Effect of antithyroid antibodies on ICSI outcome in antiphospholipid antibody-negative euthyroid women.
Antithyroid antibodies (ATA) are found in 5-15% of women at reproductive age and are not necessarily accompanied with thyroid dysfunction. ATA are associated with adverse effects such as spontaneous miscarriage, recurrent miscarriages, preterm delivery and maternal post-partum thyroiditis in women with normal thyroid hormone concentrations. The role of ATA on the outcome of IVF cycles remains to be investigated. This study evaluated the impact of ATA on the outcome of intracytoplasmic sperm injection (ICSI)-embryo transfer cycles in euthyroid women. A total of 253 women undergoing ICSI-embryo transfer cycles were prospectively enrolled in this study. Women positive for at least one of the thyroid antibodies, with normal thyroid-stimulating hormone (TSH) and free T4 concentrations and negative for anticardiolipin antibodies and lupus anticoagulant were included. ICSI was performed for fertilization in all cycles. Of 253 women, 219 were ATA negative and 34 ATA positive. Implantation rates (19.1% versus 18.4%), miscarriage rates (9.0% versus 8.3%) and ongoing pregnancy rates (37.0% versus 32.4%) did not differ significantly between the ATA-positive group and the ATA-negative group, respectively. The presence of antithyroid antibodies in euthyroid and antiphospholipid antibody-negative women was not found to significantly affect the outcome of ICSI-embryo transfer cycles. Antithyroid antibodies (ATA) can interact with thyroid hormone receptors located on the human oocyte and impair the chance of fertilization and healthy pregnancy. They are found in 5-15% of women at reproductive age and are not necessarily accompanied with thyroid dysfunction. ATA have been reported to be associated with adverse effects such as spontaneous miscarriage, recurrent miscarriages, preterm delivery and maternal post-partum thyroiditis in women with normal thyroid hormone concentrations. The role of ATA on the outcome of IVF cycles remains to be investigated. The objective of our study was to evaluate the impact of ATA on the outcome of intracytoplasmic sperm injection (ICSI)-embryo transfer cycles in euthyroid women. A total of 253 women undergoing ICSI-embryo transfer cycles were prospectively enrolled in this study. Women with at least one of the thyroid antibodies positive and normal TSH and free T4 concentrations were included in the study. Since other immunological disorders might affect the results, antiphospholipid antibodies (APA), which are the markers of antiphospholipid antibody syndrome, were also screened in all women prior to study. Women with positive for APA were excluded in the final analysis. Of 253 women, 219 (86.6%) were ATA negative and 34 (13.4%) ATA positive. Implantation rates (19.1% versus 18.4%), biochemical pregnancy rates (9.2% versus 14.3%), miscarriage rates (9.0% versus 8.3%) and ongoing pregnancy rates (37.0% versus 32.4%) did not differ significantly between the ATA-positive group and the ATA-negative group, respectively. In conclusion, presence of antithyroid antibodies in euthyroid and antiphospholipid antibody-negative women does not affect the outcome of ICSI-embryo transfer cycles.


Critically injured patients, inaccessible airways, and laryngeal mask airways.
Managing the airway of a critically injured trauma patient in the prehospital environment is challenging, especially when access to the patient's airway is limited as is often the case in vehicle entrapment incidents. This paper reports the use of the laryngeal mask airway as an adjunct to airway management when attempts using simple airway management techniques have failed to provide adequate oxygenation and ventilation and limited access to the patient precluded endotracheal intubation.


Genetic defects in hepatobiliary transport.
Bile formation, the exocrine function of the liver, represents a process that is unique to the hepatocyte as a polarized epithelial cell. The generation of bile flow is an osmotic process and largely depends on solute secretion by primary active transporters in the apical membrane of the hepatocyte. In recent years an impressive progress has been made in the discovery of these proteins, most of which belong to the family of ABC transporters. The number of identified ABC transporter genes has been exponentially increasing and the mammalian subfamily now counts at least 52. This development has been of crucial importance for the elucidation of the mechanism of bile formation, and it is therefore not surprising that the development in this field has run in parallel with the discovery of the ABC genes. With the identification of these transporter genes, the background of a number of inherited diseases, which are caused by mutations in these solute pumps, has now been elucidated. We now know that at least six primary active transporters are involved in canalicular secretion of biliary components (MDR1, MDR3, BSEP, MRP2, BCRP and FIC1). Four of these transporter genes are associated with inherited diseases. In this minireview we will shortly describe our present understanding of bile formation and the associated inherited defects.


Small business support of youth physical activity opportunities.
Describe small business support for youth physical activity opportunities (YPAO) and identify factors associated with this support. Cross-sectional analysis of quantitative data relating business characteristics and support for YPAO. Eight demographically heterogeneous, urban neighborhoods in a Midwest metropolitan area. Adult small business owners (n = 90; 65% response rate; mean age 48.4 years; 73.3% male; 45.2% minority). Neighborhood demographics from the 2000 U.S. Census and self-reported business and owner characteristics. Multivariate analysis of variance was used to contrast business and owner characteristics between businesses that did and did not support YPAO. Businesses supporting YPAO had larger annual operating (F = 7.6; p = .018) and advertising budgets (F = 8.5; p = .009) and had younger owners (F = 6.1; p = .034), with sports backgrounds (χ(2) = 5.6; p = .018) and who felt businesses should support YPAO (χ(2) = 3.8; p = .048). Of the 46 businesses not supporting YPAO, 82.6% felt small businesses should support YPAO. The major reasons for nonsupport were difficulty identifying YPAO to support and not being asked for support. Business (e.g., budgets) and business owner characteristics (e.g., age), owner connectedness with YPAO, and the approach used for garnering support (active solicitation, clearly defined support mechanism) were associated with supporting YPAO. Additional business (e.g., annual revenues), owner (e.g., perceptions of YPAO), and environmental (e.g., crime rate, land use) factors should be examined as potential correlates.


Supranodose vagotomy eliminates anandamide-evoked cardiorespiratory depression in anaesthetized rats.
Respiratory effects of an intravenous injection of anandamide were investigated in 19 urethane-chloralose anaesthetised and spontaneously breathing rats. In 10 neurally intact rats the effects of anandamide were checked to establish appropriate dose of the drug. In the second group, nine rats were challenged with anandamide while intact, following bilateral midcervical vagotomy and after subsequent supranodose vagotomy. Bolus injection of 1 mg kg(-1) of anandamide into the right femoral vein pre- and post-midcervical vagotomy induced in all nine rats prompt apnoea of similar duration: 2.97 +/- 0.5 and 3.2 +/- 0.4s, respectively. In post-apnoeic breaths tidal volume decreased below the control level by 25% (P < 0.01) prior to and by 43.4% (P < 0.001) after midcervical vagotomy. Supranodose vagotomy precluded the respiratory response to anandamide. Anandamide-induced decrease in mean arterial blood pressure in nerve-intact and vagotomised rats was abolished by supranodose vagotomy. Results indicate that the cardio-respiratory depression evoked by anandamide administered via the peripheral circulation requires intact supranodose vagi.


Activation of human CD8-positive T cells via the CD8/HLA class I complex.
Cross-linking of CD8 and HLA class I molecules with appropriate monoclonal antibodies (mAb) and goat anti-mouse Ig (GaMIg) antibody resulted in a marked proliferation of resting human CD8 cells in the presence of interleukin-2 (IL-2). These cells also expressed IL-2 receptor (IL-2R), transferrin receptor, HLA-DR and -DQ antigens. Activation of the cross-linked CD8 cells is apparently independent of accessory monocytes. Various anti-CD8 and anti-HLA class I mAb recognizing nonpolymorphic antigenic determinants were examined for the efficacy of activating CD8 cells. Among mAb specific for HLA class I molecules, PA2.6, MB40.5, BB7.7, A1.4, and W6/32 mAb markedly stimulated the proliferation of cross-linked CD8 cells, whereas BBM.1, Q1/28, and HC10 mAb were found inactive. Footprinting analysis of HLA class I molecules suggested that the activity of these anti-HLA class I mAb appeared to be related to the corresponding peptides they protect from enzymatic digestion. In contrast to the anti-HLA class I mAb, all anti-CD8 mAb examined (C8, OKT8A, and anti-Leu-2a) induced the proliferation of CD8-HLA class I cross-linked cells with similar efficacy. These results suggest that physical interaction between CD8 and at least one specific region of HLA class I molecules can trigger the activation of resting human CD8 cells.


Handedness and cerebral anatomical asymmetries in young adult males.
Using voxel-based morphometry, we measured the cerebral anatomical asymmetries in a sample of 56 young right-handed males and then compared voxelwise asymmetry indices of these subjects to those of 56 young left-handed males. In the right-handed, the clusters of grey matter asymmetry corresponding to the leftward occipital petalia and planum temporale asymmetries were retrieved. Strong rightward temporo-parietal asymmetries were also observed, but the rightward grey matter asymmetry in the frontal lobe was less massive than previously described. Group comparisons of left- and right-handed subjects' asymmetry maps, performed at a statistical threshold not corrected for multiple comparisons, revealed significant effects of handedness on this pattern of anatomical asymmetry in frontal regions, notably in the lower central and precentral sulci, and also in the planum temporale, with right-handed subjects being more leftward asymmetric. Concerning white matter, although almost no focal differences between left- and right-handed subjects were detected, volumetric analyses at the hemispheric level revealed a leftward asymmetry, which happened to be significantly less marked in the left-handed. This latter result, together with the pattern of leftward white matter asymmetries, suggested that anatomical correlates of the left hemispheric specialization for language would exist in white matter. In the population we studied, differences in anatomical asymmetry between left- and right-handed subjects provided structural arguments for a greater functional ambilaterality in left-handed subjects.


Avoidance and brightness discrimination conditioning in genetically different lines of rats.
Rats from an albino stock were selected for high (HAS) and low (LAS) avoidance scores measured in a shuttle-box. Learning performance of male rats was compared in three different tests: the shuttle-box, the pole jumping-box, and the Y-chamber. It was shown that rats of the HAS line more rapidly acquired conditioned avoidance in the shuttle-box experiment and the pole-jumping experiment than LAS, whereas we could not detect any significant differences in brightness discrimination. In the open field test rats of the HAS line were more active in comparison to LAS's, measured in terms of higher ambulation scores. In conclusion, it is verified that the shuttle-box performance as well as pole-jumping performance is highly determined by the emotional status of the animals and, moreover, that avoidance learning is based on mechanisms other than brightness discrimination learning.


