Protocol of the PANCALYZE trial: a multicenter, prospective study investigating the tumor biomarkers CXCR4, SMAD4, SOX9 and IFIT3 in patients with resected pancreatic adenocarcinoma to predict the pattern of recurrence of the disease.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies today with an urgent need for novel therapeutic strategies. Biomarker analysis helps to better understand tumor biology and might emerge as a tool to develop personalized therapies. The aim of the study is to investigate four promising biomarkers to predict the clinical course and particularly the pattern of tumor recurrence after surgical resection. Patients undergoing surgery for PDAC can be enrolled into the PANCALYZE trial. Biomarker expression of CXCR4, SMAD4, SOX9 and IFIT3 will be prospectively assessed by immunohistochemistry and verified by rt.-PCR from tumor and adjacent healthy pancreatic tissue of surgical specimen. Immunohistochemistry expression pattern of all four biomarkers will be combined into a single score. Beginning with the hospital stay clinical data from enrolled patients will be collected and followed. Different adjuvant chemotherapy protocols will be used to create subgroups. The combined biomarker expression score will be correlated with the further clinical course of the patients to test the hypothesis if CXCR4 positive, SMAD4 negative, SOX9 positive, IFIT3 positive tumors will predominantly develop metastatic spread. Pancreatic cancer is associated with different patterns of progression requiring personalized therapeutic strategies. Biomarker expression analysis might be a tool to predict the pattern of tumor recurrence and discriminate patients that develop systemic metastatic disease from those with tumors that rather develop local recurrence over time. This data might lead to personalized adjuvant treatment decisions as patients with tumors that stay localized might benefit from adjuvant local therapies like radiochemotherapy as compared to those with systemic recurrence who would benefit exclusively from chemotherapy. Moreover, the pattern of propagation might be a predefined characteristic of pancreatic cancer determined by the genetic signature of the tumor. In the future, biomarker expression analysis could be performed on tumor biopsies to develop personalized therapeutic pathways right after diagnosis of cancer. German Clinical Trials Register, DRKS00006179 .


The nature of the neutral Na+-Cl(-)-coupled entry at the apical membrane of rabbit gallbladder epithelium: I. Na+/H+, Cl-/HCO3- double exchange and Na+-Cl- symport.
Cl- influx at the luminal border of the epithelium of rabbit gallbladder was measured by 45-sec exposures to 36Cl- and 3H-sucrose (as extracellular marker). Its paracellular component was evaluated by the use of 25 mM SCN- which immediately and completely inhibits Cl- entry into the cell. Cellular influx was equal to 16.7 mu eq cm-2 hr-1 and decreased to 8.5 mu eq cm-2 hr-1 upon removal of HCO3- from the bathing media and by bubbling 100% O2 for 45 min. When HCO3- was present, cellular influx was again about halved by the action of 10(-4) M acetazolamide, 10(-5) to 10(-4) M furosemide, 10(-5) to 10(-4) M 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS), 10(-3) M amiloride. The effects of furosemide and SITS were tested at different concentrations of the inhibitor and with different exposure times: they were maximal at the concentrations reported above and nonadditive. In turn, the effects of amiloride and SITS were not additive. Acetazolamide reached its maximal action after an exposure of about 2 min. When exogenous HCO3- was absent, the residual cellular influx was insensitive to acetazolamide, furosemide and SITS. When exogenous HCO3- was present in the salines, Na+ removal from the mucosal side caused a slow decline of cellular Cl- influx; conversely, it immediately abolished cellular Cl- influx in the absence of HCO3-. In conclusion, about 50% of cellular influx is sensitive to HCO3-, inhibitable by SCN-, acetazolamide, furosemide, SITS and amiloride and furthermore slowly dependent on Na+. The residual cellular influx is insensitive to bicarbonate, inhibitable by SCN-, resistant to acetazolamide, furosemide, SITS and amiloride, and immediately dependent on Na+. Thus, about 50% of apical membrane NaCl influx appears to result from a Na+/H+ and Cl-/HCO3- exchange, whereas the residual influx seems to be due to Na+-Cl- cotransport on a single carrier. Whether both components are simultaneously present or the latter represents a cellular homeostatic counter-reaction to the inhibition of the former is not clear.


Les passions de l'ame: on obsessive and harmonious passion.
Passion is defined as a strong inclination toward an activity that people like, that they find important, and in which they invest time and energy. Two types of passion are proposed: obsessive and harmonious. Obsessive passion (OP) refers to a controlled internalization of an activity in one's identity that creates an internal pressure to engage in the activity that the person likes. Harmonious passion (HP) refers to an autonomous internalization that leads individuals to choose to engage in the activity that they like. HP promotes healthy adaptation whereas OP thwarts it by causing negative affect and rigid persistence. Results from four studies involving more than 900 participants from different populations supported the proposed conceptualization.


Cerebral palsy for the pediatric eye care team part 1: epidemiology, pathogenesis, and systemic findings.
Cerebral palsy (CP) is a term used to describe a spectrum of neurological deficits resulting from damage to the immature brain. It is a chronic, nonprogressive motor disorder that affects posture, muscle tone, and movement, and therefore commonly results in ophthalmologic abnormalities such as strabismus and eye movement disorders. A basic understanding of CP and its effects will assist the clinician in the diagnosis, prognosis, and management of associated ophthalmologic disorders. This first, in a series of three articles, reviews the definition, epidemiology, pathogenesis, and classification of CP, as well as current management of the postural and motor effects. Results include a retrospective review of 131 consecutive cases of cerebral palsy referred to the Department of Ophthalmology by the Cerebral Palsy Center at the St. Louis Children's Hospital. The second article in the series will present the frequency, diagnosis, and management of the ocular motor deficits associated with CP. Article three will discuss the evaluation of visual acuity, management of decreased vision, and the frequency and type of binocular vision deficits associated with CP.


[Postoperative cognitive deficits].
Cognitive dysfunctions are relatively common in postoperative and critically ill patients. This complication not only compromises recovery after surgery, but, if persistent, it minimizes and compromises surgery itself. Risk factors of postoperative cognitive disorders can be divided into age and comorbidity dependent, and those related to anesthesia and surgery. Cardiovascular, orthopedic and urologic surgery carries high risk of postoperative cognitive dysfunction. It can also occur in other types of surgical treatment, especially in elderly. Among risk factors of cognitive disorders, associated with comorbidity, underlying psychiatric and neurological disorders, substance abuse and conditions with elevation of intracranial pressure are in the first place in postoperative patients. Preoperative and perioperative predisposing conditions for cognitive dysfunction and their incidence were described in our paper. These are: geriatric patients, patients with substance abuse, preexisting psychiatric or cognitive disorders, neurologic disease with high intracranial pressure, cerebrovascular insufficiency, epilepsia, preeclampsia, acute intermittent porphyria, operation type, brain hypoxia, changes in blood glucose level, electrolyte imbalance, anesthetic agents, adjuvant medication and intraoperative awareness. For each of these factors, evaluation, prevention and treatment strategies were suggested, with special regard on anesthetic technique.


Effects of Blood Flow Restriction Training on Muscle Strength and Pain in Patients With Knee Injuries: A Meta-Analysis.
Due to the pain caused by knee injuries, low-load resistance training with blood flow restriction (L-BFR) may be a potential adjuvant therapeutic tool in the rehabilitation of knee injuries. This review aimed to analyze the effectiveness of L-BFR training modality in knee rehabilitation. A meta-analysis was conducted to determine the potential impact of blood flow restriction on patients with knee injuries. PubMed, EBSCO, and Web of Science databases were searched for eligible studies from January 2000 until January 2020. The mean differences of the data were analyzed using Revman 5.3 software with a 95% confidence interval. Nine studies fulfilled the inclusion criteria. These studies involved 179 patients who received L-BFR, 96 patients who underwent high-load resistance training, and another 94 patients who underwent low-load resistance training. The analysis of pooled data showed that patients in both the L-BFR (standardized mean difference, 0.83 [0.53, 1.14], P < 0.01) and high-load resistance training (standardized mean difference, -0.09 [-0.43, 0.24], P = 0.58) groups experienced an increase in muscle strength after the training. In addition, pain score was significantly reduced in the L-BFR group compared with the other two groups (standardized mean difference, -0.61 [-1.19, -0.03], P = 0.04). Muscle strength increased after L-BFR and high-load resistance training compared with low-load resistance training. Furthermore, pain score was significantly reduced after L-BFR. Hence, L-BFR is a potential intervention to be applied in rehabilitation of knee injuries.


Experiences and attitudes related to newborn feeding in central Uganda: A qualitative study.
Adequate infant nutrition is a critical cornerstone of population health, yet adherence to recommended breastfeeding practices is low in many countries in sub-Saharan Africa, including Uganda. This study aims to describe local attitudes, experiences and beliefs related to nutrition in early infancy in Central Uganda. We conducted 5 focus group discussions and 12 key informant interviews to gather information on local attitudes, experiences and beliefs related to feeding in early infancy. Urban areas of Central Uganda. Parents and healthcare and public health professionals. Participants reported numerous concerns related to infant health including inadequate infant weight, premature birth, diarrhea, fever, gastrointestinal infection and malnutrition. Awareness of the infant health benefits of exclusive breastfeeding was prevalent but experienced as in balance with maternal factors that might lead to supplementation, including employment demands, physical appearance, pain, poverty and maternal health and malnutrition. Breastfeeding was highly valued, but use of unsafe breast milk supplements was common, including cow's milk, black tea, glucose water, fruit juice, millet, maize, rice, potatoes, soy, sorghum, egg yolk, fish and ghee. Expression of breast milk was viewed as not consonant with local culture. Participants were aware of the benefits of exclusive breastfeeding but described multiple barriers to achieving it. Supplementation with unsafe breastmilk supplements was considered to be more culturally consonant than milk expression and was reported to be the only affordable potential breast milk substitute for many families.


Reply to "Molecular mechanics models for the image charge".
We have considered the system investigated by Steinmann et al. by means of the image charge model originally proposed in Iori and Corni, J. Comput. Chem. 2008, 29, 1656. Qualitatively correct results are obtained, that compare favorably with the relevant analytical benchmarks. We show that the effect of the asymmetry of the rod model can be controlled, when needed, as originally suggested, that is, by shorter rods. This strategy does not increase neither the complexity of the model nor its computational cost. © 2017 Wiley Periodicals, Inc.


