Nestin-linked green fluorescent protein transgenic nude mouse for imaging human tumor angiogenesis.
We report here a novel transgenic nude mouse for the visualization of human tumor angiogenesis. We have recently shown that the neural stem cell marker nestin is expressed in hair follicle stem cells and blood vessel networks in the skin of C57/B6 transgenic mice with nestin regulatory element-driven green fluorescent protein (ND-GFP). Others have shown ND-GFP is expressed in the brain, pancreas, and testes in these mice. In the present study, the nestin ND-GFP gene was crossed into nude mice on the C57/B6 background to obtain ND-GFP nude mice. ND-GFP was expressed in the brain, spinal cord, pancreas, stomach, esophagus, heart, lung, blood vessels of glomeruli, blood vessels of skeletal muscle, testes, hair follicles, and blood vessel network in the skin of ND-GFP nude mice. Human lung cancer, pancreatic cancer, and colon cancer cell lines as well as a murine melanoma cell line and breast cancer tumor cell line expressing red fluorescent protein were implanted orthotopically, and a red fluorescent protein-expressing human fibrosarcoma was implanted s.c. in the ND-GFP nude mice. These tumors grew extensively in the ND-GFP mice. ND-GFP was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing tumors, visualized by dual-color fluorescence imaging. Results of immunohistochemical staining showed that CD31 was expressed in the ND-GFP-expressing nascent blood vessels. The ND-GFP transgenic nude mouse model enables the visualization of nascent angiogenesis in human and mouse tumor progression. These results suggest that this model is useful for the imaging of the angiogenesis of human as well as rodent tumors and visualization of the efficacy of angiogenetic inhibitors.


Enhanced malignant transformation induced by expression of a distinct protein domain of ribonucleotide reductase large subunit from herpes simplex virus type 2.
The 1.3-kilobase (kb) Pst I DNA fragment C (Pst I-C) of herpes simplex virus type 2 (HSV-2) morphological transforming region III (mtrIII; map unit 0.562-0.570) encodes part of the N-terminal half of the large subunit of ribonucleotide reductase (RR1; amino acid residues 71-502) and induces the neoplastic transformation of immortalized cell lines. To assess directly the role of these RR1 protein sequences in cell transformation, the Pst I-C fragment was cloned in an expression vector (p91023) containing an adenovirus-simian virus 40 promoter-enhancer to generate recombinant plasmid p9-C. Expression of a protein domain (approximately 65 kDa) was observed in p9-C-transfected COS-7 and Rat2 cells but not in those transfected with plasmid pHC-14 (Pst I-C in a promoterless vector). In Rat2 cells, p9-C induced highly transformed foci at an elevated frequency compared with that of pHC-14. Introduction of translation termination (TAG) condons within the RR1 coding sequence and within all three reading frames inactivated RR1 protein expression from p9-C and reduced its transforming activity to the level seen with the standard pHC-14 construct. Wild-type p9-C specified a protein kinase capable of autophosphorylation. Computer-assisted analysis further revealed significant similarity between regions of mtrIII-specific RR1 and amino acid patterns conserved within the proinsulin precursor family and DNA transposition proteins. These results identify a distinct domain of the HSV-2 RR1 protein involved in the induction of enhanced malignant transformation. In addition, the data indicate that the mtrIII DNA itself can induce basal-level transformation in the absence of protein expression.


Tracking with (Un)Certainty.
One of the highest ambitions in educational technology is the move towards personalized learning. To this end, computerized adaptive learning (CAL) systems are developed. A popular method to track the development of student ability and item difficulty, in CAL systems, is the Elo Rating System (ERS). The ERS allows for dynamic model parameters by updating key parameters after every response. However, drawbacks of the ERS are that it does not provide standard errors and that it results in rating variance inflation. We identify three statistical issues responsible for both of these drawbacks. To solve these issues we introduce a new tracking system based on urns, where every person and item is represented by an urn filled with a combination of green and red marbles. Urns are updated, by an exchange of marbles after each response, such that the proportions of green marbles represent estimates of person ability or item difficulty. A main advantage of this approach is that the standard errors are known, hence the method allows for statistical inference, such as testing for learning effects. We highlight features of the Urnings algorithm and compare it to the popular ERS in a simulation study and in an empirical data example from a large-scale CAL application.


Delineation of HER2 gene status in breast carcinoma by silver in situ hybridization is reproducible among laboratories and pathologists.
An automated enzyme metallographic silver in situ hybridization method (SISH) has been reported to successfully determine human epidermal growth factor receptor 2 (HER2) gene amplification. We evaluated the staining and interpretative reproducibility of the HER2 SISH assay at five laboratories and compared SISH results with other in situ hybridization (ISH) methods. The HER2 gene status of 89 breast carcinomas was analyzed in parallel using manual dual-color fluorescence ISH, manual chromogenic ISH, and bright-field automated SISH. A total of 1098 SISH-stained slides were evaluated. For comparison, all specimens were stained by 4B5 immunohistochemistry for HER2 protein expression. Interpretation was performed by pathologists at five different laboratories using the algorithms provided by the manufacturers and the guidelines of American Society of Clinical Oncology/College of American Pathologists. Staining and interpretative reproducibility were measured through the computation of weighted kappa statistics. Following the optimization of SISH staining, 1077/1098 (98%) of slides were evaluable. Excellent reproducibility and efficacy of HER2 SISH staining, and interobserver interpretation (Kw = 0.91), were observed among five sites. For the 89 invasive breast cancer cases, the overall rate of concordance between consensus 4B5 and consensus SISH, fluorescence ISH, and chromogenic ISH was 96.6% (86/89), 97.8% (87/89), and 96.6% (86/89), respectively. Overall concordance between positive and negative SISH and fluorescence ISH results, as well as between individual and consensus positive and negative SISH results, was excellent (P < 0.001).


An evaluation of the dilution method for identifying metabolism-dependent inhibitors of cytochrome P450 enzymes.
Metabolism-dependent inhibition (MDI) of cytochrome P450 is usually assessed in vitro by examining whether the inhibitory potency of a drug candidate increases after a 30-min incubation with human liver microsomes (HLMs). To augment the IC(50) shift, many researchers incorporate a dilution step whereby the samples, after being preincubated for 30 min with a high concentration of HLMs (with and without NADPH), are diluted before measuring P450 activity. In the present study, we show that the greater IC(50) shift associated with the dilution method is a consequence of data processing. With the dilution method, IC(50) values for direct-acting inhibitors vary with the dilution factor unless they are based on the final (postdilution) inhibitor concentration, whereas the IC(50) values for MDIs vary with the dilution factor unless they are based on the initial (predilution) concentration. When the latter data are processed on the final inhibitor concentration, as is commonly done, the IC(50) values for MDI (shifted IC(50) values) decrease by the magnitude of the dilution factor. The lower shifted IC(50) values are a consequence of data processing, not enhanced P450 inactivation. In fact, for many MDIs, increasing the concentration of HLMs actually leads to considerably less P450 inactivation because of inhibitor depletion and/or binding of the inhibitor to microsomes. A true increase in P450 inactivation and IC(50) shift can be achieved by assessing MDI by a nondilution method and by decreasing the concentration of HLMs. These results have consequences for the conduct of MDI studies and the development of cut-off criteria.


Inhibition of PPARγ, adipogenesis and insulin sensitivity by MAGED1.
Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE family member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and loss of MAGED1 promoted preadipocyte proliferation and differentiation in vitro. MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to WT littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors and hyperplasia of white adipose tissues (WATs). Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity, normal levels of serum lipids and enhanced secretion of adipokines such as leptin and adiponectin. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.


Comparisons of historical Dutch commons inform about the long-term dynamics of social-ecological systems.
Human societies and natural ecosystems are under threat by growing populations, overexploitation of natural resources and climate change. This calls for more sustainable utilization of resources based on past experiences and insights from many different disciplines. Interdisciplinary approaches to studies of historical commons have potential to identify drivers of change and keys to success in the past, and offer advice about the management and use of shared resources in contemporary and future systems. We address these issues by applying an ecological perspective to historical data on social-ecological systems. We perform comparisons and time series analyses for nine successful Dutch commons for which high-resolution data on the regulatory activities and use of shared resources is available for on average 380 years (range 236 to 568) during the period 1300 to 1972. Within commons, institutional developments were oscillating, with periods of intense regulatory activity being separated by periods of low activity, and with the dynamics of regulations being largely independent across commons. Ecological theory posits that species that occupy similar niches should show correlated responses to environmental challenges; however, commons using more similar resources did not have more parallel or similar institutional developments. One notable exception was that sanctioning was more frequent in commons that directed more regulatory activities towards non-renewable subsoil resources, whereas there was no association between sanctioning and the use of renewable resources. This might indicate that commoners were aware of potential resource depletion and attempted to influence freeriding by actively trying to solve the underlying social dilemmas. Sanctioning regulations were more frequent during the first than during the second part of a common's life, indicating that while sanctioning might have been important for the establishment of commons it was not key to the long-term persistence of historical commons.


Biological Characteristics and Odontogenic Differentiation Effects of Calcium Silicate-Based Pulp Capping Materials.
We compared calcium silicate-based pulp capping materials to conventional calcium hydroxide in terms of their biological properties and potential effects on odontogenic differentiation in human dental pulp stem cells (hDPSCs). We cultured hDPSCs on disks (7-mm diameter, 4-mm high) of ProRoot MTA (Dentsply Tulsa Dental Specialties), Biodentine (Septodont), TheraCal LC (Bisco), or Dycal (Dentsply Tulsa Dental Specialties). Cell viability was assessed with cell counting (CCK) and scanning electron microscopy (SEM). Odontogenic activity was assessed by measuring alkaline phosphatase (ALP) activity and gene expression (quantitative real-time PCR). CCK assays showed that Dycal reduced cell viability compared to the other materials (p < 0.05). SEM showed low and absent cell attachment on TheraCal LC and Dycal disks, respectively. hDPSCs exposed to TheraCal LC and Dycal showed higher ALP activity on day 6 than the control group (p < 0.05). The day-9 Runx2 expression was higher in the ProRoot MTA and TheraCal LC groups than in the control group (p < 0.05). On day 14, the ProRoot MTA group showed the highest dentin sialophosphoprotein levels (not significant; p > 0.05). In conclusion, various pulp capping materials, except Dycal, exhibited biological properties favorable to hDPSC viability. ProRoot MTA and TheraCal LC promoted higher Runx2 expression than Biodentine. Future studies should explore the odontogenic potential of pulp capping materials.


