Specificity of immunoglobulin E and immunoglobulin G against human (recombinant DNA) insulin in human insulin allergy and resistance.
Using an enzyme-linked immunosorbent assay method, we have demonstrated immunoglobulin E (IgE) and immunoglobulin G (IgG) against human (recombinant DNA) insulin in serum samples of a patient whose insulin therapy was only with human insulin. Within 12 days of initiation of human insulin for gestational diabetes, large local reactions developed in the patient in association with high levels of IgE to human insulin. As the local reactions subsided, the levels of IgE to human insulin decreased. The patient's insulin requirement was unusually high for pregnancy and tended to decrease in parallel with falling levels of IgG to human insulin, suggesting an element of immunologic insulin resistance. In addition to IgE and IgG against human insulin, we were able to demonstrate the presence of IgE and IgG against porcine and bovine insulin in the serum samples of this patient. The patient had similar immediate cutaneous reactivity to each insulin. In inhibition studies, similar amounts of porcine insulin, bovine insulin, or human insulin were found to produce 50% inhibition of human insulin binding to IgE or IgG against human insulin. Excess porcine insulin or bovine insulin resulted in total inhibition of human insulin binding to IgE or IgG. Thus even in a patient whose initial form of insulin therapy was human insulin, there was development of insulin allergy and of IgG to human insulin that may have contributed to insulin resistance. Moreover, the antigenic determinants recognized by antibody induced by human insulin may also be present on bovine insulin and porcine insulin as demonstrated in this case.


Utility of Serial Donor-derived Cell-free DNA Measurements for Detecting Allograft Rejection in a Kidney Transplant Recipient After PD-1 Checkpoint Inhibitor Administration.
Donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker of rejection that originates from allograft cells undergoing injury. Plasma levels <1% in kidney transplant recipients have a high negative predictive value for active allograft rejection. The utility of this biomarker in kidney transplant recipients receiving immune checkpoint inhibitor therapy is unknown. We describe a case in which serial dd-cfDNA monitoring facilitated the use of immune checkpoint inhibitor therapy, which is known to be associated with high rates of rejection, in a kidney transplant recipient with metastatic cancer. A 72-y-old man with end-stage kidney disease secondary to autosomal dominant polycystic kidney disease underwent living unrelated kidney transplant in December 2010. His immunosuppression regimen included tacrolimus, mycophenolate, and prednisone. In July 2017, he presented with metastatic cutaneous squamous cell carcinoma. After his disease progressed through radiation therapy and cetuximab, he received pembrolizumab (antiprogrammed cell death protein 1). His dd-cfDNA level was undetectable at baseline, then increased during treatment but remained <1%. This trend, despite fluctuations in serum creatinine levels during therapy, allowed for continuation of pembrolizumab and successful treatment of his metastatic cancer without clinically evident allograft rejection. After discontinuation of pembrolizumab, dd-cfDNA levels fell below the level of detection. Genetic analysis of the cutaneous squamous cell carcinoma demonstrated a genetic profile distinct from the dd-cfDNA, indicating that tumor lysis did not impact increases in dd-cfDNA. Serial dd-cfDNA measurements may provide a useful, noninvasive biomarker for detecting allograft injury that may facilitate the use of immunomodulatory therapies in organ transplant recipients with cancer.


Correlates of physical activity among colorectal cancer survivors: results from the longitudinal population-based profiles registry.
Physical activity can improve health of cancer survivors. To increase physical activity levels among colorectal cancer (CRC) survivors, we need to understand which factors affect physical activity. Therefore, this study examined the longitudinal relationship between symptom-related, functioning-related, and psychological barriers and socio-demographic and clinical factors with physical activity among CRC survivors. CRC survivors identified from the population-based Eindhoven Cancer Registry (ECR) diagnosed between 2000 and 2009 were included. Survivors completed validated questionnaires measuring moderate-to-vigorous physical activity (MVPA) and barriers in 2010(T1), 2011(T2), and 2012(T3). Linear-mixed models and linear regression techniques were used. Response rates were 74 % (N = 2451, T1); 47 % (N = 1547, T2); and 41 % (N = 1375, T3). Several factors were negatively associated with MVPA: symptom-related barriers (e.g., fatigue, dyspnea, chemotherapy side effects, pain, appetite loss, and weight loss); psychological barriers (i.e., depressive symptoms and anxiety); functioning-related barriers (e.g., low physical or role functioning, unfavorable future perspective); socio-demographic (i.e., older age, female, no partner); and clinical factors (i.e., obesity). However, no within-subject effects were significantly associated with MVPA. Groups of functioning-related barriers, socio-demographic factors, symptom-related barriers, psychological barriers, and clinical factors explained 11, 3.9, 3.8, 2.4, and 2.2 % of the variance in MVPA at T1, respectively. Several functioning-related and symptom-related barriers and few socio-demographic factors were associated with physical activity among CRC survivors. Future interventions to promote physical activity among CRC survivors could benefit by taking into account functioning aspects and symptoms of cancer and its treatment, and assess the causal direction of these associations.


Real-time MRI at a resolution of 20 ms.
The desire to visualize noninvasively physiological processes at high temporal resolution has been a driving force for the development of MRI since its inception in 1973. In this article, we describe a unique method for real-time MRI that reduces image acquisition times to only 20 ms. Although approaching the ultimate limit of MRI technology, the method yields high image quality in terms of spatial resolution, signal-to-noise ratio and the absence of artifacts. As proposed previously, a fast low-angle shot (FLASH) gradient-echo MRI technique (which allows for rapid and continuous image acquisitions) is combined with a radial encoding scheme (which offers motion robustness and moderate tolerance to data undersampling) and, most importantly, an iterative image reconstruction by regularized nonlinear inversion (which exploits the advantages of parallel imaging with multiple receiver coils). In this article, the extension of regularization and filtering to the temporal domain exploits consistencies in successive data acquisitions and thereby enhances the degree of radial undersampling in a hitherto unexpected manner by one order of magnitude. The results obtained for turbulent flow, human speech production and human heart function demonstrate considerable potential for real-time MRI studies of dynamic processes in a wide range of scientific and clinical settings.


Reducing pressure ulcers across multiple care settings using a collaborative approach.
In the UK, over 700 000 patients are affected by pressure ulcers each year, and 180 000 of those are newly acquired each year. The occurrence of pressure ulcers costs the National Health Service (NHS) more than 3.8 million every day. In 2004, pressure ulcers were estimated to cost the NHS £1.4-£2.4 billion per year, which was 4% of the total NHS expenditure. The impact on patients can be considerable, due to increased pain, length of hospital stay and decreased quality of life. However, it is acknowledged that a significant number of these are avoidable. In early 2015, it was identified that for the North East and North Cumbria region the incidence of pressure ulcers was higher than the national average. Because of this, a 2-year Pressure Ulcer Collaborative was implemented, involving secondary care, community services, care homes and the ambulance service, with the aim of reducing the percentage of pressure ulcers developed by patients within their care. The Breakthrough Series Collaborative Model from the Institute for Healthcare Improvement provided the framework for this Collaborative. In year 1, pressure ulcers were reduced by 36%, and in year 2 by 33%, demonstrating an estimated cost saving during the lifespan of the Collaborative of £513 000, and a reduction in the number of bed days between 220 and 352.


Efficacy and safety study of two zinc gluconate regimens in the treatment of inflammatory acne.
This double-blind study was conducted on 67 patients with inflammatory acne who received one of two zinc gluconate regimens (Rubozinc) for three months. One was a constant-dose regimen and the other included an initial three-week loading dose, but both regimens provided the same cumulative dose at three months. The primary assessment criteria was the change with respect to baseline in the total number of superficial inflammatory lesions (papules and pustules). The two treatment groups were not statistically significantly different, with respect to this criteria, after three, five, seven or thirteen weeks of treatment. Therefore, the regimen that included a loading-dose provided no additional benefit. The results of this study are in favor of the conventional therapeutic regimen of two capsules daily for three months, as defined in the marketing authorization.


Modeling for detecting weld defects based on magneto-optical imaging.
A magneto-optical (MO) imaging nondestructive testing (NDT) method for ferromagnetic weldments has been proposed. The mechanism of MO imaging was analyzed by the Faraday MO effect, magnetic domain theory, and magnetic hysteresis loops. Then, the relation between MO images and their corresponding excitation voltages was investigated. To explain the MO imaging system, magnetic domain distribution models of various welding states were established. These models are excited by two kinds of magnetic fields. One is the external magnetic field (Hex), and the other is a weldment remanence field (Mr) after Hex is removed. Relations of magnetic field excitation voltages, thickness of the spacer plate, and the corresponding MO images were also researched, which indicates the proposed NDT method can be used to detect incomplete penetration defect. Then, an experiment that uses MO imaging to detect the defects of high-strength steel (HSS) weldment was performed. Experimental results proved this method can detect crack, sag, and incomplete penetration of weldment effectively. Finally, a series of welded joint MO images of the HSS weldment were captured, which are used as the input data of the defect classification model established by using principal component analysis and an error backpropagation neural network, and the accuracy of this classification model can achieve 92.8%.


