Alteration in expression of estrogen receptor isoforms alpha and beta, and aromatase in the testis and its relation with changes in nitric oxide during aging in mice.
The aim of present study was to investigate the changes in the testicular expression of aromatase, ER alpha, ER beta and iNOS protein and correlate these with serum testosterone and nitric oxide levels, to elucidate the role of estrogen and nitric oxide in the testis during aging. This study showed localization of aromatase and ER alpha mainly in the Leydig cell and showed close correlation of testicular aromatase level with circulating testosterone level suggesting that estrogen may be modulating testicular steroidogenesis. Localization ER alpha mainly in the mitotically active germ cell suggest possible role of estrogen in germ cell proliferation. This study showed basal level of nitric oxide during reproductively active period, whereas increased serum nitric oxide coincides with decreased testicular activity in old age. This study showed inverse correlation between aromatase and NO level. Treatment with either SNP or L-NAME on testicular steroidogenic factor (3-beta HSD/ StAR) or germ cell survival factor (Bcl2) showed that increased NO causes decreased steroidogenesis and increased germ cell apoptosis. In conclusion this study suggest that estrogen modulate steroidogenesis and germ cell survival in reproductively active period whereas in old age decreased estrogen concentration causes increased nitric oxide which in turn decreases testicular steroidogenesis and germ cell apoptosis.


High concentration of vitamin E decreases thermosensation and thermotaxis learning and the underlying mechanisms in the nematode Caenorhabditis elegans.
α-tocopherol is a powerful liposoluble antioxidant and the most abundant isoform of vitamin E in the body. Under normal physiological conditions, adverse effects of relatively high concentration of vitamin E on organisms and the underlying mechanisms are still largely unclear. In the present study, we used the nematode Caenorhabditis elegans as an in vivo assay system to investigate the possible adverse effects of high concentration of vitamin E on thermosensation and thermotaxis learning and the underlying mechanisms. Our data show that treatment with 100-200 µg/mL of vitamin E did not noticeably influence both thermosensation and thermotaxis learning; however, treatment with 400 µg/mL of vitamin E altered both thermosensation and thermotaxis learning. The observed decrease in thermotaxis learning in 400 µg/mL of vitamin E treated nematodes might be partially due to the moderate but significant deficits in thermosensation, but not due to deficits in locomotion behavior or perception to food and starvation. Treatment with 400 µg/mL of vitamin E did not noticeably influence the morphology of GABAergic neurons, but significantly decreased fluorescent intensities of the cell bodies in AFD sensory neurons and AIY interneurons, required for thermosensation and thermotaxis learning control. Treatment with 400 µg/mL of vitamin E affected presynaptic function of neurons, but had no remarkable effects on postsynaptic function. Moreover, promotion of synaptic transmission by activating PKC-1 effectively retrieved deficits in both thermosensation and thermotaxis learning induced by 400 µg/mL of vitamin E. Therefore, relatively high concentrations of vitamin E administration may cause adverse effects on thermosensation and thermotaxis learning by inducing damage on the development of specific neurons and presynaptic function under normal physiological conditions in C. elegans.


Vascular effects of endothelin-1 in stage 21 chick embryos.
Endothelin-1 is a very potent vasoconstrictor, but its function has not yet been investigated in the early stage of cardiovascular development. The purpose of the present study was to clarify whether endothelin-1 exerts a hemodynamic effect in stage 21 chick embryos. We measured vitelline artery blood pressure with a servo-null micropressure system and blood flow velocity at the dorsal aorta with a 20 MHz pulsed Doppler velocity meter. The vitelline vessels were directly measured with a microscope video system. While monitoring these parameters, endothelin-1 was infused into a vein by a microinjector and data were collected. Endothelin-1 increased the blood pressure and heart rate, but decreased the dorsal aortic blood flow. Only the vitelline veins with a diameter of between 100 and 200 microm constricted after endothelin infusion, but smaller or larger veins and the arteries did not show any significant change in size, although the resistant arteries could not be measured by this method. In conclusion, endothelin-1 has apparent constrictive effects in the selected vessel in the early stages of cardiovascular development when the endocrine and autonomic nervous systems have not yet developed.


Contribution to the Understanding of Particle Motion Perception in Marine Invertebrates.
Marine invertebrates potentially represent a group of species whose ecology may be influenced by artificial noise. Exposure to anthropogenic sound sources could have a direct consequence on the functionality and sensitivity of their sensory organs, the statocysts, which are responsible for their equilibrium and movements in the water column. The availability of novel laser Doppler vibrometer techniques has recently opened the possibility of measuring whole body (distance, velocity, and acceleration) vibration as a direct stimulus eliciting statocyst response, offering the scientific community a new level of understanding of the marine invertebrate hearing mechanism.


Differential effects of cadmium and chromium on growth, photosynthetic activity, and metal uptake of Linum usitatissimum in association with Glomus intraradices.
The current study was aimed at analyzing the differential effects of heavy metals (cadmium and chromium) and mycorrhizal fungus; Glomus intraradices on growth, chlorophyll content, proline production, and metal accumulation in flax plant (Linum usitatissimum L.). Heavy metal accumulation rate in flax varied from 90 to 95 % for Cd and 61-84 % for Cr at a concentration range of 250 to 500 ppm for both metals in 24 days of experiment. Growth and photosynthetic activity of flax reduced to an average of 21 and 45 %, respectively. However, inoculation of G. intraradices significantly increased the plant biomass even under metal stressed conditions. Additionally, mycorrhizal association also assists the Cd and Cr increased uptake by 23 and 33 %, respectively. Due to metal stress, chlorophyll contents were decreased by 27 and 45 %, while 84 and 71 % increased proline content was observed under Cd and Cr stress, respectively. The present results clearly signify the differential response and potential of flax plant towards heavy metal tolerance and accumulation that can further increase with mycorrhizal fungus.


The proliferation of multidisciplinary team meetings (MDTMs): how can radiology departments continue to support them all?
To quantify the changes in multidisciplinary team meeting (MDTM) workload for consultant radiologists working in a single UK tertiary referral cancer institution, assess its impact and suggest solutions to these challenges. The annual number of MDTM cases was collated over a 5-year period (2009 - 2013). Qualitative information was obtained through questionnaire-based interviews of 47 consultant radiologists. Data analysed included number of MDTMs involved with, type of MDTM (oncological or non-oncological), time allocation for preparation and perceived deficiencies in the current MDTM. Thirteen thousand and forty-nine cases were discussed in MDTMs in 2009 with a continued yearly increase over the 5-year period. Fifty-five percent of MDTM attendances were at oncological MDTMs. Consultant radiologists attended a median of two MDTMs per week, each requiring 4 hours time commitment; 60 % used out-of-hours time for MDTM preparation. The most frequently cited MDTM deficiency was lack of sufficient clinical input. The MDTM is a challenging but worthwhile demand on the modern radiologist's time. Solutions to the increasing MDTM workload include demonstration of the benefits of MDTMs to hospital administrators to justify additional resources required, improving MDTM efficiency and ensuring this increased workload is accurately represented and remunerated in individual job plans. • MDTMs improve cancer outcomes and are being recommended for non-oncological conditions. • MDTM cases have more than doubled over 5 years at our institution. • Incorporating MDTM workload into current consultant radiologist job plans is difficult. • Solutions include demonstrating MDTM related benefits, improved efficiency, and accurate job planning.


Cranial vascular effects of zolmitriptan, a centrally active 5-HT1B/1D receptor partial agonist for the acute treatment of migraine.
The anti-migraine drug zolmitriptan is a novel 5-HT1B/1D receptor partial agonist which, unlike sumatriptan, has been shown to cross the intact blood-brain barrier. In this study we examined whether or not the ability to access the cerebro-vascular intima affects the way in which a centrally-active 5-HT1B/1D receptor agonist influences cranial haemodynamics. The effects of zolmitriptan on carotid arterial blood flow distribution were studied in anaesthetised cats using radiolabelled microspheres. Zolmitriptan (10-1000 microg kg(-1) i.v.) selectively reduced arteriovenous-anastomotic (AVA) conductance producing a maximum decrease of 92.5+/-2.3%. The drug also produced a modest reduction in extra-cerebral conductance (23.9+/-6.5% maximum reduction at 30 microg kg(-1), i.v.), but was without effect on cerebral conductance. Using laser doppler flowmetry in anaesthetised cats, zolmitriptan (1-30 microg kg(-1), i.v.) produced dose-dependent decreases in ear microvascular conductance (15+/-5 to 60+/-6%) which mirrored decreases in carotid arterial conductance (12+/-11 to 61+/-5%). By contrast, zolmitriptan at doses up to 1000 microg kg(-1) was without effect on cerebral microvascular conductance. Although zolmitriptan crosses the blood-brain barrier and can therefore access the cerebro-vascular intima, this study suggests that this property does not adversely affect cerebrovascular function.


[Unusual aspects of the late manifestations of diaphragmatic hernia].
A 5-year-old boy investigated for abnormality in right cardiophrenic angle was found on radiologic and perioperative exploration to have a large diaphragmatic hernia allowing right intrathoracic passage of stomach and colon. The diaphragmatic defect included a wide left middle diaphragmatic Bochdalek cleft adherent to hiatal orifice due to agenesis of pillars.


