Ultrastructural study of closed macular hole- preliminary application of a novel high magnification module combining with OCT.
As a novel high magnification module (HMM) combining with OCT (OCT-HMM) is able to detect the microstructure of retina, we apply it to explore the ultrastructure of the macula after closure of the idiopathic macular hole (IMH) by surgery. This is an observational case series study in which patients with full-thickness IMHs who had undergone successful macular closure by vitrectomy and internal limiting membrane peeling and healthy subjects were recruited. After comprehensive ophthalmic examinations, the images of macular area were obtained and collected by professional operators using OCT-HMM. Then images were independently analyzed by 4 masked vitreoretinal specialists. A total of 24 IMH eyes and 42 healthy eyes were examined. HMM images were obtained in 10 IMH eyes. Among them, 4 eyes whose macula closed completely with recovery of photoreceptor layer presented a dark arc nasal to the fovea, oriented to the optic, and the notch of arc faced temporally. Six eyes in which the macula closed incompletely with photoreceptor cells loss revealed a dark ring with uneven bright spots inside. The other 14 eyes failed to obtain clear images by OCT-HMM. The contra lateral eyes of the patients and the healthy subjects' eyes succeeded to obtain the HMM images which displayed evenly grey background thickly covered with tiny bright dots that was in similar size and evenly and widely distributed and there no dark arc or ring. OCT B-scan and IR images could be acquired in all of the IMH and healthy eyes. The preliminary application of HMM has supplied us a brand-new insight into the microstructure of closed IMH. A dark arc sign could be detected with OCT-HMM in the macula which was functionally closed after surgery that was probably the healing mark on a microstructure photoreceptors level. Its existence and shape indicated that the functional closure followed by a retinal displacement mainly horizontally from temporal side to nasal side but not symmetric centripetally.


The effect of compulsory participation of medical students in problem-based learning.
Problem-based learning (PBL) is an instructional method that has attracted many advocates since its introduction in medical education almost 20 years ago. PBL features the use of student-directed tutorials, medically relevant problems to set study objectives, and independent learning. Educators have worried that not all students will do well with this method. This study compared a group of students who had chosen to be in a PBL curriculum with a group who had not, as they undertook a curriculum that contained both PBL and lecture-based courses. Academic performance was virtually identical regardless of learning method. Students slightly favoured the courses that featured the method they had originally chosen, but a significantly larger proportion of students shifted their preference from the lecture to the problem-based approach than vice versa. Students' academic performance does not appear to suffer when they are involuntarily enrolled in a PBL curriculum and many come to prefer this type of curriculum.


Models and molecular mechanisms of blood vessel co-option by cancer cells.
Cancer cells have diverse mechanisms for utilizing the vasculature; they can initiate the formation of new blood vessels from preexisting ones (sprouting angiogenesis) or they can form cohesive interactions with the abluminal surface of preexisting vasculature in the absence of sprouting (co-option). The later process has received renewed attention due to the suggested role of blood vessel co-option in resistance to antiangiogenic therapies and the reported perivascular positioning and migratory patterns of cancer cells during tumor dormancy and invasion, respectively. However, only a few molecular mechanisms have been identified that contribute to the process of co-option and there has not been a formal survey of cell lines and laboratory models that can be used to study co-option in different organ microenvironments; thus, we have carried out a comprehensive literature review on this topic and have identified cell lines and described the laboratory models that are used to study blood vessel co-option in cancer. Put into practice, these models may help to shed new light on the molecular mechanisms that drive blood vessel co-option during tumor dormancy, invasion, and responses to different therapies.


Biomarkers of response to checkpoint inhibitors beyond PD-L1 in lung cancer.
Immunotherapy, including use of checkpoint inhibitors against PD-1, PD-L1, and CTLA-4, forms the backbone of oncologic management for the majority of non-small cell lung carcinoma patients. However, response to these therapies varies widely, from patients who have complete resolution of metastatic disease and long-term remission, to those who rapidly progress and succumb to their cancer despite use of the newest checkpoint inhibitors. While PD-L1 protein expression by immunohistochemistry serves as the principle predictive biomarker for immunotherapy response, neither the sensitivity nor the specificity of this approach is optimal, and clinical PD-L1 testing is plagued by concerns around result reproducibility and confusion born from the proliferation of different companion diagnostic assays. At the same time, insights into tumor and host immune-specific factors that inform both prognosis and response prediction are beginning to define better immunotherapy biomarkers. Beyond immune checkpoint expression status, common themes in analyses of immunotherapy response prediction include cancer neoantigen production, the state of the antigen presentation pathway in both tumor and antigen presenting cells, the admixture of effector and suppressor immune cells in the tumor microenvironment, and the genomic drivers and comutations that can influence the all of these variables. This review will address the state of PD-L1 testing in lung cancer, the role for tumor mutation burden as a predictive biomarker, the evolving status of human leukocyte antigen/major histocompatibility complex expression as a marker of antigen presentation, approaches to tumor immune cell quantitation including by multiplex immunofluorescence, and the importance of tumor genomic profiling to ascertain oncogenic driver (EGFR, ALK, KRAS, MET, etc.) and co-mutation (STK11, KEAP1, SMARCA4) status.


Effect of adenosine deaminase and an adenosine analogue on insulin sensitivity in soleus muscle of the rat.
The concentration of insulin that produces half-maximal stimulation of glycolysis in stripped soleus muscle preparations is decreased from approximately 100-10 muunits/ml by the presence of adenosine deaminase in the incubation medium. This suggests that adenosine decreases insulin sensitivity. The effect of the deaminase is abolished by addition of the adenosine analogue, N6-phenylisopropyladenosine which is not metabolised by the deaminase. The effect of the deaminase in isolated soleus muscle is similar to that of a period of physical training of the rat.


Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins.
Proteomic-based techniques provide a powerful tool for identifying the full spectrum of protein targets of a drug, elucidating its mechanism(s) of action, and identifying biomarkers of its efficacy and safety. Herein, we outline the technological advancements in the field, and illustrate the contribution of proteomics to the definition of the pharmacological profile of statins, which represent the cornerstone of the prevention and treatment of cardiovascular diseases (CVDs). Statins act by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, thus reducing cholesterol biosynthesis and consequently enhancing the clearance of low-density lipoproteins from the blood; however, HMG-CoA reductase inhibition can result in a multitude of additional effects beyond lipid lowering, known as 'pleiotropic effects'. The case of statins highlights the unique contribution of proteomics to the target profiling of a drug molecule.


Boutonneuse fever in Portugal: 1995-2000. Data of a state laboratory.
From 1995 through 2000, 3239 clinical samples were tested for rickettsiosis at the Center for Vectors and Infectious Diseases Research--National Health Institute in Portugal. Boutonneuse fever due to R. conorii Malish or R. conorii Israel was laboratory confirmed in 374 samples (11.5%). Clinical and epidemiological features are discussed.


Bioaccessibility of antimony and arsenic in highly polluted soils of the mine area and health risk assessment associated with oral ingestion exposure.
In this study, the bioaccessibility and the human health risks of Sb and As in soils from Xikuangshan (XKS) Sb mine, Hunan, China were investigated using two commonly used in vitro extraction methods, Simplified Bioaccessibility Extraction Test (SBET) and Physiologically Based Extraction Test (PBET). Soils in the XKS Sb mine area were mainly co-contaminated by Sb (74.2-16,389; mean: 3061mgkg(-1)) and As (7.40-596; mean: 216mgkg(-1)). The bioaccessibility values of Sb and As in most cases were less than 30%, and the average bioaccessibility values of Sb and As were 5.89±6.44% and 2.13±2.55% for the SBET extraction; 7.83±9.82% and 6.62±6.37% for the PBET (Gastric) extraction; and 3.03±3.53% and 2.40±2.01% for the PBET (Intestinal) extraction, respectively. The bioaccessible Sb and As were significantly positively correlated with the total concentrations, but negatively correlated with the Fe, Al, Mn and organic matter (OM) contents in soils. Risk assessment results based on total concentrations might overestimate the risk existing in the studied area. After considering the bioaccessibility, the Hazard Quotient (HQ) values of Sb for most of the sampling sites and of As for all of the sampling sites became lower than 1. The Carcinogenic Risk (CR) values of As were also significantly reduced, 8.77E-06 and 1.74E-05 on average for the SBET and PBET methods, respectively. Considering the bioaccessibility can provide more applicable guidelines for risk assessments and more rational suggestions in the management of the soils contaminated with Sb and As.


Specific deletion of LKB1/Stk11 in the Müllerian duct mesenchyme drives hyperplasia of the periurethral stroma and tumorigenesis in male mice.
Nearly all older men will experience lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH), the etiology of which is not well understood. We have generated Stk11CKO mice by conditional deletion of the liver kinase B1 (LKB1) tumor suppressor gene, Stk11 (serine threonine kinase 11), in the fetal Müllerian duct mesenchyme (MDM), the caudal remnant of which is thought to be assimilated by the urogenital sinus primordial mesenchyme in males during fetal development. We show that MDM cells contribute to the postnatal stromal cells at the dorsal aspect of the prostatic urethra by lineage tracing. The Stk11CKO mice develop prostatic hyperplasia with bladder outlet obstruction, most likely because of stromal expansion. The stromal areas from prostates of Stk11CKO mice, with or without significant expansion, were estrogen receptor positive, which is consistent with both MD mesenchyme-derived cells and the purported importance of estrogen receptors in BPH development and/or progression. In some cases, stromal hyperplasia was admixed with epithelial metaplasia, sometimes with keratin pearls, consistent with squamous cell carcinomas. Mice with conditional deletion of both Stk11 and Pten developed similar features as the Stk11CKO mice, but at a highly accelerated rate, often within the first few months after birth. Western blot analyses showed that the loss of LKB1 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) induces activation of the phospho-5' adenosine monophosphate-activated protein kinase and phospho-AKT serine/threonine kinase 1 signaling pathways, as well as increased total and active β-catenin. These results suggest that activation of these signaling pathways can induce hyperplasia of the MD stroma, which could play a significant role in the etiology of human BPH.


'Giving and taking': endothelial and beta-cells in the islets of Langerhans.
The beta-cells of the islets of Langerhans are embedded in a dense capillary network. The blood vessels supply the islet cells with nutrients and oxygen, and in turn take up the secreted islet hormones to deliver them to target tissues. In addition, vessels provide a basement membrane, which optimizes islet function. In this review we focus on the dynamic interactions between blood vessels and beta-cells, which are pivotal for enhancing insulin expression and beta-cell proliferation in response to increased insulin demand during body growth, pregnancy, and virtually all conditions associated with insulin resistance. Importantly, a failure in this adaptive response might contribute to the onset of type 2 diabetes mellitus.


