Rat Chromosome 2: assignment of the genes encoding cyclin B1, interleukin 6 signal transducer, and proprotein convertase 1 to the Mcs1-containing region and identification of new microsatellite markers.
The rat Chromosome (Chr) 2 harbors several genes controlling tumor growth or development, blood pressure, and non-insulin-dependent diabetes mellitus. We report that the region (2q1) containing the mammary susceptibility cancer gene Mcs1 also harbors the genes encoding cyclin B1, interleukin 6 signal transducer (gp130), and proprotein convertase 1. We also generated 13 new anonymous microsatellite markers from Chr 2-sorted DNA. These markers, as well as a microsatellite marker in the cyclin B1 gene, were genetically mapped in combination with known markers. A cyclin B1-related gene was also cytogenetically assigned to rat Chr 11q22-q23.


The rate of change of acceleration: implications to head kinematics during rear-end impacts.
Whiplash is a mechanism of injury commonly associated with rear-impact vehicle collisions. To date, research has focused primarily on changes in velocity and acceleration as key factors for determining injuries due to whiplash mechanisms, but other characteristics of the acceleration pulse may be important. This study assessed whether the head acceleration response to whiplash-like perturbation profiles were affected by a change in the rate of the applied acceleration, or jerk. Twenty-one subjects were exposed to different low-velocity rear-impact whiplash-like perturbations using a precisely controlled robotic platform. The perturbations were divided into two groupings of peak acceleration (approximately 10 (high) and 5.7 (low) m/s2) and three groupings of jerk (approximately 260, 310, and 360 m/s3). These six profiles were repeated twice. Results demonstrated that the jerk magnitude significantly affected forehead acceleration in the vertical and horizontal directions. Increasing the magnitude of the platform acceleration also differentially affected the horizontal and vertical forehead accelerations. This indicates that the level of jerk influences the resulting head kinematics and should be considered when designing or interpreting experiments that are attempting to predict injury from whiplash-like perturbations.


The invasive twospot livebearer's biology, and its current and potential global distribution.
Poeciliids are widely recognized as successful invaders, possessing traits associated with invasion success. Native to Central America and south-eastern Mexico, the twospot livebearer (Pseudoxiphophorus bimaculatus) is a species recently recognized as invasive in both Central and northern Mexico. Despite its invasive status, limited research exists on its invasion process and the potential threats it poses to native species. In this study, we conducted a comprehensive review of the current knowledge on the twospot livebearer and mapped its current and potential distribution worldwide. The twospot livebearer shares similar traits with other successful invaders within the same family. Notably, it exhibits high fecundity throughout the year and demonstrates resilience to highly polluted and oxygen-deprived water conditions. This fish serves as a host for several parasites, including generalists, and has been extensively translocated for commercial purposes. Recently, it has also been used for biocontrol within its native range. Apart from existing outside its native range, the twospot livebearer, under current climate conditions and if transported there, could readily colonize biodiversity hotspots in tropical zones worldwide, including the Caribbean Islands, the Horn of Africa, North of Madagascar Island, south-eastern Brazil, and others located in southern and eastern Asia. Given that this fish is highly plastic and our Species Distribution Model, we consider that all areas with a habitat suitability >0.2 should prevent its arrival and establishment. Our findings underscore the urgent need to recognize this species as a threat to freshwater native topminnows and prevent its introduction and spread.


An integrative literature review of barriers and facilitators to cervical cancer screening among refugee women in the United States.
Refugee women experience disproportionally high cervical cancer-related mortality. In this integrative review, we identify and discuss factors related to cervical cancer screening among refugee women in the US according to the Social Ecological Model. Two qualitative and three quantitative studies met inclusion criteria. Individual-level factors include English-language ability, availability, and individual knowledge, attitudes, and beliefs. Interpersonal-level factors include interactions with family/friends, provider, and community health worker. Community-, organization-, and policy-level factors include sociocultural values, transportation, ability to navigate the healthcare system, and health insurance. We discuss findings in the context of related reviews and applicability to other global settings.


Routine vaginal cuff smear testing in post-hysterectomy patients with benign uterine conditions: when is it indicated?
By the age of 60 years, an estimated 33% of women will have undergone a hysterectomy. Approximately 85% of these hysterectomies are performed for benign disease. The object of this study was to evaluate cytologic findings from vaginal cuff smears in patients who have undergone hysterectomy for benign uterine conditions. We conducted a community-based retrospective study and follow-up of women with vaginal cuff cytologic smears who had had a hysterectomy for benign uterine conditions. A total of 220 women were randomly selected who had one or more vaginal cuff smears. The main outcomes measures were invasive carcinoma, dysplastic lesions, and infections detected by vaginal cuff smear testing. The setting was a large inner-city hospital. Ninety-seven percent of 220 women who underwent hysterectomy for benign uterine conditions and who were observed for an average of 89 months had no cytologic abnormalities on vaginal cuff smears. Cytologic evaluation found no invasive carcinomas. Dysplastic lesions were detected in 7 patients (3%). Seventy percent of patients (n = 154) had one or more infections; these infections included bacterial vaginosis (106), trichomoniasis (95), candidiasis (40), koilocytosis suggestive of human papilloma virus (HPV) infection (3), and cytopathic effect of herpes (4). The prevalence of koilocytosis was much higher in the patients with dysplasia (P = .0003). Most routine vaginal cuff cytology screening tests need not be performed in women who have had a hysterectomy for benign uterine conditions.


Vector autoregression: Useful in rare diseases?-Predicting organ response patterns in a rare case of secondary AA amyloidosis.
Statistical analyses of clinical data are a cornerstone in understanding pathomechanisms of disorders. In rare disorders, cross-sectional datasets of sufficient size are usually not available. Taking AA amyloidosis as an example of a life-threatening rare disorder resulting from of uncontrolled chronic inflammation, we propose techniques from time series analysis to predict organ response to treatment. The advantage of time-series analysis is that it solely relies on temporal variation and therefore allows analyzing organ response to treatment even when the cross-sectional dimension is small. The joint temporal interdependence of inflammatory activity and organ response was modelled multivariately using vector autoregression (VAR) based on a unique 4.5 year spanning data set of routine laboratory, imaging data (e.g., 18F-Florbetaben-PET/CT) and functional investigations of a 68-year-old patient with multi-organ involvement of AA amyloidosis due to ongoing inflammatory activity of a malignant paraganglioma in stable disease for >20 years and excellent response to tocilizumab). VAR analysis showed that alterations in inflammatory activity forecasted alkaline phosphatase (AP). AP levels, but not inflammatory activity at the previous measurement time point predicted proteinuria. We demonstrate the feasibility and value of time series analysis for obtaining clinically reliable information when the rarity of a disease prevents conventional prognostic modelling approaches. We illustrate the comparative utility of blood, functional and imaging markers to monitor the development and regression of AA amyloidosis.


Cerebral Effects of Neonatal Dysglycemia.
This article summarizes the available evidence reporting the relationship between perinatal dysglycemia and long-term neurodevelopment. We review the physiology of perinatal glucose metabolism and discuss the controversies surrounding definitions of perinatal dysglycemia. We briefly review the epidemiology of hypoglycemia and hyperglycemia in fetal, preterm, and term infants. We discuss potential pathophysiologic mechanisms contributing to dysglycemia and its effect on neurodevelopment. We highlight current strategies to prevent and treat dysglycemia in the context of neurodevelopmental outcomes. Finally, we discuss areas of future research and the potential role of continuous glucose monitoring.


Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder.
Trait functional abnormalities in BD patients have only been reported in the ventral prefrontal cortex (VPFC). We examined whether deficits in VPFC-related inhibitory processes, but not dorsal prefrontal (DPFC) based executive functions, represent an endophenotypic marker for bipolar disorder I (BDI). We used the Wisconsin Card Sorting Test (WCST), commonly associated with DPFC function, and the Hayling Sentence Completion Task (HSCT) which engages the VPFC. Performance on these tests of 43 healthy participants was compared to that of 10 remitted BDI patients and 15 of their unaffected offspring. Compared to healthy participants, patients and their offspring made more errors in the HSCT but offspring achieved more categories and made fewer perseverative errors in the WCST. Impaired response inhibition, predominantly a VPFC related function, may reflect familial predisposition to BDI while deficits in rule attainment, a DPFC based function, may be associated only with the clinical phenotype.


Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891.
The role of adjuvant chemoradiation in pancreatic cancer remains unclear. This report presents the long-term follow-up results of EORTC trial 40891, which assessed the role of chemoradiation in resectable pancreatic cancer. Two hundred eighteen patients were randomized after resection of the primary tumor. Eligible patients had T1-2 N0-N1a M0 pancreatic cancer or T1-3 N0-N1a M0 periampullary cancers, all histologic proven. Patients in the treatment group (n = 110) underwent postoperative chemoradiation (40 Gy plus 5-FU). Patients in the control group (n = 108) had no further adjuvant treatment. After a median follow-up of 11.7 years, 173 deaths (79%) have been reported. The overall survival did not differ between the 2 treatment groups (Chemoradiation treatment vs. death rate ratio 0.91, 95% CI: 0.68-1.23, P value 0.54). The 10-year overall survival was 18% in the whole population of patients (8% in the pancreatic head cancer group and 29% in the periampullary cancer group). These results confirm the previous short-term analysis, indicating no benefit of adjuvant chemoradiation over observation in patients with resected pancreatic cancer or periampullary cancer. Patients with pancreatic cancer may survive more than 10 years. Only 1 of 31 cases recurred after year 7.


