Airway and transpulmonary driving pressures and mechanical powers selected by INTELLiVENT-ASV in passive, mechanically ventilated ICU patients.
Driving pressure (ΔP) and mechanical power (MP) are predictors of the risk of ventilation- induced lung injuries (VILI) in mechanically ventilated patients. INTELLiVENT-ASV® is a closed-loop ventilation mode that automatically adjusts respiratory rate and tidal volume, according to the patient's respiratory mechanics. This prospective observational study investigated ΔP and MP (and also transpulmonary ΔP (ΔPL) and MP (MPL) for a subgroup of patients) delivered by INTELLiVENT-ASV. Adult patients admitted to the ICU were included if they were sedated and met the criteria for a single lung condition (normal lungs, COPD, or ARDS). INTELLiVENT-ASV was used with default target settings. If PEEP was above 16 cmH2O, the recruitment strategy used transpulmonary pressure as a reference, and ΔPL and MPL were computed. Measurements were made once for each patient. Of the 255 patients included, 98 patients were classified as normal-lungs, 28 as COPD, and 129 as ARDS patients. The median ΔP was 8 (7 - 10), 10 (8 - 12), and 9 (8 - 11) cmH2O for normal-lungs, COPD, and ARDS patients, respectively. The median MP was 9.1 (4.9 - 13.5), 11.8 (8.6 - 16.5), and 8.8 (5.6 - 13.8) J/min for normal-lungs, COPD, and ARDS patients, respectively. For the 19 patients managed with transpulmonary pressure ΔPL was 6 (4 - 7) cmH2O and MPL was 3.6 (3.1 - 4.4) J/min. In this short term observation study, INTELLiVENT-ASV selected ΔP and MP considered in safe ranges for lung protection. In a subgroup of ARDS patients, the combination of a recruitment strategy and INTELLiVENT-ASV resulted in an apparently safe ΔPL and MPL.


Dietary sodium manipulation and vascular responsiveness during pregnancy in the rabbit.
The interrelationship of sodium intake and blood pressure regulation during pregnancy is not clear. The effects of dietary sodium loading and restriction on plasma levels of catecholamines, mean arterial pressure, and vascular response to two pressor agents, Levophed and angiotensin II, were investigated in 49 chronically prepared primigravid rabbits. Sodium loading increased mean arterial pressure (p less than 0.005), but did not alter the response to either pressor agent. Sodium restriction did not alter mean arterial pressure, but did increase plasma norepinephrine (p less than 0.05) and epinephrine (p less than 0.02). Negative correlations between plasma levels of norepinephrine and vascular response to infusions of both pressor agents were observed during sodium restriction, -0.61 (p less than 0.05) for angiotensin II, and -0.74 (p less than 0.05) for norepinephrine. A similar correlation of -0.81 (p less than 0.05) was observed for angiotensin II in control animals. Norepinephrine appears to play a significant role in blood pressure maintenance and vascular response in pregnancy. This role is enhanced during sodium restriction.


Nitroimidazoles adsorption on activated carbon cloth from aqueous solution.
The objective of this study was to analyze the equilibrium and adsorption kinetics of nitroimidazoles on activated carbon cloth (ACC), determining the main interactions responsible for the adsorption process and the diffusion mechanism of these compounds on this material. The influence of the different operational variables, such as ionic strength, pH, temperature, and type of water (ultrapure, surface, and waste), was also studied. The results obtained show that the ACC has a high capacity to adsorb nitroimidazoles in aqueous solution. Electrostatic interactions play an important role at pH<3, which favors the repulsive forces between dimetridazole or metronidazole and the ACC surface. The formation of hydrogen bonds and dispersive interactions play the predominant role at higher pH values. Modifications of the ACC with NH3, K2S2O8, and O3 demonstrated that its surface chemistry plays a predominant role in nitroimidazole adsorption on this material. The adsorption capacity of ACC is considerably high in surface waters and reduced in urban wastewater, due to the levels of alkalinity and dissolved organic matter present in the different types of water. Finally, the results of applying kinetic models revealed that the global adsorption rate of dimetridazole and metronidazole is controlled by intraparticle diffusion.


Effect of lidocaine on the absorption, disposition and tolerance of intramuscularly administered cefoxitin.
The use of lidocaine HCL solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.


Development of an expert system for bacterial identification: study of a prototype for identifying beta-galactosidase positive enterobacteria.
A prototype of an expert system for the identification of beta-galactosidase positive Enterobacteriaceae has been developed, for use with the API 20 EC kit. The system is implemented in Prolog on an IBM PC AT with 640 K of central memory and 20 megabytes of secondary memory. Its objectives are to highlight errors that can occur when the kit is in use. It can indicate the presence of new groups or species and give advice or suggest additional tests for the differentiation of the new species from those included in the kit.


Nodular pulmonary amyloidosis following liver transplantation: report of a case and review of the literature.
Nodular pulmonary lesions seen in liver transplant recipients have a broad differential diagnosis including both infectious and noninfectious etiologies. Here, we report the first case of nodular pulmonary amyloidosis, an uncommon and benign localized form of amyloidosis occurring after orthotopic liver transplantation for end-stage primary biliary cirrhosis.


Parametric techniques for characterizing myocardial tissue by magnetic resonance imaging (part 1): T1 mapping.
The development of myocardial fibrosis is a common process in the appearance of ventricular dysfunction in many heart diseases. Magnetic resonance imaging makes it possible to accurately evaluate the structure and function of the heart, and its role in the macroscopic characterization of myocardial fibrosis by late enhancement techniques has been widely validated clinically. Recent studies have demonstrated that T1-mapping techniques can quantify diffuse myocardial fibrosis and the expansion of the myocardial extracellular space in absolute terms. However, further studies are necessary to validate the usefulness of this technique in the early detection of tissue remodeling at a time when implementing early treatment would improve a patient's prognosis. This article reviews the state of the art for T1 mapping of the myocardium, its clinical applications, and its limitations.


Semaphorin 4D induces articular cartilage destruction and inflammation in joints by transcriptionally reprogramming chondrocytes.
Proinflammatory cytokines play critical roles in the pathogenesis of joint diseases. Using a mass spectrometry-based cloning approach, we identified Semaphorin 4D (Sema4D) as an inflammatory cytokine that directly promoted cartilage destruction. Sema4d-deficient mice showed less cartilage destruction than wild-type mice in a model of rheumatoid arthritis. Sema4D induced a proinflammatory response in mouse articular chondrocytes characterized by the induction of proteolytic enzymes that degrade cartilage, such as matrix metalloproteinases (MMPs) and aggrecanases. The activation of Mmp13 and Mmp3 expression in articular chondrocytes by Sema4D did not depend on RhoA, a GTPase that mediates Sema4D-induced cytoskeletal rearrangements. Instead, it required NF-κB signaling and Ras-MEK-Erk1/2 signaling downstream of the receptors Plexin-B2 and c-Met and depended on the transcription factors IκBζ and C/EBPδ. Genetic and pharmacological blockade of these Sema4D signaling pathways inhibited MMP induction in chondrocytes and cartilage destruction in femoral head organ culture. Our results reveal a mechanism by which Sema4D signaling promotes cartilage destruction.


Effect of hepatic NPC1L1 on cholesterol gallstone disease and its mechanism.
Cholesterol gallstone disease (CGD) is associated with bile cholesterol supersaturation. The Niemann-Pick C1-like 1 (NPC1L1), the inhibitory target of ezetimibe (EZE), is a critical sterol transporter of cholesterol absorption. Intestinal NPC1L1 facilitates the absorption of cholesterol, whereas hepatic NPC1L1 promotes cholesterol uptake by hepatocytes and reduces bile cholesterol supersaturation. The potential of hepatic NPC1L1 to prevent CGD has yet to be established due to its absence in the mice model. In this study, we generated mice expressing hepatic NPC1L1 using adeno-associated virus (AAV) gene delivery. The biliary cholesterol saturations and gallstone formations were explored under chow diet and lithogenic diet (LD) with or without EZE treatment. The long-term (8-week) LD-fed AAV-mNPC1L1 mice exhibited no significant differences in biliary cholesterol saturation and gallstone formation compared to WT mice. EZE effectively prevented CGD in both WT and AAV-mNPC1L1 mice. Mechanistically, prolonged LD feeding induced the degradation of hepatic NPC1L1, whereas short-term (2-week) LD feeding preserved the expression of hepatic NPC1L1. In conclusion, our findings suggest that hepatic NPC1L1 is unable to prevent CGD, whereas EZE functions as an efficient bile cholesterol desaturator during CGD development.


Long noncoding RNA PTTG3P/miR-192-3p/CCNB1 axis is a potential biomarker of childhood asthma.
Increasing evidence suggests that long non-coding RNAs (lncRNAs) affect the regulation of immune responses, airway inflammation, and other pathological processes involved in asthma. LncRNA PTTG3P is associated with the development of various tumors, but its role in childhood asthma remains unknown. In this study, we investigated the functions of the lncRNA PTTG3P in the progression of childhood asthma. Twenty-six healthy children and 26 asthmatic children were monitored for disease progression for 2 years. We obtained blood samples during the chronic phase of disease for lncRNA/mRNA expression microarray analysis. A competitive endogenous RNA network (PTTG3P/miR-192-3p/CCNB1) was identified using bioinformatics analyses. Real-time qPCR and western blot were used to quantify gene and protein expression levels, respectively. Cell counting kit‑8 and transwell assays were used to evaluate the proliferation and migration of bronchial epithelial (16HBE) cells. Double luciferase reporter gene assay was used to validate the predictive targets in PTTG3P, miR-192-3p, and CCNB1. PTTG3P was highly expressed in the peripheral blood of asthmatic children. Knocking down PTTG3P inhibited epithelial-mesenchymal transition, proliferation, and migration of 16HBE cells. PTTG3P promoted progression of childhood asthma by targeting the miR-192-3p/CCNB1 axis. Childhood asthma was associated with the PTTG3P/miR-192-3p/CCNB1 axis. This study provides potential diagnostic and treatment biomarkers for childhood asthma.


