[Evaluation of the autonomic regulation of the cardiac oxygen supply of measured physical activity in patients with remitting multiple sclerosis].
Results of the study on the autonomic nervous system dysregulation in multiple sclerosis (MS), in particular, the autonomic heart regulation, are presented. The variability of cardiac rhythm at rest and after measured physical activity is evaluated. The autonomic cardiovascular balance at baseline was analyzed in 32 patients during 5 min at rest (resting awakening state) and 7 min after the cycle ergometry test (CET) during 5 min. At resting state, there was the decrease in the autonomic regulation of the cardiac rhythm assessed by the indicators of the total variability due to the parasympathetic insufficiency. All patients had low tolerability to the physical loading. After CET, patients intolerant to physical loading had significantly lower values of the indicators compared to those who completed the test. The low values of spectral indicators in patients intolerant to physical loading during the restoration may suggest the exhaustion of adaptive resources of the cardiovascular system during the CET and reduced possibilities for the restoration of autonomic reserves after the attempt to perform physical tasks.


Antiphospholipid antibody-mediated effects in an arterial model of thrombosis are dependent on Toll-like receptor 4.
Patients with antiphospholipid syndrome (APS) produce antiphospholipid antibodies (aPL) and develop vascular thrombosis that may occur in large or small vessels in the arterial or venous beds. On the other hand, many individuals produce aPL and yet never develop thrombotic events. Toll-like receptor 4 (TLR4) appears to be necessary for aPL-mediated prothrombotic effects in venous and microvascular models of thrombosis, but its role in arterial thrombosis has not been studied. Here, we propose that aPL alone are insufficient to cause thrombotic events in an arterial model of APS, and that a concomitant trigger of innate immunity (e.g. TLR4 activation) is required. We show specifically that anti-β2-glycoprotein I (anti-β2GPI) antibodies, a subset of aPL, accelerated thrombus formation in C57BL/6 wild-type, but not TLR4-deficient, mice in a ferric chloride-induced carotid artery injury model. These aPL bound to arterial and venous endothelial cells, particularly in the presence of β2GPI, and to human TLR4 by enzyme-linked immunoassay. Arterial endothelium from aPL-treated mice had enhanced leukocyte adhesion, compared to control IgG-treated mice. In addition, aPL treatment of mice enhanced expression of tissue factor (TF) in leukocytes induced by the TLR4 ligand lipopolysaccharide (LPS). aPL also enhanced LPS-induced TF expression in human leukocytes in vitro. Our findings support a mechanism in which aPL enhance TF expression by leukocytes, as well as augment adhesion of leukocytes to the arterial endothelium. The activation of TLR4 in aPL-positive individuals may be required to trigger thrombotic events.


Evaluation of the Effect of Photodynamic Therapy on CAM-Grown Sarcomas.
Resection margin adequacy plays a critical role in the local control of sarcomas. Fluorescence-guided surgery has increased complete resection rates and local recurrence-free survival in several oncological disciplines. The purpose of this study was to determine whether sarcomas exhibit sufficient tumor fluorescence (photodynamic diagnosis (PDD)) after administration of 5-aminolevulinic acid (5-ALA) and whether photodynamic therapy (PDT) has an impact on tumor vitality in vivo. Sixteen primary cell cultures were derived from patient samples of 12 different sarcoma subtypes and transplanted onto the chorio-allantoic membrane (CAM) of chick embryos to generate 3-dimensional cell-derived xenografts (CDXs). After treatment with 5-ALA, the CDXs were incubated for another 4 h. Subsequently accumulated protoporphyrin IX (PPIX) was excited by blue light and the intensity of tumor fluorescence was analyzed. A subset of CDXs was exposed to red light and morphological changes of both CAMs and tumors were documented. Twenty-four hours after PDT, the tumors were excised and examined histologically. High rates of cell-derived engraftments on the CAM were achieved in all sarcoma subtypes and an intense PPIX fluorescence was observed. PDT of CDXs resulted in a disruption of tumor-feeding vessels and 52.4% of CDXs presented as regressive after PDT treatment, whereas control CDXs remained vital in all cases. Therefore, 5-ALA mediated PDD and PDT appear to be promising tools in defining sarcoma resection margins (PDD) and adjuvant treatment of the tumor bed (PDT).


Risk assessment and communication tools for genotype associations with multifactorial phenotypes: the concept of "edge effect" and cultivating an ethical bridge between omics innovations and society.
Applications of omics technologies in the postgenomics era swiftly expanded from rare monogenic disorders to multifactorial common complex diseases, pharmacogenomics, and personalized medicine. Already, there are signposts indicative of further omics technology investment in nutritional sciences (nutrigenomics), environmental health/ecology (ecogenomics), and agriculture (agrigenomics). Genotype-phenotype association studies are a centerpiece of translational research in omics science. Yet scientific and ethical standards and ways to assess and communicate risk information obtained from association studies have been neglected to date. This is a significant gap because association studies decisively influence which genetic loci become genetic tests in the clinic or products in the genetic test marketplace. A growing challenge concerns the interpretation of large overlap typically observed in distribution of quantitative traits in a genetic association study with a polygenic/multifactorial phenotype. To remedy the shortage of risk assessment and communication tools for association studies, this paper presents the concept of edge effect. That is, the shift in population edges of a multifactorial quantitative phenotype is a more sensitive measure (than population averages) to gauge the population level impact and by extension, policy significance of an omics marker. Empirical application of the edge effect concept is illustrated using an original analysis of warfarin pharmacogenomics and the VKORC1 genetic variation in a Brazilian population sample. These edge effect analyses are examined in relation to regulatory guidance development for association studies. We explain that omics science transcends the conventional laboratory bench space and includes a highly heterogeneous cast of stakeholders in society who have a plurality of interests that are often in conflict. Hence, communication of risk information in diagnostic medicine also demands attention to processes involved in production of knowledge and human values embedded in scientific practice, for example, why, how, by whom, and to what ends association studies are conducted, and standards are developed (or not). To ensure sustainability of omics innovations and forecast their trajectory, we need interventions to bridge the gap between omics laboratory and society. Appreciation of scholarship in history of omics science is one remedy to responsibly learn from the past to ensure a sustainable future in omics fields, both emerging (nutrigenomics, ecogenomics), and those that are more established (pharmacogenomics). Another measure to build public trust and sustainability of omics fields could be legislative initiatives to create a multidisciplinary oversight body, at arm's length from conflict of interests, to carry out independent, impartial, and transparent innovation analyses and prospective technology assessment.


Rhinomanometric detection rate of rhinoscopically-assessed septal deviations.
Normal values for the flow at a transnasal pressure of 150 Pa were established with active anterior rhinomanometry (with decongestion) in a group of 33 normal subjects. These values were used to detect abnormalities in a group of 193 patients whose septum anatomy had been evaluated with rhinoscopy. About 25% of the rhinoscopically normal patients were found to have significantly low ("abnormal") flow values on one side. The same was true for patients with a small septal deviation restricted to one anatomical area. An abnormal flow was measured in about 35% of the patients with a moderate (restricted) septal deviation. In the patients whose septal deviation was not restricted to one anatomical area, about 45% had an abnormal flow. The highest detection rate was about 80% in patients with major deviations in the region of the vestibule and the valve. Such deviations were found only in a minority of the patients with complaints of nasal obstruction, which limits the importance of rhinomanometric evaluation in clinical practice.


Effects of the nasal valve on acoustic rhinometry measurements: a model study.
The influence of nasal valve on acoustic rhinometry (AR) measurements was evaluated by using simple nasal cavity models. Each model consisted of a cylindrical pipe with an insert simulating the nasal valve. The AR-determined cross-sectional areas beyond the insert were consistently underestimated, and the corresponding area-distance curves showed pronounced oscillations. The area underestimation was more pronounced in models with inserts of small passage area. The experimental results are discussed in terms of theoretically calculated "sound-power reflection coefficients" for the pipe models. The reason for area underestimation is reflection of most of the incident sound power from the barrier at the front junction between the pipe and the insert. It was also demonstrated that the oscillations are due to low-frequency acoustic resonances in the portion of the pipe beyond the insert. The results suggest that AR does not provide reliable information about the cross-sectional areas of the nasal cavity posterior to a significant constriction, such as pathologies narrowing the nasal valve area. When the passage area of the nasal valve is decreased, the role of AR as a diagnostic tool for the entire nasal cavity becomes limited.


Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain.
Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 μL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.


hNOA1 interacts with complex I and DAP3 and regulates mitochondrial respiration and apoptosis.
Mitochondria are dynamic organelles that play key roles in metabolism, energy production, and apoptosis. Coordination of these processes is essential to maintain normal cellular functions. Here we characterized hNOA1, the human homologue of AtNOA1 (Arabidopsis thaliana nitric oxide-associated protein 1), a large mitochondrial GTPase. By immunofluorescence, immunoelectron microscopy, and mitochondrial subfractionation, endogenous hNOA1 is localized within mitochondria where it is peripherally associated with the inner mitochondrial membrane facing the mitochondrial matrix. Overexpression and knockdown of hNOA1 led to changes in mitochondrial shape implying effects on mitochondrial dynamics. To identify the interaction partners of hNOA1 and to further understand its cellular functions, we performed immunoprecipitation-mass spectrometry analysis of endogenous hNOA1 from enriched mitochondrial fractions and found that hNOA1 interacts with both Complex I of the electron transport chain and DAP3 (death-associated protein 3), a positive regulator of apoptosis. Knockdown of hNOA1 reduces mitochondrial O(2) consumption approximately 20% in a Complex I-dependent manner, supporting a functional link between hNOA1 and Complex I. Moreover, knockdown of hNOA1 renders cells more resistant to apoptotic stimuli such as gamma-interferon and staurosporine, supporting a role for hNOA1 in regulating apoptosis. Thus, based on its interactions with both Complex I and DAP3, hNOA1 may play a role in mitochondrial respiration and apoptosis.


Ursolic acid treats renal tubular epithelial cell damage induced by calcium oxalate monohydrate via inhibiting oxidative stress and inflammation.
Ursolic acid (UA) has been proved to have antioxidant and anti-inflammatory effects. However, it is not clear whether it has a protective impact on kidney damage induced by crystals of calcium oxalate monohydrate (COM). This work aimed to make clear the potential mechanism of UA protecting COM-induced kidney damage. The results manifested that high- and low-dose UA reduced COM crystals in COM rats' kidney, down-regulated urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) levels in rat plasma, declined kidney tissue and HK-2 cell apoptosis, inhibited Bax expression but elevated Bcl-2 expression. Additionally, UA alleviated renal fibrosis in COM rats, repressed α-SMA and collagen I protein expressions in the kidney and COM rats' HK-2 cells, depressed COM-induced oxidative damage in vivo and in vitro via up-regulating Nrf2/HO-1 pathway, up-regulated SOD levels and reduced MDA levels, down-regulated TNF-α, IL-1β, and IL-6 levels in vivo and in vitro via suppressing activation of TLR4/NF-κB pathway. In summary, the results of this study suggest that COM-induced renal injury can be effectively improved via UA, providing powerful data support for the development of effective clinical drugs for renal injury in the future.


COVID-19 sentiment analysis using college subreddit data.
The COVID-19 pandemic has affected our society and human well-being in various ways. In this study, we investigate how the pandemic has influenced people's emotions and psychological states compared to a pre-pandemic period using real-world data from social media. We collected Reddit social media data from 2019 (pre-pandemic) and 2020 (pandemic) from the subreddits communities associated with eight universities. We applied the pre-trained Robustly Optimized BERT pre-training approach (RoBERTa) to learn text embedding from the Reddit messages, and leveraged the relational information among posted messages to train a graph attention network (GAT) for sentiment classification. Finally, we applied model stacking to combine the prediction probabilities from RoBERTa and GAT to yield the final classification on sentiment. With the model-predicted sentiment labels on the collected data, we used a generalized linear mixed-effects model to estimate the effects of pandemic and in-person teaching during the pandemic on sentiment. The results suggest that the odds of negative sentiments in 2020 (pandemic) were 25.7% higher than the odds in 2019 (pre-pandemic) with a p-value < 0.001; and the odds of negative sentiments associated in-person learning were 48.3% higher than with remote learning in 2020 with a p-value of 0.029. Our study results are consistent with the findings in the literature on the negative impacts of the pandemic on people's emotions and psychological states. Our study contributes to the growing real-world evidence on the various negative impacts of the pandemic on our society; it also provides a good example of using both ML techniques and statistical modeling and inference to make better use of real-world data.


Advancing Health Literacy Interventions.
The past 25 years has seen extraordinary growth in interest in health literacy among researchers, policy-makers and practitioners. This interest has been underpinned by academic debate about the concept, definition, and measurement of health literacy, and further strengthened by a growing volume of research that has investigated the relationship between health literacy and a wide range of health and social outcomes. A smaller but growing number of studies report on interventions to address the practical challenges of low health literacy in clinical settings - and describe approaches to improving health literacy in different clinical and community populations. This chapter examines the evolution of the concept of health literacy and its practical implications for health literacy interventions. The chapter, then, provides an updated overview of reported interventions and existing strengths and weaknesses. It concludes with recommendations on interventional research that provides practical and implementable solutions which can inform future policy, strategy, and priorities.


Delayed tooth movement in Runx2+/- mice associated with mTORC2 in stretch-induced bone formation.
Runt-related transcription factor 2 (Runx2) is an essential transcription factor for osteoblast differentiation, and is activated by mechanical stress to promote osteoblast function. Cleidocranial dysplasia (CCD) is caused by mutations of RUNX2, and CCD patients exhibit malocclusion and often need orthodontic treatment. However, treatment is difficult because of impaired tooth movement, the reason of which has not been clarified. We examined the amount of experimental tooth movement in Runx2+/- mice, the animal model of CCD, and investigated bone formation on the tension side of experimental tooth movement in vivo. Continuous stretch was conducted to bone marrow stromal cells (BMSCs) as an in vitro model of the tension side of tooth movement. Compared to wild-type littermates the Runx2+/- mice exhibited delayed experimental tooth movement, and osteoid formation and osteocalcin (OSC) mRNA expression were impaired in osteoblasts on the tension side of tooth movement. Runx2 heterozygous deficiency delayed stretch-induced increase of DNA content in BMSCs, and also delayed and reduced stretch-induced alkaline phosphatase (ALP) activity, OSC mRNA expression, and calcium content of BMSCs in osteogenic medium. Furthermore Runx2+/- mice exhibited delayed and suppressed expression of mammalian target of rapamycin (mTOR) and rapamycin-insensitive companion of mTOR (Rictor), essential factors of mTORC2, which is regulated by Runx2 to phosphorylate Akt to regulate cell proliferation and differentiation, in osteoblasts on the tension side of tooth movement in vivo and in vitro. Loss of half Runx2 gene dosage inhibited stretch-induced PI3K dependent mTORC2/Akt activity to promote BMSCs proliferation. Furthermore, Runx2+/- BMSCs in osteogenic medium exhibited delayed and suppressed stretch-induced expression of mTOR and Rictor. mTORC2 regulated stretch-elevated Runx2 and ALP mRNA expression in BMSCs in osteogenic medium. We conclude that Runx2+/- mice present a useful model of CCD patients for elucidation of the molecular mechanisms in bone remodeling during tooth movement, and that Runx2 plays a role in stretch-induced proliferation and osteogenesis in BMSCs via mTORC2 activation.


Tetrahymena meiotic nuclear reorganization is induced by a checkpoint kinase-dependent response to DNA damage.
In the ciliate Tetrahymena, meiotic micronuclei (MICs) undergo extreme elongation, and meiotic pairing and recombination take place within these elongated nuclei (the "crescents"). We have previously shown that elongation does not occur in the absence of Spo11p-induced DNA double-strand breaks (DSBs). Here we show that elongation is restored in spo11Delta mutants by various DNA-damaging agents including ones that may not cause DSBs to a notable extent. MIC elongation following Spo11p-induced DSBs or artificially induced DNA lesions is probably a DNA-damage response mediated by a phosphokinase signal transduction pathway, since it is suppressed by the ATM/ATR kinase inhibitors caffeine and wortmannin and by knocking out Tetrahymena's ATR orthologue. MIC elongation occurs concomitantly with the movement of centromeres away from the telomeric pole of the MIC. This DNA damage-dependent reorganization of the MIC helps to arrange homologous chromosomes alongside each other but is not sufficient for exact pairing. Thus, Spo11p contributes to bivalent formation in two ways: by creating a favorable spatial disposition of homologues and by stabilizing pairing by crossovers. The polarized chromosome orientation inside the crescent resembles the conserved meiotic bouquet, and crescent and bouquet also share the putative function of aiding meiotic pairing. However, they are regulated differently because in Tetrahymena, DSBs are required for entering rather than exiting this stage.


