Ectopic Wnt signal determines the eyeless phenotype of zebrafish masterblind mutant.
masterblind (mbl) is a zebrafish mutation characterised by the absence or reduction in size of the telencephalon, optic vesicles and olfactory placodes. We show that inhibition of Gsk3beta in zebrafish embryos either by overexpression of dominant negative dn gsk3beta mRNA or by lithium treatment after the midblastula transition phenocopies mbl. The loss of anterior neural tissue in mbl and lithium-treated embryos is preceded by posteriorization of presumptive anterior neuroectoderm during gastrulation, which is evident from the anterior shift of marker genes Otx2 and Wnt1. Heterozygous mbl embryos showed increased sensitivity to inhibition of GSK3beta by lithium or dn Xgsk3beta that led to the loss of eyes. Overexpression of gsk3beta mRNA rescued eyes and the wild-type fgf8 expression of homozygous mbl embryos. emx1 that delineates the telencephalon is expanded and shifted ventroanteriorly in mbl embryos. In contrast to fgf8, the emx1 expression domain was not restored upon overexpression of gsk3beta mRNA. These experiments place mbl as an antagonist of the Wnt pathway in parallel or upstream of the complex consisting of Axin, APC and Gsk3beta that binds and phosphorylates beta-catenin, thereby destabilising it. mbl maps on LG 3 close to a candidate gene axin1. In mbl we detected a point mutation in the conserved minimal Gsk3beta-binding domain of axin1 leading to a leucine to glutamine substitution at position 399. Overexpression of wild-type axin1 mRNA rescued mbl completely, demonstrating that mutant axin1 is responsible for the mutant phenotype. Overexpression of mutant L399Q axin1 in wild-type embryos resulted in a dose-dependent dominant negative activity as demonstrated by the loss of telencephalon and eyes. We suggest that the function of Axin1/Mbl protein is to antagonise the Wnt signal and in doing so to establish and maintain the most anterior CNS. Our findings provide new insights into the mechanisms by which the Wnt pathway generates anteroposterior polarity of the neural plate.


Detection of anabolic steroid administration: ratio of urinary testosterone to epitestosterone vs the ratio of urinary testosterone to luteinizing hormone.
Our goal in this study was to determine whether the urinary ratio of testosterone to luteinizing hormone (T/LH) as an indicator of exogenous anabolic steroid (AS) use is superior to the urinary ratio of testosterone to epitestosterone (T/E). After 2 weekly placebo injections, 19 subjects were given testosterone cypionate (TC) injections of 250 or 500 mg/week for 14 weeks followed by 14 weekly placebo injections. Patients were considered to have ceased taking TC if they tested negative 9 weeks after their last injection. For detection of illicit or supraphysiological TC (AS) use, the urinary T/E ratio of > or = 6 yielded a false-negative rate of 46% and a false-positive rate of 4%. However, a urinary T/LH ratio of > or = 30 produced a false-negative rate of only 24% and a false-positive rate of 13%. We conclude that the urinary T/LH ratio of > or = 30 is a more sensitive marker of AS use than the urinary T/E ratio of > or = 6 and remains sensitive for twice as long as urinary T/E.


The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of etiology in dilated cardiomyopathy.
Guidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology. Sixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step. Six physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p < 0.0005). The number of diagnoses made with low confidence reduced from 105 (29.2%) with routine clinical data to 71 (19.7%) following the addition of genetics and 37 (10.3%) with the addition of CMR. The addition of genetics and CMR led to 101 (28.1%) and 112 (31.1%) proposed changes to management, respectively. Interobserver variability showed moderate agreement with clinical data (κ = 0.44) which improved following the addition of genetics (κ = 0.65) and CMR (κ = 0.68). We demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management.


Disinfection of transvaginal ultrasound probes in a clinical setting: comparative performance of automated and manual reprocessing methods.
Transvaginal and intracavitary ultrasound probes are a possible source of cross-contamination with microorganisms and thus a risk to patients' health. Therefore appropriate methods for reprocessing are needed. This study was designed to compare the standard disinfection method for transvaginal ultrasound probes in Germany with an automated disinfection method in a clinical setting. This was a prospective randomized controlled clinical study of two groups. In each group, 120 microbial samples were collected from ultrasound transducers before and after disinfection with either an automated method (Trophon EPR®) or a manual method (Mikrozid Sensitive® wipes). Samples were then analyzed for microbial growth and isolates were identified to species level. Automated disinfection had a statistically significantly higher success rate of 91.4% (106/116) compared with 78.8% (89/113) for manual disinfection (P = 0.009). The risk of contamination was increased by 2.9-fold when disinfection was performed manually (odds ratio, 2.9 (95% CI, 1.3-6.3)). Before disinfection, bacterial contamination was observed on 98.8% of probes. Microbial analysis revealed 36 different species of bacteria, including skin and environmental bacteria as well as pathogenic bacteria such as Staphylococcus aureus, enterobacteriaceae and Pseudomonas spp. Considering the high number of contaminated probes and bacterial species found, disinfection of the ultrasound probe's body and handle should be performed after each use to decrease the risk of cross-contamination. This study favored automated disinfection owing to its significantly higher efficacy compared with a manual method. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.


Selective serotonin reuptake inhibitors' passage into human milk of lactating women.
Objective: Selective serotonin reuptake inhibitors are commonly used for the treatment of pregnancy-related and postnatal depression. However, only a few studies have evaluated the passage of these drugs into human milk, often with conflicting results. Here, we sought to evaluate the passage of selective serotonin reuptake inhibitors into human milk in the first days after delivery and their potential association with neonatal outcomes. Study design: The passage of selective serotonin reuptake inhibitors into human milk was expressed both as percentage of milk-to-plasma ratio of drug concentrations and as the relative infant dose (RID). Selective serotonin reuptake inhibitors were quantified by high-performance liquid chromatography combined with mass spectrometry. Results: Nineteen women treated with selective serotonin reuptake inhibitors during the third trimester of pregnancy and lactation were considered. Human milk-to-plasma ratios ranged from 51.1% to 703.4%. The patients had a median RID of 1.5%, with differences among the selective serotonin reuptake inhibitors. All newborns had been breastfed from birth up to day three of life. At 1 week follow up, 58% of infants were breastfed, 37% were complementary fed, and 5% were formula fed. No side effects due to passage of selective serotonin reuptake inhibitors into human milk were found. Conclusions: Selective serotonin reuptake inhibitors were detected in human milk, with milk-to-plasma ratios which in some cases exceeded 100%. Given the need for maternal therapy and the low incidence of neonatal adverse events, it is advisable not to preclude breastfeeding a priori but recommend it with careful follow-up.


Site-Specific Glycation of Human Heat Shock Protein (Hsp27) Enhances Its Chaperone Activity.
Non-enzymatic posttranslational modifications are believed to affect at least 30% of human proteins, commonly termed glycation. Many of these modifications are implicated in various pathological conditions, e.g., cataract, diabetes, neurodegenerative diseases, and cancer. Chemical protein synthesis enables access to full-length proteins carrying site-specific modifications. One such modification, argpyrimidine (Apy), has been detected in human small heat shock protein Hsp27 and closely related proteins in patient-derived tissues. Thus far, studies have looked into only artificial mixtures of Apy modifications, and only one has analyzed Apy188. We were interested in understanding the impact of such individual Apy modifications on five different arginine sites within the crucial N-terminal domain of Hsp27. By combining protein semisynthesis with biochemical assays on semisynthetic Hsp27 analogues with single-point Apy modification at those sites, we have shown how a seemingly minimal modification within this region results in dramatically altered functional attributes.


Here, there and everywhere: T follicular helper cells on the move.
T follicular helper (Tfh) cells have the important function of providing B-cell help for the induction of antigen-specific antibody production. As such, it is important to determine the factors that regulate the development, differentiation and function of Tfh cells. This review highlights some of the recent advances in our understanding of Tfh cell migration, Tfh cell memory and the origins and fate of circulating Tfh cells in the blood, that have been revealed from studies in humans and mice.


Mechanisms responsible for the effect of median nerve electrical stimulation on traumatic brain injury-induced coma: orexin-A-mediated N-methyl-D-aspartate receptor subunit NR1 upregulation.
Electrical stimulation of the median nerve is a noninvasive technique that facilitates awakening from coma. In rats with traumatic brain injury-induced coma, median nerve stimulation markedly enhances prefrontal cortex expression of orexin-A and its receptor, orexin receptor 1. To further understand the mechanism underlying wakefulness mediated by electrical stimulation of the median nerve, we evaluated its effects on the expression of the N-methyl-D-aspartate receptor subunit NR1 in the prefrontal cortex in rat models of traumatic brain injury-induced coma, using immunohistochemistry and western blot assays. In rats with traumatic brain injury, NR1 expression increased with time after injury. Rats that underwent electrical stimulation of the median nerve (30 Hz, 0.5 ms, 1.0 mA for 15 minutes) showed elevated NR1 expression and greater recovery of consciousness than those without stimulation. These effects were reduced by intracerebroventricular injection of the orexin receptor 1 antagonist SB334867. Our results indicate that electrical stimulation of the median nerve promotes recovery from traumatic brain injury-induced coma by increasing prefrontal cortex NR1 expression via an orexin-A-mediated pathway.


Multiple Network Dysconnectivity in Adolescents with Psychotic Experiences: A Longitudinal Population-Based Study.
Abnormal functional connectivity (FC, the temporal synchronization of activation across distinct brain regions) of the default mode (DMN), salience (SN), central executive (CEN), and motor (MN) networks is well established in psychosis. However, little is known about FC in individuals, particularly adolescents, reporting subthreshold psychotic experiences (PE) and their trajectory over time. Thus, the aim of this study was to investigate the FC of these networks in adolescents with PE. In this population-based case-control study, 24 adolescents (mean age = 13.58) meeting the criteria for PE were drawn from a sample of 211 young people recruited and scanned for a neuroimaging study, with a follow-up scan 2 years later (n = 18, mean age = 15.78) and compared to matched controls drawn from the same sample. We compared FC of DMN, SN, CEN, and MN regions between PE and controls using whole-brain FC analyses. At both timepoints, the PE group displayed significant hypoconnectivity compared to controls. At baseline, FC in the PE group was decreased between MN and DMN regions. At follow-up, dysconnectivity in the PE group was more widespread. Over time, controls displayed greater FC changes than the PE group, with FC generally increasing between MN, DMN, and SN regions. Adolescents with PE exhibit hypoconnectivity across several functional networks also found to be hypoconnected in established psychosis. Our findings highlight the potential for studies of adolescents reporting PE to reveal early neural correlates of psychosis and support further investigation of the role of the MN in PE and psychotic disorders.