Plasma membrane integrity of cryopreserved human sperm: an investigation of the results of the hypoosmotic swelling test, the water test, and eosin-Y staining.
[1] To examine the relationship between sperm membrane integrity and motion parameters before and after cryopreservation; [2] to determine the capacity of the membrane integrity tests to predict the outcome of cryopreservation in fertile and infertile men; and [3] to examine the degree of agreement between tail and head membrane integrity of testicular and ejaculated immotile sperm cryopreserved for intracytoplasmic sperm injection. Prospective study. Academic tertiary care institution. Fertile donors and normozoospermic oligozoospermic, and asthenozoospermic subfertile men. Semen samples were cryopreserved and thawed for analysis. Sperm membrane integrity and computer-assisted motion parameters. The hypoosmotic swelling test and water test had a significant and positive correlation in the fresh and cryopreserved ejaculates of all groups. The results of the hypoosmotic swelling test correlated positively with the percent motility in the fresh ejaculates of fertile and subfertile men. None of the membrane integrity tests correlated with the cryosurvival rate in any group. In the ejaculated and testicular samples with no postcryopreservation motility, the simultaneous assessment of hypoosmotic swelling test and eosin showed that of 33% sperm exhibiting coiling with the hypoosmotic swelling test, only 9% were eosin negative, whereas 24% were eosin positive. [1] The water test may be a simpler replacement for the hypoosmotic swelling test; [2] none of the membrane integrity tests predicted sperm motility after cryopreservation; and [3] there was a high degree of disagreement between the hypoosmotic swelling test and eosin in the samples with no postcryopreservation motility.


fingeRNAt-A novel tool for high-throughput analysis of nucleic acid-ligand interactions.
Computational methods play a pivotal role in drug discovery and are widely applied in virtual screening, structure optimization, and compound activity profiling. Over the last decades, almost all the attention in medicinal chemistry has been directed to protein-ligand binding, and computational tools have been created with this target in mind. With novel discoveries of functional RNAs and their possible applications, RNAs have gained considerable attention as potential drug targets. However, the availability of bioinformatics tools for nucleic acids is limited. Here, we introduce fingeRNAt-a software tool for detecting non-covalent interactions formed in complexes of nucleic acids with ligands. The program detects nine types of interactions: (i) hydrogen and (ii) halogen bonds, (iii) cation-anion, (iv) pi-cation, (v) pi-anion, (vi) pi-stacking, (vii) inorganic ion-mediated, (viii) water-mediated, and (ix) lipophilic interactions. However, the scope of detected interactions can be easily expanded using a simple plugin system. In addition, detected interactions can be visualized using the associated PyMOL plugin, which facilitates the analysis of medium-throughput molecular complexes. Interactions are also encoded and stored as a bioinformatics-friendly Structural Interaction Fingerprint (SIFt)-a binary string where the respective bit in the fingerprint is set to 1 if a particular interaction is present and to 0 otherwise. This output format, in turn, enables high-throughput analysis of interaction data using data analysis techniques. We present applications of fingeRNAt-generated interaction fingerprints for visual and computational analysis of RNA-ligand complexes, including analysis of interactions formed in experimentally determined RNA-small molecule ligand complexes deposited in the Protein Data Bank. We propose interaction fingerprint-based similarity as an alternative measure to RMSD to recapitulate complexes with similar interactions but different folding. We present an application of interaction fingerprints for the clustering of molecular complexes. This approach can be used to group ligands that form similar binding networks and thus have similar biological properties. The fingeRNAt software is freely available at https://github.com/n-szulc/fingeRNAt.


Assessing and Engineering Antibody Stability Using Experimental and Computational Methods.
Engineering increased stability into antibodies can improve their developability. While a range of properties need to be optimized, thermal stability and aggregation are two key factors that affect the antibody yield, purity, and specificity throughout the development and manufacturing pipeline. Therefore, an ideal goal would be to apply protein engineering methods early-on, such as in parallel to affinity maturation, to screen out potential drug molecules with the desired conformational and colloidal stability. This chapter introduces our methods to computationally characterize an antibody Fab fragment, propose stabilizing variants, and then experimentally verify these predictions.


[Identification of receptors in a system of functionally heterogeneous proteins specifically bound to androgens in rat liver cytosol].
The methods of androgen receptor (RA) isolation and identification in rat liver cytosol were studied. It was shown that male rat liver contains a system of specific androgen (A)-binding proteins consisting of at least three main components: RA, delta 4-androstendione (delta 4-A)-binding component and an unusual estrogen-binding protein interacting also with A and the first two components in females. The identity of one of A-binding components to RA was proved by cumulative properties of this component which are similar to those of RA from other tissues. These properties are as follows: 1) high values of apparent association constant, Ka, for 3H-R1881 (2.8 +/- 0.3 X 10(8) M-1) and 3H-5 alpha-dihydrotestosterone (3H-DHT) (5.0 +/- 0.4 X 10(8) M-1); 2) low binding capacity--approximately 10 fmol/mg of protein of nonfractionated cytosol; 3) pronounced specificity of affinity for active A (DHT, R1881, testosterone); 4) large size of the protein molecule (6.5 +/- 0.25 nm); 5) ability to decrease this size to 3.2 +/- 0.08 nm in a high ionic strength buffer; 6) precipitation at low concentrations of ammonium sulfate: 7) strong interaction with heparin-Sepharose. The properties of the delta 4-A-binding component do not coincide with those of RA: it has a low Ka for 3H-delta 4-A (1.15 +/- 0.5 X 10(6) M-1), a high binding capacity (1.22 +/- 0,12 pmol/mg of protein of nonfractionated cytosol) and can bind various delta 4-3-ketosteroids irrespective of the degree and nature of their biological activity. It was concluded that preliminary isolation of rat liver RA on heparin-Sepharose can be used for differential identification and characterization of this protein.


Cerebral microcirculatory changes during exposure to hypoxia.
Changes in the red blood cell content of the cat cerebral cortical vessels were monitored using reflecting light during a decrease in PIO2. The following observations were made: 1) the capillary bed red blood cell content increased during hypoxia prior to the arteriole response at an arterial oxygen tension of 52.0 mmHg; 2) at arterial oxygen tensions below 52 mmHg the red blood cell content increased in all vessels simultaneously; 3) as the PIO2 decreased, the increase in red blood cell content occurred earlier in all vessels. Capillaries, therefore, can respond to hypoxia independently of the arteriole in cat cerebral cortical tissue.


Mutation analysis in the diagnosis of cystic fibrosis.
Since the characterization of the gene encoding the cystic fibrosis transmembrane conductance regulator protein and identification of its main mutation, delta F508, causing cystic fibrosis (CF), more than 150 mutations in this gene have been reported, most of them only in a few or even single CF patients. Attempts to use mutation analysis in genetic counselling or for the diagnosis of CF depends on prevalence data of certain mutations in the respective population, and considerable ethnic differences have been reported. In this study we determined the prevalence of the mutations delta F508, G551D, R553X, and G542X and of genotypes defined by these mutations in 239 CF patients (444 independent CF chromosomes) seen in our clinic. The analysis for those four mutations alone now permits identification of approximately 75% of all mutations in our CF patients. The complete genotype can be resolved in approximately 63% of patients. This represents the diagnostic sensitivity which can be achieved by mutation analysis in patients without a family history of CF. We conclude that in situations where conventional diagnostic tests are not feasible or difficult to interpret, mutation analysis using a limited set of mutations can contribute significantly to an early and specific diagnosis of CF.


Detection of sumoylated proteins.
Small ubiquitin-related modifier (SUMO) is an ubiquitin-like protein that is covalently attached to a variety of target proteins. Unlike ubiquitination, sumoylation does not target proteins for proteolytic breakdown, but is instead involved in regulating a variety of different protein functional properties, including protein-protein interactions and subcellular targeting, to name a few. Protein sumoylation has been particularly well characterized as a regulator of many nuclear processes as well as of nuclear structure, making the characterization of this modification vital for understanding nuclear structure and function. Because sumoylation plays an important role in regulating so many important cellular processes, there has been intense interest in identifying new proteins that are targets of this modification and determining what role sumoylation plays in regulating the protein functions. This chapter presents methodologies for determining whether a particular protein is a substrate of sumoylation, and for identifying the lysine residue(s) where the modification occurs.


Effect of Individualized Preventive Care Recommendations vs Usual Care on Patient Interest and Use of Recommendations: A Pilot Randomized Clinical Trial.
This randomized clinical trial examines the feasibility and acceptability of a decision-making tool for increasing patient interest in individualized recommendations for preventive care services. To pilot a tool to help patients compare life expectancy gains from evidence-based preventive services. This randomized clinical trial examined patient and physician responses to a pilot decision tool incorporating personalized risk factors at 3 US primary care clinics between 2017 and 2020. Eligible patients were between ages 45 to 70 years with 2 or more high-risk factors. Patients were followed-up after 1 year. The gain in life expectancy associated with guideline adherence to each recommended preventive service was estimated. Personalized estimates incorporating risk factors in electronic health records were displayed in a physician-distributed visual aid. During development, physicians discussed individualized results with patients using shared decision-making (SDM). During the trial, patients were randomized to receive individualized recommendations or usual care (nonmasked, parallel, 1:1 ratio). Primary outcome was patient interest in individualized recommendations, assessed by survey. Secondary outcomes were use of SDM, decisional comfort, readiness to change, and preventive services received within 1 year. The study enrolled 104 patients (31 development, 39 intervention, 34 control), of whom 101 were included in analysis (mean [SD] age, 56.5 [5.3] years; 73 [72.3%] women; 80 [79.2%] Black patients) and 20 physicians. Intervention patients found the tool helpful and wanted to use it again, rating it a median 9 of 10 (IQR, 8-10) and 10 of 10 (8-10), respectively. Compared with the control group, intervention patients more often correctly identified the service least likely (18 [46%] vs 0; P = .03) to improve their life expectancy. A greater number of patients also identified the service most likely to improve their life expectancy (26 [69%] vs 10 [30%]; P = .07), although this result was not statistically significant. Intervention patients reported greater mean [SD] improvement in SDM (4.7 [6.9] points) and near-term readiness to change (13.8 points for top-3-ranked recommendations). Point estimates indicated that patients in the intervention group experienced greater, although non-statistically significant, reductions in percentage of body weight (-2.96%; 95% CI, -8.18% to 2.28%), systolic blood pressure (-6.42 mm Hg; 95% CI, -16.12 to 3.27 mm Hg), hemoglobin A1c (-0.68%; 95% CI, -1.82% to 0.45%), 10-year atherosclerotic cardiovascular disease risk score (-1.20%; 95% CI, -3.65% to 1.26%), and low-density lipoprotein cholesterol (-8.46 mg/dL; 95% CI, -26.63 to 9.70 mg/dL) than the control group. Nineteen of 20 physicians wanted to continue using the decision tool in the future. In this clinical trial, an individualized preventive care decision support tool improved patient understanding of primary prevention and demonstrated promise for improved shared decision-making and preventive care utilization. ClinicalTrials.gov Identifier: NCT03023813.


