A Methodology for In-Well Multiphase Flow Measurement with Strategically Positioned Local and/or Distributed Acoustic Sensors.
A new three-phase downhole flow measurement methodology is developed based on measurements of speed of sound at different locations along the well, where the pressure is greater than the bubble-point pressure at the first location and smaller at the second location. A bulk velocity measurement is also required at the second location. The fluid at the first location is a mixture of two phases, but becomes a mixture of three phases at the second location due to the liberation of gas from the oil phase. The flow equations are first solved for two-phase flow at the first location to obtain the first phase fraction, water-in-liquid ratio, and then this information is fed into the flow equations after adjustment to the local pressure and temperature conditions to solve for three-phase flow at the second location to obtain the second phase fraction, namely the liquid volume fraction. These two phase fractions along with the bulk velocity at the second location are sufficient to calculate the three-phase flow rates. The methodology is fully explained and the analytical solutions for three-phase flow measurement is explicitly provided in a step-by-step process. A Lego-like approach may be used with various sensor technologies to obtain the required measurements, although distributed acoustic sensing systems and optical flowmeters are ideal to easily and efficiently adopt the current methodology. This game-changing new methodology for measuring downhole three-phase flow can be implemented in existing wells with an optical infrastructure by adding a topside optoelectronics system.


Hydrodynamic transformation of a freestanding polymer nanosheet induced by a thermoresponsive surface.
Freestanding quasi-two-dimensional ultrathin films (e.g., 41 nm thick polymer nanosheets) were produced, on which stimuli-responsive 47 nm thick polymer brushes were constructed by atom transfer radical polymerization (ATRP) of poly(N-isopropylacrylamide). The resulting surfaces of the multilayered polysaccharide ultrathin films were evaluated by ellipsometry, IR imaging, in situ variable-temperature atomic force microscopy (AFM), and contact angle measurements. The morphological transformation of the freestanding polymer nanosheet bearing thermoresponsive polymer brushes was observed macroscopically through reversible structural color changes at the air-water interface. The dynamic shape change of the nanosheet was also monitored with the addition of a surfactant such as sodium n-dodecylsulfate to reduce the hydrophobicity of the surface. It was then demonstrated that the highly flexible freestanding polymer nanosheet is capable of acting as a unique platform for inducing stimuli-responsive behavior in nanomaterials.


Human umbilical cord blood mononuclear cell-conditioned media inhibits hypoxic-induced apoptosis in human coronary artery endothelial cells and cardiac myocytes by activation of the survival protein Akt.
We have previously demonstrated in acute myocardial infarctions that human umbilical cord blood mononuclear cells (HUCBCs), which contain hematopoietic, endothelial, and mesenchymal stem cells, reduce acute myocardial infarction size by ≥50% and preserve LV contractility. We hypothesize that the beneficial effects of HUCBCs are due to secretion of biologically active factors that activate in cardiac endothelial cells and myocytes the cell survival protein Akt. We determined by protein microarrays the growth factors and anti-inflammatory cytokines secreted by HUCBCs into culture media during 12 h of hypoxia (1% O2). We then determined by Western blots the effects of cell-free media from hypoxic-conditioned HUCBCs (HUCM) on activation of the cell survival protein Akt in human coronary artery endothelial cells and cardiac myocytes in culture during 24 h of 1% O2. We also determined in separate experiments endothelial cell and myocyte apoptosis by caspase-3 and Annexin V. In the present experiments, HUCBCs secreted multiple growth factors, anti-inflammatory cytokines, and inhibitors of metalloproteinase during normoxia and hypoxia. Human cord blood cells increased the concentration in culture media of angiopoietin, hepatocyte growth factor, interleukin-4, insulin-like growth factor, placental growth factor, vascular endothelial cell growth factor, angiogenin, and stem cell factor by 100 to >10,000% during 12 h of 1% O2 (p<0.001). HUCM, which contained these biological factors, significantly increased Akt phosphorylation/activation in coronary artery endothelial cells and cardiac myocytes subjected to 24 h of 1% O2 by more than 60% (p<0.05) and increased the antiapoptotic protein Bcl-2 expression by 34-50% in comparison with endothelial cells and myocytes treated without HUCM in 1% O2(p<0.05). HUCM also significantly decreased caspase-3 activity and decreased hypoxic endothelial cell and cardiac myocyte apoptosis by more than 40% in comparison with cells cultured without HUCM (p<0.05). Inhibition of Akt activation in endothelial cells and myocytes by the sensitive and specific antagonist API-1 during 24 h of hypoxia nearly completely prevented the beneficial effects of HUCM on inhibiting caspase-3 activity and apoptosis. We conclude that HUCBCs secrete biologically active factors during hypoxia that activate survival proteins in endothelial cells and myocytes that significantly limit apoptosis.


Multiple forms of basic fibroblast growth factor: amino-terminal cleavages by tumor cell- and brain cell-derived acid proteinases.
Basic fibroblast growth factor (FGF) was purified by heparin-Sepharose chromatography from two sources, brain and hepatoma cells. Brain cell-derived basic FGF (brFGF) and hepatoma cell-derived basic FGF (heFGF) were found to exist in multiple forms whose molecular weights depended on whether they were extracted from their respective tissue or cells at neutral or acid pH. When extracted at pH 7.0 brFGF and heFGF comigrated on NaDodSO4/PAGE with a Mr of approximately 18,400. When extracted at pHs 3.5-4.5, acid proteinases cleaved brFGF and heFGF to lower molecular weight forms but to different extents. brFGF was cleaved to a Mr 18,000 form at acid pH by a brain-derived acid proteinase that could be inhibited by pepstatin. heFGF was cleaved mostly to a Mr 16,500 form at acid pH by a hepatoma cell-derived acid proteinase that was inhibited by leupeptin. Electrophoretic transfer blot analysis using site-specific anti-FGF antibodies suggested that the cleavages occurred at the amino-terminal ends of brFGF and heFGF. Cleavage to lower molecular weight forms of brFGF and heFGF did not affect growth factor activity or chromatographic behavior on heparin-Sepharose columns.


Hypertensive Retinopathy Secondary to Anlotinib Treatment.
We report a case of a middle-aged woman who developed hypertensive retinopathy following oral administration of Anlotinib. A 48-year-old woman presented to our hospital with sudden painless loss of vision in both eyes combined with headache, nausea, and vomiting following oral administration of Anlotinib. This drug is often used to control cancer progression. Due to the deterioration of her blood pressure, which reached 167/113 mm Hg, Anlotinib was discontinued and the blood pressure was controlled by hypertension medications. This normalized her blood pressure, alleviated headache, and restored her vision. She visited our eye department 37 days later for eye check-up. The best-corrected visual acuities was 0.3 in the right eye and 0.4 in the left eye. The fundus examinations revealed a clear boundary of the optic papilla with significant stellate exudation in the macular area. The posterior pole of the retina displayed high hemorrhage, with a cotton-wool spot appearance. Optical coherence tomography (OCT) revealed atrophy in the outer segment of macular area, and hard exudations in retinal layers. Based on these findings, hypertensive retinopathy was diagnosed, as a secondary complication of Anlotinib. Anlotinib can induce hypertensive retinopathy. Patients receiving this drug should be closely monitored for potential complications.


The purification and characterisation of the human-serum binding protein for the 25-hydroxycholecalciferol (transcalciferin). Identity with group-specific component.
The binding protein for 25-hydroxyvitamin D3 has been isolated from human serum by monitoring the recovery of 3H-labeled 25-hydroxyvitamin D3. After a 500-fold purification a pure protein was obtained as judged from the constant specific activity (ratio of absorbance versus radioactivity) on agarose and DEAE-Sephadex chromatography and on the presence of a single band on both cellulose acetate and polyacrylamide gel electrophoresis. The molecular weight of the purified protein was measured by gel filtration on agarose (56000), Sephadex G-75 (58000) and dodecylsulfate-polyacrylamide gel electrophoresis (56000). On sucrose gradient ultracentrifugation a sedimentation coefficient of 4.1 S was found. The isoelectric point was 4.89 S on isoelectric focusing. The stability of the protein at 60 degrees C was enhanced by the presence of excess 25-hydroxyvitamin D3. On tandem crossed immunoelectrophoresis the purified binding protein was found to be identical to the one present in whole serum. The activity of the isolated protein was demonstrated by a Ka at 4 degrees C of 1.2 X 10(10) l-mol-1. A binding capacity of 0.8 binding site/molecule was measured on a Sephadex G-25 column. During immunological studies with this protein it became evident that the binding protein is identical with another serum protein known as group-specific component (Gc). In analogy to other serum binding proteins we propose to call this group-specific component/25-hydroxyvitamin-D3-binding protein transcalciferin.


Tug-of-War in a Dynamic Helical Peptide: Solvent-Induced Helix-Helix Transition of a Lactam-Bridged Peptide Composed of Point- and Axial Chiralities Remote from Each Other.
The dynamic axial chirality of oligopeptide-bound 2,2'-bipyridine (bpy) residues can be remote-controlled and diastereoselectively locked. A right-handed (P)-310 -helix is first induced in the dynamic helical oligopeptide by an l-valine (l-Val) far from the bpy moiety and the induced axial bpy chirality is diastereoselectively dioxidized. The resulting l-Val-containing linear oligopeptides at the 3,3'-positions retain their (P)-310 -helices independent of the axial chirality (aR or aS) of the N-terminal N,N'-dioxide-bpy unit, while a lactam-bridged dynamic helical oligopeptide exhibits a unique solvent-induced helix-helix transition as a result of competitive helix-inducing biases between the l-Val and (aR) or (aS)-N,N'-dioxide-bpy residues remote from each other along the entire oligopeptide chain in a tug-of-war like manner.