Suicidal chloroquine poisoning: clinical course, autopsy findings, and chemical analysis.
Suicidal overdose of chloroquine is rare. We present a 14-year-old girl who was admitted to our Emergency Department after intentional ingestion of 7.5 g of chloroquine base followed by cardiac and respiratory arrest. Despite early mechanical ventilation, cardiac support, and treatment with high doses of diazepam, the patient died. Laboratory investigation indicated disseminated intravascular coagulation confirmed by petechial hemorrhages in the leptomeninges at autopsy, a finding that has not previously been described. Postmortem tissue analysis demonstrated early drug distribution to the medulla oblongata and cerebellum.


Leather-Promoted Transformation of Glucose into 5-Hydroxymethylfurfural and Levoglucosenone.
The search for efficient catalysts frequently leads to new homogeneous and heterogeneous catalysts of increasing complexity, and sometimes common, natural, or hybrid natural/synthetic materials that could be used in catalysis are overlooked. For example, the leather industry has produced robust Cr-containing materials for centuries by chemical treatment of animal hides with chromium salts. Herein, the use of chromium-tanned leather as a heterogeneous catalyst for glucose dehydration to 5-hydroxymethylfurfural (5-HMF) and levoglucosenone (LGO) is reported. Four pieces of waste leather were obtained from shoe soles and a belt, characterized by a range of techniques including FTIR spectroscopy, SEM, BET surface area measurements, XRD, and X-ray photoelectron spectroscopy, and their catalytic activity was evaluated. The activity of the scrap leather pieces compares favorably to those of many recently reported catalysts for the preparation of 5-HMF, but additionally results in significant quantities of LGO. Overall, the results demonstrate that waste leather is an outstanding material for use in catalysis.


Global elemental maps of the moon: the Lunar Prospector gamma-Ray spectrometer.
Lunar Prospector gamma-ray spectrometer spectra along with counting rate maps of thorium, potassium, and iron delineate large compositional variations over the lunar surface. Thorium and potassium are highly concentrated in and around the nearside western maria and less so in the South Pole-Aitken basin. Counting rate maps of iron gamma-rays show a surface iron distribution that is in general agreement with other measurements from Clementine and the Lunar Prospector neutron detectors.


Visual outcomes for surgical treatment of large and giant carotid ophthalmic segment aneurysms: a case series utilizing retrograde suction decompression (the "Dallas technique").
The authors report their results in a series of large or giant carotid ophthalmic segment aneurysms clipped using retrograde suction decompression. A retrospective review of clinical data and treatment summaries was performed for 18 patients with large or giant carotid artery ophthalmic segment aneurysms managed operatively via retrograde suction decompression. Visual outcomes, Glasgow Outcome Scale (GOS) scores, and operative complications were determined. Postoperative angiography was assessed. During a 17-year period, 18 patients underwent surgery performed using retrograde suction decompression. The mean aneurysm size was 26 mm. Three patients presented with subarachnoid hemorrhage. Fourteen of 18 patients presented with visual symptoms. Eleven (79%) of these 14 patients experienced visual improvement and the remaining 3 (21%) experienced worsened vision after surgery. Of 3 patients without visual symptoms and a complete visual examination before and after surgery, 1 had visual worsening postoperatively. One aneurysm required trapping and bypass, and all others could be clipped. Postoperative angiography demonstrated complete occlusion in 9 of 17 clipped aneurysms and neck remnants in the other 8 clipped aneurysms. One (5.5%) of 18 patients experienced a stroke. Eighteen patients had a GOS score of 5 (good outcome), and 1 patient had a GOS score of 4 (moderately disabled). There were no deaths. There was no morbidity related to the second incision or decompression procedure. Prolonged improvement did occur, and even in some cases of visual worsening in 1 eye, the overall vision did improve enough to allow driving. Retrograde suction decompression greatly facilitates surgical clipping for large and giant aneurysms of the ophthalmic segment. Visual preservation and improvement occur in the majority of these cases and is an important outcome measure. Developing endovascular technology must show equivalence or superiority to surgery for this specific outcome.


Characterization and structural features of a chalcone synthase mutation in a white-flowering line of Matthiola incana R. Br. (Brassicaceae).
For Matthiola incana (Brassicaceae), used as a model system to study biochemical and genetical aspects of anthocyanin biosynthesis, several nearly isogenic colored wild type lines and white-flowering mutant lines are available, each with a specific defect in the genes responsible for anthocyanin production (genes e, f, and g). For gene f supposed to code for chalcone synthase (CHS; EC 220.127.116.11), the key enzyme of the flavonoid/anthocyanin biosynthesis pathway belonging to the group of type III polyketide synthases (PKS), the wild type genomic sequence of M. incana line 04 was determined in comparison to the white-flowering CHS mutant line 18. The type of mutation in the chs gene was characterized as a single nucleotide substitution in a triplet AGG coding for an evolutionary conserved arginine into AGT coding for serine (R72S). Northern blots and RT-PCR demonstrated that the mutated gene is expressed in flower petals. Heterologous expression of the wild type and mutated CHS cDNA in E. Scherichia coli, verified by Western blotting and enzyme assays with various starter molecules, revealed that the mutant protein had no detectable activity, indicating that the strictly conserved arginine residue is essential for the enzymatic reaction. This mutation, which previously was not detected by mutagenic screening, is discussed in the light of structural and functional information on alfalfa CHS and related type III PKS enzymes.


Synthesis, spectroscopic, thermal, crystal structure properties, and characterization of new Hofmann-Td-type complexes with 3-aminopyridine.
In this study, synthesis of two new tetracyanocadmate(II) and tetracyanozincate(II) complexes based on 3-aminopyridine (3AP) and investigation of their structural properties were reported. These complexes were characterized by using vibration spectroscopy, elemental, thermal analysis and single crystal X-ray diffraction (SC-XRD) techniques. Investigation of the elemental, spectral and single crystal data of these complexes showed that the formulas [Cd(3AP)2Zn(μ4-CN)4]n (1) and [Cd(3AP)2Cd(μ4-CN)4]n (2) fully explained their crystal structure. General information about the structural and chemical properties of these complexes obtained in single crystal form was obtained by observing the changes in the characteristic peaks of the 3AP with the [Zn(μ4-CN)4]2- and [Cd(μ4-CN)4]2- structures that make up these complexes. The behaviors of these complexes against changes in temperature were obtained by examining the temperature-dependent changes of their mass. The asymmetric unit of the heterometallic complexes 1 and 2 consist of half Cd(II) ion, half M ion [M = Zn1 in 1 and Cd2 in 2], two cyanide ligands and one 3AP.


Successful live births after surgical treatments for symptomatic cesarean scar pregnancies: report of 3 cases.
There is no current consensus on the best treatment modality for cesarean scar pregnancy (CSP) with favorable reproductive and pregnancy outcome. We treated 3 cases of symptomatic CSP with fetal cardiac activity. The first case underwent laparoscopic repair at 6 weeks' gestational age of unruptured CSP. The second patient underwent laparoscopic repair due to massive vaginal bleeding after suction curettage. Both patients conceived naturally 6 months later and underwent repeated cesarean section at term. These were successful live births although the second patient was treated with uterine artery embolization for postpartum hemorrhage. The last patient underwent emergency exploratory laparotomy due to ruptured CSP and delivered a preterm baby. Earlier surgical treatment of CSP is indicated for a subsequent successful pregnancy and live birth. The laparoscopic approach might be advisable prior to uterine rupture.