Impact of the pulmonary artery catheter in critically ill patients: meta-analysis of randomized clinical trials.
Randomized clinical trials (RCTs) evaluating the pulmonary artery catheter (PAC) have been limited by small sample size. Some nonrandomized studies suggest that PAC use is associated with increased morbidity and mortality. To estimate the impact of the PAC device in critically ill patients. MEDLINE (1985-2005), the Cochrane Controlled Trials Registry (1988-2005), the National Institutes of Health ClinicalTrials.gov database, and the US Food and Drug Administration Web site for RCTs in which patients were randomly assigned to PAC or no PAC were searched. Results from the ESCAPE trial of patients with severe heart failure were also included. Search terms included pulmonary artery catheter, right heart catheter, catheter, and Swan-Ganz. Eligible studies included patients who were undergoing surgery, in the intensive care unit (ICU), admitted with advanced heart failure, or diagnosed with acute respiratory distress syndrome and/or sepsis; and studies that reported death and the number of days hospitalized or the number of days in the ICU as outcome measures. Information on eligibility criteria, baseline characteristics, interventions, outcomes, and methodological quality was extracted by 2 reviewers. Disagreements were resolved by consensus. In 13 RCTs, 5051 patients were randomized. Hemodynamic goals and treatment strategies varied among trials. A random-effects model was used to estimate the odds ratios (ORs) for death, number of days hospitalized, and use of inotropes and intravenous vasodilators. The combined OR for mortality was 1.04 (95% confidence interval [CI], 0.90-1.20; P = .59). The difference in the mean number of days hospitalized for PAC minus the mean for no PAC was 0.11 (95% CI, -0.51 to 0.74; P = .73). Use of the PAC was associated with a higher use of inotropes (OR, 1.58; 95% CI, 1.19-2.12; P = .002) and intravenous vasodilators (OR, 2.35; 95% CI, 1.75-3.15; P<.001). In critically ill patients, use of the PAC neither increased overall mortality or days in hospital nor conferred benefit. Despite almost 20 years of RCTs, a clear strategy leading to improved survival with the PAC has not been devised. The neutrality of the PAC for clinical outcomes may result from the absence of effective evidence-based treatments to use in combination with PAC information across the spectrum of critically ill patients.


A general approach to identify cell-permeable and synthetic anti-CRISPR small molecules.
The need to control the activity and fidelity of CRISPR-associated nucleases has resulted in a demand for inhibitory anti-CRISPR molecules. The small-molecule inhibitor discovery platforms available at present are not generalizable to multiple nuclease classes, only target the initial step in the catalytic activity and require high concentrations of nuclease, resulting in inhibitors with suboptimal attributes, including poor potency. Here we report a high-throughput discovery pipeline consisting of a fluorescence resonance energy transfer-based assay that is generalizable to contemporary and emerging nucleases, operates at low nuclease concentrations and targets all catalytic steps. We applied this pipeline to identify BRD7586, a cell-permeable small-molecule inhibitor of SpCas9 that is twofold more potent than other inhibitors identified to date. Furthermore, unlike the reported inhibitors, BRD7586 enhanced SpCas9 specificity and its activity was independent of the genomic loci, DNA-repair pathway or mode of nuclease delivery. Overall, these studies describe a general pipeline to identify inhibitors of contemporary and emerging CRISPR-associated nucleases.


What is the level of uptake of partner notification services in HIV testing in selected health facilities in Gatanga Sub County, Muranga County - Kenya; a retrospective study.
Identification of people living with HIV is key in HIV prevention and control. Partner Notification service is a World Health Organization backed strategy of reaching out to sexual partners of people diagnosed with HIV for HIV testing. However, its adoption and success rate in Kenya remains unknown. A cross sectional facility based study was undertaken in five purposely selected health facilities in Gatanga Sub county, Muranga County, Kenya. A retrospective review of patient medical records data for HIV positive index clients and their Sexual Partners conducted. Census approach was applied to extract data for study subjects from Partner Notification Services registers for the period covering January 2017 to August 2018. Epi Info software was used for data analysis. A total of 183 index clients were offered Partner notification services. The mean age of the indexed clients studied was 39(SD ±13.1). Females comprised 64% of clients studied. Of the 183 indexed clients, 89% accepted the services and elicited 216 sexual partners for tracing. The ratio of elicited sexual partners to index client was 1.3:1. Out of the 216 sexual partners, 77% were reached and tested. A total of 46 [32%] of the sexual partners elicited and traced, tested HIV positive. The most preferred approaches were provider referral (51%) and contract referral (45%). Dual referral (4%) was the least preferred approach. Assisted Partner notification services is acceptable and an effective strategy of increasing HIV case identification and raising awareness to exposed sexual partners in low resource countries.


If the pillars are shaky, does faith in Medicare crumble?
The objectives of the study described in this article were to determine whether the faith of physicians in the Canadian system of health insurance depends on their assessment of quality and access to health services and whether their assessments of quality and access to health services affect their support of out-of-pocket and other methods of financing healthcare. To this end, a mail survey of 600 physicians in British Columbia and 240 physicians in Saskatchewan was conducted. The sample was stratified to ensure equal representation from urban and non-urban areas and between female and male specialists and family practitioners. Our conclusions indicate that physicians seem to be open minded in their views on financing. Their overriding concerns are to ensure the provision of sufficient resources to the healthcare system and to maintain full coverage of the population.


Clinical and reproductive effects of Clophen A50 (PCB) administered during gestation on pregnant guinea pigs and their offspring.
Female and male guinea pigs exposed to polychlorinated biphenyls (PCBs) in utero and via mother's milk showed growth retardation and signs of delayed onset of sexual maturation. In female young exposed to PCBs first vaginal opening occurred at a significantly older age and was of shorter duration compared with control females. The age at the first ovulation did not differ significantly between PCB-exposed females and control females. Male young exposed to PCBs had significantly lower absolute and relative testis weights at 3 months of age compared with control males. No differences in plasma testosterone concentrations were observed.


Electrophysiological properties of the bladder.
The electrophysiological properties of detrusor smooth muscle are described, in particular with regard to their influence on the contractile properties of the tissue. The Ca2+ and K+ channel activities are most important in generating action potentials, but the role of several other ionic currents is described, including Cl-, Ca2+-activated, stretch-activated and ligand-gated channels. The variable appearance and functions of different ionic currents in disease states is discussed, as well as the question of whether electrical activity can transmit between adjacent smooth muscle cells. In addition, the precise role that electrophysiological phenomena play in the regulation of the contractile state of the smooth muscle cells, as well as the generation of bladder electromyograms, is discussed.


LncRNA OIP5-AS1 Promotes Breast Cancer Progression by Regulating miR-216a-5p/GLO1.
Breast cancer is a familiar malignant tumor, which is a great threat to women's life. Long noncoding RNA Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) has been reported to be associated with numerous cancers. This study aimed to explore the role of OIP5-AS1 and the mechanism of its action in the progression of breast cancer. The expression of OIP5-AS1 and miR-216a-5p was detected by quantitative real-time polymerase chain reaction. Cell proliferation, apoptosis, migration, or invasion was assessed by 4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, flow cytometry, or transwell assay, respectively. The binding sites were predicted by bioinformatics tool starBase2.0 (http://starbase.sysu.edu.cn/starbase2/index.php). The interaction between miR-216a-5p and OIP5-AS1 or glyoxalase 1 (GLO1) was confirmed by dual-luciferase reporter assay. The expression of GLO1 was quantified by Western blot. Nude mouse tumorigenicity assays were conducted to verify the role of OIP5-AS1 in vivo. OIP5-AS1 and GLO1 were highly expressed in both clinical tumor tissues and cell lines, whereas miR-216a-5p was downregulated. Knockdown of OIP5-AS1 suppressed proliferation, migration, and invasion but promoted apoptosis of breast cancer cells. MiR-216a-5p was a target of OIP5-AS1 and interacted with GLO1. MiR-216a-5p inhibition or GLO1 overexpression reversed the effects of OIP5-AS1 knockdown on the development of breast cancer cells. OIP5-AS1 knockdown depleted tumor growth in vivo. OIP5-AS1 knockdown suppressed the progression of breast cancer by inducing GLO1 expression via competitively binding to miR-216a-5p, suggesting that OIP5-AS1 was a hopeful biomarker for the therapy of breast cancer.


Age- and position-related heterogeneity of equine tendon extracellular matrix composition.
The digital flexor tendons of the neonate and adult horse have been compared with respect to variation in extracellular matrix composition along their length. Two pepsin-sensitive, acetic acid soluble proteins, molecular weight (Mr) 52 kD (np 52) and Mr 54 kD (np 54), were prominent throughout the length of neonatal tendons. In adult tendon, np 52 and np 54 were less abundant and restricted to the cannon (metacarpal) region. In contrast, a single pepsin- and collagenase-resistant protein of Mr 55 kD (fp 55) was exclusive to the fetlock (metacarpophalangeal joint) region regardless of age, although more distinct in the adult. Pepsin extracted fp 55 precipitated at 2.0 M sodium chloride: 0.5 M acetic acid and was further purified to homogeneity by bacterial collagenase digestion. Analysis of fp 55 amino acid composition revealed the presence of a large proportion of glycine residues (379 of 1001), suggesting a possible homology with the collagen family. These data demonstrate that the composition of equine digital flexor tendons varies with age, is heterogeneous along its length, and suggests that variation in tendon extracellular matrix composition is influenced by functional requirements.


The Third Man: Robert Dunn's (1799-1877) Contribution to Aphasia Research in Mid-Nineteenth-Century England.
Throughout his medical career, Robert Dunn (1799-1877) published a number of clinical cases with postmortem reports involving acquired language disorders, with the first noted in 1842. He developed a physiologically informed approach to psychological function during the 1850s along with a group of notable colleagues Benjamin Collins Brodie, Henry Holland, Thomas Laycock, John Daniel Morell, and Daniel Noble. He was also active in ethnographic research on human origins and racial diversity. As such, Dunn represents an interesting player in the developing fields of neurology, psychology, and anthropology in England in the latter part of the nineteenth century. These various strands converged at the meeting of the British Association of the Advancement of Science in 1868, where Dunn shared the program of lectures on the cutting-edge topic of aphasia with Paul Broca (1824-1880) and John Hughlings Jackson (1835-1911). Dunn's ideas developed over a longer time frame than his younger colleagues and as such represent a unique blending of concepts from the earlier work of Franz Josef Gall (1758-1828) and Jean-Baptiste Bouillaud (1798-1881) to the perspectives on language organization in the brain developed after 1861.


