 2018 and invited to complete an objective multiple choice questionnaire pertaining to service provision of colorectal stenting (including referrals, time, location and specialty). Of 182 hospitals contacted, 79 responded (24 teaching hospitals, 55 district general hospitals). All hospitals considered stenting, with 92% performing stenting and the remainder referring. The majority (93%) performed fewer than four stenting procedures per month. Most (96%) stented during normal weekday hours, with only 25% stenting out of hours and 23% at weekends. Compared with district general hospitals, a higher proportion of teaching hospitals stented out of hours and at weekends. Stenting was performed in the radiology department (64%), the endoscopy department (44%) and operating theatres (15%), by surgeons (63%), radiologists (60%) and gastroenterologists (48%). A radiologist was present in 66% of cases. Of 14 hospitals that received referrals, 3 had a protocol, 3 returned patients the same day and 4 returned patients for management in the event of failure. All responding hospitals in England consider the use of SEMS in colonic obstruction. Nevertheless, there is great variation in stenting practices, and challenges in terms of access and expertise. Centralisation and regional referral networks may help maximise availability and expertise but more work is needed to support this.


[CT and MRT following liver transplantation].
The potential technical complications after liver transplantation are numerous. CT is most useful in the evaluation of the hepatic parenchyma and in the identification of perihepatic fluid collections. CT provides complementary data when the sonographic findings in cases with suspected vascular or biliary complications are unclear. The value of MRI in the evaluation of liver transplants has not yet been fully determined. In patients with complex venous hemodynamics MRI can add useful information.


Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease.
To explore the clinical significance of restless legs syndrome (RLS) in Parkinson's disease (PD) and the causal relationship between these two disorders, we made a comparison of both the prevalence of RLS and the severity of sleep disturbance manifested on the Pittsburg Sleep Quality Index (PSQI) between patients with PD (n=165) and age- and sex-matched control subjects (n=131). The prevalence of RLS diagnosed by clinical interview was significantly higher in PD patients than in control subjects (12% vs. 2.3%). PSQI score was significantly higher in PD patients with RLS than in both patients without RLS and controls. However, PSQI score was not statistically different between the latter two groups. Among the PD patients with RLS, only 2 had a positive family history of RLS. Only 3 PD patients had requested treatment for the disorder. Our results emphasize the etiological link between RLS and PD in a Japanese cohort, and the existence of RLS is thought to be one of the most important factors aggravating sleep disturbance in PD, despite the low RLS severity.


Phosphorylation is the switch that turns PEA-15 from tumor suppressor to tumor promoter.
Abnormal ERK signaling is implicated in many human diseases including cancer. This signaling cascade is a good target for the therapy of certain malignancies because of its important role in regulating cell proliferation and survival. The small phosphoprotein PEA-15 is a potent regulator of the ERK signaling cascade, and, by acting on this pathway, has been described to have both tumor-suppressor and tumor-promoter functions. However, the exact mechanism by which PEA-15 drives the outcome one way or the other remains unclear. We propose that the cellular environment is crucial in determining PEA-15 protein function by affecting the protein's phosphorylation state. We hypothesize that only unphosphorylated PEA-15 can act as a tumor-suppressor and that phosphorylation alters the interaction with binding partners to promote tumor development. In order to use PEA-15 as a prognostic marker or therapeutic target it is therefore important to evaluate its phosphorylation status.


T cell clones in rheumatoid arthritis (RA).
The development of T cell clones has greatly enhanced our knowledge of pathogenetic mechanisms in autoimmune diseases. Thus, it has been possible to induce experimental arthritis in susceptible animals by solely injecting arthritogenic T cell lines or clones. In contrast to many animal models, in rheumatoid arthritis the inciting antigen(s) have still not been identified. However, it has been possible to raise T cell clones from the inflammatory membrane by the addition of Interleukin-2 and/or mitogens. These clones are primarilig of the CD4+ (helper/inducer) phenotype. Molecular analyses on T cell receptor genes have not clearly shown a predominant rearrangement pattern in most studies indicating a polyclonal origin of RA synovial T cells. The availability of T cell clones will clearly help in the near future to probe for the inducing antigen(s) in inflammatory rheumatic diseases thus rendering a basis for new immunotherapeutic approaches.