Proton transfer reaction time-of-flight mass spectrometry: A high-throughput and innovative method to study the influence of dairy system and cow characteristics on the volatile compound fingerprint of cheeses.
The aim of this work was to study the effect of dairy system and individual cow-related factors on the volatile fingerprint of a large number of individual model cheeses analyzed by proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). A total of 1,075 model cheeses were produced using milk samples collected from individual Brown Swiss cows reared in 72 herds located in mountainous areas of Trento province (Italy). The herds belonged to 5 main dairy systems ranging from traditional to modern and the cows presented different daily milk yields (24.6±7.9kg × d(-1)), stages of lactation (199±138 d in milk), and parities (2.7±1.8). The PTR-ToF-MS revealed 619 peaks, of which the 240 most intense were analyzed, and 61 of these were tentatively attributed to relevant volatile organic compounds on the basis of their fragmentation patterns and data from the literature. Principal component analysis was used to convert the multiple responses characterizing the PTR-ToF-MS spectra into 5 synthetic variables representing 62% of the total information. These principal components were related to groups of volatile compounds tentatively attributed to different peaks and used to investigate the relationship of the volatile compound profile obtained by PTR-ToF-MS to animal and farm characteristics. Lactation stage is related to 4 principal components which brought together 52.9% of the total variance and 57.9% of the area of analyzed peaks. In particular, 2 principal components were positively related to peaks tentatively attributed to aldehydes and ketones and negatively related to alcohols, esters, and acids, which displayed a linear increase during lactation. The second principal component was affected by dairy system; it was higher in the modern system in which cows received total mixed rations. The third principal component was positively related to daily milk production. In summary, we report the first application of this innovative, high-throughput technique to study the effects of dairy system and individual animal factors on volatile organic compounds of model cheeses. Individual cheesemaking procedures together with this spectrometric technique open new avenues for genetic selection of dairy species with respect to both milk and cheese quality.


Selective IgA deficiency with recurrent vasculitis of the central nervous system.
We describe an unusual case of selective IgA deficiency complicated by recurrent vasculitis of the central nervous system (CNS). The patient suffered from two episodes of CNS vasculitis, one of which was located in the cerebrum and the other in the cerebellum. The vasculitic process resulted in brain tumor-like lesions shown by computed tomography. There was no evidence of associated connective tissue diseases. Vasculitis in other organs or tissues was not noted. This is the first detailed description in the English literature of pathologically proven CNS vasculitis in a patient with selective IgA deficiency. Our report demonstrates that isolated CNS angiitis can be a rare clinical feature of selective IgA deficiency.


Variability of 24-hour urinary creatinine excretion by normal subjects.
Creatinine excretion was studied in eight healthy males who collected 54 to 97 24-hour urine specimens. Significant differences among subjects in mean creatinine excretion were only partly explained by differences in body weight and surface area. Considerable daily within-subject variation in creatinine excretion during normal activity was found. Standard deviations were from 10.5 to 14.4 per cent of the mean, and ranges varied from 50 to 79 per cent of the mean. Day-to-day variation appeared to be time dependent rather than entirely random, and could not be explained by unreliability of the assay technique or by incomplete collections. Creatinine excretion values were normally distributed in seven of eight subjects. Individual variation from day to day limits the value of urinary creatinine excretion as an index of the completeness of 24-hour urine collections.


A phase II evaluation of human lymphoblastoid interferon (Wellferon) in relapsed high grade malignant glioma. Medical Research Council Brain Tumour Working Party.
During the 1980s a number of studies suggested there might be a role for interferon in the treatment of high grade gliomas. In the light of these reports a formal Phase II evaluation of human lymphoblastoid interferon (Wellferon) was undertaken in patients with high grade gliomas which had relapsed after conventional radiotherapy; 14 patients were treated and no objective clinical responses were seen. This indicates that the overall response rate to interferon therapy in this situation would be less than 20%. It is therefore concluded that interferon administration is unlikely to be of value in the management of relapsed high grade gliomas.


The Evidence of Acute Kidney Injury in the Community and for Primary Care Interventions.
Almost two-thirds of patients with acute kidney injury (AKI) damage their kidneys whilst in the community. This paper aims to review existing data on incidence, mortality, and morbidity of AKI within the community and explore the evidence base for primary care strategies aimed at reducing incidence and improving early detection and management of AKI. A literature search was carried out using PubMed; key words including AKI, primary care, community acquired, and electronic alerts (e-alerts) were used to capture relevant data. Incidence of AKI developing in the community is variable between studies due to differences in AKI definition. Community-acquired AKI (CA-AKI) but identified in hospital (CAH-AKI) is more prevalent than hospital-acquired AKI and increases short- and long-term mortality and length of stay in hospital. CA-AKI identified in primary care is less severe than CAH-AKI but is associated with increased mortality. The use of e-alerts has good diagnostic accuracy for detecting AKI but their impact on outcomes in secondary care remains uncertain; it is likely that they should be complemented with other interventions to improve management. Evidence has not yet emerged regarding the effects of e-alerts on outcomes in primary care. Given the significance of developing AKI in the community, strategies to aid early detection and promote prevention are warranted. A multifaceted approach combining e-alerts, educational programs, and care bundles across the interface between primary and secondary care has the potential to improve outcomes in the future.


Muscular proteomic profiling of deep pressure ulcers reveals myoprotective role of JAK2 in ischemia and reperfusion injury.
Pressure ulcers (PUs) are a complex and serious clinical problem. Deep tissue injury (DTI) is either the outcome or the trigger of deep PUs. However, the cellular and molecular mechanisms that contribute to the pathogenesis of deep PUs remain unclear. In this study, the degeneration characteristics and increased autophagy and apoptosis were observed in deep PU muscle tissues. Muscular proteome of deep PU revealed that a total of 520 proteins were differentially expressed, particularly, JAK2 was down-regulated. Intriguingly, expression of JAK2 in C2C12 myoblasts exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) insult was also distinctly reduced. Ex vivo, we transfected C2C12 myoblasts with lentivirus carrying the JAK2 plasmid and found that JAK2-overexpressed myoblasts exhibited a decrease in autophagy and apoptosis after OGD/R treatment, as well as less cell death. Finally, Western blot analysis determined that p-JAK2, p-AKT, p-mTOR and p-ERK1/2 levels were significantly elevated, accompanied by JAK2 overexpression but without p-STAT3, and inhibition of the AKT and ERK1/2 pathway resulted in elevated apoptosis and/or autophagy. These results demonstrated that JAK2 may play an important protective role in muscular ischemia and reperfusion injury during DTI development by inhibition of autophagy and apoptosis through the AKT and ERK1/2 pathways.


N-CQDs from reed straw enriching charge over BiO2-x/BiOCl p-n heterojunction for improved visible-light-driven photodegradation of organic pollutants.
Green bismuth-based photocatalysts have attracted extensive attention in the field of PPCPs photodegradation. The improved carrier separation efficiency still remains a key factor to enhance photocatalytic performance. Herein, N-doped biomass carbon quantum dots (N-CQDs) decorated p-n heterojunction photocatalyst BiO2-x/BiOCl was prepared using a facile ion-etching strategy, and it displayed a markedly enhanced catalytic activity in the photodegradation of sulfonamide antibiotics. Calculated by the differential charge density, the doped N-CQDs could gather photogenerated electrons, which indicated that the introduction of N-CQDs into BiO2-x/BiOCl would effectively inhibit the recombination of photogenerated charge carriers. In addition, photocatalytic performance and density functional theory (DFT) calculation results revealed that the photogenerated electrons tended to transfer from p-BiOCl to n-BiO2-x through N-CQDs, which could generate ·O2- and photogenerated h+ to oxidize the target pollutants. Benefiting from the synergistic effect of accelerated separation of e--h+ in p-n heterojunction and the electron-rich performance of N-CQDs, the superb TOC removal efficiencies (89.40% within 120 min visible-light irradiation) and toxicity reduction performance of photodegradation intermediates were achieved. As a consequence, this work will provide a design of high-quality photocatalysts and a green-promising strategy for bismuth-based photocatalysts in the water treatment of PPCPs.


Pharmacokinetics and virological efficacy after switch to once-daily lopinavir-ritonavir in treatment-experienced HIV-1-infected children.
Lopinavir-ritonavir (LPV/r) is a protease inhibitor that is used twice daily (BID) in the treatment of HIV infection in children. In the context of a single-center observational study, a switch to a once-a-day (QD) LPV/r regimen was proposed for considerations of convenience and to support adherence. The aims of this study were to compare the pharmacokinetics, viral loads, percentages of CD4(+) T cells, and lipid profiles after switching from a twice-daily to a once-daily regimen of LPV/r in experienced children. For this purpose, LPV concentrations, viral loads, CD4(+) T cells, and biochemistry data were measured in routine therapeutic drug monitoring procedures in 45 children and adolescents. Thirty-six children were switched to the QD regimen. Nine children on the BID or QD regimen were added for pharmacokinetic-study purposes only. The QD trough concentrations (C(trough)) of lopinavir in plasma were significantly lower than those observed with the BID regimen (P < 0.0001), but the 24-h exposure levels were not significantly lower with the QD than with the BID regimen (P = 0.09). Among 34 evaluable patients who switched from the BID to the QD regimen, the virological efficacy of LPV/r appeared to differ (P < 0.001), with 74% and 57% of viral loads, respectively, being <50 copies/ml (mean follow-up times, 33 and 20 months). Among 22 patients with stable virological control before the switch, 12 experienced either failure or blip (one observation of detectable viral load between two observations of undetectable viral load) after the switch. The change from the BID to the QD regimen did not result in significant differences in CD4(+) T cell percentages or total cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels. The switch from the BID to the QD LPV/r regimen led to equivalent exposure and lower C(trough) values and resulted in lower levels of virological control in these antiretroviral-experienced children.


