Challenges in Biomarker Discovery: Combining Expert Insights with Statistical Analysis of Complex Omics Data.
INTRODUCTION: The advent of high throughput technologies capable of comprehensive analysis of genes, transcripts, proteins and other significant biological molecules has provided an unprecedented opportunity for the identification of molecular markers of disease processes. However, it has simultaneously complicated the problem of extracting meaningful molecular signatures of biological processes from these complex datasets. The process of biomarker discovery and characterization provides opportunities for more sophisticated approaches to integrating purely statistical and expert knowledge-based approaches. AREAS COVERED: In this review we will present examples of current practices for biomarker discovery from complex omic datasets and the challenges that have been encountered in deriving valid and useful signatures of disease. We will then present a high-level review of data-driven (statistical) and knowledge-based methods applied to biomarker discovery, highlighting some current efforts to combine the two distinct approaches. EXPERT OPINION: Effective, reproducible and objective tools for combining data-driven and knowledge-based approaches to identify predictive signatures of disease are key to future success in the biomarker field. We will describe our recommendations for possible approaches to this problem including metrics for the evaluation of biomarkers.


Noradrenergic control of emotion-induced amnesia and hypermnesia.
Emotional memory encoding is associated with retrograde and anterograde episodic memory changes involving amnesia and hypermnesia, respectively. These effects are noradrenergic-dependent and reflect an interaction with emotional arousal and valence. Whereas anterograde amnesic effects most likely result from attentional capture by emotional arousal, retrograde amnesic and hypermnesic effects may reflect a valence-dependent filter mechanism that operates during emotional memory encoding and controls episodic memory access based upon behavioral significance. This filter mechanism may originnate in amygdala-hippocampal interactions that are modulated by both ascending locus coeruleus and descending prefrontal cortex inputs.


Organ transplantation scandal influencing corneal donation rate.
In the majority of countries, there is a shortage of donor corneas for corneal transplantations. This study investigated the impact of organ transplantation scandals on corneal donation rate at the University Hospital Tübingen. Each deceased patient was considered as a potential corneal donor. An ophthalmic resident handled with stable methods of procedures the corneal donor procurement from 2009 to 2015. The rates of corneal donation were examined and analyzed. Among the 5712 hospital deaths, consent for corneal donation was obtained in 711 cases. The mean annual corneal donation rate was 12.4%. Since 2009, the donation rate per year could be increased with exception of 2013 and 2015. In the end of 2012 and 2014 two huge organ donation scandals were known in Germany. In the following years 2013 and 2015 corneal donation rate decreased significantly (P=0.0181 and P=0.0006). We concluded that transplantation scandals have a significant impact on corneal donation rate. Improving professional's performance through full transparency and honesty is very important to earn trust of potential donors and their families.


Bacterial census of poultry intestinal microbiome.
The objective of this study was to generate a phylogenetic diversity census of bacteria identified in the intestinal tract of chickens and turkeys using a naïve analysis of all the curated 16S rRNA gene sequences archived in public databases. High-quality sequences of chicken and turkey gastrointestinal origin (3,184 and 1,345, respectively) were collected from the GenBank, Ribosomal Database Project, and Silva comprehensive ribosomal RNA database. Through phylogenetic and statistical analysis, 915 and 464 species-equivalent operational taxonomic units (defined at 0.03 phylogenetic distance) were found in the chicken and the turkey sequence collections, respectively. Of the 13 bacterial phyla identified in both bird species, Firmicutes, Bacteroidetes, and Proteobacteria were the largest phyla, accounting for >90% of all the sequences. The chicken sequences represent 117 established bacterial genera, and the turkey sequences represent 69 genera. The most predominant genera found in both the chicken and the turkey sequence data sets were Clostridium, Ruminococcus, Lactobacillus, and Bacteroides, but with different distribution between the 2 bird species. The estimated coverage of bacterial diversity of chicken and turkey reached 89 and 68% at species-equivalent and 93 and 73% at genus-equivalent levels, respectively. Less than 7,000 bacterial sequences from each bird species from various locations would be needed to reach 99% coverage for either bird species. Based on annotation of the sequence records, cecum was the most sampled gut segment. Chickens and turkeys were shown to have distinct intestinal microbiomes, sharing only 16% similarity at the species-equivalent level. Besides identifying gaps in knowledge on bacterial diversity in poultry gastrointestinal tract, the bacterial census generated in this study may serve as a framework for future studies and development of analytic tools.


Orbital and eyelid manifestations of xanthogranulomatous diseases.
Erdheim-Chester disease, adult periocular xanthogranuloma, juvenile xanthogranuloma, and necrobiotic xanthogranuloma are presumed to be separate disease entities, but they are often confused clinically because of their similar presentations and histopathology. To further describe the xanthogranulomatous diseases and to identify possible pitfalls in their diagnoses, we retrospectively reviewed charts from 1998 to 2001 for all patients with biopsy-proven xanthogranulomatous process of the eyelid and/or orbit. We found 2 patients diagnosed with adult periocular xanthogranuloma and 1 with Erdheim-Chester disease, each case initially misdiagnosed. Careful review of the clinical manifestations, histopathological review of all previous biopsy specimens, and repeat biopsy aided in the correct diagnosis and management of disease in these 3 patients.


The Emerging Role of PCSK9 Inhibitors in Preventive Cardiology.
Low-density lipoprotein cholesterol (LDL-C) is a most important risk factor for developing coronary artery disease (CAD) and other forms of atherosclerotic cardiovascular disease (CVD) and a major focus of CVD risk reduction with lifestyle and statins. Unfortunately residual risk of CVD remains in patients with familial hypercholesterolaemia and/or statin intolerance in whom adequate LDL-C lowering is not accomplished with lifestyle and statins. PCSK9 is a serine protease that binds the LDL receptor (LDL-R) and acts as a chaparone for endocytosis and shuttling the PCSK9-LDLR complex to lysosomes for degradation. In the absence of PCSK9 the LDLR-LDL-C complex dissociates and LDL-R is recycled back to the cell surface. Humanised monoclonal antibodies (evolocumab, alirocumab, bocolicumab) have been developed that increase LDL-R by ~2-fold and lower LDL-C by up to 75 percent. This effect is synergistic to that of statins with the only common adverse effect is a local injection site reaction. At present, ongoing Phase III CVD outcome trials with PCSK9 inhibitors offer promise that patients with LDL-C levels that remain elevated can decrease CVD events and related mortality.


Synthesis and cardiotonic activity of a series of substituted 4-alkyl-2(1H)-quinazolinones.
The synthesis, cardiac fraction III cyclic nucleotide phosphodiesterase (PDE-III) inhibition, and positive inotropic activity of a series of 2(1H)-quinazolinones are reported. A general synthesis of the series involved the cyclization of 2-aminoacetophenones with potassium cyanate in acetic acid. Modifications at the 4-position of the quinazoline nucleus were best achieved by formation of the intermediate N1-acyl-N3-phenylurea from the substituted phenyl isocyanate and appropriate carboxamide. PPA was used to ring close to the quinazoline product. Generally the SAR for the series paralleled the five-point model previously published for PDE-III inhibition. The most active analogue of the series was 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone (1) (ORF 16600), which had about twice the intravenous potency of amrinone. Compound 1 is currently under development as an orally active cardiotonic.


Comparison of ACUITY, CRUSADE, and GRACE Risk Scales for Predicting Clinical Outcomes in Patients Treated with Dual-Antiplatelet Therapy.
Several reliable scales have been proposed for the management and prognosis in patients with acute coronary syndromes (ACS) treated with dual-antiplatelet therapy (DAPT). We sought to compare the performance of three conventional risk scores to predict major bleeding (MB; such as ACUITY or CRUSADE), or major adverse cardiovascular event (MACE for GRACE). This study included 904 consecutive post-ACS patients from the single Korean study center who underwent coronary interventions, and were treated with DAPT. All three scores were calculated based on admission data. MB and MACE were collected at 30-day and 1-year follow-ups. MB was defined according to the Bleeding Academic Research Consortium (BARC) criteria (types 3-5), and MACE included all-cause death, myocardial infarction, target vessel revascularization, and stroke. MB occurred in 114 patients (12.6%) during 30 days, and 65 patients (7.2%) from 30 days till 1-year follow-up. MACE occurred in 28 (3.1%) and 72 (8.0%) patients during 30 and 30 days till 1 year, respectively. For 30 days MB, the discriminatory ability of ACUITY (AUC: 0.83, 95% CI: 0.81-0.86) and CRUSADE (AUC: 0.82, 95% CI: 0.79-0.84) was similar, and more reliable than GRACE (AUC: 0.74, 95% CI: 0.71-0.77; p < 0.0001 and p = 0.002, respectively). The predictive value for 1-year MB was similar between ACUITY (AUC: 0.75, 95% CI: 0.72-0.78, p < 0.0001), CRUSADE (AUC: 0.70, 95% CI: 0.70-0.73, p < 0.0001), and GRACE (AUC: 0.70, 95% CI: 0.67-0.73, p < 0.0001) classifications. All three risk scales exhibited similar prediction for 30-day and 1-year MACE. We conclude that ACUITY and CRUSADE scores were superior to GRACE in predicting 30-day MB. However, all three risk scales were similarly useful for long-term MB, and MACE assessment.


Transcatheter treatment of perimembranous ventricular septal defect, secundum atrial septal defect and patent ductus arteriosus in a child.
A 4-year-old child with patent ductus arteriosus, perimembranous ventricular septal defect and ostium secundum atrial septal defect was successfully treated with the use of a simultaneous transcatheter for all of the anomalies present. The patent ductus arteriosus was closed first by using a coil, then the perimembranous ventricular septal defect was closed by using a 10-mm Amplatzer eccentric device. Finally, a 10-mm Amplatzer atrial septal defect device was implanted to treat the atrial septal defect.