Isolated left ventricular ischemia after the Norwood procedure.
Aortic atresia is the most severe variant of hypoplastic left heart syndrome (HLHS), and has been associated with significant mortality after stage I palliation. Coronary artery abnormalities are more prominent in this group of patients, especially in the presence of a patent mitral valve. Herein, we describe a case of isolated left ventricular ischemia after the Norwood procedure in a neonate with hypoplastic left heart syndrome, left ventricular hypertrophy, mitral stenosis, aortic atresia, and anomalous left coronary artery.


Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI 187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety, Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14 Days.
To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with the selective 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in male and female patients with type 2 diabetes and overweight or obesity. Randomized, double-blind, parallel-group, placebo-controlled multiple rising dose study, with 10-360 mg BI 187004 once daily over 14 days in 71 patients. Assessments included 11beta-HSD1 inhibition in the liver and subcutaneous adipose tissue ex vivo (clinical trial registry number NCT01874483). BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 51.8% (n=29) for BI 187004 and 35.7% (n=5) for placebo. There were no clinically relevant deviations in laboratory or electrocardiogram parameters besides one patient on 360 mg discontinuing treatment due to moderate supraventricular tachycardia.BI 187004 was rapidly absorbed within 2 h; exposure increased non-proportionally. The oral clearance was low, apparent volume of distribution was moderate to large, and terminal half-life with 106-124 h was rather long. Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies was 87.9-99.4% immediately after the second dose and 73.8-97.5% 24 h after the last dose of BI 187004. BI 187004 was safe and well tolerated over 14 days and could be dosed once daily. Targeted 11beta-HSD1 enzyme inhibition of≥80% could be shown for BI 187004 doses≥40 mg. This dose should be targeted in further studies to test blood glucose lowering in patients with type 2 diabetes and overweight or obesity.


Regulation of neurite growth in purified retina neuronal cultures: effects of PNPF, a substratum-bound, neurite-promoting factor.
The responses of chick embryo retina neurons to the substratum-bound, neurite-promoting factor "PNPF" were studied using glia-free, purified neuronal monolayers. Polyornithine-coated dishes were exposed before cell seeding to either serum-containing culture medium (PNPF(-) substratum) or to the same medium supplemented with 25% rat schwannoma conditioned medium, a source of PNPF (PNPF(+) substratum). The dishes were thoroughly rinsed before receiving a suspension of 8 day chick embryo neural retina cells in serum-free medium. The presence of PNPF on the substratum determined a dramatic increase in the relative frequency of neurite-bearing cells in the cultures. After 6 hours in vitro PNPF(+) cultures contained 45% neurite-bearing cells as compared with 5-7% on PNPN(-) substrata. At 72 hours those values increased to 60% on PNPF(+) and to 40% on PNPF(-) substrata. PNPF(+) cultures also showed longer and/or more highly branched neurites, resulting in the formation of complex neurite networks. Moreover, a cell type characterized by the presence of a very long neurite could be seen on PNPF(+) but not on PNPF(-) substrata. Six hour cultures were used to analyze in more detail the response of retinal neurons to PNPF. Addition of fetal calf serum to the medium determined a concentration-dependent inhibition of neurite formation on PNPF(+) substrata. On the other hand, pretreatment of PNPF(+) substrata with concanavalin A also blocked the neurite-promoting effect of the factor. This concentration-dependent inhibitory effect of concanavalin A could be eliminated by the specific sugar alpha-methyl-D-mannoside. Wheat germ agglutinin, another lectin known to react with PNPF, did not cause any reduction in the neurite-promoting activity of this factor. Wheat germ agglutinin showed neurite-promoting properties of its own in control experiments using PNPF(-) substrata. The results indicate that the target spectrum of PNPF is broader than it was originally thought. Together with other reports from the literature, they also support the perception of neurite development as a cellular activity subject to complex regulatory mechanisms.


Tip Ligament Preservation and Suspension: Why and How?
This issue of Clinics explores the concept of "preservation" rhinoplasty. At present, this topic is gaining considerable attention. As proponents of preservation suggest, a great number of problems we encounter in rhinoplasty are problems that were not present before the surgery; therefore, they can often be attributable to the deconstruction and reconstruction that took place. Preservation rhinoplasty should be viewed generally as a mindset to limit deconstructive steps in rhinoplasty when possible, understanding that these steps and those to later reconstruct provide the potential to create new problems that did not previously exist.


Chronoampermetric detection of enzymatic glucose sensor based on doped polyindole/MWCNT composites modified onto screen-printed carbon electrode as portable sensing device for diabetes.
Doped-polyindole (dPIn) mixed with multi-walled carbon nanotubes (MWCNTs) were coated on a screen-printed electrode to improve the electroactive surface area and current response of the chronoamperometric enzymatic glucose sensor. Glucose oxidase mixed with chitosan (CHI-GOx) was immobilized on the electrode. (3-Aminopropyl) triethoxysilane (APTES) was used as a linker between the CHI-GOx and the dPIn. The current response of the glucose sensor increased with increasing glucose concentration according to a power law relation. The sensitivity of the CHI-GOx/APTES/dPIn was 55.7 μA mM-1 cm-2 with an LOD (limit of detection) of 0.01 mM, where the detectable glucose concentration range was 0.01-50 mM. The sensitivity of the CHI-GOx/APTES/1.5%MWCNT-dPIn was 182.9 μA mM-1 cm-2 with an LOD of 0.01 mM, where the detectable glucose concentration range was 0.01-100 mM. The detectable concentration ranges of glucose well cover the glucose concentrations in urine and blood. The fabricated enzymatic glucose sensors showed high stability during a storage period of four weeks and high selectivity relative to other interferences. Moreover, the sensor was successfully demonstrated as a continuous or step-wise glucose monitoring device. The preparation method employed here was facile and suitable for large quantity production. The glucose sensor fabricated here, consisting of the three-electrode cell of SPCE, were simple to use for glucose detection. Thus, it is promising to use as a prototype for real glucose monitoring for diabetic patients in the future.


Functional analysis of the nucleotide sequence surrounding the cap site for adenovirus type 5 region E1A messenger RNAs.
We have constructed a set of small, dispersed deletion mutations in the sequences surrounding the cap site of the adenovirus type 5 region E1A transcription unit. The effects of the mutations on E1A transcription were studied in vitro using a HeLa cell-free extract, and in vivo by reconstructing the mutations back into intact viral chromosomes and analyzing E1A messenger RNAs synthesized after infection of HeLa cells. The sequence between -35 and +20 (relative to the cap site at +1) was important for efficient E1A transcription and cap site selection in vitro. This region includes the "TATA" homology, which appeared essential for transcription. Sequences upstream of -35 were dispensable for transcription in vitro. Different results were found upon analysis of the same set of deletions in vivo. None of the mutations affected the steady-state levels of cytoplasmic, E1A-specific mRNAs found in infected HeLa cells by more than twofold. Deletions of the TATA homology, however, generated E1A mRNAs with heterogeneous 5' ends, and deletions downstream of the homology displaced the 5' end of mRNAs by about the size of the deletion.


Improved Charge Separation in WO₃/CuWO₄ Composite Photoanodes for Photoelectrochemical Water Oxidation.
Porous tungsten oxide/copper tungstate (WO₃/CuWO₄) composite thin films were fabricated via a facile in situ conversion method, with a polymer templating strategy. Copper nitrate (Cu(NO₃)₂) solution with the copolymer surfactant Pluronic®F-127 (Sigma-Aldrich, St. Louis, MO, USA, generic name, poloxamer 407) was loaded onto WO₃ substrates by programmed dip coating, followed by heat treatment in air at 550 °C. The Cu2+ reacted with the WO₃ substrate to form the CuWO₄ compound. The composite WO₃/CuWO₄ thin films demonstrated improved photoelectrochemical (PEC) performance over WO₃ and CuWO₄ single phase photoanodes. The factors of light absorption and charge separation efficiency of the composite and two single phase films were investigated to understand the reasons for the PEC enhancement of WO₃/CuWO₄ composite thin films. The photocurrent was generated from water splitting as confirmed by hydrogen and oxygen gas evolution, and Faradic efficiency was calculated based on the amount of H₂ produced. This work provides a low-cost and controllable method to prepare WO₃-metal tungstate composite thin films, and also helps to deepen the understanding of charge transfer in WO₃/CuWO₄ heterojunction.


The access box: an ah-ha phenomenon.
Proper access is the basis for all endodontic therapy. This article highlights a teaching tool that powerfully demonstrates to all students and dentists the concept of proper access.


Study on the micromorphology of Mycobacterium leprae.
The micromorphology of Mycobacterium leprae is described. After fixation with osmium tetroxide supplemented with calcium ions, the cell wall was seen to be composed of three layers; the cytoplasmic membrane exhibited the architecture of an elementary membrane. The mesosomes were best visualized after fixation with glutaraldehyde; they were sometimes in contact with the nuclear equivalent. Only one sort of phosphate body was found. The nucleoid was best visualized after fixation with osmium tetroxide.


Laser capture microdissection and mRNA characterization of mouse airway epithelium: methodological considerations.
The use of laser capture microdissection (LCM) to obtain epithelial cells lining the distal airways for gene profiling is described. In the mouse, the distal airways are particularly attractive for LCM as there is very high percentage of a single cell type, Clara cells, lining these airways. It is shown that the RNA from distal airway epithelial cells harvested by LCM is well preserved and that with linear amplification sufficient cRNA for microarray analysis can be attained from small numbers of cells.


Photosynthesis and water-use efficiency in pinyon-juniper communities along an elevation gradient in northern New Mexico.
We investigated plant ecophysiological response to fertilization of selected sites along an elevation gradient in a pinyon-juniper woodland. Plant density and species composition followed typical patterns for pinyon-juniper woodlands over this gradient, with a sparse juniper (Juniperus monosperma (Engelm.) Sarg.)-grassland community at the lowest elevation and gradually increasing total canopy cover and pinyon (Pinus edulis Engelm.) cover with elevation. Carbon isotope analysis showed that both tree species had higher water-use efficiency (WUE) at the lowest, and presumably driest, sites. Over most of the gradient, however, it appeared that changes in stand density compensated for changes in water availability. Contrary to initial hypotheses, the more drought-tolerant juniper did not demonstrate significantly greater WUE than pinyon, although it maintained positive carbon gain at lower predawn xylem pressure potentials than pinyon. In pinyon, both A max and WUE increased with increasing N concentration in tissues. Pinyon needles also demonstrated declining nitrogen-use efficiency with age. There was no relationship between tissue N and either A max or WUE measured at A max in juniper, although δ13C analysis indicated that WUE increased in juniper with increased N availability. Results from this study suggest that plasticity in plant physiological processes could result in nonlinear responses of organic matter production to climate change, and therefore must be accounted for in ecosystem models.