A double-blinded, randomized, controlled, crossover evaluation of a zinc methionine supplement as an adjunctive treatment for canine atopic dermatitis.
Zinc is important for skin health and proper immune system function. A zinc methionine, essential fatty acids (EFA) and biotin product (Zn supplement) was compared to an EFA and biotin product (control) in canine atopic dermatitis (CAD). Twenty seven client-owned dogs with chronic CAD receiving ciclosporin or glucocorticoids. A 24 week, randomized, double-blinded, controlled study with crossover at week 12 and 4 week period of allergy medication reduction at weeks 8 and 20. Evaluations included Canine Atopic Dermatitis Lesion Index (CADLI), pruritus Visual Analog Scale (VAS) and cytology sampling. In dogs receiving the zinc supplement and ciclosporin for eight weeks, 44% (n = 7) had significantly decreased CADLI from 11.9 to 6.0 (P = 0.0002) with no significant change in pruritus VAS (P = 1.0). In dogs receiving the zinc supplement and glucocorticoids for eight weeks, 55% (n = 6) had significantly decreased CADLI from 10.9 to 5.0 (P = 0.0043) and pruritus VAS from 7.4 to 3.2 (P = 0.0166). For dogs receiving either steroids or ciclosporin there was a reduction in use of such medications, for at least four weeks, in 63% of dogs receiving the zinc supplement and 37% of dogs receiving the control. This difference was not significant (P = 0.1027). Seventy eight percent of dogs were diagnosed and treated for superficial skin infections during the study. This study supports a potential benefit of adjunctive zinc methionine supplementation in CAD. Dogs receiving glucocorticoids may be more likely to benefit. Further studies are needed to substantiate these initial results.


Subthreshold Depression: A Systematic Review and Network Meta-Analysis of Non-Pharmacological Interventions.
Subthreshold depression (StD) is considered to be the "precursor" stage of major depressive disorder (MDD), which could cause higher risk of suicide, disease burden and functional impairment. There have been various non-pharmacological interventions for StD. However, the comparison of their effectiveness still lacks sufficient evidence. We performed a systematic review and network meta-analysis to evaluate and rank the efficacy of multiple non-pharmacological interventions targeting StD. We conducted a thorough search across various databases including PubMed, Medline, Embase, Web of Science and PsycINFO from inception to December 2022. All included studies were randomized controlled trials (RCTs) of non-pharmacological interventions for patients with StD compared with control group (CG). Several universal scales for measuring depression severity were used as efficacy outcomes. The surface under the cumulative ranking curve (SUCRA) was used to separately rank each intervention using the "Stata 17.0" software. A total of thirty-six trials were included, involving twenty-eight interventions and 7417 participants. The research found that most non-pharmacological interventions were superior to controls for StD. In each outcome evaluation by different scales for measuring depression, psychotherapy always ranked first in terms of treatment effectiveness, especially Problem-solving Therapy (PST), Behavioral Activation Therapy (BAT), Cognitive Behavioral Therapy (CBT)/Internet-based CBT (I-CBT)/Telephone-based CBT (T-CBT). Since different groups could not be directly compared, the total optimal intervention could not be determined. Here, we show that psychotherapy may be the better choice for the treatment of StD. This study provides some evidence on StD management selection for clinical workers. However, to establish its intervention effect more conclusively, the content, format and operators of psychotherapy still require extensive exploration to conduct more effective, convenient and cost-effective implementation in primary healthcare. Notably, further research is also urgently needed to find the biological and neural mechanisms of StD by examining whether psychotherapy alters neuroplasticity in patients with StD.


Hypogonadotropic hypogonadism in men with hereditary hemochromatosis.
Hereditary hemochromatosis is a genetic disease that progresses silently. This disease is often diagnosed late when complications appear. Hypogonadotropic hypogonadism (HH) is one of the classical complications of hemochromatosis. Its frequency is declining probably because of earlier diagnosis and better informed physicians. Certain symptoms linked to HH can have an impact on a patient's sexuality, such as decreased libido, erectile dysfunction, and impairment of ejaculation, as well as on his reproductive capacities. This review is based on an online search in English, French and German language publications found in PubMed/Medline, up to 23 September 2016 using the following key word: Male infertility, Hypogonadotropic Hypogonadism, Hereditary Hemochromatosis. Thirty-four papers met these inclusion criteria. This review describes the impact of iron overload on male fertility, resulting in hypogonadotropic hypogonadism and proposes treatment modalities.


Multiple-wavelength powder diffraction using imaging plates at the Australian National Beamline.
The Australian powder diffractometer at the Photon Factory is capable of recording multiple powder-diffraction scans in less than 5 min per pattern using imaging plates in Debye-Scherrer geometry. This, coupled with incrementing the X-ray beam energy in suitably small steps (down to approximately 2 eV) between exposures, allows fast collection of anomalous diffraction data. Data collected from a copper oxide-based superconductor at energies near the Cu K-absorption edge are presented, along with an account of the technique used to extract multiple-exposure powder-diffraction data from imaging plates.


Mercury and lead budgets for Lochnagar, a Scottish mountain lake and its catchment.
Lochnagar is a mountain lake located to the southeast of the Cairngorm Mountains in Scotland. The inputs and outputs of Hg and Pb and their distribution within the various ecosystem compartments were measured. Further, 17 sediment cores and 10 catchment peat cores were taken and dated using spheroidal carbonaceous particle (SCP) and 210Pb techniques. Total and anthropogenic Hg and Pb inventories since the 1860s for the lake basin and the catchment peats were calculated using this multiple core strategy. Hg sediment flux profiles based on the whole lake basin show that the flux to the sediments increased from the 1880s until the 1970s. This was followed by a relatively stable period (1970s to the present), during which the flux was approximately twice that of the 1880s. Similarly, the Pb flux increased from the 1860s until the 1940s and was also followed by a relatively stable period through to the present. Hg and Pb budgets for the whole catchment for 1998 indicated that 78% of the Hg and 91% of the Pb input to the lake were transported from the catchment. Hence, the expected decline resulting from the decrease in the atmospheric deposition of Pb was obscured in the sediment record. It is estimated that 77% of the total Hg and 90% of the total Pb deposited since the 1860s, and stored in the upper layers of the catchment peat soils, are from anthropogenic sources. The increased storage of Hg and Pb in the catchment implies that this will be a major source of these metals for the lake for many years. This will delay the restoration of the lake system, despite reductions in emissions to the atmosphere and subsequent deposition.


Host reactivity to a spontaneous tumor: generation of antitumor activity by lymph node cells following incubation in vitro.
A spontaneous fibrosarcoma (SP/T-1) which arose in a syngeneic Balb/c mouse failed to show clear evidence of immunogenicity when examined by the in vivo immunization/challenge technique. However, when the lymph node cells (LNC) of tumor-'immunized' donors were cultured in vitro for approximately 2 days in the absence of tumor cells, they were found to be markedly inhibitory to the tumor in cell transfer assays. A similar effect was also found in the LNC of tumor-bearers but this was less marked. The antitumor activity appeared to be mediated largely by the T cells, since the depletion of Thy 1 positive cells abolished or markedly decreased the LNC inhibitory activity towards the tumor cells. The activated LNC were found to be specifically cytotoxic to the SP/T-1 cells since they did not destroy cells of two other syngeneic cell types tested--a methylcholanthrene-induced fibrosarcoma, MC677 and a neonatal heart-derived normal cell line NEO/H. Neither of these cell types showed virus particles by electron microscopy and since C type virus-like particles were detected within the SP/T-1 cells by electron microscopy the possibility exists that viral antigenic determinants expressed on the tumor cell surface acted in tumor cell recognition and destruction in this tumor system. However, the possibility cannot be excluded that in vitro-activated natural killer cells also participated in tumor cell killing. These observations clearly indicate the existence of tumor-associated transplantation antigens in certain 'non-immunogenic' tumors as well as antitumor effector mechanisms which remain totally suppressed in vivo.


Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naïve chronic hepatitis B patients in the real-world setting.
The aim of this study was to determine the long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment-naïve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End-Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long-term follow-up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.


Long-term outcome in patients with takotsubo syndrome : A single center study from Vienna.
There is an increasing amount of evidence suggesting multiple fatal complications in takotsubo syndrome; however, findings on the long-term outcome are scarce and show inconsistent evidence. This is a single center study of long-term prognosis in takotsubo patients admitted to the Klinik Ottakring, Vienna, Austria, from September 2006 to August 2019. We investigated the clinical features, prognostic factors and outcome of patients with takotsubo syndrome. Furthermore, survivors and non-survivors and patients with a different cause of death were compared. Overall, 147 patients were included in the study and 49 takotsubo patients (33.3%) died during the follow-up, with a median of 126 months. The most common cause of death was a non-cardiac cause (71.4% of all deaths), especially malignancies (26.5% of all deaths). Moreover, non-survivors were older and more often men with more comorbidities (chronic kidney disease, malignancy). Patients who died because of cardiovascular disease were older and more often women than patients who died due to non-cardiovascular cause. Adjusted analysis showed no feature of an independent predictor of cardiovascular mortality for takotsubo patients. Female gender (HR = 0.32, CI: 0.16-0.64, p < 0.001), cancer (HR = 2.35, CI: 1.15-4.8, p = 0.019) and chronic kidney disease (HR = 2.61, CI: 1.11-6.14, p = 0.028) showed to be independent predictors of non-cardiovascular mortality. Long-term prognosis of takotsubo patients is not favorable, mainly due to noncardiac comorbidities. Hence, consequent outpatient care in regular intervals after a takotsubo event based on risk factor control and early detection of malignancies seems justified.


Carbohydrate and lipid metabolism during human labor: free fatty acids, glucose, insulin, and lactic acid metabolism during normal and oxytocin-induced labor for postmaturity.
This investigation was performed to study the metabolism of the major body fuels (viz. glucose and free fatty acids), insulin, and lactic acid during the stress of human labor. In addition, the role of the normal placenta in the transport of these substances between mother and the fetus was evaluated by measuring them in the mother and cord blood at delivery. To study possible alterations of this role in the placenta which had exceeded the normal period of gestation, a second comparable group of women had labor induced with oxytocin 16-18 days beyond the expected date of delivery. A dramatic twofold increase in maternal plasma free fatty acids was observed during labor. There was a lesser but definite increase in blood glucose concentrations. No rise in serum insulin levels was noted which coincided with the changes in blood glucose. Lactic acid concentrations during the course of labor were variable from baseline but at delivery, the concentrations rose to very significant levels. Free fatty acids and blood glucose levels were significantly higher in the maternal than in the fetal side. A significantly positive correlation was noted between the maternal and cord blood values except for free fatty acids in the postmature group. No significant difference, nor a correlation was found between the two compartments in the insulin nor lactic acid levels. These results suggest that during human labor free fatty acids are the principal metabolic fuel. This increase in maternal free fatty acids may serve to spare glucose as a metabolic fuel in the fetus. The mechanism responsible for the increase maternal free fatty acid mobilization remains to be determined. It is not possible to discern any consistant alteration in placental function as a consequence of prolonged gestation.