Cellular immunity to cartilage aggrecan core protein in patients with rheumatoid arthritis and non-arthritic controls.
To identify antigen(s) among purified deglycosylated aggrecan peptides spanning the chondroitin sulphate domain that may be responsible for the initiation or perpetuation of the autoimmune responses in rheumatoid arthritis (RA). Aggrecan was purified from human articular cartilage and deglycosylated with either bacterial glycosidases or trifluoromethanesulphonic acid (TFMS). Twelve overlapping peptides (15 residues) spanning the chondroitin sulphate domain with N-terminal residues offset by three amino acids were synthesised. T cell responses to these antigens in RA patients and age matched controls were assessed in vitro by antigen specific T cell proliferation assays. Enzymically deglycosylated aggrecan (EDA) stimulated proliferation of T cells isolated from the peripheral blood in a greater proportion of patients with RA than controls. In a subset (12.5%) of RA patients, the magnitude of stimulation lay outside the control range. T cell proliferative responses to TFMS treated aggrecan were greater than, but well correlated with, responses to EDA. T cells from 15 patients were also stimulated with the pooled synthetic peptides. Four of seven patients who demonstrated T cell reactivity to EDA (seven of 15) also showed enhanced T cell proliferation to synthetic peptides. These data suggest that an autoantigenic T cell epitope may lie within the chondroitin sulphate domain of aggrecan.


Incidental Detection of Sinonasal Inverted Papilloma With 68Ga-FAPI PET/CT in a Patient With Esophageal Cancer.
A 68-year-old man with newly diagnosed esophageal cancer was included in a clinical trial of 68Ga-FAPI PET/CT study in tumors (ChiCTR2100044131). Increased tracer uptake was noted in esophageal cancer. In addition, sinonasal inverted papilloma also revealed increased FAPI activity.


Impact of sex on virologic response rates in genotype 1 chronic hepatitis C patients with peginterferon alpha-2a and ribavirin treatment.
The relationship between patient sex and the effectiveness of peginterferon alpha-2a and ribavirin treatment in chronic hepatitis C (CHC) patients remains unclear. The aim of this study was to investigate the impact of sex on virologic responses rates in genotype 1 CHC patients. A matched retrospective cohort study of 630 genotype 1 patients treated with peginterferon and ribavirin derived from our hospital database was conducted. These patients were divided into three groups according to age: patients aged <40 years (n=200), patients aged 40-50 years (n=210), and patients aged 51-60 years (n=220). The rate of patients receiving ≥ 80% of the planned drug dose and virologic response rates were compared between males and females in the three groups. Factors influencing the sustained virologic response (SVR) were studied by multivariate analysis. In patients aged 51-60 years, the rate of female patients receiving ≥ 80% of the planned ribavirin dose was significantly lower than that of males (42.7%, 47/110 vs. 61.8%, 68/110; Chi-square=8.035, p=0.005). In patients aged <40 years, the SVR rate of females was significantly higher than that of males (75%, 75/100 vs. 54%, 54/100; Chi-square=9.630, p=0.002); in patients aged 40-50 years, there was no significant difference in the SVR rate between males and females (50.5%, 53/105 vs. 54.3%, 57/105; Chi-square=0.305, p=0.580); in patients aged 51-60 years, the SVR rate of females was significantly lower than that of males (33.6%, 37/110 vs. 48.2%, 53/110; Chi-square=4.814, p=0.028). In multivariate logistic regression analysis, the independent factors associated with SVR in patients aged 51-60 years were sex (p=0.013), ≥ 80% of the planned ribavirin dose (p=0.008), and the presence of a rapid virologic response (p=0.001). In the group of patients aged <40 years, the SVR rate of females was higher than that of males; in the group of patients aged 40-50 years, females and males shared similar SVR rates; in the group of patients aged 51-60 years, the SVR rate of females was lower than that of males.


Parametric sensitivity analysis of a homeomorphic model for saccadic and vergence eye movements.
A non-linear sixth order homeomorphic model, fitted with parameters based on eye movements and physiological data, was tuned so that it provided good simulations for the shapes of the magnitude, velocity and acceleration trajectories. Excellent quantitative agreement was obtained in terms of the Main Sequence diagrams for human eye movements. Parametric sensitivity analysis was done for a saccade of ten degree amplitude, a physiologically normal magnitude at which experimental data is both abundant and relatively noise free. Among the many useful results of this sensitivity analysis are that pulse width (PW) and pulse height (PH) were confirmed as the two controlling parameters for the human eye movement model. Output behavior was relatively insensitive to variations of the passive elements of the plant. This analysis also pointed out that more physiological data are needed to understand the role of the non-linear force-velocity relationship of the extraocular muscles.


Influence of oral contraceptive phase on cardiorespiratory response to exercise in endurance-trained athletes.
The aim of the study was to analyse the cardiorespiratory response to exercise during an oral contraceptive (OC) cycle in endurance-trained women. Sixteen low-dose monophasic OC pill (OCP) users performed an interval-running protocol. The protocol consisted of eight 3 min bouts at 85% of participants' maximal aerobic speed (vV̇o2peak) with a 90s recovery at 30% vV̇o2peak in two OC phases: a withdrawal phase (WP) and an active pill phase (APP). The non-parametric Wilcoxon test was applied to analyse differences (p < 0.05) in performance variables between OC cycle phases. Throughout the high-intensity intervals, higher ventilation (WP 80.90 ± 11.49 L/min, APP 83.10 ± 13.33 L/min; p < 0.001) and relative perceived exertion (WP 14.51 ± 2.58, APP 15.11 ± 3.11; p = 0.001) during the APP were found, whereas carbon dioxide production (WP 2040.92 ± 262.93 mL/min, APP 2010.25 ± 305.68 mL/min; p = 0.003) was higher in the WP. During the active recovery intervals, ventilation (WP 65.78 ± 9.90 L/min, APP 67.88 ± 12.66 L/min; p < 0.001) was higher in the APP, while heart rate (WP 159.93 ± 10.26 bpm, APP 159.74 ± 12.83 bpm; p = 0.029) was higher in the WP. An increase in ventilation occurs during the APP, which is accompanied by higher perceived exertion. Therefore, coaches and athletes should be aware of these variations, especially perceived exertion, in regard to women's training programmes, in order to improve their performance, wellness and adherence to physical activity.


Conceptualization, development, and evaluation of 'pharmaceutical product development' graduate program within pharmacy discipline.
Designing a region's need-based programs can be an exceptional complement boosting the knowledge economy of the country. United Arab Emirates (UAE) is increasingly focusing on the pharma and biotech sectors. As a result, there have been increasing demands for qualifications in pharmacy education to fit into higher roles in pharmaceutical industries and multinational companies (MNCs) in the region. This study is a case demonstration that details the design processes authors used for the graduate program 'Pharmaceutical Product Development'. The three stages in program positioning; identifying the need for the new program, program design, and development, and program effectiveness are illustrated in this manuscript. The authors believe that this manuscript serves as a valuable resource for novice curriculum developers in the development of new educational programs.


Methodological quality was critically low in 9/10 systematic reviews in advanced cancer patients-A methodological study.
To assess the methodological quality and the consideration of heterogeneity in systematic reviews (SRs). We conducted a methodological study (CRD42019134904) and searched three databases from January 2010 to July 2019. Interventional SRs with a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients were included. A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) 2 was used to evaluate the SRs' methodological quality. The consideration of heterogeneity was categorized in clinical or/and methodological heterogeneity and not explored. From 6234 identified references, 261 SRs were included. Most SRs had a critically low quality (230, 88.1%). The majority of them (209, 80.1%) was classified as critically low because of non-registration (222, 85.1%) combined with the non-reporting of excluded full-texts and missing justifications for exclusion (218, 83.5%). Heterogeneity in trial results was not explored at all in 51 (19.5%) SRs whereas clinical heterogeneity was considered in 117 (44.8%), methodological heterogeneity in 13 (5.0%), and both clinical and methodological heterogeneity in 80 (30.7%) SRs. The consideration of these findings in trainings for review authors and peer reviewers could improve the awareness of quality criteria and the quality of future SRs. PROSPERO-ID: CRD42019134904.


Advances in the Application of Cold Plasma Technology in Foods.
In the last two decades, non-thermal processing technologies have gained widespread attention from the food industry, which is interested in mild and effective processes [...].


Pine bark as bio-adsorbent for Cd, Cu, Ni, Pb and Zn: batch-type and stirred flow chamber experiments.
The objective of this work was to determine the retention of five metals on pine bark using stirred flow and batch-type experiments. Resulting from batch-type kinetic experiments, adsorption was rapid, with no significant differences for the various contact times. Adsorption was between 98 and 99% for Pb(2+), 83-84% for Cu(2+), 78-84% for Cd(2+), 77-83% for Zn(2+), and 70-75% for Ni(2+), and it was faster for low concentrations, with Pb suffering the highest retention, followed by Cu, Cd, Ni and Zn. The fitting to the Freundlich and Langmuir models was satisfactory. Desorption increased in parallel to the added concentrations, with Pb always showing the lowest levels. Stirred flow chamber experiments showed strong hysteresis for Pb and Cu, sorption being mostly irreversible. The differences affecting the studied heavy metals are mainly due to different affinity for the adsorption sites. Pine bark can be used to effectively remove Pb and Cu from polluted environments.


Complications of lung transplantation.
This article summarizes the complications of lung transplantation. Complications discussed are categorized into (1) complications of the operation itself, including hemorrhage, the reimplantation response, airway anastomotic complications, cardiac and hemodynamic complications, and gastrointestinal complications; (2) complications of transplantation, including acute and chronic rejection; and (3) complications of the immunosuppressive agents used to prevent rejection, including infection, malignancy, and direct toxicities of the medications. This article describes the usual presenting features of these complications and summarizes strategies used by transplant providers for their prevention, early diagnosis, and treatment.