In vitro antifungal activity of the new triazole D0870 against Penicillium marneffei compared with that of amphotericin B, fluconazole, itraconazole, miconazole and flucytosine.
The in vitro activity of D0870, a new triazole, was compared with that of fluconazole, itraconazole, miconazole, amphotericin B and flucytosine against recent clinical isolates of Penicillium marneffei in Thailand. The minimum inhibitory concentrations (MIC) values were determined by a microbroth dilution method using morpholinopropanesulphonic acid (MOPS)-buffered RPMI-1640 and brain heart infusion (BHI) medium. Yeast nitrogen base (YNB) medium with glucose was also used for the assay of flucytosine. D0870 was less active against P. marneffei than itraconazole, but its activity was similar to that of miconazole, superior to that of amphotericin B and markedly superior to that of fluconazole and flucytosine. Much lower MIC values of D0870 were observed with BHI medium.


Clinical response to feeding a high polyunsaturated fat diet in normal and diabetic rats.
Dietary fat composition can influence membrane composition in a variety of cell types. Changes in dietary fat can alter the structure and function of lymphocyte membranes, liver plasma membranes, brain synaptosomes and cardiac mitochondria. In diabetics, uptake of glucose is enhanced due to a greater passive permeability of the intestine to glucose. This enhanced absorption from the intestine can be partially corrected by insulin administration and islet cell transplantation. In clinical practice, however, a more commonly used therapeutic modality for diabetics is diet modification. In this study, when diabetic rats were fed a high fat diet, high or low saturated to polyunsaturated fatty acid, there was an improvement in the plasma and urine glucose. This improved clinical response was also observed in the glycosylated hemoglobin response in the animals fed the high polyunsaturated to saturated fatty acid diet. The clinical improvement observed after feeding with these diets, however, was not seen during the oral and intravenous glucose tolerance tests. This study shows that dietary alteration can improve the clinical response in diabetic animals.


[Alveolar rhabdomyosarcoma of the skin].
The authors present the case of an 18 years old male patient with a tumor localized in the skin of the nose, which had a fast evolution provoking in a month regional metastases. Histologically it proved to be an alveolar rhabdomyosarcoma. The clinical and histopathological characters are described, and considerations about the origin of this tumor are made.


[The morphological changes in the myocardium associated with the craniocerebral injury].
The objective of the present study was to evaluate the structural changes in the capillaries, arterioles, venules, and cardiomyocytes in the myocardium of the rats following the craniocerebral injury (CCI). Eighteen non-pedigree white female rats with the craniocerebral injury were used as the CCI model. All the animals were given an intraperitoneal injection of sodium thiopental (100 mg/kg b.w.) within 3, 7, and 12 days after the injury. The heart was removed after thoracotomy and the myocardial tissue was examined with the light and electron microscopes. It was shown that the rats with the craniocerebral injury developed well apparent changes in the myocardial tissue during the early post-traumatic period that affected not only the blood vessels themselves (capillaries, arterioles, venules) but also the intra- and extravascular structures. Changes in the microcirculatory system included damages to the mitochondria, myofibrils, cell nuclei, sarcoplasmic reticulum, and cardiomyocytes. It is concluded that the morphological changes in the myocardium of the animals associated with the craniocerebral injury can induce the development of functional disorders in the cardiovascular system during the early post-traumatic period.


Generation of Nutrients and Detoxification: Possible Roles of Yeasts in Leaf-Cutting Ant Nests.
The possible roles played by yeasts in attine ant nests are mostly unknown. Here we present our investigations on the plant polysaccharide degradation profile of 82 yeasts isolated from fungus gardens of Atta and Acromyrmex species to demonstrate that yeasts found in ant nests may play the role of making nutrients readily available throughout the garden and detoxification of compounds that may be deleterious to the ants and their fungal cultivar. Among the yeasts screened, 65% exhibited cellulolytic enzymes, 44% exhibited pectinolytic activity while 27% and 17% possess enzyme systems for the degradation of protease and amylase, respectively. Galacturonic acid, which had been reported in previous work to be poorly assimilated by the ant fungus and also to have a negative effect on ants' survival, was assimilated by 64% and 79% of yeasts isolated from nests of A. texana and Acromyrmex respectively. Our results suggest that yeasts found in ant nests may participate in generation of nutrients and removal of potentially toxic compounds, thereby contributing to the stability of the complex microbiota found in the leaf-cutting ant nests.


Predictors of polypharmacy and off-label prescribing of psychotropic medications: a national survey of child and adolescent psychiatrists.
We employed a national survey of child psychiatrists to examine typical prescribing practices for children with anxiety, depression, and disruptive behavior disorders. We examined the extent to which polypharmacy and off-label prescribing occur in routine practice and the degree to which child characteristics, child psychiatrist characteristics, and medication availability may influence these prescribing practices. We found that child psychiatrists most often prescribed medications that were on-label according to U.S. Food and Drug Administration (FDA) guidelines, and that they were progressively less likely to choose medications with partial approval (i.e., medications having pediatric approval but not for the patient's age or problem type), and then medications with no pediatric approval. We also found that prescribing multiple concomitant medications was the norm. We employed best subsets regression to determine the best theoretically relevant predictors to explain polypharmacy and off-label prescribing and found that the best fitting model only included number of child diagnoses. These findings suggest that comorbidity is an important issue in the pharmacotherapy of children with mental health disorders and one that must be addressed in future clinical trials.


Fertility preservation for young adults, adolescents, and children with cancer.
Options for fertility preservation (FP) through cryopreservation methods are currently available for young adults, adolescents, and children. Guidelines for FP have been provided by international clinical societies, and emergency procedures aimed at FP have been implemented into clinical practice worldwide. In this article, we review the current data on clinical standards of emergency FP in patients who are facing gonadotoxic effects of cancer treatment, and we also describe the methods that are still under development, usually denoted as experimental. In Sweden, programmes for FP have been established at large university hospitals, thus covering the whole country. The Swedish publicly financed health care covers both assisted reproduction for treatment of infertility and the cryopreservation of gametes or gonadal tissue when there is a medical indication, such as the risk to become infertile due to oncologic treatment; hence the access to FP is ensured for the whole population. At our centre at Karolinska University Hospital in Stockholm, methods for FP have been offered since 1988. In this article, we also review the oncologic indications for FP in our patient cohort of >3000 individuals during the period 1988-2018.


Use of Native Yeast Strains for In-Bottle Fermentation to Face the Uniformity in Sparkling Wine Production.
The in-bottle fermentation of sparkling wines is currently triggered by few commercialized Saccharomyces cerevisiae strains. This lack of diversity in tirage yeast cultures leads to a prevalent uniformity in sensory profiles of the end products. The aim of this study has been to exploit the natural multiplicity of yeast populations in order to introduce variability in sparkling wines throughout the re-fermentation step. A collection of 133 S. cerevisiae strains were screened on the basis of technological criteria (fermenting power and vigor, SO2 tolerance, alcohol tolerance, flocculence) and qualitative features (acetic acid, glycerol and H2S productions). These activities allowed the selection of yeasts capable of dominating the in-bottle fermentation in actual cellar conditions: in particular, the performances of FX and FY strains (isolated in Franciacorta area), and OX and OY strains (isolated in Oltrepò Pavese area), were compared to those of habitually used starter cultures (IOC18-2007, EC1118, Lalvin DV10), by involving nine wineries belonging to the two Consortia of Appellation of Origin. The microbiological analyses of samples have revealed that the indigenous strains showed an increased latency period and a higher cultivability along the aging time than the commercial starter cultures do. Results of chemical analyses and sensory evaluation of the samples after 18 months sur lies have shown that significant differences (p < 0.05) were present among the strains for alcoholic strength, carbon dioxide overpressure and pleasantness, whereas they were not observed for residual sugars content, titratable acidity or volatile acidity. Indigenous S. cerevisiae exhibited comparable values respect to the commercial starter cultures. The ANOVA has also proven that the base wine formulation is a key factor, by significantly affecting (p < 0.01) some oenological parameters of wine, like alcoholic strength, volatile acidity, carbon dioxide overpressure, titratable acidity and dry extract. The use of native yeast strains for the re-fermentation step can be considered a convenient way for introducing differentiation to the final product without modifying the traditional technology. In a perspective of "precision enology," where the wine is designed on specific vine cultivars and microorganisms, this work underlines that exploring yeast biodiversity is a strategic activity to improve the production.


Analysis by x-ray microtomography of a granular packing undergoing compaction.
Several acquisitions of x-ray microtomography have been performed on a beads packing while it compacts under vertical vibrations. An image analysis allows to study the evolution of the packing structure during its progressive densification. In particular, the volume distribution of the pores reveals a large tail, compatible to an exponential law, which slowly reduces as the system gets more compact. This is quite consistent, for large pores, with the free volume theory. These results are also in very good agreement with those obtained by a previous numerical model of granular compaction.


Virulence Genes Content and Antimicrobial Resistance in Escherichia coli from Broiler Chickens.
A total of 121 E. coli strains were isolated from broiler chickens (96 extraintestinal pathogenic (ExPEC) strains from diseased broiler chickens and 25 avian fecal E. coli (AFEC) from healthy ones). Ten of the isolates (6 from diseased chickens and 4 from healthy birds) were serogrouped and 25 were examined for 4 virulence markers (tsh, papC, colV, and iss genes) as well as for their antimicrobial resistance. Five strains were nontypable and the rest were serotyped as follows: O86:K61 (2/5), O78:K80 (1/5), and O128:K67 (1/5) were recovered from diseased chickens, while O111:K58 strain (1/4) was isolated from healthy ones. The iss gene was found in 72.2% of the examined ExPEC strains in contrast to zero percentages (0%) in the AFEC strains, which may serve as a good marker for distinguishing APEC and its knocking out may help in creation of candidate vaccine that may prove sucess in elimination of infections in broiler chickens. Antimicrobial resistance patterns revealed a complete resistance to gentamicin, pefloxacin, amoxicillin, and enrofloxacin among examined strains followed by varying degrees of resistance for the rest of tested agents. The highest resistance was recorded against norfloxacin, in 24 isolates (96%), in contrast to the lowest resistance was recorded against colistin sulphate, in 14 strains (56%). These findings suggest the need for the prudent use of antimicrobials with broiler chickens and act as a warrant for the possibility of avian sources to transmit these resistant isolates to humans.