Immunological evidence for a change in subunits of the acetylcholine receptor in developing and denervated rat muscle.
We used specific antibodies to gamma, delta, and epsilon subunits to characterize acetylcholine receptor (AChR) in extracts and at endplates of developing, adult, and denervated rat muscle. The AChRs in normal adult muscle were immunoprecipitated by anti-epsilon and anti-delta, but not by anti-gamma antibodies, whereas AChRs in denervated and embryonic muscles were precipitated by anti-gamma and anti-delta, but showed little or no reactivity to anti-epsilon antibodies. In immunofluorescence experiments, AChRs at neonatal endplates bound antibodies to gamma or delta, but not epsilon, subunit, whereas those in adult muscles bound antibodies to epsilon or delta, but not gamma, subunit. AChRs at denervated endplates and at developing endplates between postnatal days 9 and 16 bound all three antibodies. We conclude that the distribution of gamma and epsilon subunits of the AChR parallels the distribution of AChRs with embryonic and adult channel properties, respectively.


Crocodile attack in Australia: an analysis of its incidence and review of the pathology and management of crocodilian attacks in general.
Crocodilians represent one of the oldest constant animal lineages on the planet, in no small part due to their formidable array of predatory adaptations. As both human and crocodilian populations expand, they increasingly encroach on each others' territories, bringing morbidity and mortality to both populations. In this article, the medical and herpetologic literature pertaining to injuries caused by crocodilians is reviewed, and the patterns of saltwater crocodile attacks in Australia from 1971 to 2004 are analyzed. In this review, we examine the features of crocodilians that contribute to explaining their evolutionary success, as well as the potential hazard they pose to humans. Only by understanding their capabilities is it possible to mitigate the potential threat to life and limb.


The immune function of heme oxygenase-1 from grass carp (Ctenopharyngodon idellus) in response to bacterial infection.
Heme oxygenase (HO)-1, a rate-limiting enzyme in heme catabolism, results in the formation of equivalent amounts of biliverdin (BV), carbon monoxide (CO) and ferrous iron (Fe2+). Previous studies have revealed that HO-1 plays an important role in immune responses. However, the mechanism underlying the immune responses against bacterial infection of teleost HO-1 remains enigmatic. To decipher the mechanisms, we have cloned and characterized the HO-1 gene of grass carp (designated as GcHO-1) in this research. The results showed that the open reading frame (ORF) of GcHO-1 was 819 bp, which encoded a putative protein of 272 amino acids. The deduced amino acid sequence phylogenetically shared the highest identity with other teleosts, and contained two domains of heme-oxygenase and a single-pass transmembrane domain. The mRNA expressions of GcHO-1 in healthy grass carp have widely existed in examined tissues in the following order of spleen > head-kidney > middle head-kidney > intestines > liver > gills > heart > muscle > brain. Besides, the mRNA and protein transcription of GcHO-1 were both significantly up-regulated in the liver and head-kidney tissues after Staphylococcus aureus and Aeromonas hydrophila infection. In addition, overexpression of GcHO-1 in kidney cell line (CIK) cells of grass carp could reduce the expression of inflammatory cytokines (IL-1β, IL-8, TNFα, CCL1 and IL-6). Herein, we demonstrate that GcHO-1 plays an anti-inflammatory role in innate immunity. Our results shed new light on the mechanisms underlying the antibacterial immunity of teleost.


Risk of second primary malignancies of adolescent and young adult patients with germ cell cancer: A US population-based analysis.
Germ cell cancer (GCC) is a group of neoplasms with heterogeneity. Predominant in young adults, GCC potentially mitigates a high number of productive years of life lost. Indeed, long-term side effects have arisen as a problem in GCC survivors, especially in adolescent and young adult (AYA) subgroup. The objective of this study is to delineate survival and second primary malignancies (SPMs) in AYA patients with GCC. We used US population-based Surveillance, Epidemiology and End Results (SEER) 18 Regs Custom Data (1976-2016 varying) and SEER 9 Regs Research Data, November 2019 Sub (1975-2017) for survival analysis and SPM analysis, respectively. Overall, 5-, 10- and 20-year overall survival rates for AYA patients with GCC were 93%, 91.3%, and 86.9%, respectively. Compared with the general population, a significantly higher risk of SPMs was observed in multiple sites, especially stomach, (standardized incidence ratio [SIR] = 2.94), pancreas (SIR = 3.72), intrahepatic bile duct (SIR = 3.12), soft tissue including heart (SIR = 4.65), leukemia (SIR = 3.70), and testis (SIR = 562.18). The excess risks to develop leukemia were even higher in those with primary mediastinal GCC (SIR = 69.50, P < 0.05, 95% confidence interval = 30.00-136.94). Multivariate analysis indicated age of diagnosis, primary site, race, receipt of radiotherapy, and histological subtype independently correlated with risk of SPMs. The present study provides risk factors of SPM in AYA patients with GCC, which could facilitate the individualization of long-term surveillance in this population.


Tracing contacts to evaluate the transmission of COVID-19 from highly exposed individuals in public transportation.
We investigate, through a data-driven contact tracing model, the transmission of COVID-19 inside buses during distinct phases of the pandemic in a large Brazilian city. From this microscopic approach, we recover the networks of close contacts within consecutive time windows. A longitudinal comparison is then performed by upscaling the traced contacts with the transmission computed from a mean-field compartmental model for the entire city. Our results show that the effective reproduction numbers inside the buses, [Formula: see text], and in the city, [Formula: see text], followed a compatible behavior during the first wave of the local outbreak. Moreover, by distinguishing the close contacts of healthcare workers in the buses, we discovered that their transmission, [Formula: see text], during the same period, was systematically higher than [Formula: see text]. This result reinforces the need for special public transportation policies for highly exposed groups of people.


[Synthesis of 1-(difluoro-1,3,5-triazinyl)-2-methylisoindole as a fluorescent derivatization reagent and its reactivity for corticosteroids].
A fluorescence high-performance liquid chromatographic method for the determination of corticosteroids is described. Corticosteroids were labeled quantitatively by treatment with 1-(difluoro-1,3,5-triazinyl)-2-methylisoindole in an alkaline medium at room temperature for 10 s and the fluorescent adducts were eluted isocratically on a reversed-phase column by a mobile phase of aqueous methanol. The detection limit of cortisone was 3 pmol for an injection volume of 10 microliter.


Stratification of rodent carcinogenicity bioassay results to reflect relative human hazard.
Trans-species, multiple site (particularly common site between species), mutagenic rodent carcinogens are less affected by the influences of polymorphic genes than are chemicals inducing more limited carcinogenic effects. Trans-species carcinogens, therefore, should represent a first priority for attention for human health risk.


Intranigral application of substance P antagonists prevents the haloperidol-induced activation of striatal tyrosine hydroxylase.
The effect of intranigral injections of stable substance P analogs with antagonist properties, namely [D-Pro2, D-Trp7,9]-substance P and [D-Pro2, D-Phe7, D-Trp9]-substance P, on the activity of the nigrostriatal dopaminergic pathway was studied. Dopaminergic neural activity was evaluated by measuring changes in striatal tyrosine hydroxylase activity in response to systemic treatment with haloperidol. When injected into the substantia nigra of normal rats, neither of the two substance P analogs influenced the Vmax of striatal tyrosine hydroxylase or the affinity of the enzyme for its pteridine cofactor. However, when applied into the substantia nigra 10 min before systemic haloperidol, 20 micrograms of either substance P analog was able to prevent the haloperidol-induced activation of striatal tyrosine hydroxylase. The effect was not altered by concurrent microinjection of the GABA-antagonist bicuculline. These results suggests that nigral substance P plays an important role in the activation of nigrostriatal dopamine neurons produced by haloperidol. Thus, both substance P and GABA may reciprocally and independently regulate the activity of nigrostriatal dopamine neurons in response to changes in dopamine receptor activity.


Experiences of Being Heterozygous for Fabry Disease: a Qualitative Study.
Little is known about the experiences of women with Fabry disease. The aim of this study was to explore women's experiences of being heterozygous for Fabry disease. We used an explorative qualitative study design and selected ten Norwegian women who were known heterozygous for Fabry disease to participate. We conducted in-depth semi-structured interviews and analyzed the interviews using inductive thematic analysis. We found that learning about one's heterozygous status may be devastating for some. However, for most of the participants, heterozygous status, as well as doctors' acceptance of symptoms in women heterozygous for Fabry disease, provided an explanation and relief. Although many women did not consider themselves ill, they wished to be acknowledged as more than "just carriers." The participants were grateful for enzyme replacement therapy, although it had its burdens regarding time, planning, and absences from school or work. Women with Fabry disease felt that the lack of knowledge among healthcare professionals about Fabry disease was frustrating and worrisome. These findings suggest that healthcare professionals should acknowledge the different ways women react to their diagnosis, and be aware of the personal costs of receiving treatment.


Planting woody crops on dredged contaminated sediment provides both positive and negative effects in terms of remediation.
There is currently a requirement for studies focusing on the long-term sustainability of phytoremediation technologies. Trace element uptake by Salix, Populus and Alnus species planted in dredged contaminated canal sediment and concentrations in sediment and pore waters were investigated, eight years after a phytoremediation trial was initiated in NW England. Soil biological activity was also measured using invertebrate and microbial assays to determine soil quality improvements. Zinc was the dominant trace metal in foliage and woody stems, and the most mobile trace element in sediment pore water (~14 mg l(-1)). Biological activity had improved; earthworm numbers had increased from 5 to 24, and the QBS index (an index of microarthropod groups in soil) had increased from 70 to 88. It is concluded that biological conditions had improved and natural processes appear to be enhancing soil quality, but there remains a potential risk of trace element transfer to the wider environment.


Multi-column deep neural network for traffic sign classification.
We describe the approach that won the final phase of the German traffic sign recognition benchmark. Our method is the only one that achieved a better-than-human recognition rate of 99.46%. We use a fast, fully parameterizable GPU implementation of a Deep Neural Network (DNN) that does not require careful design of pre-wired feature extractors, which are rather learned in a supervised way. Combining various DNNs trained on differently preprocessed data into a Multi-Column DNN (MCDNN) further boosts recognition performance, making the system insensitive also to variations in contrast and illumination.