Sexual Orientation and Suicide Attempt Disparities Among US Adolescents: 2009-2017.
Sexual minority adolescents face mental health disparities relative to heterosexual adolescents. We evaluated temporal changes in US adolescent reported sexual orientation and suicide attempts by sexual orientation. We used Youth Risk Behavioral Surveillance data from 6 states that collected data on sexual orientation identity and 4 states that collected data on sex of sexual contacts continuously between 2009 and 2017. We estimated odds ratios using logistic regression models to evaluate changes in reported sexual orientation identity, sex of consensual sexual contacts, and suicide attempts over time and calculated marginal effects (MEs). The proportion of adolescents reporting minority sexual orientation identity nearly doubled, from 7.3% in 2009 to 14.3% in 2017 (ME: 0.8 percentage points [pp] per year; 95% confidence interval [CI]: 0.6 to 0.9 pp). The proportion of adolescents reporting any same-sex sexual contact increased by 70%, from 7.7% in 2009 to 13.1% in 2017 (ME: 0.6 pp per year; 95% CI: 0.4 to 0.8 pp). Although suicide attempts declined among students identifying as sexual minorities (ME: -0.8 pp per year; 95% CI: -1.4 to -0.2 pp), these students remained >3 times more likely to attempt suicide relative to heterosexual students in 2017. Sexual minority adolescents accounted for an increasing proportion of all adolescent suicide attempts. The proportion of adolescents reporting sexual minority identity and same-sex sexual contacts increased between 2009 and 2017. Disparities in suicide attempts persist. Developing and implementing approaches to reducing sexual minority youth suicide is critically important.


Euglycemic Diabetic Ketoacidosis in Concurrent Very Low-carbohydrate Diet and Sodium-glucose Transporter-2 Inhibitor Use: A Case Report.
With the incredibly high incidence of Type 2 Diabetes in the current population of emergency department patients, it is critical for clinicians to understand the possible complications of the treatment of this disease. Medication like canagliflozin are more common to encounter on patient's home medication lists and clinicians should be aware of how these medications, alone or combined with dietary modifications, can result in significant pathology and even mortality if not appropriately treated. We report a case of a patient with type II diabetes mellitus who presented with euglycemic diabetic ketoacidosis in the setting of concurrent use of canagliflozin, a sodium-glucose transporter-2 (SGLT-2) inhibitor, and strict adherence to a low-carbohydrate ketogenic diet for weight control. Euglycemic ketoacidosis has previously been observed in both diabetic and non-diabetic patients following strict ketogenic diets, as well as in diabetic patients being treated with SGLT-2 inhibitors. As more patients choose ketogenic diets for weight control and diabetes management, clinicians should be aware of this potentially life-threatening complication in patients concurrently taking SGLT-2 inhibitors.


Molecular classification and stratification of adult diffuse gliomas: A tertiary care center study.
Diffuse gliomas in the adult population are the most common primary central nervous system (CNS) tumors. The World Health Organization incorporated isocitrate dehydrogenase (IDH) mutations and 1p/19q co-deletion with histopathological features into an "integrated diagnosis" in the revised classification of tumors of CNS. These molecular subgroups of diffuse gliomas are found to stratify patients into prognostically distinct groups better than the histological classification. The objectives of the current study were to assess the frequency of IDH mutation, ATRX expression loss, p53 overexpression, and 1p/19q co-deletion detection in adult diffuse gliomas (Grade II, III, and IV) and to correlate them with clinicopathological and histopathological features. The current study was a tertiary care hospital-based retrospective case series of 112 cases of adult diffuse gliomas. Immunohistochemistry (IHC)-based molecular detection was performed for IDH-1, ATRX, and p53 and fluorescent in situ hybridization (FISH) was performed for 1p/19q co-deletion detection. IDH-1 mutation was present in 30.4% (n = 34/112) cases, ATRX expression was lost in 18% (n = 19/104) cases, p53 was mutated in 39.3% (n = 42/107) cases and 1p19q was co-deleted in 25% (n = 4/16) cases. In the IDH1 mutant cases, with retained ATRX, FISH for 1p/19q co-deletion was performed and was co-deleted in four cases. The results of the present study indicate that IHC including IDH1/2, ATRX, and p53 is useful for the molecular classification of diffuse gliomas, which could be useful for the evaluation of prognosis, especially Grade III and II. Although the immunohistochemical approach does not replace genetic testing completely, it is a practical and powerful means of assessing molecular genetic changes. IDH mutations are the established markers of better prognosis in diffuse gliomas.


[Anaerobic gas gangrene after the amputation of an extremity].
During 30 years of practical work the authors observed 6 patients with anaerobic mephitic gangrene after amputation of the extremity for atherosclerotic (in 3 patients), diabetic (in 2 patients) and vast wounds of the foot. Among the most substantial noninfective causes of the development of anaerobic mephitic gangrene in the postoperative period there were continuous preoperative ischemia of the extremity against the background of a decreased level of haemoglobin, total protein, lymphocytes. An early operation and intensive complex specific and nonspecific therapy resulted in recovery of 3 patients.


[Cutaneo-systemic necrotizing vasculitis occurring during desensitization].
The authors report a case of cutaneo-systemic necrotizing vasculitis, predominantly affecting the skin and digestive tract, observed in an asthmatic patient undergoing desensitization with Graminaceae pollen extract and mite-enriched house dust. Vasculitis developed 22 months after the first injections, became autonomous after the end of treatment and responded well to systemic corticosteroid therapy in daily doses of 1 mg/kg. The patient was followed up for 8 months during which the vasculitis did not recur, despite reduction in steroid dosage. Reports of necrotizing vasculitis occurring during desensitization seem to be very rare. They raise the problem of whether specific immunotherapy plays a role in the pathogenesis of vasculitis. Most of the characteristics that emerged from the cases previously published are concordant with those found in our patient: the interval between the first injections and the initial symptoms varied from 45 days to 8 years; in every case the condition followed its own course after the injections were discontinued; most patients were being desensitized to several allergens; the cutaneous symptoms were pronounced, eosinophilia was moderate and hepatitis B serology was constantly negative. The few prospective studies aimed at determining, by different methods, the levels of circulating immune complexes (CIC) have given conflicting results. Atopic subjects have high CIC levels, but these do not seem to be influenced by desensitization. The nature of the CIC remains unknown, and the various suggestions put forward (cross-reaction between blocking IgG and auto-antibodies, CIC [blocking IgG, anti-idiotype antibodies]) require confirmation, although the hypothesis of pathogenic CIC (allergen, blocking IgG) is unlikely to be correct.(ABSTRACT TRUNCATED AT 250 WORDS)


The Role of Curcumin in Cancer Treatment.
Curcumin is a polyphenol extracted from the rhizomes of the turmeric plant, Curcuma longa which has anti-inflammatory, and anticancer properties. Chronic inflammation is associated with the development of cancer. Curcumin acts on the regulation of various immune modulators, including cytokines, cyclooxygenase-2 (COX-2), and reactive oxygen species (ROS), which partly explains its anticancer effects. It also takes part in the downregulation of growth factors, protein kinases, oncogenic molecules and various signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 3 (STAT3) signaling. Clinical trials of curcumin have been completed or are ongoing for various types of cancer. This review presents the molecular mechanisms of curcumin in different types of cancer and the evidence from the most recent clinical trials.