'We have the internet in our hands': Bangladeshi college students' use of ICTs for health information.
Information and Communications Technologies (ICTs) which enable people to access, use and promote health information through digital technology, promise important health systems innovations which can challenge gatekeepers' control of information, through processes of disintermediation. College students, in pursuit of sexual and reproductive health (SRH) information, are particularly affected by gatekeeping as strong social and cultural norms restrict their access to information and services. This paper examines mobile phone usage for obtaining health information in Mirzapur, Bangladesh. It contrasts college students' usage with that of the general population, asks whether students are using digital technologies for health information in innovative ways, and examines how gender affects this. This study relies on two surveys: a 2013-2014 General Survey that randomly sampled 854 households drawn from the general population and a 2015 Student Survey that randomly sampled 436 students from two Mirzapur colleges. Select focus group discussions and in-depth interviews were undertaken with students. Icddr,b's Ethical Review Board granted ethical clearance. The data show that Mirzapur's college students are economically relatively well positioned, more likely to own mobile and smart phones, and more aware of the internet than the general population. They are interested in health information and use phones and computers to access information. Moreover, they use digital technology to share previously-discreet information, adding value to that information and bypassing former gatekeepers. But access to health information is not entirely unfettered, affecting male and female students differently, and powerful gatekeepers, both old and new, can still control sources of information. Personal searches for SRH and the resultant online information shared through discrete, personal face-to-face discussions has some potential to challenge social norms. This is particularly so for women students, as sharing information may enable them to bypass gatekeepers and make decisions about reproduction. This suggests that digital health information seeking may be exercising a disruptive effect within the health sector. However, the extent of this disruption may depend, not on students' mobile phone usage, but on the degree to which powerful new gatekeepers are able to retain control over and market SRH information through students' peer-to-peer sharing.


Chronic myeloid leukaemia.
Tyrosine-kinase inhibitors have changed the natural history of chronic myeloid leukaemia in such a way that patients with adequate access to these agents, who are properly managed, and who respond well to this treatment can expect a near-normal life expectancy. Achieving this goal requires an adequate understanding of the patient's treatment goals, careful monitoring for the achievement of optimal response hallmarks, implementation of proper interventions according to the attainment of such endpoints, adequate recognition and management of adverse events, and acknowledgment of the relevance of comorbidities. Treatment with tyrosine-kinase inhibitors, once considered lifelong, has become terminable for at least some patients, and promising new agents are emerging for those whose disease does not respond to any of the multiple therapeutic options currently available. If these advances reach all patients with chronic myeloid leukaemia, cure might eventually become a reality in most instances.


Cognitive coping and depressive symptoms in definitive infertility: a prospective study.
The objective of the present study was to examine the relationships between infertility characteristics, cognitive coping strategies, and depressive symptoms in definitive involuntarily childless people. Both cross-sectional and prospective relationships were studied in a sample of 169 persons for whom an involuntarily childless future was definitive. The Cognitive Emotion Regulation Questionnaire (CERQ) and the Symptom Check List (SCL-90) were filled out at home. Almost no infertility characteristics were related to depressive symptoms. The cognitive coping strategies self-blame, rumination, catastrophizing and positive reappraisal appeared to be related to depressive symptoms. In addition, catastrophizing was related to depressive symptoms two years later. These findings suggest that intervention programs for people with definitive involuntary childlessness should pay attention to cognitive coping strategies.


Effect of regular endurance exercises on management of cardiovascular health in middle-aged men.
This study was conducted to investigate the effect of regular endurance exercises on the management of cardiovascular health in middle-aged men. The following conclusions were drawn as the result of comparatively analyzing middle-aged men who regularly performed triathlon and cycling exercises for more than 5 years. The effect of regular endurance exercises on cardiovascular health management in middle-aged men was found to be relatively positive. However, prolonged endurance exercises can cause cardiovascular disease which can adversely affect the cardiac function, and to date, no defining limit is known about the amount of exercise that improves the cardiovascular function while reducing the cardiovascular events. Therefore, aiming for exercises at moderate intensity that befit the individual's fitness level as well as conducting regular examinations to predict and manage the risk of sudden cardiac death from exercising were considered as the more effective method of cardiovascular health management.


Elevated Body Mass Index Is Not a Risk Factor for Adverse Outcomes Following Ventricular Assist Device Implantation.
Despite ventricular assist devices (VADs) becoming more common in heart failure (HF) treatment, it is still uncertain which patients are more prone to complications. One potential risk factor is increased body mass index (BMI), which is known to increase both all-cause mortality and mortality from ischemic heart disease; however, the role of the BMI in predicting morbidity and mortality following device implantation is unclear. The study population for this single-institution retrospective chart review consisted of 136 patients with HF, who underwent VAD implantation between 2004 and 2015. Patients were divided into 2 groups based on their BMI: a nonobese group (18.5 < BMI < 30.0; n = 82) or an obese group (BMI >30.0; n = 54). These groups were compared at baseline and after implantation for survival, hospital readmission, and adverse events. No significant difference was found in initial hospital length of stay, number or length of readmissions, or readmission diagnosis. At 1 year, rates of ongoing device support, orthotopic heart transplant (OHT), and death were not significantly different between groups ( P = .89, P = .90, and P = .70, respectively). Multivariate analysis did not identify obesity as an independent predictor of mortality ( P = .90); only biventricular assist device implantation was associated with decreased survival (hazard ratio [HR] = 5.90, P = .002). Obesity in itself should not preclude the use of VAD support in patients with HF, as carefully selected obese patients were shown to have similar rates of hospital readmission, 1-year outcomes, and survival following device implantation compared to nonobese patients.


The relationship between quality of life and coping strategies in polycystic ovary syndrome patients.
There are many factors that affect the quality of life, for example, stress and the coping strategies. Polycystic ovary syndrome is a common hormonal disorder leading to menstrual disorders, hirsutism, acne, obesity, infertility and abortion. In such cases, the patients suffer from a variety of stresses and face problems in their coping strategies with life's problems which can affect the quality of life and cause psychological distress and low the quality of life. The quality of life is a descriptive term which points to health and emotional, social and physical promotion of individuals as well as their ability to perform daily living tasks. The purpose of this study was to investigate the relationship between quality of life and coping strategies in patients with polycystic ovary syndrome. To perform this study, randomly 200 women who had inclusion criteria and were referred to Ali Shariati Hospital in Isfahan were selected and responded DLQI questionnaire and Carver coping strategies and form of demographic characteristics. The mean score of quality of life in the patients was 4.14 ± 5.57. It was shown that acne has no effective role on quality of life and coping strategies in contrast in hirsute and non-hirsute patients; there was a significant difference in quality of life P value < 0.001). Also there is a significant relationship between the quality of life and coping strategies (problem solving, cognitive, emotional and social support) (P < 0.05) and quality of life has the highest correlation with emotional strategies (r = 0.46). According to results of this study, patients with PCOS are at risk pcychologicla disorders that may be led to decrease of quality of life. Thus this patients need to support by oppositions strategies. Also not only physical treatment but also psychological surveillance especially social support must be done for them.


Immunopathogenesis of neuromyelitis optica.
Neuromyelitis optica (NMO, Devic's syndrome) is a clinical syndrome characterized by optic neuritis and (mostly longitudinally extensive) myelitis. If untreated, NMO usually takes a relapsing course and often results in blindness and tetra- or paraparesis. The discovery of autoantibodies to aquaporin-4, the most abundant water channel in the CNS, in 70-80% of patients with NMO (termed NMO-IgG or AQP4-Ab) and subsequent investigations into the pathogenic impact of this new reactivity have led to the recognition of NMO as an autoimmune condition and as a disease entity in its own right, distinct from classic multiple sclerosis. Here, we comprehensively review the current knowledge on the role of NMO-IgG/AQP4-Ab, B cells, T cells, and the innate immune system in the pathogenesis of NMO.


Basics of Compounding: Providing Pharmacy Services to Bariatric Surgery Patients.
With the rise in obesity, more individuals are choosing bariatric surgery as a means to successfully lose weight and resolve co-morbidities. These patients need lifelong support from friends, family, and healthcare providers. Pharmacists need to be knowledgeable of the unique needs of these patients in order to provide information and recommendations on drug therapies and supplements. When a patient is wheeled out of the operating room following bariatric surgery, his or her life instantly changes. Like an infant, the patient has to slowly learn how to eat and drink again. Physical activity significantly increases. Taste perception changes. Serious medical problems, such as hypertension, type II diabetes, and hypercholesterolemia completely resolve within a couple of months. The patient has to be disciplined and follow the instructions of the bariatric team and other healthcare providers. Since the patient's gastrointestinal tract has been significantly altered, drug therapies may require some modifications too. Bariatric or weight loss surgery is definitely not the easy way to lose weight, but it is a very powerful tool for the patient. Weight loss, and maintaining that weight loss, is a lifelong journey for the patient that requires support from the bariatric team, healthcare provider(s), co-workers, friends, and family. Pharmacists may also provide support for these patients through counseling about their supplements, medications, and compounding medications to meet their specific needs.


Discovering and improving novel peptide therapeutics.
Peptides have a number of advantages over small molecules in terms of specificity and affinity for targets, and over antibodies in terms of size. However, sensitivity to serum and tissue proteases coupled with short serum half-life has resulted in few recombinant library derived peptides, making the transition from lead to drug on the market. Recently, a series of technologies have been developed to address both these issues: selection methodologies addressing protease resistance have been developed that when combined with methods such as pegylation antibody Fc attachment and binding to serum albumin look likely to finally turn therapeutic peptides into a widely accepted drug class.