Gas-filled microbubbles: Novel mucosal antigen-delivery system for induction of anti-pathogen's immune responses in the gut.
Despite important success in protecting individuals against many pathogenic infections, parenteral vaccination is not optimal to induce immunity at the site of pathogen entry, i.e. mucosal surfaces. Moreover, designing adequate delivery systems and safe adjuvants to overcome the inherent tolerogenic environment of the mucosal tissue is challenging, in particular in the gastrointestinal tract prone to antigen degradation. We recently demonstrated that intranasal administration of a Salmonella-derived antigen associated with gas-filled microbubbles induced specific Ab and T cell responses in the gut and was associated with a reduction in local and systemic bacterial load after oral Salmonella infection. Building on these promising data, the adequate choice of antigen(s) to be administered and how to make it suitable for possible human application are discussed. We additionally present novel data dealing with oral administration of microbubbles and describe research strategies to direct them to mucosal sampling/inductive sites.


Dynamic Coati Optimization Algorithm for Biomedical Classification Tasks.
Medical datasets are primarily made up of numerous pointless and redundant elements in a collection of patient records. None of these characteristics are necessary for a medical decision-making process. Conversely, a large amount of data leads to increased dimensionality and decreased classifier performance in terms of machine learning. Numerous approaches have recently been put out to address this issue, and the results indicate that feature selection can be a successful remedy. To meet the various needs of input patterns, medical diagnostic tasks typically involve learning a suitable categorization model. The k-Nearest Neighbors algorithm (kNN) classifier's classification performance is typically decreased by the input variables' abundance of irrelevant features. To simplify the kNN classifier, essential attributes of the input variables have been searched using the feature selection approach. This paper presents the Coati Optimization Algorithm (DCOA) in a dynamic form as a feature selection technique where each iteration of the optimization process involves the introduction of a different feature. We enhance the exploration and exploitation capability of DCOA by employing dynamic opposing candidate solutions. The most impressive feature of DCOA is that it does not require any preparatory parameter fine-tuning to the most popular metaheuristic algorithms. The CEC'22 test suite and nine medical datasets with various dimension sizes were used to evaluate the performance of the original COA and the proposed dynamic version. The statistical results were validated using the Bonferroni-Dunn test and Kendall's W test and showed the superiority of DCOA over seven well-known metaheuristic algorithms with an overall accuracy of 89.7%, a feature selection of 24%, a sensitivity of 93.35% a specificity of 96.81%, and a precision of 93.90%.


Sequential monitoring of minimal residual disease in acute lymphoblastic leukemia: 7-year experience in a pediatric hematology/oncology unit.
We evaluated minimal residual disease (MRD) in 91 children with acute lymphoblastic leukemia (ALL) by PCR amplification of clonal rearrangements, immunoglobulin (IgH; VDJ rearrangement, CDR3 region) and T-cell receptor (TCRdelta). Sequential monitoring of MRD was performed at different time points during and after chemotherapy and was correlated to patient outcome. In total, 792 bone marrow samples were assessed for MRD at the end of induction, and during and after treatment completion. MRD positivity at the end of induction was detected in 12% of patients and was associated with high incidence of relapse, 54.55% (p = 0.0002), at 5 years. On the other hand, 88% of patients were MRD-negative at the end of induction and the relapse rate at 5 years was very low, 5%. The frequency of MRD decreased to 16% in the first 6 months of chemotherapy; however, the incidence of relapse in MRD-positive patients remained high, 42.8%. After treatment completion (24-36 months from diagnosis), 32% patients were MRD-positive and the relapse rate was 36.5% (p = 0.0009). Our results indicated that monitoring of MRD constituted an essential prognostic marker, and detection of MRD particularly at the end of induction and after treatment completion was strongly predictive for patient outcome.


Digital smile planning technique applied to prosthetic rehabilitation of dental esthetic area: a case report.
Nowadays, the objective of esthetic rehabilitation is not only to guarantee the results to the patients in terms of esthetic parameters but also the possibility to show the pre-visualization of possible results and therapy planning. The aim of this study is to apply the 3D-DPS digital planning technique, in the prosthetic treatment of a patient, to produces digitally the mockup for the digital previewing and esthetic crown and veneer for the final prosthetic treatment. A case report participant is a young patient, a female, 26 years old, with no oral, periodontal, or systemic diseases. After a sign of an informed consent and an explication of a plan of treatment, technical intraoral and extraoral pictures and intraoral digital impressions were taken. The digital images improved from the 2D Smile Lynx Software and the scanner stereolithographic (STL) file was matched into the CAD Lynx to obtain a virtual previsualization of teeth and smile design. Then, the mockup was milled using a CAM system. Minimally invasive preparation was carried out on the enamel surface with the mockup as position guides. Finally, the esthetic CAD-CAM veneer and crown were produced digitally using the CAD Wax as a guide. The use of the digital project and the pre-operative mockup allowed a perfect initial evaluation and a better understanding of the patient's treatment plan. The 3D digital planning technique is a new, predictably and minimally invasive technique. It allows diagnosis and a better communication with the patient. It helps to reduce the working time and the possible errors usually associated with the classical prosthodontic manual step.


Effect of intubation in patients with functional epiphora after endoscopic dacryocystorhinostomy.
To investigate the effect of bicanalicular silicone tube intubation (BSTI) in the treatment of functional epiphora after endoscopic dacryocystorhinostomy (En-DCR). Clinical data of 84 patients (95 eyes) with functional epiphora after En-DCR were retrospectively analyzed. Functional epiphora was confirmed as persistent or recurrent epiphora by fluorescein dye disappearance test (FDDT), lacrimal irrigation test, as well as endoscopic examination. Secondary BSTIs were recommended for patients with functional epiphora. These tubes were removed 1mo after surgery. Functional success and associated complications were assessed after 2y of follow-up. Seven patients (9 eyes) refused intervention, 5 patients (6 eyes) did not complete postoperative follow-up, and 1 patient (1 eye) developed tube prolapse within 1mo after surgery. Seventy-one patients (79 eyes) were included at last. Functional success ratios at six months, one year, as well as two years post-operation were 94.9% (75/79), 92.4% (73/79), and 91.1% (72/79), respectively. Three eyes presented with punctal slitting (2 eyes without epiphora), 1 eye with proximal canaliculus slitting, 1 eye with canaliculus stenosis and 4 eyes with still present functional epiphora without detectable abnormal at the last follow-up. Secondary intubation is an effective procedure with low recurrence probability for functional epiphora after En-DCR. Punctal and canaliculus injury are the main tube-associated complications after secondary intubation.


Structure, dynamics, and evolution of centromeric nucleosomes.
Centromeres are defining features of eukaryotic chromosomes, providing sites of attachment for segregation during mitosis and meiosis. The fundamental unit of centromere structure is the centromeric nucleosome, which differs from the conventional nucleosome by the presence of a centromere-specific histone variant (CenH3) in place of canonical H3. We have shown that the CenH3 nucleosome core found in interphase Drosophila cells is a heterotypic tetramer, a "hemisome" consisting of one molecule each of CenH3, H4, H2A, and H2B, rather than the octamer of canonical histones that is found in bulk nucleosomes. The surprising discovery of hemisomes at centromeres calls for a reevaluation of evidence that has long been interpreted in terms of a more conventional nucleosome. We describe how the hemisome structure of centromeric nucleosomes can account for enigmatic properties of centromeres, including kinetochore accessibility, epigenetic inheritance, rapid turnover of misincorporated CenH3, and transcriptional quiescence of pericentric heterochromatin. Structural differences mediated by loop 1 are proposed to account for the formation of stable tetramers containing CenH3 rather than stable octamers containing H3. Asymmetric CenH3 hemisomes might interrupt the global condensation of octameric H3 arrays and present an asymmetric surface for kinetochore formation. We suggest that this simple mechanism for differentiation between centromeric and packaging nucleosomes evolved from an archaea-like ancestor at the dawn of eukaryotic evolution.


[Effects of controlled release nitrogen fertilizer on surface water N dynamics and its runoff loss in double cropping paddy fields in Dongtinghu Lake area].
By using leakage pond to simulate the double cropping paddy fields in Dongtinghu Lake area, this paper studied the effects of urea (CF) and controlled release nitrogen fertilizer (CRNF) on the dynamics of surface water pH, electrical conductivity (EC), total nitrogen (TN), ammonia nitrogen (NH4(+)-N) and nitrate nitrogen (NO3(-)-N) and the runoff loss of TN in alluvial sandy loamy paddy soil and purple calcareous clayed paddy soil, the two main paddy soils in this area. The results showed that after applying urea, the surface water TN and NH4(+)-N concentrations reached the peak at the 1st and 3rd day, respectively, and decreased rapidly then. Surface water NO3(-)-N concentration was very low, though it showed a little raise at the 3rd to 7th day after applying urea in purple calcareous clayed paddy soil. In early rice field, surface water pH rose gradually within 15 days after applying urea, while in late rice field, it did within 3 days. EC kept consistent with the dynamics of NH4(+)-N. CRNF, especially 70% N CRNF, gave rise to distinctly lower surface water pH, EC, and TN and NH4(+)-N concentrations within 15 days after application, but NO3- concentration rose slightly at late growth stages, compared with urea application. The monitoring of TN runoff loss indicated that during double cropping rice growth season, the loss amount of TN under urea application was 7.70 kg x hm(-2), accounting for 2.57% of applied urea-N. The two runoff events occurred within 20 days after urea application contributed significantly to the TN runoff loss. CRNF application resulted in a significantly lower TN concentration in runoff water from the 1st runoff event occurred within 10 days of its application, and thereafter, the total TN runoff loss for CRNF and 70% N CRNF application was decreased by 24.5% and 27.2%, respectively, compared with urea application.


Utility of Loop-mediated Isothermal Amplification Assay, Polymerase Chain Reaction, and ELISA for Diagnosis of Leptospirosis in South Indian Patients.
Leptospirosis is a zoonotic disease which requires laboratory diagnosis for confirmation. In this study serum samples from adults with acute undifferentiated fever (duration ≤15 days) were tested for IgM antibodies to Leptospira by ELISA, PCR for rrs gene and loop-mediated isothermal amplification (LAMP) assay for LipL32 and LipL41. Among the 150 sera tested, three were positive by PCR, LAMP and IgM ELISA/modified Faines' criteria, two by only PCR; seven only by LAMP assay and forty fulfilled modified Faine's criteria (illness clinically compatible and IgM ELISA positive for leptospirosis). Clinical correlation revealed renal compromise, low platelet count and severe jaundice were significantly related to leptospirosis (P < 0.05). This study suggests that LAMP assay could be useful for diagnosis of leptospirosis during the 1st week of illness whereas IgM ELISA forms the mainstay of diagnosis from the 2nd week onward. Further studies especially community based, comparing ELISA, PCR, LAMP, culture and microscopic agglutination test are required to evaluate the veracity of these findings.