Adolescent first lapse following smoking cessation: situation characteristics, precipitants and proximal influences.
Despite increased attention to adolescent smoking cessation, little is known about adolescent relapse following a quit attempt. To address this issue, the present study was designed to provide initial information regarding the characteristics of adolescent lapses to smoking following abstinence. Included in the present study were 204 adolescent participants in four independent smoking cessation trials. For the full sample, participants averaged 15.99 (1.27) years of age; 56% were female and 78% were white. Lapse characteristics and precipitants were assessed using the Adolescent Smoking Relapse Review. Three domains of the lapse experience were assessed: lapse situation characteristics, precipitants of use in the situation, and proximal influences (i.e., potential precipitants occurring on the same day, prior to the lapse situation). Participant reports indicated that the modal lapse situation occurred in the evening while socializing with friends at home. Urges or cravings and social pressure were commonly endorsed as occurring in lapse situations. The most frequently reported proximal influence was desire for a cigarette, followed by abstinence-violation cognitions (okay to smoke occasionally, wanted to see what it would be like) and negative emotions. The findings indicate that a broad range of factors appear to influence adolescent smoking lapse and commend the value of incorporating content relevant to managing social and affective cues, strategies for inhibiting the prepotent response to ask for a cigarette, addressing cognitions regarding the difficulty of not smoking (i.e., cessation expectancies) and combating perceptions of the ability to smoke occasionally.


Gas-phase isolation of diethyl guanosine 5'-monophosphate and its conformational assignment.
We show that intact neutral molecules of guanosine 5'-monophosphate can be vaporized by laser desorption when its phosphate group is esterified. The UV and IR spectroscopic measurements of this nucleotide reveal the existence of a novel internal hydrogen-bonding conformation of the phosphate group and guanine moiety.


Identifying miRNA biomarkers for breast cancer and ovarian cancer: a text mining perspective.
microRNA (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing. Numerous studies have demonstrated the critical role of miRNAs in the development of breast cancer and ovarian cancer. To reduce potential bias from individual studies, a more comprehensive approach of exploring miRNAs in cancer research is essential. This study aims to explore the role of miRNAs in the development of breast cancer and ovarian cancer. Abstracts of the publications were tokenized and the biomedical terms (miRNA, gene, disease, species) were identified and extracted for vectorization. Predictive analyses were conducted with four machine learning models: K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Random Forest (RF), and Naïve Bayes. Both holdout validation and cross-validation were utilized. Feature importance will be identified for miRNA-cancer networks construction. We found that miR-182 is highly specific to female cancers. miR-182 targets different genes in regulating breast cancer and ovarian cancer. Naïve Bayes provided a promising prediction model for breast cancer and ovarian cancer with miRNAs and genes combination, with an accuracy score greater than 60%. Feature importance identified miR-155 and miR-199 are critical for breast cancer and ovarian cancer prediction, with miR-155 being highly related to breast cancer, whereas miR-199 being more associated with ovarian cancer. Our approach effectively identified potential miRNA biomarkers associated with breast cancer and ovarian cancer, providing a solid foundation for generating novel research hypotheses and guiding future experimental studies.


Extracellular fluid viscosity enhances cell migration and cancer dissemination.
Cells respond to physical stimuli, such as stiffness1, fluid shear stress2 and hydraulic pressure3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer5. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.


[Transfusions and iron chelation in myelodysplastic syndromes].
Iron overload (IO) is probably as toxic in elderly patients with low-risk myelodysplastic syndromes (MDS) as in young thalassemic patients. This impact is more difficult to demonstrate because of associated comorbidities. Cardiovascular disease increases vulnerability to the toxic effects of IO. In recent years, registry studies have shown a survival benefit of Iron Chelation Therapy (ICT) in these patients. These findings are now corroborated by an improvement in event-free survival in a single randomized study: the Telesto study. The EFS curves separate after two years of follow-up. This indicates inertia in the occurrence of complications. The benefits of ICT are also very slowly being revealed. It is possible to offer ICT to patients with transfusion-dependent MDS with a life expectancy of at least two years. In Telesto, patients had a serum ferritin (F) level of at least 1000ng/mL, recommendations using this F threshold as a trigger for chelation seem to be reinforced. It remains an open question whether chelation should be started earlier for effective suppression of IO-related oxidative stress. ICTs could be used in transfusion-dependent MDS patients with life expectancy greater than two years. including possibly higher risk patients responding to hypomethylating agents.


Identification of the C-terminal tail domain of AHF/trichohyalin as the critical site for modulation of the keratin filamentous meshwork in the keratinocyte.
AHF/trichohyalin is a large structural protein abundant in the inner root sheath (IRS) of anagenic hair follicles, which has been thought to mediate the keratin filamentous assembly. However, its functional mechanism is largely unknown. This study aimed at the identification of the key domain in AHF for keratin association and the establishment of a plausible mechanism for the modulation of the keratin meshwork. Several keratinocyte cell lines were introduced with the full length or several mutants of AHF, together with IRS-specific keratin krt31, and the profile of the AHF granules and the cellular behaviors were carefully analyzed. Full length of AHF formed small round granules that clearly bound to and aligned on the exogenous keratin filaments in the keratinocytes, severely affected cellular growth, mobility and shape. Intriguingly, the removal of only 6 amino acids around the C-terminal tail of AHF resulted not only in the complete loss of its keratin adherent ability but also in a dramatic enlargement of the granules. We propose a model for cytoskeletal modulation in the IRS of anagenic hair follicles: AHF latches onto the keratin bundles by its C-terminus and rearranges the keratin meshwork by intrinsic cohesive activity for the granule formation.


Evaluating the Occurrence of Polystyrene Nanoparticles in Environmental Waters by Agglomeration with Alkylated Ferroferric Oxide Followed by Micropore Membrane Filtration Collection and Py-GC/MS Analysis.
Although nanoplastics (NPs) are recognized as emerging anthropogenic particulate pollutants, the occurrence of NPs in the environment is rarely reported, partly due to the lack of sensitive methods for the concentration and detection of NPs. Herein, we present an efficient method for enriching NPs of different compositions and various sizes. Alkylated ferroferric oxide (Fe3O4) particles were prepared as adsorbents for highly efficient capture of NPs in environmental waters, and the formed large Fe3O4-NP agglomerates were separated by membrane filtration. Detection limits of 0.02-0.03 μg/L were obtained for polystyrene (PS) and poly(methyl methacrylate) (PMMA) NPs by detection with pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS). When analyzing real water samples from different sources, it is remarkable that PS NPs were detected in 11 out of 15 samples with concentrations ranging from <0.07 to 0.73 μg/L, while PMMA were not detected. The wide detection of PS NPs in our study confirms the previous speculation that NPs may be ubiquitous in the environmental waters. The accurate quantification of PS NPs in environmental waters make it possible to monitor the pollution status of NPs in aquatic systems and evaluate their potential risks.


Imputation of ancient human genomes.
Due to postmortem DNA degradation and microbial colonization, most ancient genomes have low depth of coverage, hindering genotype calling. Genotype imputation can improve genotyping accuracy for low-coverage genomes. However, it is unknown how accurate ancient DNA imputation is and whether imputation introduces bias to downstream analyses. Here we re-sequence an ancient trio (mother, father, son) and downsample and impute a total of 43 ancient genomes, including 42 high-coverage (above 10x) genomes. We assess imputation accuracy across ancestries, time, depth of coverage, and sequencing technology. We find that ancient and modern DNA imputation accuracies are comparable. When downsampled at 1x, 36 of the 42 genomes are imputed with low error rates (below 5%) while African genomes have higher error rates. We validate imputation and phasing results using the ancient trio data and an orthogonal approach based on Mendel's rules of inheritance. We further compare the downstream analysis results between imputed and high-coverage genomes, notably principal component analysis, genetic clustering, and runs of homozygosity, observing similar results starting from 0.5x coverage, except for the African genomes. These results suggest that, for most populations and depths of coverage as low as 0.5x, imputation is a reliable method that can improve ancient DNA studies.


Adriamycin-induced activation of NK activity may initially involve LAF production.
C3HeB/FeJ spleen cells (unseparated or passaged over nylon wool columns) were cultured overnight (1-2 X 10(6) cells/microwell) in the presence and absence of resident or ADM-induced PEC and anti-YAC-1 (4h) NK activity was determined. The addition of resident PEC to spleen cells had little effect on NK activity. However, the addition of ADM-elicited PEC (10 mg/kg, IP, day -1 and day -5) to spleen cells prior to culture significantly augmented NK activity. If ADM-induced PEC were treated with carbonyl iron prior to coculture with spleen cells, augmentation of anti-YAC-1 activity was not observed. This suggested that ADM-activated macrophages augmented cultured splenic NK activity. Supernatants from overnight-cultured resident or ADM-induced adherent PEC were then prepared, dialyzed (to remove ADM), and tested for mitogenic activity or cocultured with spleen cells overnight. ADM-induced adherent PEC supernatants stimulated the proliferation of murine thymocytes (both LAF and IL-2 also stimulate) but not cultured CTL (only IL-2 stimulates). ADM-induced adherent PEC supernatants (as well as LAF, IL-2, and IFN) augmented overnight-cultured C3HeB/FeJ splenic NK activity. However, only IL-2 and IFN could augment overnight-cultured athymic BALB/c . nu/nu splenic NK activity. This suggested that ADM-elicited macrophages produce LAF which may act directly on NK cells or, more likely, may induce T cells to produce IL-2, IFN, or both.


Determination of the effects of fusaric acid, a mycotoxin, on cytotoxicity, gamma-H2AX, 8-hydroxy-2 deoxyguanosine and DNA repair gene expressions in pancreatic cancer cells.
Pancreatic cancer has a poor prognosis and is an important public health problem for developing countries. Oxidative stress plays an important role in cancer initiation, progression, proliferation, invasion, angiogenesis and metastasis. For this reason, one of the important strategic targets of new cancer therapeutics is to drive cancer cells into apoptosis through oxidative stress. In nuclear and mitochondrial DNA, 8-hydroxy-2'-deoxyguanosine and gamma-H2AX (γ-H2AX) are used as important oxidative stress biomarkers. Fusaric acid (FA) is a mycotoxin that mediates toxicity produced by Fusarium species and exhibits anticancer effects in various cancers via inducing apoptosis, cell cycle arrest, or other cellular mechanisms. The aim of this study was to determine the effects of fusaric acid on cytotoxic and oxidative damage in MIA PaCa-2 and PANC-1 cell lines. In this context, dose and time dependent cytotoxic effect of fusaric acid was determined by XTT method, mRNA expression levels of genes related to DNA repair were determined by RT-PCR, and its effect on 8-hydroxy-2'-deoxyguanosine and γ-H2AX levels was revealed by ELISA assay. According to XTT results, fusaric acid inhibits cell proliferation in MIA PaCa-2 and Panc-1 cells in a dose- and time-dependent manner. IC50 doses were determined as 187.74 μM at 48 h in MIA PaCa-2 cells and 134.83 μM at 48 h in PANC-1 cells, respectively. γ-H2AX and 8-OHdG changes were not found significant in pancreatic cancer cells. The mRNA expression levels of DNA repair-related genes NEIL1, OGG1, XRCC and Apex-1 change with exposure to fusaric acid. This study contributes to the therapeutic approaches to be developed for pancreatic cancer and demonstrates the potential of fusaric acid as an anticancer agent.