[Preparation and characterization of magnetic nano-particles with radiofrequency-induced hyperthermia for cancer treatment].
Mn0.5Zn0.5Fe2O4 nano-particles were prepared by the chemical co-precipitation, their characteristics were observed with transmission electron microscope (TEM), X-ray diffractometer (XRD) and thermal analysis system, and etc. The temperature changes of the nano-particles of Mn0.5Zn0.5Fe2O4 and its magnetic fluid explored in radiofrequency(RF,200 KHz, 4 KW) were measured. The proliferation ratio of L929 cells cultured in soak of Mn0.5Zn0.5Fe2O4 nano-particles were observed. The experiment indicates that the magnetic particles were about 40 nm diameter in average, round, had strong magnetism, and were proved to be consistent with the standard data of chart of XRD. Its magnetic fluid exposed to RF could be heated up to temperature range from 40 degrees C to 51 degrees C due to the amount of the magnetic nano-particles and intensity of the alternating magnetic field. Magnetic nano-particles were found to have no obvious cytotoxicity to L929 cells.


Thermally Activated Delayed Fluorescence and Aggregation Induced Emission with Through-Space Charge Transfer.
Emissive molecules comprising a donor and an acceptor bridged by 9,9-dimethylxanthene, were studied (XPT, XCT, and XtBuCT). The structures position the donor and acceptor with cofacial alignment at distances of 3.3-3.5 Å wherein efficient spatial charge transfer can occur. The quantum yields were enhanced by excluding molecular oxygen and thermally activated delayed fluorescence with lifetimes on the order of microseconds was observed. Although the molecules displayed low quantum yields in solution, higher quantum yields were observed in the solid state. Crystal structures revealed π-π intramolecular interactions between a donor and an acceptor, however, the dominant intermolecular interactions were C-H···π, which likely restrict the molecular dynamics to create aggregation-induced enhanced emission. Organic light emitting devices using XPT and XtBuCT as dopants displayed electroluminescence external quantum efficiencies as high as 10%.


Sickle cell disease in Saudi Arabs in early childhood.
Haemoglobin electrophoresis screening of 2341 infants from the oases of eastern Saudi Arabia, performed in an attempt to detect cases early and then to follow up and give better management to patients with sickle cell disease, showed 20% with S-trait and 43 with sickle cell disease (37 HbSS and 6 S-beta(0) thalassaemia). On follow-up from birth (or from 3 months) for a mean of 3 1/2 years there was more morbidity and mortality than in matched Saudi Arab controls, but these rates were lower than for affected black infants in the US or Jamaica. Serial haemoglobin levels were l g/dl lower than for controls; height and weight increases were the same. Mean fetal haemoglobin level was 32% at 4-5 years. Half of a subsample of 23 cases had evidence of coexistent alpha-thalassaemia which appeared to protect against functional asplenia, judged by the presence of Howell-Jolly bodies; however there was no difference in degree of anaemia or clinical course. Early screening is recommended for infants at risk for sickle cell disease, and comprehensive care should be given even if the infant has the less severe type.


Web-based Gene Pathogenicity Analysis (WGPA): a web platform to interpret gene pathogenicity from personal genome data.
As the volume of patient-specific genome sequences increases the focus of biomedical research is switching from the detection of disease-mutations to their interpretation. To this end a number of techniques have been developed that use mutation data collected within a population to predict whether individual genes are likely to be disease-causing or not. As both sequence data and associated analysis tools proliferate, it becomes increasingly difficult for the community to make sense of these data and their implications. Moreover, no single analysis tool is likely to capture all relevant genomic features that contribute to the gene's pathogenicity. Here, we introduce Web-based Gene Pathogenicity Analysis (WGPA), a web-based tool to analyze genes impacted by mutations and rank them through the integration of existing prioritization tools, which assess different aspects of gene pathogenicity using population-level sequence data. Additionally, to explore the polygenic contribution of mutations to disease, WGPA implements gene set enrichment analysis to prioritize disease-causing genes and gene interaction networks, therefore providing a comprehensive annotation of personal genomes data in disease. wgpa.systems-genetics.net.


Expression and antimicrobial activity of c-type lysozyme in taimen (Hucho taimen, Pallas).
Lysozymes are important defense proteins of the innate immune system and possess high antibacterial activities. In the present study, a full-length c-type lysozyme cDNA (HtLysC) was cloned and characterized from taimen (Hucho taimen, Pallas). The cDNA contains an open reading frame (ORF) of 432 bp encoding 143 amino acid (aa), with 97% identity to LysC of Rainbow trout (Oncorhynchus mykiss). The amino acid sequence possessed a LYZ1 domain (16-140 aa) which contained two conserved residues (Glu 50 and Asp 67), eight conserved cysteine residues and a calcium binding site. RT-PCR analysis showed that HtLysC transcripts were most abundant in liver and less in muscle. The expression of HtLysC was up-regulated in the liver when challenged with Yersinia ruckeri. The recombinant HtLysC (rHtLysC) had lytic activities against Micrococcus lysodeikticus, Aeromonas salmonicida and Y. ruckeri. Enzyme assay showed that the optimal temperature and pH of rHtLysC were 55 °C and 6.0, respectively. Taken together, these results indicated that HtLysC might play an important role in innate immune defense against bacterial pathogens as a functional lysozyme.


Ascaris lumbricoides: a travel joke?
Intestinal nematodes affect more than a billion people worldwide. They are commonly found in regions with poor fecal sanitation, such as developing countries. Although most of the nematode infections are non-fatal diseases, they contribute to significant morbidities such as loss of work capacity and malnutrition. We are presenting an 80-year-old male who was diagnosed with Ascaris Lumbricoides after a return from recent travel to Greece, with some clinical endoscopic images.


Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis.
Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.


DOSIMETRIC VERIFICATION OF INTENSITY MODULATED RADIOTHERAPY (IMRT) TREATMENT PLANS FOR PROSTATE CANCER PATIENTS.
Intensity modulated radiotherapy (IMRT) has become widely used as a standard radiation therapy technique for the treatment of localized prostate cancer. The transition from conformal radiotherapy (3D CRT) to a more complex IMRT technique triggered the need for more thorough verification of the accuracy in the dose delivery. In this work we present the clinical workflow and the results of patient specific quality assurance (PSQA) procedures for 40 prostate cancer patients who have been treated with step and shot IMRT ever since its implementation in our routine clinical practice. PSQA procedures include dosimetric verification of each treatment plan with dedicated rotational phantom and high-resolution matrix detector system Octavius 4D (PTW Freiburg) that allows three-dimensional comparison of the calculated and delivered radiation dose distribution. Our results proved the compliance with the universal tolerance limits recommended for those procedures (1), assuring the safety of the treatment and providing the possibility for the adoption of more stringent constraints in the future.


Modified vertical infraclavicular block: An evaluation of two methods.
The vertical infraclavicular block (VIB) of the brachial plexus is commonly used to provide local anesthesia (LA) of the upper limb. The original method involves LA injection at the mid-point of an infraclavicular line between acromion and jugular fossa. However, this method is ineffective in adult patients with variant anatomy. Two modified VIB methods have been previously suggested. This prospective observational, clinical study compared both modified VIB approaches. The study showed that modified VIB is easy, efficacious, and applicable to all adult patients; including those with small stature, extreme tallness, or variant anatomy.


Characterization of the cattle serum antibody responses against TEM beta-lactamase and the nonimmunogenic Escherichia coli heat-stable enterotoxin (STaI).
In order to test the use of a subunit recombinant vaccine for its capacity to induce antibodies against the nonimmunogenic heat-stable enterotoxin STa from Escherichia coli and the TEM-1 beta-lactamase, cattle were immunized with a hybrid protein created by insertion of the STa sequence at position 197 of the TEM-1 beta-lactamase. Specific anti-STa IgG and IgG1 antibodies were detected at low levels, while no IgG2 antibodies were detected. In contrast, high levels of the different anti-TEM IgG subtypes were detected in cattle sera. In addition, beta-lactamase activity was inhibited by the sera. The presence of antibodies against STa and TEM-1 beta-lactamase was assessed in sera from 366 cattle taken from the field. No significant level of IgGs against the toxin or the TEM-1 was detected. A comparison of the antibody level between the immunized and the nonimmunized animals clearly demonstrated that STa was not able to induce a significant level of antibodies in the vaccinated animals. In contrast, a strong antibody response against TEM-1 beta-lactamase was demonstrated.


Deeply cooled and temperature controlled microjets: Liquid ammonia solutions released into vacuum for analysis by photoelectron spectroscopy.
A versatile, temperature controlled apparatus is presented, which generates deeply cooled liquid microjets of condensed gases, expelling them via a small aperture into vacuum for use in photoelectron spectroscopy (PES). The functionality of the design is demonstrated by temperature- and concentration-dependent PES measurements of liquid ammonia and solutions of KI and NH4I in liquid ammonia. The experimental setup is not limited to the usage of liquid ammonia solutions solely.


Receptors on red cells for Plasmodium falciparum and their interaction with merozoites.
The red cell sialoglycoproteins (glycophorins, alpha (A), delta (B) and beta and gamma (C] play a crucial role in the invasion of human red cells by merozoites of Plasmodium falciparum. Red cells deficient in any of the glycophorins, including beta (also known as glycoconnectin), resist infection by this parasite to varying degrees. These cells and other naturally occurring well-characterized glycophorin variants provide extremely powerful tools to dissect the role of these molecules in invasion. The binding of merozoites to human red cells appears analogous to the binding of wheatgerm agglutinin to sialoglycoconjugates. In both systems O- and N-linked oligosaccharides may be involved. Membrane lipid has not been implicated as a receptor for merozoites, but may instead non-specifically modify binding, as may electrostatic and hydrophobic interactions. The results of data using monoclonal antibodies and lectins, although possibly helpful in identifying specific determinants, must be interpreted with caution. Overall the data suggest that the red cell receptors for all strains of P. falciparum tested to date are located on the glycophorins. Accordingly these putative receptors have been used to affinity-purify complementary parasite components which may yet prove to be of protective immunological significance in a vaccine.