Determinants of full immunization coverage among children 12-23 months of age from deviant mothers/caregivers in Ethiopia: A multilevel analysis using 2016 demographic and health survey.
Despite remarkable improvements in child health services utilization, childhood immunization has been poorly implemented in Ethiopia. However, evidence on the coverage of immunization among children from mothers/caregivers with no education (non-educated mothers were the most identified risk for underutilization of services) are scarce. Therefore, this study aimed to assess the determinants of full immunization coverage among children 12-23 months of age from deviant mothers/caregivers in Ethiopia. We analyzed data from the 2016 Ethiopia Demographic and Health Survey (EDHS) on a sample of 1,170 children 12-23 months of age identified from deviant mothers/caregivers (mothers/caregivers with no education) through a two-stage stratified sampling. A multilevel mixed-effect binary logistic regression analysis was used to identify the individual and community level determinants of full immunization coverage among children 12-23 months of age with their deviant mothers/caregivers. In the final model, a p-value of < 0.05 and adjusted odds ratio (AOR) with 95% confidence interval (CI) were used to select statistically significant determinants of full immunization coverage. The overall full immunization coverage among children 12-23 months of age identified from deviant mothers/caregivers was 27.4% (95%CI: 25.0, 31.0) in Ethiopia. Deviant mothers/caregivers who are employed (AOR = 1.69, 95%CI: 1.68, 2.45), being in the rich household wealth status (AOR = 2.54, 95%CI: 1.53, 4.22), residing in city (AOR = 5.69, 95%CI: 2.39, 13.61), having one to three (AOR: 3.28, 95% CI: 2.12-5.07) and four and more ANC follow-up during the recent pregnancy (AOR: 3.91, 95% CI: 2.45, 6.24) were the determinants that increased full immunization coverage among children 12-23 months of age. Full immunization coverage among children 12-23 months of age from non-educated mothers/caregivers was low and far behind the national target of coverage. Therefore, a system-wide intervention should be used to enhance employability, wealth status, and key maternal health services like ANC follow-up among non-educated mothers/caregivers to increase their children's full immunization coverage.


Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome.
To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.


The diagnostic significance of periportal hepatic necrosis and inflammation.
In this review the several types of cell damage and cell death which may be found in liver biopsy specimens are defined. We describe the different processes which occur at the portal/parenchymal or septal/parenchymal interface, viz. periportal spillover, periportal hepatitis, classic or lymphocytic piecemeal necrosis and biliary piecemeal necrosis. The diagnostic implications of these lesions in relation to the clinicopathological diagnosis and prognosis in various liver diseases are discussed.


The role of serotonin-1A receptor activation and alpha-1 adrenoceptor blockade in the hypotensive effect of 5-methyl-urapidil.
Our study had three purposes: 1) to determine whether 5-methyl-urapidil, topically applied to the ventrolateral medulla, produces hypotension by activating serotonin-1A (5-HT1A) receptors, 2) to determine whether 5-methyl-urapidil given i.v. produces hypotension in part by activating 5-HT1A receptors in the ventrolateral medulla, and 3) to determine the specific site within the ventrolateral medulla where 5-methyl-urapidil elicits a hypotensive response. In terms of the first purpose, 5-methyl-urapidil applied bilaterally to the intermediate area of the ventral surface of the medulla (1.2 micrograms/side) of chloralose-anesthetized cats produced a decrease in mean arterial pressure of -39 +/- 4 mm Hg (N = 8). Prior blockade of 5-HT1A receptors at this site with bilateral application of spiperone (30 micrograms/side) prevented the hypotensive effect of 5-methyl-urapidil (mean blood pressure now increased by 5 +/- 4 mm Hg). Pretreatment with the alpha-1 adrenoceptor antagonist, prazosin, did not prevent the hypotensive effect of 5-methyl-urapidil. In terms of the second purpose, spiperone applied bilaterally to the ventral surface of the medulla counteracted a significant portion of the hypotensive effect of 5-methyl-urapidil given by the i.v. route. The dose of 5-methyl-urapidil given intravenously was below the dose that produces alpha-1 adrenoceptor blockade. In terms of the third purpose, microinjection of 5-methyl-urapidil into central nervous system sites associated with the intermediate area was found to have its greatest hypotensive effect at the subretrofacial nucleus. Mean arterial pressure decreased by 74 +/- 14 mm Hg (N = 3) after bilateral microinjection of 25 ng of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)


Prostaglandin E1 (misoprostol) overcomes the adverse effect of chronic cigarette smoking on duodenal ulcer healing.
Chronic cigarette smoking adversely affects duodenal ulcer healing despite treatment by potent gastric acid-reducing agents. Prostaglandins of the E series possess antisecretory and cytoprotective properties and theoretically offer advantages over existing therapeutic agents. A double-blind randomized study was performed to compare complete duodenal ulcer healing as assessed by endoscopies every two weeks for up to 12 weeks. Two hundred twenty-nine patients were randomized to receive misoprostol, an orally stable synthetic derivative of prostaglandin E1, in 200-micrograms or 300-micrograms qid dosages, or placebo. Life-table analysis showed that (1) both regimens of misoprostol were significantly more effective than placebo, achieving healing rates of 61% and 71%, respectively, at four weeks, and (2) cigarette smoking significantly impaired healing by placebo but not by misoprostol. In fact, the time-healing curves of smokers and nonsmokers on the higher dose of misoprostol completely overlapped. Furthermore, delayed treatment and large ulcer diameter adversely affected healing by misoprostol in smokers, whereas in nonsmokers, high basal and maximal acid output were unfavorable. Misoprostol is recommended for the treatment of duodenal ulcer, particularly in chronic smokers early in a given period of symptoms.


Factitious methemoglobinemia caused by hyperlipemia.
Hyperlipemia in an acyanotic patient with diabetic ketoacidosis, alcoholism, and pancreatitis produced a falsely elevated concentration of methemoglobin (19 percent) and a lower-than-expected oxygen saturation measured with an automated spectrophotometer (IL-282 CO-Oximeter). In addition, there was a "normal" hemoglobin level despite a low hematocrit reading. In vitro studies showed that hyperlipemia corresponding to triglyceride levels of 500 mg/100 ml and greater produced erroneously high values for methemoglobin and total hemoglobin and "negative" values for carboxyhemoglobin. These abnormalities disappeared when the excessive lipids were removed by washing the erythrocytes in physiologic saline solution.


Continuous Erector Spinae and Serratus-Intercostal Block With Ketamine-Dexmedetomidine Sedation for Quadrantectomy and Axillary Dissection in a Multimorbid Patient.
Multimorbidity is a clinical presentation that poses an increased risk of perioperative and postoperative complications. Tailored anaesthetic management could potentially minimise the risk of negative outcomes. Peripheral nerve and fasciae blocks are valid strategies for perioperative and postoperative pain management, which avoid complications related to general anaesthesia and reduce the risk of intensive care unit admission as well as the hospital length of stay. We describe the case of a 56-old patient with multimorbidity, including obesity with a BMI of 45.7, unstable angina, predicted difficult airway management and obstructive sleep apnoea syndrome (OSAS) scheduled for left mastectomy with sentinel lymph node biopsy, managed with a left continuous thoracic erector spinae plane (ESP) block plus serratus-intercostal plane block (BRanches of Intercostal nerves at the Level of Mid-Axillary line (BRILMA)), and sedation with combined ketamine-dexmedetomidine. Fascial blocks combined with opioid-free anaesthesia (OFA) proved to be effective for the multimorbid patient, ensuring successful perioperative management and a proper recovery after surgery.


[Burnout's syndrome in critical care nursing professionals].
The concept of the "Burnout Syndrome" has come as a result of the chronic work-stress developed in workers involved in human services during their professional activity. The working conditions and the specific characteristics of the job developed at the Intensive Care Units by the nursing staff, involve a high risk for this group to acquire this syndrome. The main objective of this study is to assess the prevalence of the Burnout Syndrome in the nursing staff of the ICUs in different hospitals of the Alicante province, Spain, by means of the Malsach Burnout Inventory questionnaire. This questionnaire is self-administered and was handed to all the nursing staff at the ICUs in the University Hospitals of Alicante and Elche and in the Hospital Marina Baixa of Villajoyosa. form the total of 107 questionnaires, 83 proved to be valid. The average total of MBI was of 55.05, indicating low values of emotional tiredness, low depersonalisation, and an adequate level of personal accomplishment.


Abdominoperineal Pull-through with Simultaneous Extravesical Detrussoraphy: An Alternative Surgical Technique for Congenital Pouch Colon with High-grade Vesicoureteric Reflux.
Congenital pouch colon (CPC) is frequently associated with vesicoureteric reflux (VUR). These patients require long-term antibiotic prophylaxis and/or an additional surgical intervention for the management of the refluxing system. We propose a single-stage alternative approach in these patients. Two patients diagnosed to have CPC underwent pouch excision and an end colostomy at birth. Further evaluation revealed high-grade reflux in both the patients. At 6 months of age, definitive abdominoperineal pull-through (APPT) surgery along with extravesical detrusorrhaphy was performed. In the follow-up at 1 year, they are thriving well with no urinary complaints. Micturating cystourethrogram revealed complete resolution of VUR. This approach takes the advantage of the anesthesia for APPT and offers a relatively simple and quick solution for the refluxing system, thus, enabling the stoppage of antibiotic prophylaxis and obviating the need for a future endoscopy/surgery.