Intracortical recordings and fMRI: an attempt to study operational modules and networks simultaneously.
The brain can be envisaged as a complex adaptive system. It is characterized by a very high structural complexity and by massive connectivity, both of which change and evolve in response to experience. Information related to sensors and effectors is processed in both a parallel and a hierarchical fashion; the connectivity between different hierarchical levels is bidirectional, and its effectiveness is continuously controlled by specific associational and neuromodulatory centers. When questions are addressed at the level of a distributed, large-scale whole system such as that underlying perception and cognition, it is not clear what should be considered as an elementary operational unit because the behavior of integral, aggregate systems is always emergent and most often remains unpredicted by the behaviors of single cells. To localize and comprehend the neural mechanisms underlying our perceptual or cognitive capacities, concurrent studies of microcircuits, of local and long-range interconnectivity between small assemblies, and of the synergistic activity of larger neuronal populations are called for. In other words, multimodal methodologies that include invasive neuroscientific methods as well as global neuroimaging techniques are required, such as the various functional aspects of magnetic resonance imaging. These facts were the driving force behind the decision to begin animal-MRI in my lab. The wonderful idea of the editors of NeuroImage to publish a Special Issue commemorating 20years of functional fMRI provides me with the opportunity of sharing not only our first moments of frustration with the readers, but also our successful results.


Effect of nutrition on toxicity of contaminants to the epibenthic amphipod Melita plumulosa.
The amphipod Melita plumulosa is commonly used to assess the toxicity of contaminated sediments. Seven-day-old M. plumulosa are <1 mm in size, and during 10-day tests in sandy sediments with low nutritional value, starvation can cause >50% mortality. In sediment toxicity tests, therefore, it can be difficult to determine if toxicity is due to contaminants or starvation, particularly in contaminated sandy sediments. This study investigated the influence of amphipod age and food addition on amphipod survival in toxicity tests. The 4-day LC(50) increased linearly from 120 to 470 microg/L when M. plumulosa age at the beginning of the test increased from 5 to 30 days. The addition of food as algae or fish food did not significantly affect the sensitivity of 11-day-old M. plumulosa (11-d Mp) to dissolved copper over 4 days in water-only tests. The survival of 11-d Mp in water-only tests over 10 days was poor without feeding, but when fed fish food, the 10-day LC(50) was 76 +/- 15 microg/L. In sediment tests, feeding 0.063 mg fish food/amphipod on days 3 and 7 of 10-day tests consistently resulted in greater than 80% survival of 11-d Mp for a range of clean, sandy sediments, which had low amphipod survival without added food. Algae were not always suitable as a food source, as their growth can be stimulated by nutrients released from sediment and was inhibited by contaminants. The toxicity of most contaminated sediments was not ameliorated by the addition of food, suggesting that food addition was suitable for inclusion in routine testing protocols for this amphipod.


Keeping track: An intra-UK comparison of orthodontic commissioning and treatment outcome assessments.
Across the United Kingdom (UK), National Health Service (NHS) orthodontic treatment is commissioned differently across the devolved nations. There is a relative paucity in the literature describing the way in which the orthodontic services in each country are commissioned and treatment outcomes measured. To highlight the differences in the following: commissioning of primary care orthodontic services across the UK; assessment of treatment outcomes; and the potential impacts these differences have on contractors, performers and patient care. Data were collected using an online mixed-methods approach. Systematic content analysis was used to extract the required information from the websites and guidance documents of orthodontic service providers, which was then catalogued and verified electronically by senior dental advisors in the four devolved UK nations. The Index of Orthodontic Treatment Need (IOTN) is a mandatory needs assessment tool used across all four nations, with an agreed minimum threshold of a dental health component (DHC) score of 3 and an aesthetic component (AC) score of 6 for NHS treatment. While the peer assessment rating (PAR) is the most utilised method of assessing post-treatment outcomes, it is applied differently by each country. While NHS orthodontic services across the UK share mutual elements of service delivery, there are significant differences in the prior approval process and assessment of treatment outcomes. More research is required to assess the economic feasibility of orthodontic treatment from the associated treatment outcomes.


Irritable bowel syndrome in Nigerians.
Twenty-six Nigerians with irritable bowel syndrome are reported. Twenty-three patients (88.46%) belong either to the middle or upper socioeconomic class; 16 patients (61.5%) had predominantly constipation. Six of the patients (23.1%) had their first symptoms before the age of 15 years. No sex preference is shown by this study. The most common symptoms are flatulence and abdominal pain, which is relieved by bowel motion, belching, and/or passage of flatus. Cow's milk, stress, and a local diet of beans are the most common aggravating factors, while another local high-fiber diet of cassava was found helpful in reducing the intensity and frequency of symptoms in some patients.


Effect of levothyroxine replacement therapy on coagulation and fibrinolysis in severe hypothyroidism.
We previously demonstrated that patients suffering from moderate hypothyroidism were at increased risk of thrombosis contrasting with the bleeding tendency of those presenting severe hypothyroidism. The latter state is associated with hemostatic anomalies including von Willebrand type 1 disease and increased fibrinolytic capacity. With the exception of von Willebrand type 1 disease, reversibility of hemostatic changes is not established after levothyroxine replacement therapy. Therefore our objective was to analyze the reversibility of these anomalies. We analyzed the impact of levothyroxine treatment on lipid parameters, fibrinogen, platelet count, D-dimers, alpha2 antiplasmin activity, plasminogen activity, tissue plasminogen activator antigen (t-PA Ag), plasminogen activator inhibitor type 1 antigen (PAI-1 Ag) and coagulation factors (factor VIII coagulant, von Willebrand factor antigen, von Willebrand factor and factor IX) in 23 patients with severe hypothyroidism (TSH level > 50 mU/ I). Mean fibrinogen levels increased by 14.2% while t-PA Ag and PAI-1 Ag increased by 42.6 and 69%, respectively, after correction of hypothyroidism. Interestingly, post-treatment PAI-1 Ag levels tended to be higher in patients with normal-high final TSH levels than in patients with normal-low final TSH levels. Our results suggest that normalization of fibrinolysis is obtained after a transient decrease of fibrinolytic activity. We also confirmed the correction of coagulation factor abnormalities upon levothyroxine replacement therapy. We demonstrated that the coagulation disorders and the hyperfibrinolytic status of severe hypothyroid patients were corrected upon levothyroxine therapy. However, the clinical consequences of the transient decrease of the fibrinolytic activity during the course of TSH normalization need further studies.


History of Neurosurgery in Jordan.
To raise the level of awareness regarding the role of Jordan as one of the leading countries in the region in providing excellent general medical and neurosurgical care. This article is mainly a descriptive article. Data presented were collected from different sources that were available in either Arabic or English. Jordan has a well structured health care system that consists of three major sectors: public, private, and donors. The physician density is 2.86 physicians/1000 population and the bed density of 17 beds/10,000 population. Jordan has 58 neurosurgeons (1 neurosurgeon per approximately 115,000 population) who cover all neurosurgical subspecialties and provide the best modern neurosurgical care. Jordan has placed great importance on advancing the health care sector in accordance with international benchmarks yielding performance indicators that are among the best in the region. Moreover, Jordanian women are empowered to take leading roles in nursing, medicine, and surgery.


Coating uniformity improvement for a dense-wavelength-division-multiplexing filter by use of the etching effect.
The uniformity of optical narrow-bandpass filters for dense wavelength division multiplexing (DWDM) has been improved by control of the coating parameters of electron guns and the ion source. The optical film was deposited by the electron gun and was etched by the ion source during the ion-assisted deposition process. The uniformity of the coating of a 100 GHz DWDM filter is better than +/- 0.003% over a circular area of 50 mm in diameter when such an etching process is used.


Estimating the Prevalence of Treated Epilepsy Using Administrative Health Data and Its Validity: ESSENCE Study.
Few of the epidemiologic studies of epilepsy have utilized well-validated nationwide databases. We estimated the nationwide prevalence of treated epilepsy based on a comprehensive medical payment database along with diagnostic validation. We collected data on patients prescribed of antiepileptic drugs (AEDs) from the Health Insurance Review and Assessment service, which covers the entire population of Korea. To assess the diagnostic validity, a medical records survey was conducted involving 6,774 patients prescribed AEDs from 43 institutions based on regional clusters and referral levels across the country. The prevalence of treated epilepsy was estimated by projecting the diagnostic validity on the number of patients prescribed AEDs. The mean positive predictive value (PPV) for epilepsy was 0.810 for those prescribed AEDs with diagnostic codes that indicate epilepsy or seizure (Diagnosis-E), while it was 0.066 for those without Diagnosis-E. The PPV tended to decrease with age in both groups, with lower values seen in females. The prevalence was 3.84 per 1,000, and it was higher among males, children, and the elderly. The prevalence of epilepsy in Korea was comparable to that in other East Asian countries. The diagnostic validity of administrative health data varies depending on the method of case ascertainment, age, and sex. The prescriptions of AEDs even without relevant diagnostic codes should be considered as a tracer for epilepsy.


Efficacy of fexofenadine in the prophylactic control of cat allergen-induced allergic rhinitis.
To date, it is unknown whether fexofenadine mitigates the worsening of symptoms induced by the cat allergen Felis domesticus allergen 1. To determine the effects of a single dose of fexofenadine hydrochloride, 180 mg, in preventing and controlling cat allergen-induced allergic rhinitis symptoms using the cat room challenge model. This single-center, randomized, double-blind, placebo-controlled, 2-way crossover study consisted of a screening visit, 1 or 2 qualifying visits, and 2 treatment periods separated by a mean +/- SD washout period of 14 +/- 3 days. Patients were randomized to treatment sequence 1 (placebo followed by fexofenadine) or sequence 2 (fexofenadine followed by placebo). Baseline end points were obtained before study drug administration, and allergen challenges were initiated 1 1/2 hours after dosing. The primary end point was the change from predose baseline in the total symptom score (sum of rhinorrhea, itchy nose/palate/ throat, sneezing, and itchy/watery/red eyes) after 30 minutes of allergen exposure compared with placebo. Of 211 patients screened, 66 were randomized and 63 completed the study. Mean change in the total symptom score from predose baseline was significantly less with fexofenadine compared with placebo 30 minutes after initiation of the cat allergen challenge (2 hours after dosing) (P = .03). The overall incidence of treatment-emergent adverse events was low and comparable for both groups. Prophylactic treatment with a single dose of fexofenadine hydrochloride, 180 mg, significantly mitigated the worsening of allergic rhinitis symptoms induced by exposure to cat allergen compared with placebo use.