[Kinetics of mitotic rhythmic activity in oat (Avena sativa) coleoptiles following irradiation].
The analysis of different intensity (10-200 Gy) irradiation influence on rhythmical processes in mitotic activity of oats coleoptiles was carries out. Obtained results indicate that irradiation disorders phase and amplitude of the cell division rhythm in investigated material. This disturbance, as judged by doze dependence, is associated with unknown molecular structures.


Intracranial suppuration.
To evaluate prevalence, age, position, predisposing factors, bacteriology, clinical features and outcomes of children with subdural empyema (SDE) and brain abscess (BA). Retrospective hospital-based study in a tertiary children's hospital. Clinical data were reviewed on all children classified as having SDE or BA for 10.75 years from 1 January 1992 to 31 August 2003 at the Royal Alexandra Hospital for Children, Sydney, Australia. Forty-six children with intracranial suppuration were identified: 26 had BA, 16 had SDE and four children had both SDE and BA. Significant differences between SDE and BA were that: sinusitis was a predisposing factor for SDE (P = 0.01), Streptococcus milleri was the main organism isolated in SDE (P = 0.02), periorbital oedema (P = 0.005) and photophobia (P = 0.02) were clinical features specifically associated with SDE, and 75% of multiple abscesses were in females (P = 0.005). The age distribution of SDE was biphasic, with peaks at <2 years and >7 years. Cases of BA peaked at age 9-11 years. Forty-eight per cent of all children were between 9 and 13 years old; 20% were <1 year old. All the children with SDE and BA were aged 1 year or less. Three of the 46 children died, all with BA. Eighteen (39.1%) returned to normal and 25 (54.3%) had neurological complications. Neurological complications were more common in the BA group. The mortality rate of intracranial suppuration is low, but morbidity remains high. A high degree of suspicion is needed to diagnose and treat intracranial infections early.


Plasma free radical activity and antioxidant vitamin levels in dyspeptic patients: correlation with smoking and Helicobacter pylori infection.
The pathological processes by which Helicobacter pylori infection leads to the development of gastroduodenal disease are still incompletely understood. Oxygen-derived free radicals are important mediators of inflammation and potential carcinogens. Furthermore, dietary studies have suggested that antioxidant vitamins may protect against gastric cancer. To determine plasma free radical activity and antioxidant vitamin levels in dyspeptic patients and to correlate the results with H. pylori infection and tobacco smoking. Forty-three patients undergoing routine endoscopy for investigation of dyspepsia. Plasma free radical activity was determined by measurement of thiobarbituric acid-reactive substances (TBARS). Plasma samples were also assayed for the antioxidant vitamins A, C and E. Gastroduodenal biopsies were obtained from all patients for histological examination. Plasma TBARS levels were significantly higher in H. pylori positive versus negative subjects (P < 0.03), smokers versus non-smokers (P < 0.04) and males versus females (P < 0.01). Multiple regression analysis revealed that after correcting for male sex and smoking there was no significant association between plasma free radical activity and H. pylori infection. Smokers had significantly lower levels of plasma vitamin C than non-smokers (P< 0.05); no differences were seen in vitamin A and E levels. Gender and H. pylori infection did not significantly affect plasma antioxidant vitamin levels. Gastroduodenal disease was present in all of the smokers compared with 67% of the non-smokers (P < 0.05); 69% of the smokers were H. pylori positive versus 53% of the non-smokers. Tobacco smoking and male sex, both recognized risk factors for gastroduodenal disease, appear to be the major determinants of increased plasma free radical activity in dyspeptic subjects, rather than H. pylori infection. The reason for the higher prevalence of H. pylori infection and gastroduodenal disease in dyspeptic smokers is unclear but may relate to weakened antioxidant defences.


Febuxostat, a novel inhibitor of xanthine oxidase, reduces ER stress through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression.
Endoplasmic reticulum (ER) stress has been implicated in the development of various renal diseases. Thus, inhibition of ER stress using pharmacological agents may serve as a promising therapeutic approach. We postulated that febuxostat, a novel xanthine oxidase inhibitor, could suppress the ER stress through upregulation of SIRT1 (silent mating type information regulation 2 homolog 1)-AMPK (AMP activated protein kinase)-HO-1 (heme oxygenase-1)/thioredoxin expression. We examined the effect of febuxostat on the ER stress induced by a chemical inducer, tunicamycin and non-chemical agents such as angiotensin II, aldosterone, high glucose, and albumin in renal tubular cells. We further examined the in vivo effects of febuxostat using mouse model of kidney disease induced by unilateral ureteral obstruction (UUO). Expression of ER stress was measured by western blot analysis and immunohistochemical stain. Febuxostat suppressed the ER stress induced by tunicamycin and non-chemical agents, as shown by inhibition of increased GRP78 (glucose-related protein78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor 2α) expression. Inhibitory effect of febuxostat was mediated through upregulation of SIRT1-AMPK followed by induction of HO-1 and thioredoxin. In animal model of UUO, febuxostat reduced the UUO-induced ER stress, which was abolished by pretreatment with SIRT1 inhibitor (sirtinol) and AMPK inhibitor (compound C). Febuxostat could suppress the ER stress caused by various ER stress inducers through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression. Targeting these pathways might serve as one of the possible therapeutic approaches in kidney diseases under excessive ER stress.


Life satisfaction of two-year post-stroke survivors: effects of socio-economic factors, motor impairment, Newcastle stroke-specific quality of life measure and World Health Organization quality of life: bref of informal caregivers in Luxembourg and a rural area in Portugal.
Life satisfaction of stroke survivors is known to be associated with socio-economic factors and the survivor's and his/her caregiver's quality of life, but their respective influence remains to be fully elucidated. To analyse the stroke survivors' life satisfaction 2 years after the event and its relationships with quality of life, socio-economic and stroke-related characteristics, and with informal caregivers' life satisfaction and quality of life . Over 18 months, all stroke patients from Luxembourg and north-eastern Portugal who lived at home were identified from the Inspection Générale de la Sécurité Sociale and hospital records, respectively. The clinical diagnosis of cerebrovascular disease was confirmed. We excluded all patients who declared that stroke did not result in neurological impairments at the time of stroke from the statistical analysis. The samples comprised 79 patients in Luxembourg and 48 in Portugal. Patients and the people they identified as their main caregivers were interviewed using validated questionnaires measuring life satisfaction, i.e. the Newcastle Stroke-Specific Quality of Life (Newsqol - 11 subscales), which identifies the areas affected by stroke among patients, and the World Health Organization Quality of Life - bref (Whoqol-bref - 4 subscales) of informal caregivers. Survivors without neurological impairment at the time of stroke were excluded. Data were analysed via multiple-regression models. Life satisfaction was higher among women and lower among subjects with impaired motor functions. It was lower among Portuguese respondents with low-level education (<12th grade) and higher among those at work (37.6/100). In Luxembourg, retired people had more life satisfaction than did working people (-7.9/100). Controlling for socio-economic factors, life satisfaction was associated with feelings- Newsqol (slope 0.25) among Luxembourg residents, and with feelings-, mobility- and self-care-Newsqol (slopes 0.24, 0.27 and 0.33, respectively) among Portuguese respondents. Life satisfaction of patients was strongly related to that of family caregivers among the Portuguese respondents (slope 0.66) but the relationship was moderate in Luxembourg (slope 0.28). The survivors' life satisfaction was not correlated with any Whoqol-bref domain in the Luxembourg group, but was correlated with the Whoqol-bref psychological, social relationships and environment domains among the Portuguese respondents (slopes 0.55, 0.59 and 0.51, respectively). The life satisfaction scale and the Newsqol stroke instrument, which identify areas of quality of life affected by stroke, are reliable patient-centred markers of intervention outcome. They can be used within the framework of medical follow-up (such as telephone assistance, clinical practice and prevention). Depending on the stroke survivor's and the family caregiver's habitual lifestyle and material circumstances, enhancement of a caregiver's quality of life can help maintain the patient's life satisfaction, particularly in a rural setting.


Dexmedetomidine alleviates pulmonary fibrosis through the ADORA2B-Mediated MAPK signaling pathway.
Idiopathic pulmonary fibrosis (IPF) is a chronically progressive fibrotic pulmonary disease characterized by an uncertain etiology, a poor prognosis, and a paucity of efficacious treatment options. Dexmedetomidine (Dex), an anesthetic-sparing alpha-2 adrenoceptor (α2AR) agonist, plays a crucial role in organ injury and fibrosis. However, the underlying mechanisms of IPF remain unknown. In our study, the role of Dex in murine pulmonary fibrosis models was determined by Dex injection intraperitoneally in vivo. Fibroblast activation and myofibroblast differentiation were assessed after Dex treatment in vitro. The activation of MAPK pathway and the expression of Adenosine A2B receptor (ADORA2B) were examined in lung myofibroblasts. Moreover, the role of ADORA2B in Dex suppressing myofibroblast differentiation and pulmonary fibrosis was determined using the ADORA2B agonist BAY60-6583. The results revealed that Dex could inhibit Bleo-induced pulmonary fibrosis in mice. In vitro studies revealed that Dex suppressed TGF-β-mediated MAPK pathway activation and myofibroblast differentiation. Furthermore, Dex inhibits myofibroblast differentiation and pulmonary fibrosis via downregulating ADORA2B expression. Our findings suggest Dex as a potential therapeutic agent for pulmonary fibrosis. Dex may alleviate lung fibrosis and myofibroblast differentiation through the ADORA2B-mediated MAPK signaling pathway.


The Emerging Role and Promise of Biomarkers in Penile Cancer.
Penile cancer is a rare malignancy, which can be a source of devastating psychosexual distress because of its implication on sexual function and self-image. Current penile staging relies on invasive techniques and is often inaccurate. The authors review the promising biomarkers currently under investigation and their application to the staging and prognosis of penile cancer. Further development of such biomarkers provides the potential of improved clinical management of this disease.


Transient visual loss in ornithine transcarbamoylase deficiency.
We examined a 32-year-old, previously healthy man who developed episodic bilateral visual impairment and confusion. Coincident hyperammonemia led to the diagnosis of ornithine transcarbamoylase deficiency, which was established by enzymatic analysis of a liver biopsy specimen. The available data were insufficient to determine if the metabolic derangement impaired vision at the level of the optic nerves or at the cerebral level.


