Present and future drug treatment for Parkinson's disease.
Considerable advances made in defining the aetiology, pathogenesis, and pathology of Parkinson's disease (PD) have resulted in the development and rapid expansion of the pharmacopoeia available for treatment. Anticholinergics were used before the introduction of levodopa which is now the drug most commonly used. Dopamine agonists are effective when used alone or as an adjunct to levodopa, while monoamine oxidase B inhibitors improve motor function in early and advanced PD. However, treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected; the drug treatment available for the management of non-motor symptoms is limited. This article seeks to set current treatment options in context, review emerging and novel drug treatments for PD, and assess the prospects for disease modification. Surgical therapies are not considered.


A bad disease, a fatal cure: why sterilization is permissible and the autonomy of medicine is not.
The debate in this issue regarding the Roman Catholic condemnation of the morality of sterilization is puzzling for Protestants. As I will argue the puzzlement arises on two grounds. First, why would anyone object to direct sterilization for the cure or prevention of disease? Second, if one wanted to challenge such an objection on moral grounds why would one turn to medicine to do so? For Christian ethics there is nothing wrong in principle with direct sterilization when there are good reasons for precluding the possibility of an additional pregnancy; and it is a serious theological mistake to treat medicine as an independent moral authority.


Apoptosis-related genes induced in response to ketamine during early life stages of zebrafish.
Increasing evidence supports that ketamine, a widely used anaesthetic, potentiates apoptosis during development through the mitochondrial pathway of apoptosis. Defects in the apoptotic machinery can cause or contribute to the developmental abnormalities previously described in ketamine-exposed zebrafish. The involvement of the apoptotic machinery in ketamine-induced teratogenicity was addressed by assessing the apoptotic signals at 8 and 24 hpf following 20min exposure to ketamine at three stages of early zebrafish embryo development (256 cell, 50% epiboly and 1-4 somites stages). Exposure at the 256-cell stage to ketamine induced an up-regulation of casp8 and pcna at 8 hpf while changes in pcna at the mRNA level were observed at 24 hpf. After the 50% epiboly stage exposure, the mRNA levels of casp9 were increased at 8 and 24 hpf while aifm1 was affected at 24 hpf. Both tp53 and pcna expressions were increased at 8 hpf. After exposure during the 1-4 somites stage, no meaningful changes on transcript levels were observed. The distribution of apoptotic cells and the caspase-like enzymatic activities of caspase-3 and -9 were not affected by ketamine exposure. It is proposed that ketamine exposure at the 256-cell stage induced a cooperative mechanism between proliferation and cellular death while following exposure at the 50% epiboly, a p53-dependent and -independent caspase activation may occur. Finally, at the 1-4 somites stage, the defence mechanisms are already fully in place to protect against ketamine-insult. Thus, ketamine teratogenicity seems to be dependent on the functional mechanisms present in each developmental stage.


Waste dry cell derived photo-reduced graphene oxide and polyoxometalate composite for solid-state supercapacitor applications.
In the modern era, realizing highly efficient supercapacitors (SCs) derived through green routes is paramount to reducing environmental impact. This study demonstrates ways to recycle and reuse used waste dry cell anodes to synthesize nanohybrid electrodes for SCs. Instead of contributing to landfill and the emission of toxic gas to the environment, dry cells are collected and converted into a resource for improved SC cells. The high performance of the electrode was achieved by exploiting battery-type polyoxometalate (POM) clusters infused on a reduced graphene oxide (rGO) surface. Polyoxometalate (K5[α-SiMo2VW9O40]) assisted in the precise bottom-up reduction of graphene oxide (GO) under UV irradiation at room temperature to produce vanadosilicate embedded photo-reduced graphene oxide (prGO-Mo2VW9O40). Additionally, a chemical reduction route for GO (crGO) was trialed to relate to the prGO, followed by the integration of a faradaic monolayer (crGO-Mo2VW9O40). Both composite frameworks exhibit unique hierarchical heterostructures that offer synergic effects between the dual components. As a result, the hybrid material's ion transport kinetics and electrical conductivity enhance the critical electrochemical process at the electrode's interface. The simple co-participation method delivers a remarkable specific capacity (capacitance) of 405 mA h g-1 (1622 F g-1) and 117 mA h g-1 (470 F g-1) for prGO-Mo2VW9O40 and crGO-Mo2VW9O40 nanocomposites alongside high capacitance retentions of 94.5% and 82%, respectively, at a current density of 0.3 A g-1. Furthermore, the asymmetric electrochromic supercapacitor crGO//crGO-Mo2VW9O40 was designed, manifesting a broad operating potential (1.2 V). Finally, the asymmetric electrode material resulted in an enhanced specific capacity, energy, and power of 276.8 C g-1, 46.16 W h kg-1, and 1195 W kg-1, respectively, at a current density of 0.5 A g-1. The electrode materials were tested in the operating of a DC motor.


Cold-stress response during the stationary-growth phase of Antarctic and temperate-climate Penicillium strains.
Cold-induced oxidative stress during the aging of three Penicillium strains (two Antarctic and one from a temperate region) in stationary culture was documented and demonstrated a significant increase in the protein carbonyl content, the accumulation of glycogen and trehalose, and an increase in the activities of antioxidant enzymes (superoxide dismutase and catalase). The cell response to a temperature downshift depends on the degree of stress and the temperature characteristics of the strains. Our data give further support for the role of oxidative stress in the aging of fungi in stationary cultures. Comparing the present results for the stationary growth phase with our previous results for the exponential growth phase was informative concerning the relationship between the cold-stress response and age-related changes in the tested strains. Unlike the young cells, stationary-phase cultures demonstrated a more pronounced level of oxidative damage, as well as decreased antioxidant defence.


Infarct tissue heterogeneity by contrast-enhanced magnetic resonance imaging is a novel predictor of mortality in patients with chronic coronary artery disease and left ventricular dysfunction.
Strategies for prevention of sudden cardiac death focus on severe left ventricular (LV) dysfunction, although most sudden cardiac death postmyocardial infarction occurs in patients with mild/moderate LV dysfunction. We tested the hypothesis that infarct heterogeneity by cardiac magnetic resonance is associated with mortality beyond LV ejection fraction (LVEF) in patients with coronary artery disease and LV dysfunction. In addition, we examined the association between infarct heterogeneity and mortality in those with LVEF >35%. We studied 301 patients with coronary artery disease and LV dysfunction referred for cardiac magnetic resonance. We quantified total infarct mass, infarct core mass, and peri-infarct zone (PIZ) normalized for total infarct mass (%PIZ) using signal-intensity criteria of >2 SDs, >3 SDs, and 2- to -3 SDs above remote myocardium, respectively. Mean LVEF was 41 ± 14%. After 3.9 years median follow-up, 66 (22%) patients died (13 sudden cardiac death; 33 with LVEF >35%). In patients with LVEF >35%, below-median %PIZ carried an annual death rate of 2.8% versus 12% in patients with above-median %PIZ (P<0.001). In a multivariable model, %PIZ maintained strong association with mortality adjusted to patient age, LVEF, right ventricular ejection fraction, prolonged QT interval, and total infarct size and resulted in improve risk reclassification 0.492 (95% confidence interval, 0.183-0.817). Cardiac magnetic resonance infarct heterogeneity has a strong association with mortality independent of LVEF in patients with coronary artery disease and LV dysfunction, particularly in patients with mild or moderate LV dysfunction. Further studies incorporating cardiac magnetic resonance in clinical decision making for defibrillator therapy are warranted.


Two new ent-kaurane diterpenoids from Pteris semipinnata.
In this study, two new compounds and six known compounds were isolated from the aerial parts of Pteris semipinnata. The chemical structures of these two new compounds were elucidated as 6β,11α-dihydroxy-15-oxo-ent-kaur-16-en-19-oic acid (1) and 7α,11α-dihydroxy-15-oxo-ent-kaur-16-en-19-oic acid (2) by the extensive spectral methods including 2D NMR and HR-MS techniques.


Influence of carnitine supplementation on muscle substrate and carnitine metabolism during exercise.
We examined 1) the effect of L-carnitine supplementation on free fatty acid (FFA) utilization during exercise and 2) exercise-induced alterations in plasma levels and skeletal muscle exchange of carnitine. Seven moderately trained human male subjects serving as their own controls participated in two bicycle exercise sessions (120 min, 50% of VO2max). The second exercise was preceded by 5 days of oral carnitine supplementation (CS; 5 g daily). Despite a doubling of plasma carnitine levels, with CS, there were no effects on exercise-induced changes in arterial levels and turnover of FFA, the relation between leg FFA inflow and FFA uptake, or the leg exchange of other substrates. Heart rate during exercise after CS decreased 7-8%, but O2 uptake was unchanged. Exercise before CS induced a fall from 33.4 +/- 1.6 to 30.8 +/- 1.0 (SE) mumol/l in free plasma carnitine despite a release (2.5 +/- 0.9 mumol/min) from the leg. Simultaneously, acylated plasma carnitine rose from 5.0 +/- 1.0 to 14.2 +/- 1.4 mumol/l, with no evidence of leg release. Consequently, total plasma carnitine increased. We concluded that in healthy subjects CS does not influence muscle substrate utilization either at rest or during prolonged exercise and that free carnitine released from muscle during exercise is presumably acylated in the liver and released to plasma.