Accidental intoxication with 60 mg intrathecal baclofen: survived.
Intrathecal baclofen (ITB) is an effective and well-tolerated treatment for patients with severe spasticity. Intoxications are rare and usually iatrogenic, with reported intrathecal boluses varying between 0.050 and 30 mg. We here report the case of a 47-year-old woman with severe spastic paraplegia due to multiple sclerosis who, during a routine filling procedure, accidentally received a bolus of 60 mg ITB because of injection into the side-port instead of the reservoir of her ITB pump (Archimedes(®), Codman, Germany). After a short period of dizziness, she lost consciousness and stopped breathing. She was immediately intubated, mechanically ventilated, and admitted to the intensive care unit. As specific treatment, she received cerebrospinal fluid drainage through a newly implanted lumbar catheter. A series of generalized and complex partial seizures were treated with levetiracetam and lacosamide. Acute autonomic dysfunction with episodic arterial hypo- and hypertensions was controlled by catecholamines and clonidine, respectively. Recurrent hyperthermia, however, responded neither to drugs nor to physical treatment. After 3 weeks, the patient was discharged without any relevant new neurologic signs or symptoms. This case demonstrates that even excessive doses of ITB can let the patients survive without sequelae if treated promptly and offensively. A pertinent problem during detoxification is the question of when to restart ITB to avoid drug withdrawal.


Neratinib protects pancreatic beta cells in diabetes.
The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.


Pulmonary Sclerosing Pneumocytoma on 18 F-FDG PET/MRI.
Pulmonary sclerosing pneumocytoma is a rare benign neoplasm. Owing to the low incidence, its radiographic features on 18 F-FDG PET/MRI are not well-known. Herein, we described findings of pulmonary sclerosing pneumocytoma on 18 F-FDG PET/MRI in a 52-year-old woman. It showed moderate FDG uptake and hyperintensity signal on both T1WI and T2WI images.


Percutaneous closure of a giant coronary artery fistula after surgical pericardiectomy. Review of the literature.
Coronary artery fistulae (CAF) are uncommon heart defects defined as a communication between a coronary artery and a cardiac chamber or vascular structure. They are frequently asymptomatic; nevertheless, they can produce angina, dyspnea or cardiac failure. CAF are believed to be congenital; however, isolated cases of CAF have been described as rare complications of cardiac surgery. We report the percutaneous closure of a giant CAF in an adult patient with angina and previous pericardiectomy.


Functional antibodies produced by oncolytic clostridia.
Hypoxia is a hallmark of solid cancer and characterized by regions of low oxygen and necrosis due to insufficient blood perfusion. Intratumoral hypoxia triggers the transcription of genes responsible for cell survival. The transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) is a key regulator of this response. HIF activation is associated with resistance to radio- and chemotherapy and poor clinical outcome, and may therefore provide an attractive therapeutic target. Clostridium-based oncolysis is a promising therapeutic strategy for the treatment of hypoxic tumors where these microorganisms naturally home. Here, we report for the first time the isolation of transconjugants of two excellent tumor colonizing Clostridium strains, C. novyi-NT and C. sporogenes, expressing single chain antibodies specific for human HIF-1alpha. This is a first step towards Clostridium-directed antibody therapy (CDAT) that holds promise as a carrier of cancer therapeutics targeting the most resistant regions in human solid cancer.


Costimulation of CD4+ and CD8+ T cells through CD26: the ADA-binding epitope is not essential for complete signaling.
It was previously shown that CD26 (DPP IV, EC 188.8.131.52) is a binding site for adenosine deaminase (ADA, EC 220.127.116.11) on T cells and that costimulation by some anti-CD26 monoclonal antibodies (mAbs) and anti-CD3 induces CD4+ T cell proliferation. The CD26 epitopes involved in costimulation, the precise sequence of the events preceding proliferation, and the response of CD8+ compared with CD4+ T cells to CD26 were not extensively studied. We therefore compared the effects of the novel TA5.9 anti-CD26 mAb, recognizing an ADA-binding epitope, and the clearly distinct anti-Ta1 reference anti-CD26 mAb for their costimulatory properties in various T cell subsets. Both purified CD4+ and CD8+ T cells proliferated upon costimulation with anti-CD3 and either anti-CD26 mAb, but anti-TA5.9 mAb induced a more potent response than anti-Ta1. Either anti-CD26 mAb, together with anti-CD3, caused a similar sequential up-regulation of CD69, CD25 (IL-2R alpha), and CD71 (transferrin receptor) expression on CD4+ and CD8+ T cells. The activation markers appeared faster on the CD45R0+ than on the CD45R0- subsets. After costimulation, CD4+ T cell cultures contained significant amounts of the Th1 cytokines IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). In CD8+ T cell cultures relatively more IFN-gamma and TNF-alpha but almost no IL-2 was measured after triggering of CD3 and CD26. Our data demonstrate that the recognition of the ADA-binding epitope is not a prerequisite for the costimulatory capacity of anti-CD26 mAbs. Both CD4+ and CD8+ T cells and their CD45R0- and CD45R0+ subsets are sensitive to various aspects of activation via CD26, but the magnitude and/or kinetics differ according to the anti-CD26 used and the T cell subset studied.


Interactions of dicarboxylic porphyrins with membranes in relation to their ionization state.
The interactions of dicarboxylic porphyrins with membrane systems are discussed with particular emphasis on the effect of the charge of the porphyrin and the nature of the side-chains. The incorporation of hematoporphyrin or related dicarboxylic porphyrins within small unilamellar vesicles as membrane models is favored by a decrease of the pH in the range of physiological pH values. This effect might play an important role in the retention of porphyrins by tumors, which are more acidic than normal tissues. Kinetics studies also show that the partition of the porphyrin between the lipidic bilayer and the aqueous phase is governed by its release rate rather than by its incorporation rate.


Construction and in vivo evaluation of a dual layered collagenous scaffold with a radial pore structure for repair of the diaphragm.
In each organ the extracellular matrix has a specific architecture and composition, adapted to the functional needs of that organ. As cells are known to respond to matrix organization, biomaterials that take into account the specific architecture of the tissues to be regenerated may have an advantage in regenerative medicine. In this study we focussed on the diaphragm, an organ essential for breathing, and consisting of radial oriented skeletal muscle fibres diverging from a central tendon plate. To mimic this structure dual layered collagenous scaffolds were constructed with a radial pore orientation, prepared by inward out freezing, and reinforced by a layer of compressed collagen. Similar scaffolds with a random round pore structure were taken as controls. Scaffolds were first mildly crosslinked by formaldehyde vapour fixation for initial stabilization (13% and 17% crosslinking for the radial and control scaffolds, respectively), and further crosslinked using aqueous 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (38% and 37% crosslinking, respectively). Scaffolds were implanted into a surgically created diaphragm defect in rats and explanted after 12weeks. Macroscopically, integration of the radial scaffolds with the surrounding diaphragm was better compared with the controls. Cells had infiltrated further into the centre of the scaffolds (P=0.029) and there was a tendency of blood vessels to migrate deeper into the radial scaffolds (P=0.057, compared with controls). Elongated cells (SMA-positive) were aligned with the radial structures. In conclusion, collagenous scaffolds with a stable radial pore structure can be constructed which facilitate cellular in-growth and alignment in vivo.


Ca2+/calmodulin system: participation on rat sexual hypothalamic differentiation.
Modifications of male rat hypothalamic sexual differentiation after neonatal administration of drugs that participate on the Ca2+/calmodulin system (haloperidol, trifluoperazine, penfluridol, pimozide, and verapamil) were studied. Pups treated 72 h after birth were behaviorally tested on day 120 of extrauterine life. Five tests for homotypical behavior were conducted. Afterwards animals were castrated and tested twice for heterotypical (female) behavior under replacement hormonal therapy. Fifty percent (80% in the case of pimozide) of all treated males showed lordotic behavior compared with none of the controls. Haloperidol (39%, lordosis quotient) and pimozide (40%, lordosis quotient) were more active than the others. Results obtained with verapamil were not statistically different from the controls. Pimozide was the most active agent influencing the appetitive masculine behavior (mount latency, intromission latency, and postejaculatory interval). Verapamil was more efficient than the rest of the drugs on the consummatory behavior (mount latency, intromission frequency, interintromission interval, and ejaculatory latency). Our results support the participation of the Ca2+/calmodulin system in hypothalamic sexual differentiation and in the differential modulation of the masculine and feminine behavioral patterns.


New developments in the trace analysis of organic water pollutants.
Challenging tasks, increasing demands, and new generations of powerful analytical instruments initiated considerable progress in aquatic environmental analysis and led to a considerable improvement of analytical performance during the last few years. The ever growing number of emerging pollutants is tackled by specific and highly sensitive analytical methods with detection limits of a few nanogram per liter and even lower. Wide-scope monitoring techniques and multiclass and multiresidue analysis allow for the simultaneous determination of hundreds of compounds. The high mass resolution capability and mass accuracy of advanced mass spectrometric instruments, i.e., time-of-flight (TOF) MS or Fourier transform (FT)-Orbitrap MS, enable combined target and non-target analysis, including the identification of metabolites and abiotic degradation products. This minireview highlights some of the most recent developments in the trace analysis of important organic water pollutants and focuses on some specific groups of emerging contaminants, i.e., pharmaceuticals, flame retardants, disinfection by-products, surfactants, per- and polyfluorinated compounds, benzotriazoles, and benzothiazoles, as well as on the identification of transformation products and on non-target analysis. References were selected according to their exemplary and innovative character and to their practical relevance.