A new tool for nanoscale X-ray absorption spectroscopy and element-specific SNOM microscopy.
Investigations of complex nanostructured materials used in modern technologies require special experimental techniques able to provide information on the structure and electronic properties of materials with a spatial resolution down to the nanometer scale. We tried to address these needs through the combination of X-ray absorption spectroscopy (XAS) using synchrotron radiation microbeams with scanning near-field optical microscopy (SNOM) detection of the X-ray excited optical luminescence (XEOL) signal. The first results obtained with the prototype instrumentation installed at the European Synchrotron Radiation Facility (Grenoble, France) are presented. They illustrate the possibility to detect an element-specific contrast and to perform nanoscale XAS experiments at the Zn K and W L(3)-absorption edges in pure ZnO and mixed ZnWO(4)/ZnO thin films.


Impact of commercial formulations of herbicides alone and in mixtures on the antioxidant system and body condition parameters in tadpoles of Rhinella icterica (Spix 1824).
Pesticide usage has increased over the last decades, leading to concerns regarding its effects on non-target organisms, especially amphibians. Tadpoles of Rhinella icterica were collected in a pesticide-free place, acclimated in the laboratory (21 days) and exposed (7 days) to three herbicides (20 µg/L atrazine (A); 250 µg/L glyphosate (G); 20 µg/L quinclorac (Q)) and their mixtures. Only 2% mortality was observed over the 28 days of the study. Despite this, significant variations were observed for markers of oxidative balance and body condition when comparing all experimental groups. K and Kn factor showed the lowest values in the group A+G+Q, as well as the activity levels of GST and SOD. In contrast to this, the CAT activity was higher in the same group (A+G+Q). The mixture of the three herbicides proved to be more harmful, which points to the need for more restrictive laws for the use of mixed herbicides.


Reengineering transfusion and cellular therapy processes hospitalwide: ensuring the safe utilization of blood products.
Efforts to make blood transfusion as safe as possible have focused on making the blood in the bag as disease-free as possible. The results have been dramatic, and the costs have been correspondingly high. Although blood services will have to continue to deal with emerging pathogens, efforts to reduce the transfusion of infectious agents presently posing a risk will require high incremental costs and result in only improvements of a small magnitude. The other aspect of safe blood transfusion, the actual transfusion process performed primarily in hospitals, has been accorded considerably less interest. We should turn our attention to enhancing overall blood safety by focusing on improving the process of blood transfusion. Errors involving patient, specimen, and blood product identification put transfused patients at risk, increasing the mortality risk for some. Solutions that could improve the transfusion process are discussed as a focus of this article.


Evaluation of immunoserological detection of anti-liver kidney microsomal, anti-soluble liver antigen and anti-mitochondrial antibodies.
Autoantibodies are the diagnostic hallmark of autoimmune liver diseases. Indirect immunofluorescence (IFT) is the reference method for the detection of anti-mitochondrial antibodies (AMA) and anti-liver kidney microsomal type-1 (anti-LKM1) antibodies, and inhibition ELISA (iELISA) for anti-soluble liver antigen (anti-SLA) antibodies. Given the complexity of these techniques, commercial ELISAs have emerged as a practical alternative, but without head-to-head validations. This study evaluated the agreement between three commercial ELISAs and the reference techniques and the impact of polyreactive immunoglobulin G (pIgG), a recently described phenomenon in autoimmune hepatitis, on commercial ELISAs. Inter-rater reliability was assessed using Cohen-Kappa coefficient (κ). Forty-eight, 46, and 66 samples were analyzed for AMA, anti-LKM1, and anti-SLA, respectively. For AMA, one commercial assay showed high agreement (κ = 0.91 (0.78-1.00)) with the reference method, while the other two showed weak or moderate agreement. For anti-LKM1, only one commercial assay showed high agreement (κ = 0.86 (0.71-1.0)). For anti-SLA antibodies only moderate agreement was achieved (κ up to 0.71 (0.52-0.89)). There was a trend towards higher pIgG levels in false-positives in the commercial ELISAs. Patients with high suspicion of autoimmune liver diseases should be referred to reference laboratories with the capacity of performing gold standard methods if the initial ELISA-based screening was performed.


Empagliflozin inhibits neointimal hyperplasia through attenuating endothelial-to-mesenchymal transition via TAK-1/NF-κB pathway.
To investigate whether empagliflozin could prevent injury-induced vascular neointimal hyperplasia and to further explore its mechanism. Male C57BL/6J mice were divided into two groups with or without the empagliflozin treatment, and carotid ligation injury was performed to induce neointimal hyperplasia. The injured carotid arteries were collected for Western blotting (WB), histology and immunofluorescence analysis after four weeks. The inflammatory responses were analyzed by qRT-PCR to detect the inflammatory gene mRNA expression. To further explore its mechanism, HUVECs were treated with TGFβ-1 to induce EndMT followed by empagliflozin or vehicle treatment in vitro. A23187 (Calcimycin), an agonist of NF-κB signaling was used in the experiment. The wall thickness and the neointima area was significantly reduced in the empagliflozin treatment group on day 28 after artery ligation. The Ki-67 positive cells were 28.33 ± 12.66% and 48.83 ± 10.41% in the empagliflozin-treated group and control group, respectively (P < 0.05). The mRNA expression levels of the inflammatory genes and inflammatory cells were decreased in the empagliflozin treatment group, as well as the MMP2 and MMP9. Meanwhile, empagliflozin can significantly reduce the migratory ability of inflammatory-treated HUVECs. The CD31 was increased in the TGFβ1+empagliflozin group, whereas the FSP-1, phosphorylation of TAK-1 (p-TAK-1) and phosphorylation of NF-κB (p- NF-κB) expression level were decreased, compared to the control group without empagliflozin treatment. However, the expression level of FSP-1 and p-NF-κB were reversed after co-treatment with A23187, whereas the p-TAK-1 expression level was without any significant difference. Empagliflozin inhibits the inflammation-induced EndMT via the TAK-1/NF-κB signaling pathway.


CORRIGENDUM to "Steroidal aromatase inhibitors have a more favorable effect on lipid profiles than nonsteroidal aromatase inhibitors in postmenopausal women with early breast cancer: a prospective cohort study".
[This corrects the article DOI: 10.1177/1758835920925991.].


Making the Right Loop for the heart.
The developing heart begins as a seemingly straight tube, but it soon undergoes rightward looping. In this issue of Developmental Cell, Desgrange et al. report how left-right asymmetric Nodal signaling regulates heart looping.


Sorption and post-sorption performances of Cd, Pb and Zn onto peat, compost and biochar.
The development of waste-derived sorbents to immobilize potentially toxic elements (PTEs) is a promising strategy, contributing to the achievement of sustainable development goals (SDGs). Therefore, this study aimed to assess the sorption performance of cadmium (Cd), lead (Pb) and zinc (Zn), comparing sorbents derived from organic fraction of municipal solid waste (composts and biochars) with peat. The physicochemical characterization, equilibrium of sorption, post-sorption analyzes and bioaccessibility were investigated. Results showed that the sorbents have distinct characteristics; however, each material have their particularities favorable to sorption. For instance, peat and composts have the highest cation exchange capacity (800-1100 mmolc kg-1), while biochar produced at 700 °C has the highest specific surface area (91.21 m2 g-1). The sorption equilibrium data revealed the actual sorption capacity and was well explained by the Freundlich and Langmuir isotherms and, in some cases, by the Dubinin-Radushkevich model. Post-sorption analyzes indicated the occurrence of several sorption mechanisms, driven by the physicochemical properties. Electrostatic interaction stood out for peat and compost. The FTIR spectrum for peat proved the complexation with oxygenated functional groups. The composts showed variations in the released cations (e.g. Ca2+ and K+), indicating cation exchange. Differently, for biochars, the XRD patterns showed that precipitation or coprecipitation seems to be one of the main mechanisms, especially for Cd and Pb. Regarding human bioaccessibility, the results of the gastric phase simulation (pH∼1.20) revealed lower percentages of Pb (33-81%) than Cd (91-99%) or Zn (82-99%), especially for the highest concentrations. Nevertheless, in numerical terms, all bioaccessible concentrations inspire care. In conclusion, among the sorbents, composts and biochars presented the best sorption performances and, therefore, have great potential for environmental applications. Furthermore, the bioaccessibility findings indicate that these assays, still little used in experiments with sorbents, are an important tool that should be better explored in the assessment of the environmental risk associated with contamination.


Revision of Poliaspis (Hemiptera, Coccoidea, Diaspididae), with descriptions of 8 new species from Australia.
Eight new Australian species of Poliaspis are described and illustrated: Poliaspis alluviasp. n., Poliaspis araucariaesp. n., Poliaspis ceraflorasp. n., Poliaspis naambasp. n., Poliaspis nalbosp. n., Poliaspis narungga sp. n., Poliaspis ozothamnaesp. n., and Poliaspis waibenensissp. n. Two described species are transferred into Poliaspis and are redescribed and illustrated: Lineaspis callitris (Laing) originally described by Laing as a species of Poliaspis, is transferred back into Poliaspis as Poliaspis callitris Laing, comb. rev., and Leonardaspis wilga (Leonardi) is transferred to Poliaspis as Poliaspis wilga (Leonardi), comb. n. Descriptions and illustrations are also provided for six of the fourteen previously-named Poliaspis species, including five from Australia: Poliaspis attenuata Brimblecombe, Poliaspis elongata Brimblecombe, Poliaspis exocarpi Maskell, Poliaspis nitens Fuller, and Poliaspis syringae Laing. Both Poliaspis cycadis Comstock and Poliaspis gaultheriae Green become junior synonyms of Poliaspis media Maskell. The species not treated here are Poliaspis intermedia Fuller (the location of the types is unknown and Fuller's description is inadequate), Poliaspis casuarinicola Lindinger (missing types), Poliaspis incisa Takagi and de Faveri (recently, and well described in Takagi and de Faveri 2011), and the six New Zealand species recently revised by Henderson (2011). In addition, Laingaspis lanigera (Laing), the adult female of which has 8 clusters of perivulvar pores - as in Poliaspis species - is redescribed and illustrated. Lectotypes are designated for Laingaspis lanigera, Poliaspis callitris, Poliaspis exocarpi, Poliaspis media, and Poliaspis wilga. A key is provided to the species of Poliaspis, excluding Poliaspis casuarinicola and Poliaspis intermedia butincluding Poliaspis incisa and the New Zealand species: Poliaspis chathamica Henderson, Poliaspis floccosa Henderson, Poliaspis lactea (Maskell), Poliaspis media Maskell, Poliaspis raouliae Henderson and Poliaspis salicornicola Henderson.