First bisphosphonate hydrogelators: potential composers of biocompatible gels.
Recently, investigation of hydrogels has gained ever increasing attention mostly because of their biomedical and pharmaceutical properties, and novel hydrogelators are constantly studied to find functional applications. Bisphosphonates (BPs) are well-known compounds applicable in different fields but are mostly used in clinics as drugs for bone-related diseases. In this study, a novel class of BP-hydrogelators together with a BP-organogelator was found, and the gelating abilities of the compounds were studied. Several techniques to analyze the structure and the properties of the formed gels were used, including solid state 13C and 31P CPMAS and solution state NMR spectroscopy, IR spectroscopy, PXRD, thermoanalysis, as well as SEM.


Hybrid Genome Evolution by Transposition: An Update.
Contrary to the view that hybrids are lineages devoid of evolutionary value, a number of case studies that have been lately reported show how hybrids are at the origin of many species. Some well-documented cases demonstrate that bursts of transposition often follow hybridization, generating new genetic variability. Studies in hybrid transposition strongly suggest that epigenetic changes and divergence in piRNA pathways drive deregulation in TE landscapes. Here, I have focused on mechanisms acting in Drosophila hybrids between two cactophilic species. The results reported here show that while hybrid instability by transposition is a genome-wide event, deregulation by TE overexpression in hybrid ovaries is not a general rule. When piRNA pools of ovaries are studied, results show that TEs with parental differences higher than 2-fold in their piRNA amounts are not more commonly deregulated in hybrids than TEs with similar levels, partially discrediting the generality of the maternal cytotype hypothesis. Some promising results on the piRNA pathway global failure hypothesis, which states that accumulated divergence of piRNA effector proteins is responsible for hybrid TE deregulation, have also been obtained. Altogether, these results suggest that TE deregulation might be driven by several interacting mechanisms. A natural scenario is proposed in which genome instability by transposition leads to hybrid genome reorganization. Small hybrid populations, subjected to natural selection helped by genetic drift, evolve new adaptations adapted to novel environments. The final step is either introgression or even a new hybrid species.


A Comprehensive Review of Lipidomics and Its Application to Assess Food Obtained from Farm Animals.
Lipids are one of the major macronutrients essential for adequate growth and maintenance of human health. Their structure is not only complex but also diverse, which makes systematic and holistic analyses challenging; consequently, little is known regarding the relationship between phenotype and mechanism of action. In recent years, rapid advancements have been made in the fields of lipidomics and bioinformatics. In comparison with traditional approaches, mass spectrometry-based lipidomics can rapidly identify as well as quantify >1,000 lipid species at the same time, facilitating comprehensive, robust analyses of lipids in tissues, cells, and body fluids. Accordingly, lipidomics is now being widely applied in various fields, particularly food and nutrition science. In this review, we discuss lipid classification, extraction techniques, and detection and analysis using lipidomics. We also cover how lipidomics is being used to assess food obtained from livestock and poultry. The information included herein should serve as a reference to determine how to characterize lipids in animal food samples, enhancing our understanding of the application of lipidomics in the field in animal husbandry.


Traumatic intracerebellar hematomas.
Seven patients with "isolated" traumatic intracerebellar hematomas due to closed head injuries are presented. Computerized tomography parameters useful in the correct management of these hematomas include: location (hemisphere or midline), size, and appearance of the posterior fossa cisterns (intact or obliterated). Three patients with hemispheric hematomas were treated conservatively and recovered. One patient with a midline hematoma was managed conservatively and died. Three hematomas (one hemispheric and two midline) were operated on. The immediate results of surgery were good, but two patients died later due to medical complications. The results of this study support the concept that large hematomas (3 cm or greater) generally need surgery and that hemispheric hematomas of limited size (less than 3 cm) may be treated conservatively. The clinical course of prognosis of midline hematomas is grave, and evacuation of accessible hematomas should be considered early in the course of the disease.


The use of anti-D immunoglobulins for rhesus prophylaxis: audit on knowledge and practices among obstetricians.
The development of anti-D antibodies results from foetomaternal sensitisation occurring in rhesus (Rh) negative blood group women who carry an Rh-positive foetus. Despite guidelines on Rh immunoprophylaxis, isoimmunisation continues to occur, suggesting that the guidelines are not being fully applied by obstetricians. This study aims to establish the adequacy of knowledge on Rh immunoprophylaxis among obstetricians and trainees in obstetrics and gynaecology in Singapore, and their usual practice in the care of an Rh-negative mother; and hence to audit their practice in accordance with evidence-based guidelines. An anonymous questionnaire survey auditing obstetricians' knowledge of guidelines on anti-D prophylaxis and their usual practice in the clinical setting. The mean score achieved on the questionnaire was 75.9 percent. Many obstetricians did not know that anti-D immunoglobulins (Ig) should be given within 72 hours of a sensitising event for successful immunoprophylaxis. In clinical practice, all the obstetricians who participated in the questionnaire would offer anti-D Ig prophylaxis to Rh-negative women both antenatally and postnatally. However, only 12.7 percent of them would routinely perform a Kleihauer test in Rh-negative women following delivery. The knowledge on anti-D prophylaxis among obstetricians can be improved. A continual system of education to raise awareness of evidence-based practices as well as clinical audit has been implemented to address this.


The yeast SRM1 protein and human RCC1 protein share analogous functions.
The Saccharomyces cerevisiae protein SRM1 and the mammalian protein RCC1 have amino acid sequence similarity throughout their lengths. SRM1 was defined by a recessive mutation in yeast that both activates the signal transduction pathway required for mating and leads to arrest in the G1 phase of the cell cycle. RCC1 was defined by a recessive mutation in hamster cells that causes premature chromosome condensation and other characteristics of entry into mitosis. Despite the seemingly different roles implied by these phenotypes, we suggest that RCC1 and SRM1 proteins have similar functions. In particular, we find that RCC1 can complement the temperature-sensitive growth phenotype of two independent srm1 mutations and also complements, at least partially, phenotypes associated with activation of the pheromone response pathway, such as transcription induction of FUS1. However, RCC1 fails to complement an srm1 null allele. Further characterization of the srm1 mutant phenotype reveals a defect in plasmid and chromosome stability, suggesting that the mutants have a defect in DNA replication, mitosis, or their coordination. Finally, like RCC1, SRM1 is a nuclear protein. Together, these data imply that SRM1 and RCC1 have a common role in their respective organisms.


[ILO plan of action (2010-2016) on occupational safety and health and new list of occupational diseases].
ILO plan of action (2010-2016) to achieve widespread ratification and effective implementation of the occupational safety and health instruments (Convention No. 155, its 2002 Protocol and Convention No. 187) is discussed. ILO documents on recording and notification as well as new list of occupational diseases (revised 2010) are considered.


Elevated Layilin-Positive Monocyte Levels in the Peripheral Blood of Patients with Systemic Lupus Erythematosus Reflect Their Autoimmune Status.
To investigate the expression of layilin (LAYN) in human circulating monocytes and lymphocytes and its clinical significance in systemic lupus erythematosus (SLE). Blood samples were collected from 51 SLE patients and 50 healthy controls. Flow cytometry was used to analyze LAYN in lymphocytes and monocyte subsets. Functionally characterized molecules including human HLA, CD74 and CD62L were studied in LAYN+ monocytes. A correlation analysis was conducted between LAYN-related subsets and clinical indicators of SLE such as anti-double-stranded DNA and complements levels. ROC curves were used to explore the potential clinical diagnostic value of LAYN in SLE. LAYN was significantly higher in monocytes than in lymphocytes and higher in CD14+CD16+ monocytes than in CD14-CD16+ and CD14+CD16- monocytes. CD74 was upregulated and CD62L was downregulated in LAYN+ monocytes compared with LAYN- monocytes. The absolute number of LAYN+ monocytes was increased in SLE patients, and the median fluorescence intensity of HLA was decreased. LAYN+ monocytes were positively correlated with complement C4, while decreased CD62L+ percentages in LAYN+ monocytes were negatively correlated with C4. The ROC analysis revealed that the area under the curve (AUCs) for CD62L+ percentages in LAYN+ monocytes, LAYN+ lymphocyte numbers, and LAYN+ monocyte numbers to distinguish SLE from healthy individuals were 0.6245, 0.6196 and 0.6173, respectively. LAYN is differentially expressed in monocytes and their subpopulations and has corresponding functional differences. Changes in LAYN expression on monocytes are associated with complement C4 levels in SLE patients. These suggest that LAYN may be involved in the pathogenesis of SLE. ANOVA: analysis of variance; anti-dsDNA: anti-double-stranded DNA; anti-ENA: anti-extractable nuclear antigen; anti-SSA: anti-Sjogren syndrome A; anti-SSB: anti-Sjogren syndrome B; anti-U1RNP: anti-U1 ribonucleoprotein; AUC: area under the ROC curve; CBC: complete blood count; CD62L: L-selectin; CD74/Ii: MHC class II invariant chain; CD44/HCAM: homing cell adhesion molecule; cMos: classical monocytes; CRP: C-reactive protein; CXCR2: C-X-C motif chemokine receptor 2; CXCR4: C-X-C motif chemokine receptor 4; ESR: erythrocyte sedimentation rate; HCs: healthy controls; HA: hyaluronan; HLA: human leukocyte antigen; Ig: immunoglobulin; iMos: intermediate monocytes; LAYN: layilin; MFI: median fluorescence intensity; MIF: migration inhibitory factor; ncMos: nonclassical monocytes; PBMCs: peripheral blood mononuclear cells; ROC: receiver operating characteristic curve; SLE: systemic lupus erythematosus; SLEDAI, SLE disease activity index; Treg: regulatory T cells; WBCs: white blood cells.