Regression rate of metastatic neck lymph nodes after radiation treatment as a prognostic factor for local control.
This study was carried out to assess whether the regression rate of neck node metastases after radiotherapy could be a prognostic factor for local control. Measurements of 283 neck nodes were made before and at completion of treatment and at intervals during 3 years follow-up. The results indicate that complete regression at the end of treatment correlates strongly with local control. A false negative rate of 0.1 was calculated. Partial regression seems to be a prognostic factor for failure in lymph nodes because of a true positive rate of 0.8. The results suggest that accurate measurements of the response of neck lymph nodes could give early prognostic information, useful for the choice of optimal treatment.


Digital competence: What makes nurses a 'big gun' in the future health industry.
This letter aims to respond to the editorial's viewpoint by Aungsuroch, Y. and Gunawan, J. related to nurses' preparation in the industrial revolution 4.0. Without a doubt, the era of disruption creates massive changes in many sectors, including in the health industry, and nurses are demanded to adopt and adapt to the rapid development of information technology. Therefore, digital competence is highly emphasized as an essential skill for today's nurse generation in order to be the "big gun" of tomorrow.


Comparison of nutritional properties and bioactive compounds between industrial and artisan fresh tortillas from maize landraces.
Consumers are seeking for native-traditional foods to improve their intake of both nutrients and health-promoting phytochemicals. This study was designed to evaluate the difference in content of nutrients and bioactive compounds from handmade tortillas elaborated by a small-scale artisan producer and tortillas sold by a large food retailer available to consumers. All tortillas were analyzed for chemical composition, dietary fiber, calcium and phytochemical content, antioxidant capacity, and phenolic acids profile. Chemical and nutritional variation in the tortillas was estimated using principal component analysis. Data showed that artisan tortillas made from blue and white maize landraces had significantly (p < 0.05) higher content of nutritional and bioactive compounds compared to those of the supermarket. Handmade blue maize tortillas (HBMT) had a high content of free phenolics content and the highest antioxidant capacity (DPPH and ABTS methods), which was around 1.7-2.1 fold higher than that of commercially produced white maize tortillas (CWMT). Total dietary fiber was higher in HBMT (15.7 ± 1.06 g/100 g) than in CWMT (11.6 ± 0.96 g/100 g). CWMT had the lowest calcium content (42.1 ± 0.9 mg/100 g) compared to handmade tortillas (155.5 ± 4.5 mg/100 g). HPLC results indicated the presence of ferulic, p-coumaric, caffeic, syringic and 4-hydroxybenzoic acids. Interestingly, handmade tortillas from blue maize had 4.5-fold ferulic acid content compared with commercially produced white maize tortillas, consequently it can be a good source of phenolic antioxidants, particularly ferulic acid. This study showed that artisan fresh tortillas had superior nutritional-nutraceutical properties compared to CWMT.


Nurse-Led Rounds in the Pediatric Intensive Care Unit.
Pediatric intensive care units (PICUs) rely on interprofessional communication and collaboration to mitigate the risk for medical error. To operationalize these tenets, many PICUs use multidisciplinary bedside rounds as the foundation of their workflow. Bedside nurse participation in rounds is inconsistent, diminishing the return on team investment in patient safety. Given this dilemma, some institutions have shifted from provider-led to nurse-led rounds. Here, the authors explore the rationale, experiences, and outcomes of implementation of nurse-led rounds within 4 PICU service lines.


A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast, and trunk.
Since 1977, 31 patients were entered in a randomized, prospective study testing the efficacy of adjuvant chemotherapy after aggressive local treatment of high-grade sarcomas of the head, neck, breast, and trunk (excluding retroperitoneal sarcomas). All patients had complete resection of gross tumor and underwent postoperative radiotherapy (6000-6300 rads over 7-8 weeks). Seventeen patients received adjuvant chemotherapy consisting of doxorubicin (less than or equal to 550 mg/m2), cyclophosphamide (less than or equal to 5500 mg/m2), and methotrexate (less than or equal to 1000 mg/kg). Three-year actuarial disease-free survival in the chemotherapy arm was 77%, compared to 49% in the no-chemotherapy arm (P = 0.075). Three-year overall actuarial survivals in the two treatment arms, however, were 68% and 58%, respectively (P = 0.38). Considering only patients with tumors of the trunk (22 patients), 3-year actuarial disease-free survival in the chemotherapy arm was 92%, compared to 47% in the no-chemotherapy arm (P = 0.006). Actuarial 3-year overall survival in the chemotherapy arm was 82%, compared to 61% in the no-chemotherapy arm (P = 0.18). An additional 26 patients were treated in an identical fashion, but were not part of the randomized trial because of contraindications to chemotherapy, refusal to enter the randomized trial, or because they were treated before 1977 in a trial in which all patients received chemotherapy. Considering the entire group of 57 patients, follow-up ranged from 10 to 86 months (median, 35 months). Local control was achieved in 46 patients (81%); 3-year actuarial disease-free and overall survivals were 67% and 77%, respectively. A tendency toward improved disease-free survival was apparent among patients treated with chemotherapy (P = 0.018), but there was no statistically significant improvement in overall actuarial survival (P = 0.46). The subgroup of patients with sarcomas of the trunk (39 patients) demonstrated the greatest benefit from chemotherapy, with regard to disease-free survival (P less than or equal to 0.001). The most significant toxicity associated with chemotherapy was doxorubicin-induced cardiomyopathy, which resulted in clinically apparent congestive heart failure in five patients. Thus, the use of chemotherapy when combined with aggressive local measures appears to improve disease-free survival, but additional patients and longer follow-up are necessary to determine if improved overall survival will result.


Passive transmission of ischemic ST segment changes in low electrical resistance myocardial infarct scar in the pig.
To analyze the passive electrical properties of a healed infarction and assess their role on transmission of contiguous ischemic ST segment potential changes. We measured tissue resistivity (omega cm) at 1 kHz and the epicardial ST segment during 1 h of proximal reocclusion of the left anterior descending (LAD) coronary artery in 12 anesthetized pigs with one-month-old transmural infarction elicited by LAD ligature below the first branch. The impedance spectrum (1 to 1000 kHz) of normal and infarcted myocardium was measured in seven other pigs with similar infarctions. Electrical transmission of current pulses (30 microA) in infarcted tissue and in test solutions was also investigated. The infarct scar has a lower than normal resistivity (110 +/- 30 omega cm vs. 235 +/- 60 omega cm, p < 0.0001) and, unlike the normal myocardium, resistivity and phase angle of the scar did not change at increasing current frequencies, reflecting no capacitative response. LAD reocclusion induced a resistivity rise (510 +/- 135 omega cm, p < 0.01) and a ST segment elevation (0.6 +/- 0.7 to 9.5 +/- 5.1 mV, p = 0.002) in the ischemic peri-infarction zone, whereas the infarcted area showed ST segment elevation (0.5 +/- 0.5 to 3.8 +/- 2.6 mV, p = 0.03) with no resistivity changes. Potential decay of both ST segment and current pulses in the scar and in 0.9% NaCl solution was less than 1 mV/mm. Transmural deposition of connective tissue was seen in the center of the infarction. A one-month-old transmural infarction is a low resistance, noncapacitative medium that allows a good transmission of current pulses and of ST segment potential changes generated by contiguous peri-infarction ischemia.


Association of different central venous pressure levels with outcome of living-donor liver transplantation in children under 12 years.
Pediatric liver transplantation is an important modality for treating biliary atresia. The overall survival (OS) rate of pediatric liver transplantation has significantly improved compared with that of 20 years ago, but it is still unsatisfactory. The anesthesia strategy of maintaining low central venous pressure (CVP) has shown a positive effect on prognosis in adult liver transplantation. However, this relationship remains unclear in pediatric liver transplantation. Thus, this study was conducted to review the data of pediatric living-donor liver transplantation to analyze the associations of different CVP levels with the prognosis of recipients. This was a retrospective study and the patients were divided into two groups according to CVP levels after abdominal closure: low CVP (LCVP) (≤ 10 cmH2O, n = 470) and high CVP (HCVP) (> 10 cmH2O, n = 242). The primary outcome measured in the study was the overall survival rate. The secondary outcomes included the duration of mechanical ventilation in the intensive care unit (ICU), length of stay in the ICU, and postoperative stay in the hospital. Patient demographic and perioperative data were collected and compared between the two groups. Kaplan-Meier curves were constructed to determine the associations of different CVP levels with the survival rate. In the study, 712 patients, including 470 in the LCVP group and 242 in the HCVP group, were enrolled. After propensity score matching, 212 pairs remained in the group. The LCVP group showed a higher overall survival rate than the HCVP group in the Kaplan-Meier curves and multivariate Cox regression analyses (P = 0.018), and the HCVP group had a hazard ratio of 2.445 (95% confidence interval, 1.163-5.140). This study confirmed that a low-CVP level at the end of surgery is associated with improved overall survival and a shorter length of hospital stay.


Randomised, prospective evaluation of a new pericardial heart valve: outcome after seven years.
Between 2 February 1987 and 20 March 1990, 170 patients were randomly allocated to receive a new pericardial heart valve (the Bioflo) or the Carpentier-Edwards supra-annular porcine bioprosthesis. Eighty-five patients (mean age 61 years, range 38-77) received 93 Bioflo valves, 46 having aortic valve replacement (AVR), 31 mitral valve replacement (MVR) and 8 aortic and mitral valve replacement (A+MVR); 85 patients (mean age 62.1 years, range 41-77) received 99 Carpentier-Edwards porcine valves (48 AVR, 23 MVR and 14 A+MVR). Cumulative follow-up totals 926 patient-years (mean 5.45 +/- 1.93, median 6.03, maximum 7.47 years). The overall operative mortality rate for the Bioflo group was 2.4%, and 5.9% for the Carpentier-Edwards group. At 7 years, there was no statistically significant difference in survival or in any prosthesis-related complication between the pericardial and porcine valve recipients overall, or when the data were analysed according to valve implant position. The actuarial survival rate at 7 years for the Bioflo group was 80.1 +/- 5.1% and 72.3 +/- 5.9% for the Carpentier-Edwards group. Freedom from structural valve deterioration (SVD) at 7 years for Bioflo patients was 98.5 +/- 1.5% and for Carpentier-Edwards patients 91.2 +/- 4.1%. No patient in the Bioflo group has required reoperation for SVD. The randomised prospective trial has proven practical and effective and has shown the pericardial valve to perform at least as well as the porcine valve up to 7 years when all of the standard outcome measures of valve performance are assessed.