Model development and validation of noninvasive parameters based on coronary computed tomography angiography to predict culprit lesions in acute coronary syndromes within 3 years: value of plaque characteristics, hemodynamics and pericoronary adipose tissue.
Machine learning (ML) is combined with noninvasive parameters from coronary computed tomography angiography (CTA) to construct predictive models to identify culprit lesions that may lead to acute coronary syndrome (ACS). We retrospectively analyzed 132 patients with ACS at the Fourth Affiliated Hospital of Harbin Medical University who had coronary CTA between 3 months and 3 years before the ACS event, with a total of 240 lesions. Lesions from 2020 (n=154) were included in the training set, and lesions from 2021 (n=86) were included in the test set for internal validation. We evaluated the role of plaque characteristics, hemodynamic parameters and pericoronary adipose tissue (PCAT) attenuation from CTA in identifying culprit ACS lesions. In the training set, logistic regression was used to screen CTA-derived parameters with P values <0.05 for the model construction. Logistic regression, random forest, Bayesian and K-nearest neighbor algorithms were used to build classification models, and their performance was assessed using the test set. The following models were established to evaluate the effectiveness of different combinations of models to identify culprit lesions: Model 1 was established for plaque characteristics; Model 2 was established for hemodynamic parameters; Model 3 was established for PCAT attenuation; Model 4 was established for plaque characteristics and hemodynamic parameters; and Model 5 was established for plaque characteristics, hemodynamic parameters and PCAT attenuation. A total of ten high-risk factors were screened for the ML model construction, and the ML model based on the logistic regression algorithm had the best performance among the four algorithms (accuracy =0.721; sensitivity =0.892; specificity =0.592; positive prediction =0.623; and negative prediction =0.879). In this model, the minimum lumen area, positive remodeling and lesion-specific fat attenuation index (FAI) were the risk factors significantly associated with the culprit lesion. Analysis of the effect of different combinations of models to identify culprit lesions showed that Model 5 had the best predictive effect (AUC =0.819 and 95% CI: 0.722-0.916). ACS can be predicted using ML based on CTA parameters. Compared to other models, the model combining plaque characteristics, hemodynamic parameters and PCAT attenuation performed best in predicting the culprit lesion.


Decomposition of radiation energy into work and heat.
We investigate energy transfer by the radiation from a cavity quantum electrodynamics system in the context of quantum thermodynamics. We propose a method of decomposing it into work and heat within the framework of quantum master equations. We find that the work and heat correspond, respectively, to the coherent and incoherent parts of the radiation. In the derivation of the method, it is crucial to investigate the dynamics of the system that receives the radiation from the cavity.


[A case of Mondor's disease of the penis].
A case of Mondor's disease of the penis in a 40-year-old man is reported. The patient complained of a small subcutaneous induration (0.5 x 1.0 cm) with slight tenderness in the dorsal region of the penile shaft. On examination, the linear cord was palpated running both distally and proximally from the induration. This lesion was removed under local anesthesia, and the induration and the cord were found to be part of the superficial dorsal vein of the penis. The venous wall was thick and the thrombus was packed in it. Histological findings showed the proliferation of connective tissue of the vessel wall and partially granulating thrombus in the canal. From these findings, we confirmed the diagnosis of Mondor's disease of the penis. The etiology of this disease, especially in comparison with non-venereal sclerosing lymphangitis of the penis (N.S.L.P.) is discussed.


Improvement of atrial signal-averaged electrocardiographic abnormalities after radiofrequency catheter ablation in persistent atrial flutter.
It has been reported that abnormalities of atrial conduction are present in patients with atrial flutter (AFL). We analyzed the P wave signal-averaged ECG (PSE) in patients after cardioversion of chronic AFL by radiofrequency catheter ablation (RFCA) to determine whether abnormalities of atrial conduction exist in patients with AFL and whether they recover. We studied 11 patients undergoing ablation of persistent AFL (AFL group), 11 patients with paroxysmal AFL (PAFL group), and 14 patients without any evidence of arrhythmias (control group). The PSEs were recorded 1 day, 7 days, and 1 month after RFCA. The filtered P wave duration (FPD) was calculated from the PSE recording. The FPD correlated with interatrial conduction time (r = 0.644) and left atrial dimension (r = 0.675) in combined assessment of the AFL and PAFL groups. The FPD was longer in the AFL group 1 day (165 +/- 14 ms, P < 0.001) and 1 month (150 +/- 18 ms, P < 0.05) after RFCA than in the control group (134 +/- 10 ms). Our findings suggest that atrial conduction abnormalities detected by PSE are present in patients with persistent AFL and improve 1 month after cardioversion.


Utilization of Diaphragm Motion to Predict the Displacement of Liver Tumors for Patients Treated with Carbon ion Radiotherapy.
Objectives: To establish and validate a linear model utilizing diaphragm motion (DM) to predict the displacement of liver tumors (DLTs) for patients who underwent carbon ion radiotherapy (CIRT). A total of 60 pairs of planning and reviewing four-dimensional computed tomography (4DCT) sets over 23 patients were used. Method: We constructed an averaged computed tomography (CT) set for each either planning or reviewing 4DCT within respiratory phases between 20% of exhale and inhale. A rigid image registration to align bony structures was performed between planning and reviewing 4DCT. The position changes on top of diaphragm in superior-inferior (SI) direction between 2 CTs to present DM were obtained. The translational vectors in SI from matching to present DLT were obtained. The linear model was built by training data for 23 imaging pairs. A distance model utilized the cumulative probability distribution (CPD) of DM or DLT and was compared with the linear model. We conducted the statistical regression analysis with receiver operating characteristic (ROC) testing data of 37 imaging pairs to validate the performance of our linear model. Results: The DM within 0.5 mm was true positive (TP) with an area under the ROC curve (AUC) of 0.983 to predict DLT. The error of predicted DLT within half of its mean value indicated the reliability of prediction method. The 23 pairs of data showed (4.5 ± 3.3) mm for trend of DM and (2.2 ± 1.6) mm for DLT. A linear model of DLT = 0.46*DM + 0.12 was established. The predicted DLT was (2.2 ± 1.5) mm with a prediction error of (0.3 ± 0.3) mm. The accumulated probability of observed and predicted DLT with < 5.0 mm magnitude was 93.2% and 94.5%, respectively. Conclusion: We utilized the linear model to set the proper beam gating for predicting DLT within 5.0 mm to treat patients. We will investigate a proper process on x-ray fluoroscopy images to establish a reliable model predicting DLT for DM observed in x-ray fluoroscopy in the following two years.


Selenium deficiency causes immune damage by activating the DUSP1/NF-κB pathway and endoplasmic reticulum stress in chicken spleen.
Selenium (Se) is an essential trace element and its deficiency can lead to immune dysfunction. Many studies have investigated the immune damage caused by Se deficiency in chickens, but its mechanism still needs to be explored. In this study, we fed 1-day-old Hyline male chickens with Se deficient diets (the Se content was 0.008 mg kg-1 of diet) and a basal diet (the Se content was 0.15 mg kg-1 of diet). The spleen was collected at the sixth week and used for subsequent experiments. The pathological analysis showed that Se deficiency leads to the destruction of the normal nuclear structure of the spleen cell, and we can observe obvious chromatin condensation and nuclear debris. We constructed a transcriptome database and analyzed the abundance of various genes in the spleen by transcriptome sequence. The analysis of differentially expressed genes (DEGS) showed significant changes in 337 genes, including 210 up-regulations and 127 down-regulations after feeding Se deficient diets. Se deficiency can significantly change oxidative stress and inflammatory response genes in chicken spleen. This study confirmed that Se deficiency increased the IL-2 levels, whereas it down-regulated IL-17, IFN-γ and Foxp3, which indicates that the immune dysfunction of the spleen and Th1/Th2 is imbalanced. We also found that Se deficiency down-regulated some related genes for endoplasmic reticulum Ca2+ transport, leading to endoplasmic reticulum stress (ERS). Moreover, we determined that Se deficiency triggered the low expression of DUSP1/NF-κB. In summary, our results indicate that Se deficiency can inhibit the spleen immune function of chickens by regulating the DUSP1/NF-κB pathway and ERS, leading to spleen damage in chickens. Based on transcriptomics research, our results will help further study the harmful effects of Se deficiency.


The ethics of cesarean section by choice.
In responding to patient requests for cesarean section, physicians must consider ethical principles. Obstetricians have autonomy and beneficence-based obligations to the mother, and the mother and the obstetrician have beneficence-based obligations to the fetus. Maternal autonomy is usually accepted as the most compelling ethical canon. However, the physician has a right to refuse requests. Thus, when a patient requests surgery, the physician may attempt to dissuade her and failing that either acquiesce or, feeling that professional conscience would not allow him/her to honor that request, refuse. Which choice is made should reflect the provider's believe about the strength of the supporting data. Given the need to recognize patient autonomy, to respect patient values even as one tries to motivate patients to work toward the highest health values, and to acknowledge women's primacy as fetal champions, a physician should be loathe to refuse unless the data regarding cesarean section by choice are wholly tilted away from maternal-child interests. If the data are in the realm of equipoise, even if not at the tipping point, discussing options, attempting to dissuade patients but ultimately acquiescing to their judgment would not be incompatible with obstetrical ethics.


Use and diagnostic value of liver enzyme tests in the emergency department and subsequent heart failure diagnosis: a retrospective cohort study.
To determine (1) if liver function tests (LFTs) are ordered in the emergency department (ED) in patients with suspected acute decompensated heart failure (ADHF) and (2) if the pattern of LFT abnormalities are meaningfully associated with a discharge diagnosis of ADHF among patients for whom these tests were ordered. We conducted a single-centre retrospective cohort study of patients with suspected ADHF who were seen in an academic tertiary ED using electronic medical records. All ED patients admitted with suspected ADHF from January 2017 to May 2018, defined as any patient who had a brain natriuretic peptide (BNP) ordered. The primary outcome was ADHF diagnosis at discharge. In 5323 ED patients with suspected ADHF, 60% (n=3184) had LFTs ordered; 34.6% were abnormal. Men comprised 56% of patients with abnormal LFTs and the average age was 67 years. The odds of a final diagnosis of ADHF in the univariate analysis was 59% higher in patients with abnormal LFTs (OR=1.59, (95% CI 1.35 to 1.87) p<0.001) and remained significant though attenuated after adjusting for BNP, race and ethnicity and age (ORadj=1.31 (95% CI 1.09 to 1.57), p=0.004). Likelihood ratios for abnormal and normal LFTs were 1.2 (95% CI 1.21 to 1.28) and 0.76 (95% CI 0.68 to 0.84), respectively. A significant proportion (40%) of patients with suspected ADHF was missing LFTs in their ED workup. Among patients with LFTs, abnormal LFTs are associated with discharge diagnosis of ADHF after accounting for potential confounders, but their diagnostic value was relatively low. Future prospective studies are warranted to explore the role of LFTs in the workup of ADHF.