Cholera toxin enhances adenylate cyclase-dependent transport in toad urinary bladder.
Cholera toxin (CT) irreversibly ADP-ribosylates and activates the nucleotide-stimulatory (Ns) subunit of adenylate cyclase in many tissues, thereby eliciting cyclase-dependent functions. Although earlier studies performed at room temperature could not demonstrate CT-stimulated water transport in toad urinary bladder, subsequent work in other tissues has emphasized the need for incubation at 35-37 degrees C to effect ribosylation and the subsequent physiological effects. We found that incubating tissues with amphibian culture media, rather than Ringer solution, maintained tissue viability at this higher temperature and permitted prolonged incubation with CT. At 37 degrees C, in the presence of 0.1 mM phosphodiesterase inhibitor (1-methyl-3-isobutylxanthine, MIX), 0.2-200 nM mucosal CT caused a dose-dependent but submaximal enhancement of water flux and urea transport. Elimination of MIX from the bath diminished subsequent CT-induced stimulation, supporting a role for adenosine 3',5'-cyclic monophosphate (cAMP) as mediator of the CT effect. The increased water flow was stable for greater than 1 h after removal of CT from the bath, consistent with irreversible stimulation of the cyclase. Mucosal CT stimulated transport to a greater degree than serosal CT, paralleling the pattern seen in the intestine, which is compatible with passage of the toxin's a subunit across the cell to the serosal membrane cyclase. Exposure of the tissue's mucosal surface to GM1 ganglioside, (the natural receptor for the CT b subunit) yielded maximal stimulation of water flow and near-maximal urea transport, presumably by increasing CT's binding to the cell membrane.(ABSTRACT TRUNCATED AT 250 WORDS)


Methods and approaches in the analysis of gene expression data.
The application of high-density DNA array technology to monitor gene transcription has been responsible for a real paradigm shift in biology. The majority of research groups now have the ability to measure the expression of a significant proportion of the human genome in a single experiment, resulting in an unprecedented volume of data being made available to the scientific community. As a consequence of this, the storage, analysis and interpretation of this information present a major challenge. In the field of immunology the analysis of gene expression profiles has opened new areas of investigation. The study of cellular responses has revealed that cells respond to an activation signal with waves of co-ordinated gene expression profiles and that the components of these responses are the key to understanding the specific mechanisms which lead to phenotypic differentiation. The discovery of 'cell type specific' gene expression signatures have also helped the interpretation of the mechanisms leading to disease progression. Here we review the principles behind the most commonly used data analysis methods and discuss the approaches that have been employed in immunological research.


Increased Activity of β-Lactam Antibiotics in Combination with Carvacrol against MRSA Bacteremia and Catheter-Associated Biofilm Infections.
β-Lactam antibiotics are the mainstay for the treatment of staphylococcal infections, but their utility is greatly limited by the emergence and rapid dissemination of methicillin-resistant Staphylococcus aureus (MRSA). Herein, we evaluated the ability of the plant-derived monoterpene carvacrol to act as an antibiotic adjuvant, revitalizing the anti-MRSA activity of β-lactam antibiotics. Increased susceptibility of MRSA to β-lactam antibiotics and significant synergistic activities were observed with carvacrol-based combinations. Carvacrol significantly inhibited MRSA biofilms and reduced the production of exopolysaccharide, polysaccharide intercellular adhesin, and extracellular DNA and showed synergistic biofilm inhibition in combination with β-lactams. Transcriptome analysis revealed profound downregulation in the expression of genes involved in two-component systems and S. aureus infection. Mechanistic studies indicate that carvacrol inhibits the expression of staphylococcal accessory regulator sarA and interferes with SarA-mecA promoter binding that decreases mecA-mediated β-lactam resistance. Consistently, the in vivo experiment also supported that carvacrol restored MRSA sensitivity to β-lactam antibiotic treatments in both murine models of bacteremia and biofilm-associated infection. Our results indicated that carvacrol has a potential role as a combinatorial partner with β-lactam antibiotics to address MRSA infections.


Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: meta-analysis of clinical trials.
Numerous reports have appeared on lamivudine use for the treatment of hepatitis B virus (HBV) infection after renal transplantation (RT). However, the efficacy and safety of lamivudine after RT remain unclear. The authors evaluated the efficacy and safety of initial lamivudine monotherapy in RT recipients with hepatitis B by performing a systematic review of the literature with a meta-analysis of clinical trials. The primary outcomes were hepatitis B (HB) e antigen (Ag) and HBV-DNA clearance (as measures of efficacy); the secondary outcomes were biochemical response (as measures of efficacy), dropout rate, and lamivudine resistance (as measures of tolerability). The authors used the random effects model of DerSimonian and Laird, and outcomes were analyzed on an intent-to-treat basis. The authors identified 14 clinical trials (184 patients); all of these were prospective cohort studies. The mean overall estimate for HBV-DNA and HBeAg clearance, alanine aminotransferase normalization, and lamivudine resistance was 91% (95% confidence interval [CI], 86%-96%), 27% (95% CI, 16%-39%), 81% (95% CI, 70%-92%), and 18% (95% CI, 10%-37%), respectively. HBeAg seroconversion rate was assessed in four (28%) trials and ranged between 0% and 46%. The P value was greater than 0.05 for our test of study homogeneity. There was no association between rate of patients who were male patients or had cirrhosis, race, age, lamivudine dose, and HBV-DNA or HBeAg clearance. Increased duration of lamivudine therapy was positively associated with frequency of HBeAg loss (r =0.51, P =0.039) and lamivudine resistance (r =0.620, P =0.019). Only 2 (14%) of 14 studies reported a dropout rate greater than 0%. Our meta-analysis showed that the majority of RT recipients with hepatitis B had high virologic and biochemical response with lamivudine. Tolerance to lamivudine was good. However, lamivudine resistance was frequent with prolonged therapy, potentially limiting its long-term efficacy after RT.


Across-country genomic predictions in Norwegian and New Zealand Composite sheep populations with similar development history.
The goal of this study was to assess the feasibility of across-country genomic predictions in Norwegian White Sheep (NWS) and New Zealand Composite (NZC) sheep populations with similar development history. Different training populations were evaluated (i.e., including only NWS or NZC, or combining both populations). Predictions were performed using the actual phenotypes (normalized) and the single-step GBLUP via Bayesian inference. Genotyped NWS animals born in 2016 (N = 267) were used to assess the accuracy and bias of genomic estimated breeding values (GEBVs) predicted for birth weight (BW), weaning weight (WW), carcass weight (CW), EUROP carcass classification (EUC), and EUROP fat grading (EUF). The accuracy and bias of GEBVs differed across traits and training population used. For instance, the GEBV accuracies ranged from 0.13 (BW) to 0.44 (EUC) for GEBVs predicted including only NWS, from 0.06 (BW) to 0.15 (CW) when including only NZC, and from 0.10 (BW) to 0.41 (EUC) when including both NWS and NZC animals in the training population. The regression coefficients used to assess the spread of GEBVs (bias) ranged from 0.26 (BW) to 0.64 (EUF) for only NWS, 0.10 (EUC) to 0.52 (CW) for only NZC, and from 0.42 (WW) to 2.23 (EUC) for both NWS and NZC in the training population. Our findings suggest that across-country genomic predictions based on ssGBLUP might be possible for NWS and NZC, especially for novel traits.


A guide to evaluating linkage quality for the analysis of linked data.
Linked datasets are an important resource for epidemiological and clinical studies, but linkage error can lead to biased results. For data security reasons, linkage of personal identifiers is often performed by a third party, making it difficult for researchers to assess the quality of the linked dataset in the context of specific research questions. This is compounded by a lack of guidance on how to determine the potential impact of linkage error. We describe how linkage quality can be evaluated and provide widely applicable guidance for both data providers and researchers. Using an illustrative example of a linked dataset of maternal and baby hospital records, we demonstrate three approaches for evaluating linkage quality: applying the linkage algorithm to a subset of gold standard data to quantify linkage error; comparing characteristics of linked and unlinked data to identify potential sources of bias; and evaluating the sensitivity of results to changes in the linkage procedure. These approaches can inform our understanding of the potential impact of linkage error and provide an opportunity to select the most appropriate linkage procedure for a specific analysis. Evaluating linkage quality in this way will improve the quality and transparency of epidemiological and clinical research using linked data.


Leveraging host metabolism for bisdemethoxycurcumin production in Pseudomonas putida.
Pseudomonas putida is a saprophytic bacterium with robust metabolisms and strong solvent tolerance making it an attractive host for metabolic engineering and bioremediation. Due to its diverse carbon metabolisms, its genome encodes an array of proteins and enzymes that can be readily applied to produce valuable products. In this work we sought to identify design principles and bottlenecks in the production of type III polyketide synthase (T3PKS)-derived compounds in P. putida. T3PKS products are widely used as nutraceuticals and medicines and often require aromatic starter units, such as coumaroyl-CoA, which is also an intermediate in the native coumarate catabolic pathway of P. putida. Using a randomly barcoded transposon mutant (RB-TnSeq) library, we assayed gene functions for a large portion of aromatic catabolism, confirmed known pathways, and proposed new annotations for two aromatic transporters. The 1,3,6,8-tetrahydroxynapthalene synthase of Streptomyces coelicolor (RppA), a microbial T3PKS, was then used to rapidly assay growth conditions for increased T3PKS product accumulation. The feruloyl/coumaroyl CoA synthetase (Fcs) of P. putida was used to supply coumaroyl-CoA for the curcuminoid synthase (CUS) of Oryza sativa, a plant T3PKS. We identified that accumulation of coumaroyl-CoA in this pathway results in extended growth lag times in P. putida. Deletion of the second step in coumarate catabolism, the enoyl-CoA hydratase-lyase (Ech), resulted in increased production of the type III polyketide bisdemethoxycurcumin.


Nucleotide sequence of the promoter region of Sparus aurata insulin-like growth factor I gene and expression of IGF-I in eggs and embryos.
A genomic fragment of 3.1 kb, containing the promoter region of Sparus aurata insulin-like growth factor I (IGF-I) gene has been cloned and sequenced. This fragment contains exon 1 and exon 2 of Sparus aurata IGF-I gene. These two exons are identical in organization to the reported chum salmon IGF-I gene. Exon 1 contains 5' untranslated region and part of the signal peptide. Exon 2 codes for part of the signal peptide and part of the B domain. Nested polymerase chain reaction (PCR) revealed that a fragment was amplified from liver RNA when a common primer in the translated region and a primer located between 375 and 395 nucleotides upstream of the first methionine were used. No such amplification was obtained when the primer was located between 414 and 434 nucleotides upstream of the first methionine, suggesting that the first exon in Sparus IGF-I gene starts 400-410 nucleotides upstream of the first methionine. Expression of IGF-I mRNA was studied in Sparus aurata using reverse transcription (RT)-PCR. An amplified fragment was found in unfertilized eggs and in embryos 4, 8, and 12 hours after fertilization, when oligonucleotides specific for Sparus aurata IGF-I cDNA were used. A similar fragment was found when adult liver or one-day larval RNA were used. This fragment hybridized in a Southern blot to salmon IGF-I cDNA. These results demonstrate that the structure of IGF-I gene has been conserved in teleosts and IGF-I transcripts are present in fish during embryogenesis, probably of maternal origin.