Oxide Spintronics as a Knot of Physics and Chemistry: Recent Progress and Opportunities.
Transition-metal oxides (TMOs) constitute a key material family in spintronics because of mutually coupled degrees of freedom and tunable magneto-ionic properties. In this Perspective, we consider oxide spintronics as a knot of physics and chemistry and mainly discuss two current hot topics: spin-charge interconversion and magneto-ionics. First, spin-charge interconversion is focused on oxide films and heterostructures including 4d/5d heavy metal oxides (e.g., SrIrO3) and two-dimensional electron gases. Based on spin-charge interconversion, charge currents can be transformed to spin currents and generate spin-orbit torque in oxide/metal and all-oxide heterostructures. Additionally, the voltage control of magnetism in TMOs by the magneto-ionic pathway has rapidly accelerated during the past few years due to the versatile advantages of effective control, nonvolatile nature, low power cost, etc. Typical magneto-ionic oxide systems and corresponding physicochemical mechanisms will be discussed. Finally, further developments of oxide spintronics are envisioned, including material discovery, physics exploration, device design, and manipulation methods.


Second hydrogen atom abstraction by molecular ions.
We report the observation of a new physical phenomenon of the addition of 2 hydrogen atoms to molecular ions thus forming [M + 2H]+ ions. We demonstrate such second hydrogen atom abstraction onto the molecular ions of pentaerythritol and trinitrotoluene (TNT). We used both gas chromatography mass spectrometry (GC-MS) with supersonic molecular beam (SMB) with methanol added into its make-up gas and electron ionization (EI) liquid chromatography mass spectrometry (LC-MS) with SMB with methanol as the LC solvent. We found that the formation of methanol clusters resulted upon EI in the formation of dominant protonated pentaerythritol ion at m/z = 137 plus about 70% relative abundance of pentaerythritol molecular ion with 2 additional hydrogen atoms at m/z = 138 which is well above the 5.7% natural C13 isotope abundance of protonated pentaerythritol. Similarly, we found an abundant protonated TNT ion at m/z = 228 and a similar abundance of TNT molecular ion with 2 additional hydrogen atoms at m/z = 229. Upon the use of deuterated methanol (CD3 OD) as the solvent, we observed an abundant m/z = 231 (M + 2D)+ of TNT with 2 deuterium atoms. We found such abundant second hydrogen atom abstraction with butylglycolate and at low abundances in dioctylphthalate, Vitamin K3, phenazine, and RDX. At this time, we are unable to report the magnitude and frequency of occurrence of this phenomenon in standard electrospray LC-MS. This observation could have important implications on the provision of elemental formula from mass spectra that are involved with protonated molecules. Accordingly, while accurate mass measurements can serve for the generation of elemental formula, their further support and improvement via isotope abundance analysis are questionable. Consequently, if a given compound can be analyzed by both GC-MS and LC-MS, its GC-MS analysis can be superior for the provision of accurate elemental formulae if its EI mass spectrum exhibits abundant molecular ions such as with GC-MS with SMB (also known as cold EI).


Maghemite functionalization for antitumor drug vehiculization.
In this paper we describe the preparation and characterization of magnetic nanocomposites designed for applications in targeted drug delivery. Combining superparamagnetic behavior with proper surface functionalization in a single entity makes it possible to have altogether controlled location and drug loading, and release capabilities. The colloidal vehicles consist of maghemite (γ-Fe2O3) cores surrounded by a gold shell through an intermediate silica coating. The external Au layer confers the particles a high degree of biocompatibility and reactive sites for the transported drug binding. In addition, it permits to take advantage of the strong optical resonance, making it easy to visualize the particles or even control their payload release through temperature changes. The results of the analysis of relaxivity demonstrate that these nanostructures can be used as T2 contrast agents in magnetic resonance imaging (MRI), but the magnetic cores will be mainly useful in manipulating the particles using external magnetic fields. We describe how optical absorbance and electrokinetic data provide a followup of the progress of the nanostructure formation. Additionally, these techniques, together with confocal microscopy, are employed to demonstrate that the component nanoparticles are capable of loading significant amounts of the antitumor drug doxorubicin, very efficient in the chemotherapy of a wide range of tumors. Colon adenocarcinoma cells were used to test the in vitro release capabilities of the drug-loaded nanocomposites.


[Changes in the concentrations of total RNA and DNA in the cerebral cortex and internal organs (liver and heart) after prolonged hypovolemic hypotension and in the post-resuscitation period].
It was shown in experiments on dogs that after 4-hour hypovolemic hypotension the content of total RNA in brain cortex and myocardium homogenates decreased. In the liver, there was a significant decrease both in RNA and DNA content. In the postresuscitation period, the content of nucleic acids in the myocardium returned to normal after 14--21 days, and that in the liver after 3--4 months. The gray matter of the brain manifested a delayed lowering of DNA content (after 14--21 days), and the level of nucleic acid did not return ot normal over 3--4 months after resuscitation.


Serosurvey of hepatitis A virus and E virus infection among municipal sweepers working in the largest city in the south of Iran.
This study was conducted to determine the exposure rate of Hepatitis A and Hepatitis E viruses in urban solid waste collectors/sweepers in the south of Iran. The 385 samples (serums) were collected from Shiraz Municipality waste sweepers.. A questionnaire was used to gather data on their demographic and occupational characteristics, as well as their awareness of viral hepatitis disease. The viral seroprevalence was determined by commercial IgG ELISA kit. All participants were male, mean age of 41 ± 8 years. ELISA assay showed that all of them were positive for anti-HAV IgG. Also, 62 out of 385 individuals were positive for anti-HEV IgG. The statistical analysis showed that the frequency of HEV IgG antibody among age groups 20-30, 31-40, 41-50 and >50 years old had an increasing trend, 4.5%, 10.1%, 17.4%, and 36.7%, respectively, indicating age factor significance (p = .001). Based on some investigated factors including the duration of work experience, current and previous jobs, habitation, personal hygiene status, and knowledge on viral hepatitis diseasees/their transmission, there was no statistically significant difference between anti-HEV IgG positive versus negative sweepers. The results indicated a slighty higher frequency of anti-HAV and anti-HEV IgG among sweepers compared to other pre-investigated population. It doesn't seem that garbage collecting/sweeping could be a significant risk factor for HAV and HEV infection.


Chromosome territories and the global regulation of the genome.
Spatial positioning is a fundamental principle governing nuclear processes. Chromatin is organized as a hierarchy from nucleosomes to Mbp chromatin domains (CD) or topologically associating domains (TADs) to higher level compartments culminating in chromosome territories (CT). Microscopic and sequencing techniques have substantiated chromatin organization as a critical factor regulating gene expression. For example, enhancers loop back to interact with their target genes almost exclusively within TADs, distally located coregulated genes reposition into common transcription factories upon activation, and Mbp CDs exhibit dynamic motion and configurational changes in vivo. A longstanding question in the nucleus field is whether an interactive nuclear matrix provides a direct link between structure and function. The findings of nonrandom radial positioning of CT within the nucleus suggest the possibility of preferential interaction patterns among populations of CT. Sequential labeling up to 10 CT followed by application of computer imaging and geometric graph mining algorithms revealed cell-type specific interchromosomal networks (ICN) of CT that are altered during the cell cycle, differentiation, and cancer progression. It is proposed that the ICN correlate with the global level of genome regulation. These approaches also demonstrated that the large scale 3-D topology of CT is specific for each CT. The cell-type specific proximity of certain chromosomal regions in normal cells may explain the propensity of distinct translocations in cancer subtypes. Understanding how genes are dysregulated upon disruption of the normal "wiring" of the nucleus by translocations, deletions, and amplifications that are hallmarks of cancer, should enable more targeted therapeutic strategies.


Diagnosis of primary liver cancer using lectin affinity chromatography of serum alkaline phosphatase.
Serum alkaline phosphatase (sALP) can be separated into unbound liver type (L-ALP) and bound bone type (B-ALP) by means of WGA affinity chromatography. The L-ALP from the sera of normal adults and various liver diseases was found to show different chromatographic behaviours on DSA affinity column with multiple peaks of ALP activity after the L-ALP was treated with neuraminidase to remove the terminal sialic acids on the sugar chain of L-ALP. The L-ALP from normal sera contained no bound activity on DSA, whereas that from acute or chronic hepatisis, liver cirrhosis and biliary obstruction had a significant amount of bound fractions with weak and intermediate affinity. The strongly bound fraction(s) was only present in the L-ALP serum from primary liver cancer (PLC) and the positive rate of its appearance was 100% in 38 cases of PLC, including 8 alpha-fetoprotein (AFP) negative cases. The WGA chromatography can be skipped and similar results are obtained. The percentage of the strongly bound fraction in serum L-ALP was not related to the level of either sALP activity or AFP, and the appearance of the strongly bound fraction is attributed to the structural difference of sugar chains in L-ALP. Therefore, this L-ALP fraction may be assumed as a new index in the diagnosis of PLC, and the different profiles of sALP or L-ALP on DSA chromatography may be used in the differential diagnosis of benign and malignant liver diseases.


Monocytes, Macrophages, and Metabolic Disease in Atherosclerosis.
Atherosclerotic cardiovascular disease (CVD) is a lipid-driven chronic inflammatory disease, in which macrophages are responsible for taking up these lipids and driving disease progression. Over the years, we and others have uncovered key pathways that regulate macrophage number/function and identified how metabolic disorders such as diabetes and obesity, which are common risk factors for CVD, exacerbate these pathways. This ultimately accelerates the progression of atherosclerosis and hinders atherosclerotic regression. In this review, we discuss the different types of macrophages, from monocyte-derived macrophages, local macrophage proliferation, to macrophage-like vascular smooth muscle cells, that contribute to atherosclerosis as well as myeloid-derived suppressor cells that may have anti-atherogenic effects. We will also discuss how diabetes and obesity influence plaque macrophage accumulation and monocyte production (myelopoiesis) to promote atherogenesis as well as an exciting therapeutic target, S100A8/A9, which mediates myelopoiesis in response to both diabetes and obesity, shown to be effective in reducing atherosclerosis in pre-clinical models of diabetes.