Does dual antibiotic prophylaxis better prevent surgical site infections in total joint arthroplasty?
It is unclear which antibiotic regimen provides the best prophylaxis against surgical site infection (SSI) in patients undergoing hip and knee surgery. Therefore, we determined whether dual antibiotic prophylaxis (1) reduced the rate of SSI compared to single antibiotic prophylaxis and (2) altered the microbiology of SSI. We retrospectively reviewed 1828 primary THAs and TKAs performed between September 1, 2008 and December 31, 2010. We divided patients into two groups: (1) those who received a dual prophylactic antibiotic regimen of cefazolin and vancomycin (unless allergy), or (2) received cefazolin (unless allergy) as the sole prophylactic antibiotic. There were 701 males and 1127 females with an average age of 56 years (range, 15–97 years). We limited followup to 1 year, presuming subsequent infections were not related to the initial surgery. During this period, there were 22 SSIs (1.2%). The infection rates for dual antibiotic prophylaxis compared to a single antibiotic regimen were 1.1% and 1.4%, respectively. Of 1328 patients treated with dual antibiotic prophylaxis, only one (0.08%) SSI was culture positive for methicillin resistant Staphylococcus aureus (MRSA), while four of 500 patients (0.8%) receiving only cefazolin prophylaxis had culture positive MRSA infection at the time of reoperation. The addition of vancomycin as a prophylactic antibiotic agent apparently did not reduce the rate of SSI compared to cefazolin alone. Use of vancomycin in addition to cefazolin appeared to reduce the incidence of MRSA infections; however, the number needed to treat to prevent a single MRSA infection was very high. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Subcutaneous fat necrosis after moderate therapeutic hypothermia in neonates.
Therapeutic moderate hypothermia in newborns with hypoxic-ischemic encephalopathy is rapidly becoming standard clinical practice. We report here 12 cases of subcutaneous fat necrosis among 1239 cases registered with a national registry of newborns treated with moderate whole-body hypothermia. All the infants suffered from perinatal asphyxia and hypoxic-ischemic encephalopathy. Moderate-to-severe hypercalcemia was identified in 8 of 10 infants with blood calcium measurements. In all cases the skin lesions appeared after completion of the cooling treatment. Our data suggest that prolonged moderate hypothermia is an actual risk factor for subcutaneous fat necrosis. Because the lesions often develop several days after birth, physicians need to be aware of this condition as a possible complication in infants treated with moderate hypothermia after asphyxia. Blood calcium levels need to be monitored in affected infants.


The assessment of environmental and external cross-contamination in preparing ready-to-administer cytotoxic drugs: a comparison between a robotic system and conventional manual production.
The primary aim of the study was to compare environmental and external (cross-) contamination of traces of cytostatics, during preparation of 5-fluorouracil and cyclophosphamide using a robotic system (APOTECAchemo) or the conventional manual compounding procedure. The secondary aim was to validate the cleaning procedure of the robot. Eighty ready-to-administer (RTA) infusion bags with 5-fluorouracil, cyclophosphamide or sodium chloride were compounded using both techniques on 3-5 days. Wipe samples were taken from several locations in the compounding room before and after cleaning, and also from the technician's gloves. These samples were analysed for 5-fluorouracil and cyclophosphamide concentrations using GC/MS/MS. A total of 284 wipe samples were collected during the study (113 from the manual and 171 from the robotic process). External contamination on the outside of infusion bags was 3.75% for both manual and robotic compounding. For manual compounding, external cross-contamination occurred on 2.5% of the prepared infusion bags. External cross-contamination occurred on 1.25% of the infusion bags for the robotic procedure. Inside the compounding room, 9% of the environmental wipe samples were contaminated in case of manual production and 24% for robotic compounding. Since 50% of the contaminated environmental samples for the robotic system were taken after cleaning, the cleaning procedure was extended and parameter setting for cyclophosphamide handling was performed. After this, residual environmental or external contamination was no longer detectable. Comparison of both preparation methods showed that external (cross-)contamination of infusion bags was lower using the robotic system. An optimized cleaning procedure showed the best results in environmental contamination for the robot.


Cardiac resynchronisation therapy in patients with chronic heart failure.
Cardiac resynchronisation therapy (CRT) is common treatment for congestive heart failure (HF) with decreased LV function and wide QRS complex. Its foundations are set in the understanding of the pathophysiology of ventricular dyssynchrony. Over the last several decades, CRT has evolved through changes in implantation techniques, device and lead design, imaging modalities and our growing clinical experience. This review article will discuss the vast clinical experience that has led to current guidelines recommendations for CRT in patients with mild-to-severe HF. In addition, the article will also discuss recent evidence of benefits of CRT in patients beyond the guidelines. The article will also address the issue of non-responders, optimisation of CRT, postimplant evaluation and remote monitoring.


Antipsychotic drugs and involuntarily committed patients.
This summer, the U.S. Supreme Court wil rule on whether an involuntarily committed mental patient has a legal right to refuse antipsychotic drugs. In this article, two federal appellate decisions that may influence that decision are reviewed. The appellate decisions suggest that patients have a right to refuse treatment except in circumstances where there is an overriding state interest.


Correction of adolescent hyperkyphosis with posterior-only threaded rod compression instrumentation: is anterior spinal fusion still necessary?
Retrospective clinical and radiographic review. To assess the need for anterior apical release and fusion before posterior threaded rod compression instrumentation and closing-wedge lamina resection for the treatment of adolescent hyperkyphosis. Traditional treatment of adolescent hyperkyphosis has included a preliminary anterior release and fusion of apical disc segments to achieve and maintain better correction. A total of 27 patients undergoing correction of adolescent hyperkyphosis with posterior threaded rod Texas Scottish Rite Hospital instrumentation was reviewed. Of the 27 patients, 19 had strict Sorensen criteria for Scheuermann kyphosis. There were 20 patients (group 1) who underwent posterior surgery only, while 7 (group 2) underwent same day preliminary open or endoscopic anterior release and fusion of 5-7 apical segments. A closing-wedge laminar resection was used to facilitate shortening of the posterior column. All but 2 patients were braced for up to 3 months after surgery. Preoperative, immediate postoperative, and final follow-up radiographs at 24-56 months postoperatively were analyzed for the amount and loss of correction of measured kyphosis, T2-T12 kyphosis, T10-L2 kyphosis, T12-S1 lordosis, C7 plumbline sagittal balance, and correction of Voutsinas index. There was no difference in the amount of correction achieved at final follow-up between the 2 groups (group 1 = 53%, group 2 = 46%, P = 0.47). There was also no difference (P = 0.84) in the amount of correction immediately after surgery compared to final follow-up. No patient lost more than 8 degrees correction after surgery. One asymptomatic rod fracture occurred, with no loss of correction, implying no pseudarthroses. Similarly, there were no differences in any of the other sagittal plane measurements between the 2 groups, except for Voutsinas index (VI) in which group 1 patients had better normalization (VI = 0.11) compared to group 2 (VI = 0.15, P =0.05). Traditional anterior/posterior fusion technique provides no additional improvement in radiographic outcome compared to posterior-only surgery for adolescent hyperkyphosis. Preliminary anterior release and fusion is no longer performed when correcting this deformity with a posterior column shortening procedure and threaded rod compression instrumentation.


The overdenture concept.
The biomechanical rationale for the treatment of patients with overdentures, and their advantages and disadvantages are presented. The indications and contraindications for the treatment of partially edentulous patients with removable partial overdentures are discussed. The patient's and dentist's responsibilities for the success of therapy are enumerated.


Insight into novel RNA-binding activities via large-scale analysis of lncRNA-bound proteome and IDH1-bound transcriptome.
RNA-binding proteins (RBPs) play pivotal roles in directing RNA fate and function. Yet the current annotation of RBPs is largely limited to proteins carrying known RNA-binding domains. To systematically reveal dynamic RNA-protein interactions, we surveyed the human proteome by a protein array-based approach and identified 671 proteins with RNA-binding activity. Among these proteins, 525 lack annotated RNA-binding domains and are enriched in transcriptional and epigenetic regulators, metabolic enzymes, and small GTPases. Using an improved CLIP (crosslinking and immunoprecipitation) method, we performed genome-wide target profiling of isocitrate dehydrogenase 1 (IDH1), a novel RBP. IDH1 binds to thousands of RNA transcripts with enriched functions in transcription and chromatin regulation, cell cycle and RNA processing. Purified IDH1, but not an oncogenic mutant, binds directly to GA- or AU-rich RNA that are also enriched in IDH1 CLIP targets. Our study provides useful resources of unconventional RBPs and IDH1-bound transcriptome, and convincingly illustrates, for the first time, the in vivo and in vitro RNA targets and binding preferences of IDH1, revealing an unanticipated complexity of RNA regulation in diverse cellular processes.