Congenital central alveolar hypoventilation syndrome (Ondine's curse) with survival into adulthood.
Ondine's curse or central alveolar hypoventilation (CCAH) syndrome is a disorder of the autonomic nervous system resulting in respiratory dysregulation. The clinical outcome is typically poor, with few individuals living into adulthood and even fewer surviving to adulthood with normal neurological function. Our patient initially presented following an uncomplicated delivery with hypotonia, poor respiratory effort, and hypoxemia that required ventilatory support. Laboratory workup, radiographic evaluation, and ancillary testing ruled out brain stem lesions, neuromuscular diseases, cardiovascular and pulmonary disease, and metabolic disorders, resulting in a diagnosis of CCAH syndrome. The patient underwent tracheotomy and chronic ventilatory support. Close long-term management and appropriate treatment modifications have provided for an excellent outcome and good quality of life. The patient is currently 22 years old and is earning her teaching degree for K-12 art education. A combination of early recognition and a multidisciplinary approach may lead to a successful outcome in patients with CCAH syndrome.


Gamete activation: basic knowledge and clinical applications.
The first clues to the process of gamete activation date back to nearly 60 years ago. The mutual activation of gametes is a crucial event during fertilization. In the testis and ovaries, spermatozoa and oocytes are in a state of meiotic and metabolic quiescence and require reciprocal signals in order to undergo functional changes that lead to competence for fertilization. First, the oocyte activates sperm by triggering motility, chemoattraction, binding and the acrosome reaction, culminating with the fusion of the two plasma membranes. At the end of this cascade of events, collectively known as sperm capacitation, sperm-induced oocyte activation occurs, generating electrical, morphological and metabolic modifications in the oocyte. The aim of this review is to provide the current state of knowledge regarding the entire process of gamete activation in selected specific animal models that have contributed to our understanding of fertilization in mammals, including humans. Here we describe in detail the reciprocal induction of the two activation processes, the molecules involved and the mechanisms of cell interaction and signal transduction that ultimately result in successful embryo development and creation of a new individual. We carried out a literature survey with no restrictions on publication date (from the early 1950s to March 2016) using PubMed/Medline, Google Scholar and Web of Knowledge by utilizing common keywords applied in the field of fertilization and embryo development. We also screened the complete list of references published in the most recent research articles and relevant reviews published in English (both animal and human studies) on the topics investigated. Literature on the principal animal models demonstrates that gamete activation is a pre-requisite for successful fertilization, and is a process common to all species studied to date. We provide a detailed description of the dramatic changes in gamete morphology and behavior, the regulatory molecules triggering gamete activation and the intracellular ions and second messengers involved in active metabolic pathways in different species. Recent scientific advances suggest that artificial gamete activation may represent a novel technique to improve human IVF outcomes, but this approach requires caution. Although controversial, manipulation of gamete activation represents a promising tool for ameliorating the fertilization rate in assisted reproductive technologies. A better knowledge of mechanisms that transform the quiescent oocyte into a pluripotent cell may also provide new insights for the clinical use of stem cells.


Isolation of the gene for cytochrome P450L1A1 (lanosterol 14 alpha-demethylase) from Candida albicans.
The Saccharomyces cerevisiae cytochrome P450 L1A1 (lanosterol 14 alpha-demethylase)-coding gene was used as a hybridization probe to isolate two HindIII fragments of 2.5 kb and 6.85 kb from a phage lambda library of Candida albicans nucleotide sequences. Restriction endonuclease mapping and Southern blot hybridization experiments indicated that these fragments represent two allelic forms of the same gene. This cloned sequence, when introduced into S. cerevisiae or C. albicans on a multiple copy vector, produced an increase in cytochrome P450 content and resistance to imidazole antifungal agents which are inhibitors of cytochrome P450 L1A1. In addition, the cloned sequence was able to complement a cytochrome P450 L1A1 gene disruption when introduced into S. cerevisiae. These data indicate that the cloned sequence codes for the lanosterol 14 alpha-demethylase cytochrome P450 L1A1 from C. albicans.


Robust detection of undifferentiated iPSC among differentiated cells.
Recent progress in human induced pluripotent stem cells (iPSC) technologies suggest that iPSC application in regenerative medicine is a closer reality. Numerous challenges prevent iPSC application in the development of numerous tissues and for the treatment of various diseases. A key concern in therapeutic applications is the safety of the cell products to be transplanted into patients. Here, we present novel method for detecting residual undifferentiated iPSCs amongst directed differentiated cells of all three germ lineages. Marker genes, which are expressed specifically and highly in undifferentiated iPSC, were selected from single cell RNA sequence data to perform robust and sensitive detection of residual undifferentiated cells in differentiated cell products. ESRG (Embryonic Stem Cell Related), CNMD (Chondromodulin), and SFRP2 (Secreted Frizzled Related Protein 2) were well-correlated with the actual amounts of residual undifferentiated cells and could be used to detect residual cells in a highly sensitive manner using qPCR. In addition, such markers could be used to detect residual undifferentiated cells from various differentiated cells, including hepatic cells and pancreatic cells for the endodermal lineage, endothelial cells and mesenchymal cells for the mesodermal lineage, and neural cells for the ectodermal lineage. Our method facilitates robust validation and could enhance the safety of the cell products through the exclusion of undifferentiated iPSC.


ITGB4 is a novel prognostic factor in colon cancer.
Integrin β4 (ITGB4) has been reported to be involved in carcinomas. Currently, ITGB4 has been characterized in colon cancer, however, its clinical significance is not very clear. In the present study, we utilized the large public datasets from NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and collected clinical samples in our center to investigate the transcriptional expressions of ITGB4 in colon cancer, and then explored the associations of ITGB4 with clinicopathological features and overall survival. The statistical analyses suggested that ITGB4 mRNA expressions were up-regulated significantly in colon cancer. High ITGB4 expression was observed to be associated with elder onset age, proximal tumor location, and high microsatellite instability (MSH) status. Further, Kaplan-Meier curves and univariate analysis demonstrated high ITGB4 expression was significantly associated with unfavorable overall survival in colon cancer (HR=1.292, 95%CI=1.084-1.540, P=0.004). And significant association was also found after adjusting the confounding factors including age, gender, and stage (adjusted HR=1.254, 95%CI=1.050-1.497, P=0.012). The annotation of ITGB4 co-expressed genes suggested the pathways including cell growth, positive regulation of cell migration, and apoptotic signaling might be involved in the potential mechanisms of ITGB4 in colon cancer development. The molecular regulation mechanism of ITGB4 ectopic expression in colon cancer was also explored and the results indicated that ITGB4 might be up-regulated by the transcription factor FOSL1 (FOS like 1, AP-1 Transcription Factor Subunit) and its promoter hypomethylation. Our results revealed that ITGB4 might be a therapeutic target and prognosis marker for individual therapy of colon cancer.


Decriminalization thresholds for drug possession: A multi-criteria policy analysis framework.
Decriminalization of personal possession of drugs has been proposed as an approach to mitigate the harms of drug prohibition. Despite growing interest, particularly in Canadian settings, analyses of approaches to defining the parameters of what constitutes personal possession within decriminalization models are lacking. Using the Province of British Columbia, Canada, as a case study, we undertook an evidence-based multi-criteria policy analysis of three models for defining personal possession: 1) a model that defines personal possession as the absence of evidence of drug trafficking; 2) a cumulative threshold of 15 grams; and 3) a cumulative threshold of 2.5 grams. We utilized data from four sources: qualitative interviews with 16 experts, including representatives from government and law enforcement; Vancouver Police drug seizure data; self-reported drug consumption data from longitudinal cohorts of people who use drugs in Vancouver; and publicly available government documents (e.g., the Government of BC's submission for decriminalization). Data was used to identify and define evaluation criteria which reflect the stated policy objectives of decriminalization alongside other policy considerations. This framework was used to conduct a multi-criteria policy analysis of the three different models. The seven evaluation criteria included: 1) reduction in interactions with police; 2) reduction of police drug seizures; 3) coverage for those with high consumption; 4) impact on equity-deserving groups; and acceptance on the part key stakeholders, including: 5) people who use drugs; 6) law enforcement; and 7) the public. The model that performed the best was the cumulative threshold model of 15 grams. Findings highlight that different threshold models advance and constrain the stated policy objectives of drug decriminalization to varying degrees. This analysis provides a framework that other jurisdictions considering decriminalization could use to help inform determinations of threshold levels based on stated policy objectives.


Planning and dosimetric evaluation of three total body irradiation techniques: Standard SSD VMAT, Extended SSD VMAT and Extended SSD Field-in-Field.
The aim of this study was to dosimetrically compare three total body irradiation (TBI) techniques which can be delivered by a standard linear accelerator, and to deduce which one is preferable. Specifically, Extended Source to Surface Distance (SSD) Field-in-Field (FiF), Extended SSD Volumetric Modulated Arc Therapy (VMAT), and Standard SSD VMAT TBI techniques were dosimetrically evaluated. Percent depth dose and dose profile measurements were made under treatment conditions for each specified technique. After having generated treatment plans with a treatment planning system (TPS), dose homogeneity and critical organ doses were investigated on a Rando phantom using radiochromic films and optically stimulated luminescence dosimeters (OSLDs). TBI dose of 12 Gy in six fractions was prescribed for each technique. The gamma index (5%/5 mm) was used for the analysis of radiochromic films. Passing rates for Extended SSD FiF, Extended SSD VMAT and Standard SSD VMAT techniques were found to be 90%, 87% and 94%, respectively. OSLD measurements were within ± 5% agreement with TPS calculations for the first two techniques whereas the agreement was found to be within ± 3% for the Standard SSD VMAT technique. TPS calculations demonstrated that mean lung doses in the first two techniques were around 8.5 Gy while it was kept around 7 Gy in Standard SSD VMAT. It is concluded that Standard SSD VMAT is superior in sparing the lung tissue while all three TBI techniques are feasible in clinical practice with acceptable dose homogeneity. In the absence of VMAT-based treatment planning, Extended SSD FiF would be a reasonable choice compared to other conventional techniques.