An evaluation of the characteristics of orthopedic pediatric traumas during the COVID-19 pandemic lockdown period.
The purpose of this study is to investigate the effects of implemented social isolation measures on the characteristics of orthopedic pediatric traumas during this COVID-19 pandemic lockdown period. Patients who were admitted at our center between two time periods: April 3, 2019-May 31, 2019 (no lockdown period) and April 3, 2020-May 31, 2020 (lockdown period) were included to the study. Group 1 comprised 743 patients who were treated during no lockdown period, whereas Group 2 comprised 615 patients who were treated during lockdown period. Patients' medical records and radiographs were reviewed through our hospital's computer database. In addition, we recorded each patients' age and gender, their definite diagnosis, the anatomic location of the trauma, the type of trauma (fracture, dislocation, tendon injury, ligament injury, fracture dislocation, open fracture, etc.), the type of pediatric fracture (displaced fracture, torus fracture, epiphyseal fracture, pathological fracture, etc.), and the treatment method (non-operative/operative). The mean age of the patients was significantly lower in Group 2 (p<0.001). There were significant differences between the groups in terms of anatomic locations of the traumas (p<0.001). The types of the traumas, pediatric traumas, and treatment were significantly different between the groups (p<0.001, p<0.001, and p<0.001, respectively). The frequency of operative treatment was significantly higher in Group 2 (p<0.001). Our results demonstrated significant differences in patients' demographics as well as trauma characteristics during COVID-19 pandemic.


The evolution of comets in the Oort cloud and Kuiper belt.
Comets are remnants from the time when the outer planets formed, approximately 4-4.5 billion years ago. They have been in storage since then in the Oort cloud and Kuiper belt-distant regions that are so cold and sparsely populated that it was long thought that comets approaching the Sun were pristine samples from the time of Solar System formation. It is now recognized, however, that a variety of subtle but important evolutionary mechanisms operate on comets during their long storage, so they can no longer be regarded as wholly pristine.


GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome.
Identification and characterisation of monogenic causes of complex neurological phenotypes are important for genetic counselling and prognostication. Bi-allelic pathogenic variants in the gene encoding GLRX5, a protein involved in the early steps of Fe-S cluster biogenesis, are rare and cause two distinct phenotypes: isolated sideroblastic anemia and a neurological phenotype with variant non-ketotic hyperglycinemia. In this study, we analysed the evolution of clinical and MRI findings and long-term outcome of patients with GLRX5 mutations. Four patients from three Australian families of Lebanese descent were identified. All patients presented in childhood and were followed up into adult life through multiple clinical assessments. All were prescribed sodium benzoate. All patients (all females, age range 18-56 years) showed a complex neurological phenotype characterised by varying combinations of spastic paraparesis, length-dependent motor/sensory-motor axonal polyneuropathy, and psychiatric disturbances with variable intellectual disability. All had non-ketotic hyperglycinemia and a homozygous pathogenic c.151_153delAAG (p.K51del) change in GLRX5. Motor disability gradually progressed reaching moderate disability during adolescence and moderately severe disability during adult life. The major MRI finding was the upper cervical spinal cord signal changes with contrast enhancement noted in all and additional leukoencephalopathy in one. On follow up MRI, the white matter lesions diminished on a subsequent scan and then remained static over time. The spinal cord showed gliotic changes. Two patients have previously demonstrated low pyruvate dehydrogenase complex deficiency but none had plasma lactate elevation, nor biochemical evidence of branch-chain keto-dehydrogenase deficiency. Glycine levels reduced in patients that tolerated sodium benzoate, possibly stabilising clinical manifestations. This report demonstrates that the p.K51del GLRX5 variant causes a distinct and predictable neurological phenotype. The clinical assessments spanning from childhood to adult life enable physicians to infer the natural history of GLRX5 related neurological disorder. There may be widespread metabolic consequences, and optimal management is unknown.


The curious case of exploding quantum dots: anomalous migration and growth behaviors of Ge under Si oxidation.
We have previously demonstrated the unique migration behavior of Ge quantum dots (QDs) through Si3N4 layers during high-temperature oxidation. Penetration of these QDs into the underlying Si substrate however, leads to a completely different behavior: the Ge QDs 'explode,' regressing back almost to their origins as individual Ge nuclei as formed during the oxidation of the original nanopatterned SiGe structures used for their generation. A kinetics-based model is proposed to explain the anomalous migration behavior and morphology changes of the Ge QDs based on the Si flux generated during the oxidation of Si-containing layers.


Pharmacokinetics and correlation analysis of cilostazol in healthy Korean subjects.
Cilostazol is frequently used to treat and prevent thrombosis in Korean patients. We performed the pharmacokinetic and correlation analysis of cilostazol in Korean healthy subjects. A total of male 78 volunteers was subjected to three separate bioequivalence studies in which 100 mg of cilostazol was administered. AUC, t(1/2), and C(max) were 12,100 ± 4,880 ng×h/ ml, 11.1 ± 4.4 hours, and 827 ± 361 ng/ml, respectively. ALT was positively correlated with age and C(max) was positively correlated with AUC, but negatively correlated with body weight. We suggest that the unique pharmacokinetic parameters and interrelationship can help to understand the pharmacokinetics of cilostazol in Korean subjects.


Identification and molecular characterization of the murine cytomegalovirus homolog of the human cytomegalovirus UL100 gene.
The UL100 gene of human cytomegalovirus (HCMV) has been shown to encode an envelope glycoprotein that might play an important role in HCMV infection. Using the HCMV UL100 gene as a probe in low stringency hybridization studies, we were able to identify the putative UL100 homologous gene of murine cytomegalovirus (MCMV), strain Smith. The MCMV gene was sequenced and localized to the left end of the EcoRI fragment H on the MCMV physical map. This genomic location is similar to that found for the HCMV UL100 gene. The MCMV UL100 mRNA is 1.6 kb in size and is expressed exclusively in the late stages of infection. The 5' and 3' boundaries of the transcript were determined. The open reading frame (ORF) of the UL100 gene could encode a protein of 371 amino acid residues with a calculated molecular mass of 42 kDa. Computer analysis of the deduced amino acid sequence of this gene predicted the presence of eight transmembrane domains and four N-linked glycosylation sites in the protein. Sequence comparison revealed that this putative protein shares similarity with the predicted UL100 homologs of several other herpesviruses, and is most similar to the HCMV UL100 protein (47% identity).


Plexins as Regulators of Cancer Cell Proliferation, Migration, and Invasivity.
Plexins are a family of nine single-pass transmembrane receptors with a conserved GTPase activating protein (GAP) domain. The plexin family is divided into four subfamilies: Type-A, type-B, type-C, and type-D plexins. Plexins function as receptors for axon guidance factors of the semaphorin family. The semaphorin gene family contains 22 genes that are divided into eight subclasses of which subclasses three to seven represent vertebrate semaphorins. The plexins and their semaphorin ligands have important roles as regulators of angiogenesis, cancer proliferation, and metastasis. Class 3 semaphorins, with the exception of sema3E, are the only semaphorins that do not bind directly to plexins. In order to transduce their signals, they bind instead to complexes consisting of receptors of the neuropilin family and various plexins. Some plexins also form complexes with tyrosine-kinase receptors such as the epidermal growth factor receptor ErbB2, the mesenchymal epithelial transition factor receptor (MET), and the Vascular endothelial growth factor receptor 2 (VEGFR2) and, as a result, can modulate cell proliferation and tumor progression. This review focuses on the roles of the different plexins in the control of cancer cell proliferation and invasiveness. Plexins also affect tumor progression and tumor metastasis by indirect mechanisms, such as modulation of angiogenesis and immune responses. However, these topics are not covered in the present review.


Age-related thermal response: the cellular resilience of juveniles.
Understanding species' responses to environmental challenges is key to predicting future biodiversity. However, there is currently little data on how developmental stages affect responses and also whether universal gene biomarkers to environmental stress can be identified both within and between species. Using the Antarctic clam, Laternula elliptica, as a model species, we examined both the tissue-specific and age-related (juvenile versus mature adult) gene expression response to acute non-lethal warming (12 h at 3 °C). In general, there was a relatively muted response to this sub-lethal thermal challenge when the expression profiles of treated animals, of either age, were compared with those of 0 °C controls, with none of the "classical" stress response genes up-regulated. The expression profiles were very variable between the tissues of all animals, irrespective of age with no single transcript emerging as a universal biomarker of thermal stress. However, when the expression profiles of treated animals of the different age groups were directly compared, a very different pattern emerged. The profiles of the younger animals showed significant up-regulation of chaperone and antioxidant transcripts when compared with those of the older animals. Thus, the younger animals showed evidence of a more robust cellular response to warming. These data substantiate previous physiological analyses showing a more resilient juvenile population.


Effect of hycanthone administered in vivo upon the incorporation of radioactive precursors into macromolecules of Schistosoma mansoni.
Mice infected with Schistosoma mansoni were treated with hycanthone or with 8-chloro-2[2-(diethylamino)ethyl]-2H-[1]benzothiopirano-[4,3, 2-cd]-indazole-5-methanesulphonate (IA-4). Schistosomes were obtained by perfusion at various times after drug administration and tested for their ability to incorporate radioactive precursors of DNA, RNA and protein. In adult worms, male or female, the incorporation of radioactive thymidine was severely and irreversibly inhibited after treatment with either drug. Uridine and leucine incorporations were also inhibited, though to a lesser extent. On the contrary, the synthetic activities of immature worms were unaffected by hycanthone and only partially or temporarily depressed by IA-4. Hycanthone-resistant schistosomes, when tested between 1 and 7 days after treatment, showed a pattern of precursor incorporation which was virtually identical to that of untreated worms. These results are consistent with the hypothesis that hycanthone and IA-4 may kill schistosomes by interfering with their nucleic acid synthesis.