Design and application of a knowledge network for automatic prioritization of drug mechanisms.
Drug repositioning is an attractive alternative to de novo drug discovery due to reduced time and costs to bring drugs to market. Computational repositioning methods, particularly non-black-box methods that can account for and predict a drug's mechanism, may provide great benefit for directing future development. By tuning both data and algorithm to utilize relationships important to drug mechanisms, a computational repositioning algorithm can be trained to both predict and explain mechanistically novel indications. In this work, we examined the 123 curated drug mechanism paths found in the drug mechanism database (DrugMechDB) and after identifying the most important relationships, we integrated 18 data sources to produce a heterogeneous knowledge graph, MechRepoNet, capable of capturing the information in these paths. We applied the Rephetio repurposing algorithm to MechRepoNet using only a subset of relationships known to be mechanistic in nature and found adequate predictive ability on an evaluation set with AUROC value of 0.83. The resulting repurposing model allowed us to prioritize paths in our knowledge graph to produce a predicted treatment mechanism. We found that DrugMechDB paths, when present in the network were rated highly among predicted mechanisms. We then demonstrated MechRepoNet's ability to use mechanistic insight to identify a drug's mechanistic target, with a mean reciprocal rank of 0.525 on a test set of known drug-target interactions. Finally, we walked through repurposing examples of the anti-cancer drug imatinib for use in the treatment of asthma, and metolazone for use in the treatment of osteoporosis, to demonstrate this method's utility in providing mechanistic insight into repurposing predictions it provides. The Python code to reproduce the entirety of this analysis is available at: https://github.com/SuLab/MechRepoNet (archived at https://doi.org/10.5281/zenodo.6456335). Supplementary data are available at Bioinformatics online.


Cocaine dependence with and without comorbid depression: a comparison of patient characteristics.
This study compared depressed cocaine dependent patients (CD, N=50) with patients who were cocaine dependent only (CO, N=101) on pre-treatment psychiatric symptomatology, substance use, and psychosocial functioning. Results indicated that the CD group had more overall distress and poorer psychiatric functioning than the CO group. CD individuals scored higher on all subscales of the SCL-90-R, had a higher prevalence of antisocial personality disorder, reported higher craving for cocaine, lower self-efficacy to refrain from drug use, and lower perceived social support. These findings support the need for more intensive treatment approaches for dually-diagnosed patients.


The vaccinia virus mRNA (guanine-N7-)-methyltransferase requires both subunits of the mRNA capping enzyme for activity.
Plasmid vectors capable of expressing the large and small subunits of the vaccinia virus mRNA capping enzyme were constructed and used to transform Escherichia coli. Conditions for the induction of the dimeric enzyme or the individual subunits in a soluble form were identified, and the capping enzyme was purified to near homogeneity. Proteolysis of the capping enzyme in bacteria yields a 60-kDa product shown previously to possess the mRNA triphosphatase and guanyltransferase activities (Shuman, S. (1990) J. Biol. Chem. 265, 11960-11966) was isolated and shown by amino acid sequence analysis to be derived from the NH2 terminus of D1R. The individual subunits lacked methyltransferase activity when assayed alone. However, mixing the D1R and D12L subunits permitted reconstitution of the methyltransferase activity, and this appearance in activity accompanied the association of the subunits. In contrast, mixing the D12L subunit with the D1R-60K proteolytic fragment failed to yield methyltransferase activity or result in a physical association of the two proteins. These results demonstrate that the methyltransferase active site requires the presence of the D12L subunit with the carboxyl-terminal portion of the D1R subunit. Furthermore, since the mRNA triphosphatase and guanyltransferase active sites reside in the NH2-terminal domain of the D1R subunit, and the methyltransferase activity is found in the carboxyl-terminal portion of this subunit and D12L, there must be at least two separate active sites in this enzyme.


Only low levels of exogenous N-acetyltransferase can be achieved in transgenic mice.
Therapeutic and environmental aromatic amines and hydrazines are substrates for the arylamine N-acetyltransferases (NAT). In all, 10 transgenic lines containing either the human NAT1 or NAT2 transgene were developed using multiple promoters. The presence of the transgene was confirmed by determining copy number, mRNA and enzyme activity. Despite some lines having high copy numbers of the transgene, only modest or no increases in enzymatic activity could be found in a variety of tissues. The NAT1 transgene could not be bred to homozygosity. The cytomegalovirus (CMV)-promoted NAT1 transgene increased endogenous Nat1 mRNA levels in liver and had little effect on endogenous Nat2 mRNA levels. The presence of the CMV-promoted NAT2 transgene appeared to suppress endogenous hepatic Nat2 mRNA, but did not alter Nat1 mRNA levels. The failure to achieve high expression of any of the transgenes suggests that overexpression of NAT genes may have harmful effects during development.


Gene transfer of pro-IL-18 and IL-1beta converting enzyme cDNA induces potent antitumor effects in L1210 cells.
We report in a murine model of acute lymphoid leukemia L1210 the potent antitumor efficiency of a combinatorial delivery of pro-IL-18 gene modified L1210 (Lp18) and IL-1beta converting enzyme (ICE) gene modified L1210 (LpICE). Live leukemia cells Lp18 or Lp18 plus LpICE showed apparently reduced leukemogenicity with a survival rate of 40 or 50% at 50 days after intraperitoneal (i.p.) inoculation of a lethal dose of cells, respectively. Combination of Lp18 and LpICE was capable of inhibiting accumulation of bloody ascites, synergistically superior to Lp18 or LpICE alone. All surviving mice were rechallenged with parental L1210 cells at day 50, and all survived up to day 80, suggesting that gene-modified cells induced immune protection. Moreover, NK cytotoxicity and CTL activity were both enhanced in mice injected with Lp18, especially Lp18 plus LpICE. Levels of IFN-gamma were not altered significantly by inoculation of Lp18 or Lp18 plus LpICE. Our results demonstrate that IL-18 is a useful candidate gene in gene therapy of lymphoma or lymphoid leukemia, and ex vivo combinatorial delivery of Lp18 plus LpICE either as a single approach or as an adjunct to concomitant radiotherapy or chemotherapy, may be more efficient in a situation of minimal residual disease.


Risk factors and predictive markers for early and late-onset neonatal bacteremic sepsis in preterm and term infants.
The early detection and prediction of bacteremic sepsis in preterm and term neonates remains a challenging task because of their nonspecific clinical presentations. We aimed to investigate the risk factors associated with bacteremia and find the cutoff values of predictive markers to achieve accurate diagnosis of neonatal bacteremic sepsis. Not-doing-well preterm and term neonates with suspected sepsis were retrospectively enrolled between January 2015 and December 2017 in Taipei Veterans General Hospital. Blood culture, hemogram, serum procalcitonin (PCT), and C-reactive protein (CRP) were drawn at the onset of clinical signs and symptoms. All cases were divided to either early-onset or late-onset groups according to postpartum age. Nonparametric statistic, logistic regression, and receiver operating characteristic analysis were performed to evaluate the risk factors and cutoff values for predicting bacteremia. A total of 169 suspected sepsis episodes were analyzed, 68.0% of which had cardiopulmonary dysfunction and 19.5% had perinatal stress. The early-onset group had 123 (72.8%) patients, 4 of which had bacteremia and 119 had nonbacteremia conditions. The late-onset group had 46 (27.2%) patients, 8 of which had bacteremia and 38 had nonbacteremia conditions. Gestational age, birth body weight, Apgar score at 5 minutes, serum PCT, CRP, and platelet (PLT) count in the early-onset group and white blood cell (WBC) count in the late-onset group were substantially different between the patients with bacteremia and nonbacteremia conditions. PCT greater than 27 µg/L (adjusted odd ratio [aOR], 21.6; 95% CI, 1.1-435.1) and thrombocytopenia less than 100 × 109/L (aOR, 38.6; 95% CI, 1.4-1030.3) were predictive markers for bacteremia in the early-onset group. Early- and late-onset neonatal sepsis had different risk factors and predictive markers of bacteremia. PCT and PLT count in the early-onset group and WBC count in the late-onset group were accurate diagnostic serum markers for neonatal bacteremic sepsis.


Preservation of humidity and heat of respiratory gases during anaesthesia--a laboratory investigation.
Humidification and heating of anaesthetic gases are desirable to prevent respiratory tract damage and a fall in body temperature during operative procedures. Numerous studies on the humidity and temperature of inspiratory gases in different breathing systems for anaesthesia have been carried out, but comparisons are difficult since different methods have been used. In this laboratory set-up we studied a non-rebreathing system with and without humidifiers and a circle absorber system with low (0.5 l/min) or medium (5 l/min) fresh gas flows regarding their ability to heat and humidify anaesthetic gases. The humidity of inspired gases was acceptable in the non-rebreathing system using either a Bennett Cascade humidifier or disposable humidifiers and in the circle absorber system using a fresh gas flow of 5 l/min or less. The temperature of the inspired gases was highest with the Bennett Cascade humidifier, followed by the low-flow circle system. The circle absorber system used with low fresh gas flow gave higher inspiratory gas temperature and humidity than the non-rebreathing system with a good disposable humidifier.


Mapping neural circuits with CLARITY.
The use of whole-brain imaging has shed new light on the organization of the dopamine system.


Spindle epithelial tumor with thymus-like differentiation (SETTLE) of the thyroid with neck lymph node metastasis: a case report.
Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare type of thyroid tumor. It has been reported only 20 times in the English literature. This tumor occurs predominantly in young patients and has a protracted clinical course despite the occurrence of metastases. In the recent literature SETTLE has been considered to be a tumor of low malignant potential with distant metastases developing some years after diagnosis. Herein we report a case of SETTLE in a 22-yr-old man in which a lymph node metastasis developed soon after the primary tumor manifestation. Histological examination of the tumor showed the predominantly monophasic variant of SETTLE. The primary and metastatic lesions were highly cellular tumors composed of sheets of spindle cells that were positive for pan-cytokeratin and vimentin and negative for thyroglobulin, calcitonin, and S-100 protein.