Cytochrome P450 enzyme RosC catalyzes a multistep oxidation reaction to form the non-active compound 20-carboxyrosamicin.
The cytochrome P450 enzyme RosC catalyzes a two-step, hydroxylation and alcohol oxidation, oxidation reaction to form the C-20 formyl group in the biosynthesis of a 16-membered macrolide antibiotic rosamicin produced by Micromonospora rosaria IFO13697. RosC is presumed to be involved in the formation of 20-carboxyrosamicin because it has been isolated from the culture broth of M. rosaria. Here, we confirmed that RosC has catalytic activity, with E. coli expressing RosC converting rosamicin into 20-carboxyrosamicin. Therefore, it was revealed that RosC is a multifunctional P450 that catalyzes a three-step oxidation reaction that leads to the formation of the hydroxyl group, formyl group and carboxyl group at C-20 on the macrolactone ring in the rosamicin biosynthetic pathway. Moreover, the cytochrome P450 enzyme TylI, which is involved in formation of the formyl group of a 16-membered macrolide antibiotic tylosin produced by Streptomyces fradiae ATCC 19609, also converted rosamicin into 20-carboxyrosamicin.


Pharmacokinetic approach to drug dosing in the aged.
Data in the literature show that there is a constant ratio of total body fluid to lean cell mass with increasing age (1.15 for males and 1.31 for females). Since the drug receptors usually are found in the tissues, and since cell mass and total body fluid apparently decrease at a constant rate, it would seem that the volume of distribution of drugs decreases proportionally with increasing age. Kidney function, as measured by the glomerular filtration rate and transport maximum, apparently decreases with increasing age according to zero-order kinetics. Based on these data, correction factors were established for the change in volume of distribution and renal functions with increasing age. Equations were derived for calculating the loading dose and maintenance dosage of drugs in multiple-dose therapy in females and males. Equations are presented for drugs following the minimal inhibitory concentration (MIC) pattern and the log dose-response pattern, respectively. The MIC pattern is recommended in the use of bacteriostatic drugs, for which it is essential to maintain recommended in the use of bacteriostatic drugs, for which it is essential to maintain during the entire course of therapy a minimum inhibitory concentration. The log dose-response pattern is recommended for bactericidal and antiarrhythmia drugs, for which it is essential to obtain an average therapeutic steady-state concentration. Based on this pharmacokinetic approach, it would seem that elderly patients, during multiple-dose therapy, are exposed to dose sizes that are too large if no correction is made.


Retrospective evaluation of the etiology and clinical characteristics of peripheral edema in dogs.
The prevalence and clinical characteristics of different etiologies of peripheral edema in dogs are unknown. To determine the prevalence of different etiologies of peripheral edema, describe clinical characteristics that vary among etiologies, and report survival times. Five hundred twenty-seven dogs with peripheral edema. Retrospective medical record review. Differences in clinical variables among etiology groups were assessed by Kruskal-Wallis testing with post hoc pairwise Dunn's testing and Chi-square testing with Monte Carlo simulation. The most common etiologies of peripheral edema in dogs were vasculitis (n = 193, 37%), lymphatic/venous obstruction (LVO; 114, 22%), and hypoalbuminemia (94, 18%). Right-sided congestive heart failure (R-CHF) was uncommon (25, 5%). Edema was localized in 377 (72%) dogs and generalized in 142 (27%) dogs, and hypoalbuminemia was more likely to cause generalized edema compared to LVO or vasculitis (P < .0001). Concurrent abdominal effusion (155, 29%) was more common than pleural (77, 15%) or pericardial (12, 2%) effusion. Abdominal and pleural effusion occurred more commonly in dogs with hypoalbuminemia or R-CHF compared to LVO or vasculitis (P < .0001). Distribution of edema, concurrent cavitary effusions, and clinicopathological data can help predict the underlying etiology of peripheral edema in dogs.


Induction and mechanism of apoptosis by hydroxycamptothecin in human Tenon's capsule fibroblasts.
We investigated apoptosis induced by hydroxycamptothecin (HCPT) in human Tenon's capsule using fibroblasts cultured from human Tenon's capsule (HTFs), and the mechanism of induction. HTFs were treated with 0-4 mg/L HCPT for 24 hours. Cell proliferation was measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptotic cells were analyzed by Hoechst 33258 stain. The mRNA and protein levels of caspase-3, -8, and -9 were detected by RT-PCR and Western blotting. By MTT assay, HCPT induced apoptosis in HTFs in a concentration- and time-dependent manner. Hoechst 33258 staining and transmission electron microscopy showed typical apoptotic morphology, such as condensed chromatin, irregular nuclei, and apoptotic body formation. The mRNA and protein levels of caspase-3 and caspase-9 were upregulated, while caspase-8 was unchanged. Z-VAD-FMK, a caspase inhibitor, inhibited the apoptosis of fibroblasts induced by HCPT. The expression levels of caspase-3 and caspase-9 were down-regulated after Z-VAD-FMK treatment. Caspase-3 and caspase-9 are important elements in regulating HCPT-induced apoptosis in HTFs.


Accurate assessment of amino acid mass isotopomer distributions for metabolic flux analysis.
Metabolic flux analysis based on stable-isotope labeling experiments and analysis of mass isotopomer distributions (MID) of cellular metabolites is a tool of great significance for metabolic engineering and study of human disease. This method relies on accurate and precise measurements of mass isotopomers by gas chromatography/mass spectrometry. To improve flux estimates, we assessed potential errors in determining MID of tert-butyldimethylsilyl-derivatized amino acids, which were attributed to (i) the choice of integration algorithm, (ii) concentration effects, and (iii) overlapping fragments. We report 29 amino acid fragments that are useful for flux analysis and another 18 fragments that should be rejected, most importantly Val-302, Leu-200, Leu-302, Ile-302, Ser-302, and Asp-316. In addition, we provide a protocol to minimize errors for determining MID to less than 0.4 mol % for accepted fragments.


X rays from relativistic electrons in a multilayer structure.
A dynamic diffraction theory of x-ray emission by relativistic electrons crossing a finite-thickness multilayer mirror (e.g., alternating layers of W and B4C) is developed, taking into account both diffracted transition and parametric radiation mechanisms. Simple formulas describing the characteristics of the total emission from either thin nonabsorbing or thick absorbing multilayers are derived. These formulas show that a multilayer radiator can be brighter and more efficient than crystalline ones. Good agreement between theory and prior experimental results is also shown. Thus the theory and its experimental verification demonstrate the possibility of a tunable quasimonochromatic x-ray source whose efficiency can be larger than that of other novel x-ray sources.


Further cases of lead poisoning from wine.
Lead intoxication has been reported to occur as a consequence of nonoccupational exposure, the source being mostly the leaching of lead from fluid containers in domestic use. Three such cases are described, for which the cause has been identified to be in the lining of the vat used to contain home-made wine. All cases are members of the same family.


Can n-3 PUFA reduce cardiac arrhythmias? Results of a clinical trial.
Dietary n-3 polyunsaturated fatty acids (PUFA) derived from fatty fish or fish oil may reduce the incidence of lethal myocardial infarction and sudden cardiac death. This might be due to a prevention of fatal cardiac arrhythmias. So far, however, only few clinical data are available being adequate to define indications for an antiarrhythmic treatment with n-3 PUFA. In a randomized, double-blind, placebo-controlled study 65 patients with cardiac arrhythmias without coronary heart disease or heart failure were subdivided into 2 groups. One group (n = 33) was supplemented with encapsulated fish oil (3g/day, equivalent to 1g/day of n-3 PUFA) over 6 months. The other group (n = 32) was given 3g/day of olive oil as placebo. In the fish oil group a decrease of serum triglycerides, total cholesterol, LDL cholesterol, plasma free fatty acids and thromboxane B2 as well as an increase of HDL cholesterol were observed. Moreover, a reduced incidence of atrial and ventricular premature complexes, couplets and triplets were documented. Accordingly, higher grades of Lown's classification switched to lower grades at the end of the dietary period. No changes were seen in the placebo group. The data indicate an antiarrhythmic action of n-3 PUFA under conditions of clinical practice which might help to explain the reduced incidence of fatal myocardial infarction and sudden cardiac death in cohorts on a fish-rich diet or supplemented with n-3 PUFA. Further studies elucidating the possible link between the reduced incidence of cardiac arrhythmias and sudden cardiac death by dietary intake of n-3 PUFA are warranted.


Analysis of the comprehensive needs of primary caregivers of hospitalized colorectal cancer patients and characteristics analysis of high comprehensive needs population.
To identify the care needs of primary caregivers of colorectal cancer (CRC) patients and specify the characteristics of high-needs caregivers. A cross-sectional survey was conducted on the primary caregivers of CRC patients using the Comprehensive Needs Assessment Tool in Cancer Caregivers. The care needs and the characteristics of caregivers with high needs were identified using the Chi-square test and Logistic regression. The results of the survey of 364 primary caregivers of CRC patients showed that the top 2 dimensions of caregiver needs were the healthcare staff and the information dimension. The characteristics of caregivers with high demand for healthcare staff included on-the-job, a family per capita monthly income of <4000 yuan, and the CRC patients they took care of paid medical expenses through self-pay/public expense/rural insurance. The characteristics of caregivers with high information needs included living in the city, on-the-job, a family per capita monthly income of <4000 yuan, and the CRC patients they took care of paid medical expenses through self-pay/public expense/rural insurance. In clinical settings, the information needs of primary caregivers of CRC patients should be given due attention. Particular attention should be paid to the primary caregivers of CRC patients who live in cities, are on-the-job, have a per capita monthly income of <4000 yuan, and pay medical expenses through self-pay/public/rural insurance.