Apo CIII Proteoforms, Plasma Lipids, and Cardiovascular Risk in MESA.
Apo CIII (apolipoprotein CIII) is an important regulator of triglyceride metabolism and was associated with cardiovascular risk in several cohorts. It is present in 4 major proteoforms, a native peptide (CIII0a), and glycosylated proteoforms with zero (CIII0b), 1 (CIII1, most abundant), or 2 (CIII2) sialic acids, which may differentially modify lipoprotein metabolism. We studied the relationships of these proteoforms with plasma lipids and cardiovascular risk. Apo CIII proteoforms were measured by mass spectrometry immunoassay in baseline plasma samples of 5791 participants of Multi-Ethnic Study of Atherosclerosis, an observational community-based cohort. Standard plasma lipids were collected for up to 16 years and cardiovascular events (myocardial infarction, resuscitated cardiac arrest, or stroke) were adjudicated for up to 17 years. Apo CIII proteoform composition differed by age, sex, race and ethnicity, body mass index, and fasting glucose. Notably, CIII1 was lower in older participants, men and Black and Chinese (versus White) participants, and higher in obesity and diabetes. In contrast, CIII2 was higher in older participants, men, Black, and Chinese persons, and lower in Hispanic individuals and obesity. Higher CIII2 to CIII1 ratio (CIII2/III1) was associated with lower triglycerides and higher HDL (high-density lipoprotein) in cross-sectional and longitudinal models, independently of clinical and demographic risk factors and total apo CIII. The associations of CIII0a/III1 and CIII0b/III1 with plasma lipids were weaker and varied through cross-sectional and longitudinal analyses. Total apo CIII and CIII2/III1 were positively associated with cardiovascular disease risk (n=669 events, hazard ratios, 1.14 [95% CI, 1.04-1.25] and 1.21 [1.11-1.31], respectively); however, the associations were attenuated after adjustment for clinical and demographic characteristics (1.07 [0.98-1.16]; 1.07 [0.97-1.17]). In contrast, CIII0b/III1 was inversely associated with cardiovascular disease risk even after full adjustment including plasma lipids (0.86 [0.79-0.93]). Our data indicate differences in clinical and demographic relationships of apo CIII proteoforms, and highlight the importance of apo CIII proteoform composition in predicting future lipid patterns and cardiovascular disease risk.


The origin of slow potentials in semicircular canals of the frog.
Slow potentials generated in the sensory organ of the ampulla were recorded in isolated semicircular canals of the frog by means of fluid electrodes. These potentials, which may be picked up from the intrampullar fluid and those from the ampullar nerve appear to be generated at different stages of the process taking place in crista ampullaris. Slow intra-ampullar potentials apparently reflect receptor potentials of hair cells. They are preserved after degeneration of the nerve fibre endings and are relatively insensitive to DNP poisoning; their amplitude is maximum at high K+ concentrations. Slow nerve potentials appear to be due to electronic spreading of post-synaptic excitatory potentials generated at cytoneural junctions. They disappear after degeneration of the nerve fibres, in low Ca++ and high Mg++ solutions and are extremely sensitive to DNP poisoning. An analysis of the time-course of the slow ampullar and nerve potentials referred to the discharge of impulses in afferent fibres was performed with a view to interpreting the transduction mechanism of semicircular canals.


Clinical and In Silico Outcomes of the Expression of miR-130a-5p and miR-615-3p in Tumor Compared with Non-Tumor Adjacent Tissues of Patients with BC.
Breast Cancer (BC) is the most common malignancy among women with a high mortality rate. The blockade of asparagine-related pathways may be an effective measure to control the progression and reduction of BC metastasis potential. Recently, it has been shown that various miRNAs, as part of small non-coding RNAs, have a great role in cancer development, especially asparagine-related pathways, to modulate the invasiveness. This study aimed to evaluate the expression of miR-130a-5p and miR-615-3p in tumoral and nontumoral adjacent tissues of patients with BC. There is a chance that asparagine metabolism is influenced by miR-130a-5p and miR-615-3p as confirmed by bioinformatics analysis. Hence, real-time PCR was conducted on eighty BC tumoral and non-tumoral adjacent tissues to evaluate the expression level of the two miRNAs. To predict the potential biological process and molecular pathways of miR-130a-5p, an in silico analysis was performed. This study indicated that miR-130a was downregulated in tumoral tissues compared to non-tumoral adjacent tissues (P-value= 0.01443 and fold change= -2.5137), while miR-615-3p did not show a significant difference between the two groups. Furthermore, the subgroup studies did not reveal any significant correlation between the expression of these two miRNAs and subfactors. Furthermore, in silico studies unraveled several biological processes related to amino-acid metabolism, as well as pathways related to tumor development such as Phosphatase and Tensin Homolog (PTEN) and JAK-STAT pathways among miR-130a-5p target genes. Our findings indicate that miRNA-130a-5p is downregulated in BC tissues and may play a tumor suppressor role in patients with BC. Therefore, it may be suggested as a potential diagnostic and therapeutic target for BC.


Top-down control of herbivory by birds and bats in the canopy of temperate broad-leaved oaks (Quercus robur).
The intensive foraging of insectivorous birds and bats is well known to reduce the density of arboreal herbivorous arthropods but quantification of collateral leaf damage remains limited for temperate forest canopies. We conducted exclusion experiments with nets in the crowns of young and mature oaks, Quercus robur, in south and central Germany to investigate the extent to which aerial vertebrates reduce herbivory through predation. We repeatedly estimated leaf damage throughout the vegetation period. Exclusion of birds and bats led to a distinct increase in arthropod herbivory, emphasizing the prominent role of vertebrate predators in controlling arthropods. Leaf damage (e.g., number of holes) differed strongly between sites and was 59% higher in south Germany, where species richness of vertebrate predators and relative oak density were lower compared with our other study site in central Germany. The effects of bird and bat exclusion on herbivory were 19% greater on young than on mature trees in south Germany. Our results support previous studies that have demonstrated clear effects of insectivorous vertebrates on leaf damage through the control of herbivorous arthropods. Moreover, our comparative approach on quantification of leaf damage highlights the importance of local attributes such as tree age, forest composition and species richness of vertebrate predators for control of arthropod herbivory.


Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishing hype from hope.
During the past 10 years, more than 80 orally active vasodilator and inotropic agents have been tested in the clinical setting to evaluate their potential utility in the treatment of chronic heart failure. Although the initial reports of all of these drugs suggested that each represented a major therapeutic advance, only three agents--digoxin, captopril and enalapril--have produced consistent long-term hemodynamic and clinical benefits in these severely ill patients. Most of the other drugs that have been tested have not (to date) distinguished themselves from placebo therapy in large-scale, controlled trials, even though these agents produce hemodynamic effects that closely resemble those seen with digitalis and the converting-enzyme inhibitors. These observations suggest that the hemodynamic derangements that characteristically accompany the development of left ventricular dysfunction cannot be considered to be the most important pathophysiologic abnormality in chronic heart failure. Although cardiac contractility is usually depressed in this disease, positive inotropic agents do not consistently improve the clinical status of these patients. Similarly, although the systemic vessels are usually markedly constricted, drugs that ameliorate this vasoconstriction do not consistently relieve symptoms, enhance exercise capacity or prolong life. Hence, correction of the central hemodynamic abnormalities seen in heart failure may not necessarily provide a rational basis for drug development, and future advances in therapy are likely to evolve only by attempting to understand and modify the basic physiologic derangements in this disorder.


Evidence that proteases are involved in superoxide production by human polymorphonuclear leukocytes and monocytes.
The possible participation of proteases in superoxide (O2-) production by human polymorphonuclear leukocytes (PMN) and monocytes was explores using various protease inhibitors and substrates. Protease inhibitors of serine proteases and synthetic inhibitors that modify the active site of serine proteases. Substrates used were synthetic substrates of the chymotrypsin type as well as trypsin type of protease. All these inhibitors and substrates inhibited O2- oroduction by human PMN and monocytes induced by cytochalasin E and concanavalin A, though PMN were more sensitive to these inhibitors and substrates than monocytes. Inhibition appeared rapidly even when the inhibitors were added at the same time as the stimulants, during the "induction time of O2-production" or at the time of maximum O2- production, whereas much greater inhibition was observed when the cells were preincubated with the inhibitors. These observations suggest that enzymatically active serine proteases are essential for these phagocytic cells to initiate and maintain the O2- production in response to the stimuli. The inhibitory effect of the inhibitor and substrate for chymotrypsin type protease was greater than that of those substances for trypsin-type protease. Macromolecular inhibitors also inhibited the O2- production. These findings suggest that the serine proteases involved in the O2- production by human PMN and monocytes are similar to chymotrypsin rather than trypsin, and are possibly located at the cell surface membrane.


Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer's Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years.
Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.


[Ultrasound imaging of the bile ducts and assessment of gallbladder kinetics in healthy newborn infants].
The gallbladder and the biliary tract of 85 neonates were sonographically examined, in the fasting state. The gallbladder was detectable in all neonates and showed a measurable contraction. Two types of biliary contraction could be observed: a concentric contraction of length, depth and width (concentric type) or a contraction of depth and width (collapse type). The grade of postprandial contraction was independent of the level of serum bilirubin. Furthermore, sonographic criteria were established allowing the differentiation of the bile ducts and their discrimination from hepatic arteries.


Single-lung and double-lung transplantation: technique and tips.
The first successful single-lung and double-lung transplantations were performed in the eighties. Since then both surgical and anesthesiological management have improved. The aim of this paper is to describe the surgical technique of lung transplantation: from the anesthesiological preparation, to the explantation and implantation of the lung grafts, and the preparation of the donor lungs. We will also describe the main surgical complications after lung transplantation and their management. Each step of the surgical procedure will be illustrated with photos and videos.