A scanning electron microscopic study of the luteo-follicular complex. III. Repair of ovulated follicle and the formation of the corpus luteum.
As observed by SEM, the repair of an ovulated mammalian follicle is accompanied by a sequence of morphogenetic processes. In the initial phase, a mass of cells and coagulated fluids forms at the site of rupture. Shortly thereafter, connective cells, recruited from the adjacent and subjacent connective tissue stroma begin to proliferate and to migrate over this mass such that in the rabbit, the entire site of disruption is covered by a layer of connective cells by approximately 2 days following ovulation. Coincident with the migration of the connective tissue, superficial cells from undisturbed lateral and basal areas of an ovulated follicle also proliferate and begin to migrate over the newly established connective tissue matrix. By approximately 4 days following ovulation in the rabbit, the surface of an ovulated follicle is repopulated by elements of the superficial epithelium. The formation of the underlying corpus luteum (corpora lutea) involves characteristic morphological changes as granulosa cells transform into steroid secreting luteal cells. The luteal cells become organized into cords of cells which usually surround capillary vessels. When examined by SEM, the smooth-surfaced endoplasmic reticulum of the luteal cell is quite apparent and is observed to form a three-dimension network of anastomosing tubules which are continuous with the nuclear membrane. Variations in the appearance of the surface of the ovary which directly overlies corpora lutea were observed when the mouse, rat and rabbit were compared. The regression of corpora lutea involves the infiltration of the luteal mass by connective tissue and both degeneration and vacuolization of the luteal cells. The regressing corpus luteum is a honey-comb-like structure in which each space is occupied by a degenerating luteal cell.


Phenols removal by immobilized tyrosinase reactor in on-line high performance liquid chromatography.
The development of an immobilized enzyme reactor (IMER) based on tyrosinase immobilized on aminopropyl-controlled pore glass (AP-CPG) for the removal of phenols from model aqueous solutions was reported. To elucidate the influence of the substrate nature, the apparent (V'max, K'm) and the inherent (Vmax, Km) Michaelis-Menten constants were determined by Lineweaver-Burk method and the external diffusional contributions on measured enzyme activities were removed by a graphical method. The dephenolization process was realized by recycling the phenol solutions through the bioreactor connected to a chitosan trap in order to remove the colored quinone-type products of the tyrosinase reactions. The results indicated that a complete removal of phenol derivatives in the range of 150-300 min, with the exception of 60% removal for phenol reached in 400 min, was obtained. The observed sequence: cresol > 4-methylcathecol > catechol > 4-Cl-phenol phenol was in accordance to the V'max/K'm values.


TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.
Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206+ macrophages. Pharmacological blocking of the TWEAK downstream target chemokine monocyte chemoattractant protein 1 (MCP-1 or CCL2) significantly reduced CCA xenograft growth, while TWEAK overexpression drove cancer-associated fibroblast proliferation and collagen deposition in the tumour niche. Genetic Fn14 ablation significantly reduced inflammatory, fibrogenic and ductular responses during carcinogenic TAA-mediated injury. These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation.


Responses of an early and a late successional species of Polygonum to variations in resource availability.
The behavior of Polygonum pensylvanicum L., an early successional annual, and Polygonum virginianum L., a later successional perennial were compared on singlefactor gradients of light, nutrients and soil moisture and on a double-factor gradient of light and nutrients. The two species were grown together as well as alone. In most cases, the early successional species was more productive and allocated less of its biomass to belowground parts relative to its later successional congener. The early successional species was also more opportunistic in its utilization of resources as evidenced by its greater responsiveness to varying resource availability. The role of perenniality in the later successional species may be dual. Individuals of P. virginianum started from seed were more responsive to deficiencies in resources than were individuals started from rootstocks in these experiments. In the single-factor experiments where plants were started from seed, there were numerous significant interactions between levels of light, nutrients or moisture with competition in both species. In the double-factor experiment, however, there were no statistically significant interactions between light, nutrients and competition in the perennial started from rootstocks, but all possible interactions were significant in the early successional annual. The result of a large, underground reserve in the perennial was that the effects of resource availabilities of light and nutrients were uncoupled. The competitive superiority of the early successional species over the later successional species was greatly diminished when the later successional species was started from rootstocks instead of from seeds. Regardless of whether individuals of P. virginianum were started from seed or from rootstocks the results of competition between the two species indicate that the early successional species is competitively more competent when resources are abundant and that the later successional species is competitively more competent when resources are scarce.


Genotypic analysis of Candida albicans isolates obtained from removable prosthesis wearers.
To assess of the genotypic diversity of Candida albicans isolated from removable prosthesis wearers, with and without denture-related stomatitis (DRS). The occurrence of different genotypes in pathological and control cases was investigated. One hundred and sixty-four isolates of C. albicans obtained from different oral cavity locations were compared by randomly amplified polymorphic DNA (RAPD). The coherence of this analysis was confirmed by genotyping a selected group of isolates with pulsed field gel electrophoresis (PFGE). Among the 164 isolates, 150 were grouped into seven groups on the basis of their RAPD patterns. Three of these groups (comprising 54 isolates) had significant (alpha < 0.10) predominance of clinical or control cases. For the other isolates, no significant differences were observed between control and DRS cases. Occasionally, more than one genotype was found in the same person. These findings were sustained by PFGE analysis. No relevant associations between the genotypic patterns and pathology level were found. This study evidenced that C. albicans with similar genotypes may be found in individuals with DRS and in control cases. This conclusion hints the involvement of other aetiological factors that alone or in association with C. albicans may trigger the emergence of DRS.


Comparison of child adiposity indices in prediction of hypertension in early adulthood.
We aimed to compare child body mass index (BMI) in prediction of hypertension in early adulthood with 4 other adiposity indices (waist circumference [WC], waist circumference-to-height ratio [WHtR], waist-to-hip ratio [WHR], and triceps skinfold [TSF]). The cohort from the China Health and Nutrition Survey 1993-2011 consisted of 1444 adults aged 18-36 years who were examined in childhood and early adulthood. Child adiposity indices and adult blood pressure (BP) were transformed into age-, sex-, and survey year-specific Z-scores. Adult hypertension was defined as BP ≥130/80 mm Hg as per the 2017 American College of Cardiology/American Heart Association guidelines. Adult hypertension prevalence was 32.9% during a mean follow-up of 10.1 years. Childhood BMI showed stronger correlation with adult BP than WHR and TSF (PS for difference <.05). Child BMI showed the better prediction of adult hypertension compared with WHtR, WHR, and TSF using area under the receiver operating characteristic curves (PS for difference <.05). Per SD change in the predictor, child BMI (relative risk [95% confidence interval], 1.11 [1.04-1.18]) and WC (1.12 [1.05-1.20]) were significantly associated with adult hypertension using covariate-adjusted Poisson models with robust standard errors. Child BMI performed equally or better compared with 4 other adiposity indices in predicting adult hypertension.


Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK.
Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.


Characterization and discrimination of selected chicken eggs in China's retail market based on multi-element and lipidomics analysis.
The present study focuses on the differentiation of Deqingyuan (n = 90), Taihe (n = 90) and crossbred (n = 90) black-boned silky fowl eggs based on chemometrics analysis of multi-element and lipidomics data. A total of 53 chemical elements were simultaneously quantified in the eggs using inductively coupled plasma mass spectrometry. Multivariate statistical analysis of element data screened 30, 13 and 12 candidate discriminants for whole egg, egg yolk and egg white samples, respectively. Moreover, we utilized an LC-MS/MS-based lipidomics approach to profile lipids in the three types of egg yolks. In total, 1633 lipid species (including 43.78% glycerophospholipids, 25.66% glycerolipids, 16.66% fatty acyls, 6.86% sphingolipids, 4.10% sterol lipids, 1.53% polyketides, 1.10% prenol lipids and 0.31% saccharolipids) were consistently detected in all samples. A partial least squares discriminant analysis model was established based on the lipidomics data, which enables a 100% correct classification of the egg yolks. Using a cutoff of variable importance in projection value >1 and p value <.05, a panel of 22 potential lipid markers was discovered for the discrimination of Deqingyuan, Taihe and crossbred egg yolks. These results could facilitate a better understanding of the nutritional qualities of the evaluated eggs. Our method of combining chemical analysis with chemometrics offers a convenient and powerful tool to distinguish commercially-available eggs.


Thigh abscess and necrotizing fasciitis following an inside-out transobturator tape intervention: a case report.
Tension-free vaginal transobturator tapes are used worldwide in the treatment of urinary incontinence in women. Very few severe complications have been described following this procedure, with no standard treatment yet established. We present the case of a 36-year-old French white woman with no remarkable medical history, presenting with an abscess and necrotizing fasciitis 48 hours after an inside-out tension-free transobturator procedure. Samples were collected by guided puncture from the abscess, retrieving Staphylococcus aureus and Citrobacter koseri. Severe complications following this procedure are rare, although it can have the potential for significant morbidity and even mortality, which is worth highlighting. We recommend early surgical treatment in combination with broad-spectrum antibiotics and coverage for Staphylococcus aureus, which may be a causative agent.


A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia.
Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.


Materials based tumor immunotherapy vaccines.
Immunotherapy is a promising approach for treating cancer. However, there are limitations inherent to current approaches which may be addressed by integrating them with biomaterial-based strategies. Material platforms have been fabricated to interact with immune cells through spatially controlled and temporally controlled delivery of immune modulators and to promote immune cell crosstalk. Particle vaccines have been developed to specifically target and deliver agents to organs, cells and subcellular compartments. These strategies have been shown to generate antigen-specific CTL responses and, in some cases, tumor regression. Therefore, collaboration between immunology and materials engineering is likely to result in the creation of strong vaccines to combat cancer in the future.