Cortisol Dose-Dependently Impairs Migration and Tube-like Formation in a Trophoblast Cell Line and Modulates Inflammatory and Angiogenic Genes.
Several stimuli can change maternal hormone levels during pregnancy. These changes may affect trophoblastic cells and modulate the development of the embryo and the placental tissue itself. Changes in cortisol levels are associated with impaired trophoblast implantation and function, in addition to other pregnancy complications. This study aims to analyze the effects of low and high doses of cortisol on an extravillous trophoblast cell line, and the effects of various exposures to this hormone. SGHPL-4 cells were treated with cortisol at five doses (0-1000 nM) and two exposures (continuous: 24 h/day; and intermittent: 2 h/day). In intermittent treatment, cortisol acted mainly as an anti-inflammatory hormone, repressing gene expression of kinin B1 receptors, interleukin-6, and interleukin-1β. Continuous treatment modulated inflammatory and angiogenic pathways, significantly repressing angiogenic factors and their receptors. Cortisol affected cell migration and tube-like structures formation. In conclusion, both continuous and intermittent exposure to cortisol repressed the expression of inflammatory genes, while only continuous exposure repressed the expression of angiogenic genes, suggesting that a sustained increase in the levels of this hormone is more harmful than a high short-term increase. Cortisol also impaired tube-like structures formation, and kinin receptors may be involved in this response.


Association between edentulism and angina pectoris in Mexican adults aged 35 years and older: a multivariate analysis of a population-based survey.
The possible association between oral infection and chronic inflammation and cardiovascular disease risk has been studied intensively. The present study is designed to determine the strength of association between edentulism and angina pectoris in Mexican adults aged 35 years and older. Using the tools and sampling strategies of the World Health Survey of the World Health Organization, cross-sectional data were collected in Mexico in the National Performance Assessment Survey (probabilistic, multistage, and cluster sampling). Dental information was available for 20 of the 32 states of Mexico. Angina and edentulism are self-reported in this study. Statistical analysis was performed using binary logistic regression adjusting for complex samples. A total of 13,966 participants, representing a population of 29,853,607 individuals, were included. Of the complete study population, 3,052,263 (10.2%) were completely toothless, and 673,810 (2.3%) were diagnosed with angina pectoris. After adjusting for smoking, alcohol consumption, diabetes, body mass index, and sex, the effect of edentulism on angina was modified by age (interaction), being more marked in the younger age group (odds ratio [OR] = exp(2.5597) =12.93) than in the older individuals surveyed (OR = exp(2.5597 + (-0.0334)) =12.51). Additionally, low physical activity (OR = 1.51; 95% confidence interval [CI] = 1.03 to 2.22) and higher socioeconomic status (OR = 1.37; 95% CI = 1.00 to 1.90) were more likely to be associated with angina pectoris. Overall, the results of this study, conducted in a representative sample of Mexican adults, suggest that an association exists between edentulism and angina pectoris. Additional studies are necessary to elucidate the underlying mechanism for this association.


Deriving modified Rankin scores from medical case-records.
Modified Rankin score (mRS) is traditionally graded using a face-to-face or telephone interview. Certain stroke assessment scales can be derived from a review of a patient's case-record alone. We hypothesized that mRS could be successfully derived from the narrative within patient case-records. Sequential patients attending our cerebrovascular outpatient clinic were included. Two independent, blinded clinicians, trained in mRS, assessed case-records to derive mRS. They scored "certainty" of their grading on a 5-point Likert scale. Agreement between derived and traditional face-to-face mRS was calculated using attribute agreement analysis. Fifty patients with a range of disabilities were included. Case-record appraisers were poor at deriving mRS (k=0.34 against standard). Derived mRS grades showed poor agreement between observers (k=0.33). There was no relationship between certainty of derived mRS and proportion of correct grades (P=0.727). Accurate mRS cannot be derived from standard hospital records. Direct mRS interview is still required for clinical trials.


Effect of metoclopramide on the secretion and metabolism of aldosterone in man.
We performed this study to determine whether metoclopramide increases the concentration of plasma aldosterone in normal man by increasing the secretion rate of aldosterone or by decreasing aldosterone metabolic clearance. On the first day that metoclopramide was administered orally to seven normal subjects, the secretion rate of aldosterone increased significantly (P less than 0.05) from the rate during the preceding placebo period. By the fourth day of treatment, the secretion rate had returned to control values and remained there during an ensuing placebo period. The excretion rate of aldosterone followed a similar pattern. The increase in aldosterone secretion was accompanied by a transient but significant decrease in urinary sodium excretion. Metoclopramide administered iv had no effect on the metabolic clearance of aldosterone. Metoclopramide stimulated aldosterone-producing adenomas and nodular hyperplastic adrenal tissue resected from patients with primary aldosteronism to produce aldosterone in vitro. We conclude that metoclopramide increases the concentration of aldosterone in plasma by stimulating the secretion of aldosterone rather than by decreasing aldosterone metabolic clearance, and that metoclopramide probably stimulates aldosterone secretion by acting directly on adrenal tissue.


Effects of Enteric-coated Lactoferrin Tablets Containing Lactobacillus brevis subsp. coagulans on Fecal Properties, Defecation Frequency and Intestinal Microbiota of Japanese Women with a Tendency for Constipation: a Randomized Placebo-controlled Crossover Study.
The effects of oral administration of enteric-coated tablets containing lactoferrin (LF; 100 mg/tablet) and heat-killed Lactobacillus brevis subsp. coagulans FREM BP-4693 (LB; 6×10(9) bacteria/tablet) on fecal properties were examined in 32 Japanese women (20-60 years of age) with a tendency for constipation (defecation frequency at equal to or less than 10 times/2 weeks) by a double-blind placebo-controlled crossover design. A significant increase in defecation days per week was obserbed in the subjects who ingested the tablets containing LF and LB compared with the placebo group. The number of bifidobacteria in feces also significantly increased compared with the placebo group. In an in vitro study, LF and tryptic hydrolysate of LF, but not peptic hydrolysate of LF, upregulated the growth of Bifidobacterium longum ATCC15707 when added to the culture. These results demonstrate the capability of the enteric-coated tablets containing LF and LB in improving intestinal function and suggest that they have a growth promoting function for bifidobacteria.


iso-Kaurenoic acid from Wedelia paludosa D.C.
A recent reinvestigation of aerial parts of Wedelia paludosa D.C. is described and reports, for the first time, the isolation of iso-kaurenoic acid from this species.


Range of the solvation pressure between lipid membranes: dependence on the packing density of solvent molecules.
Well-ordered multilamellar arrays of liquid-crystalline phosphatidylcholine and equimolar phosphatidylcholine-cholesterol bilayers have been formed in the nonaqueous solvents formamide and 1,3-propanediol. The organization of these bilayers and the interactions between apposing bilayer surfaces have been investigated by X-ray diffraction analysis of liposomes compressed by applied osmotic pressures up to 6 X 10(7) dyn/cm2 (60 atm). The structure of egg phosphatidylcholine (EPC) bilayers in these solvents is quite different than in water, with the bilayer thickness being largest in water, 3 A narrower in formamide, and 6 A narrower in 1,3-propanediol. The incorporation of equimolar cholesterol increases the thickness of EPC bilayers immersed in each solvent, by over 10 A in the case of 1,3-propanediol. The osmotic pressures of various concentrations of the neutral polymer poly(vinylpyrrolidone) dissolved in formamide or 1,3-propanediol have been measured with a custom-built membrane osmometer. These measurements are used to obtain the distance dependence of the repulsive solvation pressure between apposing bilayer surfaces. For each solvent, the solvation pressure decreases exponentially with distance between bilayer surfaces. However, for both EPC and EPC-cholesterol bilayers, the decay length and magnitude of this repulsive pressure strongly depend on the solvent. The decay length for EPC bilayers in water, formamide, and 1,3-propanediol is found to be 1.7, 2.4, and 2.6 A, respectively, whereas the decay length for equimolar EPC-cholesterol bilayers in water, formamide, and 1,3-propanediol is found to be 2.1, 2.9, and 3.1 A, respectively. These data indicate that the decay length is inversely proportional to the cube root of the number of solvent molecules per unit volume.(ABSTRACT TRUNCATED AT 250 WORDS)


Unilateral congenital elongation of the cervical part of the internal carotid artery with kinking and looping: two case reports and review of the literature.
Unilateral and bilateral variation in the course and elongation of the cervical (extracranial) part of the internal carotid artery (ICA) leading to its tortuosity, kinking and coiling or looping is not a rare condition, which could be caused by both embryological and acquired factors. Patients with such variations may be asymptomatic in some cases; in others, they can develop cerebrovascular symptoms due to carotid stenosis affecting cerebral circulation. The risk of transient ischemic attacks in patients with carotid stenosis is high and its surgical correction is indicated for the prevention of ischemic stroke. Detection of developmental variations of the ICA and evaluation of its stenotic areas is very important for surgical interventions and involves specific diagnostic imaging techniques for vascular lesions including contrast arteriography, duplex ultrasonography and magnetic resonance angiography. Examination of obtained images in cases of unusual and complicated variations of vascular pattern of the ICA may lead to confusion in interpretation of data. Awareness about details and topographic anatomy of variations of the ICA may serve as a useful guide for both radiologists and vascular surgeons. It may help to prevent diagnostic errors, influence surgical tactics and interventional procedures and avoid complications during the head and neck surgery. Our present study was conducted with a purpose of updating data about developmental variations of the ICA. Dissections of the main neurovascular bundle of the head and neck were performed on a total 14 human adult cadavers (10 - Africans: 7 males & 3 females and 4 - East Indians: all males). Two cases of unilateral congenital elongation of the cervical part of the ICA with kinking and looping and carotid stenoses were found only in African males. Here we present their detailed case reports with review of the literature.