Integrating Quality Improvement and Continuing Professional Development at an Academic Medical Center: A Partnership Between Practice Plan, Hospital, and Medical School.
While quality improvement (QI) initiatives can be a highly effective means for improving health care delivery in academic medical centers (AMCs), many health care professionals are not formally trained in basic QI methodology, engaging clinicians in QI activities can be challenging, and there is often a lack of integration and coordination among QI functions (eg, Departments of Quality and Safety, Continuing Professional Development). In our AMC, we undertook a collaborative approach to achieve better vertical and horizontal integration of our QI education efforts. This article provides a case example describing our organizational context, what was done, and with what effect and makes our example and lessons learned available to others. We developed a new educational QI program that was jointly planned and implemented by a group comprising major QI stakeholders. This project was intended to create horizontal organizational linkages between continuing professional development, clinicians, the hospital, and QI department and produce QI activities that aligned with the strategic objectives of senior management. The group developed and implemented a curriculum based on Lean methodology and concepts from the Institute for Health Care Improvement Model for Improvement. Two cohorts (27 teams) completed the training and planned and implemented QI projects. All projects were aligned with organizational quality, safety, and patient experience goals. The majority of projects met their aim statements. This case description provides an example of successful horizontal integration of an AMCs' QI functions to disseminate knowledge and implement meaningful QI aligned with strategic objectives (vertical integration).


The Changing Hospital Landscape: An Exploration of International Experiences.
The nature of hospital activity is changing in many countries, with some experiencing a broad trend towards the creation of hospital groups or chains and multi-hospital networks. This study seeks to contribute to the understanding of experiences in other countries about the extent to which different hospital "models" may provide lessons for hospital provision in England by means of a review of four countries: France, Germany, Ireland and the United States, with England included for comparison. We find that there has been a trend towards privatisation and the formation of hospital groups in France, Germany, and the United States although it is important to understand the underlying market structure in these countries explaining the drivers for hospital consolidation. Thus, and in contrast to the NHS, in France, Germany, and the United States, private hospitals contribute to the delivery of publicly funded healthcare services. There is limited evidence suggesting that different forms of hospital cooperation, such as hospital groups, networks or systems, may have different impacts on hospital performance. Available evidence suggests that hospital consolidation may lead to quality improvements as increased size allows for more costly investments and the spreading of investment risk. There is also evidence that a higher volume of certain services such as surgical procedures is associated with better quality of care. However, the association between size and efficiency is not clear-cut and there is a need to balance "quality risk" associated with low volumes and "access risk" associated with the closure of services at the local level.


Dyspareunia: an unusual presentation of leiomyoma of the bladder.
Leiomyoma is a rare, benign tumor of the bladder. It frequently has an unusual presentation and its treatment options remain controversial. We describe a case of a leiomyoma of the bladder in a young female whose chief complaint was dyspareunia, and we review the management options.


Nutrition Risk Screening in Intensive Care Units: Agreement Between NUTRIC and NRS 2002 Tools.
The American Society for Parenteral and Enteral Nutrition recommends nutrition screening in patients admitted to the intensive care unit (ICU) and indicates the use of 2 tools: Nutritional Risk Screening 2002 (NRS 2002) or Nutrition Risk in the Critically Ill (NUTRIC). This study aims to compare nutrition risk detected by NRS 2002 and NUTRIC to identify whether both tools are equivalent for clinical practice in the ICU. A retrospective cohort study was conducted in 2 hospital centers in the south of Brazil. Adult patients (≥18 years old) who stayed in the ICU for >24 hours were included. NUTRIC and NRS 2002 were compared with each other for their agreement in screening for nutrition risk. The study included 208 patients, most of them male (63.5%). The comparison between both nutrition screening tools showed fair agreement (κ = 0.39). Nearly half of the patients were classified at high nutrition risk by NUTRIC (47.6%), whereas only approximately one-third of the sample was classified similarly by NRS 2002 (35.6%). Despite the ability to identify patients with high nutrition risk, NUTRIC and NRS 2002 performed differently and were not concordant, suggesting that are not equivalent for clinical practice in the ICU.


Opposing Effects of Oxygen Regulation on Kallistatin Expression: Kallistatin as a Novel Mediator of Oxygen-Induced HIF-1-eNOS-NO Pathway.
Oxidative stress has both detrimental and beneficial effects. Kallistatin, a key component of circulation, protects against vascular and organ injury. Serum kallistatin levels are reduced in patients and animal models with hypertension, diabetes, obesity, and cancer. Reduction of kallistatin levels is inversely associated with elevated thiobarbituric acid-reactive substance. Kallistatin therapy attenuates oxidative stress and increases endothelial nitric oxide synthase (eNOS) and NO levels in animal models. However, kallistatin administration increases reactive oxygen species formation in immune cells and bacterial killing activity in septic mice. High oxygen inhibits kallistatin expression via activating the JNK-FOXO1 pathway in endothelial cells. Conversely, mild oxygen/hyperoxia stimulates kallistatin, eNOS, and hypoxia-inducible factor-1 (HIF-1) expression in endothelial cells and in the kidney of normal mice. Likewise, kallistatin stimulates eNOS and HIF-1, and kallistatin antisense RNA abolishes oxygen-induced eNOS and HIF-1 expression, indicating a role of kallistatin in mediating mild oxygen's stimulation on antioxidant genes. Protein kinase C (PKC) activation mediates HIF-1-induced eNOS synthesis in response to hyperoxia/exercise; thus, mild oxygen through PKC activation stimulates kallistatin-mediated HIF-1 and eNOS synthesis. In summary, oxidative stress induces down- or upregulation of kallistatin expression, depending on oxygen concentration, and kallistatin plays a novel role in mediating oxygen/exercise-induced HIF-1-eNOS-NO pathway.


Short-term predictive changes in the dynamics of disparity vergence eye movements.
Repetitive stimulation of the disparity vergence system to large convergent step stimuli has been shown to increase the dynamics of subsequent responses to smaller step stimuli. Here we show that decreases in the dynamics of both disparity convergence and divergence eye movements can be induced using a frequently occurring small amplitude conditioning stimulus to modify responses to a larger, occasionally presented test stimulus. In one experiment, a simple conditioning stimulus consisting of repetitive 1 degrees step stimuli was used to modify the dynamic vergence response to an occasional 4 degrees step test stimulus. An experimental trial consisted of three phases: baseline, conditioning, and recovery. The baseline and recovery phases used only the 4 degrees test stimuli. The dynamic characteristics of the responses to test stimuli were quantified by measuring the magnitude of the peak velocity. A statistically significant change was observed between the dynamics of conditioned responses compared to baseline and recovery responses indicting modification by the conditioning stimuli. During recovery, the response dynamics returned to levels near baseline levels showing that the decrease in response dynamics was caused by the conditioning stimulus, not fatigue. Another experiment showed that the response dynamics to large stimuli could be decreased whereas the dynamics of small stimuli could be increased by the same intermediate conditioning stimulus. Other experiments suggest that the modifications are due to a predictive mechanism. The results indicate that the dynamics of disparity vergence eye movements are malleable and depend to some extent on the amplitude of preceding stimuli.


Cost conscious care: preoperative evaluation by a cardiologist prior to low-risk procedures.
Preoperative testing before low-risk procedures remains overutilised. Few studies have looked at factors leading to increased testing. We hypothesised that consultation to a cardiologist prior to a low-risk procedure leads to increased cardiac testing. 907 consecutive patients who underwent inpatient endoscopy/colonoscopy at a single academic centre were identified. Of those patients, 79 patients (8.7%) received preoperative consultation from a board certified cardiologist. 158 control patients who did not receive consultation from a cardiologist were matched by age and gender. Clinical and financial data were obtained from chart review and hospital billing. Logistic and linear regression models were constructed to compare the groups. Patients evaluated by a cardiologist were more likely to receive preoperative testing than patients who did not undergo evaluation with a cardiologist (OR 47.5, (95% CI 6.49 to 347.65). Specifically, patients seen by a cardiologist received more echocardiograms (60.8% vs 22.2%, p<0.0001) and 12-lead electrocardiograms (98.7% vs 54.4%, p<0.0001). There was a higher rate of ischaemic evaluations in the group evaluated by a cardiologist, but those differences did not achieve statistical significance. Testing led to longer length of stay (4.35 vs 3.46 days, p=0.0032) in the cohort evaluated by a cardiologist driven primarily by delay to procedure of 0.76 days (3.14 vs 2.38 days, p=0.001). Estimated costs resulting from the longer length of stay and increased testing was $10 624 per patient. There were zero major adverse cardiac events in either group. Preoperative consultation to a cardiologist before a low-risk procedure is associated with more preoperative testing. This preoperative testing increases length of stay and cost without affecting outcomes.


Systematics of the Dendropsophus leucophyllatus species complex (Anura: Hylidae): Cryptic diversity and the description of two new species.
Genetic data in studies of systematics of Amazonian amphibians frequently reveal that purportedly widespread single species in reality comprise species complexes. This means that real species richness may be significantly higher than current estimates. Here we combine genetic, morphological, and bioacoustic data to assess the phylogenetic relationships and species boundaries of two Amazonian species of the Dendropsophus leucophyllatus species group: D. leucophyllatus and D. triangulum. Our results uncovered the existence of five confirmed and four unconfirmed candidate species. Among the confirmed candidate species, three have available names: Dendropsophus leucophyllatus, Dendropsophus triangulum, and Dendropsophus reticulatus, this last being removed from the synonymy of D. triangulum. A neotype of D. leucophyllatus is designated. We describe the remaining two confirmed candidate species, one from Bolivia and another from Peru. All confirmed candidate species are morphologically distinct and have much smaller geographic ranges than those previously reported for D. leucophyllatus and D. triangulum sensu lato. Dendropsophus leucophyllatus sensu stricto occurs in the Guianan region. Dendropsophus reticulatus comb. nov. corresponds to populations in the Amazon basin of Brazil, Ecuador, and Peru previously referred to as D. triangulum. Dendropsophus triangulum sensu stricto is the most widely distributed species; it occurs in Amazonian Ecuador, Peru and Brazil, reaching the state of Pará. We provide accounts for all described species including an assessment of their conservation status.