Fighting the COVID pandemic: National policy choices in non-pharmaceutical interventions.
The COVID-19 pandemic pushed countries to adopt various non-pharmaceutical interventions (NPIs). Due to the features of the pandemic, which spread over time and space, governments could decide whether or not to follow policy choices made by leaders of countries affected by the virus before them. In this study, we aim to empirically model the adoption of NPIs during the first wave of COVID-19 in the 14 European countries with more than 10 million inhabitants, in order to detect whether a policy diffusion mechanism occurred. By means of a multivariate approach based on Principal Component Analysis and Cluster Analysis, we manage to derive three clusters representing different behaviour models to which the different European countries belong in the different periods of the first wave: pre-pandemic, summer relaxation and deep-lockdown scenarios. These results bring a two-fold contribution: on the one hand, they may help us to understand differences and similarities among European countries during the first wave of the COVID-19 outbreak and guide future quantitative or qualitative studies; on the other, our findings suggest that with minor exceptions (such as Sweden and Poland), different countries adopted very similar policy strategies, which are likely to be due more to the unfolding of the pandemic than to specific governmental strategies.


Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue of the rat.
Brown adipose tissue (BAT) is an important site of adaptive changes in thermogenesis in the rat. The sympathetic nervous system, which richly supplies BAT, is thought to play an important role in the regulation of BAT thermogenesis because catecholamines stimulate and beta adrenergic blocking agents inhibit oxygen consumption in this tissue. The present studies were carried out to assess directly sympathetic activity in BAT in response to cold exposure and to changes in dietary intake, both of which alter heat production in the rat. Sympathetic activity was determined from the rate of norepinephrine (NE) turnover in interscapular brown adipose tissue (IBAT) after preliminary experiments validated the use of NE turnover techniques in IBAT. Acute exposure to 4 degrees C increased NE turnover in IBAT 4- to 12-fold compared with ambient temperature controls, depending upon the interval over which the turnover measurement was made, while in the heart NE turnover doubled in response to the same cold stimulus. In animals exposed to cold continuously for 10 d before study, NE turnover measurements in IBAT and in the heart were elevated comparably to those obtained during acute exposure. Alterations in feeding were also associated with changes in NE turnover in IBAT. Fasting for 2 d decreased NE turnover in IBAT (-35% from 29.2+/-4.2 ng NE/h to 18.9+/-5.9) and in heart (-52%). In animals fed a "cafeteria" diet, a model of voluntary overfeeding in the rat, NE turnover was increased in both IBAT (+108% from 24.8+/-4.5 ng NE/h to 51.7+/-6.8) and heart (+66%). Because ganglionic blockade exerted a greater effect on NE turnover in IBAT in cafeteria-fed rats than in controls, the increase in NE turnover in IBAT with this overfeeding regimen reflects enhanced central sympathetic outflow. Thus NE turnover techniques can be satisfactorily applied to the assessment of sympathetic nervous system activity in IBAT. The experiments reported here demonstrate changes in sympathetic activity in IBAT that parallel known adaptive changes in heat production in the rat. These studies, therefore, support the concept that the increased thermogenesis of chronic cold exposure and of cafeteria feeding occur by similar mechanisms and imply an important role for the sympathetic nervous system, mediated in part through BAT, in the regulation of energy balance in the rat.


Effects of pregnancy on cardiac function and myosin enzymology in the rat.
Previous studies of cardiac function during pregnancy, while suggesting that this condition is associated with improved myocardial contractility, have been biased by the altered in vivo loading conditions. Therefore, we have investigated intrinsic cardiac function and contractile protein biochemistry during pregnancy in isolated rat hearts under controlled loading conditions. Animals were impregnated and studied after 1 and 3 wk and 2-3 days postpartum (gestation 21 days). The data show that hearts from pregnant animals (at 3 wk) had improved contractile performance as manifested by an 11% increase in fractional shortening, a 20% increase in velocity of circumferential fiber shortening, and an upward-shifted force-velocity relationship. These findings were paralleled by a 16% increase in Ca2+-activated myosin and an 11% increase in actin-activated ATPase activities. Thus pregnancy in the rat is associated with slightly improved cardiac contractility and biochemistry. This may relate directly to the hormonal status of the pregnant animal or to the effects of chronic volume overload.


Effects of Functional Electrical Stimulation Lower Extremity Training in Myotonic Dystrophy Type I: A Pilot Controlled Study.
Functional electrical stimulation (FES) is a new rehabilitative approach that combines electrical stimulation with a functional task. This pilot study evaluated the safety and effectiveness of FES lower extremity training in myotonic dystrophy type 1. This is a controlled pilot study that enrolled 20 patients with myotonic dystrophy type 1 over 2 years. Eight patients (age, 39-67 years) fulfilled the inclusion criteria. Four participants performed FES cycling training for 15 days (one daily session of 30 minutes for 5 days a week). A control group, matched for clinical and genetic variables, who had contraindications to electrical stimulation, performed 6 weeks of conventional resistance and aerobic training. The modified Medical Research Council Scale and functional assessments were performed before and after treatment. Cohen d effect size was used for statistical analysis. Functional electrical stimulation induced lower extremity training was well tolerated and resulted in a greater improvement of tibialis anterior muscle strength (d = 1,583), overall muscle strength (d = 1,723), and endurance (d = 0,626) than conventional training. Functional electrical stimulation might be considered a safe and valid tool to improve muscle function, also in muscles severely compromised in which no other restorative options are available. Confirmation of FES efficacy through further clinical trials is strongly advised.


The slow Arrhenius process in small organic molecules.
Equilibration, the complex set of molecular rearrangements leading to more stable states, is usually dominated by density fluctuations, occurring through the structural (α-)relaxation, whose timescale quickly increases upon cooling. Growing evidence shows, however, that equilibration can be reached also through an alternative pathway provided by the Slow Arrhenius process (SAP), a molecular mode slower than the structural processes in the liquid state and faster in glass. The SAP, widely observed in polymers, has not yet been reported in small molecules, probably because of the larger experimental difficulties in handling these systems. Here, we report the presence of the SAP in three different molecular glassformers, by investigating these systems in the thin film geometry via dielectric spectroscopy. These results reinforce the idea that the SAP is a universal feature of liquid and glassy dynamics.


The effects of a multispecies probiotic on migraine and markers of intestinal permeability-results of a randomized placebo-controlled study.
Migraine, associated with several gastrointestinal disorders, may result from increased intestinal permeability, allowing endotoxins to enter the bloodstream. We tested whether probiotics could reduce migraine through an effect on intestinal permeability and inflammation. In total, 63 patients were randomly allocated to the probiotic (n=31) or the placebo group (n=32). Participants ingested a multispecies probiotic (5x109 colony-forming units) or placebo daily for 12 weeks. Migraine was assessed with the Migraine Disability Assessment Scale (MIDAS), the Headache Disability Inventory (HDI) and headache diaries. At baseline and 12 weeks, intestinal permeability was measured with the urinary lactulose/mannitol test and fecal and serum zonulin; inflammation was measured from interleukin (IL) -6, IL-10, tumor necrosis factor-α and C-reactive protein in serum. The MIDAS migraine intensity score significantly decreased in both groups (P<0.001) and the HDI score significantly decreased in the probiotic group (P=0.032) and borderline in the placebo group (P=0.053). In the probiotics group, patients had a median of 6 migraine days in the first month, 4 in the second month (P=0.002) and 5 in the last month, which was not significantly different from the 5, 4, and 4 days in the placebo group. A ⩾2day reduction in migraine days was seen in 12/31 patients in the probiotics group versus 7/29 in the placebo group (ns). Probiotic use did not significantly affect medication use, intestinal permeability or inflammation compared to placebo. In this study, we could not confirm significant benefit from a multispecies probiotic compared to a placebo on the outcome parameters of migraine and intestinal integrity.


Interictal electromagnetic source imaging in focal epilepsy: practices, results and recommendations.
Electromagnetic source imaging of interictal epileptiform activity with electroencephalography or magnetoencephalography seems a logical first step in locating the epileptogenic zone in partial epilepsy. However, a lack of standardization contributes to an undeserved low-key 'image' of electromagnetic source imaging. After a clinical and technical review, we propose a practical guide how to apply electromagnetic source imaging. We found 25 clinical studies of electromagnetic source imaging in targeting epilepsy surgery in the recent literature, mostly using magnetoencephalography. Feasibility of electromagnetic source imaging is around 75%. Whether magnetoencephalography is superior to electroencephalography is still unresolved, because fair comparisons are lacking. Clinical studies have not yet adopted all technical possibilities. Localization accuracy seems high, but studies lack uniformity regarding methods, goals and outcome parameters. Therefore, the final place of electromagnetic source imaging in the presurgical work-up is still to be determined. The diagnostic potential is probably highest in extratemporal epilepsies, and lowest in mesial temporal lobe epilepsy. Electromagnetic source imaging has evolved technically and can provide valuable localization information in the presurgical evaluation of patients with epilepsy. Standardization of the technique is required, before further clinical studies can better establish its role in presurgical evaluation of focal epilepsy. A relatively easy, stepwise data acquisition and analysis protocol are proposed.


Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries.
Capillaries, the smallest blood vessels, are the distal end of the vasculature where oxygen and nutrients are exchanged between blood and tissue. Hence, noninvasive imaging of capillaries and function in vivo has long been desired as a window to studying fundamental physiology, such as neurovascular coupling. Existing imaging modalities cannot provide the required sensitivity and spatial resolution. We present in vivo imaging of the microvasculature including single capillaries in mice using optical-resolution photoacoustic microscopy (OR-PAM) developed in our laboratory. OR-PAM provides a lateral resolution of 5 microm and an imaging depth >0.7 mm.


High colonization rates of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in Swiss travellers to South Asia- a prospective observational multicentre cohort study looking at epidemiology, microbiology and risk factors.
International travel contributes to the worldwide spread of multidrug resistant Gram-negative bacteria. Rates of travel-related faecal colonization with extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae vary for different destinations. Especially travellers returning from the Indian subcontinent show high colonization rates. So far, nothing is known about region-specific risk factors for becoming colonized. An observational prospective multicentre cohort study investigated travellers to South Asia. Before and after travelling, rectal swabs were screened for third-generation cephalosporin- and carbapenem-resistant Enterobacteriaceae. Participants completed questionnaires to identify risk factors for becoming colonized. Covariates were assessed univariately, followed by a multivariate regression. Hundred and seventy persons were enrolled, the largest data set on travellers to the Indian subcontinent so far. The acquired colonization rate with ESBL-producing Escherichia coli overall was 69.4% (95% CI 62.1-75.9%), being highest in travellers returning from India (86.8%; 95% CI 78.5-95.0%) and lowest in travellers returning from Sri Lanka (34.7%; 95% CI 22.9-48.7%). Associated risk factors were travel destination, length of stay, visiting friends and relatives, and eating ice cream and pastry. High colonization rates with ESBL-producing Enterobacteriaceae were found in travellers returning from South Asia. Though risk factors were identified, a more common source, i.e. environmental, appears to better explain the high colonization rates.