Case Report: Dual Checkpoint Inhibition in Advanced Metastatic Osteosarcoma Results in Remission of All Tumor Manifestations-A Report of a Stunning Success in a 37-Year-Old Patient.
Patients with unresectable metastasized osteosarcoma have a poor prognosis. Current treatment options do not offer a chance to cure the disease in this situation. Despite the fact that immunotherapy has expanded its indications continuously over previous years, its use is not yet established in osteosarcoma. There is a lack of randomized controlled studies that could show a significant benefit in this rare tumor entity. So far, efficacy of immunotherapy is only reported in individual cases as well as in mouse models. To predict a response to immunotherapy, testing for programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB) can be useful, but status is not yet clear for most cancer entities. Single case study and review of the literature. This report presents the case of a 37-year-old patient with metastatic advanced osteosarcoma, who had no more established options for tumor treatment left. PD-L1 expression in the most recent tumor sample was high (tumor proportion score (TPS) 90%, combined positive score (CPS) 92%) but no MSI could be detected. In an individual therapy attempt, an ongoing and profound remission of all tumor manifestations due to four cycles of immunotherapy with ipilimumab and nivolumab was reached. Despite discontinuation of immunotherapy for 3 months due to therapy-related pneumonitis, remission of all tumor manifestations was ongoing, and no detectable relapse in restaging before onset of Nivolumab-maintenance could be observed. The present case constitutes the first report of an adult patient with metastasized advanced osteosarcoma who reached a deep remission of disease by immunotherapy with ipilimumab and nivolumab, which continued even though immunotherapy had to be interrupted. To verify whether the high expression of PD-L1, as seen in this patient, is a predictive marker for response to immunotherapy in osteosarcoma, requires further investigation.


Donor-site morbidity of the segmental rectus abdominis muscle flap.
The donor-site morbidity of the segmental rectus abdominis muscle flap was evaluated in 20 patients with an average follow-up time of 47 months. Our criteria were based on static and dynamic functional results including relaxation and hernia of the abdominal wall, aesthetic outcome and patient satisfaction. The dynamic functional tests of the abdominal wall showed good results corresponding to the reported minimal impairment of quality of life. There was one abdominal hernia after wound infection and secondary healing. There was no evidence of abdominal wall instability in any of the other patients. The aesthetic outcome was excellent when a transverse lower abdominal incision, asymmetrically elongated to the donor site, was used and moderate in the case of a paramedian vertical incision. Ninety-five per cent of the patients were completely satisfied or satisfied with the result at the donor site. In the segmental use of the free rectus abdominis flap a high degree of subjective patient satisfaction reflects the favourable outcome of our examinations. On the other hand there is a clinically significant functional donor-site defect of this flap. As this procedure is still widely used, and as its indication is closely linked to its absolute and relative donor-site defect, comparisons with the alternatives, e.g. the partial latissimus dorsi muscle flap, the extended gracilis muscle flap or the serratus anterior muscle flap will have to be made.


Classical studies of H atom trapping on a graphite surface.
The trapping and sticking of H and D atoms on the graphite (0001) surface is examined over the energy range 0.1-0.9 eV. Total electronic energy calculations based on density functional theory are used to develop a potential energy surface that allows for the full three-dimensional motion of the incident atom and the reconstruction of the bonding carbon atom, which must pucker out of the surface to form a stable bond. Classical methods are used to compute trapping cross sections as a function of incident energy. The C-H bond, once formed, rapidly dissociates without a mechanism to dissipate its excess energy. However, a number of long-lived trapping resonances exist, and for impact parameters below 1 A or so, several percent of the incident H atoms can remain trapped for 1 ps or more. This long-time trapping probability increases significantly when additional lattice degrees of freedom are added to carry energy away from the C-H stretch. Trapping can also increase with an increasing collision impact parameter, as H vibrations parallel to the surface become excited, leaving less energy in the C-H stretch. The trapping cross section at 1 ps reaches a maximum of 0.2 A2 for an H atom energy of 0.3 eV. Assuming that any atoms remaining trapped after 1 ps fully relax and stick, we estimate a lower bound for the sticking probability of H and D to be 0.024 and 0.050, respectively, about an order of magnitude below the experimental values.


Influence of accommodative and vergence adaptation on binocular motor disorders.
Tait described four categories of binocular disorders including convergence excess, convergence insufficiency, divergence excess, and divergence insufficiency. These disorders are defined by the distance where the largest heterophoria occurs (distance or near), and the amplitude of the accommodative vergence ratio (AC/A). Insufficiency corresponds to a low AC/A ratio, whereas excess corresponds to a high AC/A. The magnitude of the AC/A ratio, which may be influenced by the adaptability of the accommodation and vergence systems, has been shown to be reciprocally related to adaptability of accommodation. Likewise, the degree of vergence accommodation has been shown to be related reciprocally to adaptability of vergence to prism. An imbalance of adaptability of accommodation and vergence systems produces abnormal cross-coupling between the two motor systems. When accommodation is more adaptable than vergence, the AC/A ratio is low and the CA/C ratio is high. Conversely, when vergence is more adaptable than accommodation, the AC/A ratio is high and the CA/C ratio is low. A method is reported for temporarily restoring moderate amplitudes of abnormal AC/A and CA/C ratios by reducing excessive adaptation with fatigue. Finally, new clinical procedures for measuring adaptation of accommodation and the CA/C ratio are presented. Taken together with current measures of vergence adaptation and AC/A ratio these procedures will permit a more complete evaluation of mutual interactions between accommodation and vergence in patients diagnosed as having excessive and insufficient vergence.


Defining competencies for safe thyroidectomy: An international Delphi consensus.
Current methods for teaching and assessing competencies that characterize expert intraoperative performance are inconsistent, subjective, and lack standardization. This mixed-methods study was designed to define and establish expert consensus on the most important competencies required to perform a thyroidectomy safely. Cognitive task analyses for thyroidectomy were performed with semistructured interviews of experts in thyroid surgery. Verbal data were transcribed verbatim, coded, and categorized according to themes that were synthesized into a list of items. Once qualitative data reached saturation, 26 experts were invited to complete 2-round online Delphi surveys to rank each item on a Likert scale of importance (1-7). Consensus was predefined as a Cronbach's α ≥ 0.80. Sixty items were synthesized from 5 interviews and categorized into 8 sections: preparation (n = 8), incision/exposure (n = 11), general considerations (n = 4), middle thyroid vein (n = 1), superior pole (n = 5), inferior pole (n = 5), posterolateral dissection (n = 19), and closure (n = 7). Eighteen (69%) experts from 3 countries participated in the Delphi survey. Consensus was achieved after 2 voting rounds (Cronbach's α = 0.95). Greatest weighted sections included "Superior Pole Dissection" and "Posterolateral Dissection." Consensus was achieved on defining the most important competencies for safe thyroidectomy. This blueprint serves as the basis for instructional design and objective assessment tools to evaluate performance.


Adenosine A(2A) agonist administration improves islet transplant outcome: Evidence for the role of innate immunity in islet graft rejection.
Activation of adenosine A(2A) receptors inhibits inflammation in ischemia/reperfusion injury, and protects against cell damage at the injury site. Following transplantation 50% of islets die due to inflammation and apoptosis. This study investigated the effects of adenosine A(2A) receptor agonists (ATL146e and ATL313) on glucose-stimulated insulin secretion (GSIS) in vitro and transplanted murine syngeneic islet function in vivo. Compared to vehicle controls, ATL146e (100 nM) decreased insulin stimulation index [SI, (insulin)(high glucose)/(insulin)(low glucose)] (2.36 +/- 0.22 vs. 3.75 +/- 0.45; n = 9; p < 0.05). Coculture of islets with syngeneic leukocytes reduced SI (1.41 +/- 0.17; p < 0.05), and this was restored by ATL treatment (2.57 +/- 0.18; NS). Addition of a selective A(2A)AR antagonist abrogated ATL's protective effect, reducing SI (1.11 +/- 0.42). ATL treatment of A(2A)AR(+/+) islet/A(2A)AR(-/-) leukocyte cocultures failed to protect islet function (SI), implicating leukocytes as likely targets of A(2A)AR agonists. Diabetic recipient C57BL/6 mice (streptozotocin; 250 mg/kg, IP) received islet transplants to either the renal subcapsular or hepatic-intraportal site. Recipient mice receiving ATL therapy (ATL 146e or ATL313, 60 ng/kg/min, IP) achieved normoglycemia more rapidly than untreated recipients. Histological examination of grafts suggested reduced cellular necrosis, fibrosis, and lymphocyte infiltration in agonist-treated animals. Administration of adenosine A(2A) receptor agonists (ATL146e or ATL313) improves in vitro GSIS by an effect on leukocytes, and improves survival and functional engraftment of transplanted islets by inhibiting inflammatory islet damage in the peritransplant period, suggesting a potentially significant new strategy for reducing inflammatory islet loss in clinical transplantation.


Translational control in E. coli: the case of threonyl-tRNA synthetase.
Genetic studies have shown that expression of the E. coli threonyl-tRNA synthetase (thrS) gene is negatively auto-regulated at the translational level. A region called the operator, located 110 nucleotides downstream of the 5' end of the mRNA and between 10 and 50 bp upstream of the translational initiation codon in the thrS gene, is directly involved in that control. The conformation of an in vitro RNA fragment extending over the thrS regulatory region has been investigated with chemical and enzymatic probes. The operator locus displays structural similarities to the anti-codon arm of threonyl tRNA. The conformation of 3 constituent mutants containing single base changes in the operator region shows that replacement of a base in the anti-codon-like loop does not induce any conformational change, suggesting that the residue concerned is directly involved in regulation. However mutation in or close to the anti-codon-like stem results in a partial or complete rearrangement of the structure of the operator region. Further experiments indicate that there is a clear correlation between the way the synthetase recognises each operator, causing translational repression, and threonyl-tRNA.


C-H...pi interactions in cocrystals of bis(trimethylsilyl)acetylene and diphenylacetylene with benzene.
We present here the crystal structures of two acetylene derivatives cocrystallized with benzene, namely bis(trimethylsilyl)acetylene benzene solvate, C(8)H(18)Si(2).C(6)H(6), (I), and diphenylacetylene benzene solvate, C(14)H(10).C(6)H(6), (II). In (I), both molecules belong to the symmetry point group C(2h) and are located about special positions with site symmetry 2/m. In (II), both molecules show crystallographic inversion symmetry. In both structures, there are C-H...pi contacts between aromatic H atoms and the pi-electrons of the triple bond. In addition to these, in (II) there are C-H...pi contacts between aromatic H atoms and the pi-electron cloud of the benzene molecules.