Surface-Enhanced Infrared Spectroscopy Using Resonant Nanoantennas.
Infrared spectroscopy is a powerful tool widely used in research and industry for a label-free and unambiguous identification of molecular species. Inconveniently, its application to spectroscopic analysis of minute amounts of materials, for example, in sensing applications, is hampered by the low infrared absorption cross-sections. Surface-enhanced infrared spectroscopy using resonant metal nanoantennas, or short "resonant SEIRA", overcomes this limitation. Resonantly excited, such metal nanostructures feature collective oscillations of electrons (plasmons), providing huge electromagnetic fields on the nanometer scale. Infrared vibrations of molecules located in these fields are enhanced by orders of magnitude enabling a spectroscopic characterization with unprecedented sensitivity. In this Review, we introduce the concept of resonant SEIRA and discuss the underlying physics, particularly, the resonant coupling between molecular and antenna excitations as well as the spatial extent of the enhancement and its scaling with frequency. On the basis of these fundamentals, different routes to maximize the SEIRA enhancement are reviewed including the choice of nanostructures geometries, arrangements, and materials. Furthermore, first applications such as the detection of proteins, the monitoring of dynamic processes, and hyperspectral infrared chemical imaging are discussed, demonstrating the sensitivity and broad applicability of resonant SEIRA.


Risk Factors for Posttransplant Erythrocytosis: Parathyroid Hormone Paradox?
Posttransplant erythrocytosis affects 8% to 26% of kidney transplant recipients. In this study, our aim was to define associations among hypercalcemia, persistent hyperparathyroidism, and posttransplant erythrocytosis. We also investigated the effects of biologic sex, age, and dialysis modality before transplant on posttransplant erythrocytosis development. We enrolled 247 patients [159 (64%) male and 88 (36%) female] who underwent kidney transplant between 2009 and 2018. All demographic and laboratory parameters were retrospectively analyzed as possible factors associated with posttransplant erythrocytosis. Fifty-nine (24%) of total patients had posttransplant erythrocytosis. The median time to posttransplant erythrocytosis development was 16 months (range, 8-34 mo). Male sex, the use of peritoneal dialysis as maintenance renal replacement therapy before kidney transplant, and persistent hyperparathyroidism were defined as independent risk factors for posttransplant erythrocytosis development in our multivariate logistic regression analyses (odds ratio = 5.228, 3.963, and 4.109, respectively). In addition, high serum creatinine levels were associated with a lower incidence of posttransplant erythrocytosis (odds ratio = 0.253). Although significance did not remain after multivariate analysis, hypercalcemia was found to be significantly associated with posttransplant erythrocytosis in univariate analyses (odds ratio = 1.768). In subgroup analyses, where only male patients were evaluated, persistent hyperparathyroidism and peritoneal dialysis were found to be independent risk factors for posttransplant erythrocytosis development (odds ratio = 4.176 and 5.003). Persistent hyperparathyroidism and hypercalcemia could precipitate development of posttransplant erythrocytosis. The preserved residue renal function may be associated with increased endogenous erythropoietin, which could lead to posttransplant erythrocytosis development.


[Anatomical basis of the flap based on the perforator of the first plantar metatarsal artery ].
To investigate the morphological features of the perforator from the first plantar metatarsal artery, so as to provide anatomic basis for the reconstruction of soft-tissue defects of the forefoot. The first metatarsophalangeal joint was chosen as the landmark on 30 human cadaveric feet prefused with red latex. The following contents were observed under surgical magnifier: (1)The origin, courses,branches,distribution of the perforator of the first plantar metatarsal artery; (2)The anastomoses among the perforator of the first plantar metatarsal artery and other arteries on the medial aspect of the foot. Simulated operation was performed on one fresh specimen. The perforator of the first plantar metatarsal artery passed through the space between the tendon, the abductor hallucis and the first metatarsal bone, and its entry point into the deep fascia was located (2. 3 ± 0.7 ) cm proximal to the first metatarsophalangeal joint. The perforator anastomosed with either the medial tarsal artery, the medial anterior malleolus artery or the branch of the medial plantar artery on the superior margin of the abductor hallucis, forming a longitudinal arterial chain,through which small branches were given off to the skin of the medial aspect of the foot. The perforator was( 1. 1 ± 0.2) mm in diameter and(3.2 ± 0.2) cm in length. The flap based on the perforator of the first plantar metatarsal artery can be harvested as an axial flap to repair the defects of soft tissue on the forefoot.


Avoiding short circuits from zinc metal dendrites in anode by backside-plating configuration.
Portable power sources and grid-scale storage both require batteries combining high energy density and low cost. Zinc metal battery systems are attractive due to the low cost of zinc and its high charge-storage capacity. However, under repeated plating and stripping, zinc metal anodes undergo a well-known problem, zinc dendrite formation, causing internal shorting. Here we show a backside-plating configuration that enables long-term cycling of zinc metal batteries without shorting. We demonstrate 800 stable cycles of nickel-zinc batteries with good power rate (20 mA cm(-2), 20 C rate for our anodes). Such a backside-plating method can be applied to not only zinc metal systems but also other metal-based electrodes suffering from internal short circuits.


A heterotrimeric complex of Toxoplasma proteins promotes parasite survival in interferon gamma-stimulated human cells.
Toxoplasma gondii secretes protein effectors to subvert the human immune system sufficiently to establish a chronic infection. Relative to murine infections, little is known about which parasite effectors disarm human immune responses. Here, we used targeted CRISPR screening to identify secreted protein effectors required for parasite survival in IFNγ-activated human cells. Independent screens were carried out using 2 Toxoplasma strains that differ in virulence in mice, leading to the identification of effectors required for survival in IFNγ-activated human cells. We identify the secreted protein GRA57 and 2 other proteins, GRA70 and GRA71, that together form a complex which enhances the ability of parasites to persist in IFNγ-activated human foreskin fibroblasts (HFFs). Components of the protein machinery required for export of Toxoplasma proteins into the host cell were also found to be important for parasite resistance to IFNγ in human cells, but these export components function independently of the identified protein complex. Host-mediated ubiquitination of the parasite vacuole has previously been associated with increased parasite clearance from human cells, but we find that vacuoles from GRA57, GRA70, and GRA71 knockout strains are surprisingly less ubiquitinated by the host cell. We hypothesise that this is likely a secondary consequence of deletion of the complex, unlinked to the IFNγ resistance mediated by these effectors.


The Short Form KOOS, JR Is Valid for Revision Knee Arthroplasty.
The Knee Injury Osteoarthritis Outcome Survey, Joint Replacement (KOOS, JR) is a reliable, responsive, and validated patient-reported outcome measure (PROM) of knee health in patients with knee osteoarthritis undergoing unilateral primary total knee arthroplasty (TKA). The validity of the KOOS, JR for revision TKA remains unknown. We identified 314 patients who underwent revision TKA and had completed preoperative and 2-year postoperative PROMs. Validation included assessment of local dependence, unidimensionality, internal consistency, external construct validity, responsiveness, and floor effects preoperatively and ceiling effects at 2 years postoperatively. Among patients undergoing revision TKA, the KOOS, JR demonstrated an absence of residual item correlation, adequate unidimensionality, high internal consistency (Person Separation Index: 0.897), and high external construct validity with existing validated PROMs, including KOOS Pain (Spearman's correlation coefficient 0.89) and KOOS activities of daily living (0.90) domains. The KOOS, JR was more responsive (standardized response means: 1.14) to revision TKA than other common knee PROMs. Three percent of revision TKA patients were at the floor (lowest score) preoperatively and 9% reached the ceiling (highest possible score) postoperatively. KOOS, JR performs well in revision TKA patients with regard to internal consistency, external validity, responsiveness, and floor and ceiling effects. Our results support extending its use to revision TKA in both clinical and research settings.


Alemtuzumab Induction and Delayed Acute Rejection in Steroid-Free Simultaneous Pancreas-Kidney Transplant Recipients.
The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive. This cohort study assessed incidence and time to AREs in 73 consecutive SPKT recipients receiving alemtuzumab induction and steroid-free maintenance with tacrolimus and mycophenolate mofetil. A cohort with single high-dose antithymocyte globulin (ATG; n = 85) and triple therapy served as controls. In addition, we provided mechanistic insights in AREs after alemtuzumab depletion, including composition and alloreactivity of lymphocytes (flow cytometry and mixed lymphocyte reaction) plasma alemtuzumab levels (enzyme-linked immunosorbent assay), and maintenance drug exposure. Overall number of AREs at 3 years was significantly lower with alemtuzumab versus ATG induction (26.0% vs 43.5%; adjusted hazard ratio, 0.38; P = 0.029). Most AREs (94.6%) with ATG occurred within the first month, whereas 84.2% of AREs with alemtuzumab occurred beyond 3 months. Patients with and without an ARE in the steroid-free alemtuzumab group showed no differences in composition of lymphocytes, or in alemtuzumab levels. Of note, more than two thirds of these AREs were preceded by empiric tacrolimus and/or mycophenolate mofetil dose adjustments due to viral infections, leukopenia, or gastrointestinal symptoms. Alemtuzumab induction resulted in a significant lower incidence of AREs. Empiric dose adjustments beyond 3 months in the absence of steroids carry a significant risk for subsequent rejection in SPKT recipients.


Tumor stain in primary sphenoid sinus carcinoma: as demonstrated by selective internal carotid angiography.
Selective internal carotid arteriography was performed on a patient subsequently shown at surgery to have a primary carcinoma of the sphenoid sinus. The arteriogram demonstrated supply to the tumor from numerous hypertrophied branches of the cavernous portion of the internal carotid artery and a dense tumor stain within the sphenoid sinus. This is the first such report found in the literature.