Adult polyglucosan body disease.
A 45-years old unconscious woman was admitted to the hospital, where she died 3 days later. For the preceding month she had suffered from a headache. She had no past medical history. Cerebrospinal fluid pressure was increased, there were 350 mg/100 of protein, and 105 mg/100 of glucose. Neuropathological examination revealed that the main microscopic abnormality was massive accumulation of PAS-positive polyglucosan bodies (PB) in the cerebral hemispheres, brain stem and cerebellum. These bodies were found most frequently around the vessels, or diffusely in the nervous tissue beneath the pia, particularly in depth of the cortical sulci. They were observed in the processes of nerve cells, astrocytes, and microglia cells. The material stored in PB was strongly positive in PAS, and PAS-dimedone, weakly stained in H&E, the reaction to GFAP, RCA-1 and Bielschowsky methods appeared rather on PB periphery. The neuropathologic features are consistent with adult polyglucosan body disease and are distinctive from other conditions in which PB may accumulate.


Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series.
Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol.


Ferro-orbital order and strong magnetic anisotropy in the parent compounds of iron-pnictide superconductors.
The puzzling nature of magnetic and lattice phase transitions of iron pnictides is investigated via a first-principles Wannier function analysis of representative parent compound LaOFeAs. A rare ferro-orbital ordering is found to give rise to the recently observed highly anisotropic magnetic coupling, and drive both phase transitions--without resorting to widely employed frustration or nesting picture. The revealed necessity of the additional orbital physics leads to a correlated electronic structure fundamentally distinct from that of the cuprates. In particular, the strong coupling to the magnons advocates active roles of light orbitons in spin dynamics and electron pairing in iron pnictides.


Vesicular transmitter release from astrocytes.
Astrocytes can release a variety of transmitters, including glutamate and ATP, in response to stimuli that induce increases in intracellular Ca(2+) levels. This release occurs via a regulated, exocytotic pathway. As evidence of this, astrocytes express protein components of the vesicular secretory apparatus, including synaptobrevin 2, syntaxin, and SNAP-23. Additionally, astrocytes possess vesicular organelles, the essential morphological elements required for regulated Ca(2+)-dependent transmitter release. The location of specific exocytotic sites on these cells, however, remains to be unequivocally determined.


Understanding the disorder of the DNA base cytosine on the Au(111) surface.
Using ultrahigh vacuum scanning tunneling microscopy (STM) and ab initio density functional theory, we have investigated in detail structures formed by cytosine on the Au(111) surface in clean ultrahigh vacuum conditions. In spite of the fact that the ground state of this DNA base on the surface is shown to be an ordered arrangement of cytosine one-dimensional branches (filaments), this structure has never been observed in our STM experiments. Instead, disordered structures are observed, which can be explained by only a few elementary structural motifs: filaments, five- and sixfold rings, which randomly interconnect with each other forming bent chains, T junctions, and nanocages. The latter may have trapped smaller structures inside. The formation of such an unusual assembly is explained by simple kinetic arguments as a liquid-glass transition.


Development and Evaluation of an Internet-Based Airway Evaluation Tutorial.
Airway evaluation and basic management are essential skills for all physicians. Identifying patients for whom mask ventilation or endotracheal intubation will be difficult to impossible is vital for patient safety. Despite this, training in airway evaluation is minimal in the curricula of most medical schools. To ensure a thorough understanding of airway anatomy and evaluation, as well as exposure to various abnormal findings, we developed an Internet-based module including interactive components, graphics, animation, video, and a self-assessment tool. The site received more than 1800 visits in its first nine months of operation, with uniformly laudatory comments. Eighty subjects over a six-month period completed a pre- and post-test quiz structured to evaluate the utility of the site. Of those completing the on-line survey, more than 76% rated the site very useful. Most felt their knowledge of airway examination improved after completion of the site (p.


The catalytic mechanism of glucose 6-phosphate dehydrogenases: assignment and 1H NMR spectroscopy pH titration of the catalytic histidine residue in the 109 kDa Leuconostoc mesenteroides enzyme.
The chemical shifts of the C(epsilon1) and C(delta2) protons of His-240 from the 109 kDa Leuconostoc mesenteroides glucose 6-phosphate dehydrogenase (G6PD) were assigned by comparing 1H and 13C spectra of the wild-type and mutant G6PDs containing the His-240 to asparagine mutation (H240N). Unambiguous assignment of the His-240 1H(epsilon1) resonance was obtained from comparing 13C-1H heteronuclear multiple quantum coherence NMR spectra of wild-type and H240N G6PDs that were selectively labeled with 13C(epsilon1) histidine. The results from NOESY experiments with wild-type and H240N variants were consistent with these assignments and the three-dimensional structure of G6PD. pH titrations show that His-240 has a pK(a) of 6.4. This value is, within experimental error, identical to the value of 6.3 derived from the pH dependence of kcat [Viola, R. E. (1984) Arch. Biochem. Biophys. 228, 415-424], suggesting that the pK(a) of His-240 is unperturbed in the apoenzyme despite being part of a His-Asp catalytic dyad. The results obtained for this 109 kDa enzyme indicate that 1H NMR spectroscopy in combination with heteronuclear methods can be a useful tool for functional analysis of large proteins.


Dissecting bipolar disorder complexity through epigenomic approach.
In recent years, numerous studies of gene regulation mechanisms have emerged in neuroscience. Epigenetic modifications, described as heritable but reversible changes, include DNA methylation, DNA hydroxymethylation, histone modifications and noncoding RNAs. The pathogenesis of psychiatric disorders, such as bipolar disorder, may be ascribed to a complex gene-environment interaction (G × E) model, linking the genome, environmental factors and epigenetic marks. Both the high complexity and the high heritability of bipolar disorder make it a compelling candidate for neurobiological analyses beyond DNA sequencing. Questions that are being raised in this review are the precise phenotype of the disorder in question, and also the trait versus state debate and how these concepts are being implemented in a variety of study designs.


Influence of culture conditions of Streptomyces sp. (strain S242) on chitinase production.
The purpose of this study was to determine the influence of growth conditions and medium composition on the production ofchitinase by Streptomyces sp. (strain S242). Production of chitinase by strain S242 was detected on colloidal chitin agar (CCA) medium after 8 days of incubation at 28 degrees C resulting in a clear zone 10 mm around the colony. Chitinase activity was assayed as the amount of N-acetylglucosamine released in micromol/ml/min using the dinitrosalicylic acid assay method. The crude enzyme had maximum activity (0.162 U ml/l) after 4 days of incubation at pH 7 and 30 degrees C when the broth medium was supplemented with 1.6% of colloidal chitin. However, enzyme activity was strongly decreased at 40 degrees C and extreme acidic and alkaline pH values. SDS-PAGE and zymogram analysis revealed six distinctive bands that range from 39 to 97 kDa with chitinolytic activity. The findings of this investigation create a possibility for the use of the organism in the commercial production of chitinase. In addition, it can be a source of DNA for cloning the chitinase gene(s) to generate phytopathogen resistant transgenic plants.


Dual roles of heparanase in human carotid plaque calcification.
Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-β-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro. Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively. HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation. We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.


Contribution of Endothelial-to-Mesenchymal Transition to the Pathogenesis of Human Cerebral and Orbital Cavernous Malformations.
The analysis of gene-targeted mouse mutants has demonstrated that endothelial-to-mesenchymal transition (EndMT) is crucial to the onset and progression of cerebral cavernous malformations (CMs). It has also been shown that Notch and ephrin/Eph signaling are involved in EndMT. However, their roles in the pathogenesis of human intracranial CMs remain unclear. To elucidate the contribution of EndMT, the Notch pathway, and ephrin-B2/EphB4 signaling to the pathogenesis of human intracranial CMs. Eight human intracranial CMs (5 cerebral and 3 orbital CMs) were immunohistochemically investigated. CD31 (an endothelial marker) and EndMT markers, such as α-smooth muscle actin (a mesenchymal marker) and CD44 (a mesenchymal stem cell marker), were expressed in the endothelial layer of vascular sinusoids in all cases, suggesting that endothelial cells (ECs) have acquired mesenchymal and stem-cell-like characteristics and undergone EndMT in all cerebral and orbital CMs. EndMT was observed in about 70% and 35% of ECs in cerebral and orbital CMs, respectively. In all cases, Notch3 was expressed in the endothelial layer, indicating that ECs of vascular sinusoids have acquired mesenchymal features. In all cases, both ephrin-B2 and EphB4 were detected in the endothelial layer, suggesting that ECs of vascular sinusoids are immature or malformed cells and have both arterial and venous characteristics. EndMT plays a critical role in the pathogenesis of human cerebral and orbital CMs. Modulating EndMT is expected to be a new therapeutic strategy for cerebral and orbital CMs.


Glomus tympanicum chemodectoma: unusual radiological findings.
A 64-year-old Qatari female, with a one-year history of right otorrhoea and deafness, had a reddish-white mass projecting into the right ear canal, through the tympanic membrane, that proved histopathologically to be a paraganglioma. Computerized tomography (CT) of the temporal bones showed extensive destruction of the right mastoid bone, the posterior ear canal wall, and the sinus plate, with total disruption of the ossicles, simulating a malignant tumour, which is unusual for a middle ear paraganglioma.