Relationships between lifestyle patterns and cardio-renal-metabolic parameters in patients with type 2 diabetes mellitus: A cross-sectional study.
While individuals tend to show accumulation of certain lifestyle patterns, the effect of such patterns in real daily life on cardio-renal-metabolic parameters remains largely unknown. This study aimed to assess clustering of lifestyle patterns and investigate the relationships between such patterns and cardio-renal-metabolic parameters. The study participants were 726 Japanese type 2 diabetes mellitus (T2DM) outpatients free of history of cardiovascular diseases. The relationship between lifestyle patterns and cardio-renal-metabolic parameters was investigated by linear and logistic regression analyses. Factor analysis identified three lifestyle patterns. Subjects characterized by evening type, poor sleep quality and depressive status (type 1 pattern) had high levels of HbA1c, alanine aminotransferase and albuminuria. Subjects characterized by high consumption of food, alcohol and cigarettes (type 2 pattern) had high levels of γ-glutamyl transpeptidase, triglycerides, HDL-cholesterol, blood pressure, and brachial-ankle pulse wave velocity. Subjects characterized by high physical activity (type 3 pattern) had low uric acid and mild elevation of alanine aminotransferase and aspartate aminotransferase. In multivariate regression analysis adjusted by age, gender and BMI, type 1 pattern was associated with higher HbA1c levels, systolic BP and brachial-ankle pulse wave velocity. Type 2 pattern was associated with higher HDL-cholesterol levels, triglycerides, aspartate aminotransferase, ɤ- glutamyl transpeptidase levels, and diastolic BP. The study identified three lifestyle patterns that were associated with distinct cardio-metabolic-renal parameters in T2DM patients. UMIN000010932.


Social support from evaluative familiar persons - a buffer against stress? Preliminary evidence of neuroendocrine and psychological responses.
Background and Objectives: Social support may have a stress-buffering effect when an individual is or could be negatively judged by others, but paradoxically may also exacerbate stress. The aim of our study was to examine these findings when social support was provided by a positive or negative evaluative audience composed of familiar and close others (teachers). Design and Methods: 84 men were confronted with the Trier Social Stress Test for Groups through a 3 (negative, positive, no-audience) x 2 (familiar, unfamiliar) experimental design with four measurement points of cortisol levels and state anxiety. We also tested whether closeness with the committee members predicted these variables for the participants in the familiar conditions. Results: Using both a frequentist and a Bayesian approach, familiarity and social support did not have stress-buffering effects (or merely anecdotal effects) on cortisol levels but buffered self-reported anxiety only for the participants faced with a supportive audience composed of familiar persons. Closeness with the experimenters was not a significant predictor of the stress responses. Conclusions: Because these results are preliminary evidence, further investigations into the relations between support provider and recipient during evaluative tasks would be worthwhile to better explain opposing findings found in this growing literature.


Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire.
Expression of autoimmune regulator (Aire) by thymic medullary epithelial cells (MECs) is critical for central tolerance of self. To explore the mechanism by which such a rare cell population imposes tolerance on the large repertoire of differentiating thymocytes, we examined the proliferation and turnover of Aire(+) and Aire(-) MEC subsets through flow cytometric analysis of 5-bromo-2'deoxyuridine (BrdU) incorporation. The Aire(+) MEC subset was almost entirely postmitotic and derived from cycling Aire(-) precursors. Experiments using reaggregate thymic organ cultures revealed the presence of such precursors among Aire(-) MECs expressing low levels of major histocompatibility complex class II and CD80. The kinetics of BrdU decay showed the Aire(+) population to have a high turnover. Aire did not have a direct impact on the division of MECs in vitro or in vivo but, rather, induced their apoptosis. We argue that these properties strongly favor a "terminal differentiation" model for Aire function in MECs, placing strict temporal limits on the operation of any individual Aire(+) MEC in central tolerance induction. We further speculate that the speedy apoptosis of Aire-expressing MECs may be a mechanism to promote cross-presentation of the array of peripheral-tissue antigens they produce.


Familial achalasia, microcephaly, and mental retardation. Case report and review of literature.
Two Libyan brothers with achalasia of the cardia, microcephaly, and mental retardation are described. The parents were first cousins and were normal, as were two other male siblings and the female twin of one of the affected brothers. This is the second family to be reported with this constellation of abnormalities. The literature is reviewed for achalasia associated with other pathological conditions.


The transcription of bacterial luminescence is regulated by sigma 32.
Luminescence in the marine bacterium, Vibrio fischeri, is regulated by a small molecule, the autoinducer. The transcription of the V. fischeri lux genes also requires a regulatory protein, (luxR), cAMP and CRP. We show that, apart from these components, the transcription of the PR lux operon is also controlled by the activity of sigma 32 (htpR protein). In luminescent Escherichia coli (E. coli/pChv1), as well as in different marine luminous bacteria and their naturally occurring dark (K) variants, the luminescence system can be induced by starvation under microaerophilic conditions. Heat shock also induces luminescence in htpR+ but not in htpR- strains of E. coli/pChv1. An htpR- mutant of E. coli containing pChv1 is very dim and its luminescence is not induced by starvation or heat shock. The addition of a plasmid bearing the gene for htpR+ into such cells restores their response to starvation and heat shock. Cells of wild type E. coli/pChv1 that have been starved or heat shocked respond to lower concentrations of V. fischeri inducer than untreated cells. These cultures also produce more extracellular inducer than untreated cells. Starvation, heat shock and the presence of sigma 32 do not induce luminescence in luxl deleted E. coli/pChv1 cells. SOS-inducing agents advance the onset of luminescence in both htpR+ and htpR- strains but not in luxl deleted E. coli/pChvi cells. DNA sequencing of the luxR-luxl region reveals the presence of a promoter region of the kind typical for sigma 32 at the beginning of the luxl gene. In addition we find a LexA protein-DNA binding site in the non-consensus sequence for the -35 region of the PR operon. It is proposed that the regulatory protein-inducer complex displaces the LexA protein and allows the transcription of the right operon. SOS-inducing agents result in proteolysis of LexA protein and advance the onset of luminescence. sigma 32 enhances the transcription from the PR operon and thus initiates a positive control circuit. It seems that sigma 32 is the major controlling element in determining the onset of luminescence both in vivo and in vitro.


Evaluation of the cytotoxic and genotoxic effects by melamine and cyanuric acid co-exposure in human embryonic kidney 293 cells.
The melamine and cyanuric acid (CA) complex has been suggested to cause the toxic effects observed in melamine-contaminated food or milk. However, the cytotoxic and genotoxic effects of co-exposure to melamine and CA are not fully clear. Therefore, the cytotoxic effects of melamine and CA were first examined by co-exposure in human kidney 293 cells using the MTT assay. During a 24-h period for the three concentrations tested (0.5, 1, and 5 mg/mL), neither melamine nor CA alone showed significant toxic effects on 293 cells at 0.5 mg/mL, while higher concentrations led to decreased in cell viability. However, co-exposure to several combinations of melamine and CA [100:1, 10:1, 1:10, and 1:100 (v:v), at a final concentration of 0.5 mg/mL] did cause cytotoxicity with higher levels of CA leading to higher cytotoxicity. By contrast, while neither melamine nor CA alone induced phosphorylated-H2AX (γH2AX) foci formation, melamine and CA at a 100:1 ratio induced γH2AX foci 24 h post-treatment. The alkaline comet assay also revealed the presence of DNA damage following melamine and CA co-exposure. In vivo assay also revealed the presence of melamine-CA complex in the kidney. These data indicated that the cytotoxic and genotoxic effects of melamine and CA co-exposure differ from those of melamine or CA alone.


The role of recombinant hirudins in the management of thrombotic disorders.
Native hirudin is the most potent natural direct thrombin inhibitor currently known; it is capable of inhibiting not only fluid phase, but also clot-bound thrombin. Recombinant technology now allows production of recombinant hirudins (r-hirudins), which are available in sufficient purity and quantity with essentially unaltered thrombin-inhibitory potency. As thrombin is known to play a key role in a number of thrombotic disorders, numerous studies focused on the impact of r-hirudins on the clinical course in these diseases. R-hirudins provided significantly more stable anticoagulation than standard heparin, but demonstrated a relatively narrow therapeutic range with relevant bleeding risk even at clinically effective doses. In doses that are not associated with an increased bleeding risk, r-hirudins often failed to demonstrate significant superiority to heparin. To date, r-hirudins have a definite role in the treatment of heparin-induced thrombocytopenia, where they markedly reduce the high risk of thrombosis. For prophylaxis of deep vein thrombosis, r-hirudins have been shown to be superior to both unfractionated and low molecular weight heparin, but are not extensively used in this indication. In acute coronary syndromes, a definite role of r-hirudins has not yet been firmly established. When applied in an appropriate dose as adjunct to thrombolysis in patients with acute myocardial infarction, randomized, controlled trials did not show a consistent benefit of r-hirudins, especially in the long-term. In patients undergoing coronary balloon angioplasty for acute coronary syndromes, promising effects in the early postprocedural phase did not translate to an improved outcome after 6 months. In patients with unstable angina pectoris, efficacy and safety of r-hirudins as primary antithrombotic therapy are still under debate. In the future, r-hirudins are to be compared with alternative or additional potent antithrombotic agents or treatment strategies. This comparison will ultimately lead to their final placement in the management of thrombotic disorders.


Anopheles stephensi: a guest to watch in urban Africa.
Malaria vector control programs in Sub-Saharan Africa have invested many efforts and resources in the control of eight-sibling species of Anopheles gambiae complex and An. funestus group. The behaviour of sibling species of these vectors is well known and used for implementing the current intervention tools. The reports of An. stephensi in urban Africa with different habitats breeding behaviour is an alert on the success of malaria vector control efforts achieved so far. This communication intends to give an insight on what should be considered as a challenge for the management of An. stephensi in urban Africa to retain the achievement attained in malaria control.