Comparison of vitamin D metabolites in wild and captive baboons.
Vitamin D adequacy is essential for multiple physiologic processes. With limited exposure to sunlight for vitamin D3 synthesis, captive primates are supplemented with vitamin D3 (cholecalciferol). Vitamin D metabolite data from wild primates living indigenously could suggest optimum levels. The purpose of this study was to: 1) to explore whether baboons, a speciose genus whose members have significant exposed skin, coat color variation and wide geographical distribution, mirrors the skin pigmentation-vitamin D relationship found in humans; 2) compare vitamin D metabolite levels in wild and captive members of the same or similar baboon species; and 3) apply a recently developed method currently used in humans for measuring multiple vitamin D metabolites as a panel to explore if/how these metabolites can inform us on vitamin D sufficiency. Serum samples from males of three baboon species in the wild: Papio anubis (olive baboon, dark exposed skin), P. cynocephalus (yellow baboon, brown exposed skin), and P. hamadryas (hamadryas baboon, pink exposed skin), were compared with vitamin D supplemented captive olive baboons with sun exposure. Liquid chromatography/tandem mass spectrometry (LC/MS/MS) measured vitamin D and its main metabolites. Cholecalciferol, 25 hydroxyvitamin D2&3 (25(OH)D2&3 ), and 24,25 dihydroxyvitamin D2&3 (24,25(OH)2 D2&3 ), showed significant differences by species. The levels of cholecalciferol due to supplements in the captive olive baboons did not convert to higher 25(OH)D3 while the wild olive baboons exhibited the lowest levels for both cholecalciferol and 25(OH)D3 . Further metabolic conversion of 25(OH)D3 to 24,25(OH)2 D3 indicated that all baboons had more similar conversion ratios and these were within the same range found for humans that are depicted as having adequate vitamin D levels. This study provided evidence that exposed skin color does influence vitamin D3 levels, with lower levels in darker skinned species, but these differences are eliminated in the downstream metabolite conversion indicating strong regulatory control.


Stroboscopic motion in depth.
Temporal limits of stroboscopic apparent motion in depth have been examined. For monocular viewing the limits are similar to those obtained for motion in the frontal plane, while those for binocular viewing are greatly narrowed. In another experiment the contraction in space over which apparent movement occurs was measured. The results are discussed in terms of a filter representation proposed by Caelli and Finlay.


Intravenous gammaglobulin (Gaminume) for treatment of chronic idiopathic thrombocytopenic purpura (ITP): a two-year follow-up.
Thirteen subjects 5-20 years of age with the chronic, autoimmune form of idiopathic thrombocytopenic purpura (ITP) were given intravenous gammaglobulin (Gamimune; Cutter Biological, Berkeley, CA) in a dose of 400 mg/kg per day for 5 consecutive days. Two of the 13 children had undergone splenectomy; the other 11 had not. Eight of these 13 children had also received corticosteroid therapy with no sustained increase in platelet counts. Six of 13 children had a good or excellent response to the first 5 day course of gammaglobulin therapy, and one had a fair response. The peak platelet count occurred within 7 days of the start of therapy except in one patient, whose platelet count peaked on day 12. Six of seven patients who initially responded to Gamimune required booster doses to maintain platelet counts at a safe level. All children had marked increases in serum IgG following Gamimune except one (who had undergone splenectomy for chronic ITP), who had high baseline levels of immunoglobulin G (IgG). No untoward reactions necessitating cessation of therapy were encountered during this study. The most common side effect observed was headache. During the first year of follow-up after Gamimune, three of seven initial responders became refractory to Gamimune therapy. Two of these three refractory subjects later underwent splenectomy with excellent response. The third refractory patient who was splenectomized prior to gammaglobulin therapy had spontaneous remission of his ITP 5 months after the last dose of Gamimune. Three of the four other initial responders have continued to do well and have maintained platelet counts above 40,000/mm3 (one without booster). The fourth subject dropped out of the study. Thus our observations indicate that Gamimune is an effective form of treatment for some children with chronic ITP, and can be considered as an alternative to splenectomy or as a potential therapeutic modality in those who have failed to respond to splenectomy.


Measuring safety in older adult care homes: a scoping review of the international literature.
Safety is a key concern in older adult care homes. However, it is a less developed concept in older adult care homes than in healthcare settings. As part of study of the collection and application of safety data in the care home sector in England, a scoping review of the international literature was conducted. The aim of the review was to identify measures that could be used as indicators of safety for quality monitoring and improvement in older adult residential or nursing care homes. Systematic searches for journal articles published in English language from 1 January 1970, without restriction to the study location or country, were conducted in Web of Science, Scopus and PubMed on 28 July 2019. Inclusion criteria were: peer-reviewed journal articles; qualitative or quantitative studies of older adult nursing and/or residential care homes; and related to any aspect of safety in care homes, including the safety of healthcare provision in the care home. A total of 45 articles were included after review of the title/abstract or full text against the inclusion criteria. Key information was extracted and charted. These findings were then mapped to the Safety Measurement and Monitoring Framework in healthcare (SMMF), adapted by the research team to reflect the care home context, to determine the coverage of different aspects of safety, as well as potential gaps. Systematic searches for journal articles published in English language from 1 January 1970, without restriction to the study location or country, were conducted in Web of Science, Scopus and PubMed on 28 July 2019. Inclusion criteria were: peer-reviewed journal articles; qualitative or quantitative studies of older adult nursing and/or residential care homes; and related to any aspect of safety in care homes, including the safety of healthcare provision in the care home.A total of 45 articles were included after review of the title/abstract or full text against the inclusion criteria. Key information was extracted and charted. These findings were then mapped to the Safety Measurement and Monitoring Framework in healthcare (SMMF), adapted by the research team to reflect the care home context, to determine the coverage of different aspects of safety, as well as potential gaps.The findings indicate that there are a range of available safety measures used for quality monitoring and improvement in older adult care homes. These cover all five domains of safety in the SMMF. However, there are potential gaps. These include user experience, psychological harm related to the care home environment, abusive or neglectful care practice and the processes for integrated learning. Some of these gaps may relate to challenges and feasibility of measurement in the care home context.


Mycobacteriophage Lysis Enzymes: Targeting the Mycobacterial Cell Envelope.
Mycobacteriophages are viruses that specifically infect mycobacteria, which ultimately culminate in host cell death. Dedicated enzymes targeting the complex mycobacterial cell envelope arrangement have been identified in mycobacteriophage genomes, thus being potential candidates as antibacterial agents. These comprise lipolytic enzymes that target the mycolic acid-containing outer membrane and peptidoglycan hydrolases responsive to the atypical mycobacterial peptidoglycan layer. In the recent years, a remarkable progress has been made, particularly on the comprehension of the mechanisms of bacteriophage lysis proteins activity and regulation. Notwithstanding, information about mycobacteriophages lysis strategies is limited and is mainly represented by the studies performed with mycobacteriophage Ms6. Since mycobacteriophages target a specific group of bacteria, which include Mycobacterium tuberculosis responsible for one of the leading causes of death worldwide, exploitation of the use of these lytic enzymes demands a special attention, as they may be an alternative to tackle multidrug resistant tuberculosis. This review focuses on the current knowledge of the function of lysis proteins encoded by mycobacteriophages and their potential applications, which may contribute to increasing the effectiveness of antimycobacterial therapy.


Gunshot induced indirect femoral fracture: mechanism of injury and fracture morphology.
Indirect ballistic fractures occur when a projectile passes close to, but not contacting, the bone. The mechanism of how these fractures occur is not yet proven, but recently the acoustic shockwave has been excluded as a cause. The objective of this study is to determine whether the expanding temporary cavity, the collapse of this cavity or its oscillation causes these fractures. In addition, we describe the fracture morphology and biomechanical causes of this injury. 40 fresh deer femora were strain gauged and embedded in ballistic gelatin before being shot with four different projectiles with varying distances off the bone. Pressure recordings, chronographs and radar allowed assessment of local pressures and energy transfer. High-speed video allowed the temporal relationship between the temporary cavity and fracture formation to be analysed, while sample dissection allowed the fracture morphology to be described. The fractures produced were consistently wedge-shaped and caused by the expansion of the temporary cavity, flexing the bone beyond its yield point, causing tension failure on the cortex opposite the expanding temporary cavity and a compression wedge on the side of the cavity. Local pressure was not predictive of fracture formation but the energy transfer to the gelatin block was predictive. Indirect fractures are caused by the expansion of the temporary cavity and relate to the proximity of this cavity to the bone. Fractures occur from flexion of the bone and classically display wedge-shaped fracture patterns with the apex of the wedge pointing away from the expanding cavity.


Alterations in the heart rate and activity rhythms of three orbital astronauts on a space mission.
Environmental factors in space are dramatically different from those on Earth. The spaceflight environment has been known to influence human physiology and behavior on orbital missions. In this study, we investigated alterations in the diurnal rhythms of activity and heart rate of three Chinese astronauts on a space mission. An analysis of the heart rate data showed a significant decrease in heart rate amplitudes during flight in all three subjects. The heart rate amplitudes of all the three astronauts were significantly dampened during flight, and the minimum as well as the maximum value of heart rate increased after flight. A phase shift in heart rate was observed in one of the three astronauts after flight. These results demonstrate the influence of spaceflight on heart physiology and function. In addition, a significant decrease in body trunk activity and rhythmicity occurred during flight, demonstrating that the spaceflight environment disturbs motion adaptation and diurnal activity rhythms.