Cognitive impact of anticholinergic medication in MS: Adding insult to injury?
Cognitive impairment in Multiple Sclerosis (MS) is well recognized, being documented even in the earliest stages of the disease. Anticholinergic drugs (ACD) are frequently used to address bladdder symptoms in this population. ACD are known for their deleterious cognitive effects in older individuals; however their potential impact on cognition has received less attention in the context of MS. To explore possible detrimental effects of bladder-directed ACD on cognitive functioning in MS. 42 MS patients who had been on classical, bladder-directed ACD for ≥6 months were compared to 46 patients not receiving ACD, in terms of their scores on Symbol Digit Modality Test (SDMT) and Selective Reminding Test (SRT). Patients also completed questionnaires for fatigue (Modified Fatigue Impact Scale - MFIS) and depression (Beck Depression Inventory-Fast Screen - BDIFS). Patients using ACD showed significantly lower SDMT and SRT scores compared to those not using ACD (p<0.001; t-test). The association of lower cognitive test performance with ACD usage was robust, even when other variables (like age, gender, EDSS, etc.) were considered. Our results suggest that chronic use of classical ACD for bladder symptoms may have a negative impact on cognitive functioning in MS patients. These potential cognitive side effects need to be considered both in clinical practice and research settings.


Efficacy and safety of oxcarbazepine in the treatment of children with epilepsy: a meta-analysis of randomized controlled trials.
To assess the efficacy and safety of oxcarbazepine (OXC) in the treatment of children with epilepsy. Randomized controlled trials (RCTs) published in PubMed, Embase, Web of Science, Cochrane Library, Scopus, SinoMed (Chinese BioMedical Literature Service System, China), and Chinese National Knowledge Infrastructure (China) database were systematically reviewed. Eligible studies were those that compared the efficacy and safety of OXC with other antiepileptic drugs in epilepsy. Risk ratio (RR) with 95% confidence intervals (95% CIs) was calculated using fixed-effects or random-effects model. Eleven RCTs with a total of 1,241 patients met the inclusion criteria and were included in this meta-analysis. Compared with other antiepileptic drugs (sodium valproate, levetiracetam, phenytoin, and placebo), OXC was associated with similar seizure-free rate (RR =1.06, 95% CI: 0.94, 1.20; P=0.366) and percentage reduction from baseline in seizure frequency (for ≥75% reduction: RR =1.15, 95% CI: 0.88, 1.49; P=0.310; for 50%-75% reduction: RR =1.12, 95% CI: 0.90, 1.39; P=0.301; for <50% reduction: RR =0.79, 95% CI: 0.56, 1.12; P=0.179). Moreover, patients treated with OXC had a comparable incidence of adverse events compared with those treated with other antiepileptic drugs (RR =1.01, 95% CI: 0.92, 1.11; P=0.760). OXC showed similar effects and safety as other antiepileptic drugs in the treatment of children with epilepsy. Further well-conducted, large-scale RCTs are needed to validate these findings.


High-sensitive determination of coenzyme Q(10) in iodinate-beta-cyclodextrin medium by inclusion reaction and catalytic polarography.
A novel polarographic method for the determination of coenzyme Q(10) in beta-cyclodextrin (beta-CD) and iodinate system is proposed. The stability of coenzyme Q(10) to light was improved by the formation of coenzyme Q(10)-beta-CD inclusion complex. In addition, the sensitivity for the determination of coenzyme Q(10) was enhanced by both the formation and the polarographic catalytic wave of the inclusion complex in the presence of iodinate. In 0.1 mol/L HAc-NaAc (pH 4.7)-5.0 x 10(-5) mol/L beta-CD-1.2 x 10(-3) mol/L potassium iodinate-ethanol/water (60:40, v/v) medium, coenzyme Q(10)-beta-CD inclusion complex yielded a sensitive association/parallel catalytic wave. The second-order derivative peak current of the catalytic wave was proportional to coenzyme Q(10) concentration in the range of 6.0 x 10(-8)-2.5 x 10(-7) mol/L, and the detection limit was 1.0 x 10(-8) mol/L. The proposed method has high analytical sensitivity and is allowed to determine coenzyme Q(10) under light.


Laminin-binding integrins induce Dll4 expression and Notch signaling in endothelial cells.
Integrins play a crucial role in controlling endothelial cell proliferation and migration during angiogenesis. The Delta-like 4 (Dll4)/Notch pathway establishes an adequate ratio between stalk and tip cell populations by restricting tip cell formation through "lateral inhibition" in response to a vascular endothelial growth factor gradient. Because angiogenesis requires a tight coordination of these cellular processes, we hypothesized that adhesion, vascular endothelial growth factor, and Notch signaling pathways are interconnected. This study was aimed at characterizing the cross-talk between integrin and Notch signaling in endothelial cells. Adhesion of primary human endothelial cells to laminin-111 triggers Dll4 expression, leading to subsequent Notch pathway activation. SiRNA-mediated knockdown of α2β1 and α6β1 integrins abolishes Dll4 induction, which discloses a selective integrin signaling acting upstream of Notch pathway. The increase in Foxc2 transcription, triggered by α2β1 binding to laminin, is required but not sufficient per se for Dll4 expression. Furthermore, vascular endothelial growth factor stimulates laminin γ1 deposition, which leads to integrin signaling and Dll4 induction. Interestingly, loss of integrins α2 or α6 mimics the effects of Dll4 silencing and induces excessive network branching in an in vitro sprouting angiogenesis assay on three-dimensional matrigel. We show that, in endothelial cells, ligation of α2β1 and α6β1 integrins induces the Notch pathway, and we disclose a novel role of basement membrane proteins in the processes controlling tip vs stalk cell selection.


A model of gastric emptying using paracetamol absorption in intensive care patients.
To describe the range and factors which may affect gastric emptying in the ICU patient. Validation sample. The adult Intensive Care Unit (ICU) of a teaching hospital. Twenty-seven ICU patients, aged 18-65 years were studied within 3 days of their ICU admission. All patients had normal hepatic and renal chemistry and had no contraindications to enteral feeding. The area under the concentration curve from 0-60 min (AUC60) of a paracetamol absorption test was used as the measure of gastric emptying. The variables of the presence or absence of bowel sounds, volume of gastric aspirate ( > 50 ml or < 50 ml), an estimated risk of death (ROD), an APACHE II score calculated 24 h before the study, a pHi measurement, the use of dopamine (2.5-5 microg/kg, yes or no) and of opioids were included in a multiple regression analysis. Using Pearson correlation, AUC60 was positively correlated with the estimated ROD (r = 0.50, p < 0.05). There was a statistically significant difference in the mean AUC60 between those patients who did, and those who did not, receive dopamine (t = 3.06, p < 0.005). On multiple regression analysis the only variable which was significantly associated with AUC60 was estimated ROD, which accounted for 25% of the variance in AUC60. The results suggest that there is a wide range in gastric emptying in critically ill patients. The results may be due to the case mix of the patients. The use of dopamine may adversely affect gastric emptying and requires further investigation in the ICU patient. Prediction of gastric emptying is difficult in these patients and further investigation is necessary in order to improve our understanding of this process.


Antibacterial activity of lysozyme-loaded cream against MRSA and promotion of scalded wound healing.
Staphylococcus aureus (S. aureus) infection, especially its drug-resistant bacterial infection, is a great challenge often faced by clinicians and patients, and it is also one of the most important threats to public health. Finding a safe and effective antibacterial agent is of great significance for the prevention and treatment of S. aureus infection. Lysozyme is known to have antibacterial effects against Gram-positive bacteria including S. aureus. Here, high-quality lysozyme with a purity of more than 99% and an activity of more than 60, 000 U/mg was prepared from egg white, which showed excellent antibacterial activity against three strains of S. aureus, especially against MRSA. Furthermore, an antibacterial cream loaded with lysozyme was prepared and tested in scald wound healing. The lysozyme-loaded cream exhibited the effect of preventing wound infection and promoting wound healing on scalds, and no toxicity was found in animal organs. Overall, lysozyme showed great application potential in the prevention and treatment of infections caused by S. aureus and scalded wound healing. The most remarkable discovery in this work is the unexpectedly powerful inhibitory effect of lysozyme on the drug-resistant bacterial, especially MRSA, which is usually very difficult to deal with using normal antibacterial drugs.


Anomeric and Enantiomeric 2'-Deoxycytidines: Base Pair Stability in the Absence and Presence of Silver Ions.
Dodecamer duplex DNA containing anomeric (α/β-d) and enantiomeric (β-l/β-d) 2'-deoxycytidine mismatches was studied with respect to base pair stability in the absence and presence of silver ions. Stable duplexes with silver-mediated cytosine-cytosine pairs were formed by all anomeric and enantiomeric combinations. Stability changes were observed depending on the composition of the mismatches. Most strikingly, the new silver-mediated base pair of anomeric α-d-dC with enantiomeric β-l-dC is superior to the well-noted β-d/β-d-dC pair in terms of stability. CD spectra were used to follow global helical changes of DNA structure.


Continuous Monitoring Reveals Protective Effects of N-Acetylcysteine Amide on an Isogenic Microphysiological Model of the Neurovascular Unit.
Microphysiological systems mimic the in vivo cellular ensemble and microenvironment with the goal of providing more human-like models for biopharmaceutical research. In this study, the first such model of the blood-brain barrier (BBB-on-chip) featuring both isogenic human induced pluripotent stem cell (hiPSC)-derived cells and continuous barrier integrity monitoring with <2 min temporal resolution is reported. Its capabilities are showcased in the first microphysiological study of nitrosative stress and antioxidant prophylaxis. Relying on off-stoichiometry thiol-ene-epoxy (OSTE+) for fabrication greatly facilitates assembly and sensor integration compared to the prevalent polydimethylsiloxane devices. The integrated cell-substrate endothelial resistance monitoring allows for capturing the formation and breakdown of the BBB model, which consists of cocultured hiPSC-derived endothelial-like and astrocyte-like cells. Clear cellular disruption is observed when exposing the BBB-on-chip to the nitrosative stressor linsidomine, and the barrier permeability and barrier-protective effects of the antioxidant N-acetylcysteine amide are reported. Using metabolomic network analysis reveals further drug-induced changes consistent with prior literature regarding, e.g., cysteine and glutathione involvement. A model like this opens new possibilities for drug screening studies and personalized medicine, relying solely on isogenic human-derived cells and providing high-resolution temporal readouts that can help in pharmacodynamic studies.