Genetic diversity of porcine circovirus type 2 in China between 1999-2017.
Porcine circovirus type 2 (PCV-2), is linked to PCV-2 associated disease, which has caused considerable economic loss in the swine industry. Here, we report the genetic diversity of PCV-2 in China. A total of 74 Chinese PCV-2 strains sequenced between 1999 and 2017 were studied. Based on the ORF2 and complete genomes, we found that apart from the PCV-2a, PCV-2b, and PCV-2d genotypes, two unstable recombination genotypes also exist, referred to as IM1 and IM2 genotypes. We found that the patterns of PCV-2 genetic shift in China are similar to the patterns at the global level. Additionally, for the PCV-2 ORF2 gene of Chinese isolates, we found a similar time to the most recent common ancestor and evolutionary rate to the global values. This indicates that PCV2 genetic diversity in China is driven by genetic drift/recombination of local strains and by the sporadic introduction of foreign genotypes from other countries. Overall, our study illustrates the genetic diversity and evolution dynamics of PCV-2 in China.


Percutaneous intraductal radiofrequency ablation for treatment of biliary stent occlusion: A preliminary result.
To assess the feasibility and effectiveness of a novel application of percutaneous intraductal radiofrequency (RF) for the treatment of biliary stent obstruction. We specifically report a retrospective study presenting the results of percutaneous intraductal RF in patients with biliary stent occlusion. A total of 43 cases involving biliary stent obstruction were treated by placing an EndoHPB catheter and percutaneous intraductal RF was performed to clean stents. The stent patency was evaluated by cholangiography and follow-up by contrast enhanced computed tomography or ultrasound after the removal of the drainage catheter. Following the procedures, of the 43 patients, 40 survived and 3 died with a median survival of 80.5 (range: 30-243) d. One patient was lost to follow-up. One patient had the stent patent at the time of last follow-up. Two patients with stent blockage at 35 d and 44 d after procedure underwent percutaneous transhepatic drain insertion only. The levels of bilirubin before and after the procedure were 128 ± 65 μmol/L and 63 ± 29 μmol/L, respectively. There were no related complications (haemorrhage, bile duct perforation, bile leak or pancreatitis) and all patients' stent patency was confirmed by cholangiography after the procedure, with a median patency time of 107 (range: 12-180) d. This preliminary clinical study demonstrated that percutaneous intraductal RF is safe and effective for the treatment of biliary stent obstruction, increasing the duration of stent patency, although randomized controlled trials are needed to confirm the effectiveness of this approach.


Imaging of Metastatic Cancer Cells in Sentinel Lymph Nodes using Affibody Probes and Possibility of a Theranostic Approach.
The accurate detection of lymph node metastases is essential for treatment success in early-stage malignant cancer. Sentinel lymph node (SLN) biopsy is the most effective procedure for detecting small or micrometastases that are undetectable by conventional imaging modalities. To demonstrate a new approach for developing a more efficient SLN biopsy procedure, we reported a two-stage imaging method combining lymphoscintigraphy and near-infrared (NIR) fluorescence imaging to depict metastatic cancer cells in SLNs in vivo. Furthermore, the theranostic potential of the combined procedure was examined by cell culture and xenograft mouse model. Anti-HER2 and anti-epidermal growth factor receptor (EGFR) affibody probes were used for NIR fluorescence imaging. Strong NIR fluorescence signal intensity of the anti-EGFR affibody probe was observed in SAS cells (EGFR positive). Radioactivity in the SLNs was clearly observed in the in vivo studies. High anti-EGFR affibody NIR fluorescence intensity was observed in the metastatic lymph nodes in mice. The addition of the IR700-conjugated anti-EGFR affibody to the culture medium decreased the proliferation of SAS cells. Decreased proliferation was shown in Ki-67 immunohistochemistry in xenograft tumors. Our data suggest that a two-stage combined imaging method using lymphoscintigraphy and affibody probes may offer the direct visualization of metastatic lymph nodes as an easily applied technique in SLN biopsy. Although further animal studies are required to assess the effect of treating lymphatic metastasis in this approach, our study results provide a foundation for the further development of this promising imaging and treatment strategy for earlier lymph node metastasis detection and treatment.


Real-world Experience With Neurotrophic Tyrosine Receptor Kinase Fusion-positive Tumors and Tropomyosin Receptor Kinase Inhibitors in Veterans.
Neurotrophic tyrosine receptor kinase 1-3 (NTRK1-3) gene fusions are found in a broad range of tumor types. Clinical trials demonstrated high response rates to tropomyosin receptor kinase (TRK) inhibitors in NTRK fusion-positive cancers, but few reports have described real-world experience with these targeted agents. We evaluated the prevalence of NTRK fusions and the outcomes with TRK inhibitor therapy in a real-world population of patients in the Veterans Health Administration. Patients with NTRK fusions or rearrangements were identified from the Veterans Affairs (VA) National Precision Oncology Program (NPOP), and patients who were prescribed TRK inhibitors were identified from the Corporate Data Warehouse. Baseline data and clinical outcomes were obtained by retrospective review of medical records. A total of 33 patients with NTRK fusions or rearrangements were identified, including 25 patients comprising 0.12% of all patients with solid tumors sequenced through VA NPOP. Twelve patients with NTRK fusions or rearrangements were treated with TRK inhibitors, none of whom had objective responses. Eight patients experienced toxicities leading to drug interruption, dose reduction, or discontinuation. In this retrospective study of VA patients, NTRK fusions and rearrangements were less common than in previous studies, and objective responses to TRK inhibitors were not observed. Real-world experience with TRK inhibitors differs markedly from clinical trial findings, possibly due to differences in patient demographics, tumor types, and sequencing methods. Our findings highlight the need to study TRK inhibitors in the real-world setting and in populations underrepresented in clinical trials.


Toward revitalizing the role of physician-scientists in academic medicine.
There has been a growing recognition over the past 25 years that it is increasingly difficult for physicians to develop careers as physician-scientists. This commentary reviews the traditional culture of academic medicine, factors that are altering that culture, and several grassroots suggestions for revitalizing academic medicine in our departmental programs. It is based on a presentation, "Basic Scientist or Translational Scientist? Changing Roles of Physician-Scientists in Biomedical Research," delivered in the President's Symposium at the Thirty-First Midwinter Meeting of the Association for Research in Otolaryngology on February 17, 2008.


The bovine nasal fungal community and associations with bovine respiratory disease.
Effective identification and treatment of bovine respiratory disease (BRD) is an ongoing health and economic issue for the dairy and beef cattle industries. Bacteria pathogens Pasteurellamultocida, Mycoplasmabovis, Mannheimia haemolytica, and Histophilus somni and the virus Bovine herpesvirus-1 (BHV-1), Bovine parainfluenza-3 virus (BPIV-3), Bovine respiratory syncytial virus (BRSV), Bovine adenovirus 3 (BAdV3), bovine coronavirus (BoCV) and Bovine viral diarrhea virus (BVDV) have commonly been identified in BRD cattle; however, no studies have investigated the fungal community and how it may also relate to BRD. The objective of this study was to understand if the nasal mycobiome differs between a BRD-affected (n = 56) and visually healthy (n = 73) Holstein steers. Fungal nasal community was determined by using Internal Transcribed Spacer (ITS) sequencing. The phyla, Ascomycota and Basidiomycota, and the genera, Trichosporon and Issatchenkia, were the most abundant among all animals, regardless of health status. We identified differences between healthy and BRD animals in abundance of Trichosporon and Issatchenkia orientalis at a sub-species level that could be a potential indicator of BRD. No differences were observed in the nasal fungal alpha and beta diversity between BRD and healthy animals. However, the fungal community structure was affected based on season, specifically when comparing samples collected in the summer to the winter season. We then performed a random forest model, based on the fungal community and abundance of the BRD-pathobionts (qPCR data generated from a previous study using the same animals), to classify healthy and BRD animals and determine the agreement with visual diagnosis. Classification of BRD or healthy animals using ITS sequencing was low and agreed with the visual diagnosis with an accuracy of 51.9%. A portion of the ITS-predicted BRD animals were not predicted based on the abundance of BRD pathobionts. Lastly, fungal and bacterial co-occurrence were more common in BRD animals than healthy animals. The results from this novel study provide a baseline understanding of the fungal diversity and composition in the nasal cavity of BRD and healthy animals, upon which future interaction studies, including other nasal microbiome members to further understand and accurately diagnose BRD, can be designed.


The role of spinal cord extrasynaptic α5 GABAA receptors in chronic pain.
Chronic pain is an incapacitating condition that affects a large population worldwide. Until now, there is no drug treatment to relieve it. The impairment of GABAergic inhibition mediated by GABAA receptors (GABAA R) is considered a relevant factor in mediating chronic pain. Even though both synaptic and extrasynaptic GABAA inhibition are present in neurons that process nociceptive information, the latter is not considered relevant as a target for the development of pain treatments. In particular, the extrasynaptic α5 GABAA Rs are expressed in laminae I-II of the spinal cord neurons, sensory neurons, and motoneurons. In this review, we discuss evidence showing that blockade of the extrasynaptic α5 GABAA Rs reduces mechanical allodynia in various models of chronic pain and restores the associated loss of rate-dependent depression of the Hoffmann reflex. Furthermore, in healthy animals, extrasynaptic α5 GABAA R blockade induces both allodynia and hyperalgesia. These results indicate that this receptor may have an antinociceptive and pronociceptive role in healthy and chronic pain-affected animals, respectively. We propose a hypothesis to explain the relevant role of the extrasynaptic α5 GABAA Rs in the processing of nociceptive information. The data discussed here strongly suggest that this receptor could be a valid pharmacological target to treat chronic pain states.


Assesment of myocardial ischemia by combination of tissue synchronisation imaging and dobutamine stress echocardiography.
Dobutamine stress echocardiography (DSE) is an important non-invasive imaging method for evaluating ischemia. However, wall motion interpretation can be impaired by the experience level of the interpreter and the subjectivity of the visual assessment. In our study we aimed to combine DSE and tissue syncronisation imaging to increase sensitivity for detecting ischemia. 50 patients with indications for DSE were included in the study. In 25 patients we found DSE positive for ischemia and in the other 25 patients we found it to be negative. The negative group was accepted as the control group. There was no significant difference in terms of risk factors and echocardiographic parameters between the two groups, except for wall motion scores. In both groups, left ventricular dyssychrony was accepted as the difference between time to peak systolic velocity (Ts) in the reciprocal four couple of non-apical segments at rest and during peak stress. Timings were corrected for heart rate. We compared the differences of the dyssynchronisation value at rest and during peak stress to determine the distinctions within the groups and between the groups of DSE positive and negative patients. We found that stress and ischemia did not create any significant difference over the left intraventricular dyssynchrony with DSE, although at the segmenter level it prolonged the time to peak systolic velocity (p<0.05). These alterations did not show any significant difference between positive and negative DSE groups. As a result, this segmenter dyssynchrony and the time to peak systolic velocity, which is corrected for heart rate, did not enhance any new value over DSE for detecting ischemia.