Using feature optimization and LightGBM algorithm to predict the clinical pregnancy outcomes after in vitro fertilization.
According to a recent report by the WHO, approximately 17.5\% (about one-sixth) of the global adult population is affected by infertility. Consequently, researchers worldwide have proposed various machine learning models to improve the prediction of clinical pregnancy outcomes during IVF cycles. The objective of this study is to develop a machine learning(ML) model that predicts the outcomes of pregnancies following in vitro fertilization (IVF) and assists in clinical treatment. This study conducted a retrospective analysis on provincial reproductive centers in China from March 2020 to March 2021, utilizing 13 selected features. The algorithms used included XGBoost, LightGBM, KNN, Naïve Bayes, Random Forest, and Decision Tree. The results were evaluated using performance metrics such as precision, recall, F1-score, accuracy and AUC, employing five-fold cross-validation repeated five times. Among the models, LightGBM achieved the best performance, with an accuracy of 92.31%, recall of 87.80%, F1-score of 90.00\%, and an AUC of 90.41%. The model identified the estrogen concentration at the HCG injection(etwo), endometrium thickness (mm) on HCG day(EM TNK), years of infertility(Years), and body mass index(BMI) as the most important features. This study successfully demonstrates the LightGBM model has the best predictive effect on pregnancy outcomes during IVF cycles. Additionally, etwo was found to be the most significant predictor for successful IVF compared to other variables. This machine learning approach has the potential to assist fertility specialists in providing counseling and adjusting treatment strategies for patients.


Renin-expressing cells are associated with branching of the developing kidney vasculature.
To define the relationship between renal vascular development and renin distribution during kidney ontogeny, the complete renal arterial tree of Sprague Dawley rats during fetal (20 d) and postnatal (1 to 90 d) life was microdissected and immunostained for renin. A shift in renin distribution from interlobar and arcuate arteries in the fetus to the afferent arterioles in the adult was observed. In addition, seven types of renin distribution along the afferent arterioles were identified. In type I, renin was distributed continuously along the whole length of the afferent vessel. This pattern was most frequently observed in the fetus. In type II, renin extended upstream from the glomerulus but did not occupy the whole length of the arteriole. This type was relatively constant throughout postnatal life. In type III, renin was present as bands along the afferent vessel; it was most frequently observed in the fetal and early perinatal periods. In type IV, renin was restricted to the "classical" juxtaglomerular localization. It was the most frequent type observed in the adult rat. In type V, no renin was found in the arteriole. It was the second most frequent type observed in the adult rat. In addition, two "mixed" patterns, type III/IV and type III/II, were occasionally observed. The distribution of renin-expressing cells was spatially and temporally associated with the development of blood vessels. Development of a new arterial branch was preceded by the appearance of renin-expressing cells at the point of branching. This was followed by an outpouching of the arterial wall that progressively elongated to form a new arteriole. During this process, renin-expressing cells were distributed along the whole of the newly formed vessel. As the vessel matured, renin-expressing cells became restricted to the juxtaglomerular portion of the afferent arteriole. It is concluded that throughout life and within each individual arterial tree, expression of renin is heterogeneous, following patterns that are unique for each developmental stage. Furthermore, the association of renin-expressing cells with branching of renal arterioles suggests a role for these cells in the development of the kidney vasculature.


Host-mediated effects of phytonutrients in ruminants: A review.
Plants produce an extensive array of organic compounds derived from secondary metabolism that may be useful in animal nutrition because of their chemical makeup. These plant-derived bioactive compounds, also referred to as phytonutrients (PN) or phytobiotics, have been shown to express antimicrobial activities against a wide range of bacteria, yeast, and fungi and have been investigated as rumen modifiers in ruminant nutrition. Studies have reported that PN may inhibit deamination of AA and methanogenesis in the rumen and shift fermentation toward propionate and butyrate. Most of the experiments, however, have been conducted in vitro, and responses have been highly variable and inconsistent in animal experiments. In addition, some studies have reported that PN had positive effects on productivity, although rumen fermentation was not affected. Other than antimicrobial effects in the gut, PN are known to bind specific receptors expressed in neurons, intestines, and other cells and exhibit related physiological effects in nonruminants. The receptor-mediated effects include immune responses, oxidative stress, and insulin secretion and activity. Some PN, due to their phenolic nature, are likely less susceptible to microbial degradation in the rumen and may exhibit activities postruminally, similar to their mode of action in nonruminant species. This opens a new area of research in ruminants, including effects of PN on the animal's immune system, postruminal nutrient use, and animal physiology. Although limited, studies with ruminants provide first evidence of PN's regulatory effects on the host responses. For example, PN were reported to regulate immune cells related to adaptive and innate immunity in challenged or nonchallenged dairy cows. Supplementation of PN reduced oxidative stress by decreasing lipid peroxidation and increasing endogenous antioxidants in ruminants. Additionally, insulin secretion and sensitivity were reportedly regulated by PN in dairy cows. The regulatory effects of PN on immunity may be beneficial for immune suppression and inflammation in dairy cows. In addition, PN could positively affect energy partitioning for milk production through their effects on insulin secretion and sensitivity. Further research is needed to elucidate the effect and mode of action of PN on immune function and animal energetics.


The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB.
mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) signaling pathways and plays an important role in the viability response of these cytokines. In this study, we demonstrated that cytokine stimulation of mcl-1 mRNA and protein expression were attenuated by pretreatment of cells with phosphatidylinositol 3-kinase (PI3-K) inhibitors. Reporter gene assays further showed that the PI3-K/Akt signaling pathway was involved in IL-3 activation of mcl-1 gene transcription. Analysis of the mcl-1 promoter revealed that both promoter elements, SIE at position -87 and CRE-2 at -70, contribute to IL-3 stimulation of mcl-1 gene expression. Although either the SIE site or the CRE-2 site alone was sufficient to confer IL-3 inducibility on a heterologous promoter, only IL-3 activation of the CRE-2 reporter was mediated via the PI3-K/Akt pathway. The SIE binding activity was constitutively high in cells deprived of or stimulated by IL-3. In contrast, the CRE-2 binding activity was low in cytokine-starved cells and was strongly induced within 1 h following cytokine treatment of cells. In addition, cytokine induction of the CRE-2 but not of the SIE binding activity was dependent on activation of the PI3-K/Akt signaling pathway. Lastly, we showed that CREB was one component of the CRE-2 binding complex and played a role in IL-3 activation of the mcl-1 reporter gene. Taken together, our results suggest that both PI3-K/Akt-dependent and -independent pathways contribute to the IL-3 activation of mcl-1 gene expression. Activation of mcl-1 by the PI3-K/Akt-dependent pathway is through a transcription factor complex containing CREB.


Xf phage invading the host cells with their protein coats.
The Xf phage coat protein associated with infected cells could not be removed by washing with antiserum and tris-EDTA buffer. Although the infected cells were consecutively washed 6 times with tris-EDTA buffer, the ratios of parental phage 6H-DNA to 14C-protein were not changed. A considerable amount of the parental 14C-protein and 3H-DNA in the original ratio were detected in the membrane and the soluble cytoplasmic fractions of infected cells. The studies of the change in Xf 14C-protein and 3H-DNA incorporation into the host cells and their release showed that DNA and protein penetrate together into the host cells during the first 60 min after infection (p.i.). While virtually all parental DNA was conserved, re-utilized and released from the infected cell 60 min p.i., no apparent release of parental protein was observed. Approx. 40% of the parental protein became degraded and could be washed from the infected cell after 90 min; the rest of the parental protein remained and probably was re-utilized by the host.


Secretory process in Brunner's glands during recovery from stimulation with a single dose of pilocarpine.
The secretory pathway and kinetics of the secretory process were studied in Brunner's glands of mice after stimulation of secretion with a parasympatho-mimetic drug. Adult male mice were injected with pilocarpine, while unstimulated controls received saline. The animals were subsequently administered an intravenous injection of 3H-threonine, and tissue was prepared for electron microscope autoradiography at intervals ranging from 5 minutes to 2 hours after injection of the radioactive precursor. Stimulation with pilocarpine resulted in discharge of secretory granules, which was reflected in a significantly lower percentage of the cell volume occupied by granules. In both control and stimulated mice, at 5 minutes after injection of 3H-threonine, the highest percentage of silver grains was found over the rough endoplasmic reticulum. The proportion of silver grains over the rough endoplasmic reticulum declined at later intervals, and a peak of labeling was observed over the Golgi apparatus at 1 hour. Labeling of the secretory granules increased in the 1- and 2-hour samples from both control and stimulated mice, although the relative concentration of radioactivity in both Golgi-associated and apical secretory granules was greater in stimulated than control glands at 1 hour. The results suggest that the secretory protein produced by Brunner's glands was synthesized by the rough endoplasmic reticulum and transported to the Golgi apparatus where secretory granules were formed in both stimulated and control glands. Depletion of secretory granules by prior stimulation resulted in no change in the kinetics of arrival of radioactivity in the cell organelles involved in the secretory process. However, the drainage of the radioactive label from the rough endoplasmic reticulum was significantly slower in the stimulated glands than in the controls. The existence of two subcompartments within the rough endoplasmic reticulum is among the possible explanations for the latter observation.


Targeting CXCR2 enhances chemotherapeutic response, inhibits mammary tumor growth, angiogenesis, and lung metastasis.
Breast cancer is one of the leading causes of cancer deaths among females. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often because of therapy resistance. How breast cancer cells evade chemotherapy and the underlying mechanism remains unclear. We and others have observed that malignant cells that survive initial chemo- and radiation therapy express higher levels of CXCR2 ligands, which may provide a survival benefit leading to therapy resistance. In this report, we test the hypothesis that CXCR2-dependent signaling in malignant cells may be critical for chemotherapy resistance and targeting this signaling axis may enhance the antitumor and antimetastatic activity of chemotherapeutic drugs and limit their toxicity. We used Cl66-wt, 4T1-wt, Cl66sh-CXCR2, and 4T1sh-CXCR2 cells expressing differential levels of the CXCR2 receptor to evaluate the role of targeting CXCR2 on chemotherapeutic responses. Knockdown of CXCR2 enhances paclitaxel and doxorubicin-mediated toxicity at suboptimal doses. Moreover, we observed an increase in the expression of CXCL1, a CXCR2 ligand in paclitaxel and doxorubicin-treated mammary tumor cells, which were inhibited following CXCR2 knockdown. Knockdown of CXCR2 enhanced antitumor activity of paclitaxel in an in vivo mammary tumor model. We observed significant inhibition of spontaneous lung metastases in animals bearing CXCR2 knockdown tumors and treated with paclitaxel as compared with the control group. Our data suggest the novel role of CXCR2 and its ligands in maintaining chemotherapy resistance and provide evidence that targeting CXCR2 signaling in an adjuvant setting will help circumvent chemotherapy resistance.