Variables decreasing tip movement of peripherally inserted central catheters in pediatric patients.
The position of the tip of a peripherally inserted central catheter (PICC) is crucial; malposition can lead to malfunction of the line or life-threatening events (e.g., arrhythmias, perforation). To determine what factors other than arm position and accessed vein might influence the tip position of a PICC. Inclusion criteria were upper limb PICC placement, body weight <20 kg, intraoperative imaging with the arm in 0°, 45° and 90° abduction and an arm view marking the skin entry site relative to the shoulder. Evaluated variables included patient demographics, and PICC and insertion site characteristics. We measured central tip movement in rib units. We included 112 children who received a PICC (42 girls/70 boys, mean age 31±13 months, mean weight 6.5±4.9 kg). The overall range of central tip movement was -1 to +4 rib units (mean +0.8±0.7 rib units). Silicone PICCs moved significantly less than polyurethane PICCs (P<0.05). PICCs placed in the cephalic vein moved significantly less than those placed in other veins (P<0.05). Patient demographics and PICC characteristics (size, number of lumens, left or right arm accessed, length of the line) did not influence the range of central tip movement of a PICC (P>0.05). Silicone PICCs and PICCs inserted into the cephalic vein move less than PICCs made of polyurethane and PICCs inserted into the brachial and basilic veins. These findings might assist operators in deciding which PICC to place in children in a given clinical context.


Quantitative meta-analysis of gray matter abnormalities in semantic dementia.
Cumulative evidence of gray matter abnormalities in semantic dementia (SD) has been reported using voxel-based morphometry (VBM). However, these studies have not been reviewed quantitatively. To estimate gray matter changes in SD quantitatively, we systematically searched whole-brain VBM studies comparing SD patients with healthy controls in the PubMed, ISI Web of Science, and EMABSE databases from January 1990 to August 2011. Coordinates with significant differences between the gray matter volumes of SD patients and healthy controls were extracted from clusters. Meta-analysis was performed using anatomic likelihood estimation. Seven studies, with 68 SD patients and 167 healthy controls, were included. Gray matter volume reductions were found in bilateral fusiform and inferior temporal gyri, extending to the medial portion of the temporal lobes (including amygdala and parahippocampal gyri), left temporal pole, middle temporal gyrus, and caudate. No significant increase in gray matter volume was found. Our findings provide strong evidence of atrophy in bilateral temporal lobes with predominate impairment on the left side, parahippocampal gyrus/amygdala, and left caudate, representing the pathophysiology of SD.


Comparing the Effectiveness of Honey Consumption With Anti-Cough Medication in Pediatric Patients: A Systematic Review.
Coughing is one of the most prevalent symptoms in children presenting at outpatient departments. This systematic review aimed to review previous literature in order to compare the use of honey and antitussive medications for treating coughs in children. Literature was screened across five databases using Medical Subject Heading (MeSH) strategy, keywords, and inclusion and exclusion criteria. The remaining literature was evaluated using a quality appraisal tool checklist. This review includes systematic reviews, meta-analyses, randomized controlled trials (RCTs), observational studies, cross-sectional studies, and articles without a defined methodology section. This review suggests that honey is effective in treating children above 12 months of age, while cold and cough medications (CCMs) are safe if administered at therapeutic doses. Since fatalities can occur in children under two years of age, further RCT studies on CCMs are required to establish safety across all age groups.


Genome-wide characterization and identification of Trihelix transcription factors and expression profiling in response to abiotic stresses in Chinese Willow (Salix matsudana Koidz).
Trihelix transcription factors (TTF) are a class of light-responsive proteins with a typical triple-helix structure (helix-loop-helix-loop-helix). Members of this gene family play an important role in plant growth and development, especially in various abiotic stress responses. Salix matsudana Koidz is an allotetraploid ornamental forest tree that is widely planted for its excellent resistance to stress, but no studies on its Trihelix gene family have been reported. In this study, the Trihelix gene family was analyzed at the genome-wide level in S. matsudana. A total of 78 S. matsudana Trihelix transcription factors (SmTTFs) were identified, distributed on 29 chromosomes, and classified into four subfamilies (GT-1, GT-2, SH4, SIP1) based on their structural features. The gene structures and conserved functional domains of these Trihelix genes are similar in the same subfamily and differ between subfamilies. The presence of multiple stress-responsive cis-elements on the promoter of the S. matsudana Trihelix gene suggests that the S. matsudana Trihelix gene may respond to abiotic stresses. Expression pattern analysis revealed that Trihelix genes have different functions during flooding stress, salt stress, drought stress and low temperature stress in S. matsudana. Given that SmTTF30, as a differentially expressed gene, has a faster response to flooding stress, we selected SmTTF30 for functional studies. Overexpression of SmTTF30 in Arabidopsis thaliana (Arabidopsis) enhances its tolerance to flooding stress. Under flooding stress, the leaf cell activity and peroxidase activity (POD) of the overexpression strain were significantly higher than the leaf cell activity and POD of the wild type, and the malondialdehyde (MDA) content was significantly lower than the MDA content of the wild type. Thus, these results suggest that SmTTF30 enhances plant flooding tolerance and plays a positive regulatory role in plant flooding tolerance.


Estimation of trace metal elements in oral mucosa specimens by using SR-XRF, PIXE, and XAFS.
The effects of dissolved elements from metal dental restorations are a major concern in lesions of the oral mucosa, and the evaluation of accumulated metal elements, especially their distribution and chemical state, is essential for determining the precise effects of trace metals. In this study, X-ray fluorescence with synchrotron radiation (SR-XRF) and particle-induced X-ray emission (PIXE) were applied for distribution analysis of the trace metal elements contained in the oral mucosa, and the chemical states of the elements were estimated using X-ray absorption fine structure (XAFS) analysis. Appropriate combination of these analysis techniques, particularly SR-XRF and PIXE, to visualize the distributions of the elements in the oral mucosa allowed for the observation and evaluation of accumulated metal ions and debris. Importantly, the analyses in this study could be carried out using conventional histopathological specimens without damaging the specimens. Therefore, this method would be applicable for the detection of accumulated trace metal elements in biopsy specimens from the oral mucosa.


Chronic infection of a seminal vesicle cyst as depicted on MR imaging.
Chronic infection of a seminal vesicle cyst is an extremely rare disorder worldwide. To date, only two cases, which were diagnosed initially by the use of contrast-enhanced CT or non-enhanced MR imaging, have been reported in the literature. We report here a case of a 78-year-old man with chronic infection of a seminal vesicle cyst to illustrate the usefulness of the pelvic contrast-enhanced MRI in making a definitive diagnosis of the rare disorder. In addition, a brief review of the relevant literature is presented.


Insulin-like growth factors augment steroid production and expression of steroidogenic enzymes in human fetal adrenal cortical cells: implications for adrenal androgen regulation.
The fetal zone is a unique adrenal cortical compartment that exists only during fetal life in humans and higher primates and produces large amounts of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S). Growth of the fetal zone is primarily regulated by ACTH, the actions of which are mediated in part by locally produced autocrine/paracrine growth factors. We previously demonstrated that one of these growth factors, insulin-like growth factor II (IGF-II), is mitogenic for cultured fetal zone cells and is produced in high abundance by these cells in response to ACTH. In the present study, we determined whether IGF-II also modulates the differentiated function of fetal zone cells. We examined the effects of recombinant human IGF-II and the closely related peptide, IGF-I, on 1) basal and agonist-stimulated [ACTH-(1-24), forskolin, or 8-bromo-cAMP] cortisol and DHEA-S production, 2) basal and ACTH-stimulated steady state abundance of messenger ribonucleic acids (mRNAs) encoding the steroidogenic enzymes cytochrome P450 side-chain cleavage (P450scc) and cytochrome P450 17alpha-hydroxylase/17,20-lyase (P450c17), and 3) basal and ACTH-stimulated steady state abundance of mRNA encoding the ACTH receptor. Basal cortisol (23.93 +/- 1.20 pmol/10(5) cells x 24 h) and DHEA-S (548.87 +/- 43.17 pmol/10(5) cells x 24 h) productions were significantly (P < 0.05) increased by IGF-I (2.3- and 1.8-fold, respectively) and IGF-II (2.8- and 1.8-fold, respectively). As expected, ACTH, forskolin, and cAMP markedly increased the production of cortisol by 26-, 10-, and 13-fold, respectively, and that of DHEA-S by 5.4-, 4.6-, and 5.5-fold, respectively, compared with basal levels. IGF-II (100 ng/mL) significantly (P < 0.001) increased ACTH-, forskolin-, and cAMP-stimulated production of cortisol by 2.4-, 4.3-, and 3.2-fold, respectively, and that of DHEA-S by 1.4, 1.6-, and 1.4-fold, respectively. IGF-I (100 ng/mL) had similar effects as IGF-II and significantly (P < 0.001) increased ACTH-, forskolin-, and cAMP-stimulated production of cortisol by 2.8-, 3.9-, and 3.1-fold, respectively, and that of DHEA-S by 1.3-, 1.6-, and 1.4-fold, respectively. The similar potencies of IGF-I and IGF-II suggest that the actions of these factors were mediated via a common receptor, most likely the type I IGF receptor. The effects of IGF-II on ACTH-stimulated steroid production were dose-dependent (EC50, 0.5-1.0 nmol/L), and IGF-II markedly increased the steroidogenic responsiveness of fetal zone cells to ACTH. With respect to cortisol production, IGF-II shifted the ACTH dose-response curve to the left by 1 log10 order of magnitude. IGF-II also increased ACTH-stimulated abundance of mRNA encoding P450scc (1.9-fold) and P450c17 (2.2-fold). Basal expression of P450scc was not affected by IGF-II. In contrast, basal expression of P450c17 was increased 2.2-fold by IGF-II and IGF-I in a dose-responsive fashion. Neither IGF-I nor IGF-II affected basal or ACTH-stimulated abundance of mRNA encoding the ACTH receptor, suggesting that the increase in ACTH responsiveness was not mediated by an increase in ACTH-binding capacity. Taken together, these data indicate that activation of the type I IGF receptor increases ACTH responsiveness in fetal zone cells by modulating ACTH signal transduction at some point distal to ACTH receptor activation. These data also indicate that locally produced IGF-II modulates fetal adrenal cortical cell function by increasing responsiveness to ACTH and possibly (based on its direct stimulation of P450c17 expression) augmenting the potential for adrenal androgen synthesis. Thus, activation of the type I IGF receptor on adrenal cortical cells may play a pivotal role in adrenal androgen production, both physiologically in utero and at adrenarche, and in pathophysiological conditions ofhyperandrogenemia, such as the polycystic ovary syndrome.