Determination of Rheumatoid Arthritis Incidence and Prevalence in Alberta Using Administrative Health Data.
The objective of the study was to estimate the incidence and prevalence of rheumatoid arthritis (RA) in Alberta using administrative health data. We identified RA cases in patients 16 years and older by applying a national case definition to linked administrative health data (ie, hospital discharge abstract records, physician claims, and health insurance registry records) using a unique personal identifier. Incidence and prevalence are reported for the 2015-2016 fiscal year and a trend analysis from 2011-2012 to 2015-2016. Incidence and prevalence estimates were standardized using the 2011 Canadian census population. In 2015-2016, the overall crude incidence was 0.74 [95% confidence interval (CI): 0.71-0.77] per 1000 and crude prevalence was 1.08% (95% CI: 1.07-1.09). The women-to-men crude incidence and prevalence sex ratios were 2.04 and 2.19, respectively. People aged 65 to 79 years had the highest incidence of RA, and the highest prevalence was observed among those 80 years and older. From 2011-2012 to 2015-2016, the overall age-standardized incidence decreased [0.97 (95% CI: 0.94-1.01) to 0.79 (95% CI: 0.76-0.82) per 1000], whereas age-standardized prevalence remained constant [1.17 (95% CI: 1.15-1.18) to 1.18 (95% CI: 1.17-1.19)]. In Alberta, there was a decreasing trend in RA incidence over the study period, whereas prevalence was stable. These estimates, combined with clinical data, will be used to measure system performance for quality improvement and to inform simulation modeling for planning the expected demand for health services for patients living with RA.


[Blood conservation approaches in orthopedic surgery].
In addition to more restrictive "transfusion triggers", presently available allogeneic blood conservation strategies in surgery include preoperative increase in red blood cells (RBC) mass, techniques or pharmaceutical agents that reduce blood loss, and perioperative blood salvage. Because of very important risk reduction in allogeneic blood, benefit/risk of preautologous blood donation (PAD) is quite questionable at this moment. Indeed, at this moment in France, we focus to avoid any transfusion (allogeneic and autologous blood). Therefore the most important techniques used are pharmacological: erythropoietin before surgery with a number of injections related to baseline Hb, and tranexamic acid during and after surgery. Cell saving is used only if bleeding is enough important like arthroplasty revisions. All blood conservation techniques carry their own efficiency limits, constraints and risks that, in addition to institutional considerations and individual patient characteristics are determinant to settle a blood conservation strategy. The choice of a technique should take into account (a) the delay before surgery, (b) the anticipated blood loss for the procedure that varies among institutions, (c) the tolerable blood loss without transfusion for the patient, and (d) the efficacy of the blood conservation technique in the given setting. Nevertheless, at this moment in France, it is quite important to notice that the risk of delay or lack of transfusion induces much more deaths that the transfusion itself during or after anesthesia [Anesthesiology 105, 1087-97].


Incorporation of [18O]water in the formation of p-hydroxybenzyl alcohol by the p-cresol methylhydroxylase from Pseudomonas putida.
In the hydroxylation of the methyl group of p-cresol by an enzyme from Pseudomonas putida the oxygen atom is derived from water. Although a second reaction by the same enzyme converts the product, p-hydroxybenzyl alcohol, into the aldehyde, the alcohol is an enzyme-free intermediate.


Focus issue: series on computational and systems biology.
The application of computational biology and systems biology is yielding quantitative insight into cellular regulatory phenomena. For the month of September, Science Signaling highlights research featuring computational approaches to understanding cell signaling and investigation of signaling networks, a series of Teaching Resources from a course in systems biology, and various other articles and resources relevant to the application of computational biology and systems biology to the study of signal transduction.


Social mobility and alcoholism a comparison of alcholics with their fathers and brothers.
Men alcoholics entered the work force at a low socioeconomic level and though their status gradually increased, it never reached their fathers' or their brothers' level. Downward mobility in relation to significant others seems to play a role in the etiology of alcoholism.


Determination of Reactive Carbonyl Species, Which Mediate Reactive Oxygen Species Signals in Plant Cells.
Responses of plant cells to reactive oxygen species (ROS), e.g., reprogramming of defense genes or progression of cell death, should include the ROS signal transmission to target proteins, but the biochemistry of this process is largely unknown. Lipid peroxide-derived α,β-unsaturated aldehydes and ketones (reactive carbonyl species; RCS), downstream products of ROS stimuli, are recently emerging endogenous agents that can mediate ROS signal to proteins via covalent modification. The involvement of RCS in certain ROS signaling in plants (oxidative injury of leaves and roots, ROS-induced programmed cell death, senescence, and abscisic acid and auxin signaling) has been verified by the determination of RCS with the use of conventional HPLC. Because distinct kinds of RCS act differently in the cell and so are metabolized, identification and quantification of each RCS in plant tissues provide central information to decipher biochemical mechanisms of plant responses to ROS. This article illustrates practical methods of plant sample preparation and extraction and analysis of RCS.


Autonomous development of decorrelation filters in neural networks with recurrent inhibition.
We perform a quantitative analysis of information processing in a simple neural network model with recurrent inhibition. We postulate that both excitatory and inhibitory synapses continually adapt according to the following Hebbian-type rules: for excitatory synapses correlated pre- and post-synaptic activity induces enhanced excitation; for inhibitory synapses it induces enhanced inhibition. Following synaptic equilibration in unsupervised learning processes, the model is found to perform a novel type of principal-component analysis which involves filtering and decorrelation. In the light of these results we discuss the possible role of the granule-/Golgi-cell subnetwork in the cerebellum.


Long-term outcome of arthroscopic massive rotator cuff repair: the importance of double-row fixation.
The purpose of this study was to (1) evaluate the long-term functional outcome of arthroscopic rotator cuff repair of massive rotator cuff tears (RCTs) and (2) compare double-row (DR) and single-row (SR) repairs. This was a retrospective review of massive RCTs treated with an arthroscopic rotator cuff repair over an 8-year period. Minimum 5-year follow-up was available for 126 repairs at a mean of 99 months. Among 107 complete repairs, there were 62 SR and 45 DR repairs. Functional outcome was determined by University of California, Los Angeles (UCLA) and American Shoulder and Elbow Surgeons scores. A multivariate analysis was performed to examine the role of a DR repair. For all repairs combined, improvements were observed in forward flexion (132° v 168°), pain (6.3 v 1.3), UCLA score (15.7 v 30.7), and American Shoulder and Elbow Surgeons score (41.7 v 85.7) (P < .001). A good or excellent outcome, obtained in 78% of cases, was associated with a complete repair (P = .035) and a DR repair (P = .008). When we excluded partial repairs, postoperative UCLA gain was greater after a DR repair (P = .007). Patients reported their shoulder as feeling closer to normal after a DR repair compared with an SR repair (93.5% v 84.4%, P = .006). A DR repair was 4.9 times more likely to lead to a good or excellent outcome (P = .021). When a DR repair of a massive RCT is possible, on the basis of the ability to mobilize the tendons, a better long-term functional outcome can be expected compared with an SR repair. Given the known high risk of recurrence after repair of massive RCTs and the knowledge that functional outcome is related to recurrence, a DR repair of massive RCTs should be performed when there is sufficient tendon mobility.


Paced latissimus dorsi used for dynamic cardiomyoplasty of left ventricular aneurysms.
Two patients are described, each with a large left ventricular aneurysm and severe coronary artery disease, and each with an ejection fraction lower than 30% and in congestive heart failure. In both, the left latissimus dorsi (LD) muscle was used in the repair of the ventricular aneurysm because preoperative studies demonstrated that there was concomitant coronary artery disease, and there was a strong suggestion that resection of the entire aneurysm would seriously compromise the residual ventricular capacity. One patient had an 18-year history of coronary occlusion with two infarctions. A large, calcified ventricular aneurysm developed, and despite vigorous medical treatment, intractable congestive heart failure and angina persisted. The diffuse coronary artery disease made this patient a poor candidate for bypass grafting. The other patient sustained an acute myocardial infarction 5 months prior to operation. The left anterior descending coronary artery was totally occluded, and a large apical aneurysm developed along with an akinetic anterior wall and septum. After his heart attack, the patient had progressive dyspnea on exertion. Following operation in both patients, the transpositioned LD, then a component in the repair of the left ventricular wall, was electrically trained to synchronously contract with each systole, driven by a standard dual-chamber cardiac pacemaker. Steady improvement and a return to normal activities were observed in both patients. There was an indication of improved ejection fraction with synchronous contraction of the skeletal muscle.


Mini Nutritional Assessment May Identify a Dual Pattern of Perturbed Plasma Amino Acids in Patients with Alzheimer's Disease: A Window to Metabolic and Physical Rehabilitation?
Conflicting results about alterations of plasma amino acid (AA) levels are reported in subjects with Alzheimer's disease (AD). The current study aimed to provide more homogeneous AA profiles and correlations between AAs and cognitive tests. Venous plasma AAs were measured in 54 fasting patients with AD (37 males, 17 females; 74.63 ± 8.03 yrs; 3.2 ± 1.9 yrs from symptom onset). Seventeen matched subjects without neurodegenerative symptoms (NNDS) served as a control group (C-NNDS). Patients were tested for short-term verbal memory and attention capacity and stratified for nutritional state (Mini Nutritional Assessment, MNA). Compared to C-NNDS, patients exhibited lower plasma levels of aspartic acid and taurine (p < 0.0001) and higher 3-methylhistidine (p < 0.0001), which were independent of patients' MNA. In comparison to normonourished AD, the patients at risk of and with malnutrition showed a tendency towards lower ratios of Essential AAs/Total AAs, Branched-chain AAs/Total AAs, and Branched-chain AAs/Essential AAs. Serine and histidine were positively correlated with verbal memory and attention capacity deficits, respectively. Total AAs negatively correlated with attention capacity deficits. Stratifying patients with AD for MNA may identify a dual pattern of altered AAs, one due to AD per se and the other linked to nutritional state. Significant correlations were observed between several AAs and cognitive tests.