Use of coronary computed tomography or polygenic risk scores to prompt action to reduce coronary artery disease risk: the CAPAR-CAD trial.
The traditional primary prevention paradigm for coronary artery disease (CAD) centers on population-based algorithms to classify individual risk. However, this approach often misclassifies individuals and leaves many in the 'intermediate' category, for whom there is no clear preferred prevention strategy. Coronary artery calcium (CAC) and polygenic risk scoring (PRS) are 2 contemporary tools for risk prediction to enhance the impact of effective management. To determine how these CAC and PRS impact adherence to pharmacotherapy and lifestyle measures in asymptomatic individuals with subclinical atherosclerosis. The CAPAR-CAD study is a multicenter, open, randomized controlled trial in Victoria, Australia. Participants are self-selected individuals aged 40 to 70 years with no prior history of cardiovascular disease (CVD), intermediate 10-year risk for CAD as determined by the pooled cohort equation (PCE), and CAC scores >0. All participants will have a health assessment, a full CT coronary angiogram (CTCA), and PRS calculation. They will then be randomized to receive their risk presented either as PCE and CAC, or PCE and PRS. The intervention includes e-Health coaching focused on risk factor management, health education and pharmacotherapy, and follow-up to augment adherence to a statin medication. The primary endpoint is a change in low-density lipoprotein cholesterol (LDL-C) from baseline to 12 months. The secondary endpoint is between-group differences in behavior modification and adherence to statin pharmacotherapy. As of July 31, 2021, we have screened 1,903 individuals. We present the results of the 574 participants deemed eligible after baseline assessment.


Thrombin receptor regulates hematopoiesis and endothelial-to-hematopoietic transition.
Hematopoietic development and vascular development are closely related physiological processes during vertebrate embryogenesis. Recently, endothelial-to-hematopoietic transition (EHT) was demonstrated to be critical for hematopoietic stem and progenitor cell induction, but its underlying regulatory mechanisms remain poorly understood. Here we show that thrombin receptor (F2r), a protease-activated G protein-coupled receptor required for vascular development, functions as a negative regulator during hematopoietic development. F2r is significantly upregulated during hematopoietic differentiation of mouse embryonic stem cells (mESCs) and zebrafish hematopoietic development. Pharmacological or genetic inhibition of F2r promotes hematopoietic differentiation, whereas F2r overexpression shows opposite effects. Further mechanistic studies reveal that F2r-RhoA/ROCK pathway inhibits EHT in vitro and negatively regulates zebrafish EHT and hematopoietic stem cell induction in vivo. Taken together, this study demonstrates a fundamental role of F2r-RhoA/ROCK pathway in vertebrate hematopoiesis and EHT, as well as an important molecular mechanism coordinating hematopoietic and vascular development.


Pasireotide treatment in Cushing's disease: A single tertiary center's experience.
Patients who were followed up for CD and treated with pasireotide between 2014-2020 at Cerrahpaşa Medical Faculty, were evaluated retrospectively. The efficacy and adverse effects of pasireotide were evaluated in this study. Thirty-two patients were evaluated. The mean duration of treatment was 26.5 [range, 12.0-37.0] months. The 24-h urinary free cortisol (UFC) decreased 46% during the treatment and normalized in 37.5% of patients. A significant decrement was found between pretreatment and last follow-up UFC (p = 0.001). Plasma ACTH decreased by 21%. A significant decrement was found between pre-treatment and the 3rd month, 6th month, and last follow-up ACTH levels (p = 0.014, p = 0.017, and p = 0.017, respectively). Serum cortisol levels decreased by 18% and a significant decrement was found between pretreatment and the 3rd month, and between pretreatment and the last follow-up (p = 0.034 and p = 0.013, respectively). While fasting blood glucose at the 3rd month was significantly higher than pretreatment fasting blood glucose, no significant difference was found between pretreatment fasting blood glucose and 6th month and last follow-up fasting blood glucose. Although there was a significant difference between pretreatment HbA1c levels and the HbA1c levels at the 3rd month (5.9% vs. 6.6% p = 0.007), 6th month (5.9% vs. 6.7% p = 0.003), and the last follow-up (5.9% vs. 7.1% p = 0.001), in the last follow-up, the majority (77%) of patients had adequate glycemic control (HbA1c ≤ 7.0 %).</AbstractText> <AbstractText Label="RESULTS">The authors declare that there is no conflict of interest. Pasireotide treatment is an alternative treatment in CD, remission is obtained in the first months of treatment, and continues for an extended period. Although hyperglycemia is the most common adverse effect, it can be successfully controlled.


Relevance of maternal sodium level for preeclampsia-associated adverse pregnancy outcomes.
To evaluate maternal sodium levels in women with preeclampsia (PE) or at high risk for preeclampsia and their relevance for severe PE-associated adverse pregnancy outcome and remaining pregnancy duration. In a retrospective cohort of 198 patients presenting with signs and symptoms of preeclampsia (PE), we investigated maternal sodium level and the sFlt-1/PlGF-ratio within 14 days prior to delivery. In total, 88 patients (44.4%) developed a maternal and/or fetal and neonatal preeclampsia-associated adverse outcome (AO). The median sodium level was lower in the cohort with vs. without AO (136 vs. 137 mmol/l) and correlated negatively with the sFlt-1/PlGF-ratio (r = -0.19, 95% CI: -0.31 to -0.05) in both groups. Logistic regression revealed a significant association of the maternal sodium level with the development of an AO (+1 mmol/l reduced the odds by 21%, [Odds ratio (OR) of 0.79 (95% CI 0.67-0.93), p < 0.01], whereas the sFlt-1/PlGF showed a contrary effect (+10 units OR of 1.05 (95% CI: 1.02-1.08, p < 0.01)). Linear mixed effects models showed consistent results, with sodium level positively associated with the remaining pregnancy duration. Our results confirm the relevance of decreased maternal sodium level as a severity marker for PE-associated adverse outcomes.


MIPS: analysis and annotation of genome information in 2007.
The Munich Information Center for Protein Sequences (MIPS-GSF, Neuherberg, Germany) combines automatic processing of large amounts of sequences with manual annotation of selected model genomes. Due to the massive growth of the available data, the depth of annotation varies widely between independent databases. Also, the criteria for the transfer of information from known to orthologous sequences are diverse. To cope with the task of global in-depth genome annotation has become unfeasible. Therefore, our efforts are dedicated to three levels of annotation: (i) the curation of selected genomes, in particular from fungal and plant taxa (e.g. CYGD, MNCDB, MatDB), (ii) the comprehensive, consistent, automatic annotation employing exhaustive methods for the computation of sequence similarities and sequence-related attributes as well as the classification of individual sequences (SIMAP, PEDANT and FunCat) and (iii) the compilation of manually curated databases for protein interactions based on scrutinized information from the literature to serve as an accepted set of reliable annotated interaction data (MPACT, MPPI, CORUM). All databases and tools described as well as the detailed descriptions of our projects can be accessed through the MIPS web server (http://mips.gsf.de).


Highly accurate and sensitive diagnostic detection of SARS-CoV-2 by digital PCR.
The outbreak of COVID-19 caused by a novel Coronavirus (termed SARS-CoV-2) has spread to over 210 countries around the world. Currently, reverse transcription quantitative qPCR (RT-qPCR) is used as the gold standard for diagnosis of SARS-CoV-2. However, the sensitivity of RT-qPCR assays of pharyngeal swab samples are reported to vary from 30% to 60%. More accurate and sensitive methods are urgently needed to support the quality assurance of the RT-qPCR or as an alternative diagnostic approach. A reverse transcription digital PCR (RT-dPCR) method was established and evaluated. To explore the feasibility of RT-dPCR in diagnostic of SARS-CoV-2, a total of 196 clinical pharyngeal swab samples from 103 suspected patients, 77 close contacts and 16 supposed convalescents were analyzed by RT-qPCR and then measured by the proposed RT-dPCR. For the 103 fever suspected patients, 19 (19/25) negative and 42 (42/49) equivocal tested by RT-qPCR were positive according to RT-dPCR. The sensitivity of SARS-CoV-2 detection was significantly improved from 28.2% by RT-qPCR to 87.4% by RT-dPCR. For 29 close contacts (confirmed by additional sample and clinical follow up), 16 (16/17) equivocal and 1 negative tested by RT-qPCR were positive according to RT-dPCR, which is implying that the RT-qPCR is missing a lot of asymptomatic patients. The overall sensitivity, specificity and diagnostic accuracy of RT-dPCR were 91%, 100% and 93%, respectively. RT-dPCR is highly accurate method and suitable for detection of pharyngeal swab samples from COVID-19 suspected patients and patients under isolation and observation who may not be exhibiting clinical symptoms.


A conserved processing mechanism regulates the activity of transcription factors Cubitus interruptus and NF-kappaB.
The proteasome degrades some proteins, such as transcription factors Cubitus interruptus (Ci) and NF-kappaB, to generate biologically active protein fragments. Here we have identified and characterized the signals in the substrate proteins that cause this processing. The minimum signal consists of a simple sequence preceding a tightly folded domain in the direction of proteasome movement. The strength of the processing signal depends primarily on the complexity of the simple sequence rather than on amino acid identity, the resistance of the folded domain to unraveling by the proteasome and the spacing between the simple sequence and folded domain. We show that two unrelated transcription factors, Ci and NF-kappaB, use this mechanism to undergo partial degradation by the proteasome in vivo. These findings suggest that the mechanism is conserved evolutionarily and that processing signals may be widespread in regulatory proteins.


Parathyroid hormone and insulin resistance in distinct phenotypes of severe obesity: a cross-sectional analysis in middle-aged men and premenopausal women.
High levels of PTH are reported in obese individuals and related to increased cardiometabolic risk. Our objective was to evaluate whether the relationship between PTH, insulin resistance, and related metabolic parameters differ between metabolically healthy obese (MHO) and insulin-resistant obese (IRO) subjects. We conducted a cross-sectional study among patients evaluated for bariatric surgery in our University Hospital. Patients initially included were 174 severely obese subjects (114 women, aged 40 ± 5 yr, body mass index of 45 ± 6 kg/m(2)) without diabetes, chronic kidney disease, or hyperparathyroidism. MHO (n = 43) and IRO (n = 86) subjects were identified according to quartiles of insulin resistance. Fasting and postload glucose, insulin, total and high-density lipoprotein cholesterol, triglycerides, creatinine, calcium, phosphorus, PTH, 25-hydroxyvitamin D (25OHD), fibrinogen, and high-sensitivity C-reactive protein were assessed. Insulin sensitivity index was derived from a 75-g oral glucose tolerance test. Fat distribution and bone mineral density were assessed with dual-energy x-ray absorptiometry. Although 25OHD levels were higher in MHO than in IRO subjects [72.23 (59.41-80.36) vs. 52.36 (41.98-62.57) nmol/liter, P = 0.002], PTH levels were comparable between groups (74.4 ± 13.2 vs. 72.1 ± 15.1 ng/liter, P = 0.34). No differences in serum calcium, phosphorus, bone mineral density, and renal function were detected. An independent inverse association between 25OHD and insulin resistance was seen in both groups. In contrast to IRO subjects, after adjusting for covariates, PTH levels were unrelated to insulin sensitivity index, fasting and postload glucose, insulin, and high-sensitivity C-reactive protein in MHO subjects. MHO and IRO subjects show comparably high levels of circulating PTH, which are not associated with insulin resistance and related metabolic parameters in MHO subjects. Most of the associations observed in IRO subjects appear to be mediated by greater truncal fat mass.