Airborne brake wear debris: size distributions, composition, and a comparison of dynamometer and vehicle tests.
Particle size distributions of light-duty vehicle brake wear debris are reported with careful attention paid to avoid sampling biases. Electrical low-pressure impactor and micro-orifice uniform deposit impactor measurements yield consistent size distributions, and the net particulate matter mass from each method is in good agreement with gravimetric filter measurements. The mass mean diameter of wear debris from braking events representative of urban driving is 6 microm, and the number-weighted mean is 1-2 microm for three currently used classes of lining materials: low metallic, semimetallic, and non-asbestos organic (NAO). In contrast, the wear rates are very material dependent, both in number and mass of particles, with 3-4 times higher emissions observed from the low metallic linings as compared to the semimetallic and NAO linings. Wind tunnel and test track measurements demonstrate the appearance of micron size particles that correlate with braking events, with approximately 50% of the wear debris being airborne for the test vehicle in this study. Elemental analysis of the wear debris reveals a consistent presence of the elements Fe, Cu, and Ba in both dynamometer and test track samples.


Solid lipid nanoparticles for the delivery of 1,3,5-triaza-7-phosphaadamantane (PTA) platinum (II) carboxylates.
The use of solid lipid nanoparticles (SLN) is a promising route for the delivery of platinum complexes aimed to anticancer activity. This paper describes the production and characterization of SLN suitable for the loading of Pt complexes containing the biocompatible phosphine 1,3,5-triaza-7-phosphaadamantane (PTA) as neutral ligand. After a screening of several lipidic phases, stearic acid-based SLN were identified as the most appropriate for the purpose. They were produced by emulsion-dilution method and then characterized in terms of dimension, polydispersity, time stability, pH balance and morphological aspect. Stearic acid SLN are designed as a system able to coordinate to platinum, acting as anionic carboxylic ligands, replacing the base carbonate of the Pt synthon [PtCO3(DMSO)2], where also DMSO can subsequently be substituted by phosphinic ligands, namely PTA. SLN functionalised with Pt-PTA were produced and characterized by this synthetic route. The toxicity of plain SLN and the antiproliferative effect of SLN functionalised with Pt-PTA were evaluated on two human cancer cell lines K562 and A2780. The results indicate that SLN can be exploited as a delivery system for Pt complexes with potential anticancer activity.


Silyamandin, a new flavonolignan isolated from milk thistle tinctures.
Our investigations into the stability of tincture preparations of milk thistle fruit [ Silybum marianum L. Gaertn. (Asteraceae)] have led to the characterization of a new flavonolignan 4-(4-hydroxy-3-methoxyphenyl)-7-[(2 R,3 R)-3,5,7-trihydroxy-4-oxochroman-2-yl]-1-oxo-1,3,3a,4,5,7a-hexahydro-2-benzofuran-5-carboxylic acid called silyamandin (1). Incubation of the tincture at 40 degrees C for 3 months resulted in an increase in the level of this compound, as observed in the LC/DAD silymarin profile.


Bootstrap Statistics and Its Application in Disintegration and Dissolution Data Analysis.
Disintegration time (DT) and rate of drug dissolution in different media are among the most widely studied crucial parameters for various types of drug products. In the ever-evolving landscape of generic formulation development, dissolution comparison of reference and test products is the major reliable in vitro method of establishing product similarity. This is one of the most widely accepted methods of proving pharma equivalency between two drug products. A well-studied match between the disintegration and dissolution profile of the test and reference formulations can ensure in vitro product similarity. Various statistical approaches have been employed to establish product performance similarity; among them, the similarity factor (f2) calculation based approach is the most widely accepted and explored method to date. However, the f2 statistics fail to predict the similarity of batches with unit-to-unit variability. Bootstrap statistical analysis of dissolution data between the test and reference products was introduced to overcome the problems associated with batches with unit variability. Bootstrap can also be applied to extract statistically significant results by treating a series of data from different batches, which can further help to understand the trend. The current review depicts different case study based approaches to show the applications of bootstrap statistics in disintegration and dissolution similarity evaluation for both conventional and additively manufactured solid dosage forms. It is concluded that bootstrap statistics can be a very promising and reliable data analytical tool for establishing in vitro product similarity for both conventional and additively manufactured formulations with a high level of intraunit variability.