Fc Gamma Receptors and Complement Component 3 Facilitate Anti-fVIII Antibody Formation.
Anti-factor VIII (fVIII) alloantibodies, which can develop in patients with hemophilia A, limit the therapeutic options and increase morbidity and mortality of these patients. However, the factors that influence anti-fVIII antibody development remain incompletely understood. Recent studies suggest that Fc gamma receptors (FcγRs) may facilitate recognition and uptake of fVIII by recently developed or pre-existing naturally occurring anti-fVIII antibodies, providing a mechanism whereby the immune system may recognize fVIII following infusion. However, the role of FcγRs in anti-fVIII antibody formation remains unknown. In order to define the influence of FcγRs on the development of anti-fVIII antibodies, fVIII was injected into WT or FcγR knockout recipients, followed by evaluation of anti-fVIII antibodies. Anti-fVIII antibodies were readily observed following fVIII injection into FcγR knockouts, with similar anti-fVIII antibody levels occurring in FcγR knockouts as detected in WT mice injected in parallel. As antibodies can also fix complement, providing a potential mechanism whereby anti-fVIII antibodies may influence anti-fVIII antibody formation independent of FcγRs, fVIII was also injected into complement component 3 (C3) knockout recipients in parallel. Similar to FcγR knockouts, C3 knockout recipients developed a robust response to fVIII, which was likewise similar to that observed in WT recipients. As FcγRs or C3 may compensate for each other in recipients only deficient in FcγRs or C3 alone, we generated mice deficient in both FcγRs and C3 to test for potential antibody effector redundancy in anti-fVIII antibody formation. Infusion of fVIII into FcγRs and C3 (FcγR × C3) double knockouts likewise induced anti-fVIII antibodies. However, unlike individual knockouts, anti-fVIII antibodies in FcγRs × C3 knockouts were initially lower than WT recipients, although anti-fVIII antibodies increased to WT levels following additional fVIII exposure. In contrast, infusion of RBCs expressing distinct alloantigens into FcγRs, C3 or FcγR × C3 knockout recipients either failed to change anti-RBC levels when compared to WT recipients or actually increased antibody responses, depending on the target antigen. Taken together, these results suggest FcγRs and C3 can differentially impact antibody formation following exposure to distinct alloantigens and that FcγRs and C3 work in concert to facilitate early anti-fVIII antibody formation.


Surface charge interactions of the FMN module govern catalysis by nitric-oxide synthase.
The FMN module of nitric-oxide synthase (NOS) plays a pivotal role by transferring NADPH-derived electrons to the enzyme heme for use in oxygen activation. The process may involve a swinging mechanism in which the same face of the FMN module accepts and provides electrons during catalysis. Crystal structure shows that this face of the FMN module is electronegative, whereas the complementary interacting surface is electropositive, implying that charge interactions enable function. We used site-directed mutagenesis to investigate the roles of six electronegative surface residues of the FMN module in electron transfer and catalysis in neuronal NOS. Results are interpreted in light of crystal structures of NOS and related flavoproteins. Neutralizing or reversing the negative charge of each residue altered the NO synthesis, NADPH oxidase, and cytochrome c reductase activities of neuronal NOS and also altered heme reduction. The largest effects occurred at the NOS-specific charged residue Glu(762). Together, the results suggest that electrostatic interactions of the FMN module help to regulate electron transfer and to minimize flavin autoxidation and the generation of reactive oxygen species during NOS catalysis.


Effect of orthographic processes on letter identity and letter-position encoding in dyslexic children.
The ability to identify letters and encode their position is a crucial step of the word recognition process. However and despite their word identification problem, the ability of dyslexic children to encode letter identity and letter-position within strings was not systematically investigated. This study aimed at filling this gap and further explored how letter identity and letter-position encoding is modulated by letter context in developmental dyslexia. For this purpose, a letter-string comparison task was administered to French dyslexic children and two chronological age (CA) and reading age (RA)-matched control groups. Children had to judge whether two successively and briefly presented four-letter strings were identical or different. Letter-position and letter identity were manipulated through the transposition (e.g., RTGM vs. RMGT) or substitution of two letters (e.g., TSHF vs. TGHD). Non-words, pseudo-words, and words were used as stimuli to investigate sub-lexical and lexical effects on letter encoding. Dyslexic children showed both substitution and transposition detection problems relative to CA-controls. A substitution advantage over transpositions was only found for words in dyslexic children whereas it extended to pseudo-words in RA-controls and to all type of items in CA-controls. Letters were better identified in the dyslexic group when belonging to orthographically familiar strings. Letter-position encoding was very impaired in dyslexic children who did not show any word context effect in contrast to CA-controls. Overall, the current findings point to a strong letter identity and letter-position encoding disorder in developmental dyslexia.


Ultrastructural study of internalization and recycling of antigen by antigen presenting cells.
The evidence which suggests that a helper T (Th) cell recognizes a processed form of a soluble protein antigen in association with a class II MHC antigen on the surface of an antigen presenting cell (APC) has raised many questions and much controversy. A major question that remains unanswered is what is the cellular site(s) and mechanism(s) in which such an antigen is handled by an APC. The controversy relates to the issue of whether a protein antigen is required to be processed by an APC before it is presented to a Th cell. A currently favored hypothesis of antigen presentation, which stems mainly from analyses of T cell reactivity to peptides of protein antigens, is that such antigens are internalized by an APC, processed intracellularly, recycled to the cell surface and then presented to Th cells. As a first test of this hypothesis, we reasoned that although it is currently difficult to study the biochemistry of antigen processing, it is possible to study whether a protein antigen is internalized by an APC and recycled to its surface. In this report, colloidal gold conjugates of pork insulin (PI-Au), a tryptic peptide of pork insulin lacking the insulin receptor-binding portion of the molecule (TI-Au), myoglobin (MYO-Au), and apomyoglobin (APO-Au) were used to follow the pathway(s) and kinetics of antigen internalization and recycling in TA3 B hybridoma cells. Transmission electron micrographs of the routes followed by the PI-Au and TI-Au conjugates suggest that these antigens are internalized and recycled to the surface of an antigen presenting cell within 2-4 hr. In contrast, the patterns obtained for MYO-Au and APO-Au suggest that either the internalization of these antigens serves to channel them into a degradative pathway or that the kinetics of recycling of these antigens is slower. The two types of patterns observed may not be mutually exclusive and the purpose of internalization may vary, depending on the nature of the antigen. These data represent the first analysis of the kinetics and pathways of internalization and recycling of an antigen by an APC. It is impossible to formally prove that the pathway we have demonstrated is the one responsible for processing for antigen presentation. Nevertheless, these results support the notion that a protein antigen is handled intracellularly by an APC and recycled to the surface before it is presented to a Th cell.


Identified neurons in an insect embryo: the pattern of neurons innervating the metathoracic leg of the locust.
The population of motorneurons which send axons to the metathoracic leg of the locust embryo has been stained by a cobalt backfilling technique. Embryogenesis lasts 11 days and an adultlike distribution of motorneuron cell bodies is seen as early as day 6: Several identified adult motorneurons can be recognized in the embryo. The total number of filled cells, the overall distribution of stained cell bodies, and the relative positions of identified neuron cell bodies do not change between 6 days and hatching. No motorneurons are stained which are clearly not leg motorneurons, and an adult pattern of axon branching at the level of peripheral nerve roots is already present at day 6. These observations provide information about the timing of motorneuron production and motor axon growth into the embryonic limb. The development of central dendritic arborizations can also be followed. The results are discussed with respect to mechanisms for neuron determination and differentiation.


Occupational noise in rice mills.
A major occupational hazard for the workers in rice mills is the noise during the operation of various machines. A noise survey was conducted in the workrooms of eight renowned rice mills of the north-eastern region of India established during the period between 1980 and 1985. The rice mills were selected on the basis of the outcome of a walk-through noise survey involving several rice mills of the region. A noise survey map of each rice mill was drawn to identify the predominant noise sources and the causes of high noise in the workrooms of the rice mill. The sound-pressure level (SPL) in the workrooms of the rice mill varied from 78 to 92 dBA. The paddy cleaner, rubber roll sheller, compartment separator, rice cleaner, auxiliary sieve shaker and an electric motor without enclosure were found to be the predominant noise sources in the workrooms of the mill. The causes of high noise in the rice mills may be attributed to the use of a long flat belt drive, crank-and-pitman mechanism, absence of an electric motor enclosure, poor machine maintenance and inadequate acoustic design of the workroom of the rice mill. About 26% of the total labourers were found to be exposed to higher levels of noise than 85 dBA. Subjective response indicated that about 26% of the total labourers felt noise interferes in their work and about 49% labourers were of opinion that noise interferes with their conversation. Noise from machines in the rice mills was found to be the major occupational hazard for the rice mill workers. The predominant noise sources need to be identified and the causes of high noise need to be studied to undertake the appropriate measures to reduce the noise level. To identify the predominant noise sources and their distributions in rice mills, to study the causes of high levels of noise in rice mills and to examine the response of the workers towards noise. A noise survey was conducted in eight renowned rice mills of the north-eastern region of India. The mills were selected based on a walk-through survey conducted for the identification of rice mills with high noise. A noise survey map of each rice mill was collected by following the guidelines of Canadian Centre for Occupational Health and Safety (CCOHS). The distribution of high noise in rice mills was studied and the causes of high noise were identified. The subjective response to noise in rice mills was assessed by conducting personal interview with all the workers of the rice mills using a structured form. The guidelines of CCOHS were followed during the noise survey. A sound level meter (SLM; Model-824) was used to record the noise level at each grid point marked at 1 m x 1 m. SPL in weighting scale "A" and the noise spectrum were recorded at each grid point for 30 s and data were stored in SLM. A noise survey map of equivalent SPL was drawn for each rice mill by drawing contour lines on the sketch of the rice mill between the points of equal SPL. The floor area in the rice mill where SPL exceeded 85 dBA was identified from the noise survey map of each rice mill to determine the causes of high levels of noise. In order to study the variation in SPL in the workroom of the rice mill throughout the shift, equivalent SPL was measured at six locations in each rice mill. The subjective response to noise in rice mills was assessed by conducting personal interview with all the workers of the rice mills using a structured form. Demographic information, nature of work, working hours, rest period, experience of working in mill, degree of noise annoyance, activity interference, and psychological and physiological effects of machine noise on the worker were asked during the interview. Nil. The noise survey in eight select rice mills of the major paddy-growing regions of India revealed that the workrooms of five rice mills had SPL more than 85 dBA in the locations where workers were engaged for most of the time. The predominant noise sources in the rice mills were paddy cleaner, rubber roll sheller, compartment separator, rice cleaner, sieve shaker and an electric motor without enclosure. The causes of high noise in the rice mills may be due to the use of a long flat belt drive, crank-and-pitman mechanism, absence of an electric motor enclosure, poor machine maintenance and inadequate acoustic design of the workroom in the rice mill. In general, a well-maintained rice mill with each machine being run individually using an electric motor produced less noise than that being run using a single electric motor along with flat belt drives. The normal working period in the rice mill was 48 h/week and it was 56 h/week during the peak season of rice milling. About 26% of the total workers were exposed to noise of more than 85 dBA. Subjective response indicated that about 26% of the total workers felt noise interferes in their work and about 49% workers were of opinion that noise interferes with their conversation. The workers in the rice mills are exposed to high noise, which will have detrimental effect on their health. Apart from undertaking appropriate noise control measures, preventive maintenance of machines needs to be given due importance in all the rice mills.