Development of a telehealth obesity OSCE and reliable checklist for assessment of resident physicians: a pilot study.
Obesity is a major public health problem, yet residents undergo little formal training and assessment in obesity-related care. Given the recent growth of telehealth, physicians must further learn to apply these skills using a virtual platform. Therefore, we aimed to develop an objective structured clinical examination (OSCE) with reliable checklists to assess resident ability to take a patient-centered obesity-focused history that was feasible over telehealth based on published obesity competencies for medical education. We developed a 15-minute telehealth OSCE to simulate an obesity-related encounter for residents modified from a script used to assess medical student obesity competencies. We designed three checklists to assess resident skills in history taking, communication and professionalism during the obesity-related encounter. Resident performance was assessed as the percentage of obesity-related history taking questions asked during the encounter and as the mean communication and professionalism scores on a scale of 1 through 5 with 1 representing unacceptable/offensive behavior and 5 representing excellent skills. Encounters and assessments were completed by two commissioned actors (standardized patients) and 26 internal medicine residents over a secure online platform. We assessed the reliability of each checklist by calculating the percent agreement between standardized patients and the kappa (κ) statistic on each checklist overall and by each checklist item. Overall agreement between standardized patients on the history taking, communication and professionalism checklists were 83.2% (κ = 0.63), 99.5% (κ = 0.72) and 97.8% (κ =0.44), respectively. On average, residents asked 64.8% of questions on the history taking checklist and scored 3.8 and 3.9 out of 5 on the communication and professionalism checklists, respectively. Results from this pilot study suggest that our telehealth obesity OSCE and checklists are moderately reliable for assessing key obesity competencies among residents on a virtual platform. Integrating obesity OSCEs and other educational interventions into residency curricula are needed to improve resident ability to take an obesity-focused history.


Effect of dietary copper on colonic tumor production and aortic integrity in the rat.
Gastrointestinal malignancy has been associated with aortic aneurysmal disease in humans, while metabolic derangement of copper has been incriminated as a possible promotor of aneurysmal development of the aorta. An animal model utilizing the carcinogen 1,2-dimethylhydrazine (DMH) was selected to evaluate levels of dietary copper on both colonic tumor production and morphologic changes in the rat aorta. Six groups, each including 10 Sprague-Dawley rats, received 16 weekly doses (20 mg/kg) of DMH beginning at 4 weeks of age. Groups were maintained on either normal (25 ppm), low (0.6 ppm), or high (100 ppm) copper chow during the entire experimental period. After 25 weeks, all animals were sacrificed to assess colonic tumor production and to perform scanning (SEM) and transmission electron microscopic (TEM) studies of the rat aorta. Results showed a significant increase in colonic tumor production (3.14 +/- 0.39 tumors per centimeter colon) in rats treated with low-copper chow and DMH when compared with rats on normal chow and DMH (0.74 +/- 0.07 tumors per centimeter colon) and animals maintained on high-copper diets and DMH (0.76 +/- 0.08 tumors per centimeter colon). In addition, morphologic study showed disruption of the intima and media in rats maintained on low-copper diet alone, and also on low-copper diet plus DMH. The results of this study showed that DMH and low dietary copper significantly increase (P less than 0.001) the yield of colonic tumors and produce loss of aortic integrity when studied morphologically. Copper levels may be important in the association of neoplasia and aneurysm formation in the clinical setting.


Primary Hypothyroidism and Alzheimer's Disease: A Tale of Two.
Hypothyroidism (HPT) HPT could be a risk factor for the development and progression of Alzheimer's disease (AD). In addition, progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. Hence, the present review aimed to clarify the potential association between HPT and AD. HPT promotes the progression of AD by inducing the production of amyloid beta (Aβ) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aβ and tau protein phosphorylation leading to local brain HPT. Additionally, HPT can affect AD neuropathology through various mechanistic pathways including dysregulation of transthyretin, oxidative stress, ER stress, autophagy dysfunction mitochondrial dysfunction, and inhibition of brain-derived neurotrophic factor. Taken together there is a potential link between HPT and AD, as HPT adversely impacts AD neuropathology and the reverse is also true.


Dynamic structure of phospholipid bilayers on the path for oxygen diffusion in the ox lung.
The dynamic properties of the phospholipid bilayer of cell membranes were studied with a nanosecond fluorometer to obtain information on the microstructure of the path for oxygen diffusion in the ox lung. The viscosity in membranes of pneumocytes, endothelial cells from pulmonary artery, and erythrocytes was 47, 54 and 162 mPa . sec respectively. The wobbling angle representing the oscillation of phospholipid molecules was 47, 44 and 38 degrees, respectively.


Two systemic lupus erythematosus (SLE) global disease activity indexes--the SLE Disease Activity Index and the Systemic Lupus Activity Measure--demonstrate different correlations with activation of peripheral blood CD4+ T cells.
Global disease activity measurement in systemic lupus erythematosus (SLE) patients is important for the clinical estimation and adjustment of therapy. By contrast, immune system activation plays a significant role in disease pathogenesis, with CD4+ lymphocytes acting as central cells in the immune response. We investigated which scale better correlates with immunologic changes in the blood of SLE patients, the SLE Disease Activity Index (SLEDAI) or the Systemic Lupus Activity Measure (SLAM) scale. Samples of peripheral blood were obtained from 45 SLE patients with different disease activity as assessed by the SLEDAI and the SLAM scales on the same day. We assessed the percentage of CD4+ T cells with activation-associated receptors: CD69, CD25int, CD95, HLA-DR, and CD4+ T cells with killing properties containing perforin and granzyme B. Our results indicated that the percentage of CD4+CD69+ and CD4+CD25(int) cells did not correlate with either the SLEDAI or the SLAM scale. Significant and positive correlations were observed between percentages of CD4+CD95+ and CD4+HLA-DR+ lymphocytes and SLE activity, but only when activity was measured using the SLAM scale, not with the SLEDAI scale. The percentage of CD4+perforin+ and CD4+granzyme B+ cells also strongly correlated with disease activity measured only with the SLAM scale. We conclude that the SLAM scale better reflects changes of immune system activity in SLE patients compared with the SLEDAI scale.


Social and Structural Determinants of Cervical Health among Women Engaged in HIV Care.
Cervical cancer prevention/control efforts among women living with HIV/AIDS (WLH) are socially and structurally challenging. Healthcare access and perceived HIV stigma and discrimination are factors that may challenge risk reduction efforts. This study examined socio-structural determinants of cervical cancer screening among women engaged in HIV care. One hundred forty-five WLH seeking health/social services from AIDS Service Organizations in the southeastern US completed a questionnaire assessing factors related to cervical cancer prevention/control. Ninety percent were African American, mean age 46.15 ± 10.65 years. Eighty-one percent had a Pap test <1 year ago. Low healthcare access was positively associated with having a Pap test <1 year ago, (Odds ratio [OR] 3.80; 95 % Confidence interval [CI] 1.34-10.78). About 36 % reported ≥2 Pap tests during the first year after HIV diagnosis. Lower educational attainment was positively associated with having ≥2 Pap tests, OR 3.22; CI 1.08-9.62. Thirty-five percent reported more frequent Pap tests after diagnosis. Lower income was moderately associated with more frequent Pap tests post-diagnosis, OR 2.47; CI .98-6.23. Findings highlight the successes of HIV initiatives targeting socio-economically disadvantaged women and provide evidence that health policy aimed at providing and expanding healthcare access for vulnerable WLH has beneficial health implications.


Needle biopsy in the diagnosis of testicular leukemia in children.
Aggressive chemotherapy in patients with acute lymphoblastic leukemia has resulted in a marked upsurge in patient survival. In the course of their management, testicular biopsy and rebiopsy have an important role. We evaluated the histological findings in 50 sets of open wedge and simultaneous needle core biopsy specimens from 44 testes of children with acute lymphoblastic leukemia to determine the accuracy of the needle biopsy technique in the evaluation of testis involvement in acute lymphoblastic leukemia. We conclude that needle biopsy of the testis in acute lymphoblastic leukemia is highly accurate and correlates well with the conventional open wedge biopsy, and it may have a role in the management of children with acute lymphoblastic leukemia.


A family-based association study of dopamine receptor D4 and mental retardation in Qinba region of China.
Dopamine receptor D4 (DRD4) is activated by the neurotransmitter dopamine and links to many neurological and psychiatric conditions because of its close relationship with prefrontal cortex and other important brain regions. To explore the possibility that genetic variants of DRD4 gene predispose to children with mental retardation (MR), five target SNPs of DRD4 were selected and genotyped in the samples of 163 MR pedigrees from the Qinba region of China. Two SNPs (rs752306 and rs3758653) showed weak association with MR (the P values were 0.022 and 0.015 for dominant model, and 0.027 and 0.015 for recessive model, respectively). Although they did not bear the multiple testing corrections, the haplotype which contained rs3758653 exhibited a significant association with MR (global P values were 0.018 for dominant model and 0.028 for recessive model, respectively). The in silico analysis also indicated that rs752306 and rs3758653 would be biologically meaningful SNPs. Therefore, the present study suggested that the genetic variants of DRD4 gene may play an important role in human MR. Further investigations, such as confirmation with other independent samples and functional studies, may elucidate their effect on gene expression and MR susceptibility.


Adjuvant immunotherapy of lung cancer with BCG cell wall skeleton (BCG-CWS).
Four hundred fifty-five patients with lung cancer were treated with oil-attached cell-wall skeleton of bacillus Calmette-Guérin (BCG-CWS) as adjuvant immunotherapy following initial conventional therapy. The overall survival period of the patients was prolonged significantly as compared with that of 380 patients in a historical control group receiving initial conventional therapy alone (p less than 0.0001). The prolongation of the survival period of the patients was also statistically significant when classified according to clinical stages and histological cell types. The therapeutic effect was remarkable in patients combined with malignant pleurisy. Intrapleural injection of BCG-CWS resulted in not only prevention of accumulation of pleural effusion and abrogation of tumor cells but also in prolongation of survival period (P = 0.016). No serious side effects due to BCG-CWS were experienced. From the previous experimental studies and clinical experiences with human tumors, it can be concluded that adjuvant immunotherapy with BCG-CWS is a useful therapeutic modality for lung cancer, especially in cases combined with malignant pleurisy.