Pitfalls in efficacy testing--how important is the validation of neutralization of chlorhexidine digluconate?
Effective neutralization of active agents is essential to obtain valid efficacy results, especially when non-volatile active agents like chlorhexidine digluconate (CHG) are tested. The aim of this study was to determine an effective and non-toxic neutralizing mixture for a propan-1-ol solution containing 2% CHG. Experiments were carried out according to ASTM E 1054-02. The neutralization capacity was tested separately with five challenge microorganisms in suspension, and with a rayon swab carrier. Either 0.5 mL of the antiseptic solution (suspension test) or a saturated swab with the antiseptic solution (carrier test) was added to tryptic soy broth containing neutralizing agents. After the samples were mixed, aliquots were spread immediately and after 3 h of storage at 2 - 8 degrees C onto tryptic soy agar containing a neutralizing mixture. The neutralizer was, however, not consistently effective in the suspension test. Immediate spread yielded a valid neutralization with Staphylococcus aureus, Staphylococcus epidermidis and Corynebacterium jeikeium but not with Micrococcus luteus (p < 0.001) and Candida albicans (p < 0.001). A 3-h storage period of the neutralized active agents in suspension resulted in significant carry-over activity of CHG in addition against Staphylococcus epidermidis (p < 0.001) and Corynebacterium jeikeium (p = 0.044). In the carrier test, the neutralizing mixture was found to be effective and non toxic to all challenge microorganisms when spread immediately. However, after 3 h storage of the neutralized active agents significant carry-over activity of CHG against Micrococcus luteus (p = 0.004; Tukey HSD) was observed. Without effective neutralization in the sampling fluid, non-volatile active ingredients will continue to reduce the number of surviving microorganisms after antiseptic treatment even if the sampling fluid is kept cold straight after testing. This can result in false-positive antiseptic efficacy data. Attention should be paid during the neutralization validation process to the amount of antiseptic solution, the storage time and to the choice of appropriate and sensitive microorganisms.


A Patient-reported Outcome Measure for Effect of Glucocorticoid Therapy in Adults with Inflammatory Diseases Is Needed: Report from the OMERACT 2016 Special Interest Group.
The need for a standardized instrument to measure the effect of glucocorticoid (GC) therapy has been well documented in the literature. The aim of the first GC Special Interest Group was to define a research agenda around the development of a patient-reported outcome measure (PROM) in this area. The results of a background literature search and the preliminary results of a pilot survey and 2 qualitative studies were presented to facilitate the development of a research agenda. It was agreed that there was a need for a data-driven PROM that identified both positive and negative effects of GC therapy to be used across all inflammatory indications for systemic GC use in adults. A research agenda was developed, consisting of further qualitative work to assess the effect of GC across different groups including various indications for GC use, different age groups, different dosages, and duration of treatment. There was agreement on the need for a PROM in this area and a research agenda was set.


Idiopathic sudden sensorineural hearing loss in dialysis patients.
Although sudden sensorineural hearing loss (SSNHL) affects chronic kidney disease (CKD) patients more frequently than non-CKD patients, few reports have described SSNHL in dialysis patients. We aimed to review the characteristics of SSNHL in chronic dialysis patients and evaluate treatment responses to steroid therapy. We retrospectively reviewed the records of dialysis patients diagnosed with idiopathic SSNHL at Asan Medical Center between January 2000 and December 2014. Pure tone and speech audiometry analyzes were performed before and 2 weeks and 2 months after treatment onset to evaluate outcomes. Twenty-two patients (11 men, 11 women; mean age: 49.9 ± 11.7 years) were included; 16 (72%) and 6 (28%) had undergone hemodialysis and peritoneal dialysis, respectively, for a median of 49.2 ± 41.4 (1-144) months. End-stage renal disease was most frequently caused by diabetic nephropathy (11 cases), chronic glomerulonephritis (1 case) and unknown factors (7 cases). Common accompanying symptoms included tinnitus (68.2%), ear fullness (45.5%) and vertigo (27.3%). The mean pure tone audiometry threshold at the initial presentation was 82.6 ± 22.4 dB. At 2 months post-steroid treatment, 4 (18.2%), 4 (18.2%) and 6 (27.3%) patients exhibited a complete, partial, or slight recovery, respectively; 8 patients (36.3%) showed no improvement. Although we could not identify the specific cause of SSNHL in this population, our relatively large case series elucidates the precise clinical features of SSNHL in this population and demonstrates the outcomes of steroid treatment.


The management of episiotomy technique and its effect on pelvic floor muscles during a malposition childbirth.
Vaginal childbirth is the leading cause of pelvic floor muscles injury, which contributes to pelvic floor dysfunction, being enhanced by fetal malposition. Therefore, the aim of the present study is to verify the influence of mediolateral episiotomies in the mechanics of the pelvic floor with the fetus in occiput posterior position when compared to the occiput anterior position. Numerical simulations of vaginal deliveries, with and without episiotomy, are performed based on the Finite Element Method. The biomechanical model includes the pelvic floor muscles, a surface to delimit the anterior region of the birth canal and a fetus. Fetal malposition induces greater extension of the muscle compared to the normal position, leading to increases of stretch. The faster enlargement may be responsible for a prolonged second stage of labor. Regarding the force required to achieve delivery, the difference between the analyzed cases are 35 N, which might justify the increased need of surgical interventions. Furthermore, episiotomy is essential in reducing the damage to values near the ones obtained with normal position, making the fetal position irrelevant. These biomechanical models have become extremely useful tools to provide some understanding of pelvic floor function during delivery helping in the development of preventative strategies.


Microtubule disruption induced by estradiol in estrogen receptor-positive and -negative human breast cancer cell lines.
Effects of estrogens on the cytoplasmic microtubule network were examined by the indirect immunofluorescence method using anti-beta-tubulin antibody. Estradiol, a naturally occurring estrogen, decreased the amount of cytoplasmic microtubule fibers during interphase in the human breast cancer cell lines MCF-7 and MDA-MB-231. Since MDA-MB-231 is an estrogen receptor-negative cell line, estradiol-induced microtubule disruption seems to be independent of estradiol binding to receptors. The effective concentration of estradiol required for induction of microtubule disruption in 50% of the cells (EC50) was 81 microM for MCF-7 cells and 82 microM for MDA-MB-231 cells. A synthetic estrogen, diethylstilbestrol, also induced a decrease in microtubule fibers, with an EC50 value of 48 microM for MCF-7 cells and 50 microM for MDA-MB-231 cells. When estrogen-treated and microtubule-depolymerized cells were washed and the medium was replaced with fresh, intracellular microtubule networks reappeared within 3 h. When MCF-7 cells were cultured for 4 days with estradiol (50 microM), cell growth was completely inhibited. However, estrone affected the microtubule network and cell proliferation only slightly. These results suggest that estradiol-induced microtubule disruption is closely related to its inhibitory effect on cell growth.


Smoking cessation counseling by residents in an outpatient clinic.
Training residents in smoking cessation counseling could be part of tobacco control policy. The effect of such an intervention is unknown in Europe. This study provides an assessment of smoking cessation counseling practices by Swiss residents after an intervention based on behavioral modification. In a pre-post blind test trial on smoking cessation counseling practices, residents' perceptions about their own ability to counsel smoking behavior among smoking patients were evaluated for 15 residents trained in general internal medicine and in 247 and 155 smoking patients' reports, respectively before and after a training intervention targeting residents, based on behavioral theory of smoking cessation. Changes in counseling were assessed by interviews with patients. After the intervention, residents asked about smoking habits (77 vs 68%), advised to quit (43 vs 28%), provided counseling for cessation (25 vs 10%), gave self-help materials (7 vs 1%), and arranged follow-up visits (5 vs 1%) more often than before. Residents' self-perception of confidence (5.4 vs 4.6/10) and effectiveness (5.3 vs 4.0/10) in counseling also increased after the intervention. After adjusting for daily cigarette consumption and smoking duration, the likelihood of attempting to quit smoking at either 6 or 12 months was increased in the group of patients attended after the intervention (odds ratio 1.52, 95% confidence intervals 1.07-2.48). However, the likelihood of quitting smoking was not increased among these patients (odds ratio 1.07, 95% CI 0.96-1.14). Short-term smoking cessation counseling by residents was substantially improved by the intervention. Smokers attended after the intervention were more likely to attempt to quit smoking, but not to have quit at 6- or 12-month follow-up.


On the Time of the Intellect: The Interpretation of De Anima 3.6 (43ob 7-20) in Renaissance and Early Modern Italian Philosophy.
This article argues that an original debate over the relationship between time and the intellect took place in Northern Italy in the second half of the sixteenth century, which was part of a broader reflection on the temporality of human mental acts. While human intellectual activity was said to be 'above time' during the Middle Ages, Renaissance scholars such as Marcantonio Genua (1491-1563), Giulio Castellani (1528-1586), Antonio Montecatini (1537-1599) and Francesco Piccolomini (1520-1604), greatly influenced by the Simplician and Alexandrist interpretations of Aristotle's works, proposed alterna- tive conceptions based on the interpretation of De anima 3.6 (430b 7-20) according to which intellectual acts happen in a both 'undivided' and 'divisible time'. In order to explain Aristotle's puzzling claim, they were led to conceive of intellectual activity as a process similar to sensation, corresponding to a certain lapse of time (Castellani), an instant (Montecatini), or a mix of instantaneousness and concrete duration (Piccolomini), depending on their theoretical options.


Subcellular location of serum- and glucocorticoid-induced kinase-1 in renal and mammary epithelial cells.
Serum- and glucocorticoid-induced kinase-1 (SGK1) is involved in aldosterone-induced Na(+) reabsorption by increasing epithelial Na(+) channel (ENaC) activity in cortical collecting duct (CCD) cells, but its exact mechanisms of action are unknown. Although several potential targets such as Nedd4-2 have been described in expression systems, endogenous substrates mediating SGK1's physiological effects remain to be identified. In addition, subcellular localization studies of SGK1 have provided controversial results. We determined the subcellular location of SGK1 using SGK1-autofluorescent protein (AFP) fusion proteins. Rabbit CCD (RCCT-28A) cells were transiently transfected with a construct encoding for SGK1-AFP and were stained or cotransfected with markers for various subcellular compartments. In live cells, transiently expressed SGK1-AFP clearly colocalized with the mitochondrial marker rhodamine 123. Similarly, SGK1-AFP colocalized with the mitochondrial marker MitoTracker when stably expressed using a retroviral system in either RCCT-28A cells or the mammary epithelial cell line MCF10A. To determine which region of SGK1 is responsible for this subcellular localization, we generated RCCT-28A cell lines stably expressing SGK1 mutants. The results indicate that the NH(2)-terminal 60-amino acid region of SGK1 is necessary and sufficient for its subcellular localization. Localization of SGK1 to the mitochondria raises the possibility that SGK1 may play a role in regulating energy metabolism.