Exogenous progesterone or indomethacin delays parturition in the viviparous lizard Sceloporus jarrovi.
Female Sceloporous jarrovi in late pregnancy given an ip injection of progesterone (50 ng/g body wt) or indomethacin (4 micrograms/g body wt) exhibited no change in the length of pregnancy when compared to saline-treated controls. In contrast, pregnant females given subcutaneous implants (constant release pellets) containing progesterone or indomethacin exhibited significantly delayed parturition when compared with females given control implants. Indomethacin treatment also disrupted the normal birth process when it occurred, as all females receiving this compound exhibited parturition of only a portion (24-32%) of the total clutch. A similar phenomenon occurred in one experiment following implantation of progesterone pellets. Histological examination of the corpora lutea and oviduct indicated no obvious difference in structure among any of the treatment groups.


Parasite immunology and lymphocyte population dynamics.
We propose that parasites use "antigenic mimicry", the presentation of host-type antigens, not merely as a disguise, but as a means of actively diverting the immune system into an ineffective mode of response that actually protects the parasites. This suggestion is the outcome of analyzing the immune system by the principle of Darwinian selection--among lymphocyte populations differing in their relative growth capacities under particular environmental conditions. In particular, it is proposed that proliferation can be uncoupled from differentiation under certain predictable conditions; and moreover, clones that proliferate for prolonged periods of time without significant maturation into effector cells may gain a selective advantage and reach prominence. This mode of "latent proliferation" is a key to self-non-self discrimination: under physiologic conditions, those T and B cells are selected that react "proliferatively" with certain classes of self-antigens, ensuring tolerance to self. We suggest that parasites which present host-type antigens generate the same kind of dynamic selection among responding lymphocytes. The hypothesis links polyclonal activation and "immunosuppression" to "antigenic mimicry", predicts "concomitant immunity" to the same parasite and suggests a pathway leading to autoimmunity. It is also amenable to testing.


Prospective analysis of urokinase in the treatment of catheter sepsis in pediatric hematology-oncology patients.
Use of right atrial catheters (RACs) in children with cancer improves the comfort and efficacy of therapy. However, catheter-related infections are responsible for significant morbidity leading to the removal of approximately 20% of implanted RACs. Sepsis has been linked to thrombus and fibrin sheath formation within the RAC. Gram-negative and fungal infections appear to be particularly resistant to antibiotic therapy alone and most of these infections have required catheter removal. Urokinase has been effectively used for reopening thrombus occluded RACs. Theoretically, thrombolytic agents could improve the treatment of catheter-related infections by removing luminal sites of bacterial/fungal colonization. We prospectively monitored the use of urokinase and antibiotics for catheter-related sepsis in our pediatric hematology/oncology population from 1985 to 1991. Sepsis episodes were treated with 2 doses of urokinase and antibiotics (10 to 42 days) infused through the RAC. One to 2 mL of urokinase (5,000 U/mL) was instilled in the RAC for 1 hour, then removed and repeated 24 hours later. During the study, 224 RACs were placed in 177 children. RACs were in place for a total of 71,134 days (median, 274 days). There were 67 blood culture-positive sepsis episodes occurring in 50 RACs. Fifty-nine sepsis episodes were treated with urokinase and antibiotics and all responded by clearance of organisms from the blood. Three patients (5.1% of urokinase treated) had recurrent sepsis with the same organism within 2 months, were considered treatment failures and had RACs removed. Only 1 of 16 episodes of multiple organism/Candida sepsis led to RAC removal due to inability to cure the infection.(ABSTRACT TRUNCATED AT 250 WORDS)


Dependence of infrared-to-ultraviolet emission enhancement on Yb3+, Er3+:CaF2 nanoparticle dimension.
In the nanocomplexes with Yb3+, Er(3+)-codoped calcium fluoride (CaF2:Yb3+, Er3+) nanoparticles, the infrared (IR)-to-ultraviolet (UV) upconversion (UC) properties were explored under 980 nm laser diode (LD) excitation. The strong enhancement of UV emission at 407 nm was observed. An UP mechanism of the materials was discussed.


[Early embryonic mortality in water vole (Arvicola terrestris L.)].
A morphological study of forty-eight 3-4-day embryos from eight females of the water vole (Arvicola terrestris L.) was conducted. The data obtained demonstrated that early embryonic losses in the water vole can be 30-35%, and the main cause of these losses is anomalies of oogenesis.


Efficacy of cyclic and extended regimens of ethinylestradiol 0.02 mg -levonorgestrel 0.09 mg for dysmenorrhea: A placebo-controlled, double-blind, randomized trial.
We aimed to evaluate the efficacy and safety of 28-day Cyclic and 84-day Extended regimens of NPC-16 (ethinylestradiol 0.02 mg plus levonorgestrel 0.09 mg) in patients with dysmenorrhea. This was a placebo-controlled, double-blind, randomized trial conducted in Japan. A total of 251 primary and secondary dysmenorrhea patients were randomly assigned to the NPC-16-Cyclic group, NPC-16-Extended group, or the Placebo group. The primary end point was a comparison of the efficacy and safety of the Cyclic and Extended NPC-16 regimen for the treatment of dysmenorrhea relative to the Placebo. Significantly greater reductions in total dysmenorrhea score and visual analog scale score were observed in the Cyclic and Extended groups compared with the Placebo group. Compared with the Cyclic regimen as a secondary end point, the Extended regimen exhibited greater efficacy in the treatment of dysmenorrhea over the course of the study period, particularly in patients with severe dysmenorrhea. The incidence of adverse drug reactions (ADRs) was significantly higher in the Cyclic and Extended groups than in the Placebo group. The Cyclic and Extended regimens of NPC-16 significantly reduced dysmenorrhea severity compared to placebo. The Extended regimen was superior to cyclic regimen in reducing the dysmenorrhea.


The phylogeny of cobras inferred from mitochondrial DNA sequences: evolution of venom spitting and the phylogeography of the African spitting cobras (Serpentes: Elapidae: Naja nigricollis complex).
We use phylogenetic analysis of 1333 bp of mitochondrial DNA sequence to investigate the phylogeny and historical biogeography of the cobra-like elapid snakes, with special reference to the evolution of spitting and the phylogeography of the African spitting cobras, a radiation widespread in open vegetational formations throughout sub-Saharan Africa. Our results suggest that spitting adaptations appear to have evolved three times in cobras, but alternative scenarios cannot be rejected. The Asiatic Naja are monophyletic and originate from a single colonization of Asia from Africa. The radiation of the African spitting Naja appears to date back to the early Miocene and many speciation events in the group predate the Pliocene expansion of grasslands and the radiation of large grazing mammals in Africa. The cladogenic events in this complex appear to have been triggered by both ecological changes and tectonic events associated with the formation and expansion of the African Rift Valley. Taxonomically, our data confirm the inclusion of Boulengerina and Paranaja within Naja, and reveal a clade of African rainforest cobras including N. melanoleuca, Paranaja multifasciata and Boulengerina that constitutes the sister clade of the African open-formation non-spitting cobras. Naja nigricollis is polyphyletic, and we therefore recognize N. nigricincta as a separate species, more closely related to N. ashei and N. mossambica than to N. nigricollis.


Device monitoring strategies in acute heart failure syndromes.
Acute heart failure syndromes (AHFS) represent the most common discharge diagnoses in adults over age 65 and translate into dramatically increased heart failure-associated morbidity and mortality. Conventional approaches to the early detection of pulmonary and systemic congestion have been shown to be of limited sensitivity. Despite their proven efficacy, disease management and structured telephone support programs have failed to achieve widespread use in part due to their resource intensiveness and reliance upon motivated patients. While once thought to hold great promise, results from recent prospective studies on telemonitoring strategies have proven disappointing. Implantable devices with their capacity to monitor electrophysiologic and hemodynamic parameters over long periods of time and with minimal reliance on patient participation may provide solutions to some of these problems. Conventional electrophysiologic parameters and intrathoracic impedance data are currently available in the growing population of heart failure patients with equipped devices. A variety of implantable hemodynamic monitors are currently under investigation. How best to integrate these devices into a systematic approach to the management of patients before, during, and after AHFS is yet to be established.


CBF4/DREB1D represses XERICO to attenuate ABA, osmotic and drought stress responses in Arabidopsis.
Water stress can severely impact plant growth, productivity and yield. Consequently, plants have evolved various strategies through which they can respond and adapt to their environment. XERICO (XER) is a stress-responsive RING E3 ubiquitin ligase that modulates abscisic acid (ABA) levels and promotes drought tolerance when overexpressed. To better understand the biological role of XER in stress responses, we characterized a xer-1 hypomorphic mutant and a CRISPR/Cas9-induced xer-2 null mutant in Arabidopsis. Both xer mutant alleles exhibited increased drought sensitivity, supporting the results from overexpression studies. Furthermore, we discovered that both xer mutants have greater stomatal indices and that XER is expressed in epidermal cells, indicating that XER functions in the epidermis to repress stomatal development. To explore XER spatiotemporal and stress-dependent regulation, we conducted a yeast one-hybrid screen and found that CBF4/DREB1D associates with the XER 5' untranslated region (5'-UTR). We generated three cbf4 null mutants with CRISPR/Cas9 and showed that CBF4 negatively regulates ABA responses, promotes stomatal development and reduces drought tolerance, in contrast to the roles shown for XER. CBF4 is induced by ABA and osmotic stress, and localizes to the nucleus where it downregulates XER expression via the DRE element in its 5'-UTR. Lastly, genetic interaction studies confirmed that xer is epistatic to cbf4 in stomatal development and in ABA, osmotic and drought stress responses. We propose that the repression of XER by CBF4 functions to attenuate ABA signaling and stress responses to maintain a balance between plant growth and survival under adverse environmental conditions.