Correlation between regional cerebral blood flow and oxidative metabolism. In vivo studies in man.
To test the hypothesis that regional cerebral blood flow (rCBF) is normally regulated by regional metabolic activity, rCBF and the regional cerebral metabolic rate for oxygen (rCMRO2) were compared in selected human subjects. In normal subjects and patients with chronic, stable diseases of brain, rCBF correlated well with rCMRO2. In one individual with mild dementia, rCBF and rCMRO2 were measured before and during exercise of the hand and forearm contralateral to the hemisphere studied. Appropriate parallel changes occurred in both rCBF and rCMRO2 during hand exercise. In patients with acute diseases affecting the hemisphere studied, however, the correlation between rCBF and rCMRO2 was unpredictable.


Congestive heart failure in elderly patients.
The prevalence of congestive heart failure (CHF) is increasing. Most patients with CHF are elderly, and CHF is the most common dismissal diagnosis in elderly hospitalized patients. As many as 50% of elderly patients with heart failure may have normal systolic function and isolated diastolic heart failure. Assessment and management of elderly patients are complicated by comorbidities, increased susceptibility to side effects, and concerns about the appropriate use of costly and invasive procedures. The basics of the approach to the evaluation and management of heart failure in elderly patients are reviewed.


Prior event rate ratio adjustment for hidden confounding in observational studies of treatment effectiveness: a pairwise Cox likelihood approach.
Observational studies provide a rich source of information for assessing effectiveness of treatment interventions in many situations where it is not ethical or practical to perform randomized controlled trials. However, such studies are prone to bias from hidden (unmeasured) confounding. A promising approach to identifying and reducing the impact of unmeasured confounding is prior event rate ratio (PERR) adjustment, a quasi-experimental analytic method proposed in the context of electronic medical record database studies. In this paper, we present a statistical framework for using a pairwise approach to PERR adjustment that removes bias inherent in the original PERR method. A flexible pairwise Cox likelihood function is derived and used to demonstrate the consistency of the simple and convenient alternative PERR (PERR-ALT) estimator. We show how to estimate standard errors and confidence intervals for treatment effect estimates based on the observed information and provide R code to illustrate how to implement the method. Assumptions required for the pairwise approach (as well as PERR) are clarified, and the consequences of model misspecification are explored. Our results confirm the need for researchers to consider carefully the suitability of the method in the context of each problem. Extensions of the pairwise likelihood to more complex designs involving time-varying covariates or more than two periods are considered. We illustrate the application of the method using data from a longitudinal cohort study of enzyme replacement therapy for lysosomal storage disorders. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.


War in the Middle East and the Incidence of Cleft Lip and Palate.
The aim of this retrospective study was to study the effects of the war against ISIS during period (2014-2018) on the incidence of cleft lip and palate and the appearance of different congenital anomalies. The collected sample consists of 320 newborn babies (160 patients and 160 infants as a control). The examined patients and controls were all included in this study, while the authors exclude those who born to relative parents, and if the mothers had taken any medications during pregnancy.All newborn cases and controls were physically examined by the research team, and a questionnaire was completed after obtaining the informed consent of mothers and/or fathers. In this study, the authors found that 160 patients out of 40,500 live births were born with cleft lip and/or cleft palate, so their percentage was 0.39% from population, that is mean approximately 4 infants affected per each 1000 live births. The risk of cleft development among children who born to fathers who participated in long fighting against the terrorists was (OR = 44.333, 95% CI: 20.176-97.417). The associated combined anomalies were found in 88 patients (79%) especially among those whom fathers participated in the war CONCLUSION:: From this study the authors can conclude that the dramatic increase in the incidence of cleft lip and palate and the appearance of different associated anomalies in the south of Iraq is due to the direct effect and impact of the war and the used toxic bombs on the chromosomal changes of the parents and the developing fetus.


Acute pancreatitis secondary to intramural duodenal hematoma: Case report and literature review.
Nontraumatic intramural duodenal hematoma (IDH) is rare disease and it is generally related to coagulation abnormalities. Reports of nontraumatic IDH associated with pancreatic disease are relatively rare, and various conditions including acute or chronic pancreatitis are thought to be associated with nontraumatic IDH. However, the association between IDH and acute pancreatitis remains unknown. We report the case of a 45-year-old man who presented with vomiting and right hypochondrial pain. He had no medical history, but was a heavy drinker. The diagnosis of IDH was established by computed tomography, ultrasonography and endoscopy, and it was complicated by acute pancreatitis. The lesions resolved with conservative management. We discuss this case in the context of previously reported cases of IDH concomitant with acute pancreatitis. In our patient, acute pancreatitis occurred concurrently with hematoma, probably due to obstruction of the duodenal papilla, or compression of the pancreas caused by the hematoma. The present analysis of the published cases of IDH with acute pancreatitis provides some information on the pathogenesis of IDH and its relationship with acute pancreatitis.


The Peter Brojde lung cancer centre: a model of integrative practice.
The generally poor prognosis and poor quality of life for lung cancer patients have highlighted the need for a conceptual model of integrative practice. Although the philosophy of integrative oncology is well described, conceptual models that could guide the implementation and scientific evaluation of integrative practice are lacking. The present paper describes a conceptual model of integrative practice in which the philosophical underpinnings derive mainly from integrative oncology, with important contributions from Traditional Chinese Medicine (TCM) and the discipline of nursing. The conceptual model is described in terms of its purpose, values, concepts, dynamic components, scientific evidence, clinical approach, and theoretical underpinnings. The model argues that these components delineate the initial scope and orientation of integrative practice. They serve as the needed context for evaluating and interpreting the effectiveness of clinical interventions in enhancing patient outcomes in lung cancer at various phases of the illness. Furthermore, the development of relevant and effective integrative clinical interventions requires new research methods based on whole-systems research. An initial focus would be the identification of interrelationship patterns among variables that influence clinical interventions and their targeted patient outcomes.


The impact of unemployment on marriage and divorce.
"The present study was designed to explore whether unemployment has a deleterious impact on family life, resulting in lower rates of marriage and births and higher rates of divorce. Time series data were available for twelve nations for the 35 year period of 1950 to 1985, and the present paper reports analyses of these data sets." The results indicate that unemployment is associated with lower marriage and birth rates and higher divorce rates.


Molecular characterization of the BMP7 gene and its potential role in shell formation in Pinctada martensii.
Bone morphogenetic protein 7 (BMP7), also called osteogenetic protein-1, can induce bone formation. In this study, the obtained full-length cDNA of BMP7 from Pinctada martensii (Pm-BMP7) was 2972 bp, including a 5'-untranslated region (UTR) of 294 bp, an open reading fragment of 1290 bp encoding a 429 amino acid polypeptide and a 3'-UTR of 1388 bp. The deduced protein sequence of Pm-BMP7 contained a signal peptide, a pro-domain and a mature peptide. The mature peptide consisted of 135 amino acids and included a transforming growth factor β family domain with six shared cysteine residues. The protein sequence of Pm-BMP7 showed 66% identity with that from Crassostrea gigas. Two unigenes encoding Pm-BMPRI (Pm-BMP receptor I) and Pm-BMPRII were obtained from the transcriptome database of P. martensii. Tissue expression analysis demonstrated Pm-BMP7 and Pm-BMPRI were highly expressed in the mantle (shell formation related-tissue), while Pm-BMPRII was highly expressed in the foot. After inhibiting Pm-BMP7 expression using RNA interference (RNAi) technology, Pm-BMP7 mRNA was significantly down-regulated (p < 0.05) in the mantle pallium (nacre formation related-tissue) and the mantle edge (prismatic layer formation related-tissue). The microstructure, observed using a scanning electron microscope, indicated a disordered growth status in the nacre and obvious holes in the prismatic layer in the dsRNA-Pm-BMP7 injected-group. These results suggest that Pm-BMP7 plays a crucial role in the nacre and prismatic layer formation process of the shell.


Architecture and sequence stratigraphy of the Upper Coralline Limestone formation, Malta-Implications for Eastern Mediterranean restriction prior to the Messinian Salinity Crisis.
The Eastern and Western Mediterranean are separated by an elevated plateau that regulates water exchange between these two basins. The Maltese archipelago, situated atop this topographic high, offers a unique window into the evolution of this plateau in the lead up to the Messinian Salinity Crisis. The Upper Coralline Limestone Formation was deposited between the late Tortonian and the early Messinian and was probably terminated by palaeoceanographic events related to the Messinian Salinity Crisis. It represents the youngest Miocene sedimentary deposits outcropping in the Maltese archipelago. This shallow-water carbonate unit can be used to trace palaeoenvironmental changes atop the sill between the Eastern and Western Mediterranean and to explain the possible water flow restrictions to the Eastern Mediterranean that could have preceded the Messinian Salinity Crisis. Here field surveys, and analysis of the depositional environment within the Upper Coralline Limestone in Malta, are combined with recently acquired multichannel seismic reflection profiles between Malta and Gozo, to reconstruct the depositional sequence in the Malta Plateau during the late Miocene. The Upper Coralline Limestone consists of multiple coralline and larger benthic foraminifera dominated facies, extending from subtidal to intertidal environments. These accumulated in two depositional cycles observed in both outcrop and seismic reflection data. Each cycle exhibits an early aggradation-progradation phase followed by a progradation phase and a final aggradation phase. These manifest themselves in the outcrops as shallowing and deepening upwards phases. These were deposited above a deep water unit and are indicative of a preceding uplift phase followed by filling of the accommodation space through the deposition of the Upper Coralline Limestone Formation in shallow marine depths. The presence of this highly elevated sill during the late Miocene could have restricted circulation to the eastern basin.