The prognostic potential of alkaline phosphatase and lactic acid dehydrogenase in bmCRPC patients without significant PSA response under enzalutamide.
In patients with bone metastatic castration-resistant prostate cancer (bmCRPC) on systemic treatment, it is difficult to differentiate between continuous rise of prostate specific antigen (PSA) representing progression, and PSA-surge, which is followed by clinical response or stable disease. The purpose of this study was to evaluate the prognostic value of dynamic changes of alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels as a predictor of clinical efficacy or therapeutic resistance of patients who do not show a sufficient initial PSA decline of ≥50% from baseline during early therapy with Enzalutamide. Forty-eight men with bmCRPC on Enzalutamide 07/2010-09/2019 with initially rising PSA were analyzed. We monitored PSA, LDH and ALP at week 0, 2, 4, and every 4 weeks thereafter and analyzed the correlation between ALP rising at 12 weeks with or without LDH-normalization and the association with survival. For this we used Kaplan Meier analysis and uni- and multivariate cox-regression models. In Kaplan-Meier analysis, ALP rising at 12 weeks with or without LDH-normalization was associated with significantly worse median progression-free survival (PFS) of 3 months vs. 5 months (Log rank P = 0.02) and 3 months vs. 5 months (P = 0.01), respectively and overall survival (OS) with 8 months vs. 15 months (P = 0.02) and 8 months vs. 17 months (P < 0.01). In univariate analysis of PFS, ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization and application of Enzalutamide after chemotherapy showed a statistically significant association towards shorter PFS (hazard ratio (HR): 0.51, P = 0.04; HR: 0.48, P = 0.03; HR: 0.48, P = 0.03). Worse OS was significantly associated with ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization, and application of Enzalutamide after chemotherapy (HR: 0.47, P = 0.02; HR: 0.36, P < 0.01; HR: 0.31, P < 0.01). In multivariate analysis only the application of Enzalutamide after chemotherapy remained an independent prognostic factor for worse OS (HR: 0.36, P = 0.01). Dynamic changes of ALP (non-rise) and LDH (normalization) under therapy with Enzalutamide may be associated with clinical benefit, better PFS, and OS in patients with bmCRPC who do not show a PSA decline.


Synthesis, topoisomerase I inhibition and structure-activity relationship study of 2,4,6-trisubstituted pyridine derivatives.
For the development of new anticancer agents, phenyl, 2-pyridyl, 2-furyl, 2-thienyl, 2-furylvinyl and 2-thienylvinyl substituted derivatives on 2,4,6-position in pyridine moiety were prepared and evaluated for their topoisomerase I inhibitory activity. Among the thirteen prepared compounds, four compounds exhibited strong topoisomerase I inhibitory activity. A structure-activity relationship study indicated that the 2-thienyl-4-furylpyridine skeleton was important for topoisomerase I inhibitory activity.


Design, synthesis and biological evaluation of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives.
Based on our previous work, a series of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that some compounds possessed significant antiproliferative activities against four cancer cell lines, HepG2, HCT116, PC-3, and Hela. Particularly, the most promising compound 8d displayed 184-, 18-, and 17-fold improvement compared to fluorouracil in inhibiting HCT116, Hela and PC-3 cell proliferation with IC50 values of 0.37, 2.94, and 31.31μM, respectively. Most interestingly, the compound did not affect the normal human embryonic kidney cells, HEK-293. Moreover, mechanistic investigation showed that the representative compound 8d induced apoptosis and blocked cell cycle in G2/M phase in Hela cells in a dose-dependent manner. These findings suggest that compound 8d may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs.


Association of baseline urodynamic measures of urethral function with clinical, demographic, and other urodynamic variables in women prior to undergoing midurethral sling surgery.
To explore how baseline demographic, clinical, and urodynamic (UDS) variables correlate with measures of urethral function in women planning midurethral sling surgery. Women with predominant stress urinary incontinence (SUI) as part of the trial of mid-urethral slings (TOMUS) were characterized preoperatively including: demographics, body mass index (BMI), responses to the Medical and Epidemiologic Social Aspects of Aging (MESA) and Urogenital Distress Inventory (UDI) questionnaires, pad weight (PW), incontinence duration, prior SUI surgery, prolapse, strength of pelvic contraction, Q-tip test, uroflow, cystometrogram, and detrusor pressures at maximum flow (Pdet at Qmax). Multivariate regression analysis and modeling confirmed variables with significant correlations with maximal urethral closure pressure (MUCP), functional urethral length (FUL), and Valsalva leak point pressure (VLPP). Five-hundred thirty-nine women were included in the analysis. In multivariable analyses, PW (P = 0.045) and age (P < 0.0001) were negatively correlated with MUCP (as PW and age increased, MUCP decreased); BMI (P = 0.02) and Pdet at Qmax (P < 0.0001) were positively correlated with MUCP (as BMI and Pdet at Qmax increased, MUCP increased). Age (P = 0.002) was negatively correlated with FUL; Qtip delta (P = 0.006), pelvic organ prolapse quantification examination (POPQ) stage (P = 0.002) and strength of pelvic contraction (P = 0.03) were positively correlated with FUL. Duration of incontinence (P = 0.01) was negatively correlated with VLPP; Qtip delta (P = 0.02), BMI (P = 0.0005) and Pdet at Qmax (P = 0.0005) were positively correlated with VLPP. Age, BMI, Qtip delta, and Pdet at Qmax were variables that correlated with two or more measures of urethral function. These correlations may help direct future research in female urethral function.


Prediction of heat-illness symptoms with the prediction of human vascular response in hot environment under resting condition.
The thermoregulatory control of human skin blood flow is vital to maintain the body heat storage during challenges of thermal homeostasis under heat stress. Whenever thermal homeostasis disturbed, the heat load exceeds heat dissipation capacity, which alters the cutaneous vascular responses along with other body physiological variables. Whole body skin blood flow has been calculated from the forearm blood flow. Present model has been designed using electronics circuit simulator (Multisim 8.0, National Instruments, USA), is to execute a series of predictive equations for early prediction of physiological parameters of young nude subjects during resting condition at various level of dry heat stress under almost still air to avoid causalities associated with hot environmental. The users can execute the model by changing the environmental temperature in degrees C and exposure time in minutes. The model would be able to predict and detect the changes in human vascular responses along with other physiological parameters and from this predicted values heat related-illness symptoms can be inferred.


Glycosaminoglycans: oligosaccharide analysis by liquid chromatography, capillary electrophoresis, and specific labeling.
Glycosaminoglycans (GAGs) are a class of biopolymers that include chondrotin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, heparin, and heparan sulfate. The GAGs are linear polysaccharides that are microheterogeneous in composition and polydisperse in size. Because they have the most complex structures, this article is aimed at describing a step-by-step procedure for processing and analyzing heparin and heparan sulfate-derived oligosaccharides, although the basic protocols and procedures apply equally well to other members of the GAG family. The methods described in this manuscript include the preparation of oligosaccharides through enzymatic depolymerization, size fractionation by preparative scale size-exclusion chromatography (SEC), and disaccharide isomer analysis by reverse-phase ion-pair high-performance liquid chromatography (RPIP-HPLC) and capillary electrophoresis (CE).


Management of personal protective equipment during the COVID-19 pandemic in England and the state of New York: A comparative case study.
The COVID-19 crisis placed extraordinary demands on the supply of personal protective equipment (PPE) at the beginning of 2020. These were coupled with shocks to the supply chain resulting from the disease. Many typically well-resourced health systems faced subsequent shortages of equipment and had to implement new strategies to manage their stocks. Stockpiles of protective equipment were held in both the United States and United Kingdom intended to prevent shortages. Cross-comparative case study approach by applying Pettigrew and Whipp's framework for change management. The health systems of England and New York state from January 2020 to the end of April 2020. Both cases reacted slowly to their outbreaks and faced problems with supplying enough PPE to their health systems. Their stockpiles were not enough to prevent shortages, with many distribution problems resulting from inadequate governance mechanisms. No sustainable responses to supply disruptions were implemented during the study period in either case. Health systems planned interventions along each part of the supply chain from production and importing, to usage guidelines. Global supply chains are vulnerable to disruptions caused by international crises, and existing mitigation strategies have not been wholly successful. The existence of stockpiles is insufficient to preventing shortages of necessary equipment in clinical settings. Both the governance and quality of stockpiles, as well as distribution channels are important for preventing shortages. At the time of writing, it is not possible to judge the strength of strategies adopted in these cases.


Differences between attendings' and residents' operative notes for laparoscopic cholecystectomy.
Operative notes are the gold standard for detecting adverse events and near misses and form the basis for scientific research. In order to guarantee safe patient care, operative notes must be objective, complete, and accurate. This study explores the current routine of note writing for laparoscopic cholecystectomy (LC) and the differences between the notes of attendings and residents. Attendings and residents were sent a DVD with footage of three LCs and were asked to "write" the corresponding notes and to complete a questionnaire. Dictation tapes were transcribed and items in the notes were analyzed for each procedure ("item described" or "item not described"). Fisher's exact tests were performed using SPSS 16.0 for Mac. Thirteen sets of typewritten notes and 10 dictation tapes were returned. The results of the questionnaire showed that 16 of the 23 sets of notes were dictated. Eight participants found the current system for generating notes inadequate. 14 items (31 %) were included more often in the attendings' notes and 25 items (56 %) were included more often in the residents' notes. Overall, residents significantly more often described the location of the epigastric trocar (P = 0.018), the size of both working trocars (P = 0.019), the opening of the peritoneal envelope (P = 0.002), Critical View of Safety reached (P = 0.002), and the location for removing the gallbladder (P = 0.019). With the exception of "gallbladder perforation" (20 of 21 notes), complications were underreported. In this study residents described more items than attendings. All notes lacked information concerning complications in the procedure, which makes the notes subjective and incomplete. A procedure-specific template or black-box-based operative notes based on established guidelines could improve the quality of the notes of both attendings and residents.


The isolation and partial characterization of trypsin from the pancreas of the ostrich Struthio camelus.
Cationic trypsin was isolated and purified from the pancreas of the ostrich (Struthio camelus) by affinity chromatography on a Trasylol-Sepharose column. External activation of trypsinogen was required before trypsin could be isolated. The final preparation was homogeneous by SDS-PAGE and by sedimentation equilibrium centrifugation studies, resulting in Mr values of 24,547 and 22,091, respectively. The Mmin value obtained from amino acid analysis was 22,450. A mean sedimentation coefficient of 2S was obtained by sedimentation velocity centrifugation. Results obtained from N-terminal and amino acid analyses were similar to those from trypsins of other species. The effects of pH, temperature and inhibitors (LBTI, KBPTI and PMSF) on the tryptic activity were examined. The effect of calcium ions and enzyme concentration on the rate of self-digestion of ostrich trypsin was also investigated.