Neural processing of nouns and verbs in spontaneous speech of patients with schizophrenia.
Previous fMRI-studies investigating the production of nouns and verbs in healthy participants reported predominantly activation in the left inferior frontal gyrus (IFG) for both classes of words with increased neural responses for verbs. To date, comparable imaging data for spontaneous speech in patients with schizophrenia is missing. These results are novel and may contribute to understand the neural basis of noun and verb production in a "natural" environment. Fifteen patients with schizophrenia and fifteen healthy control participants described pictures for one minute each while BOLD signal changes were measured with fMRI. In an event-related design, activations related to noun and verb production were extracted in the imaging analysis. Imaging results revealed increased activation for nouns and decreased activation for verbs in the left IFG in the patients. A post-hoc analysis revealed that patients produced significantly more transitive verbs which were negatively associated with activation in the left IFG. We conclude that a subtle linguistic processing deficit in schizophrenia may lead to an increased use of transitive as compared to intransitive verbs in connected speech and to a deviant pattern of brain activation related to the processing of verbs.


Disordered Leptin signaling in the retrotrapezoid nucleus is associated with the impaired hypercapnic ventilatory response in obesity.
Sleep-disordered breathing is characterized by disruptions of normal breathing patterns during sleep. Obesity is closely related to hypoventilation or apnea and becomes a primary risk factor for sleep-disordered breathing. Leptin, a peptide secreted by adipose tissue, has been implicated in central control of breathing. Activation of the retrotrapezoid nucleus (RTN) neurons, a critical central respiratory chemoreceptor candidate, potentiates a central drive to breathing. Here, we ask whether the disordered leptin signaling in the RTN is responsible for obesity-related hypoventilation. In a diet induced obesity (DIO) mouse model, the hypercapnic ventilatory response (HCVR) was assessed and the cellular leptin signaling in the RTN was examined. Our main findings demonstrate that DIO mice exhibit overweight, hypercapnia, high levels of serum and cerebrospinal leptin. During exposure to room air, DIO mice manifest basal hypoventilation with a rapid and shallow breathing pattern. Exposure to CO2 elicits the impaired HCVR in DIO mice. In addition, both the number of CO2-activated neurons and expression of TASK-2 channels in the RTN are dramatically reduced in DIO mice. Moreover, there is leptin signaling disorder in RTN neurons in DIO mice, including a significant decrease in leptin-activated RTN neurons, downregulation of phosphorylated STAT3 and upregulation of SOCS3. Altogether, we suggest that the disordered leptin/STAT3/SOCS3 signaling pathway in the RTN plays a role in obesity-related hypoventilation.


Statistical histometry in the diagnostic assessment of tissue sections.
A statistical histometric model to distinguish adenoma of the colon from normal colon is described. The model, based on the number and location of glandular nuclei, with a dependency scheme based upon displacement, was tested and shown to be significant and capable of simulating the architecture of an adenoma.


Stage IV Kienböck's disease: Proximal row carpectomy and application of RCPI implant.
Kienböck disease is an aseptic osteonecrosis of the lunate, which gradually leads to total carpal collapse. Lichtman's classification relates radiographic evidence of wrist damage to four different stages and supports surgical decision-making. This study pertains to six patients (2 males and 4 females) affected by stage IV Kienböck's disease who underwent proximal row carpectomy and received an RCPI implant. The clinical outcomes consisted of wrist range of motion (ROM), pain on a VAS scale (0-10), the DASH score and the patient's level of satisfaction. The mean follow-up was 27.6 months (16-36). Pain relief and improvements in wrist flexion - extension ROM, radial - ulnar deviation and strength were achieved in every patient. There were no cases of implant failure or dislocation. Considering the good results obtained, we believe that proximal row carpectomy associated with the use of a pyrocarbon RCPI implant is a valid surgical technique for the treatment of stage IV Kienböck's disease. It is a good alternative to carpal fusion, which leads to wrist immobility, and to total wrist joint replacement, which has a high incidence of dislocation and fracture.


Sarcoidosis with cryptococcal infection apparently engaging only immune-privileged body compartments: a case report.
Infection with the Cryptococcus neoformans yeast fungus is largely restricted to patients with HIV, sarcoidosis or immunosuppressive therapies. In sarcoidosis, there is intense local immune response in granuloma lesions, coupled with a paradoxical systemic anergy. An analysis of cryptococcal infection in sarcoidosis may therefore shed light on whether opportunistic pathogens preferentially engage immune-privileged tissues. A 54-year-old man was admitted to our hospital after 2 months with palpitations and activity-related presyncope. A chest X-ray was normal, electrocardiography showed type-II atrioventricular-block, and there was a tentative diagnosis of myocarditis. Computed tomography reported minor hilar lymph glands and multiple nodular lesions in the lungs. Magnetic resonance imaging showed oedema and nodular structures in the heart, and fibrosis and granulomas were found in endomyocardial biopsies. The diagnosis was revised to cardiac sarcoidosis, and prednisone was initiated. In parallel, positron-emission tomography had revealed a marked uptake in the right thyroid lobe, a thyroid lobectomy was then performed, and the pathology showed a BRAF-positive papillary thyroid carcinoma. Four days postoperatively the patient developed symptoms suggestive of meningoencephalitis. Cerebrospinal fluid and blood cultures yielded growth of C. neoformans. Fungal staining of the thyroid specimen revealed cryptococcal elements in the carcinoma and in granulomas close to the tumour. Notably, there was no evidence of cryptococci in the heart sarcoid sections or in the normal thyroid parenchyma. The patient was successfully treated with antifungal agents and at the 2-year follow-up there was no evidence of thyroid cancer relapse. This sarcoidosis patient had a remarkable clinic with evidence of cryptococcal infection only in body compartments commonly regarded to be immune-privileged. The findings suggest that an opportunistic and environmentally abundant pathogen, when infecting an immunocompromised host, primarily engages immunodeficient locations such as the brain, a tumour microenvironment and some forms of granuloma.


Assessment of conjugal transfer of antibiotic resistance genes in Salmonella Typhimurium exposed to bile salts.
This study was designed to evaluate the transfer potential of antibiotic resistance genes in antibiotic-resistant Salmonella Typhimurium (S. Typhimurium(R)) in the presence of bile salts. The resistance of S. Typhimurium(R) to ampicillin, kanamycin, and tetracycline was increased by 64-, 64-, and 512-fold, respectively. The highest transfer frequency from S. Typhimurium(R) to Escherichia coli was observed at the bile salt concentration of 160 μg/ml (3.8 × 10(-3) transferrants/cells). The expression of traJ and traY was suppressed in S. Typhimurium(R) by bile salt. This study provides useful information for understanding the conjugative transfer of antibiotic resistance genes in S. Typhimurium under intestinal conditions.


Application of the IWA ADM1 model to simulate anaerobic co-digestion of organic waste with waste activated sludge in mesophilic condition.
Anaerobic digestion model no. 1 model of international water association was applied to a full scale anaerobic co-digestion process for the treatment of the organic fraction of municipal solid wastes along with activated sludge wastes originating from a municipal wastewater treatment plant. This operation was carried out in a digester of 2000 m(3) in volume. It is operates at an average hydraulic retention time of 26.9 days with an average organic loading rate of 1.01 kg TVS/m(3) day, at a temperature of 37 degrees C with an average gas production rate of 0.296 m(3)/m(3) day. The aim of the present study is to compare the results obtained from the simulation with the experimental values. The simulated results showed a good fit for pH, methane and carbon dioxide percentages, biogas volume, chemical oxygen demand, total volatile fatty acids, inorganic nitrogen and inorganic carbon.


Micturition studies and sexual function in operated hypospadiacs.
Micturition patterns in 33 males, aged 15 to 34 years, were investigated after hypospadias repair in childhood. Spraying of the urinary stream was the most common complaint (13 patients). Urinary flow was low in five patients as compared with controls, but in only one of these patients was an obstruction found that required treatment. Five patients had persistent curvature of the penis. One of them was unable to perform sexual intercourse.


[Evolutionary ontogenetic aspects of pathogenetics of chronic human diseases].
This article is a review of scientific publications, in which issues of pathogenetics of multifactorial diseases (MFDs) are considered from the viewpoint of evolution and ontogeny. Concepts explaining significance of evolutionary processes in the formation of genetic architecture of human chronic diseases ("thrifty" genomes and phenotypes, "drifting genes," decanalization) are analyzed. The roles of natural selection and genetic drift in the formation of hereditary diversity of genes for susceptibility to MFDs are considered. The modern concept of disease ontogeny (somatic mosaicism, loss ofheterozygosity, paradominant inheritance, epigenetic variability) is discussed. It is demonstrated that the evolutionary and ontogenetic approaches to analysis of genimuc and other "-omic" data are essential for understanding the biology of diseases.


Differential glycosylation of MHC class II molecules on gastric epithelial cells: implications in local immune responses.
Class II major histocompatibility complex (MHC) expression is a hallmark of antigen presenting cells (APC). Human gastric epithelial cells (GEC) express class II MHC and this expression increases during infection with Helicobacter pylori as does the number of CD4 T cells found adjacent or in between epithelial cells. These observations suggested that human GEC act as APCs. To characterize and compare class II MHC complexes with those present in conventional APC, immunoprecipitated class II MHC from GEC and B cells, as prototypic APC, were separated by two-dimensional electrophoresis. Although the composition of class II MHC from both cell phenotypes was similar, their electrophoretic mobility differed. Methodical elimination of carbohydrates, either enzymatically with endoglycosidase-H or blocking with tunicamycin, revealed that the deviations were due to differences in glycosylation in both cell phenotypes. When deglycosylated class II MHC alpha chains, beta chains, and the invariant chain from both cell phenotypes were mixed and run in the same gel, the core proteins had identical migration patterns. Because differences in glycosylation of class II MHC proteins may affect peptide selection and/or recognition by T cells, the noted differences in glycosylation of class II MHC expressed by GEC could be important in considering their potential role as APC locally.