Anatomical and functional outcomes one year after vitrectomy and retinal massage for large macular holes.
The aim of this study was to report results of macular hole closure, visual benefit and longitudinal changes in foveal architecture over 1 year following macular hole surgery with retinal massage. Records of patients with full thickness macular hole (FTMH) with minimum basal diameter of 550 μ who underwent vitrectomy, internal limiting membrane (ILM) peeling and retinal massage were drawn up. Retinal massage was performed after dye assisted ILM peeling, using a 27G flute needle with a long and soft silicone tip under air in a centripetal direction around the FTMH. At the end, 10% C3F8 gas was used as tamponade. The foveal contour at 1 year follow up was recorded based on its cross sectional appearance on OCT and was classified into U, V and irregular types of closure as previously described. Forty-one eyes of 41 patients with a mean age of 70.4 ± 6.9 years were included. The mean preoperative vision was 0.99 ± 0.07 logMAR and mean maximum basal diameter of the FTMH was 835 ± 208 μ. Macular hole closure was seen in all patients at 1-month follow up. The BCVA improved to 0.5 ± 0.1 log MAR at 6 months (P < 0.001) and then stabilized. The U shaped closure was the commonest pattern (n = 22, 54%), followed by V-shaped closure (n = 16, 39%) while irregular closure was seen in 3 eyes (7%). Retinal massage after ILM peeling is a very simple, and as yet under-utilized manoeuvre that may improve hole closure rates and lead to potentially greater improvement in vision compared to existing techniques for large holes.


Acute myocardial infarction under-diagnosis and mortality in a Tanzanian emergency department: A prospective observational study.
Growing evidence suggests that under-diagnosis of acute myocardial infarction (AMI) may be common in sub-Saharan Africa. Prospective studies of routine AMI screening among patients presenting to emergency departments in sub-Saharan Africa are lacking. Our objective was to determine the prevalence of AMI among patients in a Tanzanian emergency department. In a prospective observational study, consecutive adult patients presenting with chest pain or shortness of breath to a referral hospital emergency department in northern Tanzania were enrolled. Electrocardiogram (ECG) and troponin testing were performed for all participants to diagnose AMI types according to the Fourth Universal Definition. All ECGs were interpreted by two independent physician judges. ECGs suggesting ST-elevation myocardial infarction (STEMI) were further reviewed by additional judges. Mortality was assessed 30 days following enrollment. Of 681 enrolled participants, 152 (22.3%) had AMI, including 61 STEMIs and 91 non-STEMIS (NSTEMIs). Of AMI patients, 91 (59.9%) were male, mean (SD) age was 61.2 (18.5) years, and mean (SD) duration of symptoms prior to presentation was 6.6 (12.2) days. In the emergency department, 35 (23.0%) AMI patients received aspirin and none received thrombolytics. Of 150 (98.7%) AMI patients completing 30-day follow-up, 65 (43.3%) had died. In a northern Tanzanian emergency department, AMI is common, rarely treated with evidence-based therapies, and associated with high mortality. Interventions are needed to improve AMI diagnosis, care, and outcomes.


Murine lymphocytes lack clearly defined receptors for muscarinic and dopaminergic ligands.
[3H]Quinuclidinyl benzilate and [3H]spiperone binding to murine lymphocytes is displaceable but differs from binding to brain receptor sites for these ligands: (1) binding to intact lymphocyte preparations was not saturable; (2) disruption of intact lymphocytes was associated with a marked loss of displaceable ligand binding; (3) drugs differentially displace these ligands in lymphocytes compared to brain. Displaceable binding was increased following incubation of lymphocytes under phospholipid methylating conditions; however, marked effects on cell viability and cell recovery make it difficult to interpret these binding changes. If dopaminergic and cholinergic receptors do exist on lymphocytes, their binding characteristics are profoundly different from comparable cns receptors.


Epigallocatechin-3-gallate suppressed the over-expression of HSP 70 and MDR1 induced by heat shock in SGC 7901.
This study investigated the effects of epigallocatechin-3-gallate (EGCG) on the expression of HSP 70 and MDR 1. SGC-7901 cells were cultured with RPMI 1640 medium. The single or combined effects of EGCG (0.1, 1, 10, 20, and 40 micromol/L) and heat shock were examined by MTT assay. The expression of HSP 70 and MDR 1 was semi-quantified by the reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry method (SP staining). EGCG suppressed cell proliferation at a time- and dose-dependent manner. The effects of combined treatment with EGCG and heat shock on the growth of SGC-7901 cells were stronger than single effects of EGCG. After using EGCG for 24 h, 48 h and 72 h, the IC50s were 112.5 micromol/l, 21.41 micromol/l and 5.24 micromol/l, respectively. Heat shock stimulated the over-expression of HSP 70, especially after heat shock for 8 h, as well as MDR1 after heat shock for 24 h. But EGCG suppressed the over-expression induced by heat shock. The authors conclude that EGCG inhibited the proliferation of SGC-7901, and EGCG combined with heat shock strengthened the effects. Heat shock weakened the over-expression of HSP 70 and MDR1; however, EGCG suppressed the over-expression of HSP 70 and MDR1 induced by heat shock. EGCG combined with heat shock may enhance the sensitivity of drugs to tumors.


Prospects for a group A streptococcal vaccine: rationale, feasibility, and obstacles--report of a National Institute of Allergy and Infectious Diseases workshop.
Infections due to group A streptococci (GAS) represent a public health problem of major proportions in both developing and developed countries. Currently available methods of prevention are either inadequate or ineffective, as attested to by the morbidity and mortality associated with this ubiquitous pathogen worldwide. Advances in molecular biology have shed new light on the pathogenesis of GAS infections and have identified a number of virulence factors as potential vaccine targets. Therefore, the National Institute of Allergy and Infectious Diseases convened an expert workshop in March 2004 to review the available data and to explore the microbiologic, immunologic, epidemiologic, and economic issues involved in development and implementation of a safe and effective GAS vaccine. Participants included scientists and clinicians involved in GAS research, as well as representatives of United States federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, Department of Defense, and National Institute of Allergy and Infectious Diseases), the World Health Organization, and the pharmaceutical industry. This report summarizes the deliberations of the workshop.


Selection of voxel size and photon number in voxel-based Monte Carlo method: criteria and applications.
The voxel-based Monte Carlo method (VMC) is now a gold standard in the simulation of light propagation in turbid media. For complex tissue structures, however, the computational cost will be higher when small voxels are used to improve smoothness of tissue interface and a large number of photons are used to obtain accurate results. To reduce computational cost, criteria were proposed to determine the voxel size and photon number in 3-dimensional VMC simulations with acceptable accuracy and computation time. The selection of the voxel size can be expressed as a function of tissue geometry and optical properties. The photon number should be at least 5 times the total voxel number. These criteria are further applied in developing a photon ray splitting scheme of local grid refinement technique to reduce computational cost of a nonuniform tissue structure with significantly varying optical properties. In the proposed technique, a nonuniform refined grid system is used, where fine grids are used for the tissue with high absorption and complex geometry, and coarse grids are used for the other part. In this technique, the total photon number is selected based on the voxel size of the coarse grid. Furthermore, the photon-splitting scheme is developed to satisfy the statistical accuracy requirement for the dense grid area. Result shows that local grid refinement technique photon ray splitting scheme can accelerate the computation by 7.6 times (reduce time consumption from 17.5 to 2.3 h) in the simulation of laser light energy deposition in skin tissue that contains port wine stain lesions.


Record linkage studies of drug-related deaths among former adult prisoners who have been released to the community: a scoping review protocol.
Prisoners often have a complex mix of health and care needs including needs relating to mental and physical ill-health conditions. In addition, substance use disorders are common in prisoners. The transition between prison and community poses risks in terms of a disruption to treatment and care and a deterioration in health. Studies have demonstrated an increased risk of drug-related deaths among former prisoners during the first weeks following release from custody. The aim of this scoping review is to provide an up-to-date account of evidence from record linkage studies about drug-related deaths among former adult prisoners. This is a protocol for a scoping review. The framework for conducting scoping reviews by Arksey and O'Malley, in addition to the methodology and guidance developed by the Joanna Briggs Institute (JBI) and the JBI Collaboration will be followed. MEDLINE, EMBASE, PsychINFO and Web of Science will be searched for studies from 2011 to 2021 using search terms relating to 'mortality', 'drugs' and 'ex-prisoner'. A preliminary search in MEDLINE identified at least 473 potentially eligible papers. Two authors will independently screen all titles and abstracts for eligibility using the inclusion and exclusion criteria. There will be no geographical restrictions but non-English language papers will be excluded. Data will be extracted using a piloted customised charting form and the findings will be mapped (guided by the population, concept and context inclusion criteria) and grouped by main conceptual categories (including methodology, key findings and gaps in the research). This scoping review will identify, map and summarise publicly available sources of research and therefore does not require ethical approval. The results will inform our empirical investigation of ex-prisoner mortality as well as being shared with key stakeholders, disseminated in a peer-reviewed journal and presented at relevant conferences.


Distribution of ureteral stones and factors affecting their location and expulsion in patients with renal colic.
To evaluate the distribution of ureteral stones and to determine their characteristics and expulsion rate based on their location. We retrospectively reviewed computed tomography (CT) findings of 246 patients who visited our Emergency Department (ED) for renal colic caused by unilateral ureteral stones between January 2013 and April 2014. Histograms were constructed to plot the distribution of stones based on initial CT findings. Data from 144 of the 246 patients who underwent medical expulsive therapy (MET) for 2 weeks were analyzed to evaluate the factors responsible for the stone distribution and expulsion. The upper ureter and ureterovesical junction (UVJ) were 2 peak locations at which stones initially lodged. Stones lodged at the upper ureter and ureteropelvic junction (group A) had a larger longitudinal diameter (4.21 mm vs. 3.56 mm, p=0.004) compared to those lodged at the lower ureter and UVJ (group B). The expulsion rate was 75.6% and 94.9% in groups A and B, respectively. There was no significant difference in the time interval from initiation of renal colic to arrival at the ED between groups A and B (p=0.422). Stone diameter was a significant predictor of MET failure (odds ratio [OR], 1.795; p=0.005) but the initial stone location was not (OR, 0.299; p=0.082). The upper ureter and UVJ are 2 peak sites at which stones lodge. For stone size 10 mm or less, initial stone lodge site is not a significant predictor of MET failure in patients who have no previous history of active stone treatment in the ureter.