Identification of a novel agarolytic γ -Proteobacterium Microbulbifer maritimus and characterization of its agarase.
The phenotypic and agar degrading features of an unidentified marine bacteria was investigated. The strain was Gram-negative, obligatory aerobic and non motile. On the basis of several morphological features and a phylogenetic analysis of the genes coding for the 16S rDNA, this strain was identified as Microbulbifer maritimus. On solid agar medium, this isolate produced extracellular agarase which causes agar liquefaction around the colonies. An extracellular agarase was purified by ammonium sulfate precipitation, gel filtration and ion-exchange chromatography on DEAE-cellulose. The purified protein migrated as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and it had a molecular mass of 75.2 kDa. The enzyme exhibited maximal activity at pH 7.5. The kinetic parameters of the enzyme were K(m) = 3 ± 0.19 mM, K(cat) = 160 ± 10 S(-1) and K(cat) /K(m) = 53 ± 10 S(-1) · mM(-1) .


Social dominance orientation predicts drive for muscularity among British men.
The present study tested the hypothesis that men's drive for muscularity would be associated with their valuation of domination, power, status, and aggression over others. A community sample of 359 men from London, UK, completed measures of drive for muscularity, social dominance orientation, right-wing authoritarianism, trait aggression, and need for power, as well as their demographic details. Bivariate correlations showed that greater drive for muscularity was significantly correlated with most of the measures and their subscales. However, in a multiple regression analysis, the only significant predictor of drive for muscularity was support for group-based dominance hierarchies (Adj. R(2)=.17). These results suggest that men's drive for muscularity is associated with a socio-political ideology that favours social dominance.


Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line.
Triple-negative breast cancers (TNBCs) are aggressive cancers that do not benefit from hormonal therapy or therapies that target HER2 receptors. Insulin-like growth factor 1 receptor (IGF-1R), which has been shown to be overexpressed in breast cancer, activates numerous downstream kinases that associate with cell proliferation and survival. This study compared the effects caused by dual treatments targeting IGF-1R, PI3K, mTORC, or MEK with those by single treatments in a TNBC cell line, MDA-MB-231. We used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 demonstrated a significant synergistic growth inhibition. These dual treatments increased apoptosis and/or cell cycle arrest at G0/G1 phase and enhanced the inhibition of phosphorylation of Akt or downstream molecules of mTORC1, as compared to the single treatments. Our study suggests that targeting multiple kinases in IGF-1R signaling may be a promising therapeutic approach.


An unusual presentation of congenital adrenocortical carcinoma: a case report and review of the literature.
We describe a case of congenital non-functional adrenocortical carcinoma in a male infant who presented with recurrent pneumonia, paraparesis and sclerotic skeletal metastasis. To the best of our knowledge such presentation has never been reported.


Effect of pretreatment on Er:YAG laser-irradiated dentin.
Erbium:yttrium-aluminum-garnet (Er:YAG) laser preparation of tooth cavities for restoration is an increasingly popular method, but its compatibility with existing composite material bonding protocols has not been fully defined. This study evaluated the effect of laser and etchant pretreatments on the performance of one-bottle self-etch adhesives in Er:YAG laser-prepared dentin. Eight groups of 20 extracted teeth were established to investigate bonding in tested dentin disks. Various combinations of laser preparation (with/without), pretreatment (none/acid-etch/low-fluence Er:YAG irradiation), and self-etching adhesive (G-Bond Plus or Xeno V) were tested. Samples were then restored with composite resin and subjected to a tensile bond strength (TBS) test. We also performed scanning electron microscopy (SEM) on dentin disks from some of these groups before and after adhesive application to evaluate their microscopic morphological appearance. Statistical analysis (Dunnett T3 test coupled with the general linear model at 5% significance level) revealed that the laser preparation of dentin did not impact on TBS (p = 0.914), whereas pretreatment with either phosphoric acid (p < 0.0001) or low-fluence Er:YAG laser irradiation (p < 0.0001) significantly increased TBS, although there was no difference between them in their respective elevation of TBS. SEM analysis demonstrated that both acid and laser pretreatments reduced irregularities and produced a more homogeneous surface. Er:YAG laser preparation does not compromise the efficacy of one-step self-etch dentin adhesives, and pretreatment with phosphoric acid or low-fluence Er:YAG laser can significantly increase the TBS of adhesion to this irradiated dentin.


Metabolic alterations in genetically selected Drosophila strains with different longevities.
Sometime ago we obtained biomarker data suggesting that the earliest determining event in the expression of the extended longevity phenotype in our selected strains of Drosophila took place early in adult life at about 5-7 days of age. In a later series of experiments we documented that our La and Lb long lived strains underwent a specific up-regulation of the antioxidant defense system (ADS) genes and enzymes. This led to a reduction in oxidative damage and an extended longevity. In the current work, we assayed the activity of 17 metabolically important enzymes in 5-7 day old flies of 13 strains variously selected for different longevities. We conclude that the two sets of replicated long-lived strains have an altered metabolic pattern (relative to normal-lived animals) which is consistent with an increased flux through the pentose shunt and an enhanced NADP+ reducing system to support the increased activity of the ADS enzymes. This result can be interpreted as a shift of energy expenditure from reproduction to somatic maintenance. We conclude that theories based on differential energy allocations appear to empirically explain, at least in part, the mechanisms underlying the transformation of a normal longevity phenotype to an extended longevity phenotype.


Correlation between anatomical parameters of intertubercular sulcus and retroversion angle of humeral head.
To obtain anatomical data on intertubercular sulcus of humerus, evaluate the correlation between intertubercular sulcus and retroversion angle of humeral head, to guide the positioning of torsion angle of prosthesis during total shoulder arthroplasty and provide references for shoulder prosthesis design. Using a Siemens Ultrahigh speed 64- rows multi-slices spiral CT scanner and 20 dried adult humeral specimens (intact specimen, no fractures or pathological damage), of these, left lateral in 10 cases, right lateral in 10 cases, male or female all inclusive, specimens are all provided by Anatomy Department of Weifang Medical College, scan ranged from the highest point of humeral head to the distal ends of trochlea. And scanned data were subjected to statistical analysis. There is a linear correlation between the distance from intertubercular sulcus to central axis line of humeral head, position angle of intertubercular sulcus and retroversion angle of humeral head at the beginning slice of intertubercular sulcus. There is a linear correlation between position angle of intertubercular sulcus and retroversion angle of humeral head at the slice of surgical neck. There is a linear correlation between position of intertubercular sulcus and retroversion angle of humeral head, in total shoulder arthroplasty, using intertubercular sulcus as anatomical landmark will help to accurately position torsion angle of individualized prosthesis. Position angle of intertubercular sulcus is an objective, flexible positioning indicator.


Efficacy of Chemotherapy in Survival of Stage I Nasopharyngeal Carcinoma.
To identify whether chemoradiotherapy improves survival of stage I nasopharyngeal carcinoma (NPC). NPC patients were extracted from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. Pathologically confirmed stage T1N0M0 (the 7th edition AJCC) were investigated. Overall survival (OS) and cancer-specific survival (CSS) were compared between the radiotherapy and chemoradiotherapy groups using the Kaplan-Meier method and propensity score matching (PSM) analyses. This study included 91 (40.27%) patients in the chemoradiotherapy group and 135 (59.73%) patients in the radiotherapy group. Before PSM, chemoradiotherapy was associated with worse 3-year OS (74.31 vs 87.23%; P = 0.025) and 5-year OS (64.28 vs 83.12%; P = 0.001) compared to those associated with radiotherapy. Similarly, chemoradiotherapy showed worse 3-year CSS (87.01 vs 96.97%; P = 0.028) and 5-year CSS (80.39 vs. 96.97%; P = 0.002) than those of radiotherapy. After PSM, chemoradiotherapy revealed worse 5-year OS (63.10 vs. 82.49%; P = 0.031) and CSS (80.95 vs. 93.70%; P = 0.016) than radiotherapy. The multivariate regression analysis revealed that chemoradiotherapy was an independent risk prognostic factor for OS and CSS before and after PSM. Radiotherapy alone is recommended for stage I NPC patients.


IL-8-mediated overexpression of ZNF274 promotes the proliferation and migration of colorectal cancer cells through the transactivation of MRPL40.
Colorectal cancer (CRC) is one of the most prevalent malignant tumors with high morbidity and mortality rates worldwide. ZNF274, a member of the zinc-finger-protein family of transcription factors, is critical in chromosomal remodelling and tumorigenesis. However, the role of ZNF274 in CRC and the underlying molecular mechanisms remain unclear. Immunohistochemical analysis was performed to quantify the expression of ZNF274 in human CRC tissues. The Kaplan‒Meier method was used to analyse the relationship between ZNF274 expression and CRC prognosis. The correlation between ZNF274 expression and clinical features was analyzed using Cox regression analysis. Cell proliferation and migration were evaluated by CCK-8, colony formation, and Transwell assays. The limma R package was used to analyse IL-8-related differentially expressed genes in the GSE30364 dataset. The DAVID method was used to screen significantly enriched pathways. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were performed to determine the transcriptional regulation of MRPL40 by ZNF274. ZNF274 was overexpressed in CRC tissues and indicated poor prognosis. High ZNF274 expression was linked to larger tumor size, invasion, lymph node metastasis, and AJCC stage. Ectopic expression promoted CRC cell proliferation and migration. Mechanistically, MRPL40 was identified as the direct target gene that transactivates the expression of ZNF274. Moreover, IL-8 upregulated ZNF274 expression in a dose-dependent manner. Downregulation of either ZNF274 or MRPL40 expression abrogated the effect of IL-8 on promoting the proliferation and migration of CRC. This study revealed an oncogenic role of ZNF274 and the mechanism by which ZNF274 participated in IL-8-induced promotion of CRC progression. These findings demonstrate that ZNF274 could be used as a prognostic factor and potential therapeutic target for CRC treatment.