MLL associates with telomeres and regulates telomeric repeat-containing RNA transcription.
Mammalian telomeres consist of TTAGGG repeats organized in nucleosomes and associated with a six-protein complex known as shelterin, which preserves telomere structure and protects chromosome ends from the cellular DNA damage response. Recent studies have found that telomeres are transcribed into telomeric UUAGGG repeat-containing RNA (TERRA) starting from subtelomeric regions. TERRA binding at telomeres appears to be involved in cis-based mechanisms of telomeric chromatin organization and maintenance. A number of histone methyltransferases (HMTs) are known to influence telomeric chromatin status; however, the regulatory mechanisms of telomere transcription are poorly understood. Here, we show that the histone 3/lysine 4 (H3/K4) HMT and the transcriptional regulator MLL associate with telomeres and contribute to their H3/K4 methylation and transcription in a telomere length-dependent manner. In human diploid fibroblasts, RNA interference-mediated MLL depletion affects telomere chromatin modification and transcription and induces the telomere damage response. Telomere uncapping through either TRF2 shelterin protein knockdown or exposure to telomere G-strand DNA oligonucleotides significantly increases the transcription of TERRA, an effect mediated by the functional cooperation between MLL and the tumor suppressor p53. In total, our findings identify a previously unrecognized role of MLL in modifying telomeric chromatin and provide evidence for the functional interaction between MLL, p53, and the shelterin complex in the regulation of telomeric transcription and stability.


Genomic Characterization and Antimicrobial Susceptibility of Dromedary-Associated Staphylococcaceae from the Horn of Africa.
Members of the Staphylococcaceae family, particularly those of the genus Staphylococcus, encompass important human and animal pathogens. We collected and characterized Staphylococcaceae strains from apparently healthy and diseased camels (n = 84) and cattle (n = 7) in Somalia and Kenya. We phenotypically characterized the strains, including their antimicrobial inhibitory concentrations. Then, we sequenced their genomes using long-read sequencing, closed their genomes, and subsequently compared and mapped their virulence- and resistance-associated gene pools. Genome-based phylogenetics revealed 13 known Staphylococcaceae and at least two novel species. East African strains of different species encompassed novel sequence types and phylogenetically distant clades. About one-third of the strains had non-wild-type MICs. They were resistant to at least one of the following antimicrobials: tetracycline, benzylpenicillin, oxacillin, erythromycin, clindamycin, trimethoprim, gentamicin, or streptomycin, encoded by tet(K), blaZ/blaARL, mecA/mecA1, msrA/mphC, salA, dfrG, aacA-aphD, and str, respectively. We identified the first methicillin- and multidrug-resistant camel S. epidermidis strain of sequence type (ST) 1136 in East Africa. The pool of virulence-encoding genes was largest in the S. aureus strains, as expected, although other rather commensal strains contained distinct virulence-encoding genes. We identified toxin-antitoxin (TA) systems such as the hicA/hicB and abiEii/abiEi families, reported here for the first time for certain species of Staphylococcaceae. All strains contained at least one intact prophage sequence, mainly belonging to the Siphoviridae family. We pinpointed potential horizontal gene transfers between camel and cattle strains and also across distinct Staphylococcaceae clades and species. IMPORTANCE Camels are a high value and crucial livestock species in arid and semiarid regions of Africa and gain importance giving the impact of climate change on traditional livestock species. Our current knowledge with respect to Staphylococcaceae infecting camels is very limited compared to that for other livestock species. Better knowledge will foster the development of specific diagnostic assays, guide promising antimicrobial treatment options, and inform about potential zoonotic risks. We characterized 84 Staphylococcaceae strains isolated from camels with respect to their antimicrobial resistance and virulence traits. We detected potentially novel Staphylococcus species, resistances to different classes of antimicrobials, and the first camel multidrug-resistant S. epidermidis strain of sequence type 1136.


Building a replisome from interacting pieces: sliding clamp complexed to a peptide from DNA polymerase and a polymerase editing complex.
We have solved the crystal structures of the bacteriophage RB69 sliding clamp, its complex with a peptide essential for DNA polymerase interactions, and the DNA polymerase complexed with primer-template DNA. The editing complex structure shows a partially melted duplex DNA exiting from the exonuclease domain at an unexpected angle and significant changes in the protein structure. The clamp complex shows the C-terminal 11 residues of polymerase bound in a hydrophobic pocket, and it allows docking of the editing and clamp structures together. The peptide binds to the sliding clamp at a position identical to that of a replication inhibitor peptide bound to PCNA, suggesting that the replication inhibitor protein p21CIP1 functions by competing with eukaryotic polymerases for the same binding pocket on the clamp.


[Modern aspects of wound sepsis in war surgical trauma].
The results of the treatment of 1020 wounded with symptoms of wound infection have been studied. The wounded were admitted with developed complications from the hospitals in Afghanistan. The syndrome of systemic inflammatory reaction detected in 239 (23.4%) wounded was the indication for application of the whole complex of antiseptic treatment. Sepsis in patients with complicated gunshot wounds was revealed only in 54 wounded, i.e. in 5.4%. Early diagnosis and multicomponent therapy resulted in a decrease of mortality rate in wound sepsis up to 9.3%.


Changes in measles seroepidemiology of healthcare workers in southern Taiwan.
To assess the measles seroepidemiology of healthcare workers (HCWs), from 2004 to 2009 all newly recruited staff at a university hospital in Taiwan, were tested for specific immunoglobulin G antibodies for measles virus using enzyme-linked immunosorbent assays. A total of 1584 HCWs were included. The positivity rate of measles antibody for physicians and nurses was about 90%. The positivity of measles antibody in different age groups was 78·1%, 93·9% and 94·2% for 20-29, 30-39 and ≥40 years age groups, respectively. Equivocal results were more frequent in the 20-29 (17·1%) years age group. A lack of antibody against measles was reported for 66 (4·2%) of those tested. Medical student (8·3%) and housekeeping personnel (5·3%) had the greatest lack of antibodies. This study demonstrates the waning measles immunity in younger HCWs in Taiwan, which poses the potential risk of nosocomial transmission of measles. Periodic surveillance and revaccination of susceptible HCWs is recommended.


Specialty-specific multi-source feedback: assuring validity, informing training.
The white paper 'Trust, Assurance and Safety: the Regulation of Health Professionals in the 21st Century' proposes a single, generic multi-source feedback (MSF) instrument in the UK. Multi-source feedback was proposed as part of the assessment programme for Year 1 specialty training in histopathology. An existing instrument was modified following blueprinting against the histopathology curriculum to establish content validity. Trainees were also assessed using an objective structured practical examination (OSPE). Factor analysis and correlation between trainees' OSPE performance and the MSF were used to explore validity. All 92 trainees participated and the assessor response rate was 93%. Reliability was acceptable with eight assessors (95% confidence interval 0.38). Factor analysis revealed two factors: 'generic' and 'histopathology'. Pearson correlation of MSF scores with OSPE performances was 0.48 (P = 0.001) and the histopathology factor correlated more highly (histopathology r = 0.54, generic r = 0.42; t = - 2.76, d.f. = 89, P < 0.01). Trainees scored least highly in relation to ability to use histopathology to solve clinical problems (mean = 4.39) and provision of good reports (mean = 4.39). Three of six doctors whose means were < 4.0 received free text comments about report writing. There were 83 forms with aggregate scores of < 4. Of these, 19.2% included comments about report writing. Specialty-specific MSF is feasible and achieves satisfactory reliability. The higher correlation of the 'histopathology' factor with the OSPE supports validity. This paper highlights the importance of validating an MSF instrument within the specialty-specific context as, in addition to assuring content validity, the PATH-SPRAT (Histopathology-Sheffield Peer Review Assessment Tool) also demonstrates the potential to inform training as part of a quality improvement model.


Why direct or reversed Hofmeister series? Interplay of hydration, non-electrostatic potentials, and ion size.
A modified Poisson-Boltzmann analysis is made of the double layer interaction between two silica surfaces and two alumina surfaces in chloride electrolyte. The analysis incorporates nonelectrostatic ion-surface dispersion interactions based on ab initio ionic excess polarizabilities with finite ion sizes. A hydration model for the tightly held hydration shell of kosmotropic ions is introduced. A direct Hofmeister series (K > Na > Li) is found at the silica surface while the reversed series (Li > Na > K) is found at alumina, bringing theory in line with experiment for the first time. Calculations with unhydrated ions also suggest that surface-induced dehydration may be occurring at the alumina surface.


4π-Periodic Supercurrent from Surface States in Cd_{3}As_{2} Nanowire-Based Josephson Junctions.
The combination of superconductivity and surface states in Dirac semimetal can produce a 4π-periodic supercurrent in a Josephson junction configuration, which can be revealed by the missing of odd Shapiro steps (especially the n=1 step). However, the suppression of the n=1 step is also anticipated in the high-power oscillatory regime of the ordinary 2π-periodic Josephson effect, which is irrelevant to the 4π-periodic supercurrent. Here, in order to identify the origin of the suppressed n=1 step, we perform the measurements of radio frequency irradiation on Nb-Dirac semimetal Cd_{3}As_{2} nanowire-Nb junctions with continuous power dependence at various frequencies. Besides the n=1 step suppression, we uncover a residual supercurrent of first node at the n=0 step, which provides a direct and predominant signature of the 4π-periodic supercurrent. Furthermore, by tuning the gate voltage, we can modulate the surface and bulk state contribution and the visibility of the n=1 step. Our results provide deep insights to explore the topological superconductivity in Dirac semimetals.