Tazemetostat synergistically combats multidrug resistance by the unique triple inhibition of ABCB1, ABCC1, and ABCG2 efflux transporters in vitro and ex vivo.
ATP-binding cassette (ABC) drug efflux transporters and drug metabolizing enzymes play crucial roles in pharmacokinetic drug-drug interactions and multidrug tumor resistance (MDR). Tazemetostat (EPZ-6438, Tazverik) is a novel epigenetic drug that has been recently approved for the therapy of advanced epithelioid sarcoma and follicular lymphoma. Additionally, this medication is currently being clinically tested to treat several other cancers such as non-small cell lung cancer (NSCLC). This study aimed to investigate the inhibitory effects of tazemetostat on selected ABC transporters/cytochrome P450 3A4 (CYP3A4) enzyme to comprehensively explore its role in MDR. First, our accumulation and molecular docking studies showed that tazemetostat is a unique triple inhibitor of ABCB1, ABCC1, and ABCG2 transporters. In contrast, tazemetostat exhibited only low level of interaction with the CYP3A4 isozyme. Drug combination assays confirmed that tazemetostat is a multipotent MDR modulator able to synergize with various conventional chemotherapeutics in vitro. Subsequent caspase activity assays and microscopic staining of apoptotic nuclei proved that the effective induction of apoptosis is behind the observed synergies. Notably, a potent MDR-modulatory capacity of tazemetostat was recorded in primary ex vivo NSCLC explants generated from patients' biopsies. On the contrary, its possible position of pharmacokinetic MDR's victim was excluded in comparative proliferation assays. Finally, tested drug has not been identified as an inducer of resistant phenotype in NSCLC cell lines. In conclusion, we demonstrated that tazemetostat is a unique multispecific chemosensitizer, which has strong potential to overcome limitations seen in the era of traditional MDR modulators.


Unraveling the key drivers of community composition in the agri-food trade network.
In the complex global food system, the dynamics associated with international food trade have become crucial determinants of food security. In this paper, we employ a community detection approach along with a supervised learning technique to explore the evolution of communities in the agri-food trade network and to identify key factors influencing their composition. By leveraging a large dataset that includes both volume and monetary value of trades, we identify similarities between countries and uncover the primary drivers that shape trade dynamics over time. The analysis also takes into account the impact of evolving climate conditions on food production and trading. The results highlight how the network's topological structure is continuously evolving, influencing the composition of communities over time. Alongside geographical proximity and geo-political relations, our analysis identifies sustainability, climate and food nutrition aspects as emerging factors that contribute to explaining trade relationships. These findings shed light on the intricate interactions within the global food trade system and provide valuable insights into the factors affecting its stability.


Structure of the cholera toxin secretion channel in its closed state.
The type II secretion system (T2SS) is a macromolecular complex spanning the inner and outer membranes of Gram-negative bacteria. Remarkably, the T2SS secretes folded proteins, including multimeric assemblies such as cholera toxin and heat-labile enterotoxin from Vibrio cholerae and enterotoxigenic Escherichia coli, respectively. The major outer membrane T2SS protein is the 'secretin' GspD. Cryo-EM reconstruction of the V. cholerae secretin at 19-Å resolution reveals a dodecameric structure reminiscent of a barrel, with a large channel at its center that contains a closed periplasmic gate. The GspD periplasmic domain forms a vestibule with a conserved constriction, and it binds to a pentameric exoprotein and to the trimeric tip of the T2SS pseudopilus. By combining our results with structures of the cholera toxin and T2SS pseudopilus tip, we provide a structural basis for a possible secretion mechanism of the T2SS.


Assessment of Three Breast Volume Measurement Techniques: Single Marking, MRI and Crisalix 3D Software®.
Measuring breast volume is important to obtain satisfactory breast surgery results, and many techniques are used for this purpose. Thus, the aim of the present study was to compare 3 breast volume techniques: Pessoa's single marking technique, magnetic resonance imaging (MRI) and Crisalix 3D software®. Fourteen patients indicated for mammoplasty were selected. Three breast volume measurement techniques were compared: Pessoa's single marking technique, MRI and Crisalix 3D software®. The volumes were tabulated and analyzed using R software. Average age was 30.93 ± 10.25 years. The breast volume was 1554.54 ± 512.54 cm3, as measured by the MRI technique (considered the gold standard), 1199.64 ± 403.13 cm3 using Crisalix 3D software® and 1518.04 ± 468.72 cm3 by Pessoa's single marking technique. Comparison between the Crisalix 3D software® and MRI techniques using the pairwise t test demonstrated a statistically significant difference (t = 4.3957, df = 27, p value = 0001543), but no significant difference between the single marking and MRI techniques (t = 1.3841, df = 27, p value = 0.1777). When compared to MRI, breast volume measurement using Pessoa's single marking technique showed no statistically significant difference between them. However, the Crisalix 3D® technique exhibited a difference in relation to MRI. Anthropometric measurements are useful in measuring breast volume because they are easy to obtain, practical and inexpensive, and should be part of a plastic surgeon's arsenal. This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Quantification of surgical resident stress "on call".
We hypothesized that surgical resident stress involves both psychologic and physiologic components that manifest as changes in heart rate (HR) and circulating white blood cell (WBC) count. The purposes of this series of experiments were to monitor HR as a measure of stress "on call"; to monitor WBC count (1,000 cells/microL) during "on call" periods as a measure of stress; and to relate maximum HR and WBC count "on call" to surgical resident training level. HR was continuously documented by Holter monitor for 24hours "on call" in interns (n = 6), junior residents (n = 5), and senior residents (n = 5). Interns (n = 4), junior residents (n = 4), and senior residents (n = 4) during periods devoid of clinical responsibilities served as controls. WBC counts were obtained from residents "off" and "on call" for interns (n = 5) and junior residents (n = 5). Mean HR "on call" increased in all resident groups as compared with controls: intern mean HR increased from 71 +/- 3 to 87 +/- 2 beats per minute (bpm) (p = 0.003), junior resident mean HR increased from 74 +/- 3 to 88 +/- 4 bpm (p = 0.03), and senior resident mean HR increased from 69 +/- 2 to 80 +/- 2 bpm (p = 0.004). Intern maximum control HR was 119 +/- 3 and increased to 149 +/- 6 bpm (p = 0.005). The increase in maximum HR (control versus "on call") did not reach significance in junior residents (123 +/- 5 to 136 +/- 6 bpm, p = 0.14) and senior residents (115 +/- 6 to 116 +/- 3 bpm, p = 0.9). WBC count in interns increased from control values of 5.2 +/- 0.6 x 1,000 cells/microL to 7.5 +/- 0.9 x 1,000 cells/microL"on call" (p = 0.005). The WBC change in juniors was not significant (control: 6.8 +/- 0.7 x 1,000 cells/microL, "on call": 7.1 +/- 0.7 x 1,000 cells/microL; p = 0.37). When heart rate is used as an indicator of combined physiologic and psychologic stress, surgical residents achieve stress levels of tachycardia "on call." Surgical residents also exhibit an increase in circulating WBC count "on call." Both the degree of tachycardia and the increase in WBC count are inversely related to the level of training. Senior residents cope better with stress "on call" than junior residents and interns.


#CardioOncology: Twitter chat as a mechanism for increasing awareness of heart health for cancer patients.
Consideration of heart health for cancer survivors is increasingly important, as improved cancer survivorship has resulted in a growing number of survivors affected by cardiovascular disease. However, there is limited knowledge of cardio-oncology among both patients and a variety of health professionals. Thus, efforts are needed to increase awareness about cardio-oncology. Social media represents one potential opportunity to disseminate information about cardio-oncology to a large audience. We highlight one example of a social media educational/advocacy campaign conducted on Twitter (a "Twitter Chat") that garnered nearly 1.2 million impressions (views by Twitter users) in just 24 h. We provide both quantitative and qualitative data to support the efficacy of using Twitter for such educational/advocacy campaigns, and describe key features that contributed to its success. Twitter Chats inexpensively utilize innovative technology to provide education and foster community. Long-term studies are needed to understand whether Twitter Chats can change knowledge and behavior related to cardio-oncology.


Gleason score, surgical and distant metastasis are associated with cancer-specific survival and overall survival in middle aged high-risk prostate cancer: A population-based study.
According to statistics, patients with high-risk prostate cancer (PC) account for about 15% of prostate cancer diagnoses, and high-risk patients usually have a poor prognosis due to metastasis and recurrence and have a high mortality rate. Therefore, the accurate prediction of prognostic-related risk factors in middle-aged high-risk PC patients between 50 and 65 can help reduce patient mortality. We aimed to construct new nomograms for predicting cancer-specific survival (CSS) and Overall survival (OS) in middle-aged high-risk PC patients. Data for patients aged between 50 and 65 years old and diagnosed with high-risk PC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression models were used to identify independent risk factors for CSS and OS in patients. Nomograms predicting CSS and OS were developed based on multivariate Cox regression models. The concordance index (C-index), the area under the receiver operating characteristic curve (AUC), and the calibration curve are used to detect the accuracy and discrimination of the model. Decision curve analysis (DCA) is used to detect the potential clinical value of this model. Between 2010 and 2018, 1,651 patients diagnosed with high-risk PC and aged 50-65 years were included. In this study, the training group (n = 1,146) and the validation group (n = 505) were randomly assigned in a ratio of 7:3. The results showed that M stage, Gleason (GS) and surgical mode were independent risk factors for CSS; marital status, T stage, M stage, surgical mode, and GS were independent risk factors for OS. The C-index for predicting CSS in the training and validation groups are 0.84 and 0.811, respectively; the C-index for predicting OS in the training and validation groups are 0.824 and 0.784, respectively. The AUC and the calibration curves also showed good accuracy and discrimination. We constructed new nomograms to predict CSS and OS in middle-aged high-risk PC patients. The prediction tools showed good accuracy and reliability, which can help clinicians and patients to make better clinical decisions.