Functional Role of N-Terminal Extension of Human AP Endonuclease 1 In Coordination of Base Excision DNA Repair via Protein-Protein Interactions.
Human apurinic/apyrimidinic endonuclease 1 (APE1) has multiple functions in base excision DNA repair (BER) and other cellular processes. Its eukaryote-specific N-terminal extension plays diverse regulatory roles in interaction with different partners. Here, we explored its involvement in interaction with canonical BER proteins. Using fluorescence based-techniques, we compared binding affinities of the full-length and N-terminally truncated forms of APE1 (APE1NΔ35 and APE1NΔ61) for functionally and structurally different DNA polymerase β (Polβ), X-ray repair cross-complementing protein 1 (XRCC1), and poly(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP1), in the absence and presence of model DNA intermediates. Influence of the N-terminal truncation on binding the AP site-containing DNA was additionally explored. These data suggest that the interaction domain for proteins is basically formed by the conserved catalytic core of APE1. The N-terminal extension being capable of dynamically interacting with the protein and DNA partners is mostly responsible for DNA-dependent modulation of protein-protein interactions. Polβ, XRCC1, and PARP1 were shown to more efficiently regulate the endonuclease activity of the full-length protein than that of APE1NΔ61, further suggesting contribution of the N-terminal extension to BER coordination. Our results advance the understanding of functional roles of eukaryote-specific protein extensions in highly coordinated BER processes.


Everting closure for interrupted aortic arch, ventricular septal defect, and severe subaortic stenosis.
Interrupted aortic arch with ventricular septal defect in the neonate is sometimes complicated by severe subaortic stenosis from posterior deviation of the infundibular septum. We have developed a novel approach to the treatment of this condition. The infundibular septum is penetrated from the right-ventricular side to the left-ventricular outflow tract. It is compressed with patch fixation. The lower margin of the infundibular septum is everted. Three consecutive neonates were treated. The smallest diameters of the left-ventricular outflow tract were 3,4, and 2.5 mm. All patients survived the operation and were discharged from the hospital. They remained well 2 to 7 years after the repair and were in normal sinus rhythm without a left bundle branch block or any significant pressure gradient between the upper and lower extremities. Follow-up two-dimensional and Doppler echocardiography demonstrated no residual shunt, no left-ventricular outflow-tract pressure gradient, and no aortic regurgitation. This technique provides effective widening of the left-ventricular outflow tract, and is more safely and easily performed than conventional methods.


Potential applications of biphosphonates in dental surgical implants.
Biphosphonates are largely used for their unquestionable properties of inhibiting bone resorption by osteoclasts in the treatment of various osteometabolic illnesses such as osteoporosis, multiple myeloma, tumors which metastasize to the bone and malignant hypercalcemia. In this literature review the physico-chemical properties, biologic activities and the mechanisms of action of biphosphonates are described. The use of these drugs is discussed, analyzing the quantity of results which have emerged through in vitro and in vivo experiments on animal models. In this study the efficiency of these drugs is demonstrated in contrasting the osteolitic processes of the alveolar bone, in promoting the neoformation and in bettering the quality of bone implants. However, it is important to draw attention to a worrying correlation which has emerged during the last 3-4 years, between osteonecrosis of the jaw (ONJ) and the systemic administration of aminobiphosphonates. This collateral effect did not emerge following the use of non-aminobiphosphonates. The aim of this review is to identify the guidelines for the use of biphosphonates in oral implant surgery.


Induction of atherosclerosis by human chylomicron remnants: a hypothesis.
Epidemiologic studies have provided support for the association between delayed remnant removal and premature atherosclerosis. Triglyceride-rich particles such as chylomicrons and chylomicron remnants that carry dietary derived fats, may play a role in the early stages of developing arteriosclerosis. Currently research focuses on these lipoprotein classes seeking distinguishing factors that causes some lipoproteins to be atherogenic while others are not. Such lipoproteins could be involved in atherogenesis directly or indirectly. Direct involvement occurs by interaction of triglyceride-rich particles with the arterial wall, possibly affecting the artery wall by oxidative stress, direct endothelial toxicity by constituents such as lysophosphatidylcholine or oxysterols, induction of prothrombotic changes, stimulation of endothelial expression of cell adhesion molecules and direct interaction with circulating blood cells. Indirect involvement refers to the influence of triglyceride-rich lipoproteins on other lipoproteins on the composition of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles. We propose that in individuals with delayed removal of chylomicron remnants, the prolonged exposure of areas of endothelium that have been partially activated by turbulent flow, to specific components of the remnants, results in the endothelial cells becoming further activated and able to bind monocytes. During or shortly after the transcytosis to the intima and transformation of monocytes to macrophages, the macrophages become engorged with remnant derived lipids and form the nidus of a fatty streak.


Assessing blood flow control through a bootstrap method.
In order to assess blood flow control, the relationship between blood pressure and blood flow can be modeled by linear filters. We present a bootstrap method, which allows the statistical analysis of an index of blood flow control that is obtained from constrained system identification using an established set of pre-defined filters.


Predictive representation of other people's actions in joint action planning: an EEG study.
It has been postulated that when people engage in joint actions they form internal representations not only of their part of the joint task but of their co-actors' parts of the task as well. However, empirical evidence for this claim is scarce. By means of high-density electroencephalography, this study investigated whether one represents and simulates the action of an interaction partner when planning to perform a joint action. The results showed that joint action planning compared with individual action planning resulted in amplitude modulations of the frontal P3a and parietal P3b event-related potentials, which are associated with stimulus classification, updating of representations, and decision-making. Moreover, there was evidence for anticipatory motor simulation of the partner's action in the amplitude and peak latency of the late, motor part of the Contingent Negative Variation, which was correlated with joint action performance. Our results provide evidence that when people engage in joint tasks, they represent in advance each other's actions in order to facilitate coordination.


Impacts on food web properties of island invertebrate communities vary between different human land uses.
Human land use is of growing concern for island ecosystems. Besides direct impacts on biodiversity, land uses can alter the functioning and structure of ecosystems. Central to this are impacts on food webs. The release of additional nutrients from human origin, habitat homogenization, or environmental filtering due to human land use can change the diet of individual consumer species (i.e., their trophic niches) and the distribution and overlap of trophic niches within a food web. However, it remains largely unclear whether the effects on food web properties vary between the different and predominant human land uses present on islands. Here, we investigated the impact of two dominant human land uses on small oceanic islands (i.e., urban and tourism development) and tested if and how different land uses on islands affect food web structure. To disentangle human land uses, we investigated islands, which were either privately owned by a tourist facility (i.e., exclusively tourism land use) or experienced urban development from the local population (i.e., urban land use), or remained uninhabited, serving as reference sites free of direct land use. Using stable isotope analysis, we show that isotope signature, trophic (isotopic) niches, and overall food web properties of the investigated island invertebrate communities were significantly changed under both land use regimes. While trophic diversity was reduced and trophic niche widths increased under tourism land use, the investigated food webs showed reduced trophic diversity at the food web base and a more uneven trophic niche distribution under urban land use. In summary, these findings show that different human land uses can have contrasting impacts on oceanic island food webs. As oceanic islands experience rapidly growing human land conversion, our results indicate that they may also face increasing yet unpredictable long-term changes in food web dynamics.


Impact of disease on markers of macronutrient status.
It is apparent that illness, particularly acute illness, affects most tests which are used to assess macronutrient status. In acutely-ill patients, the best tests in terms of specificity for nutritional status are in vivo neutron-activation analysis for body composition and N balance as an assessment of recent intake. Changes in plasma protein concentration must be interpreted with great care, and this is best done in conjunction with changes in the acute-phase-protein response. Measurement of plasma IGF-1 may be helpful in the presence of an acute-phase response, but this requires further validation. In many such patients, the most important part of the assessment continues to be the clinical and dietary history, together with a careful physical examination. However, the need for accurate measurement remains, so that nutritional status and its progress can be accurately quantified. This was best expressed many years ago by William Thompson, Lord Kelvin, when he stated '... when you can measure what you are speaking about and express it in numbers you know something about it... when you cannot express it in numbers your knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science...'.


Dual modal plasmonic substrates based on a convective self-assembly technique for enhancement in SERS and LSPR detection.
In this study, surface-enhanced Raman scattering (SERS) scheme is combined with localized surface plasmon resonance (LSPR) detection on a thin gold film with stripe patterns of gold nanoparticles (GNPs) via convective self-assembly (CSA) method. The potential of dual modal plasmonic substrates was evaluated by binding 4-ABT and IgG analytes, respectively. SERS experiments presented not only a high sensitivity with a detection limit of 4.7 nM and an enhancement factor of 1.34 × 105, but an excellent reproducibility with relative standard deviation of 5.5%. It was found from plasmonic sensing experiments by immobilizing IgG onto GNP-mediated gold film that detection sensitivity was improved by more than 211%, compared with a conventional bare gold film. Our synergistic SERS-LSPR approach based on a simple and cost-effective CSA method could open a route for sensitive, reliable and reproducible dual modal detection to expand the application areas.