Interictal spikes, fast ripples and seizures in partial epilepsies--combining multi-level computational models with experimental data.
Epileptic seizures, epileptic spikes and high-frequency oscillations (HFOs) are recognized as three electrophysiological markers of epileptogenic neuronal systems. It can be reasonably hypothesized that distinct (hyper)excitability mechanisms underlie these electrophysiological signatures. The question is 'What are these mechanisms?'. Solving this difficult question would considerably help our understanding of epileptogenic processes and would also advance our interpretation of electrophysiological signals. In this paper, we show how computational models of brain epileptic activity can be used to address this issue. With a special emphasis on the hippocampal activity recorded in various experimental models (in vivo and in vitro) as well as in epileptic patients, we confront results and insights we can get from computational models lying at two different levels of description, namely macroscopic (neural mass) and microscopic (detailed network of neurons). At each level, we show how spikes, seizures and HFOs can (or cannot) be generated depending on the model features. The replication of observed signals, the prediction of possible mechanisms as well as their experimental validation are described and discussed; as are the advantages and limitations of the two modelling approaches.


Disruption of CD8+ Treg activity results in expansion of T follicular helper cells and enhanced antitumor immunity.
Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs CD8 Treg suppressive activity. Here, we report that the growth of B16 melanoma is substantially delayed in these Qa-1-mutant mice after therapeutic immunization with B16 melanoma cells engineered to express granulocyte macrophage colony-stimulating factor compared with Qa-1 B6-WT controls. Reduced tumor growth is associated with enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor-infiltrating T cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8(+) T effectors compared with CD8 Tregs. These data suggest that the CD8(+) T effector-Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Tregs represents a potentially effective strategy to enhance antitumor immunity.


Radionuclide measurement of liquid and solid gastric emptying in normal subjects in Singapore.
Scintigraphic methods for liquid and solid gastric emptying were utilised to study normal patterns in 21 volunteers. Of these, 19 had solid emptying studies and 14 had liquid emptying studies. The liquid study lasted 1/2 hour, while the solid study was for 1 hour. The gastric emptying half-time (T 1/2), as well as percentage retention at 15 minutes (liquids), and at 60 minutes (for solids) were noted. The time-activity curves were also corrected for tissue attenuation. Results indicated normal average liquid emptying T 1/2 to be 14.2 minutes, while that for solids was 116 minutes.


COMT Val(158)Met genotypes differentially influence subgenual cingulate functional connectivity in healthy females.
Brain imaging studies have consistently shown subgenual Anterior Cingulate Cortical (sgACC) involvement in emotion processing. catechol-O-methyltransferase (COMT) Val(158) and Met(158) polymorphisms may influence such emotional brain processes in specific ways. Given that resting-state fMRI (rsfMRI) may increase our understanding on brain functioning, we integrated genetic and rsfMRI data and focused on sgACC functional connections. No studies have yet investigated the influence of the COMT Val(158)Met polymorphism (rs4680) on sgACC resting-state functional connectivity (rsFC) in healthy individuals. A homogeneous group of 61 Caucasian right-handed healthy female university students, all within the same age range, underwent rsfMRI. Compared to Met(158) homozygotes, Val(158) allele carriers displayed significantly stronger rsFC between the sgACC and the left parahippocampal gyrus, ventromedial parts of the inferior frontal gyrus (IFG), and the nucleus accumbens (NAc). On the other hand, compared to Val(158) homozygotes, we found in Met(158) allele carriers stronger sgACC rsFC with the medial frontal gyrus (MFG), more in particular the anterior parts of the medial orbitofrontal cortex. Although we did not use emotional or cognitive tasks, our sgACC rsFC results point to possible distinct differences in emotional and cognitive processes between Val(158) and Met(158) allele carriers. However, the exact nature of these directions remains to be determined.


No evidence for a physiological coupling between melatonin and glucocorticoids.
Much has been speculated about the existence of a physiological coupling between melatonin and glucocorticoid secretion and about a possible anti-stress action of melatonin. We examined the relationship between melatonin and glucocorticoid secretion under close-to-physiological conditions, when the plasma concentration of either melatonin or glucocorticoids was elevated acutely or chronically in both rats and humans. Tryptophan administration caused a massive rise of plasma melatonin, but had no effect on corticosterone levels in rats or on cortisol levels in humans. The acute and long-lasting exposure of rats to uncontrollable stress resulted in a significant rise of adrenal corticosterone secretion, but had no effect on circulating melatonin levels. Orchectomy caused an initial increase in circulating corticosterone (when melatonin was unaffected) and a delayed rise in circulating melatonin (when corticosterone levels were normalized). In humans, no correlation was found between the nocturnal urinary excretion of melatonin and cortisol, either among healthy subjects, or among patients suffering from panic disorder (with an increased urinary excretion of cortisol) or among insomnia patients (with a high incidence of low melatonin secretion). Furthermore, no evidence was found for a suppressive action of melatonin on dexamethasone-mediated thymus regression in rats and on dexamethasone-mediated suppression of lymphocyte proliferation in vitro. Taken together, the results of this study provide no evidence for the existence of mutual influences between melatonin and glucocorticoid secretion, nor do they support the proposed attenuation of glucocorticoid-mediated effects on target cells or tissues by melatonin under physiological conditions.


Parental genome unification is highly error-prone in mammalian embryos.
Most human embryos are aneuploid. Aneuploidy frequently arises during the early mitotic divisions of the embryo, but its origin remains elusive. Human zygotes that cluster their nucleoli at the pronuclear interface are thought to be more likely to develop into healthy euploid embryos. Here, we show that the parental genomes cluster with nucleoli in each pronucleus within human and bovine zygotes, and clustering is required for the reliable unification of the parental genomes after fertilization. During migration of intact pronuclei, the parental genomes polarize toward each other in a process driven by centrosomes, dynein, microtubules, and nuclear pore complexes. The maternal and paternal chromosomes eventually cluster at the pronuclear interface, in direct proximity to each other, yet separated. Parental genome clustering ensures the rapid unification of the parental genomes on nuclear envelope breakdown. However, clustering often fails, leading to chromosome segregation errors and micronuclei, incompatible with healthy embryo development.


Double-blind evaluation of reinforcing and anorectic actions of weight control medications. Interaction of pharmacological and behavioral treatments.
Within a behavioral self-management treatment program for overweight, 59 patients were randomly assigned to receive as an adjunct either dextroamphetamine sulfate, fenfluramine hydrochloride, or placebo in a double-blind procedure. Patients self-regulated their drug intake during a four-week medication period. Two types of behavioral-pharmacological interaction were observed: (1) drug assignment influenced participation in the behavioral treatment; and (2) drug assignment influenced the extent of medication self-administration. The dextroamphetamine group was superior in terms of behavioral treatment participation, extent of eating and exercise habit change, and weight loss. Self-administration of dextroamphetamine was most well-maintained--showing it to be a reinforcer--and self-administration of fenfluramine was suppressed below placebo levels. No patient taking either drug showed excessive drug intake, and all were, in fact, conservative in drug use. These data concerning relative reinforcing efficacy within a therapeutic medication setting are discussed in relation to data from animal models used to assess relative abuse liability of these drugs.


Physiological Uptake Characteristics of Breast on 68Ga-FAPI-04 PET/CT.
Gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/CT is sensitive on breast cancer staging, but its clinical utility may be limited by the high physiological 68Ga-FAPI-04 uptake in normal breast tissue that can obscure primary tumors. The aim of this study was to elucidate the characteristics of physiological 68Ga-FAPI-04 uptake in normal breast. A total of 143 consecutive women with 68Ga-FAPI-04 PET/CT data were reviewed retrospectively. SUVmax, density and thickness of breast, as well as SUVmax of nipple, were measured. Univariate and multivariate regression analyses were used to identify factors related to the breast and nipple SUVs. Twenty-eight premenopausal, 62 menopausal and 10 post-operative (after bilateral adnexectomy) women with 103 examinations were included. All had a diffuse, symmetrical uptake in breast. There was no difference in 68Ga-FAPI-04 uptake between bilateral breasts (right: median, 1.14[IQR, 0.85-1.54] vs. left: median, 1.09[IQR, 0.86-1.54]; P = 0.253). Patients in menstrual status with expected high estrogen level (late follicular, ovulatory and mid luteal phases) had higher breast SUVs (median SUV, 3.91 [IQR, 2.85-4.35]) than those with expected moderate (early follicular, early luteal and late luteal phases; median SUV, 1.57 [IQR, 1.39-2.08]; P < 0.001) or low level (menopause and post-operation; median SUV, 0.98 [IQR, 0.83-1.21]; P < 0.001). Menstrual status was an independent predictors of breast SUV (r2 = 0.689, P < 0.001). All the patients had a focal, symmetrical uptake in nipples. Nipple SUV did not correlate with menstrual status (P = 0.913).


Interstitial fluid dynamics in conscious renal hypertensive rats.
Interstitial fluid pressure (IFP) was measured in conscious rats with one-kidney one-clip Goldblatt hypertension using implanted capsules. No significant differences in IFP were found between rats with hypertension of 3, 28, or 56 days duration and the one-kidney controls. To estimate interstitial compliance in the 28-day hypertensive and control rats, hyperosmotic albumin solution was infused intravenously. The subsequent transfer of tissue fluid into the intravascular space was associated with increased diuresis and decreased IFP. The changes in tissue fluid volume (TFV) were estimated from the changes in plasma volume and urine output. In the hypertensive rats 3 h postinfusion, TFV decreased by 36.3 +/- 2.9 ml/kg, and IFP decreased from -1.2 +/- 0.2 to -4.7 +/- 0.6 mmHg. In the normotensive rats TFV decreased by 36.7 +/- 2.7 ml/kg, and IFP decreased from -1.2 +/- 0.2 to -4.3 +/- 0.4 mmHg. Interstitial compliance, estimated from the regression of delta IFP and delta TFV, averaged 7.3 +/- 1.2 and 8.1 +/- 0.7 ml.kg-1.mmHg-1 (P greater than 0.5) in the hypertensive and normotensive rats, respectively. These results suggested that the rats with one-kidney one-clip Goldblatt hypertension had normal interstitial fluid dynamics.