The feasibility of sensitization studies using fewer test animals.
The possibility of reducing the number of animals in sensitization studies (maximization method) is discussed on the basis of results from 20 sensitization tests. It appears that the number of test animals in sensitization studies may be reduced to ten treated animals and five control animals without prejudice to the quality of the test.


Characteristics of a thrombin inhibitor secreted by activated platelets.
A 77-kDa complex of thrombin and a protein secreted by activated platelets had little if any thrombin amidolytic activity, indicating that the secreted protein is an inhibitor. The molecular weight of the inhibitor before reaction with thrombin was approximately 50,000. The apparent second-order rate constant for complex formation was estimated to be 1.3 x 10(6) M-1 s-1 (mean of four measurements); it was not affected by heparin or heparinase. These properties distinguish this inhibitor from other protease inhibitors secreted by platelets. The inhibitor reacted with trypsin and possibly with urokinase but not with factor Xa.


Boundary optimization of inclined coal seam open-pit mine based on the ISSA-LSSVR coal price prediction method.
As an important link in the complex system engineering project of open pit mining, the quality of the boundary determines the performance of the project to a large extent. However, changes in economic indicators may raise doubts about the optimality of mining boundaries. In this article, a coal price time series forecasting model that considers some amount of redundancy is proposed, which combines an improved sparrow search algorithm (ISSA) and a least squares support vector regression machine regression (LSSVR) algorithm. The optimal values of the penalty factor and kernel function parameter of the LSSVR model are selected by ISSA, which improves the prediction accuracy and generalization performance of the forecasting model. A multistep decision optimization method under fluctuating coal price conditions is proposed, and the model prediction results are applied to the boundary optimization design process. Using the widely applied block model as the basis, a set of optimal production nested pits is obtained, allowing the realm design results to fit the coal price fluctuation trend and further enhance enterprise efficiency. The applicability and effectiveness of this method were verified by taking an ideal two-dimensional model and an inclined coal seam open-pit coal mine in Xinjiang as an example.


Assessment of collateral blood flow in patients with distal branch occlusion of the middle cerebral artery.
Aim of this study was to evaluate the collateral blood flow between more distal branches of the middle cerebral artery (MCA) in the case of peripheral MCA branch occlusion on dynamic 4D angiograms. We sought to individually predict the finally resulting infarction volume with regard to the extent of collateral blood flow. Overall, 35 acute ischemic stroke patients with peripheral MCA branch occlusion were included. Volumes of the ischemic infarctions and perfusion deficits were measured on diffusion-weighted images DWI and time-to-peak TTP (> 4 s). Collateral flow on 4D MR angiograms were classified as previously specified. On DWI, the ischemic lesions had a mean volume of 3.4 ± 15.1 mL while the mean volume on TTP (> 4 s) was significantly larger 22.0 ± 18.1 mL (P < 0.001). On dynamic 4D angiograms we observed grade 1 in 8 (22.9%), grade 2 in 4 (11.4%), grade 3 in 10 (28.6%), and grade 4 in 13 (37.1%) patients. In comparison to patients with better collateralization (grade 3-4) patients with less sufficient collateralization (grade 0-2) demonstrated larger infarction volumes on initial (11.1 mL (IQR 2.9-35.5) vs. 2.1 mL (IQR 0.5-4.5), P = 0.03) and follow-up DWI (15.5 mL (IQR 12.6-23.3) vs. 1.9 mL (IQR 0.5-4.5), P = 0.03) with prominent infarction growth (7.4 mL (IQR 2.6-10.1) vs. 0.9 mL (IQR 0.2-2.6), P = 0.08). In the majority of cases with distal MCA branch occlusion a good collateral blood flow has been observed. Nevertheless, in approximately one quarter of patients an insufficient collateral blood flow has been detected that was associated with substantial infarction growth.


Bacterial communities are sensitive indicators of contaminant stress.
With many environments worldwide experiencing at least some degree of anthropogenic modification, there is great urgency to identify sensitive indicators of ecosystem stress. Estuarine organisms are particularly vulnerable to anthropogenic contaminants. This study presents bacterial communities as sensitive indicators of contaminant stress. Sediments were collected from multiple sites within inner and outer zones of three heavily modified and three relatively unmodified estuaries. Bacterial communities were censused using Automated Ribosomal Intergenic Spacer Analysis and analysed for a suite of metal and PAH contaminants. Shifts in both bacterial community composition and diversity showed strong associations with sediment contaminant concentrations, particularly with metals. Importantly, these changes are discernable from environmental variation inherent to highly complex estuarine environments. Moreover, variation in bacterial communities within sites was limited. This allowed for differences between sites, zones and estuaries to be explained by variables of interest such as contaminants that vary between, but not within individual sites.


Methyl-p-hydroxyphenyllactate-esterase activity and type-II estrogen-binding sites in ovarian cancer: correlation with biological and clinico-pathological parameters.
We examined the levels of activity of methyl-p-hydroxyphenyllactate esterase (MeHPLA-ase) and cytosolic Type-II-estrogen-binding sites (Type-II EBS) in 61 and 71 cases, respectively, of primary ovarian cancer. MeHPLA-ase activity and Type-II EBS were seen to by asymmetrically distributed, in that levels were skewed towards the lower values. A statistically significant direct correlation was found between MeHPLA-ase activity and Type-II EBS. MeHPLA-ase activity and Type-II EBS were inversely correlated with ER and PR levels and showed a trend towards inverse correlation with the percentage of cells in S-phase of the cell cycle. MeHPLA-ase activity and Type-II EBS did not correlate with clinico-pathological parameters. The median MeHPLA-ase activity tended to be higher in responders than in unresponsive patients, but statistical significance was not reached. Higher Type-II-EBS levels were found in cases showing complete and partial response to chemotherapy than in cases which did not respond. A statistically significant relationship was found between high MeHPLA-ase activity and longer overall survival.


Radiology-pathology conference: neutrophilic fasciitis and panniculitis of the feet (Sweet's syndrome).
Sweet's syndrome is characterised by pyrexia, cutaneous lesions, neutrophilia and an infiltrate of mature neutrophils in the dermis. While extracutaneous disease is not uncommon, neutrophilic fasciitis has rarely been described. We report the imaging appearances with clinical and histological correlation of a case of drug-induced neutrophilic fasciitis in a 56-year-old man.


How do I implement an automated screen for high-titer ABO antibody as an inventory management tool for ABO plasma-incompatible platelets?
Plasma volume reduction (PVR) may reduce the risk of hemolysis associated with transfusion of plateletpheresis blood products (PLTs) containing ABO-incompatible plasma. But PVR may delay PLT issue. In collaboration with our blood donor center we evaluated an automated screen of PLT for high-titer ABO antibody and to apply PVR to high-titer PLTs. At the donor center, plasma from PLT donors was tested using an automated microplate system (PK7300, Beckman). PK settings were set for a detection cutoff equivalent to 1 in 256 using a manual tube method. The donors associated with high-titer PLTs were characterized by sex and age. In the transfusion service, the number of PVR procedures was evaluated before and after implementation of the high-titer screen. During validation, 157 of 1008 PLT units (15%) were positive by the automated method versus 121 (12%) by manual method. After implementation, 2112 of 15,240 PLT units were high-titer, with higher frequency in donations from females versus males (18% vs. 12%, p < 0.0001). The PLT PVR rate was reduced by 50%. Implementation of an automated method to screen PLTs for high-titer ABO antibody at the donor center improves the inventory management of PLTs containing ABO-incompatible plasma at the hospital transfusion service.


Muscle Tension Dysphonia: A Sequeale of Chemoradiotherapy in Patients of Head and Neck Cancer.
It's very important to demarcate that voice is the production of sound by the larynx while speech is articulation of the produced sound by tongue movements, soft palate and the lips. Mucositis, dysphagia, change in speech and voice are the common sequelae of Radiotherapy (RT) alone or in combination with chemotherapy (CRT) which is commonly used in the treatment of head and neck cancer (HNC). The aim of this study was to investigate the patient-reported voice impairment among non laryngeal head and neck cancer survivors who were treated with curative RT/CRT with or without surgery. This tertiary institutional assessor blinded study consists of a study cohort of 128 patients who after of completion of treatment for HNC reported to the laryngology clinic for voice complaints and throat discomfort. The assessment included laryngeal endoscopic and stroboscopic imaging, acoustics assessment and VHI (Vocal handicap index). This study cohort consisted of 89.8% males and 11.2% females. There was hyperadduction and strain of ventricular bands in almost all the cases. There was hyperactivity and compression of both true and false cords in 80.5% of the cases. DSI impairment level showed significant association with gender, VHI, GRBAS score and RT/CRT and it did not show significant association with smoking and surgery, while VHI showed significant association with DSI and RT/CRT and it did not show significant association with gender, smoking and surgery. Muscle tension is a very common effect of RT/RCT and dysphonia can be easily associated with it. Future research needs to focus on specific voice treatment regimens in HNC treated with RT/CRT to improve the quality of life of these patients.