Human-health impacts of controlling secondary air pollution precursors.
Exposure to ozone and fine particle (PM2.5) air pollution results in premature death. These pollutants are predominantly secondary in nature and can form from nitrogen oxides (NOX), sulfur oxides (SOX), and volatile organic compounds (VOCs). Predicted health benefits for emission reduction scenarios often incompletely account for VOCs as precursors as well as the secondary organic aerosol (SOA) component of PM2.5. Here, we show that anthropogenic VOC emission reductions are more than twice as effective as equivalent fractional reductions of SOX or NOX at reducing air pollution-associated cardiorespiratory mortality in the United States. A 25% reduction in anthropogenic VOC emissions from 2016 levels is predicted to avoid 13,000 premature deaths per year, and most (85%) of the VOC-reduction benefits result from reduced SOA with the remainder from ozone. While NOX (-5.7 ± 0.2 % yr-1) and SOX (-12 ± 1 % yr-1) emissions have declined precipitously across the U.S. since 2002, anthropogenic VOC emissions (-1.8 ± 0.3 % yr-1) and concentrations of non-methane organic carbon (-2.4 ± 1.0 % yr-1) have changed less. This work indicates preferentially controlling VOCs could yield significant benefits to human health.


Diagnostics for the biased electrode experiment on NSTX.
A linear array of four small biased electrodes was installed in NSTX in an attempt to control the width of the scrape-off layer by creating a strong local poloidal electric field. The set of electrodes was separated poloidally by a 1 cm gap between electrodes and were located slightly below the midplane of NSTX, 1 cm behind the rf antenna, and oriented so that each electrode is facing approximately normal to the magnetic field. Each electrode can be independently biased to +/-100 V. Present power supplies limit the current on two electrodes to 30 A and the other two to 10 A each. The effect of local biasing was measured with a set of Langmuir probes placed between the electrodes and another set extending radially outward from the electrodes, and also by the gas puff imaging diagnostic located 1 m away along the magnetic field lines intersecting the electrodes. Two fast cameras were also aimed directly at the electrode array. The hardware and controls of the biasing experiment will be presented and the initial effects on local plasma parameters will be discussed.


[Complete surgical correction of congenital hip dislocation (one-stage surgery)].
A 3-10 years follow-up and the evaluation of the 55 cases operated 1980 through 1988 on the Orthopaedic University Hospital in Pécs is presented. The age of the patients at operation was 4.5-10 years, in average 4 years. The operation consisted of four components: operative reduction, varus derotation femoral osteotomy, acetabular plasty and transposition of the iliopsoas muscle. In 53 cases excellent or good Roentgen anatomical and functional results were found. In one case after the operation complete femoral head necrosis has developed, in two cases a transient ischaemic state was observed that healed however without functional deficiency.


Epstein-Barr virus associated Hodgkin lymphoma in a 9-year-old girl receiving long-term methotrexate therapy for juvenile idiopathic arthritis.
We describe a case of Hodgkin lymphoma developing in a 9-year-old girl with polyarticular, rheumatoid factor-positive juvenile idiopathic arthritis treated with methotrexate (MTX), prednisone, and naproxen for 5 years. Pathologic and molecular analyses revealed that the Hodgkin cells contained Epstein-Barr virus and the viral DNA was monoclonal. She achieved complete remission after MTX withdrawal, chemotherapy, and radiation. To the best of my knowledge, this is the sixth report of Hodgkin lymphoma in patients with juvenile idiopathic arthritis receiving low dose MTX therapy.


[Expression of the quantitative trait radius incompletus, temperature effects and localization of mobile genetic elements in Drosophila. II. Mobile genetic elements Dm-412].
Two "selection" sub-populations (ris- and ris+), as well as two "temperature" ones (ric113 and ric149) were earlier developed from the control ric sub-population with interrupted vein of the fly wing. All five sub-populations were investigated for hybridization of MGE Dm-412 with drosophila polytene chromosomes in situ. The tree of similarity of MGE Dm-412 hybridization patterns was built by the methods of matrix clusterization. The sub-populations with the most resembling expressions of characters (ris- and ric113, ris+ and ric149) were found to be also most similar in patterns of MGE localization and their changes. Nonrandomness of these changes was shown, the similarity of patterns being demonstrated to be mainly the result of the changes. There is evidence that such effects cannot be accounted for by genetic drift and independent stochastic changes in MGE localization.


Effect of preinfarction angina on heart rate variability in the early phase of the first anterior wall acute myocardial infarction.
The aim of this study was to clarify the effect of preinfarction angina on heart rate variability (HRV) in anterior wall acute myocardial infarction (AMI). A total of 36 patients experiencing their first anterior wall AMI were prospectively examined. The patients were divided into 2 groups according to the presence (group A, n=24) or absence (group B, n = 12) of preinfarction angina. HRV was assessed on 24-h Holter electrocardiograms recorded on day 3. Peak creatine kinase activity was significantly lower in group A than in group B (2,747+/-1,939 vs 4,891+/-2,639 IU/L, p<0.05). The SD of all RR intervals and ultra-low frequency, very low frequency, and low frequency powers was significantly less reduced in group A than in group B (86+/-24 vs 64+/-22 ms, p<0.05; 2,098+/-1,462 vs 867+/-502 ms2, p<0.01; 1,430+/-1,042 vs 546+/-344ms2, p<0.01; and 354+/-272 vs 186+/-136ms2, p<0.05; respectively). High frequency power, low frequency/high frequency, and pNN50 did not differ significantly between the 2 groups. In conclusion, preinfarction angina has a favorable influence on HRV in the early phase of anterior wall AMI.


High fat diet augments amphetamine sensitization in mice: Role of feeding pattern, obesity, and dopamine terminal changes.
High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3 d/week) or extended (24 h 7 d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed mice coincided with elevated DAT function and increased AMPH potency; however, the enhanced behavioral response to AMPH after HF exposure was unique in that it coincided with reduced DAT function and diet pattern-specific adaptations.


Parents as partners: investigating the role(s) of mothers in coordinating health and education activities for children with chronic care needs.
Interprofessional collaboration (IPC) between health professionals, and educators is an essential component of academic success and well-being for children who experience chronic illnesses. This study sought to understand parents' roles in and perceptions of IPC between their child's healthcare professionals and educators. We recruited 23 mothers to participate in our study. Data were analyzed using a combination of univariate analyses and content analysis. Overall, parents reported that they could effectively communicate their child's health and educational needs with health and educational professionals, but statistical analysis determined moderately increased challenges presenting information across professions. Most participants (n = 19) indicated that IPC between health and educational professionals could be improved. Effectively engaging parents as partners in IPC can promote more seamless collaboration and communication of a child's needs and offer a greater likelihood of achieving a child's health and educational goals.


The reassessment of trial perspectives from interim data--a critical view.
If an interim analysis is performed during a trial it is tempting to determine the conditional power to reach a rejection in the trial given the observed results in the interim analysis. Since the true effect size is unknown the conditional power may be calculated by using the effect size, which the study has been powered for in the planning phase or by using an interim estimate of the true size (or a combination of both). In either case the conditional power is a random variable and its density is investigated depending on the analysis time and the true effect size. Under the null hypothesis, in early interim analyses after a small proportion of sample units, the conditional power typically will be close to the overall power when the effect size from the planning stage is used for calculation. In this case the majority of observations must still be made and the small first-stage sample in general will be dominated by the hypothetical second-stage chance based on the wrong parameter value. It is shown that the conditional power in moderately underpowered studies can have a distribution symmetric around 0.5. When using the interim estimate for calculating the conditional power the density in general will be u-shaped. The impact of using conditional power to reassess the sample size using flexible two-stage combination tests is shown for a specific example in terms of overall power and average sample size as compared to the corresponding group sequential design. For small true effect sizes mid-trial sample size recalculation based on an interim estimate may lead to an overly large price to be paid in average sample size in relation to the gain in overall power. Finally, the problem is discussed in terms of estimating the true conditional power.


Bedshift: perturbation of genomic interval sets.
Functional genomics experiments, like ChIP-Seq or ATAC-Seq, produce results that are summarized as a region set. There is no way to objectively evaluate the effectiveness of region set similarity metrics. We present Bedshift, a tool for perturbing BED files by randomly shifting, adding, and dropping regions from a reference file. The perturbed files can be used to benchmark similarity metrics, as well as for other applications. We highlight differences in behavior between metrics, such as that the Jaccard score is most sensitive to added or dropped regions, while coverage score is most sensitive to shifted regions.


Metabolic engineering of microorganisms for L-alanine production.
L-alanine is extensively used in chemical, food, and medicine industries. Industrial production of L-alanine has been mainly based on the enzymatic process using petroleum-based L-aspartic acid as the substrate. L-alanine production from renewable biomass using microbial fermentation process is an alternative route. Many microorganisms can naturally produce L-alanine using aminotransferase or L-alanine dehydrogenase. However, production of L-alanine using the native strains has been limited due to their low yields and productivities. In this review, metabolic engineering of microorganisms for L-alanine production was summarized. Among them, the Escherichia coli strains developed by Dr. Lonnie Ingram's group which can produce L-alanine with anaerobic fermentation process had several advantages, especially having high L-alanine yield, and it was the first one that realized commercialization. L-alanine is also the first amino acid that could be industrially produced by anaerobic fermentation.