An Empirical Analysis of Japan's Drug Development Lag Behind the United States.
The "drug lag" (ie, the approval lag for new drugs) hinders patients' access to innovative new medicines. The drug lag was heavily debated in Japan from the late 2000s to the early 2010s. It consists of "development lag" (ie, the submission date lag for new drug applications) and "review lag" (ie, the difference in review periods). As the 2 lags have different causes and display significantly different recent trends in Japan, we focus on the development lag-in contrast with most previous literature-between Japan and the United States, based on a database we created for all new drugs from 2008 to 2018 using publicly available data sources. First, we found that Japan's development lag relative to the United States did not shrink in terms of the overall distribution rather than the median, which was the focus of most prior studies. Second, we examined the factors (product characteristics) that significantly affected the development lag and found that products that underwent multiregional clinical trials and those that were certified as "breakthrough therapies" in the United States had significantly shorter development lags with high robustness, whereas products receiving price premiums did not. Finally, we discussed the policy implications of these results. For instance, innovative new drugs that are presumed to receive price premiums require enhanced policy support for early application from the initial stages of clinical trials. It is also essential to promote information sharing regarding evaluations by foreign reviewing authorities for efficient use in the home country.


Retraction notice to: Enlarged anterior cerebral artery bifurcation angles may induce abnormally enhanced hemodynamic stresses to initiate aneurysms [WNEU 120 (2018) e783-e791/9025].
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. It includes data and figures from patients that were cared for by Dr. Malek at the Cerebrovascular Hemodynamics laboratory in the Department of Neurosurgery at Tufts Medical Center. The Editor-in-Chief has been informed by Tufts Medical Center that the authors of the paper did not have clinical privileges for these patients and played no clinical role in their care.


Warfarin treatment of chronic idiopathic urticaria and angio-oedema.
Chronic idiopathic urticaria is a disabling condition that does not always respond to antihistamine drugs and other agents are sometimes needed to control disease activity. Warfarin has demonstrated efficacy in single unblinded case studies [1] but has been dismissed by others [2]. We investigated the effect of warfarin treatment in eight patients with chronic idiopathic urticaria unresponsive to antihistamines in an open study. Six of the eight patients responded to treatment and three had a dramatic response. These three were included in a double-blind placebo-controlled trial of warfarin therapy to confirm significant benefit from treatment. The three warfarin responders had their stable warfarin dose encapsulated and placebo capsules were provided. A double-blind placebo-controlled crossover trial was performed on each patient. Visual analogue scores recorded disease activity. Comparison of visual analogue scores showed a significant benefit while on warfarin with a reduction in pruritus and angio-oedema. This is the first double-blind placebo-controlled study to show a response of chronic idiopathic urticaria to warfarin. The mechanisms of action are unclear and require further study.


Oncology nurses' use of nondrug pain interventions in practice.
Cancer pain management guidelines recommend nondrug interventions as adjuvants to analgesic medications. Although physicians typically are responsible for pharmacologic pain treatments, oncology staff nurses, who spend considerable time with patients, are largely responsible for identifying and implementing nondrug pain treatments. Oncology nurses' use of nondrug interventions, however, has not been well studied. The purpose of this study was to describe oncology nurses' use of four nondrug interventions (music, guided imagery, relaxation, distraction) and to identify factors that influence their use in practice. A national sample of 724 oncology staff nurses completed a mailed survey regarding use of the nondrug interventions in practice, beliefs about the interventions, and demographic characteristics. The percentages of nurses who reported administering the strategies in practice at least sometimes were 54% for music, 40% for guided imagery, 82% for relaxation, and 80% for distraction. Use of each nondrug intervention was predicted by a composite score on beliefs about effectiveness of the intervention (e.g., perceived benefit; P<0.025) and a composite score on beliefs about support for carrying out the intervention (e.g., time; P<0.025). In addition, use of guided imagery was predicted by a composite score on beliefs about characteristics of patients who may benefit from the intervention (e.g., cognitive ability; P<0.05). Some nurse demographic, professional preparation, and practice environment characteristics also predicted use of individual nondrug interventions. Efforts to improve application of nondrug interventions should focus on innovative educational strategies, problem solving to secure support, and development and testing of new delivery methods that require less time from busy staff nurses.


Do birch-feeding caterpillars make the right feeding choices?
The effects of leaf quality on caterpillar performance are frequently investigated, as are the feeding preferences of caterpillars, but rarely are the two considered together to see how preferences match performance. I looked at the preferences and performance of the specialist feeder Achlya flavicornis and the generalist Spilosoma luteum on Betula pendula leaves which were artificially damaged, mined or left undamaged, and on leaves of different ages. Often feeding preferences were not for the leaf types that gave faster development, larger pupae or greater survival. A. flavicornis preferred medium aged to older leaves though medium aged leaves produced smaller pupae. They did not discriminate between young and medium aged leaves, though larvae fed young leaves developed more slowly, and had lower survival and lower adult emergence. S. luteum larvae did not discriminate between damaged and undamaged leaves, though feeding on damaged leaves gave smaller pupae and lower adult emergence. I suggest that generalists like S. luteum might be unable to make feeding choices between leaves that are on the same tree and vary only slightly because populations are exposed to much greater variation across the wide range of potential food plants individuals may encounter. Possible differences in within-plant feeding selectivity between generalists and specialists should be investigated. A. flavicornis is a leaftier for which selection of a suitable leaf for tying could be more important in the first instance than feeding considerations. Larvae preferred younger to older leaves for tying, and larvae tended to feed on the tied leaves, so tying preferences explain the initial feeding preferences.


Improving the Knowledge Gap of Sepsis Identification by Training First Responders in Prehospital Sepsis Screening.
First responders play a crucial role in caring for patients with sepsis, as they are often first on the scene in emergency medical situations. Many first responders lack the advanced knowledge and skill set needed to identify patients with sepsis or those at risk for sepsis. This mixed-methods study examined if the implementation of a sepsis education program would impact and reduce the knowledge gap in first responders' ability to identify patients at risk for sepsis. Two hundred and thirteen first responders participated in an online sepsis education program, during which their knowledge was evaluated using a pretest and posttest. The difference in the mean of the preeducation test scores and the posteducation test scores' mean was significantly different. The mean of the pretest scores was lower than the mean of the posttest scores, thus suggesting that the education of first responders is effective in increasing their knowledge of sepsis. After completing the program, participants felt better prepared to encounter instances of sepsis. standardizing communication between first responders and the emergency room through a "Sepsis Alert" can improve treatment times and allow for more timely intervention.


Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages.
IFN regulatory factor (IRF) 8 is a transcription factor that directs macrophage differentiation. By fluorescence recovery after photobleaching, we visualized the movement of IRF8-GFP in differentiating macrophages. Recovery data fitted to mathematical models revealed two binding states for IRF8. The majority of IRF8 was highly mobile and transiently interacted with chromatin, whereas a small fraction of IRF8 bound to chromatin more stably. IRF8 mutants that did not stimulate macrophage differentiation showed a faster recovery, revealing little interaction with chromatin. A macrophage activation signal by IFN-gamma/LPS led to a global slowdown of IRF8 movement, leading to increased chromatin binding. In fibroblasts where IRF8 has no known function, WT IRF8 moved as fast as the mutants, indicating that IRF8 does not interact with chromatin in these cells. However, upon introduction of IRF8 binding partners, PU.1 and/or IRF1, the mobility of IRF8 was markedly reduced, producing a more stably bound component. Together, IRF8-chromatin interaction is dynamic in live macrophages and influenced by partner proteins and immunological stimuli.


Adhesion and spreading of osteoblast-like cells on surfaces coated with laminin-derived bioactive core peptides.
Functional peptides are attractive as novel therapeutic reagents because their amino acid sequences are flexible in adopting and mimicking the local functional features of proteins. These peptides are of low molecular weight, synthetically versatile and inexpensive to produce, suggesting that they can be used as drug targeting, potent, stable and bioavailable agents. A short bioactive peptide is expected to be more beneficial in regenerative medicine than an entire protein because of the lower antigenicity of short amino acid sequences. We detected core peptides from human laminin that are involved in adhesion and spreading, which are the first steps of various cells including osteogenic cells, in becoming functional. In this experiment, we detected adhesion and spreading of osteoblast-like cells seeded on the core peptide-coated surface. These in vitro data are related to the research article, entitled "Identification of a bioactive core sequence from human laminin and its applicability to tissue engineering" (Yeo et al., 2015) [1].


Immunochemical characterization and biosynthesis of major antigens of iodo-bead surface-labeled Brugia malayi microfilariae.
The objectives of the present study were to identify and characterize biochemically the major antigens of Brugia malayi microfilariae, a filarial parasite that infects humans. IgG antibodies in sera of mice which had cleared parasites from the bloodstream reacted with 30, 55, 94 and 150 kDa molecules of living microfilariae radioiodinated by the Iodo-bead method. Sera of humans infected with the related filariae Wuchereria bancrofti, Loa loa or Onchocerca volvulus immunoprecipitated molecules of similar size as well as two additional proteins of 22 and 43 kDa. Sera of uninfected North Americans or mice infected with Trichinella spiralis or Schistosoma mansoni did not recognize these radioiodinated antigens. Experiments to examine the possible surface localization and metabolism of these antigens showed that they were removed from intact parasites exposed to chymotrypsin or trypsin and that immunogenic molecules of 30, 55, and 150 kDa were released into excretory-secretory products by viable microfilariae. [35S]Methionine biosynthetically labeled polypeptide antigens of 22, 30, 35 and 150 kDa were detected by antibody reacted with intact microfilariae and/or their excretion products. Antigens of 30, 55, and 150 kDa appear to be glycoproteins as they bound wheat germ agglutinin and were biosynthetically labeled with [14C]N-acetyl-D-glucosamine. These data suggest that the surface of B. malayi microfilariae is a dynamic structure which synthesizes and sheds antigens.


The role of bone marrow biopsy and FDG-PET/CT in identifying bone marrow infiltration in the initial diagnosis of high grade non-Hodgkin B-cell lymphoma and Hodgkin lymphoma. Accuracy in a multicenter series of 372 patients.
Bone marrow infiltration (BMI), categorized as an extra-nodal site, affects stage and is associated with poor prognosis in newly diagnosed lymphoma patients. We have evaluated the accuracy of PET/CT and bone marrow biopsy (BMB) to assess BMI in 372 lymphoma patients [140 Hodgkin Lymphoma (HL) and 232 High Grade B-cell non-Hodgkin Lymphoma (HG B-NHL), among them 155 Diffuse Large B-Cell Lymphoma (DLCL)]. For HL cases, and taking into account PET/CT, sensitivity, negative predictive value (NPV) and accuracy were 96.7, 99.3, and 99.3% while those of BMB were 32.3, 83.8, and 85%, respectively. For HG B-NHL and considering PET/CT, sensitivity, NPV, and accuracy were 52.7, 81.7, and 84.1%, while those of BMB were 77.6, 90.2, and 90.7%, respectively. In the HG B-NHL group, 25 patients would have been under-staged without BMB. These results lead us to recommend PET/CT and the avoidance of BMB to assess BMI in HL. In the case of HG B-NHL, bone marrow status should be assessed firstly by means of PET/CT; only in either focal or diffuse PET/CT with low borderline SUV max values or in negative cases, should BMB be carried out afterwards. In the HG B-NHL setting and at the present moment, both techniques are complementary.