Synthesis, evaluation, and mechanism of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as potent reversible SARS-CoV-2 entry inhibitors.
A class of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones were designed and synthesized via Michael addition, cyclization, aldol condensation, and deprotonation to inhibit the human transmembrane protease serine 2 (TMPRSS2) and Furin, which are involved in priming the SARS-CoV-2 Spike for virus entry. The most potent inhibitor 2f (81) was found to efficiently inhibit the replication of various SARS-CoV-2 delta and omicron variants in VeroE6 and Calu-3 cells, with EC50 range of 0.001-0.026 μM by pre-incubation with the virus to avoid the virus entry. The more potent antiviral activities than the proteases inhibitory activities led to discovery that the synthesized compounds also inhibited Spike's receptor binding domain (RBD):angiotensin converting enzyme 2 (ACE2) interaction as a main target, and their antiviral activities were enhanced by inhibiting TMPRSS2 and/or Furin. To further confirm the blocking effect of 2f (81) on virus entry, SARS-CoV-2 Spike pseudovirus was used in the entry assay and the results showed that the compound inhibited the pseudovirus entry in a ACE2-dependent pathway, via mainly inhibiting RBD:ACE2 interaction and TMPRSS2 activity in Calu-3 cells. Finally, in the in vivo animal model of SARS-CoV-2 infection, the oral administration of 25 mg/kg 2f (81) in hamsters resulted in reduced bodyweight loss and 5-fold lower viral RNA levels in nasal turbinate three days post-infection. Our findings demonstrated the potential of the lead compound for further preclinical investigation as a potential treatment for SARS-CoV-2.


[Virus, provirus and cancer].
Our purpose here is to retrace the history of the concept of prophage, to show how it expands into that of the episome and provirus. Its prehistory is that of lysogeny. We stress the relations between heredity and infection, the discovery of a non infectioius phase of the phage. André Lwoff is responsible for the concept of prophage. We then examine the research, discoveries and interpretations of François Jacob, Elie Wollman, William Hayes and Joshua Lederberg.


[Study on intermediate products in chloroform formation from L-tyrosine treated with sodium hypochlorite].
Possible intermediates in the formation of chloroform during by the sodium hypochlorite (NaClO) treatment of L-tyrosine were investigated using HPLC and LC/MS. One product showed the same MS characteristics as the substance formed by the NaClO treatment of 4-hydroxybenzyl cyanide (4-HBC), and it was suggested to be m-chloro-4-hydroxybenzyl cyanide (m-C-4-HBC). Since m-C-4-HBC is not commercially available it was synthesized by treating 4-HBC with NaClO, and purified by extraction with ethyl acetate, followed by HPLC on preparative isolation columns, using a column switching method. The product was confirmed to be 3-chloro-4-hydroxybenzyl cyanide (3-C-4-HBC), by means of NMR spectral analysis. When L-tyrosine or 4-HBC was treated with NaClO, 3-C-4-HBC and CHCl3 were generated. When 3-C-4-HBC was treated with NaClO, CHCl3 was generated. Judging from these results, 3-C-4-HBC was confirmed to be an intermediate in the formation of CHCl3 from L-tyrosine. Thus, the reaction pathway of CHCl3 formation from L-tyrosine treated with NaClO is concluded to be: L-tyrosine-->4-HBC-->3-C-4-HBC-->CHCl3.


[Five-years experience with urinary derivation by Sygma-Rectum pouch at the department for urology in Smederevo].
Bladder cancer has poor prognosis. Outcome of the treated patients is dependent on correct staging, histologic grade of the tumor, and correctly realized surgical intervention, i.e. radicality of the operation. During the period from 2002. to 2004, on the Department for Urology in Smederevo, 120 patients were surgically treated because of bladder tumors. Of that number, in 34 patients radical cystectomy and derivation by Sygma-Rectum pouch was done. Of these 34 patients, 22 (64.7%) were being followed during the five-years period.


Progression of neurogenesis in the inner ear requires inhibition of Sox2 transcription by neurogenin1 and neurod1.
Sox2 is required for proper neuronal formation in the CNS, but the molecular mechanisms involved are not well characterized. Here, we addressed the role of Sox2 in neurogenesis of the developing chicken inner ear. Overexpressing Sox2 from a constitutive (β-actin) promoter induces the expression of the proneural gene, Neurogenin1 (Ngn1); however, the expression of a downstream target of Ngn1, Neurod1, is unchanged. As a result, there is a reduction of neural precursors to delaminate and populate the developing cochleo-vestibular ganglion. In contrast, overexpression of either Ngn1 or Neurod1 is sufficient to promote the neural fate in this system. These results suggest that high levels of Sox2 inhibit progression of neurogenesis in the developing inner ear. Furthermore, we provide evidence that Ngn1 and Neurod1 inhibit Sox2 transcription through a phylogenetically conserved Sox2 enhancer to mediate neurogenesis. We propose that Sox2 confers neural competency by promoting Ngn1 expression, and that negative feedback inhibition of Sox2 by Ngn1 is an essential step in the progression from neural precursor to nascent neuron.


Enzymatic activity necessary to restore the lethality due to Escherichia coli RNase E deficiency is distributed among bacteria lacking RNase E homologues.
Escherichia coli RNase E (Eco-RNase E), encoded by rne (Eco-rne), is considered the global RNA decay initiator. Although Eco-RNase E is an essential gene product in E. coli, some bacterial species, such as Bacillus subtilis, do not possess Eco-RNase E sequence homologues. B. subtilis instead possesses RNase J1/J2 (Bsu-RNase J1/J2) and RNase Y (Bsu-RNase Y) to execute RNA decay. Here we found that E. coli lacking the Eco-rne gene (Δrne E. coli) was viable conditional on M9 minimal media by introducing Bsu-RNase J1/J2 or Bsu-RNase Y. We also cloned an extremely short Eco-RNase E homologue (Wpi-RNase E) and a canonical sized Bsu-RNase J1/J2 homologue (Wpi-RNase J) from Wolbachia pipientis, an α-proteobacterial endosymbiont of arthropods. We found that Wpi-RNase J restored the colony-forming ability (CFA) of Δrne E. coli, whereas Wpi-RNase E did not. Unexpectedly, Wpi-RNase E restored defective CFA due to lack of Eco-RNase G, a paralogue of Eco-RNase E. Our results indicate that bacterial species that lack Eco-RNase E homologues or bacterial species that possess Eco-RNase E homologues which lack Eco-RNase E-like activities have a modest Eco-RNase E-like function using RNase J and/or RNase Y. These results suggest that Eco-RNase E-like activities might distribute among a wide array of bacteria and that functions of RNases may have changed dynamically during evolutionary divergence of bacterial lineages.


Reconstruction of an early viola da gamba informed by physical modeling.
The reconstruction of an early viola da gamba is considered, using virtual prototyping by means of the finite element method. Based on iconographic sources, previous research has postulated an instrument design lacking a soundpost and a bass bar. This led to the hypothesis of a top plate with variable thickness. In order to investigate the acoustic efficiency of such a design, a finite element model of the instrument is formulated. The structural accuracy of the model is qualitatively verified by comparing calculated modal shapes with those of a reconstructed instrument, visualized with the aid of Chladni patterns and electronic speckle pattern interferometry. Furthermore, simulating the interaction between the vibrating surfaces of the instrument and the surrounding air shows that the posited asymmetric design can radiate sound more efficiently than a design involving a symmetric top plate. However, the asymmetry introduced by the gradually thickening top plate is weaker than that usually enforced by the presence of a soundpost and a bass bar. Therefore, low frequency structural modes of the instrument are less easily excited by a force acting parallel to the top plate.


Two-beam energy exchange in a hybrid photorefractive-flexoelectric liquid-crystal cell.
We develop a semiquantitative theory to describe the experimentally observed energy gain when two light beams intersect in hybrid organic-inorganic photorefractives. These systems consist of a nematic liquid-crystal (LC) layer placed between two photorefractive windows. A periodic space-charge field is induced by the interfering light beams in the photorefractive windows. The field penetrates into the LC, interacting with the nematic director and giving rise to a diffraction grating. LC flexoelectricity is the principal physical mechanism driving the grating structure. Each light beam diffracts from the induced grating, leading to an apparent energy gain and loss within each beam. The LC optics is described in the Bragg regime. In the theory the exponential gain coefficient is a product of a beam interference term, a flexoelectricity term and a space-charge term. The theory has been compared with results of an experimental study on hybrid cells filled with the LC mixture TL 205. Experimentally the energy gain is maximal at much lower grating wave numbers than is predicted by naïve theory. However, if the director reorientation is cubic rather than linear in the space-charge field term, then good agreement between theory and experiment can be achieved using only a single fitting parameter. We provide a semiquantitative argument to justify this nonlinearity in terms of electric-field-induced local phase separation between different components of the liquid crystal.


Interaction of rat liver lysosomal membranes with actin.
Membranes were prepared from lysosomes purified 80-fold by centrifugation in a discontinuous metrizamide gradient. When salt-washed membranes were combined with rabbit muscle actin, an increase in viscosity could be measured using a falling ball viscometer. The lysosomal membrane-actin interaction was actin- and membrane-concentration dependent and appeared to be optimal under presumed physiological conditions (2 mM MgCl2, 1 mM MgATP, neutral pH, and free calcium concentration less than 10(-8) M). The actin cross-linking activity of the membrane was optimal at pH 6.4. The interaction was maximal between 10(-7) and 10(-9) M free calcium ions and inhibited by approximately 50% at concentrations of calcium greater than 0.5 x 10(-7) M. The actin-lysosomal membrane interaction was destroyed if the membranes were pretreated with Pronase, or if the membranes were purified in the absence of protease inhibitors. The interaction was not destroyed if membranes were washed with high salt or extracted with KCl and urea. In addition, a sedimentation assay for the actin-lysosomal membrane interaction was also performed to corroborate the viscometry data. The results suggest the existence of an integral lysosomal membrane actin-binding protein.