In vivo assessment of genotoxic, antigenotoxic and anticarcinogenic activities of Solanum lycocarpum fruits glycoalkaloidic extract.
The fruits of Solanum lycocarpum, known as wolf-fruit, are used in folk medicine, and because of that we have evaluated both the genotoxic potential of its glycoalkaloidic extract (SL) and its influence on the genotoxicity induced by methyl methanesulfonate. Furthermore, the potential blocking effect of SL intake in the initial stage of colon carcinogenesis in Wistar rats was investigated in a short-term (4-week) bioassay using aberrant crypt foci (ACF) as biomarker. The genotoxic potential was evaluated using the Swiss mice peripheral blood micronucleus test. The animals were treated with different doses of SL (15, 30 and 60 mg/kg b.w.) for 14 days, and the peripheral blood samples were collected at 48 h, 7 days and 14 days after starting the treatment. For antigenotoxicity assessment, MMS was administered on the 14th day, and after 24 h the harvesting of bone marrow and liver cells was performed, for the micronucleus and comet assays, respectively. In the ACF assay, male Wistar rats were given four subcutaneous injections of the carcinogen 1,2-dimethylhydrazine (DMH, 40 mg/kg b.w.), twice a week, during two weeks to induce ACF. The treatment with SL (15, 30 and 60 mg/kg b.w.) was given for four weeks during and after carcinogen treatment to investigate the potential beneficial effects of SL on DMH-induced ACF. The results demonstrated that SL was not genotoxic in the mouse micronucleus test. In animals treated with SL and MMS, the frequencies of micronucleus and extensions of DNA damage were significantly reduced in comparison with the animals receiving only MMS. Regarding the ACF assay, SL significantly reduced the frequency of ACF induced by DMH.


Hepatitis B genotypes and surface antigen mutants present in Pakistani blood donors.
The prevalence of chronic Hepatitis B Virus (HBV) infection is 2-4% in the Pakistani population, defining Pakistan as an intermediate prevalence country. In this study, hepatitis B surface antigen (HBsAg) reactive blood donations were screened using a combination of serological and molecular methods to identify immune escape HBV mutant strains and to determine the HBV genotypes and subtypes present in Pakistan. Blood donations were collected at the Armed Forces Institute of Transfusion (AFIT) located in northern Pakistan and the Hussaini Blood Bank (HBB) located in the south. From 2009 to 2013 a total of 706,575 donations were screened with 2.04% (14,409) HBsAg reactive. A total of 2055 HBsAg reactive specimens, were collected and screened using a monoclonal antibody based research assay to identify immune escape mutants followed by PCR amplification and DNA sequencing to identify the mutation present. DNA sequences obtained from 192 specimens, including mutant candidates and wild type strains, were analyzed for escape mutations, genotype, and HBsAg subtype. Mutations were identified in approximately 14% of HBsAg reactive donations. Mutations at HBsAg amino acid positions 143-145 are the most common (46%) with the mutation serine 143 to leucine the most frequently occurring change (28%). While regional differences were observed, the most prevalent HBV strains are subgenotypes of D with subgenotype D1/subtype ayw2 accounting for the majority of infections; 90.2% at AFIT and 52.5% at HBB. The high frequency of immune escape HBV mutants in HBV infected Pakistani blood donors highlights the need for more studies into the prevalence of escape mutants. Differences between vaccinated and unvaccinated populations, the correlation of escape mutant frequency with genotype, and impact of escape mutations in different genotype backgrounds on the performance of commercially available HBsAg assays represent avenues for further investigation.


A bacterial-like Pictet-Spenglerase drives the evolution of fungi to produce β-carboline glycosides together with separate genes.
Diverse β-carboline (βC) alkaloids are produced by microbes, plants, and animals with myriad bioactivities and drug potentials. However, the biosynthetic mechanism of βCs remains largely elusive, especially regarding the hydroxyl and glucosyl modifications of βCs. Here, we report the presence of the bacterial-like Pictet-Spenglerase gene Fcs1 in the entomopathogenic Beauveria fungi that can catalyze the biosynthesis of the βC skeleton. The overexpression of Fcs1 in Beauveria bassiana led to the identification of six βC methyl glycosides, termed bassicarbosides (BCSs) A-F. We verified that the cytochrome P450 (CYP) genes adjacent to Fcs1 cannot oxidize βCs. Alternatively, the separated CYP684B2 family gene Fcs2 was identified to catalyze βC hydroxylation together with its cofactor gene Fcs3. The functional homologue of Fcs2 is only present in the Fcs1-containing fungi and highly similar to the Fcs1-connected yet nonfunctional CYP. Both evolved quicker than those from fungi without Fcs1 homologues. Finally, the paired methyl/glucosyl transferase genes were verified to mediate the production of BCSs from hydroxy-βCs. All these functionally verified genes are located on different chromosomes of Beauveria, which is in contrast to the typical content-clustered feature of fungal biosynthetic gene clusters (BGCs). We also found that the production of BCSs selectively contributed to fungal infection of different insect species. Our findings shed light on the biosynthetic mechanism of βC glycosides, including the identification of a βC hydroxylase. The results of this study also propose an evolving process of fungal BGC formation following the horizontal transfer of a bacterial gene to fungi.


Identification and expression analysis of three XCR1-like receptors from Epinephelus coioides after Cryptocaryon irritans infection.
The unique receptor XCR1 of the XC subfamily of chemokines is specially expressed in CD8α-like dendritic cells. This receptor has one ligand in mice (XCL1) and two ligands in humans (XCL1 and XCL2). In mammals, the XCR1-XCL1 complex performs a vital role in regulating the localization and function of T cells, dendritic cells, and other cell types. In this study, three XCR1-like receptors (EcXCR1, EcXCR1L, and EcCCR12) were identified from a transcriptome database of orange-spotted grouper. The open reading frames (ORFs) of EcXCR1, EcXCR1L, and EcCCR12 predictably encode 337, 348, and 358 amino acids, respectively. All receptors are seven trans-membrane proteins, and contain conserved functional regions, and conserved sites, that are crucial for the role of chemokine receptors in mammals. Conserved features include four cysteine residues in the extracellular regions, a "DRY" motif in the second intracellular loop, and common characteristics at the N-terminus that are important for ligand interaction. In healthy grouper, EcXCR1, EcXCR1L, and EcCCR12 were broadly expressed in all the tissues tested. EcXCR1 was expressed at high levels in the liver, and EcXCR1L, and EcCCR12 in the thymus. After grouper infection with Cryptocaryon irritans, EcXCR1 and EcCCR12 were up-regulated in the skin and the spleen, and EcCCR12 in the skin, gill, and spleen. EcXCR1L expression changed only slightly. These results imply that EcXCR1 and EcCCR12 may be involved in host defense against parasite infection. A polyclonal antibody was produced against EcCCR12, and used to detect EcCCR12-positive cells in peripheral blood. These results will contribute considerably to elucidate the biological role of piscine XCR1-like receptors and their ligands system in the future.


Duration of Untreated Psychosis in Chinese and Mauritian: Impact of Clinical Characteristics and Patients' and Families' Perspectives on Psychosis.
Duration of untreated psychosis (DUP) is a potentially modifiable prognostic factor of course and prognosis of psychiatric disorders. Few studies have demonstrated that different cultural backgrounds or perspectives on psychosis may be important factors to the DUP. This study attempted to explore whether the DUP was different in Chinese and Mauritians and to clarify potential influencing factors to a long DUP (>3 months). 200 patients from China and 100 patients from Mauritius were enrolled in the study. Their respective family members were also recruited. Demographic and clinical characteristics were collected, and the Internalized Stigma of Mental Illness (ISMI) scale was adapted to measure the stigma in all subjects. Binary logistic regression analysis was used to find the potential influencing factors to the long DUP. 35.3% of the enrolled patients had a long DUP. No significant difference was found in frequency of long DUP between the two countries. Chinese patients had relatively less perceptions of stigma. Furthermore, Chinese patients with a long DUP had more perception of breakup due to mental illness (OR = 2.22, p = 0.04) and more families' perception of the patient being disinherited due to mental illness (OR = 6.47, p = 0.01). Mauritian patients with a long DUP were less likely to have high monthly income (OR = 0.12, p<0.01), while they had less patients' awareness of mental illness (OR = 0.31, p<0.05) and less families' awareness of mental illness (OR = 0.14, p<0.01). The results of this study underlined the importance of DUP in economic conditions, racial and sociocultural factors, and public awareness on psychosis in developing countries.


Bacteriology of middle ear fluid specimens obtained by tympanocentesis from 111 Colombian children with acute otitis media.
We cultured middle ear fluid specimens obtained by tympanocentesis from 111 Colombian infants and children, ages 11 days to 11 years, with acute otitis media. Bacteria were isolated in 82 patients (74%). Haemophilus influenzae, the most common isolate, was present in 40 cases (36%); 32 were nontypable strains and 8 were type b. Streptococcus pneumoniae, identified in 26 cases (22%), was the second most common pathogen. All H. influenzae and S. pneumoniae strains were susceptible to ampicillin and penicillin, respectively. We conclude that amoxicillin remains the drug of choice for treatment of acute otitis media in our country.