Urinary proteomic analysis to identify a potential protein biomarker panel for the diagnosis of tuberculosis.
Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is one of the primary causes of death worldwide. Rapid and accurate diagnosis of TB is one of the most direct means to reduce the incidence of TB. In this study, urinary proteomic profiling of TB patients and non-TB individual controls (HCs) was performed, and differentially expressed urinary proteins between TB and HCs were compared and exclusively expressed proteins in TB patients were selected to establish a clinically useful disease marker panel. In total, these top 11 targeted proteins with 265 peptides were scheduled for multiple reaction monitoring validation analysis by using urine samples from 52 TB patients and 52 HCs. The result demonstrated that a three-protein combination out of the five-protein panel (namely P22352, Q9P121, P15151, Q13291, and Q8NDA2) exhibited sensitivity rate of 82.7% in the diagnosis of TB. Furthermore, the three-protein combination could differentiate TB from the latent tuberculosis (LTB) effectively, which exhibited specificity rate of 92.3% for the diagnosis of TB from the LTB category. Although more numbers of clinical samples are required for further verification, the results provided preliminary evidence that this "three-protein combination" out of the five-protein panel could probably be a novel TB diagnostic biomarker in clinical application.


Meningitis and brain abscess due to Haemophilus paraphrophilus.
A case of meningitis and brain abscess due to Haemophilus paraphrophilus in a patient with congenital heart disease is reported. The abscess communicated with the cerebral ventricular system. Although the infecting strain was found to be highly sensitive to ampicillin, the patient died despite appropriate antimicrobial therapy. Characteristics distinguishing Haemophilus paraphrophilus and related species are discussed.


Empiric treatment of multidrug-resistant Burkholderia cepacia lung exacerbation in a patient with cystic fibrosis: application of pharmacodynamic concepts to meropenem therapy.
A 31-year-old man with cystic fibrosis was diagnosed with multidrug-resistant Burkholderia cepacia pneumonia. Meropenem 2000 mg every 8 hours was administered as a 3-hour infusion to maximize pharmacodynamic exposure; oral minocycline 100 mg twice/day was also given. Blood samples were collected to confirm meropenem concentrations. Concentrations above the mimimum inhibitory concentration (MIC) of 8 microg/ml were achieved for 52% of the dosing interval, which is greater than what is required for a bactericidal effect. The patient's condition improved, he was discharged, and completed a 3-week course of the antibiotic regimen. After 6 months, he had remained at his baseline level of health. This case demonstrates that pharmacodynamic principles can be used to design an antibiotic dosing regimen that can achieve optimal exposures when the MIC is above that considered susceptible to conventional dosing strategies.


Recurrent upper lumbar disc herniation treated via the transforaminal approach using microendoscopy-assisted lumbar discectomy: a case report.
Although microendoscopy-assisted lumbar discectomy for lateral or extraforaminal lumbar disc herniations via the lateral approach has previously been reported, microendoscopy-assisted lumbar discectomy for central or paramedian disc herniations via the lateral approach has not been reported. We report the first case of recurrent upper lumbar disc herniation (L2-L3) treated with microendoscopy-assisted lumbar discectomy via the transforaminal approach. No microendoscopy-assisted lumbar discectomy for recurrent upper lumbar disc herniation via the transforaminal approach has previously been reported. Percutaneous endoscopic lumbar discectomy via the transforaminal approach is very useful as a minimally invasive surgery for disc herniations. We applied percutaneous endoscopic lumbar discectomy via the transforaminal approach, and invented a new microendoscopy-assisted lumbar discectomy via the transforaminal approach. A 79-year-old Japanese man was operatively managed for recurrent L2-L3 herniation. An 18 mm skin incision was made approximately 70 mm from the midline to the lateral side to allow a sufficiently angled trajectory to the extraforaminal space. The transforaminal approach was used. The exiting nerve root was identified along its course inferior to the pedicle. The lateral portion of the pars interarticularis and the facet joint was removed using a high-speed drill under the guidance of an endoscope. The tip of the endoscope was set at the lateral side of the dura mater. The dura mater was retracted medially and gently, and the herniated disc fragments were removed safely. All symptoms were relieved postoperatively. Postoperative magnetic resonance imaging demonstrated disappearance of all herniated disc fragments. A postoperative three-dimensional computed tomographic scan demonstrated the complete preservation of the facet joint. This is the first report of a case of recurrent upper lumbar disc herniation treated with microendoscopy-assisted lumbar discectomy via the transforaminal approach. This procedure allows for the use of a nerve retractor and other instruments to detach adhesions from the dura mater. This procedure has the advantages of clear visualization of the dura mater, exiting nerve root, and traversing nerve root, and diminished risk of nerve injury, and complete preservation of the articular surface of the facet joint.


The poly dA helix: a new structural motif for high performance DNA-based molecular switches.
We report a pH-dependent conformational transition in short, defined homopolymeric deoxyadenosines (dA(15)) from a single helical structure with stacked nucleobases at neutral pH to a double-helical, parallel-stranded duplex held together by AH(+)-H(+)A base pairs at acidic pH. Using native PAGE, 2D NMR, circular dichroism (CD) and fluorescence spectroscopy, we have characterized the two different pH dependent forms of dA(15). The pH-triggered transition between the two defined helical forms of dA(15) is characterized by CD and fluorescence. The kinetics of this conformational switch is found to occur on a millisecond time scale. This robust, highly reversible, pH-induced transition between the two well-defined structured states of dA(15) represents a new molecular building block for the construction of quick-response, pH-switchable architectures in structural DNA nanotechnology.


[Experiences with ileoanal anastomosis and ileal pouch formation following colectomy and proctomucosectomy].
Since 1981 12 patients (11 adenomatosis coli = AC/1 ulcerative colitis = CU) had a colectomy and mucosal proctectomy with ileo-anal anastomosis (IA) and formation of an ileal-S-pouch (IP). The mean age of 7 men and 5 women was 33 years (21-46 yrs). We preferred the synchronous abdomino-peranal operation. Protective ileostomy was closed after a mean of 4.6 months in 11 patients. Postoperative complications: IA-insufficiency = 4, sacral abscess = 1, stenosis = 3, ileus and reoperation = 2). Late results: spontaneous defecation: 11/11, continence 10/11, evacuation 6-8/day. This operative procedure seems to be good for AC and CU.


Late conversion to everolimus complicated with necrotizing glomerulonephritis in a renal allograft recipient: case report.
Conversion from calcineurin inhibitors (CNI) to proliferation signal inhibitors (PSI), such as sirolimus or everolimus (EV), may improve the course of chronic allograft nephropathy. Herein we have presented a case of a kidney recipient with chronic cyclosporine (CsA) nephrotoxicity who was converted from CsA to EV at 5.5 years posttransplantation. There were no significant changes in immunofluorescence (IFL) or in electron microscopy (EM) in the preconversion biopsy. Two months after conversion, proteinuria and creatinine increased. The biopsy showed focal, segmental necrosis of the glomerular tuft with the formation of segmental cellular crescents and increased endocapillary cellularity. IFL showed granular deposits of IgG, IgM, and C3 mostly along the capillary walls; it was negative for C4d. EM revealed electron-dense deposits within the glomerular basement membrane (GBM) and in the subendothelial region with significant reduction in the capillary lumina due to GBM reduplication and widening of lamina rara interna with the formation of fibrillary structures therein: focal, segmental glomerulosclerosis. EV was withdrawn and we administered tacrolimus and steroid pulses with improvement. Five months after the withdrawal of EV, a third graft biopsy showed remission of the necrotizing glomerulonephritis. However, the patient demanded dialysis at 17 months after conversion to EV. We concluded that necrotizing glomerulonephritis with immune complex deposition in a renal allograft was possibly induced by late conversion from CNI to EV. Reconversion to CNI may be recommended in cases of PSI-associated posttransplantation glomerulonephritis but the long-term prognosis is uncertain.


[Stumbling-blocks: initiating a psychosomatic pain clinic].
Despite psychosocial factors playing an important role in the course of chronic pain disorder, there is a noticeable imbalance between demand and availability of psychosomatic care for these patients. This led us to establish a psychosomatic pain clinic within the framework of our outpatient clinic at the Department of Psychosomatic Medicine and Psychotherapy at the Central Institute of Mental Health, Mannheim, Germany. A recent study aimed at the evaluation of sociodemographic variables, state of chronification, symptom load and psychiatric comorbidity. Additionally we wanted to determine whether existing conditions at our hospital can be considered suitable for those patients. During the clinic's first year we assessed 40 consecutive patients based on a psychosomatic interview as well as a set of psychometric questionnaires (BDI, STAI, SCL-90-R). To detect differences between pain patients and psychotherapy inpatients, we compared the two groups in terms of sociodemographic variables and symptom load. Most pain patients were in advanced states of chronification, showing extensive psychiatric comorbidity, particularly anxiety and depressive syndromes. Drug addiction was found more infrequently. Use of the before mentioned questionnaires prevented us from underestimating existing anxiety syndromes. Pain patients differed substantially from psychotherapy inpatients in terms of age, education, family status and symptom load. Our examination routine effectively demonstrated the special needs of chronic pain patients. As there is significant demand for psychosomatic intervention in those patients, earlier referral appears highly desirable. As pain patients differ also greatly from the remaining hospital population, specialized therapeutic concepts must be developed.


Percutaneous transhepatic cholangiographic endobiliary forceps biopsy versus endoscopic ultrasound fine needle aspiration for proximal biliary strictures: a single-centre experience.
Endoscopic ultrasound fine needle aspiration (EUS-FNA) and percutaneous transhepatic cholangiographic endobiliary forceps biopsy (PTC-EFB) are valid procedures for histological assessment of proximal biliary strictures (PBS), but their performances have never been compared. This study aimed to compare the diagnostic performance of these two techniques. The diagnostic performances of EUS-FNA and PTC-EFB were compared in a retrospective cohort of patients assessed for PBS from 2011 to 2015 at a single tertiary centre. An inverse probability of treatment weighting (IPTW) was performed to adjust for covariate imbalance. A total of 102 EUS-FNAs and 75 PTC-EFBs (performed in 137 patients) were compared. Patients in the PTC-EFB group had higher preoperative bilirubin (243 versus 169 μmol/l, p = 0.005) and a higher incidence of malignancy (87% versus 67%, p = 0.008). Both techniques showed specificity and positive predictive value of 100%, and similar sensitivity (69% versus 75%, p = 0.45), negative predictive value (58% versus 38%, p = 0.15) and accuracy (78% versus 79%, p = 1.00). After IPTW, the diagnostic performance of the two techniques remained similar. Compared to EUS-FNA, PTC-EFB provides similar sensitivity, negative predictive value and accuracy. It should therefore be considered as the preferred tissue-sampling procedure, if biliary drainage is indicated.