Complexity of ethical decision making in psychiatry.
Psychiatric residents and psychiatrists have little difficulty in making judgments about a clinical course of action to take with patients. However, making ethical clinical decisions is more challenging, because psychiatric residents are usually provided little formal training in ethics. Further, many ethical dilemmas are complex, requiring knowledge of the psychiatric profession's ethics code, moral principles, law, and practice standards and of how they should be weighed in the decision-making process. The purpose of this article is to demonstrate this complexity in regard to the identification of potential ethical dilemmas, understanding the issues that these dilemmas raise, and formulating potential solutions to them. Two common but important areas of treatment in which ethical dilemmas arise (informed consent and competence of care) are used as examples for our presentation. The article demonstrates that to successfully engage in ethical analysis in psychiatry is impossible without substantial formal training in the process.


Response to Preoperative Therapy in Localized Pancreatic Cancer.
Evaluation of response to preoperative therapy for patients with pancreatic adenocarcinoma has been historically difficult. Therefore, preoperative regimens have generally been selected on the basis of baseline data such as radiographic stage and serum CA 19-9 level and then typically administered for a pre-specified duration as long as 6 months or more. The decision to proceed with resection following preoperative therapy likewise has rested upon the absence of disease progression rather than evidence for tumor response. This article reviews the basis for the evaluation of therapeutic response after preoperative therapy for pancreatic cancer in the existing scientific literature, and providing updates and new perspectives.


First report of harpellales from the Dominican Republic (Hispaniola) and the insular effect on gut fungi.
We present the first report of Harpellales (Kickxellomycotina) from Hispaniola. The Dominican Republic was surveyed, and members of the ecological group trichomycetes were encountered in the gut of their arthropod hosts. Among Harpellales we describe a new species, Smittium caribense, and report the presence of seven previously known species that are new for Hispaniola: Genistellospora homothallica, Harpella amazonica, Harpella tica, Legerio-m myces rarus, Smittium culisetae, Smittium dipterorum and Stachylina grandispora. The dominance of cosmopolitan, dipteran-associated species is the most outstanding effect resulting from the insularity on gut fungi.


Hypohydration, Functional Constipation, and Physical Activity in Elementary School Students.
This school-based, cross-sectional study aimed to evaluate whether hypohydration is related to functional constipation and physical activity in school-aged children. The study included 452 students aged 6-12 years. Hypohydration, defined as urinary osmolality >800 mOsm/kg, was more prevalent ( P = 0.002) in boys (72.1%) than in girls (57.5%). The difference in the prevalence of functional constipation according to sex (20.1% in boys and 23.8% in girls) was not statistically significant ( P = 0.81). In bivariate analysis, functional constipation was associated with hypohydration in girls (odds ratio = 1.93, 95% confidence interval: 1.07-3.49), and multiple logistic regression did not reach statistical significance ( P = 0.082). Low proportions of active commuting to school in both sexes were associated with hypohydration. However, there were no associations between functional constipation, active commuting to school, and physical activity scores. In conclusion, multiple logistic regression did not demonstrate an association between hypohydration and functional constipation in school-aged children.


Antifungal Microbial Agents for Food Biopreservation-A Review.
Food spoilage is a major issue for the food industry, leading to food waste, substantial economic losses for manufacturers and consumers, and a negative impact on brand names. Among causes, fungal contamination can be encountered at various stages of the food chain (e.g., post-harvest, during processing or storage). Fungal development leads to food sensory defects varying from visual deterioration to noticeable odor, flavor, or texture changes but can also have negative health impacts via mycotoxin production by some molds. In order to avoid microbial spoilage and thus extend product shelf life, different treatments-including fungicides and chemical preservatives-are used. In parallel, public authorities encourage the food industry to limit the use of these chemical compounds and develop natural methods for food preservation. This is accompanied by a strong societal demand for 'clean label' food products, as consumers are looking for more natural, less severely processed and safer products. In this context, microbial agents corresponding to bioprotective cultures, fermentates, culture-free supernatant or purified molecules, exhibiting antifungal activities represent a growing interest as an alternative to chemical preservation. This review presents the main fungal spoilers encountered in food products, the antifungal microorganisms tested for food bioprotection, and their mechanisms of action. A focus is made in particular on the recent in situ studies and the constraints associated with the use of antifungal microbial agents for food biopreservation.


Integrated analysis of high-resolution DNA methylation profiles, gene expression, germline genotypes and clinical end points in breast cancer patients.
Breast cancer is a heterogeneous disease for which alterations in DNA methylation patterns have been shown to be of biological and clinical importance. Here we report on the integrated analysis of molecular alterations including the methylation status of 27 gene promoters analyzed by highly quantitative pyrosequencing, and the association to gene expression, germline genotype and clinical parameters including survival. Breast cancer specific deregulation of DNA methylation (both hyper- and hypomethylation) was found in twenty genes including ACVR1, OGG1, IL8 and TFF1. The methylation level in the promoter regions was significantly negatively correlated to gene expression for twelve genes (such as MST1R, ST6GAL1 and TFF1) indicating that a gain of aberrant methylation (hypermethylation) inhibits gene expression. Multiple associations between molecular and clinical parameters were identified, and multivariate statistical analysis demonstrated that methylation was more strongly associated to clinical parameters than gene expression for the investigated genes. The methylation level of BCAP31 and OGG1 showed significant association to survival, and these associations were validated in a larger patient cohort (The Cancer Genome Atlas). Our study provides evidence for the promise of DNA methylation alterations for clinical applications.


The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation.
Activation of NF-κB-dependent transcription represents an important hallmark of inflammation. While the acute inflammatory response is per se beneficial, it can become deleterious if its spatial and temporal profile is not tightly controlled. Classically, NF-κB activity is limited by cytoplasmic retention of the NF-κB dimer through binding to inhibitory IκB proteins. However, increasing evidence suggests that NF-κB activity can also be efficiently contained by direct ubiquitination of NF-κB subunits. Here, we identify the HECT-domain ubiquitin ligase HERC3 as novel negative regulator of NF-κB activity. We find that HERC3 restricts NF-κB nuclear import and DNA binding without affecting IκBα degradation. Instead HERC3 indirectly binds to the NF-κB RelA subunit after liberation from IκBα inhibitor leading to its ubiquitination and protein destabilization. Remarkably, the regulation of RelA activity by HERC3 is independent of its inherent ubiquitin ligase activity. Rather, we show that HERC3 and RelA are part of a multi-protein complex containing the proteasome as well as the ubiquitin-like protein ubiquilin-1 (UBQLN1). We present evidence that HERC3 and UBQLN1 provide a link between NF-κB RelA and the 26S proteasome, thereby facilitating RelA protein degradation. Our findings establish HERC3 as novel candidate regulating the inflammatory response initiated by NF-κB.


Barriers to and facilitators of partner notification for chlamydia trachomatis among health care professionals.
Partner notification (PN) is an essential case-finding tool in the management of sexually transmitted infections (STIs). Yet, data on the effectiveness and factors impacting implementation of PN in the Netherlands are lacking. With the aim of further exploring and improving the PN process, the current study assessed perceived barriers and facilitators among health care professionals in the STI clinical setting. In particular, we explored the management of PN in young heterosexual patients diagnosed with Chlamydia trachomatis (Ct). We conducted semi-structured interviews among 22 health care professionals (response rate 52%) from 5 of the 8 national STI clinics in the Netherlands. We carried out qualitative content analysis using a framework approach. All participants were nurses, aged mid 20's to late 50's, and all but one were female. All health care professionals felt comfortable discussing PN. Other perceived facilitators for PN included: time, one-on-one consultations, interviewing skills (i.e. Motivational Interviewing) and a proactive helping style. Important barriers were identified as: sub-optimal guidelines, inaccurate sexual history, a lack of feedback regarding the motivational strategies that were used, and the lack of feedback regarding overall PN effectiveness. The health care professionals placed an emphasis on the care and treatment of the individual index patient rather than on discussion of PN, or on motivating and helping patients to engage in PN. Health care professionals identified several barriers that need to be overcome, and facilitators which need to be maintained. Future efforts should concentrate on introducing PN protocols, providing feedback on both the effectiveness of strategies used by health care professionals, and on the PN process as a whole, and educating health care professionals about Motivational Interviewing strategies. Moreover, the possible implementation of an Internet-based PN system should be explored.


Insect herbivory increases from forest to alpine tundra in Arctic mountains.
Current theory holds that the intensity of biotic interactions decreases with increases in latitude and elevation; however, empirical data demonstrate great variation in the direction, strength, and shape of elevational changes in herbivory. The latitudinal position of mountains may be one important source of this variation, but the acute shortage of data from polar mountains hampers exploration of latitude effects on elevational changes in herbivory. Here, we reduce this knowledge gap by exploring six elevation gradients located in three Arctic mountain ranges to test the prediction that a decrease in herbivory occurs with increasing elevation from forest to alpine tundra. Across the 10 most abundant evergreen and deciduous woody plant species, relative losses of foliage to insect herbivores were 2.2-fold greater at the highest elevations (alpine tundra) than in mid-elevation birch woodlands or low-elevation coniferous forests. Plant quality for herbivores (quantified by specific leaf area) significantly decreased with elevation across all studied species, indicating that bottom-up factors were unlikely to shape the observed pattern in herbivory. An experiment with open-top chambers established at different elevations showed that even a slight increase in ambient temperature enhances herbivory in Arctic mountains. Therefore, we suggest that the discovered increase in herbivory with elevation is explained by higher temperatures at the soil surface in open habitats above the tree line compared with forests at lower elevations. This explanation is supported by the significant difference in elevational changes in herbivory between low and tall plants: herbivory on low shrubs increased fourfold from forest to alpine sites, while herbivory on trees and tall shrubs did not change with elevation. We suggest that an increase in herbivory with an increase in elevation is typical for high-latitude mountains, where inverse temperature gradients, especially at the soil surface, are common. Verification of this hypothesis requires further studies of elevational patterns in herbivory at high latitudes.