A Molecular-Level Account of the Antigenic Hantaviral Surface.
Hantaviruses, a geographically diverse group of zoonotic pathogens, initiate cell infection through the concerted action of Gn and Gc viral surface glycoproteins. Here, we describe the high-resolution crystal structure of the antigenic ectodomain of Gn from Puumala hantavirus (PUUV), a causative agent of hemorrhagic fever with renal syndrome. Fitting of PUUV Gn into an electron cryomicroscopy reconstruction of intact Gn-Gc spike complexes from the closely related but non-pathogenic Tula hantavirus localized Gn tetramers to the membrane-distal surface of the virion. The accuracy of the fitting was corroborated by epitope mapping and genetic analysis of available PUUV sequences. Interestingly, Gn exhibits greater non-synonymous sequence diversity than the less accessible Gc, supporting a role of the host humoral immune response in exerting selective pressure on the virus surface. The fold of PUUV Gn is likely to be widely conserved across hantaviruses.


Effects of divalent cations and of phospholipase A activity on excretion of cloacin DF13 and lysis of host cells.
Induction of cloacin DF13 synthesis in Escherichia coli harbouring plasmid CloDF13 results in the release of cloacin DF13, inhibition of growth and ultimately in lysis of the host cells. Expression of the pCloDF13-encoded protein H is essential for both the release of cloacin DF13 and the lysis of the cells. The divalent cations Mg2+ and Ca2+ interfered with the mitomycin C-induced protein H-dependent lysis, but hardly affected the release of cloacin DF13. Essentially all of the bacteriocin was released from the cells before a detectable degradation of the peptidoglycan occurred, independent of the presence of mitomycin C. Experiments with phospholipase A mutants revealed that activation of detergent-resistant phospholipase A was essential for the export of cloacin DF13 across the outer membrane and the lysis of induced cells. Transport of cloacin DF13 across the cytoplasmic membrane was mainly dependent on protein H. A revised model for the excretion of cloacin DF13 is presented.


Demodex spp. Infestation in a breast-cancer patient: A case report.
Demodex folliculorum and Demodex brevis are obligatory parasites that live in sebaceous glands and follicles. When immune system becomes suppressed by any reason, patients become vulnerable to obligatory parasites like D. folliculorum and D. brevis. Immune system becomes suppressed in cancer patients who undergo chemotherapy, and as a result these patients become vulnerable to infestations. In our case, a 45 year-old female has been admitted to oncology clinic for a medical treatment of breast cancer. Her systematic physical examination was normal, except redness on her cheeks and forehead. There was no abnormality in biochemical and haematological laboratory values. We have decided to apply chemotherapy of Adriamycin, cyclophosphamide and 5-fluorouracil. Due to the itchy redness on her cheeks and forehead, we had performed an examination for demodex before chemotherapy; and we have identified 20 mites/cm(2) on her right and left cheeks, and 15 mites/cm(2) on her forehead. When our patient had came our clinic with increasing complaint of itchy rash, after the first course of chemotherapy we have reexamined demodex. The result of microscopic examination revealed large amount of demodex of 50 mites/cm(2) on her right and left cheeks and 30 mites/cm(2) on her forehead, which were nearly 2.5-times higher than the previous examination. This increase probably was associated with immune suppression of chemotherapy.


Measuring the job stickiness of community nurses in Ontario (2004-2010): implications for policy and practice.
Utilize the concept of stickiness to examine the retention of community nurses across time and draw comparisons by subsector, nurse group and work status. Secondary analysis of College of Nurses of Ontario (CNO) registration database (2004-2010). Nurses' yearly registration records were linked to create a longitudinal database of nursing employment which was used to generate year-to-year stickiness figures. Analysis was carried out by sector/subsector of employment, nurse group and work status. Analysis revealed an active movement of nurses between the hospital and community sectors during the period of analysis, with a positive balance of 3002 nurses toward the latter. A wide variation in the stickiness of community subsectors of employment was noted, with those subsectors involving direct patient care and community visitation displaying relatively lower stickiness figures. Subsector stickiness increased with the offering of full-time jobs and the employment of Registered Nurses. Examining the working conditions and human resources management practices in the subsectors with lower stickiness, especially those involving patient care at home, and enhancing career stability of Registered Practical Nurses are priority issues. Decision-makers should support the offering of full-time jobs focusing attention on subsectors offering direct patient care in the community.


Parameningeal rhabdomyosarcoma: results of an international workshop.
A retrospective analysis was performed on children with nonmetastatic rhabdomyosarcomas (RMS) involving a parameningeal site treated by one of the four major cooperative groups: Intergroup Rhabdomyosarcoma Study (IRS), International Society of Pediatric Oncology (SIOP), German Cooperative Group (CWS), and Italian Cooperative Group (ICS) to analyse survival and prognostic factors. Between 1979 and 1989, 230 children (median age 6 years) were treated in the IRS III, SIOP 84, CWS 81, and ICS 79 studies. All patients received chemotherapy, and 203 were irradiated. Radiotherapy doses were similar in the four studies, although treatment volumes were not similar. The SIOP patients had smaller volumes treated. In addition, the SIOP patients with a low risk of meningeal involvement and children under 5 years of age were not irradiated if they had a complete response (CR) to chemotherapy. Time to initiation of irradiation was earlier in the IRS and Italian studies. Median follow-up was 62 months (range 22-140). The 5-year survival and 5-year event-free survival were better for the IRS study (74% and 71%) than for the other study groups (55% and 36% for SIOP, 47% and 47% for CWS, and 39% and 39% for ICS). The low-risk (LR) patients in the IRS study had improved survival. However, patients with high risk of meningeal involvement had similar survival in all four studies. The most significant prognostic factor was the size of tumor (> 5 cm). The improved results from the IRS group, especially among the LR patients, could be related to the IRS treatment employed, particularly the systematic use of radiation, to the inclusion of patients with smaller tumors, and to the routine use of quality control of radiation.


Two-dimensional hierarchically porous carbon nanosheets for flexible aqueous supercapacitors with high volumetric capacitance.
Two-dimensional carbon nanomaterials can be assembled into a dense film and used for flexible supercapacitors, but the high packing density leads to restacking problems and poor volumetric capacitance. To address this challenge, we report two-dimensional hierarchically porous carbon (2D-HPC) consisting of micro-, meso-, and macro-pores on the 2D sheet, which shows superior capacitance and rate capability compared with a 2D carbon nanosheet consisting predominantly of micro-pores. A flexible supercapacitor fabricated with the 2D-HPC presents a high volumetric capacitance of 412 F cm-3, a high volumetric energy density of 9.2 mW h cm-3 and a power density of 120 mW cm-3.


Characterization of the Inflammatory Response to Severe COVID-19 Illness.
Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.


Lung cancer risk associated with occupational exposure to nickel, chromium VI, and cadmium in two population-based case-control studies in Montreal.
Nickel, chromium VI, and cadmium have been identified as lung carcinogens in highly exposed cohorts. The purpose of this study was to examine the etiological link between lung cancer and these metals in occupations, that usually entail lower levels of exposure than those seen in historical cohorts. Two population-based case-control studies were conducted in Montreal, from 1979 to 1986 and from 1996 to 2001, comprising 1,598 cases and 1,965 controls. A detailed job history was obtained to evaluate lifetime occupational exposure to many agents, including nickel, chromium VI, and cadmium compounds. Lung cancer odds ratios were increased only among former or non-smokers: 2.5 (95% CI: 1.3-4.7) for nickel exposure, 2.4 (95% CI: 1.2-4.8) for chromium VI, and 4.7 (95% CI: 1.5-14.3) for cadmium. The metals did not increase risk among smokers. While excess risks due to these metal compounds were barely discernable among smokers, carcinogenic effects were seen among non-smokers.


[Content of basic lipid classes in the blood plasma of patients with the renal hypertensive syndrome].
The main classes of serum lipids (fatty acids, phospholipids, triglycerides, cholesterol) were studied and compared in 36 patients aged 20 to 41 years with the renal hypertensive syndrome of different etiology, in 25 patients aged 30 to 51 years with essential hypertension, and in 20 practically healthy subjects aged 20 to 42 years. The mechanism of changes in the content of serum lipids in different diseases associated with the hypertensive renal syndrome and in patients with essential hypertension allows an assumption that these changes are linked to a large degree with arterial hypertension.


Structure and immunological properties of thymosin beta 9 Met, a new analog of thymosin beta 4 isolated from porcine thymus.
During the course for the studies of thymosin beta 4 and prothymosin alpha from porcine thymus, a new analog of thymosin beta 4 has been identified. This peptide consists of 41 amino acid residues. The amino terminus is blocked by an acetyl group as revealed by fast atom bombardment mass spectrometric analysis. Amino acid sequence studies disclosed that this peptide is identical to bovine thymosin beta 9 except that leucine at position 6 in beta 9 is substituted by methionine. Thus, this new peptide has been termed thymosin beta 9 Met. The recoveries of beta 9 Met, beta 4, and prothymosin alpha in porcine tissues have been determined (in micrograms/g tissue) as follows: thymus (43, 85, 133); spleen (68, 203, 37); liver (10, 31, 27); heart (1.5, 10, 0); kidney (5, 51, 37); brain (0.8, 31, 5). Biologically, thymosin beta 9 Met was found to be more active than beta 4 in enhancing gamma-interferon production in cord blood lymphocytes. However, beta 4 appeared to stimulate higher amounts of interleukin 2 and tumor necrotic factor. The significance for the coexistence of two homologous peptides with similar functions in the thymus and a number of other organs is not clear, and deserves further investigation.