Characterization of the high molecular weight Cd-binding complex in water hyacinth (Eichhornia crassipes) when exposed to Cd.
Water hyacinth ( Eichhornia crassipes) is a rapid-growing freshwater vascular plant that has been used to remove heavy metals in contaminated water. But the transportation and distribution of the absorbed heavy metal in the plant are not clear. In this study, water hyacinth was exposed to cadmium (Cd, 10 microM, pulse) and then transferred to a Cd-free solution (chase). The Cd content in the tissues was measured, and the Cd-binding complexes were isolated and identified. We found that (1) in two days, up to 80% of the Cd in the solution was absorbed by the plant, and the Cd could not be released back to the growth solution in the chase period; (2) approximately 1 mg of Cd was accumulated in the water hyacinth/g of dry weight in this condition; (3) invading Cd was bound rapidly as the low-molecular-weight (LMW) complex serving as the transient form for further sequestration; (4) the LMW complex in water hyacinth contained no phytochelatins and was different from the LMW complex in fission yeast; (5) the Cd absorbed in the plant was essentially stored in the high-molecular-weight (HMW) form after 1 week; (6) a small fraction of the absorbed Cd was found in the upper part of the plant (stem and leaves) in the form of complexes; (7) the HMW complex was composed of phytochelatins PC 3 and PC 4 primarily, with only a small amount of PC 2; (8) a rare PC-related peptide was found in the HMW complex that might be derived from PC 3. These observations contribute to the further understanding of water hyacinth in serving as an efficient and reliable accumulator for heavy metals.


Methodological investigation into the noise influence on nanolasers' large signal modulation.
Nanolasers are considered ideal candidates for communications and data processing at the chip-level thanks to their extremely reduced footprint, low thermal load and potentially outstanding modulation bandwidth, which in some cases has been numerically estimated to exceed hundreds of GHz. The few experimental implementations reported to date, however, have so-far fallen very short of such predictions, whether because of technical difficulties or of overoptimistic numerical results. We propose a methodology to study the physical characteristics which determine the system's robustness and apply it to a general model, using numerical simulations of large-signal modulation. Changing the DC pump values and modulation frequencies, we further investigate the influence of intrinsic noise, considering, in addition, the role of cavity losses. Our results confirm that significant modulation bandwidths can be achieved, at the expense of large pump values, while the often targeted low bias operation is strongly noise- and bandwidth-limited. This fundamental investigation suggests that technological efforts should be oriented towards enabling large pump rates in nanolasers, whose performance promises to surpass microdevices in the same range of photon flux and input energy.


Effect of Uterine Artery Ligation and Uterine Artery Embolization on Postpartum Hemorrhage Due to Uterine Asthenia after Cesarean Section and Its Effect on Blood Flow and Function of Uterine and Ovarian Arteries.
To investigate the efficacy of uterine artery ligation (UAL) and uterine artery embolization (UAE) in the treatment of uterine asthenia postpartum hemorrhage (PPH) after cesarean section and its effect on uterine and ovarian artery blood flow and function. 100 patients with uterine asthenia PPH after cesarean section in our hospital from January 2018 to November 2020 were randomly divided into 50 cases in the UAL group and 50 cases in the UAE group. They were followed up for 12 months. The bleeding volume, operation time, immediate hemostasis rate, and hemostasis effective rate; lochia clearance time and menstrual rehydration time; RI and S/D; and serum FSH, E2, and LH levels were compared between the two groups. Compared with the UAL group, the amount of bleeding in the UAE group was significantly increased and the operation time was significantly shortened (p < 0.05). There was no significant difference in the immediate hemostatic rate and hemostatic effective rate between the two groups (p > 0.05). There was no significant difference in lochia clearance time and menstrual rehydration time between the two groups (p > 0.05). There was no significant difference in RI and S/D between the two groups (p > 0.05). Compared with before the operation, the levels of FSH and LH in the two groups decreased significantly, and the level of E2 increased significantly (p < 0.05). There was no significant difference between the two groups (p > 0.05). The efficacy of UAL and UAE in the treatment of PPH with uterine asthenia after cesarean section and its effect on the blood flow and function of uterine and ovarian arteries are equivalent, but the amount of bleeding in UAL is less and the operation time of UAE is shorter. The appropriate operation method can be selected according to the actual situation.


Selection of optimized candidate reference genes for qRT-PCR normalization in rice (Oryza sativa L.) during Magnaporthe oryzae infection and drought.
Drought and rice blast disease caused by Magnaporthe oryzae are two of the most serious threats to global rice production. To explore the mechanisms underlying gene expression induced in rice by stresses, studies involving transcriptome analyses have been conducted over the past few years. Thus, it is crucial to have a reliable set of reference genes to normalize the expression levels of rice genes affected by different stresses. To identify potential reference genes for studies of the differential expression of target genes in rice under M. oryzae infection and drought conditions, the present study evaluated five housekeeping genes for the normalization of gene expression. The stability of the expression of these genes was assessed using the analytical software packages geNorm and NormFinder. For all samples analyzed, the stability rank was UBQ5 > GAPDH > eIF-4α> β-TUB > 18S rRNA. The data showed that the UBQ5, GAPDH, and eIF-4αgenes are appropriate, high-performing reference genes and will be highly useful in future expression studies of fungal infections and drought in rice.


Why should we pay?
Pay all nursing students a salary and implement a two-year contract post-qualification so they work at the hospitals they trained at.


A case of tuberculosis verrucosa cutis in Brazil undiagnosed for 15 years.
Tuberculosis verrucosa cutis is a rare medical condition that is caused by the inoculation of Mycobacterium tuberculosis into the skin of a previously sensitized individual. This clinical form of tuberculosis corresponds to 1-2% of all cases of tuberculosis and due to the paucibacillary characteristic of the lesions, patients can be misdiagnosed, accounting for the chronification of the skin infection. Herein, we report the case of a 26-year-old male farmer, presenting plaques with verrucosa and hyperkeratosis features in the left thigh and buttocks during 15 years. M. tuberculosis was identified by PCR and the patient was treated with standard anti-tuberculosis drugs, with subsequent improvement of the skin lesions.


Photochromic Dithienylethene-Containing Boron(III) Ketoiminates: Modulation of Photo-Responsive Behavior through Variation of Intramolecular Motion.
A series of dithienylethene-containing boron(III) ketoiminates, as well as their corresponding β-ketoimine ligands, have been synthesized and characterized. The photophysical, electrochemical, and photochromic properties of the compounds have been studied. Photocyclization has been found to be suppressed upon introduction of a phenyl substituent on the nitrogen atom of the β-ketoiminate core, whereas photochromism could be observed by replacement of the phenyl substituent with a bulky mesityl group. It is believed that the steric effect of the mesityl unit restricts molecular rotation, resulting in such a prominent difference in the photochromic properties.


Aerobic capacity & perceived exertion after practice of Hatha yogic exercises.
Reports on the effect of yogic exercises on aerobic capacity are few. There is also no literature available on the effect of yogic exercise on perceived exertion (PE) after maximal exercise. In this study the effect of training in Hatha yogic exercises on aerobic capacity and PE after maximal exercise was observed. Forty men from the Indian army (aged 19-23 yr) were administered maximal exercise on a bicycle ergometer in a graded work load protocol. The oxygen consumption, carbon dioxide output, pulmonary ventilation, respiratory rate, heart rate (HR) etc., at maximal exercise and PE score immediately thereafter were recorded. The subjects were divided into two equal groups. Twelve subjects dropped out during the course of study. One group (yoga, n = 17) practiced Hatha yogic exercises for 1 h every morning (6 days in a week) for six months. The other group (PT, n = 11) underwent conventional physical exercise training during the same period. Both groups participated daily in different games for 1 h in the afternoon. In the 7th month, tests for maximal oxygen consumption (VO2Max) and PE were repeated on both groups of subjects. Absolute value of VO2Max increased significantly (P < 0.05) in the yoga group after 6 months of training. The PE score after maximal exercise decreased significantly (P < 0.001) in the yoga group after 6 months but the PT group showed no change. The practice of Hatha yogic exercises along with games helps to improve aerobic capacity like the practice of conventional exercises (PT) along with games. The yoga group performed better than the PT group in terms of lower PE after exhaustive exercise.


Hormonal regulation of osteocalcin plasma production and clearance in sheep.
The plasma osteocalcin (OC) concentration correlates with histological parameters of bone formation and has been used as an index of osteoblast activity. Although the rate of OC synthesis is likely to be a major determinant of the plasma OC level, the contribution of other processes, for example, OC plasma clearance, should be evaluated if changes in the plasma OC concentration are to be interpreted meaningfully. We have treated oophorectomized sheep with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and glucocorticoids to alter the plasma OC concentration and used an 125I-OC infusion method to measure changes in the OC plasma clearance (PCR) and to calculate production (PPR) rates. 1,25-(OH)2D3 (8 micrograms/day by iv injection) increased plasma OC levels from 15.8 +/- 2.1 to 52.7 +/- 5.3 ng/ml (n = 10; P less than 0.0005) and the OC PPR from 0.9 +/- 0.08 to 2.6 +/- 0.17 mg/day (n = 5, P less than 0.0005). There was no effect on the OC PCR. Both triamcinolone acetonide (TA) and cortisol, administered by iv infusion, decreased the plasma OC concentration to less than 4 ng/ml and the OC PPR to less than 0.4 mg/day when infused in the doses 0.05-1.0 mg/h (TA) and 2.0 mg/h (cortisol). TA (0.05 mg/h) decreased plasma OC to an undetectable level within 24 h. The effect of cortisol infusion on the plasma OC level and the OC PPR was dose dependent in the range 0.2-2.0 mg/h. TA, infused at the rates of 0.25 and 1.0 mg/h, increased the OC PCR from 3.0 +/- 0.10 to 4.0 liters/h (P less than 0.005; n = 4) and from 2.6 +/- 0.10 to 3.9 +/- 0.10 liters/h (P less than 0.01; n = 3), respectively. It is concluded that the OC PPR and the plasma OC concentration in sheep are responsive to treatment with 1,25-(OH)2D3 and glucocorticoids. Although the changes in plasma OC concentration were attributable largely to effects on OC production, high infusion rates of the glucocorticoid TA led to a highly significant increase in OC plasma clearance. These findings suggest that alterations in OC clearance may contribute to the changes in plasma OC levels seen in some disease states, for example, glucocorticoid excess.