Human Induced Pluripotent Stem Cells as a Disease Model System for Heart Failure.
Heart failure is among the most prevalent disease complexes overall and is associated with high morbidity and mortality. The underlying aetiology is manifold including coronary artery disease, genetic alterations and mutations, viral infections, adverse immune responses, and cardiac toxicity. To date, no specific therapies have been developed despite notable efforts. This can especially be attributed to hurdles in translational research, mainly due to the lack of proficient models of heart failure limited translation of therapeutic approaches from bench to bedside. Human induced pluripotent stem cells (hiPSCs) are rising in popularity, granting the ability to divide infinitely, to hold human, patient-specific genome, and to differentiate into any human cell, including cardiomyocytes (hiPSC-CMs). This brings magnificent promise to cardiological research, providing the possibility to recapitulate cardiac diseases in a dish. Advances in yield, maturity, and in vivo resemblance due to straightforward, low-cost protocols, high-throughput approaches, and complex 3D cultures have made this tool widely applicable. In recent years, hiPSC-CMs have been used to model a wide variety of cardiac diseases, bringing along the possibility to not only elucidate molecular mechanisms but also to test novel therapeutic approaches in the dish. Within the last decade, hiPSC-CMs have been exponentially employed to model heart failure. Constant advancements are aiming at improvements of differentiation protocols, hiPSC-CM maturity, and assays to elucidate molecular mechanisms and cellular functions. However, hiPSC-CMs are remaining relatively immature, and in vitro models can only partially recapitulate the complex interactions in vivo. Nevertheless, hiPSC-CMs have evolved as an essential model system in cardiovascular research.


A randomised study of carboplatin vs sequential ifosfamide/carboplatin for patients with FIGO stage III epithelial ovarian carcinoma. The London Gynaecologic Oncology Group.
In a study designed to compare response rates of patients with stage III epithelial ovarian carcinoma to ifosfamide and carboplatin, 152 patients were randomised to receive either sequential therapy with three cycles of ifosfamide followed by three cycles of carboplatin, or to six cycles of single agent carboplatin. Ifosfamide was given every 3 weeks in a dose of 5 gm m-2 as a 24 h infusion with mesna, 1 gm m-2 by i.v. bolus prior to ifosfamide, 3 gm m-2 with ifosfamide, and 1 gm m-2 as an 8 h infusion after ifosfamide. Carboplatin was given in a dose of 400 mg m-2 by short i.v. infusion every 4 weeks. Sixty-eight evaluable patients were randomised to sequential ifosfamide/carboplatin, and 67 to single agent carboplatin. Median follow-up is 36 months (range 5.5-82.3). After three cycles of treatment two patients in the ifosfamide/carboplatin arm achieved complete remission (CR), and 12 partial remission (PR) for an overall response rate of 29%, whereas in the carboplatin arm ten patients achieved CR, and 23 PR, for an overall response rate of 63% (P = 0.0008). Seven of 15 patients with progressive disease, and nine of 20 patients with stable disease at the initial response evaluation, following three cycles of ifosfamide, subsequently responded to carboplatin therapy so that the final response rate to the complete regimen was 65% for the ifosfamide/carboplatin arm, compared to 71% for the carboplatin arm (NS). For the ifosfamide/carboplatin arm, median recurrence free survival and overall survival were 14.1 months and 18.7 months. Corresponding figures for the carboplatin arm were 14.5 months and 21.5 months (NS). Both treatments were generally well tolerated. However 47% of patients in the ifosfamide/carboplatin arm developed alopecia sufficient to require a wig, compared to only 2% in the carboplatin arm. Ifosfamide is clearly less effective, and more toxic than carboplatin. Ifosfamide failures can however be effectively salvaged by subsequent carboplatin treatment. Ifosfamide cannot be recommended for single agent therapy in ovarian carcinoma, however the combination of carboplatin plus ifosfamide might be a suitable treatment to be tested in a future randomised study against carboplatin alone.


Cardiac fibroblast miR-27a may function as an endogenous anti-fibrotic by negatively regulating Early Growth Response Protein 3 (EGR3).
Pathological myocardial fibrosis and hypertrophy occur due to chronic cardiac stress. The microRNA-27a (miR-27a) regulates collagen production across diverse cell types and organs to inhibit fibrosis and could constitute an important therapeutic avenue. However, its impact on hypertrophy and cardiac remodelling is less well-known. We employed a transverse aortic constriction (TAC) murine model of left ventricular pressure overload to investigate the in vivo effects of genetic miR-27a knockout, antisense inhibition of miR-27a-5p and fibroblast-specific miR-27a knockdown or overexpression. In silico Venn analysis and reporter assays were used to identify miR-27a-5p's targeting of Early Growth Response Protein 3 (Egr3). We evaluated the effects of miR-27a-5p and Egr3 upon transforming growth factor-beta (Tgf-β) signalling and secretome of cardiac fibroblasts in vitro. miR-27a-5p attenuated TAC-induced cardiac fibrosis and myofibroblast activation in vivo, without a discernible effect on cardiac myocytes. Molecularly, miR-27a-5p inhibited transforming growth factor-beta (Tgf-β) signalling and pro-fibrotic protein secretion in cardiac fibroblasts in vitro through suppressing the pro-fibrotic transcription factor Early Growth Response Protein 3 (Egr3). This body of work suggests that cardiac fibroblast miR-27a may function as an endogenous anti-fibrotic by negatively regulating Egr3 expression.


Chemical properties of rare earth elements in typical medical waste incinerator ashes in China.
Medical waste (MW) ashes from different types of MW incinerators were examined to detect the characteristics and environmental impact of rare earth elements (REEs). The results showed that total REE contents in the ash samples ranged from 10.2 to 78.9 mg/kg. REEs in bottom ash were apparently higher than those in fly ash. Average REE contents in the ashes followed the sequence of Ce>La>Nd>Y>Gd>Pr>Sm>Dy>Er>Yb>Ho>Eu>Tb>Lu>Tm. Some of the elements, such as Sm, Dy, Ho, Er, Yb in the ash samples were in normal or nearly normal distribution, but Y, La, Ce, Pr, Nd, Eu, Gd, Tb, Tm, Lu were not normally distributed, indicating some of the ash samples were enriched with these elements. Crust-normalized REE patterns indicated that two types of the MW ashes were obviously enriched with Gd and La. Sequential extraction results showed that REEs in the ash mainly presented as residual fraction, while exchangeable and carbonate fractions were relatively low. DTPA- and EDTA-extraction tests indicated that REEs in the MW ashes were generally in low bioavailability.


Management of obstructive sleep apnea in an edentulous patient with a mandibular advancement splint: a clinical report.
Literature on the treatment of obstructive sleep apnea in edentulous patients with a mandibular advancement splint is sparse. This clinical report describes a clinical and laboratory method of splint fabrication and discusses the rationale for its use.


The control of visual attention and its influence on prioritized processing in a location negative priming paradigm.
In a location-based negative priming paradigm, the possibility of a disengagement option of the underlying inhibitory mechanism was tested. Whereas in previous studies disengagement was observed when providing utility information about the probe trial structure, in the present study the allocation of visual attention to the stimuli was manipulated. In the first step an automatic deployment of visual attention was implemented by presenting all stimuli as abrupt onsets (Experiment 1), which demonstrated commonly observed negative priming effects. In further conditions of non-automatic allocation of visual attention in which target and distractor were presented as no-onset stimuli, negative priming effects were eliminated (Experiments 2 and 3). The preferred interpretation is that in conditions of automatic control of attention, target and distractor compete for control of action. A non-automatic control of visual attention, on the other hand, leads to a top-down modulated selection, which results in prioritized target encoding and a loss of distractor impact on the selection process. Alternative accounts and the role of no-onset distractor processing were investigated in Experiment 4.


Assisting the School in Responding to a Suicide Death: What Every Psychiatrist Should Know.
When a child or adolescent dies by suicide, many individuals are affected, most of whom are attending school. Child and adolescent psychiatrists can be called on during the wake of such tragic events in order to help schools navigate the difficult tasks following a student suicide. Being familiar with suicide postvention guidelines is crucial for anyone involved in managing the events following a student suicide. By understanding the tenets of suicide postvention and resources that are available to schools and clinicians, the tragedy of suicide can also be an opportunity to improve school mental health and suicide prevention.


Management of ureteropelvic junction obstruction in neonate.
Fetal hydronephrosis demonstrated by maternal ultrasonography should lead to early investigation during the neonatal period. Postnatal confirmation of the diagnosis of ureteropelvic junction obstruction usually can be established by combining the radiologic modalities of ultrasound, diuretic isotope renal scan, and voiding cystourethrography. Rarely should intravenous urography, antegrade pyelography, or cystoscopy and retrograde pyelography be necessary. Findings of high-grade obstruction and/or significantly diminished function on the affected side(s) should prompt early neonatal reconstruction. Pyeloplasty was performed within the first month of life in 17 infants (20 kidneys) diagnosed as having significant ureteropelvic junction obstruction. Early reconstruction in the neonatal period can be performed successfully with minimal complications and a relatively brief period of hospitalization. This may ultimately achieve maximal preservation of renal function.


Retroaortic Variant of Reverse Horseshoe Kidney With Butterfly Vertebrae Presenting as Neurogenic Bladder.
Horseshoe kidney is a relatively common congenital anomaly. In 95% of the cases, lower poles are connected to each other. In a small subset, an isthmus connects both upper poles (reverse horseshoe kidney). Almost always, the fusion of kidney poles occurs anterior to the aorta and vena cava. The fusion of renal poles posterior to both aorta and vena cava is extremely rare. Herein, we present a case with multiple rare congenital anomalies-retroaortic variant of reverse horseshoe kidney, retroaortic left renal vein, and butterfly vertebrae.


Analysis of intracardiac shunting in the lizard, Varanus niloticus: a new model based on blood oxygen levels and microsphere distribution.
The central sites of the cardiovascular system (right and left aortic arches, RAo and LAo, pulmonary artery, PA, and right and left atria, RAt and LAt) were chronically and non-occlusively cannulated for an analysis of intracardiac shunting in Varanus niloticus. Oxygen partial pressure (PO2) and oxygen concentration (CO2) were significantly higher in right aortic blood than values determined in left aortic blood. The difference was larger in animals acclimated to 25 degrees C (RAo CO2 = 4.5 +/- 1.00 vol %, LAo CO2 = 3.8 +/- 1.14, X +/- SD, n = 19) than at 35 degrees C (RAo CO2 = 5.8 +/- 1.24, LAo CO2 = 5.4 +/- 1.35, n = 18) (P less than 0.001 for both temperatures, paired t-test). These data are explained by a new model describing the differential shunting patterns of the two aortae in addition to the conventional overall right-to-left and left-to-right shunt fractions. This model was solved on the basis of blood gas data collected by simultaneous multiple-site gas analysis, together with data on the differential blood flow in the central vascular system, collected by application of the microsphere method. At 35 degrees C both right-to-left and left-to-right shunts were relatively small (about 9%), with the right-to-left shunt fraction directed exclusively into the left aorta. Thus right aortic blood represented left atrial blood, whereas left aortic blood was composed of 80% left atrial and 20% right atrial blood. Ninety percent of the pulmonary arterial blood was derived from the right atrium and 10% from the left atrium. At 25 degrees C the composition pattern of effluent blood for each vessel was similar, the absolute flow distribution, however, was different from that at 35 degrees C. These findings are discussed with respect to their significance and compatibility with the wash-out shunt model.