Benzophenones, bisphenols and other polychlorinated/phenolic substances in Danish infants and their parents - including longitudinal assessments before and after introduction to mixed diet.
Humans are widely exposed to chemicals with known or suspected endocrine disrupting effects. Among those are several benzophenones, bisphenols and other phenols commonly used in consumer products. To provide human biomonitoring data from young families including infants and their parents as well as longitudinal data of infants exclusively breastfed versus on mixed diet. Twenty-two benzophenones, bisphenols and other phenols, were measured in urine sample sets collected from more than 100 infants and their parents (the TRIO study) and in paired samples from 61 infants when exclusively breastfed and after introduction of mixed diet (the FOOD study). Twelve out of 22 substances were detectable in more than half of the urine samples from infants, mothers or fathers. Large variation in excreted levels of almost all the substances were observed. The TRIO study showed that infants had comparable or even significantly higher daily urinary excretion (DUE) of benzophenone, 4-hydroxy-benzophenone, bisphenol A, bisphenol S, triclosan and 2-phenylphenol than their parents. In the FOOD study, exclusively breastfed infants had higher or similar DUE of triclosan and benzophenones compared to when they received mixed diet. Urinary levels of triclosan and the benzophenones, BP-1 and BP-3 were significantly correlated between all trio members, indicating exposure from the same sources at home. For triclosan, BP-1 and BP-3, the within family variation was lower than between families in the TRIO study. Many substances were positively correlated both within infants and parents, indicating that some families were exposed to several of these substances concurrently. Participants in this study excreted relatively low chemical levels, however, simultaneous exposure to several chemicals with endocrine disrupting abilities is of concern due to the dose-additive effects of these substances in combination with other chemicals.


[Various practical aspects of the problem of epilepsy].
The paper treats of the problems of early diagnosis, the necessity of treatment initiation at the prodromal stage (before typical epileptic seizures appear), problems of remission estimation and crossing off the register as well as of the problems of education and prevention of psychopathological disorders, deviant behavior, problems of the formation of pathological stereotypes, and antisocial behavior. Emphasis is laid on the importance of inserting corrections by the physicians into educational issues.


Maternal and fetal outcome of mothers with gestational diabetes mellitus attending BIRDEM Hospital.
Gestational diabetes mellitus, most of which progress to type-2 diabetes mellitus is increasing worldwide. Identification of gestational diabetes and control of glucose can reduce such complications and improve maternal and neonatal health. A hospital based cross sectional study was conducted to find out maternal and fetal outcome of gestational diabetes from January to July 2011. Data were collected from 109 gestational diabetes mothers attending Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) hospital for delivery. Study revealed that gestational diabetes was more common among mothers aged >25 years old and multiparaous women. Mean gestational age of diagnosis was 16.82±9.54 weeks. Sixty eight (68%) mothers were diagnosed before 20 weeks of gestation and more than 90% mothers with gestational diabetes delivered by caesarean section. Mean pregnancy weight gain was 6.8±1.18kg. Adverse maternal outcome observed in 24% cases and adverse fetal outcome was present in 34% cases. In univariate analysis weeks of delivery and fasting blood sugar were statistically significantly associated with adverse pregnancy outcome. Babies born to mothers with only diet restriction had less birth weight than mothers with insulin therapy. Pregnancy thought to be the most vulnerable stage of women's life and protecting her health along with her fetus during this period yields a positive impact on the health of future generation. Particular attention should be given during antenatal period to initiate screening programme and treatment protocol for gestational diabetic mothers.


Cost-effectiveness analysis of selexipag for the combined treatment of pulmonary arterial hypertension.
Objective: Adding selexipag to the combined treatment of endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitor (PDE5i) reduces the risk of clinical worsening events in patients with pulmonary arterial hypertension (PAH) but at a considerably higher cost. This study evaluated the cost-effectiveness of adding selexipag to the combined treatment of ERA and PDE5i in patients with PAH from a Chinese healthcare system perspective. Methods: A Markov model was developed to assess costs and quality-adjusted life years (QALYs) of macitentan + tadalafil + selexipag vs. macitentan + tadalafil for the treatment of PAH. Markov states included WHO Functional Class (FC) (I-IV) and death. Transition probabilities were based on data from the TRITON trial. Mortality rates, costs, and utilities were obtained from published literature and public databases. Results: In the base case analysis, compared with macitentan + tadalafil, selexipag + macitentan + tadalafil increased costs ($357,807.588 vs. $116,534.543, respectively) and QALYs (7.234 QALYs vs. 6.666 QALYs, respectively). The resulting incremental cost-effectiveness ratio was $424,746.070 per QALY, which was higher than the willingness-to-pay (WTP) of $38,223.339 per QALY. The results were most sensitive to HR for mortality of patients with FC IV relative to the general population, discount rate, and the cost of selexipag. The probability was greater than 50% for the selexipag + macitentan + tadalafil only if the WTP was more significant than $426,019.200 per QALY. Conclusion: In China, adding selexipag may not be cost-effective for patients with PAH who failed to control their condition after combined treatment of ERA and PDE5i. Results of the analysis can aid discussions on the value and position of selexipag for the combined treatment of PAH.


Pre-treatment deep curettage can significantly reduce tumour thickness in thick Basal cell carcinoma while maintaining a favourable cosmetic outcome when used in combination with topical photodynamic therapy.
Topical photodynamic therapy (PDT) has limitations in the treatment of thick skin tumours. The aim of the study was to evaluate the effect of pre-PDT deep curettage on tumour thickness in thick (≥2 mm) basal cell carcinoma (BCC). Additionally, 3-month treatment outcome and change of tumour thickness from diagnosis to treatment were investigated. At diagnosis, mean tumour thickness was 2.3 mm (range 2.0-4.0). Pre- and post-curettage biopsies were taken from each tumour prior to PDT. Of 32 verified BCCs, tumour thickness was reduced by 50% after deep curettage (P ≤ 0.001). Mean tumour thickness was also reduced from diagnosis to treatment. At 3-month followup, complete tumour response was found in 93% and the cosmetic outcome was rated excellent or good in 100% of cases. In conclusion, deep curettage significantly reduces BCC thickness and may with topical PDT provide a favourable clinical and cosmetic short-term outcome.


The role of methylation in urological tumours.
Alterations in DNA methylation have been described in human cancer for more than thirty years now. Since the last decade DNA methylation gets more and more important in cancer research. In this review the different alterations of DNA methylation are discussed in testicular germ cell tumours, Wilms'tumours, renal cell carcinomas, urothelial cell carcinomas of the bladder and adenocarcinomas of the prostate. Eventually, the potential use in diagnostics, prognostics and therapy are discussed.


Long-term cumulative depressive symptom burden and risk of cognitive decline and dementia among very old women.
Depressive symptoms and cognitive outcomes are strongly interrelated. Despite that rates of depressive symptoms fluctuate during late life, little is known about the impact of long-term cumulative depressive symptom burden on cognitive decline and dementia in older adults. This study examines the association of nearly 20 years of cumulative depressive symptoms with cognitive outcomes in a cohort of older women. We assessed depressive symptoms in 7,240 women using the Geriatric Depression scale (GDS) at serial visits. We used a Poisson model with random slopes to estimate GDS trajectories for each participant from baseline to death or end of follow-up, and then characterized depressive symptom burden by quartile of the area under the curve. We assessed cognitive outcomes using repeated measures of the Mini-Mental State Examination (MMSE) and Trails B score over 20 years, Year-20 neuropsychological test battery, and adjudicated dementia and mild cognitive impairment (MCI). Adjusting for potential confounders, compared with women in the lowest quartile of cumulative depressive symptoms burden, women in the highest quartile had 21% more MMSE errors over time (95% CI = 17%, 26%), 20% worse Trails B score over time (95% CI = 17%, 23%), worse scores on most of the Year-20 cognitive tests, and a twofold greater likelihood of developing dementia or MCI (95% CI = 1.48, 3.11). Long-term cumulative depressive symptom burden was associated with cognitive decline and risk of dementia or MCI. Older adults with a history of depression should be closely monitored for recurrent episodes or unresolved depressive symptoms as well as any cognitive deficits.


Unique presynaptic alpha 2-receptor selectivity and specificity of the antihypertensive agent moxonidine.
The characteristics of the alpha-receptor activating property of the new antihypertensive agent moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methyl-2-methyl-5-pyrimidinamine, BDF 5895) was studied using peripheral vasculature and brain membranes of various animals. Moxonidine exerted a full agonist effect in elevating diastolic blood pressure in the pithed rat. Activation of postsynaptic alpha 1- and alpha 2-receptors contribute to the vasoconstrictory effect in rats. In the vasculature of the rabbit, moxonidine was a full agonist at presynaptic alpha 2-receptors in inhibiting transmitter release induced by electrical stimulation of pulmonary artery strips. At postsynaptic sites, exogenously applied moxonidine was a full agonist at alpha 1-receptors in the isolated aorta, pulmonary artery and vena cava of the rabbit. Selectivity for alpha 2-receptors in the pulmonary artery was 106-fold. In rat brain membranes, moxonidine showed 288-fold greater selectivity for alpha 2-receptors, when the displacement of [3H]-rauwolscine was compared with the displacement of [3H]-prazosin. On the whole, clonidine exhibited greater potency than moxonidine on both alpha-receptor subtypes, but moxonidine consistently showed greater alpha 2-receptor selectivity than clonidine. In the guinea pig myocardium, moxonidine caused neither bradycardia nor tachycardia in the isolated right atrium and produced a negligible positive inotropic effect at 100 mumol/l in the isolated papillary muscle.


Synthesis and hypolipidemic activities of 5-thienyl-4-oxazoleacetic acid derivatives.
A series of 2,5-disubstituted 4-oxazoleacetic acid derivatives was synthesized and evaluated for hypolipidemic activity. Among them, those with a thienyl group at C-5 of the oxazole ring exerted highly potent hypolipidemic effects in rats. 2-(4-Fluorophenyl)-5-(3-thienyl)-4-oxazoleacetic acid (88) was the most potent derivative: it was about 2 times as active in normal SD male rats and about 4 times as active in hereditary hyperlipidemic rats (THLR/1) as clofibrate with an improved antiarteriosclerosis index (HDL-Cho/Total-Cho). In addition, it showed inhibition of platelet aggregation ex vivo.