Tracking repeats using significance and transitivity.
Internal repeats in coding sequences correspond to structural and functional units of proteins. Moreover, duplication of fragments of coding sequences is known to be a mechanism to facilitate evolution. Identification of repeats is crucial to shed light on the function and structure of proteins, and explain their evolutionary past. The task is difficult because during the course of evolution many repeats diverged beyond recognition. We introduce a new method TRUST, for ab initio determination of internal repeats in proteins. It provides an improvement in prediction quality as compared to alternative state-of-the-art methods. The increased sensitivity and accuracy of the method is achieved by exploiting the concept of transitivity of alignments. Starting from significant local suboptimal alignments, the application of transitivity allows us to (1) identify distant repeat homologues for which no alignments were found; (2) gain confidence about consistently well-aligned regions; and (3) recognize and reduce the contribution of non-homologous repeats. This re-assessment step enables us to derive a virtually noise-free profile representing a generalized repeat with high fidelity. We also obtained superior specificity by employing rigid statistical testing for self-sequence and profile-sequence alignments. Assessment was done using a database of repeat annotations based on structural superpositioning. The results show that TRUST is a useful and reliable tool for mining tandem and non-tandem repeats in protein sequence databases, capable of predicting multiple repeat types with varying intervening segments within a single sequence. The TRUST server (together with the source code) is available at http://ibivu.cs.vu.nl/programs/trustwww


miRNA-186 inhibits prostate cancer cell proliferation and tumor growth by targeting YY1 and CDK6.
microRNAs (miRNAs) are known to be important in tumor initiation and progression. Recent studies have demonstrated that miR-186 is critical in several types of cancer, including human non-small cell lung cancer, bladder cancer and pancreatic ductal adenocarcinoma. However, the functions of miR-186 in prostate cancer (PCa) are still unclear. In the present study, downregulation of miR-186 in PCa cells was detected when compared with the normal prostate cell line. When miR-186 overexpressed in PCa cells, cell proliferation in vitro was evidently inhibited as shown using cell counting kit-8 assays and cell-cycle analysis, and tumor growth in vivo was decreased as shown by tumor growth assays in nude mice. Furthermore, through bioinformatics prediction and biochemical analyses, Yin Yang 1 (YY1) and cyclin-dependent kinase 6 (CDK6) have been proven to act as direct targets of miR-186. These results indicate that miR-186 is a negative regulator in PCa by inhibiting PCa cell proliferation via targeting YY1 and CDK6.


Development and Validation of a Novel Prognostic Nomogram Combined With Desmoplastic Reaction for Synchronous Colorectal Peritoneal Metastasis.
The prognostic value of desmoplastic reaction (DR) has not been investigated in colorectal cancer (CRC) patients with synchronous peritoneal metastasis (SPM). The present study aimed to identify whether DR can predict overall survival (OS) and develop a novel prognostic nomogram. CRC patients with SPM were enrolled from a single center between July 2007 and July 2019. DR patterns in primary tumors were classified as mature, intermediate, or immature according to the existence and absence of keloid-like collagen or myxoid stroma. Cox regression analysis was used to identify independent factors associated with OS and a nomogram was developed subsequently. One hundred ninety-eight and 99 patients were randomly allocated into the training and validation groups. The median OS in the training group was 36, 25, and 12 months in mature, intermediate, and immature DR categories, respectively. Age, T stage, extraperitoneal metastasis, differentiation, cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and DR categorization were independent variables for OS, based on which the nomogram was developed. The C-index of the nomogram in the training and validation groups was 0.773 (95% CI 0.734-0.812) and 0.767 (95% CI 0.708-0.826). The calibration plots showed satisfactory agreement between the actual outcome and nomogram-predicted OS probabilities in the training and validation cohorts. DR classification in the primary tumor is a potential prognostic index for CRC patients with SPM. The novel prognostic nomogram combined with DR classification has good discrimination and accuracy in predicting the OS for CRC patients with SPM.


Alpha male chimpanzee grooming patterns: implications for dominance "style".
In social primates, individuals use various tactics to compete for dominance rank. Grooming, displays and contact aggression are common components of a male chimpanzee's dominance repertoire. The optimal combination of these behaviors is likely to differ among males with individuals exhibiting a dominance "style" that reflects their tendency to use cooperative and/or agonistic dominance tactics. Here, we examine the grooming behavior of three alpha male chimpanzees at Gombe National Park, Tanzania. We found that (1) these males differed significantly in their tendency to groom with other males; (2) each male's grooming patterns remained consistent before, during and after his tenure as alpha, and (3) the three males tended to groom with high- middle- and low-ranking partners equally. We suggest that body mass may be one possible determinant of differences in grooming behavior. The largest male exhibited the lowest overall grooming rates, whereas the smallest male spent the most time grooming others. This is probably because large males are more effective at physically intimidating subordinates. To achieve alpha status, a small male may need to compensate for reduced size by investing more time and energy in grooming, thereby ensuring coalitionary support from others. Rates of contact aggression and charging displays conformed to this prediction, suggesting that each male exhibited a different dominance "style."


The use of tacrolimus in the treatment of inflammatory bowel disease.
Tacrolimus is a calcineurin inhibitor that suppresses pro-inflammatory cytokine production and T-cell activation. These immunosuppressant effects have been used to treat inflammatory bowel disease, especially fistulising Crohn's disease and refractory ulcerative colitis. The more predictable oral bioavailability and better side-effect profile makes tacrolimus a more favourable choice as compared with ciclosporin. Dose-dependent side effects, such as nephrotoxicity, are reported but are mostly reversible with dose reduction or cessation of therapy. Topical tacrolimus has also been used to treat pyoderma gangrenosum, an extra-intestinal manifestation of inflammatory bowel disease. Tacrolimus is well-tolerated and should be considered as an alternative agent in the treatment of inflammatory bowel disease, especially those intolerant or refractory to the more conventional immunomodulators.


Monolithic Cylindrical Fused Silica Resonators with High Q Factors.
The cylindrical resonator gyroscope (CRG) is a typical Coriolis vibratory gyroscope whose performance is determined by the Q factor and frequency mismatch of the cylindrical resonator. Enhancing the Q factor is crucial for improving the rate sensitivity and noise performance of the CRG. In this paper, for the first time, a monolithic cylindrical fused silica resonator with a Q factor approaching 8 × 10⁵ (ring-down time over 1 min) is reported. The resonator is made of fused silica with low internal friction and high isotropy, with a diameter of 25 mm and a center frequency of 3974.35 Hz. The structure of the resonator is first briefly introduced, and then the experimental non-contact characterization method is presented. In addition, the post-fabrication experimental procedure of Q factor improvement, including chemical and thermal treatment, is demonstrated. The Q factor improvement by both treatments is compared and the primary loss mechanism is analyzed. To the best of our knowledge, the work presented in this paper represents the highest reported Q factor for a cylindrical resonator. The proposed monolithic cylindrical fused silica resonator may enable high performance inertial sensing with standard manufacturing process and simple post-fabrication treatment.


Locally advanced colon cancer with cutaneous invasion: case report.
Locally advanced colon cancer with direct abdominal wall and skin invasion is an extremely rare finding with most data being derived from case reports, historical autopsy-based or single-center retrospective studies. We present a unique case of a colon cancer with direct cutaneous invasion and colocutaneous fistulization. Eighty-six year old Caucasian female with multiple comorbidities, referred to Surgical Consultation due to ulcerated skin lesion in the abdomen. She had a long-standing large umbilical hernia but with no previous episodes of incarceration or occlusive symptoms. She denied any digestive or constitutional symptoms. Physical examination showed a large non-reducible umbilical hernia, with an associated painless firm mass within the hernia sac and cutaneous ulcerated growth. Colonoscopy revealed transverse colon cancer (endoscopic biopsy of the tumor and skin punch biopsy confirmed adenocarcinoma of the colon). Computed tomography showed a tumoral mass within the umbilical hernia, with cutaneous infiltration and enlarged regional lymph nodes. Rapid local progression led to colocutaneous fistula with total fecal diversion. We performed an extended right hemicolectomy with en bloc excision of the hernia sac and infiltrating cutaneous mass. In the current era of widespread use of screening colonoscopies, initial diagnosis of locally advanced colon cancer is decreasing. However, this unique case presented an opportunity to recall the advantages of multivisceral resections.


[Qualitative differences between ranibizumab from original and ready to use syringes].
The aim of this study was to determine the influence of time, temperature and light exposure on ranibizumab (Genentech, San Francisco, USA) in plastic syringes. Samples of ranibizumab were drawn from the original vials into plastic tuberculin syringes, capped and analyzed after different storage intervals under varying temperature conditions (4 °C and room temperature) and light exposure (protected and room light). The samples were tested for the pH value, protein stability and concentration as well as for the binding affinity to VEGF-165 in an ELISA (enzyme linked immunoassay). Additionally, original freshly drawn samples were compared to commercially available ready to use ranibizumab syringes analyzed up to 14 days after sampling. Samples stored under the described conditions retained a stable pH. Both SDS-PAGE analysis as well as protein concentration measurements shows slightly decreasing values over time that were not additionally influenced by light exposure or room temperature. The binding affinity to VEGF-165, however, was significantly decreased (p<0.05) over time starting from the first day after sampling. A similar effect could be observed in commercially available ready to use syringes. Exposure to light and room temperature led to additional decreases in the binding affinity to VEGF-165. Until now different socioeconomic and legal aspects have influenced the choice whether to use original vials or pre-sampled ranibizumab. A new aspect is the effect of storage in plastic syringes on the quality and biological efficacy of the antibody fragment.


Lung Cancer Surgical Regionalization Disproportionately Worsens Travel Distance for Rural Patients.
Major cancer surgeries have regionalized to fewer and higher-volume hospitals, with the goal of improving the quality of surgical care. However, regionalization may have negative effects on geographic access to care. We hypothesize that lung cancer patients have been traveling further for surgery over time as regionalization has occurred, and this increased travel has primarily impacted rural patients. A North Carolina all-payer state discharge database was used to capture discharges from 2005 to 2015 for patients undergoing lung cancer resection. Changes in patterns of care over time in high-volume centers (HVC) were examined. Adjusted patient straight-line travel distance was estimated over time and stratified by rural-urban location. The number of hospitals performing lung cancer resections decreased from 49 to 31 over the study period (P = .0006), and the proportion of patients receiving care at HVC increased from 23% to 44% (P < .0001). Rural patient travel distance increased over time by 8.5 miles (95% CI: 0.56-17.10, P = .048), from 45.1 to 53.6 miles. There was no change in urban patient travel distance. The difference in adjusted travel distance between rural and urban patients nearly doubled from 2005 to 2015 (9.6 to 17.9 miles,P < .0001). In North Carolina, lung cancer surgical regionalization occurred over the study period and was accompanied by increases in travel distance for rural patients only. Further work is needed to determine the effects of greater travel distance on patterns of cancer care for rural patients.