Thrombus distribution and changes in aneurysm size following endovascular aortic aneurysm repair.
To determine (a) changes in aneurysm size following endovascular repair, (b) the significance of collateral lumbar artery blood flow and (c) the relationship between thrombus distribution within the aneurysm sac and the development of a "lumbar endoleak". 72 patients treated with endovascular stent-grafts were followed up with spiral computed tomography for a median of 11 (range 3-27) months. The cross-sectional area of the aneurysm was measured at the point of maximum diameter pre- and post-operatively. The distribution and quantity of thrombus was recorded pre-operatively and this was related to changes in aneurysm size and the development of lumbar endoleaks post-operatively. An increase in aneurysm size occurred in 22 patients, of whom 10 had endoleaks. Fifteen aneurysms did not change in size, including four with endoleak, and 35 aneurysms decreased in size with no endoleaks. There was a significant difference between the endoleak and no endoleak groups (Chi-squared test = 17.1 with 2 degrees of freedom (d.f.), p < 0.001). Nine endoleaks were from patent lumbar arteries. No patients with thick circumferential or posteriorly placed thrombus developed an endoleak arising from lumbar vessels (0/23 cases) compared to those with minimal or anteriorly placed thrombus (9/49 cases) (Chi-squared test with Yate's correction = 3.17 with 1 d.f., p < 0.1). Aneurysms do not decrease in size in the presence of a lumbar endoleak, and some expand significantly. A number of aneurysms increase in size despite no evidence of an endoleak on computed tomography (CT). Patterns of thrombus distribution may be able to predict patients at risk from persistent endoleak via lumbar vessels.


A cluster expansion method for the complete resolution of microscopic ionization equilibria from NMR titrations
The NMR chemical shift of spin 1/2 nuclei in a polyprotic molecule represents a sensitive probe of microscopic protonation equilibria. However, these equilibria are commonly parametrized in terms of microscopic equilibrium constants, whose number increases very rapidly with the number of ionizable groups. For that reason their determination was considered to be basically impossible except for the cases of the simplest molecules. On the basis of a cluster expansion of the free energy of a microstate, we propose a novel parametrization of this problem that drastically reduces the number of necessary parameters needed to specify the microscopic equilibria. Such cluster parameters can be extracted from NMR titration data in a straightforward way. Once these parameters are known, all microscopic equilibrium constants can be obtained.


Laparoscopic Transperitoneal Para-Aortic Lymphadenectomy in 10 Steps.
Laparoscopic transperitoneal lymphadenectomy has a few advantages. First, it is a minimally invasive approach, and the transperitoneal approach is also the best option when intra-abdominal surgery is indicated. Although the procedure was described more than 2 decades ago, there is a lack of diffusion of the technique. The main objective of this video is standardization and a simple description of the technique. We described this procedure in 10 logical steps, which should help to understand and perform this procedure. This video presents a systematic approach to transperitoneal lumboaortic lymphadenectomy, which is clearly divided in 10 steps ordered in a counterclockwise direction. The 10 steps are as follows: step 1, retroperitoneal access; step 2, creating a space for subsequent lymphadenectomy and identification of anatomic landmarks; step 3, left common iliac lymph node dissection; step 4, right common iliac lymph node dissection; step 5, presacral lymph node dissection; step 6, lateroaortal lymph node dissection; step 7, laterocaval lymph node dissection; step 8, aortocaval lymph node dissection; step 9, vaginal extraction of bags with specimens; and step 10, vaginal suture. Laparoscopic transperitoneal access to lumboaortic lymph nodes is an effective method of lymphadenectomy, which may bring benefits to a patient and physician. The presented 10 steps help to perform each part of surgery in a logical sequence, making the procedure ergonomic and easier to adopt and learn. Standardization of laparoscopic techniques could help to reduce the learning curve.


Regulation of the yeast pheromone response pathway by G protein subunits.
The yeast GPA1, STE4, and STE18 genes encode proteins homologous to the respective alpha, beta and gamma subunits of the mammalian G protein complex which appears to mediate the response to mating pheromones. Overexpression of the STE4 protein by the galactose-inducible GAL1 promoter caused activation of the pheromone response pathway which resulted in cell-cycle arrest in late G1 phase and induction of the FUS1 gene expression, thereby suppressing the sterility of the receptor-less mutant delta ste2. Disruption of STE18, in turn, suppressed activation of the pheromone response induced by overexpression of STE4, suggesting that the STE18 product is required for the STE4 action. However, overexpression of both the STE4 and STE18 proteins did not generate a stronger pheromone response than overexpression of STE4 in the presence of wild-type levels of STE18. These results suggest that the beta subunit is the limiting component for the pheromone response and support the idea that beta and gamma subunits act as a positive regulator. Furthermore, overexpression of GPA1 prevented cell-cycle arrest but not FUS1 induction mediated by overexpression of STE4. This implies that the alpha subunit acts as a negative regulator presumably through interacting with beta and gamma subunits in the mating pheromone signaling pathway.


[Intraoperative radiotherapy in locally advanced carcinoma of the kidney: initial experience].
Intraoperative radiotherapy (IORT) is a rather interesting therapeutic modality in multidisciplinary oncology. Its greatest advantages reside in the approach of deeply seeded abdomino-pelvic tumors. Its inclusion in the therapeutic approach of renal carcinoma with a high local relapse rate has been analyzed in this study in relation to its technical aspects and preliminary clinical results. 11 stage III or IV patients or with local relapse in lumbar fossa were treated with nephrectomy or exeresis surgery and OIRT (10-20 Gy). Surgical exposure of the lumbar fossa and nodal drainage areas was appropriate in dal cases. No toxic signs or sequellae relating to OIRT were observed. Local tumor controls at 8 months of follow-up on the average (range from 2 to 33 months), was 82%. The data obtained in this series suggest the viability of the combined approach nephrectomy or rescue surgery and IORT. The initial clinical results suggest HIGH local tumor control without an increase in the toxicity rate or complications.


Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies.
Recently, arsenic trioxide (ATO) has been proved to induce complete remission (CR) at a high rate in patients with acute promyelocytic leukemia (APL). We prospectively investigated the safety and efficacy of ATO therapy in patients with relapsed and refractory APL and examined the duration of CR and the postremission therapies. Initially, 0.15 mg/kg ATO was administered until bone marrow remission to a maximum of 60 days. After the patient achieved CR, 1 additional ATO course at the same dosage was administered for 25 days. Of 34 patients, 31 (91%) achieved CR. PML-RAR3 messenger RNA was not detected in the bone marrow of 18 (72%) of the 25 patients evaluated by reverse transcriptase-polymerase chain reaction analysis. At a median follow-up of 30 months, the estimated 2-year overall survival rate was 56%, and the estimated 2-year event-free survival rate was 17%. During the ATO therapy, QTc prolongation was observed in most cases. Fifteen patients developed ventricular tachycardia, and 1 of them showed torsades de pointes. Other adverse events were nausea, water retention, APL differentiation syndrome, skin eruption, liver dysfunction, and peripheral neuropathy, all of which were quite tolerable. ATO therapy was remarkably effective for relapsed APL; however, postremission therapies were necessary to maintain a durable remission.


Long-term evaluation of cytoarchitectonic characteristics of prefrontal cortex pyramidal neurons, following global cerebral ischemia and neuroprotective melatonin treatment, in rats.
Global cerebral ischemia induces alterations of working memory, as evidenced in the eight-arm radial maze, in the absence of significant changes of pyramidal neuron population in the prefrontal cortex. These alterations can be prevented by a neuroprotective melatonin treatment. Thus, the cytoarchitectonic characteristics of the pyramidal neurons located at layers III and V in the prefrontal cortex of rats that had been submitted 120 days earlier to acute global cerebral ischemia (15 min four-vessel occlusion), and melatonin (10 mg/(kgh) for 6h, i.v.) or vehicle administration, starting 30min after the end of cerebral blood flow interruption, were evaluated in order to gain information on the changes of the neural substrate underlying disruption of prefrontocortical functioning. Soma size, rough length and number of bifurcations of basilar and apical dendrites, as well as spine density and proportions of the different types of spines in a 50 microm length segment of a secondary dendrite branching from the apical and the basilar dendrites, of pyramidal neurons of the dorsal medial prefrontal cortex, were evaluated in Golgi material. A significant reduction of soma size, apical and basilar dendrite length, number of dendritic bifurcations, and spine density were observed in pyramidal neurons at layers III and V after cerebral ischemia, while these alterations were prevented by melatonin treatment. These cytoarchitectural differences between groups seem to underlie the observed alterations in spatial working memory of ischemic, vehicle-treated rats in the absence of pyramidal neuron loss, as well as the better display of these functions long after ischemia and melatonin neuroprotection.


Ultrasonography of the pancreas. 6. Endoscopic imaging.
EUS is a high-resolution technique for pancreatic imaging. EUS has applictions in detecting and staging pancreatic tumors, EUS guided FNA of the pancreas for tissue diagnosis, and evaluation of chronic pancreatitis as well as EUS guided therapy such as celiac plexus block. This is a review of EUS imaging (EUS) of the pancreas covering technical aspects, clinical indications, advantages, and pitfalls as well as emerging trends in the field.


Structure and electrical properties of BCZT ceramics derived from microwave-assisted sol-gel-hydrothermal synthesized powders.
A novel microwave-assisted sol-gel-hydrothermal method was employed to rapidly synthesize Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) powders. The effects of reaction time on the structure, crystallinity, purity and morphology of the products were investigated. The results of XRD, FTIR, SEM and TEM indicated that BCZT powders could be obtained in even 60 min at a low synthesis temperature of 180 °C, which were well-crystallized with stoichiometric composition and uniform grain size (~ 85 nm). BCZT ceramic derived from the rapidly-synthesized powders had a dense microstructure and good electrical properties (εm = 9579, d33 = 496 pC/N, 2Pr = 25.22 µC/cm2, 2Ec = 7.52 kV/cm). The significant electrical properties were closely related to the high activity of the BCZT powders, resulting from the rapid microwave-assisted sol-gel-hydrothermal process.