Treatment of Keloids Using Plasma Skin Regeneration Combined with Radiation Therapy Under the Evaluation of Patient and Observer Scar Assessment Scale.
Keloids are caused by uncontrolled excessive proliferation of fibrous tissue. Multiple treatment strategies including steroid injection, surgical excision, laser therapy and radiation therapy have been reported. Few studies have evaluated the performance of plasma skin regeneration (PSR) in the treatment of keloid. This study aimed to evaluate the effectiveness of PSR combined with radiation therapy for keloids on different body parts. A total of 71 patients with 98 keloids were enrolled in this study. Keloids <4 mm thick underwent single-dose PSR, while keloids ≥4 mm thick were administered compound betamethasone injection beforehand. Radiation therapy was administered after 24 hours and again 7 days later after PSR. The outcome was evaluated using the patient and observer scar assessment scale at 12 months post-treatment. Patient-reported average scores for all keloids significantly decreased from 35.05±9.94 to 21.84±7.04 (p < 0.05). Keloids on face and neck, chest, and back responded better than those on shoulders and limbs. The recurrence rate was observed to be 15.3% (15 out of 98). Adverse effects were mild. PSR combined with radiation therapy is an effective and safe strategy to treat keloids. Location could be a factor that affects curative effects.


Effects of exposure to estradiol and estradiol plus testosterone on the Mongolian gerbil (Meriones unguiculatus) female prostate.
The female prostate is a differentiated organ found in several mammal species, including humans and rodents. This gland has been related to important functions on female reproductive biology. Although the factors, which regulate prostate's development and activity are not well known, its functionality has been related to steroid hormones. It is well established that cyclic changes of estradiol and progesterone levels promote histophysiological adaptations of the whole female body. In contrast, only a few is found about those adaptations in female prostate. Thus, this study aimed to evaluate the effect of estradiol and estradiol + testosterone association on gerbil female prostate in order to verify, which hormonal associations are necessary to its homeostasis. For this, adult females had the ovaries surgically removed. After recovering, they received estradiol and estradiol + testosterone doses through 30 days, each 48 h. The prostatic tissue underwent morphological and morphometric-estereological analysis. Hormonal restriction caused great gland involution and decreased secretory activity, aspects that were reverted by exposure to estradiol and estradiol + testosterone. However, these hormones were not able to re-establish the normal prostate histoarchitecture. The immunoreaction of steroid receptors (ER-α, ER-β, and AR) responded differently among the experimental and control groups, and PCNA assay showed a decrease in epithelial cell proliferation within groups that had hormone privation. Therefore, we conclude that estradiol and testosterone are able to influence prostate morphophysiology and the maintenance of gland homeostasis depends on a balance among these and other hormones.


High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria.
In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. Achieving this throughput necessitates the development of efficient ultra-high-throughput screening methods. Here, we report the development and evaluation of a luciferase-based phenotypic screen of malaria exoerythrocytic-stage parasites optimized for a 1536-well format. This assay uses the exoerythrocytic stage of the rodent malaria parasite, Plasmodium berghei, and a human hepatoma cell line. We use this assay to evaluate several biased and unbiased compound libraries, including two small sets of molecules (400 and 89 compounds, respectively) with known activity against malaria erythrocytic-stage parasites and a set of 9886 diversity-oriented synthesis (DOS)-derived compounds. Of the compounds screened, we obtain hit rates of 12-13 and 0.6% in preselected and naïve libraries, respectively, and identify 52 compounds with exoerythrocytic-stage activity less than 1 μM and having minimal host cell toxicity. Our data demonstrate the ability of this method to identify compounds known to have causal prophylactic activity in both human and animal models of malaria, as well as novel compounds, including some exclusively active against parasite exoerythrocytic stages.


Mutational studies on the alpha-sarcin loop of Escherichia coli 23S ribosomal RNA.
The alpha-sarcin loop, located in domain VI of Escherichia coli 23S rRNA, is a universally conserved sequence involved in the binding of elongation factors to the ribosome and is the site of action of ribosome-inactivating proteins. Six mutations were created in this loop with the aim of establishing whether the mutant 23S rRNA could be assembled into functional ribosomes. In order to distinguish between plasmid-derived (mutant) and chromosome-derived (wild-type) 23S rRNAs, an oligonucleotide tag sequence was introduced into the plasmid-borne 23S rRNA gene. The tag sequence had no apparent effect on ribosome assembly or function. Two of the bases mutated (at positions A2660 and G2661) have been implicated in the binding of both elongation factor Tu and elongation factor G to the ribosome [Moazed, D., Robertson, J. M. & Noller, H. F. (1988) Nature 334, 362-364]. A further two bases (at positions C2658 and G2663) have been proposed to form a Watson-Crick base pair involved in the formation of a tetraloop structure required for ribosome function [Szewczak, A. A., Moore, P. B., Chan, Y. L. & Wool, I. G. (1993) Proc. Natl Acad. Sci. USA 90, 9581-9585]. It is inferred that the identity of the bases at positions 2658 and 2663 are of critical importance for ribosome structure and function, and that this function cannot be restored by a second mutation which potentially restores a Watson-Crick base pair, but with reversed position. Of five single mutants (each mutant containing one of the mutations C2658G, A2660G, G2661A, G2663C and G2664C) and one double mutant (containing both mutations C2658G and G2663C) only the two mutants with the single mutations G2661A and G2664C were incorporated into ribosomes at a level comparable to that of 23S rRNA expressed from a wild-type plasmid. However, the G2664C mutation resulted in a decrease in growth rate and a gradual loss of viability. rRNAs containing the G2663C single mutation and the C2658G and G2663C double mutation showed reduced incorporation into 50S subunits and these did not enter into ribosome couples.


Separation of Floating Oil Drops Based on Drop-Liquid Substrate Interfacial Tension.
Though various strategies exist for the transport of oil drops suspended on a liquid substrate, selective manipulation of different kinds of drops based on their respective characteristics remains a challenge. In practice, it is possible to have multiple drops having different wetting states with the liquid substrate, whose separation is desired. In this work, we exploit curvature-induced capillary forces for the selective manipulation (transport as well as separation) of oil droplets based on their interfacial tension (IFT) with the underlying liquid substrate. To demonstrate this, we have selected two oils having different IFTs with the aqueous liquid substrate and tuned their curvature-induced capillary interaction (inward or outward from the source) by controlled addition of the surfactant. We experimentally realize three droplet manipulation regimes: repulsion, attraction, and separation regime. In the repulsion and attraction regimes, both the drops behave in a similar manner. Strikingly, in the separation regime, drops can be effectively separated based on their IFT; low IFT droplets are attracted toward the source, while high IFT droplets do the reverse.


Estimating the spatial distribution of wintering little brown bat populations in the eastern United States.
Depicting the spatial distribution of wildlife species is an important first step in developing management and conservation programs for particular species. Accurate representation of a species distribution is important for predicting the effects of climate change, land-use change, management activities, disease, and other landscape-level processes on wildlife populations. We developed models to estimate the spatial distribution of little brown bat (Myotis lucifugus) wintering populations in the United States east of the 100th meridian, based on known hibernacula locations. From this data, we developed several scenarios of wintering population counts per county that incorporated uncertainty in the spatial distribution of the hibernacula as well as uncertainty in the size of the current little brown bat population. We assessed the variability in our results resulting from effects of uncertainty. Despite considerable uncertainty in the known locations of overwintering little brown bats in the eastern United States, we believe that models accurately depicting the effects of the uncertainty are useful for making management decisions as these models are a coherent organization of the best available information.


Long-range control of gene expression via RNA-directed DNA methylation.
RNA-mediated transcriptional silencing, in plants known as RNA-directed DNA methylation (RdDM), is a conserved process where small interfering RNA (siRNA) and long non-coding RNA (lncRNA) help establish repressive chromatin modifications. This process represses transposons and affects the expression of protein-coding genes. We found that in Arabidopsis thaliana AGO4 binding sites are often located distant from genes differentially expressed in ago4. Using Hi-C to compare interactions between genotypes, we show that RdDM-targeted loci have the potential to engage in chromosomal interactions, but these interactions are inhibited in wild-type conditions. In mutants defective in RdDM, the frequency of chromosomal interactions at RdDM targets is increased. This includes increased frequency of interactions between Pol V methylated sites and distal genes that are repressed by RdDM. We propose a model, where RdDM prevents the formation of chromosomal interactions between genes and their distant regulatory elements.