Economic impact of asthma therapy with fluticasone propionate, montelukast, or zafirlukast in a managed care population.
To compare asthma-related health care expenditures among patients newly prescribed fluticasone propionate 44 or 110 microg, montelukast 5 or 10 mg, or zafirlukast 20 mg. Retrospective cohort analysis of medical and pharmacy claims. University-affiliated health outcomes research center. Seven hundred eighty-one patients (aged > or = 4 yrs) with asthma treated with controller therapy for 9 months (postindex period), with no claim for an inhaled corticosteroid or leukotriene modifier in the previous 9 months (preindex period). Asthma-related medical and pharmacy data from insurance claims of four managed care plans (two Northeastern, one Midwestern, and one Western) were tabulated over the pre- and postindex periods. Numbers of patients identified were 284 beginning fluticasone propionate; 302, montelukast; and 195, zafirlukast. Fluticasone propionate treatment was associated with significantly (p<0.001) lower risk-adjusted asthma-related charges compared with montelukast and zafirlukast treatment: $528, $967, and $1359, respectively In this cohort, fluticasone propionate also was associated with fewer hospitalizations, less need for additional controller agents, and longer maintenance on the index drug compared with montelukast and zafirlukast. Based on these real-world data, as well as established national and international asthma guidelines, consideration should be given to inhaled corticosteroid therapy, particularly fluticasone propionate, for first-line, long-term effective management of asthma.


A specific B2-bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril.
To evaluate the role of bradykinin in the antihypertrophic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, we investigated the influence of HOE 140, a specific B2-receptor antagonist, on the effects of ramipril on left ventricular hypertrophy (LVH) in rats with aortic banding. Ramipril at a dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and development of LVH after aortic banding; plasma ACE activity was significantly inhibited. A lower dose of ramipril (10 micrograms kg-1 day-1 for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but prevented LVH after aortic banding. The antihypertrophic effects of the higher and the lower dose ramipril, as well as the antihypertensive action of the higher dose of ramipril were abolished by the coadministration of HOE 140 (500 micrograms kg-1 day-1). The present data show for the first time that the beneficial effects of an ACE-inhibitor on LVH in rats with hypertension caused by aortic banding can be prevented by a specific B2-receptor antagonist.


Modeling dengue fever risk based on socioeconomic parameters, nationality and age groups: GIS and remote sensing based case study.
Dengue fever (DF) and its impacts are growing environmental, economic, and health concerns in Saudi Arabia. In this study, we have attempted to model areas with humans at risk of dengue fever prevalence, depending on the spatial relationship between dengue fever cases and different socioeconomic parameters. We have developed new methods to verify the quality of neighborhoods from high resolution satellite images based on several factors such as density of houses in each neighborhood in each district, width of streets, and roof area of houses. In the absence of detailed neighborhood quality information being available for each district, we felt this factor would best approximate the reality on the ground at local scales. Socioeconomic parameters, such as population numbers, population density, and neighborhood quality were analyzed using Geographically Weighted Regression (GWR) to create a prediction model identifying levels of risk of dengue and to describe the association between DF cases and the related socio-economic factors. Descriptive analysis was used to characterize dengue fever victims among Saudis and non-Saudis in various age groups. The results show that there was a strong positive association between dengue fever cases and socioeconomic factors (R²=0.80). The prevalence among Saudis was higher compared to non-Saudis in 2006 and 2007, while the prevalence among non-Saudis was higher in 2008, 2009 and 2010. For age groups, DF was more prevalent in adults between the ages of 16 and 60, accounting for approximately 74% of all reported cases in 2006, 67% in 2007, 81% in 2008, 87% in 2009, and 81% in 2010.


Nesfatin-1 regulates the HMGB1-TLR4-NF-κB signaling pathway to inhibit inflammation and its effects on the random skin flap survival in rats.
Random skin flaps are often placed by plastic surgeons to treat limb deformities and dysfunction. Nesfatin-1 (NES) is a peptide that exerts angiogenic, anti-inflammatory, and anti-oxidant effects. We assessed the impact of NES on flap survival and the underlying mechanism. We modified the McFarlane random skin flap rat model. Thirty-six male Sprague-Dawley rats were randomly divided into a control group (corn oil solution with DMSO), low-dose group (NES-L at 10 µg/kg/day), and high-dose group (NES-H at 20 µg/kg/day). On day 7 after surgery, average flap survival areas were calculated. Laser Doppler blood flow monitoring and lead oxide/gelatin angiography were used to evaluate blood perfusion and neovascularization, respectively. Flap histopathological status was evaluated by hematoxylin and eosin (H&E) staining. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical techniques were used to evaluate the expression of angiogenetic and inflammatory factors. In the experimental groups, the mean skin flap survival areas and blood perfusion increased considerably. The SOD activities in the experimental groups increased and the MDA contents decreased. Immunohistochemically, VEGF expression was upregulated in the experimental groups and the expression levels of inflammatory factors decreased markedly. NES inhibited ischemic skin flap necrosis, promoted angiogenesis, and reduced ischemia-reperfusion injury and inflammation. Inhibition of the inflammatory HMGB1-TLR4-NF-κB signal pathway, which reduced flap inflammation and oxidative stress, may explain the enhanced flap survival.


Are Celebrities Really Admired for Their Morality?
This study examines whether the admiration of celebrities is the same or different from admiration of other persons. The Multidimensional Admiration Scale, Rubin's Liking Scale, and the Celebrity Attitude Scale were administered to 190 participants from four American universities. Participants were randomly assigned to fill out either the "most admired person" version or the "favorite celebrity" version (n = 96) of the three scales. We hypothesized that the Multidimensional Admiration Scale is a valid measure of admiration for individuals who are familiar with the morality of the target person, but is invalid for measuring admiration for celebrities. Arguably, this is partly because celebrities are admired mostly for their ability to entertain, and not their morality, which is often unknown or little is known to their fans. The results generally confirmed our hypotheses. The Multidimensional Admiration Scale was not intended as a measure of admiration for celebrities and is not recommended to be used for that purpose.


Serum concentrations of C-reactive protein in healthy term-born Norwegian infants 48-72 hours after birth.
To determine serum C-reactive protein (CRP) concentrations in healthy term-born infants shortly after birth. We sampled blood from 182 infants along with the routine neonatal screening programme at 48-72 hours of age from consecutively recruited healthy infants without signs of infection and a gestational age (GA) of at least 37 weeks. The blood was stored at minus 20°C until analysis in one assay after the end of the study. The CRP levels were positively skewed. The median concentration was 5.0 mg/L, 48.9% of the neonates had values <5.0 mg/L, 19.8% ≥10.0 mg/L, 7.1% ≥20.0 mg/L and 1.1% (2 neonates) >30 mg/L. The CRP level was positively related to GA and duration of labour, slightly higher in boys than girls and after vaginal compared to Caesarean delivery. In healthy neonates born at term, the CRP concentrations did not vary substantially with various common perinatal clinical conditions, and levels above 30 mg/L were uncommon at two to three days of age.


The presence of RNA cargo is suspected to modify the surface hydrophobicity of the MS2 phage.
The surface hydrophobicity of native or engineered non-enveloped viruses and virus-like particles (VLPs) is a key parameter regulating their fate in living and artificial aqueous systems. Its modulation is mainly depending on the structure and environment of particles. Nevertheless, unexplained variations have been reported between structurally similar viruses and with pH. This indicates that some modulating factors of their hydrophobicity remain to be identified. Herein we investigate the potential involvement of RNA cargo in the MS2 phage used as non-enveloped RNA virus model, by examining the SDS-induced electrophoretic mobility shift (SEMS) determined for native MS2 virions and corresponding RNA-free VLPs at various pH. Interestingly, the SEMS of VLPs was larger and more variable from pH 5 to 9 compared to native virions. These observations are discussed in term of RNA-dependent changes in surface hydrophobicity, suggesting that RNA cargo may be a major modulator/regulator of this viral parameter.


Copper Nanoparticles as Growth Promoter, Antioxidant and Anti-Bacterial Agents in Poultry Nutrition: Prospects and Future Implications.
Copper (Cu) is a vital trace mineral involved in many physiological functions of the body. In the poultry industry, copper sulfate is being used as a major source of Cu. Copper in the bulk form is less available in the body, and much of its amount excreted out with feces causing environmental pollution and economic loss. The application of nanotechnology offers promise to address these issues by making nanoparticles. Copper nanoparticles (Cu-NP) are relatively more bioavailable due to their small size and high surface to volume ratio. Although, there is limited research on the use of Cu-NP in the poultry industry. Some researchers have pointed out the importance of Cu-NP as an effective alternative of chemical, anti-bacterial agents, and growth promoters. The effect of Cu-NP depends on their size, dose rate and the synthesis method. Apart from there, high bioavailability Cu-NP exhibited positive effects on the immunity of the birds. However, some toxic effects of Cu-NP have also been reported. Further investigations are essentially required to provide mechanistic insights into the role of Cu-NP in the avian physiology and their toxicological properties. This review aims to highlight the potential effects of Cu-NP on growth, immune system, antioxidant status, nutrient digestibility, and feed conversion ratio in poultry. Moreover, we have also discussed the future implications of Cu-NP as a growth promoter and alternative anti-bacterial agents in the poultry industry.