Biochemical Effects of Petroselinum crispum (Umbellifereae) Essential Oil on the Pyrethroid Resistant Strains of Aedes aegypti (Diptera: Culicidae).
In ongoing screening research for edible plants, Petroselinum crispum essential oil was considered as a potential bioinsecticide with proven antimosquito activity against both the pyrethroid susceptible and resistant strains of Aedes aegypti. Due to the comparative mosquitocidal efficacy on these mosquitoes, this plant essential oil is promoted as an attractive candidate for further study in monitoring resistance of mosquito vectors. Therefore, the aim of this study was to evaluate the impact of P. crispum essential oil on the biochemical characteristics of the target mosquito larvae of Ae. aegypti, by determining quantitative changes of key enzymes responsible for xenobiotic detoxification, including glutathione-S-transferases (GSTs), α- and β-esterases (α-/β-ESTs), acetylcholinesterase (AChE), acid and alkaline phosphatases (ACP and ALP) and mixed-function oxidases (MFO). Three populations of Ae. aegypti, comprising the pyrethroid susceptible Muang Chiang Mai-susceptible (MCM-S) strain and the pyrethroid resistant Pang Mai Dang-resistant (PMD-R) and Upakut-resistant (UPK-R) strains, were used as test organisms. Biochemical study of Ae. aegypti larvae prior to treatment with P. crispum essential oil revealed that apart from AChE, the baseline activity of most defensive enzymes, such as GSTs, α-/β-ESTs, ACP, ALP and MFO, in resistant UPK-R or PMD-R, was higher than that determined in susceptible MCM-S. However, after 24-h exposure to P. crispum essential oil, the pyrethroid susceptible and resistant Ae. aegypti showed similarity in biochemical features, with alterations of enzyme activity in the treated larvae, as compared to the controls. An increase in the activity levels of GSTs, α-/β-ESTs, ACP and ALP was recorded in all strains of P. crispum oil-treated Ae. aegypti larvae, whereas MFO and AChE activity in these mosquitoes was decreased. The recognizable larvicidal capability on pyrethroid resistant Ae. aegypti, and the inhibitory effect on AChE and MFO, emphasized the potential of P. crispum essential oil as an attractive alternative application for management of mosquito resistance in current and future control programs.


Consensus report from the 7th International Forum for Liver Magnetic Resonance Imaging.
Liver-specific MRI is a fast-growing field, with technological and protocol advancements providing more robust imaging and allowing a greater depth of information per examination. This article reports the evidence for, and expert thinking on, current challenges in liver-specific MRI, as discussed at the 7th International Forum for Liver MRI, which was held in Shanghai, China, in October 2013. Topics discussed included the role of gadoxetic acid-enhanced MRI in the differentiation of focal nodular hyperplasia from hepatocellular adenoma and small hepatocellular carcinoma (HCC) from small intrahepatic cholangiocarcinoma (in patients with chronic liver disease), the differentiation of low-grade dysplastic nodule (DN) from pre-malignant high-grade DN and early HCC, and treatment planning and assessment of treatment response for patients with HCC and colorectal liver metastasis. Optimization of the gadoxetic acid-enhanced MRI protocol to gain robust arterial and hepatobiliary phase images was also discussed. Gadoxetic acid-enhanced MRI demonstrates added value for the detection and characterization of focal liver lesions and shows promise in a number of new indications, including regional liver functional assessment and patient monitoring after therapy; however, more data are needed in some areas, and further developments are needed to translate cutting-edge techniques into clinical practice. Liver-specific MRI is a fast-growing field, with many technological and protocol advancements. Gadoxetic acid-enhanced MRI demonstrates value for detecting and characterizing focal liver lesions. Gadoxetic acid-enhanced MRI shows promise in regional functional assessment and patient monitoring. Further developments are needed to translate cutting-edge techniques into clinical practice.


Isolated Castleman's disease in the neck.
It can be difficult for the clinician to diagnose Castleman's disease when cervical lymphadenopathy is its only manifestation. The diagnostic challenge may be compounded by the presence of a profound fibrotic reaction secondary to multiple biopsy attempts that are frequently required to establish a diagnosis. Castleman's disease is a benign lymphoproliferative disorder and it most frequently involves the mediastinal lymph nodes. The recognition of an occasional variant of this disorder with a potential malignant course and its association with AIDS calls for a greater awareness of this disease among all clinicians.


Uncertainty in illness in family caregivers of palliative care patients and associated factors.
to describe the level of uncertainty in illness in family caregivers of palliative care patients and detect associations between the profile of the caregiver and the levels of uncertainty. descriptive correlational study conducted with 300 family caregivers of hospitalized patients. The sociodemographic characterization of caregiver and patient was used to assess the caregiver profile, as well as the Uncertainty in Illness scale for family caregivers. Spearman's Rho correlation test was applied to detect associations. the average score of illness uncertainty was 91.7 points. The analysis showed significant correlations between the level of uncertainty and patient dependence (r=0.18, p=0.001), symptom assessment (r=0.312, p<0.001), length of service as a caregiver (r=0.131, p=0.023), perception of support from health professionals (r=-0.16, p=0.048), family (r=-0.145, p=0.012) and religious support (r=-0.131, p=0.050). there were high levels of uncertainty in caregivers about their patient's illness. These levels are associated with the health condition and symptoms of the patient who is cared for, the length of service as a caregiver and the perceived support from health professionals, family and religion.


Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus.
Monkeypox is a zoonotic disease caused by brick-shaped enveloped monkeypox (Mpox) virus that belongs to the family of ancient viruses known as Poxviridae. Subsequently, the viruses have been reported in various countries. The virus is transmitted by respiratory droplets, skin lesions, and infected body fluids. The infected patients experience fluid-filled blisters, maculopapular rash, myalgia, and fever. Due to the lack of effective drugs or vaccines, there is a need to identify the most potent and effective drugs to reduce the spread of monkeypox. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Mpox virus. In our study, the Mpox protein thymidylate kinase (A48R) was targeted because it is a unique drug target. We screened a library of 9000 FDA-approved compounds of the DrugBank database by using various in silico approaches, such as molecular docking and molecular dynamic (MD) simulation. Based on docking score and interaction analysis, compounds DB12380, DB13276, DB13276, DB11740, DB14675, DB11978, DB08526, DB06573, DB15796, DB08223, DB11736, DB16250, and DB16335 were predicted as the most potent. To examine the dynamic behavior and stability of the docked complexes, three compounds-DB16335, DB15796, and DB16250 -along with the Apo state were simulated for 300ns. The results revealed that compound DB16335 revealed the best docking score (-9.57 kcal/mol) against the Mpox protein thymidylate kinase. Additionally, during the 300 ns MD simulation period, thymidylate kinase DB16335 showed great stability. Further, in vitro and in vivo study is recommended for the final predicted compounds.


Patterns of Post-Endodontic Restoration: A Nationwide Survey of Dentists in Turkey.
Developments in materials and techniques, geographical locations, age, specialty, and affiliations of dental practitioners affect the preference of post-endodontic restoration. Thus, this survey aimed to evaluate the trends of dentists in Turkey in terms of post-endodontic restorations. An anonymous survey containing 10 questions regarding demographics, post-endodontic restoration patterns, and factors affecting restoration selection was electronically delivered to the dentists registered in the database of the Turkish Dental Association. The data were analyzed using by a chi-square test and ordinal logistic regression analysis. A total of 1093 surveys from 20,564 participants were collected with a response rate of 5.3%. Half of the participants (52%) preferred composite resins for post-endodontic restorations. Usage of posts was less prevalent amongst prosthodontists and dentists with clinical experience of more than 20 years compared to endodontists (p < 0.001) and dentists with clinical experience of less than 5 years (p = 0.004). More than half of the participants (56%) utilized fiber posts. Composite resins and fiber posts were the most common preferences in post-endodontic restoration. Endodontists had a higher tendency to use posts than prosthodontists and general dental practitioners.


Mapping isoflavone QTL with main, epistatic and QTL × environment effects in recombinant inbred lines of soybean.
Soybean (Glycine max (L.) Merr.) isoflavone is important for human health and plant defense system. To identify novel quantitative trait loci (QTL) and epistatic QTL underlying isoflavone content in soybean, F5:6, F5:7 and F5:8 populations of 130 recombinant inbred (RI) lines, derived from the cross of soybean cultivar 'Zhong Dou 27' (high isoflavone) and 'Jiu Nong 20' (low isoflavone), were analyzed with 95 new SSR markers. A new linkage map including 194 SSR markers and covering 2,312 cM with mean distance of about 12 cM between markers was constructed. Thirty four QTL for both individual and total seed isoflavone contents of soybean were identified. Six, seven, ten and eleven QTL were associated with daidzein (DZ), glycitein (GC), genistein (GT) and total isoflavone (TI), respectively. Of them 23 QTL were newly identified. The qTIF_1 between Satt423 and Satt569 shared the same marker Satt569 with qDZF_2, qGTF_1 and qTIF_2. The qGTD2_1 between Satt186 and Satt226 was detected in four environments and explained 3.41%-10.98% of the phenotypic variation. The qGTA2_1, overlapped with qGCA2_1 and detected in four environments, was close to the previously identified major QTL for GT, which were responsible for large a effects. QTL (qDZF_2, qGTF_1 and qTIF_2) between Satt144-Satt569 were either clustered or pleiotropic. The qGCM_1, qGTM_1 and qTIM_1 between Satt540-Sat_244 explained 2.02%-9.12% of the phenotypic variation over six environments. Moreover, the qGCE_1 overlapped with qGTE_1 and qTIE_1, the qTIH_2 overlapped with qGTH_1, qGCI_1 overlapped with qDZI_1, qTIL_1 overlapped with qGTL_1, and qTIO_1 overlapped with qGTO_1. In this study, some of unstable QTL were detected in different environments, which were due to weak expression of QTL, QTL by environment interaction in the opposite direction to a effects, and/or epistasis. The markers identified in multi-environments in this study could be applied in the selection of soybean cultivars for higher isoflavone content and in the map-based gene cloning.