Severe pan-sensory neuropathy in leprosy.
The sensory loss which occurs in leprosy is essentially cutaneous, resulting from centripetally ascending infection, the host cellular response and fibrosis, from dermal to certain mixed nerves. The hallmark is pain/temperature and touch/pressure loss. Muscle denervation is a byproduct of mixed nerve involvement. Leprous sensory and motor neuropathy presents a stereotyped picture, with preservation of position sense, noninvolvement of the large girdle muscles, and retained deep tendon reflexes. We report clinical and investigative details of 7 patients (3 males, 4 females) with mild-to-moderate polyneuritic leprosy who manifested severe proprioceptive loss in the upper per limbs; the lower limbs were similarly affected in 4 of them. Tendon reflexes were absent in the ataxic limbs. No other cause was found for the ataxia. Electrophysiological studies confirmed damage to large cutaneous and muscle afferents, and a normal EMG pattern in hip and shoulder muscles. Of great interest was the histology of a lumbar sensory ganglion biopsied in a severely disabled patient. There was extensive neuron loss and degeneration and reactive proliferation of capsular cells ("nodules of Nageotte"), an inflammatory focus of lymphocytes, and no bacilli. This suggests to us that the proprioceptive loss in these patients could well be the result of an unusual "leprous ganglionitis." Further clarification of the mechanism of ganglion degeneration and the frequency of inflammation could come from immunohistology of tissues from African green monkeys with experimental polyneuritic leprosy.


Is intrauterine exposure to acetaminophen associated with emotional and hyperactivity problems during childhood? Findings from the 2004 Pelotas birth cohort.
Longitudinal studies have consistently reported that prenatal exposure to acetaminophen can to lead to an increased risk of attention deficit-hyperactivity disorder during childhood. This study aimed to investigate the association between intrauterine exposure to acetaminophen and the presence of emotional and behavioral problems at the ages of 6 and 11 years in a low-middle income country. We performed a prospective longitudinal population-based study using data from the 2004 Pelotas birth cohort. From the 4231 initial cohort participants, 3722 and 3566 children were assessed at 6 and 11 years of age, respectively. The outcomes were assessed using the parent version of Strengths and Difficulties Questionnaire (SDQ). The cut-off points established for the Brazilian population were used to categorize the outcomes. Crude and adjusted odds ratio were obtained through logistic regression. Acetaminophen was used by 27.5% (95% confidence interval [CI]: 26.1-28.9) of the mothers at least once during pregnancy. The prevalence of emotional problems at 6 and 11 years was 13.6 and 19.9%, respectively. For hyperactivity problems, prevalence was 13.9 and 16.1%, respectively. Intrauterine exposure to acetaminophen increased the odds of having emotional (odds ratio [OR] = 1.47; 95% CI: 1.07-2.02) and hyperactivity/inattention (OR = 1.42; 95% CI: 1.06-1.92) problems in 6-year-old boys. At the age of 11, a small decrease in the effect was observed for both outcomes after adjustment: OR = 1.31 (95% CI: 0.99-1.73) for emotional problems and OR = 1.25 (95% CI: 0.95-1.65) for hyperactivity/inattention in boys. No association for any phenotypes at both ages was observed for girls. The effect of intrauterine exposure to acetaminophen in emotional and hyperactivity symptoms was dependent on sex in a Brazilian cohort. While it seemed to be important for boys, mainly at 6 years of age, for girls, no association was observed.


Morphometry of cervical spinal cord in cat using design-based stereology.
The spinal cord harbours nerve fibres that facilitate reflex actions and that transmit impulses to and from the brain. The cervical spinal cord is an area of particular interest in medicine and veterinary due to frequent pathologic alterations in this region. This study describes the morphometric features of the cervical spinal cord in cat using design-unbiased stereological methods. The cervical spinal cords of four male cats were dissected and samples were taken according to systematic uniform random sampling. Each sample was embedded in agar and cut into 60-µm thick sections and stained with cresyl violet 0.1% for stereological estimations. The total cervical spinal cord volume obtained by the Cavalieri estimator was 2,321.21 ± 285.5 mm3 . The relative volume of grey matter and white matter was 23.8 ± 1.3% and 76.1 ± 1.3%. The dorsal horn and ventral horn volume were 12.3 ± 1.2% and 11.4 ± 0.7% of the whole cervical spinal cord. The volume of central canal was estimated to 3.8 ± 1 mm3 . The total number of neurons was accounted 3,405,366.2 ± 267,469.4 using the optical disector/fractionator method. The number of motoneurons and interneurons was estimated to be 1,120,433.2 ± 174,796.7 and 2,284,932.9 ± 127,261.5, respectively. The average volume of the motoneurons and interneurons was estimated to 1980 µm3 and 680 µm3 , respectively, using the spatial rotator method. This knowledge of cat spinal cord findings may serve as a foundation as a translational model in spinal cord experimental research and provide basic findings for diagnosis and treatment of spinal cord disorders.


Biophysical characterization of interactions involving importin-alpha during nuclear import.
Proteins containing the classical nuclear localization sequences (NLSs) are imported into the nucleus by the importin-alpha/beta heterodimer. Importin-alpha contains the NLS binding site, whereas importin-beta mediates the translocation through the nuclear pore. We characterized the interactions involving importin-alpha during nuclear import using a combination of biophysical techniques (biosensor, crystallography, sedimentation equilibrium, electrophoresis, and circular dichroism). Importin-alpha is shown to exist in a monomeric autoinhibited state (association with NLSs undetectable by biosensor). Association with importin-beta (stoichiometry, 1:1; K(D) = 1.1 x 10(-8) m) increases the affinity for NLSs; the importin-alpha/beta complex binds representative monopartite NLS (simian virus 40 large T-antigen) and bipartite NLS (nucleoplasmin) with affinities (K(D) = 3.5 x 10(-8) m and 4.8 x 10(-8) m, respectively) comparable with those of a truncated importin-alpha lacking the autoinhibitory domain (T-antigen NLS, K(D) = 1.7 x 10(-8) m; nucleoplasmin NLS, K(D) = 1.4 x 10(-8) m). The autoinhibitory domain (as a separate peptide) binds the truncated importin-alpha, and the crystal structure of the complex resembles the structure of full-length importin-alpha. Our results support the model of regulation of nuclear import mediated by the intrasteric autoregulatory sequence of importin-alpha and provide a quantitative description of the binding and regulatory steps during nuclear import.


Crystal structure of precorrin-8x methyl mutase.
The crystal structure of precorrin-8x methyl mutase (CobH), an enzyme of the aerobic pathway to vitamin B12, provides evidence that the mechanism for methyl migration can plausibly be regarded as an allowed [1,5]-sigmatropic shift of a methyl group from C-11 to C-12 at the C ring of precorrin-8x to afford hydrogenobyrinic acid. The dimeric structure of CobH creates a set of shared active sites that readily discriminate between different tautomers of precorrin-8x and select a discrete tautomer for sigmatropic rearrangement. The active site contains a strictly conserved histidine residue close to the site of methyl migration in ring C of the substrate. Analysis of the structure with bound product suggests that the [1,5]-sigmatropic shift proceeds by protonation of the ring C nitrogen, leading to subsequent methyl migration.


3D phase contrast MRI in models of human airways: Validation of computational fluid dynamics simulations of steady inspiratory flow.
Knowledge of airflow patterns in the large airways is of interest in obstructive airways disease and in the development of inhaled therapies. Computational fluid dynamics (CFD) simulations are used to study airflow in realistic airway models but usually need experimental validation. To develop MRI-based methods to study airway flow in realistic 3D-printed models. Case control. Two 3D-printed lung models. 1.5-3T, flow MRI. Two human airway models, respectively including and excluding the oral cavity and upper airways derived from MR and CT imaging, were 3D-printed. 3D flow MRI was performed at different flow conditions corresponding to slow and steady airflow inhalation rates. Water was used as the working fluid to mimic airflow. Dynamic acquisition of 1D velocity profiles was also performed at different locations in the trachea to observe variability during nonsteady conditions. Linear regression analysis to compare both flow velocity fields and local flow rates from CFD simulations and experimental measurement with flow MRI. A good agreement was obtained between 3D velocity maps measured with flow MRI and predicted by CFD simulations, with linear regression R-squared values ranging from 0.39 to 0.94 when performing a pixel-by-pixel comparison of each velocity component. The flow distribution inside the lung models was also similar, with average slope and R-squared values of 0.96 and 0.99, respectively, when comparing local flow rates assessed at different branching locations. In the model including the upper airways, a turbulent laryngeal jet flow was observed with both methods and affected remarkably the velocity profiles in the trachea. We propose flow MRI using water as a surrogate fluid to air, as a validation tool for CFD simulations of airflow in geometrically realistic models of the human airways. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1400-1409.