Trichloroacetyl chloride, CCl3COCl, as an alternative Cl atom precursor for laboratory use and determination of Cl atom rate coefficients for n-CH2[double bond, length as m-dash]CH(CH2)xCN (x = 3-4).
An investigation of CCl3COCl was conducted with the purpose of using the compound as an alternative Cl atom precursor in laboratory settings. CCl3COCl can be used with or without O2 as a source of Cl atoms and photolysis studies in air and N2 diluent displayed COCl2 and CO as being the major photolysis products. Relative rate studies were performed to determine the Cl atom rate coefficients for reaction with CH3Cl and C2H2 and the results were in agreement with literature values. Cl atom rate coefficients for reaction with n-CH2[double bond, length as m-dash]CH(CH2)3CN and n-CH2[double bond, length as m-dash]CH(CH2)4CN were determined as (2.95 ± 0.58) × 10-10 and (3.73 ± 0.60) × 10-10 cm3 molecule-1 s-1, respectively. CCl3COCl requires UV-C irradiation, so not all molecules are feasible for use in e.g. relative rate studies. Furthermore, it is recommended to perform experiments with O2 present, as this minimizes IR feature disturbance from product formation.


[Iodine 131: biokinetics, radiation exposure and risk assessment with reference to the reactor accident at Chernobyl].
Following the reactor accident at Chernobyl, this paper describes the biokinetics of radioiodine in man and discusses the radiation exposure resulting from intake of 131I. The risk of radiation-induced thyroid carcinomas and of congenital abnormalities is evaluated. Assuming a linear dose/risk relationship, one can calculate an increase in mortality from thyroid carcinomas amongst children in southern Germany of 100 to 101 per million children. For adults in southern Germany, and for the rest of the population in Germany, the figure is considerably lower. Gonadal dose from the 131I released is so small, compared with the annual natural radiation exposure, that it is not appropriate to discuss genetic effects.


Chaotic saddles and interior crises in a dissipative nontwist system.
We consider a dissipative version of the standard nontwist map. Nontwist systems present a robust transport barrier, called the shearless curve, that becomes the shearless attractor when dissipation is introduced. This attractor can be regular or chaotic depending on the control parameters. Chaotic attractors can undergo sudden and qualitative changes as a parameter is varied. These changes are called crises, and at an interior crisis the attractor suddenly expands. Chaotic saddles are nonattracting chaotic sets that play a fundamental role in the dynamics of nonlinear systems; they are responsible for chaotic transients, fractal basin boundaries, and chaotic scattering, and they mediate interior crises. In this work we discuss the creation of chaotic saddles in a dissipative nontwist system and the interior crises they generate. We show how the presence of two saddles increases the transient times and we analyze the phenomenon of crisis induced intermittency.


Opiate-induced analgesia: contributions from mu, delta and kappa opioid receptors mouse mutants.
The three opioid receptors, mu, delta and kappa all mediate analgesia, and knockout mice with opioid receptor deletion have proven unique tools to investigate in vivo opioid pharmacology. Since a few years, a number of new mouse lines have been engineered, with several distinct mutations of the mu receptor, to assess the role of specific amino acid residues or peptidic sequences of this receptor in analgesia and tolerance. The analysis of analgesia in mice deleted in kappa receptor and triple mu/delta/kappa receptor knockout mice have provided advances in opioid-induced analgesia. Also, the global and conditional deletion of the delta receptor in peripheral nociceptive neurons has revealed the participation of the targeted receptors in opioid-induced analgesia. Another approach for the study of opioid receptors is the visualization of these receptors in vivo, by engineering of knock-in mice with fluorescently tagged receptors. A mouse line with a fluorescent delta receptor has allowed live imaging of this receptor in behavioral paradigms and first studies on ligand-biased agonism at this receptor in vivo. The studies with mutant mouse lines for opioid receptors, combined with novel molecular and pharmacological approaches, will allow to develop novel strategies for opioid-based analgesia. This review summarizes the different genetically modified mouse lines for opioid receptors as well as the data and concepts inferred from analgesia results on these mutant mouse lines.


Some aspects of sodium nitroprusside reaction with human erythrocytes.
Sodium nitroprusside is an excellent agent for lowering blood pressure in hypertensive emergencies, for producing controlled hypotension during anesthesia, and for treating acute myocardial infarction and chronic heart failure. Toxic effects of this drug have been reported and above-normal cyanide and thiocyanate concentrations have been observed in the blood of a small proportion of subjects receiving nitroprusside. Nitrite, syanide, and thiocyanate are major decomposition products of nitroprusside, resulting from an in vitro reaction with human blood. On the basis of the conversion mechanism, we suggest that, in the cyanide/thiocyanate cycle, only cyanide is directly responsible for any acute toxicity attributed to sodium nitroprusside. In this work, the extent of cyanide production by erythrocytes in vitro was studied. The rate of detoxification of cyanide by human liver in vitro was experimentally determined and data from a search for a possible inhibitor of the nitroprusside/hemoglobin reaction are presented. Also, the possible mechanism of the nitroprusside/hemoglobin reaction is discussed.


A stoichiometric perspective of the effect of herbivore dung on ecosystem functioning.
Ungulate herbivores play a prominent role in maintaining the tree-grass balance in African savannas. Their top-down role through selective feeding on either trees or grasses is well studied, but their bottom-up role through deposition of nutrients in dung and urine has been overlooked. Here, we propose a novel concept of savanna ecosystem functioning in which the balance between trees and grasses is maintained through stoichiometric differences in dung of herbivores that feed on them. We describe a framework in which N2-fixing trees and grasses, as well as ungulate browsing and grazing herbivores, occupy opposite positions in an interconnected cycle of processes. The framework makes the testable assumption that the differences in dung N:P ratio among browsers and grazers are large enough to influence competitive interactions between N2-fixing trees and grasses. Other key elements of our concept are supported with field data from a Kenyan savanna.


Effect of vitamin B6 deficiency on S-adenosylhomocysteine hydrolase activity as a target point for methionine metabolic regulation.
The objective of this study was to clarify the relationship between the accumulation of S-adenosylhomocysteine (SAH) and the change in the SAH hydrolase activity in vitamin B6 (B6). Male Wistar rats were fed a control diet (control and pair-fed groups) or B6-free diet (B6-deficient group) for 5 wk. Although the SAH-synthetic activity of SAH hydrolase significantly increased in the B6-deficient group, SAH-hydrolytic activity of SAH hydrolase showed no significant difference in the liver among the three groups. On the other hand, SAH hydrolase mRNA in the liver did not show any significant change. Thus, the accumulation of SAH would be due to the increased SAH-synthetic activity of SAH hydrolase. The disturbed methionine metabolism by B6-deficiency, such as a significant increase of plasma homocysteine, might induce the activation of SAH hydrolase in the direction of SAH synthesis.


Avascular necrosis of the femoral head after femoral neck fracture.
Trauma-induced avascular necrosis of the femoral head represents the most common femoral head aseptic necrosis. An alteration in blood supply to the femoral head is the cause of the vascular necrosis. Another mechanism in the genesis of femoral head necrosis is the tamponade effect. Femoral head necrosis may be asymptomatic for a long time, even in patients in whom late segmental collapse already is present. Radiography does not allow diagnostic reliability until 6 months after fracture. The presence of a low signal intensity band away from the fracture line on magnetic resonance images clearly delimits the necrotic area. Once segmental collapse has developed, the diagnosis becomes simple using plain radiographs. The treatment of established femoral necrosis complicating fractures of the upper end of the femur is approached as a therapeutic problem lacking an optimal solution. The main therapeutic options are femoral head-preserving procedures and joint reconstruction. Among the procedures that preserve the femoral head are joint unloading, femoral head core decompression, electric stimulation, osteotomy, and bone grafting. Joint reconstruction procedures including cup arthroplasty, hemiresurfacing, total hip resurfacing, femoral head replacement, femoral head endoprosthesis, and total arthroplasty will be reviewed.


Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma.
Complete surgical resection is the mainstay of treatment for patients with adrenocortical cancer (ACC). Use of laparoscopy has been questioned in patients with ACC. This study compares the outcomes of patients undergoing laparoscopic versus open resection (OR) for ACC. A retrospective review (2003-2008) of patients with ACC was performed. Data were collected for demographics, operative and pathologic data, adjuvant therapy, and outcome. Chi-square analysis was performed. Eighty-eight patients (66% women; median age, 47 (range, 18-81) years) were identified. Seventeen patients underwent laparoscopic adrenalectomy (LA). Median tumor size of those who underwent LA was 7.0 (range, 4-14) cm versus 12.3 (range, 5-27) cm for OR. Recurrent disease in the laparoscopic group occurred in 63% versus 65% in the open group. Mean time to first recurrence for those who underwent LA was 9.6 months (+/-14) versus 19.2 months (+/-37.5) in the open group (p < 0.005). Fifty percent of patients who underwent LA had positive margins or notation of intraoperative tumor spill versus 18% of those who underwent OR (p = 0.01). Local recurrence occurred in 25% of the laparoscopic group versus 20% in the open group (p = 0.23). Mean follow-up was 36.5 months (+/-43.6). ACC continues to be a deadly disease, and little to no progress has been made from a treatment standpoint in the past 20 years. Careful and complete surgical resection is of the utmost importance. Although feasible in many cases and tempting, laparoscopic resection should not be attempted in patients with tumors suspicious for or known to be adrenocortical carcinoma.