Evaluation of Analgesic Activity of Papaver libanoticum Extract in Mice: Involvement of Opioids Receptors.
Papaver libanoticum is an endemic plant to Lebanese region (family Papaveraceae) that has not been investigated before. The present study aimed to explore the analgesic activity of dried ethanolic extract of Papaver libanoticum (PLE) using tail flick, hot plate, and acetic acid induced writhing models in mice. The involvement of opioid receptors in the analgesic mechanism was investigated using naloxone antagonism. Results demonstrated that PLE exhibited a potent dose dependent analgesic activity in all tested models for analgesia. The analgesic effect involved activation of opioid receptors in the central nervous system, where both spinal and supraspinal components might be involved. The time course for analgesia revealed maximum activity after three hours in both tail flick and hot plate methods, which was prolonged to 24 hours. Metabolites of PLE could be responsible for activation of opioid receptors. The EC50 of PLE was 79 and 50 mg/kg in tail flick and hot plate tests, respectively. The total coverage of analgesia by PLE was double that of morphine in both tests. In conclusion, PLE proved to have opioid agonistic activity with a novel feature of slow and prolonged effect. The present study could add a potential tool in the armaments of opioid drugs as a natural potent analgesic and for treatment of opioid withdrawal syndrome.


New data on the clearwing moth fauna of the Altai Mountains, Russia, with the description of two new species (Lepidoptera, Sesiidae).
The clearwing moth fauna of the Altai Mountains, Russia is reviewed. Two new species Synanthedon altaica sp. nov. and Bembecia aktashica sp. nov. are described and illustrated. Synanthedon polaris (Staudinger, 1877) is recorded as new for the region. New information on the bionomics and distribution of Dipchasphecia altaica O. Gorbunov, 1991 is provided.


Activation of phosphatidylinositol 3-kinase by interleukin-13. An inhibitory signal for inducible nitric-oxide synthase expression in epithelial cell line HT-29.
The human colonic epithelial cell line HT-29 can be induced by a combination of the cytokines interleukin (IL)-1alpha, tumor necrosis factor alpha, and interferon-gamma to express the inducible form of nitric-oxide synthase (iNOS; Kolios, G., Brown, Z., Robson, R., Robertson, D. A. F., & Westwick, J. (1995) Br. J. Pharmacol. 116, 2866-2872). IL-13 is a potent inhibitor of cytokine-induced iNOS mRNA expression and nitric oxide generation in HT-29 cells via an unknown mechanism. We report here that in HT-29 cells, IL-13 induces a concentration and time-dependent increase in the formation of the lipid products of phosphatidylinositol (PtdIns) 3-kinase, namely phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. IL-13 also induces a parallel concentration and time-dependent increase in the in vitro lipid kinase activity present in immunoprecipitates of the p85 regulatory subunit of PtdIns 3-kinase. In addition, we also demonstrate that IL-13 stimulates the tyrosine phosphorylation of the adaptor molecule insulin receptor substrate 1, which may facilitate receptor coupling to PtdIns 3-kinase. Both the increases in D-3 phosphatidylinositol lipids and the increased in vitro lipid kinase activity of p85 immunoprecipitates were inhibited by wortmannin and LY294002. Inhibition of the PtdIns 3-kinase activity was paralleled by a reversal of the ability of IL-13 to inhibit iNOS mRNA expression and nitrite generation in HT-29 cells. These data demonstrate that the activation of PtdIns 3-kinase by IL-13 is a key signal that is responsible for the inhibition of iNOS transcription in activated epithelial cells.


Effects of bone marrow derived mesenchymal stem cells transplantation in acutely infarcting myocardium.
Cellular cardiomyoplasty (CCM) is considered to be a novel therapeutic approach for post-myocardial infarction (MI) heart failure. In this study, the functional effects of cultured mesenchymal stem cells (MSCs) transplantation and the associated histopathologic changes were evaluated in a rat model of MI. Rats were subjected to 5 h of coronary ligation followed by reperfusion and, 10 days after MI, animals were randomized into either the MSCs transplantation (MI-MSC, n=8) group or the control (n=8) group. Allogeneic MSCs (3x10(6) cells) or media were epicardially injected into the center and the border area of the infarct scar. Four weeks after the MSCs transplantation, the echocardiogram showed preserved anterior regional wall motion and increases in fractional shortening in the MI-MSC heart relative to the control heart. Left ventricular (LV) end-diastolic pressure was smaller in the MI-MSC than in the control group. Implanted MSCs formed islands of cell clusters on the border of the infarct scar, and the cells were positively immunostained by sarcomeric alpha-actinin and cardiac troponin T. In addition, the number of microvessels on the border area of the infarct scar was greater in the MI-MSC than in the control group. Allogeneic MSCs transplanted into the MI scar formed clusters of cell grafts on the border of the infarct, expressed cardiac muscle proteins, increased microvessel formation, and improved regional and global LV function. Our data indicate that CCM using MSCs may have a significant role in the treatment of post-MI heart failure.


A psychometric assessment of the H & H Lactation scale in a sample of thai mothers using a repeated measurement design.
The H & H Lactation (H & H) scale is a useful instrument for understanding mothers' perceptions of insufficient milk supply, which is the common reason given for premature cessation of breastfeeding. This instrument may be used to intervene in postbirth dropoff in breastfeeding among mothers. To examine construct and nomological validity and related psychometric evidence for the translated H & H scale using a repeated measurement design in a sample of Thai mothers. A repeated measurement design with 196 mother-infant dyads. Data were collected at two time periods. At Time 1, data on the H & H and Index of Breastfeeding Status (IBS) scales were obtained between 36 and 48 hr postbirth. For Time 2, the same mothers completed the same instruments at 1 month postbirth. Psychometricproperties of the H & H scale were examined using convergent, discriminant, and nomological validity principles with instructural equation modeling. Based on judgment/classification task, exploratory/confirmatory factor analysis, and cross-validation using multisample analysis, only nine items of the H & H scale measured at Time 1 and Time 2 were found to be psychometrically sound for measuring insufficient milk supply for Thai mothers. An analysis of the influence of the nine-item of the H & H scale measured at Time 1 and Time 2 on the IBS measured at Time 2 showed that (a) the direct effects of two subscales of the H & H scale measured at Time 2 on the IBS were significant and positive, providing support for the nomological validity of the H & H scale; (b) each H& H factor at Time 1 had a significant influence on its corresponding factor at Time 2, supporting convergent validity; and (c) the crossover effects for each H & H factor for Time 1 and Time 2 data were nonsignificant, indicating discriminant validity. Overall, the 20-item H & H scale appears to be unreliable and invalid for measuring the concept of insufficient milk supply in cross-cultural studies. However, the short form of nine items is reliable and valid for Thai mothers. Further testing and development of the H & H scale and the proposed short form in other cultures and contexts is warranted.


Soluble Fibrinogen-like protein 2 plays a role in varicocele induced male infertility.
Varicocele is the most common cause of male infertility. Several theories have been proposed to explain how varicocele induces infertility. The role of epididymis in male infertility is not fully well established. Fibrinogen-like protein 2 is one of serine proteases and is a potent coagulant in membranous form and immune-modulator in soluble form (sFGL-2) and expressed in the epididymis. There are no previous reports about its possible role in varicocele. This case-controlled study aimed to evaluate the seminal level of sFGL-2 in infertile men with varicocele and in men with idiopathic infertility. This study included 85 participants divided into three groups; 25 normal fertile men, 30 infertile men with varicocele and 30 infertile men of idiopathic cause. Clinical examination, Doppler ultrasound, semen analysis and measurement of seminal level of sFGL-2 were done to all participants. Seminal level of sFGL-2 was significantly elevated in infertile than normal fertile men. Seminal level of sFGL-2 showed negative correlations with sperm concentration, motility and normal morphology. Seminal level of sFGL-2 had a positive correlation with seminal liquefaction time. This study concluded that seminal level of sFGL-2 is increased in infertile men with idiopathic cause and with varicocele induced infertility and affects seminal liquefaction.


The Smartphone-Based Offline Indoor Location Competition at IPIN 2016: Analysis and Future Work.
This paper presents the analysis and discussion of the off-site localization competition track, which took place during the Seventh International Conference on Indoor Positioning and Indoor Navigation (IPIN 2016). Five international teams proposed different strategies for smartphone-based indoor positioning using the same reference data. The competitors were provided with several smartphone-collected signal datasets, some of which were used for training (known trajectories), and others for evaluating (unknown trajectories). The competition permits a coherent evaluation method of the competitors' estimations, where inside information to fine-tune their systems is not offered, and thus provides, in our opinion, a good starting point to introduce a fair comparison between the smartphone-based systems found in the literature. The methodology, experience, feedback from competitors and future working lines are described.


Electro-optic metasurfaces.
We numerically study metasurfaces that incorporate electro-optic materials and show that they can achieve large amplitude and phase modulations across a distance that is a fraction of the operation wavelength. We show that the metasurfaces made of dielectric discs placed on a film of lithium niobate can exhibit three main types of resonances, associated with the Fabry-Perot modes in the structure, guided modes of the film and Mie modes of the disks. We compare metasurface performance in these different regimes for achieving largest electro-optic modulation and find that in the proposed geometry the strongest amplitude modulation can be achieved through excitation and re-emission of the guided modes in the substrate. We further show that to achieve larger 70 degrees phase modulation while maintaining high transmission, we need to utilise more complex metasurfaces that have at least two resonators per unit cell.


Best practices in pediatric sepsis: building and sustaining an evidence-based pediatric sepsis quality improvement program.
Pediatric sepsis is a common problem worldwide and is associated with significant morbidity and mortality. Best practice recommendations have been published by both the American College of Critical Care Medicine and the Surviving Sepsis Campaign to guide the recognition and treatment of pediatric sepsis. However, implementation of these recommendations can be challenging due to the complexity of the care required and intensity of resources needed to successfully implement programs. This paper outlines the experience with implementation of a pediatric sepsis quality improvement program at Primary Children's Hospital, a free-standing, quaternary care children's hospital in Salt Lake City. The hospital has implemented sepsis projects across multiple care settings. Challenges, lessons learned, and suggestions for implementation are described.PLAIN LANGUAGE SUMMARYSepsis is a life-threatening condition that results from an inappropriate response to an infection by the body's immune system. All children are potentially susceptible to sepsis, with nearly 8,000 children dying from the disease in the US each year. Sepsis is a complicated disease, and several international groups have published guidelines to help hospital teams treat children with sepsis appropriately. However, because recognizing and treating sepsis in children is challenging and takes a coordinated effort from many different types of healthcare team members, following the international sepsis guidelines effectively can be difficult and resource intensive. This paper describes how one children's hospital (Primary Children's Hospital in Salt Lake City, Utah) approached the challenge of implementing pediatric sepsis guidelines, some lessons learned from their experience, and suggestions for others interested in implementing sepsis guidelines for children.