Diagnosis and Treatment of Paroxysmal Sympathetic Hyperactivity in Medical ICU, University of Gondar Hospital, Northwest Ethiopia: A Case Report.
Paroxysmal sympathetic hyperactivity (PSH) is a neurologic syndrome characterized by paroxysmal and simultaneous occurrence of hypertension, hyperpyrexia, tachycardia, tachypnea, diaphoresis and dystonic posturing due to surge in sympathetic outflow after acquired brain injuries. Diagnosis of PSH is made using the paroxysmal sympathetic hyperactivity-assessment measure (PSH-AM) score, which comprises "clinical features severity" (CFS) score and "diagnosis likelihood tool" (DLT) score. A 35-year-old woman diagnosed to have echo-proven chronic rheumatic heart disease for 25 years. Percutaneous balloon mitral valvotomy was done 6 weeks previously for severe mitral stenosis. Left atrial thrombus was detected after the procedure and anticoagulant (warfarin) was initiated. She presented with severe headache and repeated vomiting of 1 day duration on arrival to the hospital. She had frequent seizure attacks with subsequent loss of consciousness on third day of admission. Diagnosis of status epilepticus secondary to intracranial hemorrhage due to warfarin toxicity was made after CT-scan revealed acute subdural hematoma and ventricular bleeding. Then she was transferred to medical intensive care unit (ICU), intubated and put on mechanical ventilator. Anti-epileptic drugs, antibiotics, vitamin K and fresh frozen plasma were given. She developed paroxysms of hypertension, tachycardia, tachypnea, hyperpyrexia, diaphoresis and decerebrate posturing after 7 days of neurological insult. She had normal inter-ictal EEG tracing during cyclic autonomic surge. CFS score was 11 and DLT score was 10. In sum, PSH-AM score was 21, suggested "probable" diagnosis of PSH. Morphine, diazepam, propranolol and gabapentin were given in combination to treat PSH. Severity of autonomic storm started to improve on second week of ICU admission. On the third week of admission, her clinical condition deteriorated suddenly, she developed asystole and died of cardiac arrest despite cardiopulmonary resuscitation (CPR). 'Clinical scoring' was used used to diagnose PSH, since there was no any confirmatory test. Cocktail of drugs were required to treat catecholamine surge in PSH.


Effects of perfusion pressure on energy and work of isolated rat hearts.
A chemomechanical study of hypertrophied hearts of 6-month-old spontaneously hypertensive rats (SHR) and that of age-matched Wistar-Kyoto (WKY) rats was carried out, analyzing the response of the heart to steady-state changes in coronary perfusion pressure. The ratio of heart (dry)-to-body (wet) weight of WKY rats was 0.37 +/- 0.02 (10(-3] and for SHR was 0.58 +/- 0.03 (10(-3] (p less than 0.01). In the apex-ejecting, isolated, pyruvate-perfused working hearts of WKY rats and SHR, coronary flow was constant when coronary perfusion pressure was set between 140 and 190 cm H2O (range of autoregulation). Coronary flow was perfusion pressure dependent when the coronary perfusion pressure was set below 110 cm H2O for both WKY rats and SHR. Cardiac output, developed pressure, rate of pressure development (dP/dt), and oxygen consumption were constant in the range of autoregulation but decreased in the direction of coronary flow when coronary flow was reduced by a drop in perfusion pressure. Similarly, the phosphorylation potential, phosphocreatine, adenosine triphosphate, and cyclic adenosine monophosphate were constant in the range of autoregulation but decreased directionally with coronary perfusion pressure below 110 cm H2O for both SHR and WKY rats. There was a significantly lower phosphorylation potential in SHR as compared with WKY rats when coronary perfusion pressure was reduced to 80 cm H2O. In the region of autoregulation, coronary flow and oxygen consumption were significantly less in SHR, although developed pressure was significantly greater at both high and low workloads.(ABSTRACT TRUNCATED AT 250 WORDS)


Automatisation of a localising technique in aphasia based upon averaged evoked potentials.
Averaged evoked potentials were utilised as a localising technique in aphasia. Based on a set of measurements extracted from various evoked potentials, subjects from four diagnostic categories were correctly classified in more than 70% of the cases. The measurements were derived from amplitudes and latencies of significant peaks which were selected by human judgement from plots of the recorded evoked potentials. An algorithm has been developed which simulates the manual procedure and reduces the processing time per patient by several magnitudes. The automated method yields results which are more consistent with expected results than those from the manual method. The percentage of correct classification is in both cases essentially the same.


Cost-utility analysis of duloxetine in osteoarthritis: a US private payer perspective.
Duloxetine has recently been approved in the USA for chronic musculoskeletal pain, including osteoarthritis and chronic low back pain. The cost effectiveness of duloxetine in osteoarthritis has not previously been assessed. Duloxetine is targeted as post first-line (after acetaminophen) treatment of moderate to severe pain. The objective of this study was to estimate the cost effectiveness of duloxetine in the treatment of osteoarthritis from a US private payer perspective compared with other post first-line oral treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), and both strong and weak opioids. A cost-utility analysis was performed using a discrete-state, time-dependent semi-Markov model based on the National Institute for Health and Clinical Excellence (NICE) model documented in its 2008 osteoarthritis guidelines. The model was extended for opioids by adding titration, discontinuation and additional adverse events (AEs). A life-long time horizon was adopted to capture the full consequences of NSAID-induced AEs. Fourteen health states comprised the structure of the model: treatment without persistent AE, six during-AE states, six post-AE states and death. Treatment-specific utilities were calculated using the transfer-to-utility method and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total scores from a meta-analysis of osteoarthritis clinical trials of 12 weeks and longer. Costs for 2011 were estimated using Red Book, The Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project database, the literature and, sparingly, expert opinion. One-way and probabilistic sensitivity analyses were undertaken, as well as subgroup analyses of patients over 65 years old and a population at greater risk of NSAID-related AEs. In the base case the model estimated naproxen to be the lowest total-cost treatment, tapentadol the highest cost, and duloxetine the most effective after considering AEs. Duloxetine accumulated 0.027 discounted quality-adjusted life-years (QALYs) more than naproxen and 0.013 more than oxycodone. Celecoxib was dominated by naproxen, tramadol was subject to extended dominance, and strong opioids were dominated by duloxetine. The model estimated an incremental cost-effectiveness ratio (ICER) of US$47,678 per QALY for duloxetine versus naproxen. One-way sensitivity analysis identified the probabilities of NSAID-related cardiovascular AEs as the inputs to which the ICER was most sensitive when duloxetine was compared with an NSAID. When compared with a strong opioid, duloxetine dominated the opioid under nearly all sensitivity analysis scenarios. When compared with tramadol, the ICER was most sensitive to the costs of duloxetine and tramadol. In subgroup analysis, the cost per QALY for duloxetine versus naproxen fell to US$24,125 for patients over 65 years and to US$18,472 for a population at high risk of cardiovascular and gastrointestinal AEs. The model estimated that duloxetine was potentially cost effective in the base-case population and more cost effective for subgroups over 65 years or at high risk of NSAID-related AEs. In sensitivity analysis, duloxetine dominated all strong opioids in nearly all scenarios.


High Throughput Multidimensional Kinetic Screening in Continuous Flow Reactors.
An automated high throughput multidimensional reaction screening platform based on an inline Fourier-transform infrared spectroscopy is presented. By combining flow chemistry, machine automation and inline analysis, the platform is able to screen reactions in multidimensions (residence time, monomer concentration, degree of polymerization, reaction temperature and monomer conversion) rapidly and efficiently way. Kinetic data libraries associated with high data precision (absolute error <4 %), high reproducibility and high data density are built with ease from the platform. To test the method, we screened the reversible addition-fragmentation chain transfer polymerization of methyl acrylate in unmatched detail, and the ring opening metathesis polymerization of methyl-5-norbornene-2-carboxylate. The method we introduce is a key step in providing "big data" for data driven research in the future, and already at present allows for precise prediction of reaction outcomes within the high-dimensional chemical parameter space that is screened.


In vitro cultivation of Ostertagia ostertagi, the medium stomach worm of cattle. I. Development from infective larvae to egg-laying adults.
When a 70-min exsheathing process and two-step roller culture system were used, infective larvae of Ostertagia ostertagi developed in large numbers to mature adult males and females in 28 and 29 days, respectively. Females laid fertile eggs in the 2- to 16-cell stages from day 34 on. Some of the expelled eggs developed to the morula stage, in the culture fluid, by day 52. Yields of mature adults and eggs were best when cultures were started with 100,000 larvae in 100 ml of medium. The optimal culture system produced from 20% to 35% mature adults, from days 28 through 52.


Determination of extracellular glutathione in livers of anaesthetized rats by microdialysis with on-line high-performance liquid chromatography.
An on-line analytical system for the continuous in vivo monitoring of extracellular glutathione (gamma-glutamyl-cysteinylglycine) (GSH) concentrations in the livers of anaesthetized rats was developed. Microdialysates perfused through implanted microdialysis probes were collected with a loading loop of an on-line injector for direct and automatic injection into a high-performance liquid chromatographic system equipped with an electrochemical detector with Au-Hg electrodes. This method shortened the analysis time and circumvented the sample preparation process which is essential for accurate determination of GSH levels in biological samples. Additionally, this method provided continuous and real-time monitoring of extracellular GSH levels. Basal extracellular GSH concentrations in the livers of anaesthetized rate were found to vary over a wide range (from 4.16 to 76.5 microM). The method was applied to study the effect of global liver ischaemia on extracellular GSH concentrations and it was found that extracellular GSH levels in livers increased immediately with the onset of ischaemia and remained elevated for the 30-min ischaemic period. Ensuing reperfusion did reduce the GSH increase; however, the GSH levels did not return to the basal value.