Efficacy of dual-task training on stability and function in children with ataxia after medulloblastoma resection: A randomized controlled trial.
In children, medulloblastoma (MB) is the most prevalent posterior fossa tumor. The first line of treatment is maximal safe resection. Therefore, symptoms of ataxia are commonly seen. Training the brain on balance and cognitive tasks makes balance more automatic than without cognitive tasks. The goal was to assess the effectiveness of dual-task practice on balance after MB excision in children with ataxia. Thirty children with ataxia after MB resection at Children Cancer Hospital Egypt were randomized into two equal groups. Exercises for mobility, balance, and gait training were given to both groups. The research group underwent a specific dual-task program (balance and cognitive). The program ran 3 days per week for 8 weeks. Children were evaluated before and after the treatment regimen using the Scale of Assessment and Rating of Ataxia (SARA), the HUMAC Balance System, Pediatric Balance Scale, and Functional Independent Measurement. All children's legal guardians signed an ethical agreement. A notable improvement in balance was found in the dual group in Pediatric Balance Scale (PBS) (p = .028) and stability test (p = .0001) in favor of the study group. No discernible difference was observed in the Functional Independent Measurement score among the two groups (p = .158), although there was a statistically significant increase in both groups after treatment. Dual-task program is more effective than traditional physical therapy alone in improving balance in children with ataxia after MB resection.


Correction to: Weight changes associated with antiepileptic mood stabilizers in the treatment of bipolar disorder.
In the original version of this article unfortunately two tables have been missing. By mistake they have been published as Supplementary Material. We apologize for any inconvenience caused. The original article has been corrected.


Glutamine protects intestinal immunity through microbial metabolites rather than microbiota.
Glutamine has anti-inflammatory properties as well as the ability to maintain the integrity of the intestinal barrier. In our previous study, we found that 1.0% glutamine promoted SIgA (secretory immunoglobulin A) synthesis in the gut via both T cell-dependent and non-dependent processes, as well as via the intestinal microbiota. The purpose of this study was to investigate whether the intestinal microbiota or microbial metabolites regulate SIgA synthesis. In the mouse model, supplementation with 1.0% glutamine had no significant effect on the intestinal microbiota, but KEGG function prediction showed the difference on microbiota metabolites. Therefore, in this study, untargeted metabolomics techniques were used to detect and analyze the metabolic changes of glutamine in intestinal luminal contents. Metabolomics showed that in the positive ion (POS) mode, a total of 1446 metabolic differentials (VIP ≥ 1, P < 0.05, FC ≥ 2 or FC ≤ 0.5) were annotated in samples treated with glutamine-supplemented group compared to control group, of which 922 were up-regulated and 524 down-regulated. In the negative ion (NEG) mode, 370 differential metabolites (VIP ≥ 1, P < 0.05, FC ≥ 2 or FC ≤ 0.5) were screened, of which 220 were up-regulated and 150 down-regulated. These differential metabolites mainly include bile secretion synthesis, ABC transporters, diterpenoids and other secondary metabolites. KEGG analysis showed that propionic acid metabolism, TCA cycle, endoplasmic reticulum protein processing, nitrogen metabolism and other metabolic pathways were active. The above metabolic pathways and differential metabolites have positive effects on intestinal development and intestinal immunity, and combined with our previous studies, we conclude that glutamine supplementation can may maintain intestinal homeostasis and improving intestinal immunity through intestinal microbial metabolites.


Challenges in Cardiovascular Imaging in Women with Breast Cancer.
Cardiovascular imaging in breast cancer patients is paramount for the surveillance of cancer therapy-related cardiac dysfunction (CTRCD); however, it comes with specific limitations. PURPOSE OF REVIEW: This review aims to describe the unique challenges faced in cardiovascular imaging of breast cancer patients, discuss evidence to support the utility of various imaging modalities, and provide solutions for improvement in imaging this unique population. RECENT FINDINGS: Updated clinical society guidelines have introduced more unifying surveillance of CTRCD, although there remains a lack of a universally accepted definition. Traditional and novel multi-modality imaging can be used to detect CTRCD and myocarditis in breast cancer patients. Cardiovascular imaging in breast cancer patients is difficult due to reconstructive surgery. Although echocardiography with myocardial strain is the cornerstone, multi-modality imaging can be used to evaluate for CTRCD and myocarditis. Novel imaging techniques to improve the diagnosis of cardiotoxicities in breast cancer patients are needed.


Clinical parameters predictive of outcomes in sorafenib-treated patients with advanced hepatocellular carcinoma.
Sorafenib is an orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, clinical parameters that may predict the treatment outcomes in sorafenib-treated advanced HCC patients remains unknown. A total of 99 advanced (BCLC C) HCC patients treated with sorafenib as an initial treatment modality from January 2007 to December 2011 were retrospectively reviewed. Overall survival was the primary endpoint for the analysis. Various clinical parameters including tumour stage and adverse effects to sorafenib were analysed. Univariate and multivariate analysis were carried out to identify clinical parameters predictive of the effect of sorafenib. There were 86 males and 13 females included in this study, with a median age of 53 years. The median overall survival was 91 days. Sixty-nine patients had Child-Pugh class A cirrhosis and 30 patients had Child-Pugh class B cirrhosis. Hepatitis B virus was the predominant cause of HCC (75.8%). Noted adverse effects were hand-foot syndrome, diarrhoea, fatigue, abdominal pain, nausea and stomatitis. The presence of hand-foot syndrome and diarrhoea and the absence of portal vein thrombosis and lymph node metastasis predicted a better overall survival in the multivariate analysis. Excluding the absence of lymph node metastasis, the same parameters were associated with a longer radiological time to progression. Advanced HCC patients treated with sorafenib who experienced hand-foot syndrome and diarrhoea showed better overall survival than patients without these side effects. These side effects may be used as clinical parameters predictive of sorafenib response in patients with HCC.


PROTEFLAZID®: clinical studies as evidence base of its antiviral activity.
The article contains the results of many years of clinical studies of efficiency and safety of the preparation Proteflazid®, obtained from the wild cereals Deschampsia caespitosa L. and Calamagrotis epigeios L. Proteflazid® has direct antiviral and anti-relapsing effects in various disease of viral etiology, registered in more than 230 clinical studies.


Definition of T-cell specific DNA-binding factors that interact with a 3'-silencer in the CD4+ T-cell gene Rpt-1.
Analysis of the region 3' to the CD4+ T-cell gene Rpt-1 (encoding regulatory protein T-lymphocyte 1) led to the definition of a silencer element that inhibits heterologous gene expression in certain CD4+ T-cell lines but not in B-cell or non-lymphoid cell lines. Functional silencer activity in vivo was associated with the presence of a specific silencer-DNA-protein complex in electrophoretic mobility shift assays with T-cell extracts. Formation of this complex was selectively inhibited by the region in HIV-1 containing a silencer element. We discuss the possibility that DNA-binding factors may coregulate HIV-1 and Rpt-1 gene expression through a common transcriptional silencer element.


Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies.
The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic diseases that include the familiar disease entities of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients has unique autoantibodies which are specific for IIM (myositis specific autoantibodies; MSAs). We studied the clinical and serological characteristics of IIM in 125 Dutch patients. Sera were analysed by immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation. The most frequently encountered MSA was the anti-Jo-1 autoantibody (20%), followed by anti-tRNAHis (6%), anti-Mi-2 (6%), and anti-SRP (4%). The presence of certain MSAs was clearly associated with specific clinical characteristics. Anti-Jo-1 and anti-tRNAHis were associated with the anti-synthetase syndrome, anti-SRP with PM with severe myalgia and arthralgia and a moderate response to immunosuppressive treatment. A novel finding was the presence of anti-Mi-2, not only in DM, but also in PM. MSAs were frequently present in DM/PM sera, but were hardly ever detected in the sera of IBM patients. The few IBM patients with MSAs demonstrated a significant response to immunosuppressive treatment. It can be concluded that MSAs define specific clinical syndromes within the spectrum of IIM and that they can assist in the differential diagnosis and treatment plan of these enigmatic disorders by virtually excluding IBM by their presence, and by potentially identifying a subgroup of steroid-responsive IBM patients.


Poly(ADP-ribose) Polymerase-1 is required for hepatocyte proliferation and liver regeneration in mice.
Liver regeneration is an orchestrated cellular response and the mechanisms underlying it have been extensively studied using the partial hepatectomy (PHx) model. Poly(ADP-Ribose) Polymerase-1 (PARP1) is a common enzyme for post-translational modification of proteins. Here, we aimed to determine the role of PARP1 in liver regeneration. We found that PARP1 activity was strongly associated with hepatocyte proliferation after PHx. PARP1 knockout mice showed impaired liver recovery and suppressed hepatocyte proliferation after PHx. Mechanistically, PARP1 knockout repressed YAP activity and inhibited expression of cell cycle-associated proteins in liver tissues. Therefore, our findings highlight specialized roles for PARP1 in regulating hepatocytes proliferation and liver regeneration.


Inositol-phosphate-induced enhancement of natural killer cell activity correlates with tumor suppression.
In recent studies, we have demonstrated that inositol hexaphosphate (InsP6) inhibits experimental colon carcinogenesis. Since natural killer (NK) cells are involved in tumor cell destruction, we investigated the effect of InsP6 on murine NK cell activity. We show that; (i) 1,2-dimethylhydrazine (DMH), a colon carcinogen, depresses NK activity; (ii) in vivo treatment of mice with InsP6 enhances baseline NK activity and reverses DMH-induced depressed NK activity with an inverse correlation (r = -0.9811) with tumor incidence, (iii) short-term in vitro treatment of spleen cells and NK-enriched fraction with InsP6 also enhances NK cytotoxicity in a dose-dependent manner, (iv) inositol potentiates the action of InsP6. Our data suggest yet another important role of inositol phosphates in the regulation of cellular activity.


Hypergravity speeds up the development of T-lymphocyte motility.
The effect of altered gravity on single cells has been reported in a number of studies. From the investigation of the immune system response to spaceflight conditions, interest has focused on the influence of gravity on single lymphocytes. Microgravity has been shown to decrease lymphocyte activation and to influence motility. On the other hand, the effect of hypergravity on lymphocyte motility has not been explored. We studied the migration of human peripheral blood T lymphocytes cultured in vitro in a hypergravity environment (10g). After hypergravity culture for 1-11 days, T cells were seeded on a fibronectin-coated glass surface, observed by time-lapse bright-field microscopy, and tracked by a computer program. We found that T cells, activated and then cultured in hypergravity, become motile earlier than cells cultured at normal gravity. These results suggest that hypergravity stimulates T cell migration.