Personalized, relevance-based Multimodal Robotic Imaging and augmented reality for Computer Assisted Interventions.
In the last decade, many researchers in medical image computing and computer assisted interventions across the world focused on the development of the Virtual Physiological Human (VPH), aiming at changing the practice of medicine from classification and treatment of diseases to that of modeling and treating patients. These projects resulted in major advancements in segmentation, registration, morphological, physiological and biomechanical modeling based on state of art medical imaging as well as other sensory data. However, a major issue which has not yet come into the focus is personalizing intra-operative imaging, allowing for optimal treatment. In this paper, we discuss the personalization of imaging and visualization process with particular focus on satisfying the challenging requirements of computer assisted interventions. We discuss such requirements and review a series of scientific contributions made by our research team to tackle some of these major challenges.


Diaphragmatic rupture resulting from gastrointestinal barotrauma in a scuba diver.
A fit young man sustained a ruptured diaphragm during a recreational scuba dive three months after undergoing an uncomplicated laparoscopic Nissen fundoplication for gastro-oesophageal reflux disease. It is proposed that this rare occurrence was attributable to gastrointestinal barotrauma. The injury was treated by laparotomy, mobilisation of herniated abdominal viscera back into the abdomen, repair of the crura and gastropexy. He made a full postoperative recovery. It is concluded that scuba diving should be avoided in patients who have undergone fundoplication.


Growth hormone treatment in Japan: past, present, and future.
Growth hormone (GH) treatment was approved for growth hormone deficiency (GHD) in Japan in 1975. Since then, GH treatment has been approved for treating five other diseases with short stature. However, available data on adult height after long-term GH treatment is limited to patients with GHD and Turner syndrome. Although adult height of patients with GHD has improved with early diagnosis and early initiation of treatment, the adult height after long-term GH treatment is still not so satisfactory because the therapeutic dose used in Japan is smaller than that used in US and Europe. With early diagnosis, early high-dose treatment, and low-dose estrogen replacement therapy, both adult height and quality of life (QOL) of the patients with Turner syndrome have been improved.


Initial Experience with a Novel Pericardiocentesis Training Simulator Incorporating a Three-dimensional Printed Cardiac Model.
Pericardial effusion is a rare but serious complication in cardiac electrophysiology procedures. To avoid progression to acute tamponade and reduce the risk of adverse patient outcomes, emergent pericardiocentesis is often necessary. The conduct of more pericardiocentesis training may further mitigate this risk. However, teaching and practice opportunities are rare, creating the need for pericardiocentesis simulators. While various pericardiocentesis simulators exist, their applications have been limited; further, commercial simulators are anatomically realistic but can be expensive. As such, cheaper homemade simulators have been developed, yet these may lack the cardiac anatomical features for a high-fidelity simulation or may be overly complex to assemble. The purpose of this study is to report initial findings from a pericardiocentesis simulator that incorporates a three-dimensional (3D) cardiac model that is economical, simple to assemble, and anatomically accurate. A 3D-printed cardiac model was printed from a computed tomography file. The model was fitted with a latex balloon-in-a-balloon pericardium filled with colored saline and placed in an ultrasound-compatible gelatin mold to create a pericardiocentesis simulator. The simulator was then tested with experienced and novice trainees at an academic hospital. A total of 10 participants (four interventional cardiology faculty members and six cardiology fellows) performed simulated pericardiocentesis using the simulator and completed a questionnaire to evaluate the model's features and usefulness. The overall feedback regarding this novel simulation approach was positive and the model exhibited important anatomical features to accurately simulate ultrasound-guided pericardiocentesis. All participants were able to successfully insert the needle into the pericardial space and all but one successfully placed the pericardial drain. Survey results indicated that the model was largely perceived as useful for training. This work suggests incorporating a 3D-printed cardiac model into a gelatin mold results in a simple and inexpensive yet high-fidelity pericardiocentesis simulation experience. This novel approach may be useful for teaching pericardiocentesis in an academic hospital.


[Successful treatment of the intracranial hemorrhage after the cardiac surgery for infective endocarditis].
We report an extremely rare case of a successful treatment of the intracranial hemorrhage after the cardiac surgery for infective endocarditis(IE). A 34-year-old woman was admitted to our hospital with a diagnosis of active IE due to Staphylococcus aureus, complicated with cerebral infarctions. Preoperative echocardiography showed mobile vegetations on both leaflets of the mitral valve with 15 and 6 mm diameters. Mitral valve repair was performed on hospital day 10. There were mobile vegetations on the A2 and P3. Five days after the cardiac surgery, brain magnetic resonance imaging(MRI) and angiography demonstrated intracranial hemorrhage due to the rupture of the intracranial aneurysm, which was urgently clipped. No neurological sequel has been noted since the successful treatment.


Giant cell and Takayasu's arteritis.
Giant cell arteritis is a generalized vasculitis mainly affecting elderly people. The incidence is increasing, but only for women. The etiology is still unknown, but evidence suggests a cellular immunologic reaction against a local antigen present in the arterial wall. The disease can present itself with a great variety of symptoms. Constitutional symptoms such as fever, weight loss, and anorexia seem to be more common than hitherto believed. Onset of large artery involvement is independent of the evolution of the classic clinical symptoms. Peripheral synovitis is rarely seen in patients with polymyalgia rheumatica, and when it occurs, it is transient, nonerosive, and nondeforming. Glucocorticosteroids are the only generally accepted treatment in giant cell arteritis. After a higher initial dose of corticosteroids, most patients can be treated with a low maintenance dose, with little risk of steroid-induced osteoporosis. The erythrocyte sedimentation rate is still the best test for monitoring the disease.


Lisinopril as an antioxidant in hypertension?
Lisinopril is an inhibitor of the renin-angiotensin system. Does lisinopril minimize oxidative damage in spontaneously hypertensive rats (SHR) in comparison with the normotensive genetic controls Wistar Kyoto (WKY)? The authors note that lisinopril contained lipid peroxidation, elevated tissue glutathione levels, and influenced the activity of antioxidant enzymes such as catalase and glutathione peroxidase. Studies in humans testing the hypothesis that lisinopril has antioxidant function in vivo are warranted.


Current trends in stabilizing high thoracic and thoracolumbar spinal fractures.
Studying treatment data for 1,385 patients with traumatic paraplegia registered with the National Spinal Cord Injury Data Research Center during 1973-1979, we investigated: (1) current treatment trends; (2) continuity or change in such trends; (3) trend implications; and (4) whether current practices reflect the controversy in the literature. The data showed little change in the proportion of patients treated surgically, but statistically significant changes in the procedures, especially as related to Harrington rod instrumentation, which increased dramatically both with bony fusion (from none to 24.4%) and in the triple procedure, which adds laminectomy (from 6.1% to 23.2%). These changes have clearly improved health care, as the two predominant surgical treatments were associated with the shortest hospital stays in both the acute and rehabilitation settings.


Esophageal and gastric carcinoma in Norway 1958-1992: incidence time trend variability according to morphological subtypes and organ subsites.
The occurrence of adenocarcinoma (AC) of the esophagus and gastric cardia has shown large increases in many but not all examined populations. This trend is in contrast with a decrease in distal gastric AC and a relative stability of esophageal squamous cell carcinoma. Our study aimed to describe esophageal and gastric carcinoma time trends in the Norwegian population between 1958 and 1992 based on data from the Cancer Registry of Norway. Estimated esophageal AC rates have accelerated over the study period, reaching average annual increases of 17% in men and 14% in women between 1983 and 1992. The occurrence of esophageal squamous cell carcinoma was relatively stable in both sexes. Proximal gastric cancer rates were stable in males and decreased somewhat in females. Distal gastric tumors showed decreases in both sexes, but were more pronounced in females. The strong increase in esophageal AC incidence parallels similar increases in the United States and some other countries. Although the observed increase may be explained to some extent by a shift in the classification of esophago-cardial adenocarcinomas, the figures are compatible with a real increase. AC of the esophagus, the proximal stomach and the distal stomach exhibit different epidemiological features, both in terms of sex ratios and time trends, suggesting risk factor differences between the subsites.


Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics.
The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer. Tumour cells have shown high susceptibility to mTOR inhibitors. Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers. To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR. Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition. More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression. Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms. The mTOR pathway is a promising target by miRNAs for anticancer therapy. Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer. Here, we summarize current findings of the role of mTOR inhibitors and miRNAs in carcinogenesis through targeting mTOR signalling pathways and determine their potential as novel anti-cancer therapeutics.


A transmissible Creutzfeldt-Jakob disease-like agent is prevalent in the human population.
The etiology of most human dementias is unknown. Creutzfeldt-Jakob disease (CJD), a relatively uncommon human dementia, is caused by a transmissible virus-like agent. Molecular markers that are specific for the agent have not yet been defined. However, the infectious disease can be transmitted to rodents from both brain and infected buffy coat (blood) samples. To determine whether human CJD infections are more widespread than is apparent from the low incidence of neurological disease, we attempted to transmit CJD from buffy coat samples of 30 healthy volunteers who had no family history of dementing illness. Primary transmissions from 26 of 30 individuals produced CJD-like spongiform changes in the brains of recipient hamsters at 200-500 days postinoculation. This positive evidence of viremia was found for individuals in all age groups (20-30, 40-50, and 61-71 years old), whereas 12 negatively scored brain samples failed to produce similar changes in hamsters observed for > 900 days in the same setting. We suggest that a CJD agent endemically infects humans but only infrequently produces an infectious dementia. Disease expression is likely to be influenced by several host factors in combination with viral variants that have altered neurovirulence.