Caffeine during High-Intensity Whole-Body Exercise: An Integrative Approach beyond the Central Nervous System.
Caffeine is one of the most consumed ergogenic aids around the world. Many studies support the ergogenic effect of caffeine over a large spectrum of exercise types. While the stimulatory effect of caffeine on the central nervous system is the well-accepted mechanism explaining improvements in exercise performance during high-intensity whole-body exercise, in which other physiological systems such as pulmonary, cardiovascular, and muscular systems are maximally activated, a direct effect of caffeine on such systems cannot be ignored. A better understanding of the effects of caffeine on multiple physiological systems during high-intensity whole-body exercise might help to expand its use in different sporting contexts (e.g., competitions in different environments, such as altitude) or even assist the treatment of some diseases (e.g., chronic obstructive pulmonary disease). In the present narrative review, we explore the potential effects of caffeine on the pulmonary, cardiovascular, and muscular systems, and describe how such alterations may interact and thus contribute to the ergogenic effects of caffeine during high-intensity whole-body exercise. This integrative approach provides insights regarding how caffeine influences endurance performance and may drive further studies exploring its mechanisms of action in a broader perspective.


Weighting Nonprobability and Probability Sample Surveys in Describing Cancer Catchment Areas.
The Population Health Assessment initiative by NCI sought to enhance cancer centers' capacity to acquire, aggregate, and integrate data from multiple sources, as well as to plan, coordinate, and enhance catchment area analysis activities. Key objectives of this initiative are pooling data and comparing local data with national data. A novel aspect of analyzing data from this initiative is the methodology used to weight datasets from sites that collected both probability and nonprobability samples. This article describes the methods developed to weight data, which cancer centers collected with combinations of probability, and nonprobability sampling designs. We compare alternative weighting methods in particular for the hybrid probability and nonprobability sampling designs employed by different cancer centers. We also include comparisons of local center data with national survey data from large probability samples. This hybrid approach to calculating statistical weights can be implemented both within cancer centers that collect both probability and nonprobability samples with common measures. Aggregation can also apply to cancer centers that share common data elements, and target similar populations, but differ in survey sampling designs. Researchers interested in local versus national comparisons for cancer surveillance and control outcomes should consider various weighting approaches, including hybrid approaches, when analyzing their data.


First report of Phyllosticta citricarpa and description of two new species, P. paracapitalensis and P. paracitricarpa, from citrus in Europe.
The genus Phyllosticta occurs worldwide, and contains numerous plant pathogenic, endophytic and saprobic species. Phyllosticta citricarpa is the causal agent of Citrus Black Spot disease (CBS), affecting fruits and leaves of several citrus hosts (Rutaceae), and can also be isolated from asymptomatic citrus tissues. Citrus Black Spot occurs in citrus-growing regions with warm summer rainfall climates, but is absent in countries of the European Union (EU). Phyllosticta capitalensis is morphologically similar to P. citricarpa, but is a non-pathogenic endophyte, commonly isolated from citrus leaves and fruits and a wide range of other hosts, and is known to occur in Europe. To determine which Phyllosticta spp. occur within citrus growing regions of EU countries, several surveys were conducted (2015-2017) in the major citrus production areas of Greece, Italy, Malta, Portugal and Spain to collect both living plant material and leaf litter in commercial nurseries, orchards, gardens, backyards and plant collections. A total of 64 Phyllosticta isolates were obtained from citrus in Europe, of which 52 were included in a multi-locus (ITS, actA, tef1, gapdh, LSU and rpb2 genes) DNA dataset. Two isolates from Florida (USA), three isolates from China, and several reference strains from Australia, South Africa and South America were included in the overall 99 isolate dataset. Based on the data obtained, two known species were identified, namely P. capitalensis (from asymptomatic living leaves of Citrus spp.) in Greece, Italy, Malta, Portugal and Spain, and P. citricarpa (from leaf litter of C. sinensis and C. limon) in Italy, Malta and Portugal. Moreover, two new species were described, namely P. paracapitalensis (from asymptomatic living leaves of Citrus spp.) in Italy and Spain, and P. paracitricarpa (from leaf litter of C. limon) in Greece. On a genotypic level, isolates of P. citricarpa populations from Italy and Malta (MAT1-2-1) represented a single clone, and those from Portugal (MAT1-1-1) another. Isolates of P. citricarpa and P. paracitricarpa were able to induce atypical lesions (necrosis) in artificially inoculated mature sweet orange fruit, while P. capitalensis and P. paracapitalensis induced no lesions. The Phyllosticta species recovered were not found to be widespread, and were not associated with disease symptoms, indicating that the fungi persisted over time, but did not cause disease.


Effects of Exergame and Music on Acute Exercise Responses to Graded Treadmill Running.
Recreational athletes may listen to music or watch videos to prolong their exercise routines. In recent years, use of active videogames has increased. The effects of audiovisual encouragements have not been compared for their potential ergogenic effects on physiological variables during moderate- to high-intensity exercises. Here 60 sedentary healthy male students were divided into four groups-control (CON), audio feedback (A), videogame feedback (V), and a combination of A and V (AV)-based on previous measurement of maximum oxygen uptake using covariate adaptive randomization. Participants completed a bout of running (Balke treadmill test) until exhaustion based on the type of feedback. Exercise responses (time, heart rate, blood sugar level, and creatine kinase level) were compared in all groups before and after participation. Participants in group A ran significantly more than those in the CON group, and those in group AV ran significantly more than those in groups CON and V. In other physiological responses, the differences were not significant among groups. It is proposed that intentional functions from internal (physical feelings) to external perspective (music and video) may have been involved in increasing exercise time but were not strong enough to change levels of other physiological parameters. However, these findings have strong applications for improving fitness exercise programs while using a new generation of videogames.


Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity.
In an evaluation of 213 patients from 15 kindreds with familial medullary thyroid carcinoma (MTC), we detected 41 subjects from two kindreds (L and O) who had MTC but no extra-thyroidal manifestations (hyperparathyroidism, phaeochromocytomas or mucosal neuromas) of multiple endocrine neoplasia (MEN) type IIa or IIb. In screening 178 members of the L and O kindreds, we found no evidence that any of them had died from MTC. To assess whether the malignancy was relatively indolent in these families, 20 selected subjects from the two kindreds were compared with 33 MEN IIa subjects. Both groups had clinically occult disease which was diagnosed biochemically by documenting elevated plasma calcitonin (CT) levels following stimulation with intravenous calcium and pentagastrin. There were no differences in the peak stimulated plasma CT levels at the time of diagnosis (1055 +/- 236 pg/ml versus 1096 +/- 191 pg/ml) or the incidence of regional lymph node metastases (0/20 versus 1/33) in the two groups. The mean age at diagnosis, however, was significantly higher in patients of the L and O kindreds than in patients with MEN IIa (43.1 +/- 3.4 years versus 21.1 +/- 2.2 years; P less than 0.001) indicating that in the two kindreds the MTC either developed at a later age or grew more slowly. This study demonstrates that MTC may occur in a familial pattern distinct from its presentation as MEN IIa or MEN IIb. In this setting it appears to be the least aggressive form of MTC yet described.


A systematic literature review of Releasing Time to Care: The Productive Ward.
This systematic review provides an overview of the literature published on Releasing Time to Care: The Productive Ward between 2005 and June 2011. Releasing Time to Care: The Productive Ward programme was developed by the NHS Institute for Innovation and Improvement and launched in England in 2007. The programme comprises thirteen modules that aim to increase time for direct patient care, improve the patient and staff experience and make changes to the ward environment to improve efficiency. A systematic literature review. The terms 'Releasing Time to Care' and 'Productive Ward' were applied to key healthcare databases; CINAHL, Medline, Science Direct, ProQuest, Health Business Elite, British Nursing Index, Embase, Health Management Information Consortium and PsychInfo. All papers were read and subject to a quality assessment. The literature search identified 95 unique sources. A lack of research on The Productive Ward programme meant it was necessary to include non-empirical literature. In total, 18 articles met the inclusion criteria. Seven key themes were identified: the patient and staff experience, direct care time, patient safety, financial impact, embedding and sustainability, executive support and leadership, and common barriers and determinants of success. It also highlighted areas that require further exploration such as long-term sustainability of the programme and consistent data measurement between organisations. The review tentatively reports how The Productive Ward programme has been used to transform nursing practice for the benefit of patients and frontline staff, and how it resulted in cost savings. The literature review identified a potential positive results bias in the current literature whereby favourable outcomes were reported. This paper summarises the types of evidence and current literature on The Productive Ward providing a reference for frontline staff implementing the programme.


An Economic Perspective on the Affordable Care Act: Expectations and Reality.
The Affordable Care Act (ACA) was enacted in 2010 to address both high uninsured rates and rising health care spending through insurance expansion reforms and efforts to reduce waste. It was expected to have a variety of impacts in areas within the purview of economics, including effects on health care coverage, access to care, financial security, labor market decisions, health, and health care spending. To varying degrees, legislative, executive, and judicial actions have altered its implementation, affecting the extent to which expectations in each of these dimensions have been realized. We review the ACA's reforms, the subsequent actions that countered them, and the expected and realized effects on coverage, access to care, financial security, health, labor market decisions, and health care spending.


The mTOR signaling network: insights from its role during embryonic development.
Target of Rapamycin (TOR) signaling, originally discovered as the pathway affected by an antifungal macrolide, exemplifies the potential of medicinal chemistry as a discovery tool. Three decades from its identification, signaling involving the TOR kinase has evolved into a complex network with a crucial role in vertebrate growth control. Specifically, it integrates signals to coordinate cell growth (i.e., enhanced mass and size) and cell cycle progression with sufficiency of nutrients, energy, and growth factors. In this review, we discuss multiple aspects of TOR signaling, including cellular regulators and mediators, human diseases related to TOR dysregulation such as cancer, and signaling nodes in the pathway amenable to targeted drug inhibition. The functions and mechanisms of TOR during embryonic development highlight the dynamic role of TOR signaling and reveal additional functions beyond cell growth control. Embryonic TOR signaling has differential tissue-specific and temporal effects, and is involved in organogenesis, sexual differentiation, and epithelial-to-mesenchymal transition signaling. Molecular mechanisms that may contribute to embryonic-specific TOR functions are also examined here. Finally, this review discusses the complex signaling of mTOR in cancer and the development of mTOR inhibitors for cancer therapy.