Metacognition and Body Image in Predicting Alexithymia in Substance Abusers.
Substance dependency is one of the biggest problems and worries of the world. It stunts the growth of society and causes various problems such as reduction in public health, increase in mortality, rise in social and domestic traumas, loss of educational and occupational opportunities, involvement with the judicial system, and development of the substance-abuse cycle. The aim of this study was to determine the role of metacognition and body image in predicting alexithymia in substance abusers. The research sample included addicts (males and females aged 10 to 70 years) who referred to the addiction treatment and counseling centers of three Iranian cities of Zahedan, Sari, and Neyriz. Participants were selected by random sampling. The metacognitive strategy questionnaire (MCQ-30), physical self-description questionnaire (PSDQ), and Toronto alexithymia scale (TAS-20) were used for data collection. The hypotheses were tested using the Pearson's correlation method and regression analysis. According to the results of the current study, the highest correlation was between alexithymia and the cognitive awareness subscale (r = 0.305; P < 0.01).There was no significant correlation between alexithymia and body image. Based on the multiple regression analysis, the three predictors explained 11% of the variance (R(2) = 0. 11, F = 3.981; P < 0.01). Cognitive awareness significantly predicted 9% of the variance (β = 0.305; P < 0.01), and the other subscales predicted about 2%. These findings demonstrated that metacognition had an important role in predicting alexithymia in the substance abusers, which underscores the necessity of precautionary measures.


Multicore optical fiber Y-splitter.
In future high capacity multicore optical fiber (MCF) networks, signal-processing devices should be able to manipulate data without sacrificing network capacity or MCFs advantages. Thus, it is crucial to have high performance novel devices that can be connected directly to MCFs without conversion to conventional single-core fibers. In this work, a novel Y-splitter for multicore optical fibers is proposed and numerically demonstrated for the first time. The splitter can directly split the power of input MCF cores by 50/50 splitting-ratio into two output MCFs cores. The splitter principle of operation mainly depends on novel double-hump graded-index (DHGI) profile that can space-division split (SDS) optical power by half. Both finite-difference-time-domain and eigenmode-expansion simulations are performed to design, verify, and characterize performance of Y-splitter. It shows wideband operation over the S, C, L, U-bands with polarization insensitivity. It also demonstrates high performance with reasonable insertion-loss, in addition to very low excess-loss and return-loss. Moreover, the splitter shows good performance tolerance to both MCF and design parameters variations.


Complete heart block associated with device closure of perimembranous ventricular septal defects.
The development of the Amplatzer Membranous VSD Occluder (AGA Medical Corp, Plymouth, Minn) for closure of the perimembranous ventricular septal defect has ameliorated many of the technical difficulties of previous devices. Application of this new technology requires comparative evaluation with the current standard of surgical repair. We report our experience of complete heart block associated with device closure of a large perimembranous ventricular septal defect with unequivocal indications for intervention. We performed a retrospective review of 20 patients between January 2003 and August 2005 who underwent perimembranous ventricular septal defect device closure, 18 with hemodynamically large shunts meeting the surgical criteria for intervention. The median age was 1.6 years (range, 0.5-16.2 years), and the median weight was 9.7 kg (range, 6.2-43 kg). Acute complete shunt occlusion was achieved in all patients. There were no acute procedural complications. The median follow-up time was 23.1 months (range, 1-37.8 months). Four (22%) had complete heart block at 17 days, 4.2 months, 8.8 months, and 37.5 months after implantation, respectively. No risk factors were identified for development of complete heart block, including age, weight, trisomy 21, preceding conduction abnormalities, perimembranous ventricular septal defect size related to body surface area or device size, and progressive device flattening. Device closure of large perimembranous ventricular septal defects in infants and children with the Amplatzer Membranous VSD Occluder resulted in excellent closure rates but an unacceptably high rate of complete heart block.


Bisphenol S- and bisphenol A-induced adipogenesis of murine preadipocytes occurs through direct peroxisome proliferator-activated receptor gamma activation.
The use of bisphenol A (BPA) in consumer products and food packaging has been associated under certain conditions with a risk of negative health outcomes. This prompted its removal from many products and replacement with structural analogs. Bisphenol S (BPS) is one such analog, but its metabolic effects have not been fully characterized. The objective of our study was to determine whether BPS functions similarly to BPA at inducing adipogenesis. Murine 3T3-L1 preadipocytes were used to evaluate and compare the adipogenic potential of BPS to BPA. Cells were treated with 0.01-50 μM BPS or 0.01-50 μM BPA and adipogenic effects were measured. Further, their ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), an adipogenic transcription factor, was also determined. Our results indicate that treatment of 3T3-L1 cells with BPS induced lipid accumulation and increased mRNA and protein expression of key adipogenic markers (1-50 μM; P<0.05). BPS treatment resulted in a higher expression of adipogenic markers as well as greater lipid accumulation when compared with BPA treatment. We showed that BPS can upregulate lipoprotein lipase, adipocyte protein 2, PPARγ, perilipin, adipsin and CCAAT/enhancer-binding protein alpha mRNA expression levels. Furthermore, using transcriptional assays, we showed that BPS and BPA can modestly activate PPARγ using a PPRE (PPARγ response element)-dependent luciferase construct by 1.5-fold (P<0.05). However, BPS but not BPA was able to competitively inhibit rosiglitazone (ROSI)-activated PPARγ, suggesting that BPS interacts with PPARγ distinctly from BPA. Co-treatment of cells with the selective PPARγ antagonist GW9662 inhibits BPS-, BPA-, ROSI- but not dexamethasone-dependent adipogenic differentiation. Both BPA and BPS can enhance 3T3-L1 adipocyte differentiation in a dose-dependent manner and require PPARγ to induce adipogenesis. Through direct comparison, we show that BPS is a more potent adipogen than BPA.


Comparative effectiveness of different platelet-rich plasma for arthroscopic rotator cuff repair: A protocol for systematic review and network meta-analysis.
Rotator cuff tears are one of the most common injuries of the shoulder joint in adults. Arthroscopic rotator cuff repair (ARCR) has become the gold standard for the treatment of rotator cuff injuries, but it still has a high rate of retear. Platelet-rich plasma (PRP) has been widely used as an adjunct to ARCR. However, the comparative efficacy of different PRP for ARCR remain unclear. In order to evaluate the relative efficacy of PRP for individuals with ARCR, we will conduct a systematic review and network meta-analysis of randomized controlled trials. A systematic literature search will be conducted in Embase, PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, and Chinese Biomedical Literature Database will be searched up to October 2022. The primary outcome will focus on the retear rate at the last follow-up. The secondary outcomes include the Visual Analogue Scale for postoperative pain and functional capacity scores. The risk of bias for individual studies will be assessed according to the revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0). Data analysis will be performed using R 4.1.2. Publication bias will be examined using comparison-adjusted funnel plots and Egger's test using STATA 15.0. The quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. The results of this study will be submitted to a peer-reviewed journal for publication. The review will compare the efficacy of different PRP for patients with ARCR. The result of the study will provide evidence-based medical evidence for ARCR with PRP augmentation.


Identifying the Origin of the Limiting Process in a Double Perovskite PrBa0.5Sr0.5Co1.5Fe0.5O5+δ Thin-Film Electrode for Solid Oxide Fuel Cells.
Oxygen reduction reaction in a double perovskite material, PrBa0.5Sr0.5Co1.5Fe0.5O5+δ (PBSCF), was studied for application as a cathode in a solid oxide fuel cell (SOFC). Electrochemical measurements were performed on a geometrically well-defined dense thin-film (0.8-2 μm thickness) electrode, fabricated as a symmetric cell. In combination with density functional theory (DFT) and molecular dynamics (MD) simulations, experiments provided an insight into the operating mechanism of the SOFC material tested at an open-circuit voltage. The dense thin-film electrode of PBSCF showed a thickness-dependent electrochemical performance, suggesting bulk diffusion limitation. To understand the origin of this diffusion-limiting electrochemical performance, DFT calculations were utilized to calculate the surface (γ) and oxygen vacancy formation (EOV) energies. For example, EOV in the Pr plane (190 kJ/mol) of PBSCF was measured to be lower than that of the BaSr plane (EOV = 297 kJ/mol). In addition, oxygen vacancies were difficult to be created in the BaSr/CoFe terminal surface (EOV = 341.6 kJ/mol) as compared to other terminal surfaces. MD simulations further elaborated on the nature of cation disordering in the surface and subsurface regions, consequently leading to the preferential segregation of the Ba cations to the surface, which is a known phenomenon in such double perovskite materials. Because of cation disordering and segregation of Ba species, the oxygen anion diffusivity (∼10-12 cm2 s-1), calculated from MD, in the near-surface region was observed to be 2 orders of magnitude lesser than that of the bulk (D = 2.98 × 10-10 cm2 s-1) of the material at 973 K. Surface characterization of the thin-film electrode using X-ray photoelectron spectroscopy was indicative of a nonperovskite Ba2+ phase on the electrode surface. The segregation of Ba cations was linked with the transport of oxygen anions, which was limiting the electrochemical performance of the electrode.


A Global Survey on Changes in the Supply, Price, and Use of Illicit Drugs and Alcohol, and Related Complications During the 2020 COVID-19 Pandemic.
Background and Aims: COVID-19 has infected more than 77 million people worldwide and impacted the lives of many more, with a particularly devastating impact on vulnerable populations, including people with substance use disorders (SUDs). Quarantines, travel bans, regulatory changes, social distancing, and "lockdown" measures have affected drug and alcohol supply chains and subsequently their availability, price, and use patterns, with possible downstream effects on presentations of SUDs and demand for treatment. Given the lack of multicentric epidemiologic studies, we conducted a rapid global survey within the International Society of Addiction Medicine (ISAM) network in order to understand the status of substance-use patterns during the current pandemic. Design: Cross-sectional survey. Setting: Worldwide. Participants: Starting on April 4, 2020 during a 5-week period, the survey received 185 responses from 77 countries. Measurements: To assess addiction medicine professionals' perceived changes in drug and alcohol supply, price, use pattern, and related complications during the COVID-19 pandemic. Findings: Participants reported (among who answered "decreased" or "increased") a decrease in drug supply (69.0%) and at the same time an increase in price (95.3%) globally. With respect to changes in use patterns, an increase in alcohol (71.7%), cannabis (63.0%), prescription opioids (70.9%), and sedative/hypnotics (84.6%) use was reported, while the use of amphetamines (59.7%), cocaine (67.5%), and opiates (58.2%) was reported to decrease overall. Conclusions: The global report on changes in the availability, use patterns, and complications of alcohol and drugs during the COVID-19 pandemic should be considered in making new policies and in developing mitigating measures and guidelines during the current pandemic (and probable future ones) in order to minimize risks to people with SUD.