Conformity does not perpetuate suboptimal traditions in a wild population of songbirds.
Social learning is important to the life history of many animals, helping individuals to acquire new adaptive behavior. However despite long-running debate, it remains an open question whether a reliance on social learning can also lead to mismatched or maladaptive behavior. In a previous study, we experimentally induced traditions for opening a bidirectional door puzzle box in replicate subpopulations of the great tit Parus major Individuals were conformist social learners, resulting in stable cultural behaviors. Here, we vary the rewards gained by these techniques to ask to what extent established behaviors are flexible to changing conditions. When subpopulations with established foraging traditions for one technique were subjected to a reduced foraging payoff, 49% of birds switched their behavior to a higher-payoff foraging technique after only 14 days, with younger individuals showing a faster rate of change. We elucidated the decision-making process for each individual, using a mechanistic learning model to demonstrate that, perhaps surprisingly, this population-level change was achieved without significant asocial exploration and without any evidence for payoff-biased copying. Rather, by combining conformist social learning with payoff-sensitive individual reinforcement (updating of experience), individuals and populations could both acquire adaptive behavior and track environmental change.


Simultaneous broadband Raman cascading and parametric conversion in potassium titanyl phosphate.
We generated a broad spectrum of light between 1064 and 1300 nm in the infrared by cascading stimulated Raman scattering in a potassium titanyl phosphate crystal while broadband conversion of the infrared Raman cascade was simultaneously achieved in the visible through second-harmonic generation (SHG) and sum-frequency mixing. We observed that odd- and even-order cascaded Stokes components were spatially addressed at different angles of propagation in the crystal. The efficiency of SHG and sum-frequency mixing is discussed as a function of the pump polarization. We also report on significant spatial distortions of the output Stokes beams.


Case Management on the Front Lines of COVID-19: The Importance of the Individualized Care Plan Across Care Settings.
Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease known as COVID-19, case management has emerged as a critical intervention in the treatment of cases, particularly for patients with severe symptoms and medical complications. In addition, case managers have been on the front lines of the response across the health care spectrum to reduce risks of contagion, including among health care workers. The purpose of this article is to discuss the case management response, highlighting the importance of individual care plans to provide access to the right care and treatment at the right time to address both the consequences of the disease and patient comorbidities. The COVID-19 response spans the full continuum of health and human services, including acute care, subacute care, workers' compensation (especially catastrophic case management), home health, primary care, and community-based care. From the earliest days of the pandemic, case managers have assumed an important role on the front lines of the medical response to COVID-19, ensuring that procedures are in place for managing a range of patients: those who were symptomatic but able to self-isolate and care for themselves at home; those who had serious symptoms and needed to be hospitalized; and those who were asymptomatic and needed to be educated about the importance of self-isolating. Across the care spectrum, individualized responses to the clinical and psychosocial needs of patients with COVID-19 in acute care, subacute care, home health, and other outpatient settings have been guided by the well-established case management process of screening, assessing, planning, implementing, following up, transitioning, and evaluating. In addition, professional case managers are guided by values such as advocacy, ensuring access to the right care and treatment at the right time; autonomy, respecting the right to self-determination; and justice, promoting fairness and equity in access to resources and treatment. The value of justice also addresses the sobering reality that people from racial and ethnic minority groups are at an increased risk of getting sick and dying from COVID-19. Going forward, case management will continue to play a major role in supporting patients with COVID-19, in both inpatient and outpatient settings, with telephonic follow-up and greater use of telehealth.


Cathepsin K levels in the crevicular fluid of dental implants: a pilot study.
To determine the concentration of cathepsin K secreted into the crevicular fluid around dental implants and its correlation with clinical parameters of healthy implants and implants showing clinical signs of peri-implantitis. Nineteen patients with 40 implants with and without peri-implantitis were enrolled in the study. Peri-implantitis was diagnosed by the pocket probing depth (PD), the modified bleeding index (MBI), the modified plaque index (MPI) and by radiographic signs of bone loss. Gingival crevicular fluid collected from the buccal and lingual sites was adsorbed to filter strips. Cathepsin K levels and total protein within the crevicular fluid were determined by immunoassay and the bicinchoninic method, respectively. Cathepsin K per filter strip normalized to the time of collection was 10.1 (0-33.5) pmol/sample around control implants and 22.4 (3.7-56.3) pmol/sample in the peri-implantitis group. The difference between the medians was significant (p < 0.01). Absolute cathepsin K levels in the crevicular fluid of all implants investigated showed a positive correlation with PD (R = 0.25; p = 0.03), MPI (R = 0.28; p = 0.01) and MBI (R = 0.32; p < 0.01). Absolute cathepsin K levels in the crevicular fluid also correlated with the adsorbed volume of gingival crevicular fluid (R = 0.51; p < 0.01). When normalized to the adsorbed volume of gingival crevicular fluid, the concentration of cathepsin K was 2.2 (0.01-6.4) nM around control implants and 1.7 (0.4-4.6) nM in the peri-implantitis group (p = 0.33). Patients' age correlated with sample volume and with cathepsin K normalized to the adsorbed volume of gingival crevicular fluid (R = 0.39; p < 0.01). Moreover, significant differences between male and female (p < 0.01, p < 0.01), and between mandible and maxilla (p < 0.05, p < 0.01), but not between buccal and lingual sites (p = 0.99, p= 0.93), were observed when analysed for the parameters adsorbed volume and absolute cathepsin K levels. Clinical parameters of peri-implantitis are associated with a higher amount of cathepsin K and a higher volume adsorbed to filters strips. To establish cathepsin K as a biochemical parameter to monitor peri-implant tissue health, age, sex and collection site should be considered to avoid interfering influences because of sample inhomogenity. Also a prospective study over time including more patients would be necessary.


Percutaneous endoscopic cellular transplantation into the lower lumbar spinal cord.
To explore the feasibility of performing percutaneous endoscopic cellular transplantation into the lumbar spinal cord of pigs to create intramedullary cellular trails. The lumbar subarachnoid space was accessed using a 10-gauge needle inserted between L5 and L6. A 12.5-French flexible introducer sheath was fed over the needle into the subarachnoid space. A 3.2-mm-diameter flexible, steerable endoscope was then directed intradurally through the sheath. The thecal space was distended by saline infusion. A microcatheter with an attached needle then was advanced through the working channel into the dorsal surface of the lumbar spinal cord. Five microliters of Hoechst-labeled fibroblasts were injected while the catheter was withdrawn slowly to create a trail of cells within the spinal cord. The spinal canal then was perfused with fixative. The injected spinal cord segment was removed and studied histologically. Endoscopic video was analyzed offline. The endoscope could be navigated under visual guidance. The sacral and lumbar rootlets, the spinal cord, and associated vessels were visualized. In fixed sagittal sections, a linear trail of fluorescent fibroblasts could be seen within the lumbar spinal cord in each specimen. Percutaneous endoscopic cellular injection may be useful for cellular transplantation, may reduce surgical and anesthetic time, may be compatible with local anesthesia, may eliminate the need to disrupt spinal instrumentation and bone grafts, and may allow greater flexibility in the respective timing of spinal fixation and cellular transplantation after spinal cord injury. This is the first report of the use of endoscopic intraspinal cellular transplantation.


Interactive Web Tool for Standardizing Proteomics Workflow for Liquid Chromatography-Mass Spectrometry Data.
The proteomics experiments involve several steps and there are many choices available for each step in the workflow. Therefore, standardization of proteomics workflow is an essential task for design of proteomics experiments. However, there are challenges associated with the quantitative measurements based on liquid chromatography-mass spectrometry such as heterogeneity due to technical variability and missing values. We introduce a web application, Proteomics Workflow Standardization Tool (PWST) to standardize the proteomics workflow. The tool will be helpful in deciding the most suitable choice for each step of the experimentation. This is based on identifying steps/choices with least variability such as comparing Coefficient of Variation (CV). We demonstrate the tool on data with categorical and continuous variables. We have used the special cases of general linear model, analysis of covariance and analysis of variance with fixed effects to study the effects due to various sources of variability. We have provided various options that will aid in finding the contribution of sum of squares for each variable and the CV. The user can analyze the data variability at protein and peptide level even in the presence of missing values. The source code for "PWST" is written in R and implemented as shiny web application that can be accessed freely from https://ulbbf.shinyapps.io/pwst/.


[Pancreatoduodenal resection in treatment of cancer of pancreatic head and periampullar zone].
Results of 120 pancreatoduodenal resections are analyzed. Early postoperative period complications were seen in 51 (42.5%) patients. Overall lethality during 30 days after surgery was 13.3%. Over the last decade lethality reduced to 5%. Life time was studied in 91 patients with cancer of the pancreas (PS) and periampullar zone (PAZ) with Kaplan-Meyer method. Median of life of patients with cancer of PS was 14 months, Vater's papilla (VP)--37 months, terminal part of common bile duct (TPCBD)--30 months, duodenum--30 months. One-, 3-, 5-year survival in cancer of PS was 53, 11 and 3%, in cancer of VP--80, 50 and 31%, in cancer of TPCBD--80, 20% and 0, in duodenal cancer--80, 50 and 33%, respectively. Prognosis factors correlating with the survival were following: 1) primary location of tumor; 2) size of tumor; 3) radicality of surgery; 4) regional lymphatic metastases; 5) invasion of vessels by tumor; 6) index of oncomarker CA 19-9. Early diagnosis of cancer of PS and PAZ, optimization of surgical policy and techniques, using other methods in complex improve results of pancreatoduodenal resections.


Neutrophilic urticaria.
We studied 241 consecutive skin biopsies from patients with urticaria. Ten of the 241 specimens showed inflammation of dermal venules primarily with polymorphonuclear leukocytes, without evidence of necrotizing vasculitis. We speculated that this finding might represent an early histological form of urticarial vasculitis. However, review of the clinical histories and laboratory data from these 10 cases showed that most were associated with dermographism, normocomplementaemia, and negative direct immunofluorescence. These findings suggest that urticarial lesions with the histological picture of neutrophils in vessel walls may imply the presence of physical urticaria.