Two distinct histological Richter's transformations 23 years apart in a patient with chronic lymphocytic leukaemia.
A 53-year-old man with a 1-year history of chronic lymphocytic leukaemia (CLL) presented with a left bicep mass. Biopsy and staging workup revealed Richter's transformation (RT) Ann Arbor stage 1E diffuse large B-cell lymphoma in the bicep. The patient was treated with combination chemotherapy with cyclophosphamide, doxorubicin, Vincristine and prednisone followed by site radiation and did well thereafter. His CLL progressed and required treatment on two more occasions 11 and 18 years after his initial diagnosis with fludarabine, Cytoxan and Rituxan and then with bendamustine and rituximab. 23 years after initial presentation, he developed diffuse lymphadenopathy and B-symptoms. A biopsy of an enlarged cervical lymph node demonstrated only CLL for which he was started on ibrutinib. Treatment was shortly discontinued thereafter due to intolerance and worsening symptoms. A second biopsy was performed which revealed concurrent CLL and Hodgkin's lymphoma representing a second and histologically distinct RT.


Removal trend of amoxicillin and tetracycline during groundwater recharging reusing: Redox sensitivity and microbial community response.
The abundant existence of antibiotics within the effluent of wastewater treatment plant seriously threatened their safety recharging. To investigate the fate and biodegradation of those toxic antibiotics within the soil aquifer system, typical antibiotics of amoxicillin (AMX) and tetracycline (TC) were selected and their removal mechanisms were investigated. Experimental results revealed that totally 93.4% and 87.2% of the AMX and TC recharged (10 μg/L) were, respectively, removed within 1 m depth column operation. Specifically, the aerobic biodegradation, abiotic processes and anoxic/anaerobic microorganism contributed as higher as 37.5%, 33.7% and 28.8% of the AMX reduction, via the controlling tests of NaN3 inhibition and soil sterilisations. By contrast, the percentage contribution of the TC was aerobic (54.3%) ˃abiotic processes (32.7%) ˃anoxic/anaerobic (13.0%), a higher aerobic degradation whereas weaker anoxic/anaerobic microorganism. Column systems (CSs) were constructed to study the effect of redox conditions (methanogenic, sulfate-reducing, nitrate-reducing, aerobic) on antibiotics degradation, and microbial community results revealed that Verrucomicrobia, Actinobacteria, Deinococcus-Thermus and Armatimonadetes contributed to the aerobic biodegradation of TC. For comparison, AMX could be efficiently degraded under nitrate reduction (19.95%) > sulfate reduction (16.64%) > methanogenic (9.53%), and Actinobacteria, Bacteroidetes and Verrucomicrobia were the dominant bacteria for AMX degradation. This study provided optimal directions for antibiotics removal within the groundwater recharging systems and is conducive to obtain highly value-added reclaimed water.


Fitness selection in human pluripotent stem cells and interspecies chimeras: Implications for human development and regenerative medicine.
A small number of pluripotent cells within early embryo gives rise to all cells in the adult body, including germ cells. Hence, any mutations occurring in the pluripotent cell population are at risk of being propagated to their daughter cells and could lead to congenital defects or embryonic lethality and pose a risk of being transmitted to future generations. The observation that genetic errors are relatively common in preimplantation embryos, but their levels reduce as development progresses, suggests the existence of mechanisms for clearance of aberrant, unfit or damaged cells. Although early human embryogenesis is largely experimentally inaccessible, pluripotent stem cell (PSC) lines can be derived either from the inner cell mass (ICM) of a blastocyst or by reprogramming somatic cells into an embryonic stem cell-like state. PSCs retain the ability to differentiate into any cell type in vitro and, hence, they represent a unique and powerful tool for studying otherwise intractable stages of human development. The advent of PSCs has also opened up a possibility of developing regenerative medicine therapies, either through PSC differentiation in vitro or by creating interspecies chimeras for organ replacement. Here, we discuss the emerging evidence of cell selection in human PSC populations in vivo and in vitro and we highlight the implications of understanding this phenomenon for human development and regenerative medicine.


A prognostic immune predictor, HLA-DRA, plays diverse roles in non-muscle invasive and muscle invasive bladder cancer.
There is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Tissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa. Patients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers. High expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology.


Incidence of penile intraepithelial neoplasia and incidence and survival of penile cancer in Denmark, 1997 to 2018.
Squamous cell carcinoma (SCC) of the penis is rare. Some studies have suggested that the incidence is increasing but the available literature is equivocal. We examined the incidence of high-grade penile intraepithelial neoplasia (PeIN), the incidence and 5-year relative survival as well as mortality of penile SCC in Denmark over the latest 20 years. New cases of high-grade PeIN and penile cancer were identified from high-quality nationwide registries. Age-standardized (World) incidence rates per 100,000 person-years and average annual percentage change (AAPC) were estimated. For penile SCC, 5-year relative survival was calculated, and Cox regression was used to examine the effect of selected characteristics on mortality. Altogether, 1,070 new cases of high-grade PeIN were diagnosed (1997-2018) and the incidence increased from 0.87 to 1.84 per 100,000 person-years from 1997-1998 to 2017-2018 (AAPC = 4.73; 95% CI: 3.54-5.94). We identified 1,216 penile cancer cases (1997-2018) (95.7% SCC). The incidence of penile SCC increased slightly from 0.85 per 100,000 person-years in 1997-1998 to 1.13 per 100,000 person-years in 2017-2018 (AAPC = 1.01; 95% CI: 0.24-1.79). The 5-year relative survival of penile SCC did not change substantially, whereas the mortality tended to decrease. Penile SCC is increasing slightly in Denmark, while a pronounced increase in the incidence of high-grade PeIN is seen. The 5-year relative survival from penile cancer was relatively stable over time. Increasing exposure to HPV infection at the population level may have contributed to the observed increase in PeIN and penile SCC. Awareness of HPV may also have contributed to the increased detection of PeIN.


Variations in serum alpha-L-fucosidase activity during childhood and pregnancy.
Variations in serum alpha-L-fucosidase activity (AFU) have been studied during childhood and pregnancy. 994 children, ages 1 day to 15 yr, were examined; no sex-linked difference was found, but significant variations according to age were demonstrated. AFU activity rose during the first 10-15 days after birth, remained high during the second month then decreased till the end of the first year, thereafter no significant changes were observed. In pregnancy, AFU activity rose and dropped quickly after delivery; neither hypertension nor fetal distress led to AFU activity changes during pregnancy. Thus, in addition to the great variability of AFU linked to the genetic polymorphism, the physiological factors such as age or pregnancy have to be taken into account to establish the significance of AFU variations in pathological situations.


Contributions of GRACE to understanding climate change.
Time-resolved satellite gravimetry has revolutionized understanding of mass transport in the Earth system. Since 2002, the Gravity Recovery and Climate Experiment (GRACE) has enabled monitoring of the terrestrial water cycle, ice sheet and glacier mass balance, sea level change and ocean bottom pressure variations and understanding responses to changes in the global climate system. Initially a pioneering experiment of geodesy, the time-variable observations have matured into reliable mass transport products, allowing assessment and forecast of a number of important climate trends and improve service applications such as the U.S. Drought Monitor. With the successful launch of the GRACE Follow-On mission, a multi decadal record of mass variability in the Earth system is within reach.


Dislocation nucleation governed softening and maximum strength in nano-twinned metals.
In conventional metals, there is plenty of space for dislocations-line defects whose motion results in permanent material deformation-to multiply, so that the metal strengths are controlled by dislocation interactions with grain boundaries and other obstacles. For nanostructured materials, in contrast, dislocation multiplication is severely confined by the nanometre-scale geometries so that continued plasticity can be expected to be source-controlled. Nano-grained polycrystalline materials were found to be strong but brittle, because both nucleation and motion of dislocations are effectively suppressed by the nanoscale crystallites. Here we report a dislocation-nucleation-controlled mechanism in nano-twinned metals in which there are plenty of dislocation nucleation sites but dislocation motion is not confined. We show that dislocation nucleation governs the strength of such materials, resulting in their softening below a critical twin thickness. Large-scale molecular dynamics simulations and a kinetic theory of dislocation nucleation in nano-twinned metals show that there exists a transition in deformation mechanism, occurring at a critical twin-boundary spacing for which strength is maximized. At this point, the classical Hall-Petch type of strengthening due to dislocation pile-up and cutting through twin planes switches to a dislocation-nucleation-controlled softening mechanism with twin-boundary migration resulting from nucleation and motion of partial dislocations parallel to the twin planes. Most previous studies did not consider a sufficient range of twin thickness and therefore missed this strength-softening regime. The simulations indicate that the critical twin-boundary spacing for the onset of softening in nano-twinned copper and the maximum strength depend on the grain size: the smaller the grain size, the smaller the critical twin-boundary spacing, and the higher the maximum strength of the material.


The association between recreational cannabis use and posttraumatic stress disorder: A systematic review and methodological critique of the literature.
Given recent changes in the legal status of cannabis, the risks and benefits associated with its use have become an important public health topic. A growing body of research has demonstrated that posttraumatic stress disorder (PTSD) and recreational cannabis use (RCU) frequently co-occur, yet findings are inconsistent (e.g., direction of effect) and methodological variability makes comparison across studies difficult. We conducted a comprehensive systematic review of all studies (N = 45) published before May 2020 regarding etiologic models of co-occurring RCU and PTSD, as well as provided a methodological critique to inform suggestions for future research initiatives. Findings indicate that a majority of studies (n = 37) demonstrated a significant association between RCU and PTSD. Findings provide evidence for the self-medication and high-risk models posited to explain co-occurring RCU and PTSD despite variability in assessment of RCU, which includes commonly used non-standardized self-report questions. The association between RCU and PTSD is likely bidirectional. Results inform clinicians and researchers working in the mental health and cannabis use fields how the variability in findings on the association between RCU and PTSD may be attributable, in part, to methodological issues that permeate the extant literature pertaining to RCU and PTSD.