Nucleotide sequence and complementation studies of the gene 10 region of bacteriophage T3.
The nucleotide sequence of bacteriophage T3 gene 10 and surrounding regulatory elements has been determined and compared to the analogous region of bacteriophage T7. T3 genes 9, 10 and 11 have been shown to complement T7 mutants. The DNA sequences of T3 and T7 gene 10A are homologous, as are the amino acid sequences of the respective products. The translational shift to the -1 frame is predicted to occur at the same position in gene 10 of T3 and T7, though different nucleotide sequences are probably responsible. The resulting gp10B products have completely different C termini.


Pulmonary Toxicities of Immunotherapy.
Immune checkpoint inhibitors are a form of immunotherapy that are increasingly being used in a wide variety of cancers. Immune-related adverse events (irAEs) pose a major challenge in the treatment of cancer patients. Pneumonitis, the most common lung irAE, can cause significant disruptions in the treatment of cancer and may be life-threatening. The goal of this chapter is to instruct readers on the incidence and clinical manifestations of pneumonitis and to offer guidance in the evaluation and treatment of patients with pneumonitis.


Dual Antiplatelet Therapy After Drug-Eluting Stents Implantation in East Asians: A Network Meta-Analysis of Randomized Controlled Trials.
Dual antiplatelet therapy (DAPT) is essential to prevent the risk of ischemia events, but it is difficult to avoid concurrent bleeding events. East Asians are associated with a higher tendency of bleeding than Caucasians, which may affect the DAPT duration. Therefore, this network meta-analysis to explore optimum DAPT duration for East Asians. The related randomized controlled trials that compared the different DAPT duration in East Asian patients were included by searching PubMed, EMBASE, and Cochrane Library database. The outcomes included myocardial infarction, stent thrombosis, all-cause death, stroke, and major bleeding. In addition, net adverse cardiac and cardiovascular events was defined as a composite outcome in this study. We calculated the odds ratio (OR) and 95% confidence intervals for end point events by the fixed effects model in the Bayesian's network frame. We included a total of 12 randomized controlled trials with 30,640 patients. Compared with 12-month DAPT, 1- to 3-month DAPT is effective in myocardial infarction (OR 0.72, 0.46-1.08), stents thrombosis (OR 1.27, 0.59-2.84), all-cause death (OR 0.91, 0.65-1.28), and stroke (OR 0.89, 0.57-1.39). The 1- to 3-month DAPT was associated with a lower risk of major bleeding compared with 12-month DAPT (OR 0.55, 0.4-0.76), 6-month DAPT (OR 0.54, 0.31-0.94), and >12-month DAPT (OR 0.43, 0.28-0.65). In addition, more than 12 months of DAPT did not reduce the incidence of myocardial infarction (OR 0.75, 0.51-1.11) and increased the risk of major bleeding (OR 1.28, 0.88-1.87) compared with 12-month DAPT. The 1- to 3-month DAPT was more secure and effective than the other 3 DAPT strategies. Although East Asians have a higher risk of bleeding, more than 12 months of DAPT does not increase this incidence of major bleeding.


Xanthogranulomatous Pituitary Adenoma in a Dog with Typical Hyperadrenocorticism.
Xanthogranuloma of the sellar region has been reported in both humans and animals. The lesion is rare, and its aetiology and pathogenesis are not fully understood. The association of sellar xanthogranuloma with an adenoma, known as xanthogranulomatous pituitary adenoma (XPA), is an extremely rare condition in humans and is usually associated with anterior pituitary insufficiencies, headache, vomiting and visual deficits. We present the first report of XPA in an animal. A 7-year-old male neutered Labrador Retriever was presented for investigation of progressive lethargy, vomiting and hyporexia, having been previously diagnosed with chronic kidney disease, pituitary-dependent hyperadrenocorticism and hypoparathyroidism. The dog was euthanized due to lack of response to medical treatment and post-mortem examination revealed XPA. Although rare, xanthogranulomatous lesions should be considered in patients with pituitary disease.


An efficient (1)H/(31)P double-resonance solid-state NMR probe that utilizes a scroll coil.
The construction and performance of a scroll coil double-resonance probe for solid-state NMR on stationary samples is described. The advantages of the scroll coil at the high resonance frequencies of (1)H and (31)P include: high efficiency, minimal perturbations of tuning by a wide range of samples, minimal RF sample heating of high dielectric samples of biopolymers in aqueous solution, and excellent RF homogeneity. The incorporation of a cable tie cinch for mechanical stability of the scroll coil is described. Experimental results obtained on a Hunter Killer Peptide 1 (HKP1) interacting with phospholipid bilayers of varying lipid composition demonstrate the capabilities of this probe on lossy aqueous samples.


CXCL12/CXCR4 signal transduction in diseases and its molecular approaches in targeted-therapy.
Chemokines are small molecules called "chemotactic cytokines" and regulate many processes like leukocyte trafficking, homing of immune cells, maturation, cytoskeletal rearrangement, physiology, migration during development, and host immune responses. These proteins bind to their corresponding 7-membrane G-protein-coupled receptors. Chemokines and their receptors are anti-inflammatory factors in autoimmune conditions, so consider as potential targets for neutralization in such diseases. They also express by cancer cells and function as angiogenic factors, and/or survival/growth factors that enhance tumor angiogenesis and development. Among chemokines, the CXCL12/CXCR4 axis has significantly been studied in numerous cancers and autoimmune diseases. CXCL12 is a homeostatic chemokine, which is acts as an anti-inflammatory chemokine during autoimmune inflammatory responses. In cancer cells, CXCL12 acts as an angiogenic, proliferative agent and regulates tumor cell apoptosis as well. CXCR4 has a role in leukocyte chemotaxis in inflammatory situations in numerous autoimmune diseases, as well as the high levels of CXCR4, observed in different types of human cancers. These findings suggest CXCL12/CXCR4 as a potential therapeutic target for therapy of autoimmune diseases and open a new approach to targeted-therapy of cancers by neutralizing CXCL12 and CXCR4. In this paper, we reviewed the current understanding of the role of the CXCL12/CXCR4 axis in disease pathology and cancer biology, and discuss its therapeutic implications in cancer and diseases.


Vasopressin and oxytocin express excitatory effects on respiratory and respiration-related neurones in the nuclei of the tractus solitarius in the cat.
The effects of the iontophoretic application of vasopressin and oxytocin were examined on the activity of single neurones recorded in the region of the nuclei of the tractus solitarius (NTS) of the cat that were functionally classified as respiratory neurones or presumed reflex interneurones. The excitatory effects observed in half to two-thirds of these neurones tested (n = 37) suggest a role of these peptides in respiratory control and further support recent evidence that their involvement in autonomic control may include an action in NTS.


Care Intensity During Transport to the Critical Care Resuscitation Unit: Transport Clinician's Role.
Patients are often transferred between hospitals for a higher level of care. Critically ill patients require high-intensity care after transfer, but their care intensity during transport is unknown. We studied transport clinicians' management for patients who had time-sensitive or critical illnesses and were transferred to a critical care resuscitation unit (CCRU) at a quaternary academic center. We prospectively surveyed transport clinicians who brought interhospital transport patients to the CCRU between March 1, 2019, and January 8, 2020. The primary outcome was care intensity during transport, which was defined as new interventions rendered by transport clinicians. We analyzed 852 surveys. Seventy-four percent of transports occurred by ground, and 54% originated from emergency departments. Up to 19% of patients received 2 or more interventions, whereas 29% received at least 1 intervention during transport. Ventilator management occurred in 25% of cases. When adjusting for known confounders, respiratory failure or acute respiratory distress syndrome, air transport, and contacting the CCRU attending physicians en route were associated with a higher likelihood of an intervention during transport. Transport clinicians provided new interventions in 48% of patients being transferred to the CCRU. Patients with respiratory failure or acute respiratory distress syndrome and those transported by helicopter emergency medical services were more likely to receive interventions en route.


The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells.
Evidence that membrane-bound and extracellular heat shock proteins (HSPs) with molecular weights of 70 and 90 kDa are potent stimulators of the immune responses has accumulated over the last decade. In this review, we discuss the modulation of Hsp70 expression, a major stress-inducible member of the HSP70 family, in the cytoplasm and on the plasma membrane of tumor cells by clinically applied interventions such as radio- and chemotherapy.


Antiepileptic drug teratogenesis: what are the risks for congenital malformations and adverse cognitive outcomes?
Antiepileptic drug (AED) exposure in utero has been associated with major congenital malformations (MCMs) and adverse cognitive outcomes in the offspring of women with epilepsy (WWE). However, determining the exact risk and the relative risks of AEDs for these outcomes has been challenging, and only in recent years has improved study designs enabled us to get a clearer picture of the risks. Still, there is a startling lack of information for many of the newer and widely used AEDs. At this point of time, studies clearly show that valproate (VPA) as a part of polytherapy or when used as a monotherapy is associated with an increased risk of MCMs, and that it poses about threefold the risk of carbamazepine (CBZ). It is unclear if any other AEDs studied pose an increased risk of MCM occurrence; in the best available large study the absolute rates of MCMs with other several other AEDs were not different from untreated WWE. The absolute risks have been reported as CBZ 2.2%, lamotrigine (LTG) 3.2%, phenytoin (PHT) 3.7%, untreated WWE 3.5%, with VPA as the outlier at 6.2%. In utero VPA exposure is also associated with a risk of lower verbal intelligence quotient (IQ) in children, at approximately 10 points lower than controls. CBZ appears to pose no risk to cognitive outcome, and there is some evidence that PHT and phenobarbital (PB) may be associated with risk of reduced cognitive outcome. Polytherapy is associated with greater risk than monotherapy for both MCMs and cognitive outcome. Although more information is needed and hopefully will be obtained from ongoing prospective studies, it is clear that WWE taking VPA and planning pregnancy should have a discussion with their physician about considering changing to another AED before pregnancy, if possible.


Extinction dynamics, population growth and seed banks : An example using an age-structured annual.
The goal of this paper is to test theoretical predictions about the effects of seed banks on population dynamics and extinction rates in variable environments using simulations based on data from a natural population of the winter annual Collinsia verna. In the simulations, we varied the frequency of demographically good and bad years and the autocorrelation between conditions in consecutive years to examine the impact of seed dormancy on population growth rate, extinction rate and time to extinction. The existence of a seed bank enhanced population growth rates under all environmental regimes except when good years were very frequent, but this enhancement was minimal. In addition, the presence of the seed bank decreased the likelihood of extinctions and increased the time to extinction. The time to extinction was longest when the environmental conditions were most unpredictable.