Detection of apoptotic cells based on in situ hybridization chain reaction using specific hairpins.
There are an increasing number of experiments to study programmed cell death/apoptosis, one of the characteristics of which is DNA fragmentation. The only current method for in situ detection of DNA fragmentation is Terminal deoxynucleotidyl transferase mediated-dUTP Nick End Labeling, TUNEL. In this study, a new method for in situ detection of apoptotic DNA fragments, namely In Situ Hybridization Chain Reaction, isHCR, was established. The principle of the assay is that the sticky end sequence of the apoptotic cell DNA fragment non-specifically initiates a hybridization chain reaction that specifically detects the apoptotic cell. The results of the combined TUNEL and isHCR method demonstrated that the majority of isHCR-positive cells were also labeled by TUNEL. In situ HCR often detect DNA fragments in the cytoplasm that the classical TUNEL method couldnot, and these cells may be in the early stages of apoptosis. It also indicates that DNA fragments are transferred to the cytoplasm during apoptosis. Because the staining process does not require terminal deoxynucleotidyl transferase as TUNEL staining does, isHCR staining cost low and can be performed on a large number of tissue specimens. It is believed that isHCR has the potential to detect DNA fragmentation of apoptotic cells in situ.


Effect of temperature on the activity of AMP-deaminase from rat heart.
In the presence of 1 mM ATP, the plots of Michaelis dependence of the reaction catalysed by AMP-deaminase from rat heart were hyperbolic at all temperatures between 10 and 40 degrees C. Calculation of the energy of activation for ATP-activated enzyme and of the enzyme-substrate complex formation is presented.


Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium.
The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.


Formation and oral administration of alginate microspheres loaded with pDNA coding for lymphocystis disease virus (LCDV) to Japanese flounder.
Oral delivery of plasmid DNA (pDNA) is a desirable approach for fish immunization in intensive culture. However, its effectiveness is limited because of possible degradation of pDNA in the fish's digestive system. In this report, alginate microspheres loaded with pDNA coding for fish lymphocystis disease virus (LCDV) and green fluorescent protein were prepared with a modified oil containing water (W/O) emulsification method. Yield, loading percent and encapsulation efficiency of alginate microspheres were 90.5%, 1.8% and 92.7%, respectively. The alginate microspheres had diameters of less than 10 microm, and their shape was spherical. As compared to sodium alginate, a remarkable increase of DNA-phosphodiester and DNA-phosphomonoester bonds was observed for alginate microspheres loaded with pDNA by Fourier transform infrared (FTIR) spectroscopic analysis. Agarose gel electrophoresis showed a little supercoiled pDNA was transformed to open circular and linear pDNA during encapsulation. The cumulative release of pDNA in alginate microspheres was <or=10% in pH 2.0 acidic media, and it was less than 6.5% in pH 9.0 alkaline media in 12h. RT-PCR and immunofluorescence imaging indicated that pDNA expressed RNA and green fluorescent protein in tissues of fish 10-90 days after oral administration. An indirect enzyme-linked immunosorbent assay (ELISA) showed that sera were positive (OD >or=0.3) for anti-LCDV antibody from week 3 to week 16 for fish orally vaccinated with alginate microspheres loaded with pDNA, in comparison with fish orally vaccinated with naked pDNA. Our results display that alginate microspheres obtained by W/O emulsification are promising carriers for oral delivery of pDNA. This encapsulation technique has the potential for DNA vaccine delivery applications due to its ease of operation, low cost and significant immune effect.


New-designed measurement device for radon and thoron activity concentration based on gas direct detection.
A new-designed measurement device for radon and thoron activity concentration is developed based on gas direct measurement to support their in-situ calibration. It consists of a 2000 mm2 Passivated Implanted Planar Silicon (PIPS) detector, a Multi-Channel Analyzer (MCA), a Micro Controller Unit (MCU), and a small electrostatic chamber with a volume of nearly 23 ml. The device records those alpha particles emitted from radon and thoron gas, and the detection efficiency and the crosstalk factor of 218Po/216Po are determined by Monte Carlo simulation. Measurement results have been compared with AlphaGUARD DF2000 in pure radon and thoron environments, respectively. Results show that the measurement results of the devices and the reference monitor agree well with each other, with an average relative deviation of 0.48% for radon gas from about 3300 Bq/m3 to 38 kBq/m3 and -3.25% for thoron gas from about 25 kBq/m3 to 70 kBq/m3. Uncertainty assessment has also been done, and a relative system uncertainty of radon is about 6.8%, while that of thoron is nearly 7.3%.


Teratogenic effect of windowing eggs at early stages of avian development.
The chick embryo is widely used as an experimental model for embryological and teratological studies. Treatment may be iether across the intact shell or through a window cut in the shell above the embryo. However, it is apparent from the present investigation that merely windowing eggs at early stages of development is highly teratogenic. Abnormal development can be attributed to the presence of an introduced air space above the early embryo. Obliteration of this artificial air space by three different methods significantly reduced the teratogenic response.


Is the routine abdominal ultrasound a sufficiently sensitive method for the detection of colonic malignancy?
This study examined the sensitivity of routine abdominal ultrasound scanning in the detection of colonic malignancy. A case control prospective study included 101 patients hospitalized at the Department of Gastroenterology and Liver Diseases of Zemun Clinical Hospital over a four-year period. Since the complaints pointed to colonic malignancy, the patients underwent routine golden standard diagnostic procedures. These patients were referred to an experienced abdominal ultrasound operator who searched for some characteristic signs of colonic malignancy. All of the participants were surgically treated after the completion of relevant procedures for diagnosing colonic malignancy. SPSS for Windows 10.0 was used for data analysis. The sensitivity of an abdominal ultrasound scan in the detection and location of pathological changes pointed to colonic malignancy was different- 76% and 84% respectively. This method was very reliable in detecting right-sided colonic carcinoma (100%). Some specific ultrasonographic signs of colonic carcinoma were observed at the advanced stages of disease. The routine abdominal ultrasonography can be used for the screening of colonic malignancy owing to its high sensitivity, particularly in advanced disease, but solely in conjunction with other methods. Finally, abdominal ultrasonography cannot be a definitive diagnostic tool for colonic carcinoma.


Meta-Analysis on Risk Stratification of Asymptomatic Individuals With the Brugada Phenotype.
The prognosis of asymptomatic subjects remains the most controversial issue in Brugada syndrome (BS). A meta-analysis on the prognostic role of spontaneous type 1 electrocardiographic (ECG) pattern and programmed ventricular stimulation (PVS) in asymptomatic subjects with Brugada electrocardiogram was performed. Current databases were searched until March 2014. Fourteen prospective observational studies were included in the present meta-analysis, accumulating data on 3,536 asymptomatic subjects (2,820 men) with BS phenotype. The mean follow-up period varied from 20 and 77 months. Data regarding 1,398 asymptomatic subjects with spontaneous type 1 ECG pattern of BS were retrieved from 6 studies. During follow-up, arrhythmic events (sustained ventricular tachycardia/fibrillation, appropriate device therapies, or arrhythmic death) occurred in 42 patients (3%). The meta-analysis of these studies demonstrated that asymptomatic subjects with spontaneous type 1 ECG pattern of BS exhibit an increased risk of future arrhythmic events (odds ratio = 3.56, 95% confidence interval 1.70 to 7.47, Z = 3.37, p = 0.0008); 1,104 asymptomatic subjects with BS ECG pattern from 12 studies underwent PVS and were available for analysis. During follow-up, arrhythmic events occurred in 36 subjects (3.3%). Inducible ventricular arrhythmias at PVS were predictive of future arrhythmic events (odds ratio = 3.51, 95% confidence interval 1.60 to 7.67, Z = 3.14, p = 0.002). In conclusion, this meta-analysis showed that asymptomatic subjects with either spontaneous diagnostic ECG pattern or inducible ventricular arrhythmias at PVS are at increased risk.


The potential for citrate to reinforce epigenetic therapy by promoting apoptosis.
Epigenetic drugs induce ATP depletion, promoting a glycolysis-to-oxidative phosphorylation (OXPHOS) shift which sometimes favors tumor growth by promoting necroptosis over apoptosis. To restore effective apoptosis in tumors, we propose that the administration of citrate could inhibit ATP production, activate caspase-8 (a key necroptosis inhibitor), and downregulate key anti-apoptotic proteins (Bcl-xL and MCL1).


The loci of stuttering: grammar or prosody?
Much of the research dealing with linguistic dimensions in stuttering has emphasized the various aspects of grammar, particularly as these aspects contribute to the meaning of utterances. However, data from several sources indicate that meaning and grammatical features are not likely to be the important language variables related to stuttering, but that stuttering occurrence is linked more closely to the prosodic dimension. The published literature in this area reports work done with English-speaking subjects; comparable material from other languages would be of considerable value to our understanding of linguistic determinants in stuttering.


Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review.
Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects. This was a structured review of published ketamine pharmacokinetics, safety and tolerability data for any ketamine formulation. The ratio of ketamine:norketamine was calculated from reported Cmax values, as a measure of first pass metabolism. The effect of formulation and route of administration on safety was evaluated by measuring mean changes in systolic blood pressure and tolerability by changes in dissociation ratings. Data were correlated using Spearman's method. A total of 41 treatment arms were identified from 21 publications, and included formulation development studies in healthy volunteers, and studies in clinical populations (patients undergoing anaesthesia, or being treated for pain or depression). Ketamine:norketamine ratios were strongly positively correlated with change in dissociation ratings (r = 0.89) and change in blood pressure (r = 0.96), and strongly negatively correlated with ketamine Tmax (r = - 0.87; p < 0.00001 for all). Ketamine Tmax strongly positively correlated with a change in dissociation ratings (r = - 0.96) and change in blood pressure (r = - 0.99; p < 0.00001 for all). Ketamine formulations that maximize first pass metabolism and delay Tmax will be better tolerated and safer than formulations which lack those characteristics.