The isolation of parvalbumin isoforms from the tail muscle of the American alligator (Alligator mississipiensis).
Multiple parvalbumin isoforms have been detected in the tail (skeletal) muscle of the American alligator (Alligator mississipiensis). One of these isoforms (APV-1) has been highly purified and partially characterized. Protein purification involved mainly gel filtration and anion exchange chromatography, and characterization included gel electrophoresis, amino acid composition analysis, metal ion analysis, MALDI-TOF and ESI mass spectrometry, ultraviolet and fluorescence spectroscopy, and one- and two-dimensional 500 MHz proton NMR spectroscopy. The alligator isoforms are rich in phenylalanine and deficient in the other aromatic residues as is typical for parvalbumins. In fact, the one highly purified isoform that forms the basis of this study has only phenyl-alanine as an aromatic residue. Ion exchange chromatography further indicates that this isoform has a relatively high isoelectric point (pl approximately 5.0), indicating that it is an alpha-lineage parvalbumin. This alligator parvalbumin isoform is unusual in that it has an atypically high Ca2+ content (almost 3.0 mole of Ca2+ per mole of protein) following purification, a fact supported by terbium fluorescence titration experiments. Preliminary comparative analysis of the highly purified alligator parvalbumin isoform (in the Ca2-loaded state) by two-dimensional 1H-NMR (2D 1H TOCSY and 2D 1H NOESY) indicates that there is considerable similarity in structure between the alligator protein and a homologous protein obtained from the silver hake (a saltwater fish species).


Tc-99m-pertechnetate scanning in metastatic thyroid carcinoma: a case report.
Radionuclide imaging with Tc-99m-pertechnetate in a patient with a mixed papillary-follicular carcinoma of the thyroid gland showed evidence of increased radioactivity at sites of functioning metastases. The use of Tc-99m-pertechnetate as well as I-131 for imaging in search of functioning thyroid metastases is discussed.


Factors associated with delayed treatment initiation in an unselected cohort of patients with small-cell lung cancer.
Small-cell lung cancer (SCLC) is an aggressive, rapidly progressive malignancy. Thus, expedient diagnosis and treatment initiation is important. This study identifies and quantifies factors associated with delayed diagnosis and treatment initiation in patients with SCLC and compares time to treatment in SCLC with a cohort of patients with non-small cell lung cancer (NSCLC). The study included all patients diagnosed with SCLC at a hospital in southern Norway in a ten-year period (2007-2016), and all NSCLC patients during the period 2013-2016. Total time to treatment (TTT), was defined as the number of days from date of referral due to suspicion of lung cancer to first day of treatment. Factors associated with prolonged TTT were estimated using multivariate median regression analysis. The median TTT and interquartile range (IQR) for the 183 patients with SCLC was 16 (10-23) days. Factors associated with delayed TTT included outpatient versus inpatient evaluation (+8.4 days), number of diagnostic procedures (+4.3 days per procedure), stage I-III versus stage IV (+3.6 days) and age (+2.1 days per 10 years). In 2013-16, TTT in SCLC was 3.5 days shorter than in the period before and less than half that of NSCLC in the same period, 15 (9-22) versus 33 (22-50) days (p = 0.001). Shorter TTT is seen in higher stage, while longer TTT is a result of increasing complexity of the diagnostic process and treatment decisions of patients with curative intent treatment. Knowledge on delaying factors can shorten TTT and improve clinical practice.


The impact of grey zones on the accuracy of agreement measures for ordinal tables.
In an inter-rater agreement study, if two raters tend to rate considering different aspects of the subject of interest or have different experience levels, a grey zone occurs among the levels of a square contingency table showing the inter-rater agreement. These grey zones distort the degree of agreement between raters and negatively impact the decisions based on the inter-rater agreement tables. In this sense, it is important to know how the existence of a grey zone impacts the inter-rater agreement coefficients to choose the most reliable agreement coefficient against the grey zones to reach out with more reliable decisions. In this article, we propose two approaches to create grey zones in simulations setting and conduct an extensive Monte Carlo simulation study to figure out the impact of having grey zones on the weighted inter-rater agreement measures for ordinal tables over a comprehensive simulation space. The weighted inter-rater agreement coefficients are not reliable against the existence of grey zones. Increasing sample size and the number of categories in the agreement table decreases the accuracy of weighted inter-rater agreement measures when there is a grey zone. When the degree of agreement between the raters is high, the agreement measures are not significantly impacted by the existence of grey zones. However, if there is a medium to low degree of inter-rater agreement, all the weighted coefficients are more or less impacted. It is observed in this study that the existence of grey zones has a significant negative impact on the accuracy of agreement measures especially for a low degree of true agreement and high sample and tables sizes. In general, Gwet's AC2 and Brennan-Prediger's κ with quadratic or ordinal weights are reliable against the grey zones.


Genotypic differences relative photochemical activity, inorganic and organic solutes and yield performance in clones of the forage cactus under semi-arid environment.
Plants with the crassulacean acid metabolism commonly present good adaptation to arid and semi-arid environments, but it highly depends on the type of species. In this study, chlorophyll fluorescence, the concentration of inorganic and organic solutes and the productive performance were evaluated along with their relationships in different clones of the genera Opuntia and Nopalea. The experiment was conducted from 2016 to 2018. Four clones of genus Opuntia were evaluated: 'Orelha de Elefante Mexicana' (OEM), 'Orelha de Elefante Africana' (OEA), V19 and F8; and two clones of genus Nopalea: 'IPA Sertânia' and 'Miúda'. The experiment was arranged in a randomised block design, with six treatments and three replications. The following parameters were measured when harvesting: initial, maximum and variable fluorescence; the quantum yield of PSII (Fv/Fm); light-induction curves of the photochemical parameters (ΔF/Fm', qP, NPQ and ETR); the chlorophyll and carotenoid content; carbohydrates; the sodium (Na+) and potassium (K+) content; morphometry; and dry matter accumulation. The values for the effective quantum yield of PSII (ΔF/Fm') and the alterations in photochemical quenching were higher in the OEM clone (P < 0.05). There was a difference between clones for non-photochemical quenching, with the F8 clone having the highest values. The Fv/Fm was 0.87 for the OEM. 'IPA Sertânia' obtained the greatest Chl a/b, and the highest values for carbohydrate concentration were found in the OEA clone. The OEM clone showed the greatest accumulation of K+, in addition to a higher cladode area index and greater dry matter accumulation. The results of this study show the high physiological tolerance of the forage cactus to a semi-arid environment, which varies according to the clone.


Class-Specific Relationship Between Use of Immunosuppressants and Risk for Community-Acquired Clostridioides difficile Infection.
Immunosuppressant exposure is associated with risk for Clostridioides difficile infection (CDI). It is unknown whether this risk is shared equally across immunosuppressant classes. This was a retrospective cohort study. Adults were included if they were tested for community-acquired CDI (CA-CDI) by stool polymerase chain reaction within 72 hours of hospitalization between 2010 and 2019. The primary outcome was CA-CDI requiring hospitalization, defined as a positive stool test. The primary exposure was use of a home immunosuppressant, at any dose or duration, defined based on the medication reconciliation, and categorized as systemic steroids, calcineurin inhibitors, antimetabolites, anti-tumor necrosis factor-alpha agents, anti-CD20 antibody, and all others. A total of 10 992 hospitalized patients met criteria for the study including 1793 (16%) with CA-CDI; 23% used 1 or more immunosuppressant class. Among those immunosuppressed, 27% tested positive for CA-CDI compared with 22% among those who were not immunosuppressed (P < .01). After adjustment, calcineurin inhibitors (adjusted odds ratio [aOR], 1.19; 95% confidence interval [CI], 1.01-1.44) were associated with increased risk for CA-CDI. Risk for CA-CDI rose with multiple immunosuppressant classes: aOR, 1.22; aOR, 1.53; and aOR, 2.40 for 2, 3, and 4 classes, respectively. After excluding those with solid organ transplant, the relationship between use of calcineurin inhibitors and CDI increased (aOR, 2.21; 95% CI, 1.40-3.49). The greatest risk for CA-CDI was observed among patients using multiple classes of immunosuppressants and those using calcineurin inhibitors. Future studies should recognize that CDI risk differs based on immunosuppressant class.


Homebound older persons: prevalence, characteristics, and longitudinal predictors.
The current study examines the prevalence and correlates of homebound status aiming to elucidate the predictors and implications of being homebound. Analyzed sample was drawn from two representative cohorts of older persons in Israel, including 1191 participants (mean age=83.10 ± 5.3 years) of the first wave of the Cross-Sectional and Longitudinal Aging Study (CALAS) and 418 participants (mean age=83.13 ± 5.2 years) of the Israeli Multidisciplinary Aging Study (IMAS). Cross-sectional and longitudinal analyses were conducted. Homebound prevalence rates of 17.7-19.5% were found. Homebound participants tended to be older, female, have obese or underweight body mass index (BMI), poorer health, lower functional status, less income, higher depressed affect, were significantly lonelier (in CALAS), and more likely to have stairs and no elevators, than their counterparts. Predictors of becoming homebound include low functional IADL status, having stairs and no elevator (in both cohorts), old age, female gender, and being obese or underweight (in CALAS). The study shows that homebound status is a prevalent problem in old-old Israelis. Economic and socio-demographic resources, environment, and function play a role in determining the older person's homebound status. Implications for preventing homebound status and mitigating its impact with regards to the Israeli context are discussed.


Room temperature light emission from the low-dimensional semiconductors AZrPS6 (A = K, Rb, Cs).
The new semiconducting thiophosphate compounds KZrPS(6), RbZrPS(6), and CsZrPS(6) exhibit red light emission at room temperature. The materials have longer photoluminescence lifetimes than most of the inorganic chalcogenide semiconductors. They can be solution processed into thin films for potential device fabrication.


Metabolic dissociation of short-lived barium-137m from its cesium-137 parent.
At 4 to 7 days after Cs(137) administration, Ba(137m) was found to exceed Cs(137)-Ba(137m) equilibrium proportions in bone and plasma by factors of 3 and 14, respectively, in the living animal. This demonstrated the in vivo escape of Ba(137m) from sites of Cs(137) accumulation. Liver tissue was slightly deficient in Ba(137m), whereas tissues such as bone marrow and spleen showed little or no deviation from equilibrium.


Piezoelectric actuator design for MR elastography: implementation and vibration issues.
MR elastography (MRE) is an emerging technique for tumor diagnosis. MRE actuation devices require precise mechanical design and radiofrequency engineering to achieve the required mechanical vibration performance and MR compatibility. A method of designing a general-purpose, compact and inexpensive MRE actuator is presented. It comprises piezoelectric bimorphs arranged in a resonant structure designed to operate at its resonant frequency for maximum vibration amplitude. An analytical model was established to understand the device vibration characteristics. The model-predicted performance was validated in experiments, showing its accuracy in predicting the actuator resonant frequency with an error < 4%. The device MRI compatibility was shown to cause minimal interference to a 1.5 tesla MRI scanner, with maximum signal-to-noise ratio reduction of 7.8% and generated artefact of 7.9 mm in MR images. A piezoelectric MRE actuator is proposed, and its implementation, vibration issues and future work are discussed.