Use of the absolute phase in frequency modulated continuous wave plasma reflectometry.
In frequency modulated continuous wave reflectometry, used for density profile measurement in fusion plasmas, it is usual to measure the beat frequency between the launched wave and the reflected wave, and from this to calculate the position of the reflecting layer in the plasma. The absolute phase of the beat signal is usually neglected. The reason is that the phase shift between sweeps is usually comparable with or more than 2pi, leading to an ambiguity that is impossible to resolve. However, recent observations on the MAST tokamak have shown that, under quiet plasma conditions (this term has to be defined), the phase shift between sweeps is small compared with 2pi and the phase ambiguity can be readily resolved. The reflectometer signal is then being analyzed as an interferometer signal would normally be, and there is a substantial improvement in spatial resolution. The method is illustrated by application to small edge localized mode precursor and allows what is believed to be the first quantitative measurement of the displacement of the plasma boundary by such a precursor mode. The errors in both the absolute phase measurement and the more conventional frequency measurement are also estimated.


Identification and evaluation of circulating small extracellular vesicle microRNAs as diagnostic biomarkers for patients with indeterminate pulmonary nodules.
The identification of indeterminate pulmonary nodules (IPNs) following a low-dose computed tomography (LDCT) is a major challenge for early diagnosis of lung cancer. The inadequate assessment of IPNs' malignancy risk results in a large number of unnecessary surgeries or an increased risk of cancer metastases. However, limited studies on non-invasive diagnosis of IPNs have been reported. In this study, we identified and evaluated the diagnostic value of circulating small extracellular vesicle (sEV) microRNAs (miRNAs) in patients with IPNs that had been newly detected using LDCT scanning and were scheduled for surgery. Out of 459 recruited patients, 109 eligible patients with IPNs were enrolled in the training cohort (n = 47) and the test cohort (n = 62). An external cohort (n = 99) was used for validation. MiRNAs were extracted from plasma sEVs, and assessed using Small RNA sequencing. 490 lung adenocarcinoma samples and follow-up data were used to investigate the role of miRNAs in overall survival. A circulating sEV miRNA (CirsEV-miR) model was constructed from five differentially expressed miRNAs (DEMs), showing 0.920 AUC in the training cohort (n = 47), and further identified in the test cohort (n = 62) and in an external validation cohort (n = 99). Among five DEMs of the CirsEV-miR model, miR-101-3p and miR-150-5p were significantly associated with better overall survival (p = 0.0001 and p = 0.0069). The CirsEV-miR scores were calculated, which significantly correlated with IPNs diameters (p < 0.05), and were able to discriminate between benign and malignant PNs (diameter ≤ 1 cm). The expression patterns of sEV miRNAs in the benign, adenocarcinoma in situ/minimally invasive adenocarcinoma, and invasive adenocarcinoma subgroups were found to gradually change with the increase in aggressiveness for the first time. Among all DEMs of the three subgroups, five miRNAs (miR-30c-5p, miR-30e-5p, miR-500a-3p, miR-125a-5p, and miR-99a-5p) were also significantly associated with overall survival of lung adenocarcinoma patients. Our results indicate that the CirsEV-miR model could help distinguish between benign and malignant PNs, providing insights into the feasibility of circulating sEV miRNAs in diagnostic biomarker development. Chinese Clinical Trials: ChiCTR1800019877. Registered 05 December 2018, https://www.chictr.org.cn/showproj.aspx?proj=31346 .


Flavonoids in oral cancer prevention and therapy.
Oral cancer, representing all the malignancies arising in the oral cavity, is the eighth most diffused neoplasm worldwide. Despite therapeutic improvements, its survival rate has not changed significantly over the past few decades, with a 5-year survival rate slightly above 50%. In this context, a search for new therapeutic strategies is mandatory. Flavonoids, polyphenolic compounds derived from plants, have a broad spectrum of biological activities, including antioxidant and anticancer. They have been proved to counteract the growth of several types of cancer through multiple mechanisms including the inhibition of cell cycle progression, apoptosis induction, and the modulation of intracellular pathways. Because of their multiple biological activities and their safe toxicological profile, flavonoids have been studied widely in the last decade as potential leads for anticancer therapy. Several studies have reported different flavonoid effects according to cancer cell type. In the present review, therefore, we have evaluated the data available on the effect of flavonoids on oral cancer, with the aim of identifying the molecular mechanisms underlying their potential anticancer properties.


Halogenated triphenylgallium and -indium in frustrated Lewis pair activations and hydrogenation catalysis.
The Lewis acids Ga(C6F5)3, In(C6F5)3 and Ga(C6Cl5)3 are prepared and their Lewis acidity has been probed experimentally and computationally. The species Ga(C6F5)3 and In(C6F5)3 in conjunction with phosphine donors are shown to heterolytically split H2 and catalyse the hydrogenation of an imine. In addition, frustrated Lewis pairs (FLPs) derived from Ga(C6F5)3 and In(C6F5)3 and phosphines react with diphenyldisulfide to phosphoniumgallates or indates of the form [tBu3PSPh][PhSE(C6F5)3] and [tBu3PSPh][(μ-SPh)(E(C6F5)3)2] (E = Ga, In). The potential of the FLPs based on Ga(C6F5)3, In(C6F5)3 and Ga(C6Cl5)3 and phosphines is also shown in reactions with phenylacetylene to give pure or mixtures of the products [tBu3PH][PhCCE(C6X5)3] and R3P(Ph)C=C(H)E(C6X5)3 A number of these species are crystallographically characterized. The implications for the use of these species in FLP chemistry are considered.This article is part of the themed issue 'Frustrated Lewis pair chemistry'.


Effectiveness of platinum-based adjuvant chemotherapy for muscle-invasive bladder cancer: A weighted propensity score analysis.
To evaluate the clinical benefit of adjuvant platinum-based chemotherapy after radical cystectomy for muscle-invasive bladder cancer in routine clinical practice. The present observational study was carried out to compare the effectiveness of adjuvant chemotherapy versus observation post-radical cystectomy in patients with clinically muscle-invasive bladder cancer. Cancer-specific survival and overall survival between the adjuvant chemotherapy group and radical cystectomy alone group were compared using Kaplan-Meier method and log-rank test. After adjusting for background factors using propensity score weighting, differences in cancer-specific survival and overall survival between these two groups were compared. Subgroup analyses by the pathological characteristics were carried out. In total, 322 patients were included in the present study. Of these, 23% received adjuvant chemotherapy post-radical cystectomy. Clinicopathological characteristics showed that patients in the adjuvant chemotherapy group were pathologically more advanced and were at higher risk than the radical cystectomy alone group. In the unadjusted population, although it is not significant, the adjuvant chemotherapy group had lower overall survival (3-year overall survival; 61.5% vs 73.6%, HR 1.33, P = 0.243, log-rank test, adjuvant chemotherapy vs radical cystectomy alone). In the weighted propensity score analysis, although it is not significant, the adjuvant chemotherapy group were superior to radical cystectomy alone groups (overall survival: HR 0.65, 95% CI 0.39-1.09, P = 0.099, log-rank test, adjuvant chemotherapy vs radical cystectomy alone). Subgroup analyses showed that adjuvant chemotherapy significantly reduced the hazard ratio of overall survival and cancer-specific survival in the ≥pT3, pN+, ly+ and v+ subgroups. Platinum-based adjuvant chemotherapy might be associated with increased cancer-specific survival and overall survival in patients with high-risk invasive bladder cancer.


Retroperitoneal malignancy masquerading as ureteric colic.
This study reviews 6 patients who were referred with severe loin pain radiating to the groin and in whom a presumptive diagnosis of ureteric colic was made. Of these, 3 patients were found to have carcinoma of the pancreas and the remaining 3 had retroperitoneal lymph node metastases. Retroperitoneal malignancies rarely present with loin pain, but this diagnosis should be considered in patients with long-standing loin pain in whom an obvious diagnosis is not apparent.


Autologous bone-marrow transplantation: host effects of high-dose BCNU.
Thirty-five patients with solid tumors received 44 courses of bis-chlorethylnitrosourea (BCNU) at doses ranging between 600 and 1,400 mg/m2 with cryopreserved or fresh autologous bone-marrow support. Eight patients treated at 600 mg/m2 received no bone-marrow support for their first course of BCNU. Maximum follow-up was 25 months (median, four months). Myelosuppression was severe and dose related but was less prolonged in the marrow-supported groups (p = 0.01) and was not dose limiting. Myelosuppression-related toxicity of infection and hemorrhage occurred in 21 (47%) of 44 courses of treatment. Pulmonary toxicity occurred in seven of 35 patients; abnormal liver function occurred in 18 of 30 patients greater than one month from treatment; and central nervous system symptoms that may have been drug related occurred in six of 35 patients. There was no renal or cardiac toxicity. Except for myelosuppression, toxicity was not dose related. Treatment-related deaths included four with pulmonary toxicity, two with liver toxicity, sepsis in four, and gastrointestinal tract toxicity in one patient. We conclude that the limiting side effect of high-dose BCNU (greater than or equal to 600 mg/m2) is visceral toxicity; the extent of myelosuppression is shortened by the infusion of bone marrow, whether cryopreserved or fresh; and marked tumor regression can be achieved with high-dose BCNU.


Children's Intergroup Relations and Attitudes.
The existence of warm, intimate, supportive, and egalitarian relationships between members of differing social outgroups is likely, at the societal level, to facilitate cooperation and cohesion, and at the individual level, to promote positive social, educational, and occupational outcomes. The developmental pathway from intergroup contact to intergroup attitudes as it operates among children is not, however, well understood. In our chapter, we review and integrate selected social and developmental science related to intergroup relations and attitudes with the goal of proposing a conceptual model of the pathway from intergroup contact to positive intergroup attitudes among youth.


Political liberalism and religious claims: Four blind spots.
This article gives an overview of 4 important lacunae in political liberalism and identifies, in a preliminary fashion, some trends in the literature that can come in for support in filling these blind spots, which prevent political liberalism from a correct assessment of the diverse nature of religious claims. Political liberalism operates with implicit assumptions about religious actors being either 'liberal' or 'fundamentalist' and ignores a third, in-between group, namely traditionalist religious actors and their claims. After having explained what makes traditionalist religious actors different from liberal and fundamentalist religious actors, the author develops 4 areas in which political liberalism should be pushed further theoretically in order to correctly theorize the challenge which traditional religious actors pose to liberal democracy. These 4 areas (blind spots) are: (1) the context of translation; (2) the politics of exemptions; (3) the multivocality of theology; and (4) the transnational nature of norm-contestation.


Can the Dielectric Constant of Fullerene Derivatives Be Enhanced by Side-Chain Manipulation? A Predictive First-Principles Computational Study.
The low efficiency of organic photovoltaic (OPV) devices has often been attributed to the strong Coulombic interactions between the electron and hole, impeding the charge separation process. Recently, it has been argued that by increasing the dielectric constant of materials used in OPVs, this strong interaction could be screened. In this work, we report the application of periodic density functional theory together with the coupled perturbed Kohn-Sham method to calculate the electronic contribution to the dielectric constant for fullerene C60 derivatives, a ubiquitous class of molecules in the field of OPVs. The results show good agreement with experimental data when available and also reveal an important undesirable outcome when manipulating the side chain to maximize the static dielectric constant: in all cases, the electronic contribution to the dielectric constant decreases as the side chain increases in size. This information should encourage both theoreticians and experimentalists to further investigate the relevance of contributions to the dielectric constant from slower processes like vibrations and dipolar reorientations for facilitating the charge separation, because electronically, enlarging the side chain of conventional fullerene derivatives only lowers the dielectric constant, and consequently, their electronic dielectric constant is upper bound by the one of C60.


[Depression and risk factors in patients with Crohn's disease].
This study was conducted to determine the risk factors among patients with depression with Crohn's disease. Data were collected by questionnaire from 276 patients who were diagnosed with Crohn's disease at a tertiary hospital located in Seoul. Measurements included patients' demographic characteristics, clinical characteristics, depression level, and health-related quality of life. Data were analyzed using t-test, χ²-test, Wilcoxon rank sum test, and logistic regression analyses. The incidence rate of depression (BDI-II ≥ 14 scores) was 31.9% (n=88). Univariate analysis revealed that being a woman, school graduation status, economic status (low), BMI(<18.5 Kg/m²), disease duration (≥ 3 years), CDAI (≥ 150 scores), frequency of hospital admission (≥ 2), extra-intestinal manifestation (arthralgia, stomatitis), administration of 5-aminosalicylic acid, and disease related quality of life (SIBDQ<50 scores) were associated with depression. Multivariate analysis revealed that economic status (low), school graduation status, and quality of life (SIBDQ<50 scores) were more likely to report high level of depression. Future research should consider managing depression as an essential component of comprehensive care for patients with Crohn's disease. In addition, further research is needed to develop strategies to better improve quality of life among patients with Crohn's disease who are depressed.


Differential roles for beta2 integrins in experimental autoimmune bullous pemphigoid.
Bullous pemphigoid (BP) is an autoimmune disease associated with autoantibodies directed against the hemidesmosomal antigens anti-BP230 and anti-B180. Neonatal mice injected with rabbit anti-mouse BP180 (mBP10) IgG develop a BP-like disease. Complement, immune complexes, mast cells, and neutrophils play a key role in subepidermal blistering in this animal model. In this study we investigated the role of beta2 integrins in experimental BP. Wild-type (WT) mice pretreated with neutralizing antibody against CD11a (LFA-1), CD11b (Mac-1), CD11a plus CD11b, or CD18 alone failed to develop BP when injected with pathogenic anti-mBP180 IgG. This was associated with a significant reduction in neutrophil accumulation in neutralizing antibody-treated mice. Mac-1-deficient (Mac-1 knockout [KO]) mice were resistant to experimental BP despite normal complement deposition and mast cell and neutrophil degranulation. Neutrophil infiltration in Mac-1 KO mice was severely impaired at 24 hours. However, more neutrophils accumulated in the skin of Mac-1 KO mice compared with WT mice at early time points (2-4 hours), which was associated with an increase in their survival as determined by apoptosis markers. These data suggest that beta2 integrins play differential roles in experimental BP: LFA-1 is required for neutrophil recruitment, while Mac-1 mediates late neutrophil accumulation and apoptosis of infiltrating neutrophils.


Flow cytometric FRET analysis of erbB receptor interaction on a cell-by-cell basis.
Lateral interaction of c-erbB family receptors resulting in dimer formation is the key event initiating signal transduction. Consequently cross-activation and intracellular signaling is triggered with immediate impact on cell proliferation, migration, cell survival, and differentiation. In order to elucidate the connection of signal input (receptor activation) and signal output (altered cellular behavior) we dynamically assessed cell proliferation of BT474 and SK-BR-3 breast cancer cell lines. We quantitated c-erbB2 receptor homodimerization upon treatment with the therapeutic monoclonal anti-c-erbB2 antibodies trastuzumab (Herceptin) and pertuzumab by flow cytometric FRET (FCET) measurements on a cell-by-cell basis and calculated the extent of antibody-induced cell cycle exit. The results confirm that trastuzumab does not decrease c-erbB2 homodimers despite its strong potency to drive c-erbB2-overexpressing cells into quiescence. Pertuzumab, however, is able to prevent c-erbB2 homodimerization and thereby enhance the antiproliferative effect of trastuzumab when administered in combination.


Risk of gestational hypertension-preeclampsia in women with preceding endometriosis: A nationwide population-based study.
To investigate the association between preceding endometriosis and gestational hypertension-preeclampsia (GH-PE). In this nationwide population-based longitudinal study, data from 1998-2012 Taiwan National Health Insurance Research Database were used. We used ICD9-CM codes 617.X and 642.X respectively for the diagnoses of endometriosis and GH-PE, which were further confirmed by examining medical records of surgeries, blood pressure and urine protein to ensure the accuracy of the diagnoses. The study excluded women diagnosed with endometriosis at < 15 or > 45 years of age, chronic hypertension, and GH-PE prior to endometriosis. Each pregnant woman with a prior diagnosis of endometriosis was matched to 4 pregnant women without endometriosis by age. Logistic regression analysis was used to calculate odds ratios (ORs) for the risk of GH-PE with adjustment for age, occupation, urbanization, economic status and comorbidities. Among 6,300 women with a prior endometriosis diagnosis who were retrieved from a population of 1,000,000 residents, 2,578 (40.92%) had subsequent pregnancies that were eligible for further analysis and were compared with 10,312 pregnant women without previous endometriosis. GH-PE occurred more in women with prior endometriosis as compared to those without endometriosis (3.88% vs. 1.63%, p<0.0001). Further analysis revealed prior endometriosis was associated with GH-PE (adjusted OR = 2.27; 95% CI:1.76-2.93). For danazol-treated and non-danazol-treated subgroups, the incidences of GH-PE were 3.13% (15/480) and 4.05% (85/2,098), respectively. Although the risk for subsequent GH-PE was lower (adjusted OR = 1.49; 95% CI:0.86-2.56) after receiving danazol treatment than average (adjusted OR = 2.27; 95% CI:1.76-2.93) for women with preceding endometriosis, the reduction of risk was not statistically remarkable for danazol-treated (adjusted OR = 1.49) vs. non-danazol-treated (adjusted OR = 2.48) subgroups (p heterogeneity = 0.12). Preceding endometriosis is an independent and significant risk factor for the occurrence of GH-PE.


Relation between insulin and glucose flux rates in the dog.
A constant infusion isotope dilution procedure for measurement of plasma insulin flux rates was performed in acutely eviscerated dogs receiving an infusion of nonlabeled insulin; the calculated rate of insulin flux corresponded closely to that of the administered rate, thus validating the isotope dilution procedure. Flux rates of insulin and glucose were measured simultaneously at different steady levels in intact dogs. There was a linear relationship between plasma insulin concentration and insulin flux rate. In each animal there was also a linear relationship between glucose flux rate and insulin concentration, and between rates of glucose flux and insulin flux, but there was considerable inter-animal variation in the slope of the regression lines.


Perceptions of important outcomes of moral case deliberations: a qualitative study among healthcare professionals in childhood cancer care.
In childhood cancer care, healthcare professionals must deal with several difficult moral situations in clinical practice. Previous studies show that morally difficult challenges are related to decisions on treatment limitations, infringing on the child's integrity and growing autonomy, and interprofessional conflicts. Research also shows that healthcare professionals have expressed a need for clinical ethics support to help them deal with morally difficult situations. Moral case deliberations (MCDs) are one example of ethics support. The aim of this study was to describe the MCD-related outcomes that healthcare professionals in childhood cancer care considered important, before MCDs were implemented, in order to facilitate the implementation of MCDs in childhood cancer care in Sweden. This study is based on qualitative data. Healthcare professionals, mostly representing registered nurses, nursing assistants and physicians, working at childhood cancer care centres in Sweden, were invited to respond to the translated and content validated European MCD Outcomes Instrument, before participating in regular MCDs. Answers to the main open-ended question, included in the questionnaire, was analysed according to systematic text condensation. Data was collected from 161 responses from the healthcare professionals. The responses included healthcare professionals' perceptions of which MCD-related outcomes they found important for handling moral challenges. Three different themes of important outcomes from the analysis of the data are presented as follows: Interprofessional well-being in team interactions on a team level; Professional comfort when dealing with moral challenges on a personal level; and Improved quality of care for the child and the family on a care level. Healthcare professionals in childhood cancer care considered it important that ethics support could enhance the well-being of interprofessional teams, support healthcare professionals on an individual level and improve quality of care. The results of this study can be used in current and future training for MCD-facilitators. When knowing the context specific important MCD-outcomes, the sessions could be adapted. Managers in childhood cancer care would benefit from knowing about the specific important outcomes for their target group because they could then create relevant working conditions for clinical ethics support.


Between paranoia and creativity: candidates' experience of psychoanalytic training.
There is widespread concern regarding various aspects of psychoanalytic education. A recent paper by Patrick Casement, drawn widely from his long experience as a supervisor both in the U.K. and abroad, implied that the British Psychoanalytical Society is not exempt from these concerns. To investigate this, a semistructured, anonymous questionnaire was devised and sent to all candidates and all recently qualified analysts at the society. Overall there was a 58% response rate, with 77% of candidates and 39% of recently qualified analysts responding. Concerns were expressed about aspects of the training, but on the whole these were balanced by appreciation. Although strong criticism was expressed by a minority, it seems that when something goes wrong for a candidate, this experience is felt keenly by the peer group as well. The results are discussed in the context of the current training and ethos of the British Society, as well as in relation to a more widespread move toward "competency-based" education. The maturational tasks facing both candidates and trainers are also addressed.