Ursolic acid inhibits growth and induces apoptosis in gemcitabine-resistant human pancreatic cancer via the JNK and PI3K/Akt/NF-κB pathways.
Pancreatic cancer is one of the most deadly carcinomas worldwide. Although gemcitabine as the standard chemotherapy agent has been proven to be effective, the response rate remains at 5.4% and the 5-year survival rate is extremely poor. Ursolic acid (UA) is a small molecule compound extracted from Chinese herbs as well as edible vegetables and a well-known anti-inflammatory and immunosuppressive agent. Here, we show that UA has potential to be developed into an anti-neoplastic agent against gemcitabine-resistant pancreatic cancer and to explore its molecular mechanism of action. In vitro, we used three different malignancy grades of pancreatic resistant cancer cell lines including MIA PaCa-2, PANC-1 and Capan-1 to assess the antitumor effect of UA. We found that UA inhibited growth and induced apoptosis in a dose-dependent manner in all of the three pancreatic cancer cell lines. Both extrinsic and intrinsic pathways were found to be involved in apoptotic cascade. The potential signaling pathways are concerned with inactivation of the PI3K/Akt/NF-κB pathway and activation of the c-Jun-terminal kinase (JNK) pathway. The JNK inhibitor SP600125 partly abrogated the caspase-9 activation caused by UA. The Akt inhibitor LY294002 did not mimic the effect of UA on caspase-8 and -9, but inhibited the viability of MIA PaCa-2 cells to some extent. Equally, UA also overcame the chemoresistance in the chemoresistant endometrial and ovarian carcinoma cell lines (HEC-1A and OVCAR-3). Moreover, UA caused cytotoxicity to a nude mouse xenograft model in vivo. Therefore, our present data suggest that UA can act as a novel and potent therapeutic agent in gemcitabine-resistant pancreatic cancer and even as a promising candidate in other chemoresistant cancers.


Synergistic doping effects of a ZnO:N/BiVO4:Mo bunched nanorod array photoanode for enhancing charge transfer and carrier density in photoelectrochemical systems.
One-dimensional heterojunction nanorods are highly attractive as photoanodes for developing efficient photoelectrochemical (PEC) systems for the effective photogeneration of charge carriers and transport. ZnO/BiVO4 nanorod arrays (NRAs) are excellent candidates if their charge transferring and recombination issues can be improved. In the current work, we have studied the synergistic doping effects of N-doped ZnO/Mo-doped BiVO4 NRAs for enhancing the photoanode activity in PEC devices. The N-doping of ZnO NRs enhances the charge carrier density ∼3-fold over undoped ZnO NRs through increased oxygen vacancies induced by N dopants. The Mo dopants in BiVO4 improve the mobility of photogenerated charge carriers and contribute to reducing charge recombination. The synergistic doping effects of both ZnO and BiVO4 could increase the charge transfer rate constant (kct) of the ZnO:N/BiVO4:Mo heterojunction by ∼40% and decrease the charge transfer resistance ∼1.9-fold compared to those of undoped ZnO/BiVO4, which were confirmed by time resolved photoluminescence (PL) and electrochemical impedance (EIS) analyses. Our optimally fabricated ZnO:N/BiVO4:Mo NRA photoanode could achieve an excellent photocurrent of 3.62 mA cm-2 without the application of any co-catalysts. This work presents a useful strategy for designing efficient heterojunction photoanodes in PEC systems.


Experimental model for treatment of extended spectrum betalactamase producing-Klebsiella pneumoniae.
Animal models are useful to evaluate the efficacy of antimicrobials in experimental sepsis. To elucidate the steps of producing an experimental model for the treatment of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae sepsis Several ESBL inoculums ranging from 1.5x109 colony-forming units per milliliter (CFU/mL) to 2.0x1010 CFU/mL were administered by peritoneal injection in adults Wistar rats. Outcomes and microbiological data of quantitative peritoneal and blood cultures were observed in untreated animals. Animals which received 2.0x1010 CFU/mL inoculums were treated with single meropenem dose (30mg/kg) after one hour and those which received 1.0x1010 CFU/mL inoculums were treated immediately with three doses of meropenem 50 mg/kg. Outcomes were observed for 24 hours after inoculation. Solutions with 1.5 x109 and 6.0x109 CFU/mL were not lethal within 24 hours. Inoculums of 1.0x1010 CFU/mL were lethal in 80% and solutions with 2.0x1010 CFU/mL were lethal in 100% of animals. ESBL lethal sepsis (1.0x1010CFU/mL) was treated immediately with 50 mg/kg of meropenem every eight hours for 24 hours and presented 40% mortality compared with 80% mortality of the control group (p=0.033). Quantitative cultures of peritoneal fluid presented 104 CFU/mL or less for treated animals compared to more than 105 for untreated animals (p=0.001). Inoculums of 1.0x1010CFU/mL achieved the best results to study a model of lethal sepsis and this model of treatment of carbapenem-susceptible Enterobacteriaceae can serve as control to further evaluation of treatment of carbapenemase-producing Enterobacteriaceae models.


Holo-retinol-binding protein and its receptor STRA6 drive oncogenic transformation.
Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, RBP is recognized by STRA6, a plasma membrane protein that serves a dual role: it transports retinol from extracellular RBP into cells and it transduces a signaling cascade mediated by the Janus kinase JAK2 and the transcription factors STAT3 and STAT5. We show here that expression of RBP and STRA6 is markedly upregulated in human breast and colon tumors, that holo-RBP/STRA6 signaling promotes oncogenic properties, and that STRA6 expression is critical for tumor formation by colon carcinoma cells in vivo. The holo-RBP/STRA6 pathway also efficiently induces fibroblasts to undergo oncogenic transformation, rendering them highly tumorigenic. These data establish that holo-RBP and its receptor STRA6 are potent oncogenes and suggest that the pathway is a novel target for therapy of some human cancers.


Headache Incidence and Characteristics in COVID-19 Patients: A Hospital-Based Study.
Headache is one of the commonly reported symptoms of coronavirus disease-2019 (COVID-19) illness. A number of studies have been done so far focusing on headache associated with COVID-19 with variable incidence and characteristics. This study is a prospective study conducted on 120 patients with confirmed COVID-19 illness. Critically ill and ventilated patients were excluded. Demographic data, COVID illness symptom profile, headache characteristics were documented. Patients were followed up at 2 weeks and 4 weeks. For the statistical analysis, Statistical Package for the Social Sciences (SPSS), version 24.0 was used. 120 COVID-19 positive cases were included in the study with a mean age of 54.59 ± 14.89 years (range 21-84 years) with male-to-female ratio of 3:2. 78.33% (94) of patients had various comorbidities. 43.33% (52) cases were diabetic. The presenting symptoms were fever (65%), cough (53.33%), shortness of breath (35%) and myalgia (31.66%). 26 (21.66%) patients reported headache during the COVID illness. 18 (15%) cases had headache attributed as secondary to COVID-19 illness. Out of them, 12 cases were new onset with no past history of headache and 6 cases had a significant change in previous headache episodes. COVID-19 illness precipitated headache episodes similar to past headache type in 8 cases. Headache was the presenting symptom in 8 (6.66%) patients with COVID-19 being detected in the regular hospital screening protocol. Headache was a common symptom in COVID-19 patients. New onset headaches or change in past headache type in patients in the setting of ongoing pandemic should be screened for COVID-19.


[An elderly man with known heart failure admitted with cardiogenic shock].
A 75-year-old man with post-MI heart failure and an ejection fraction of 15 % was treated with an ACE-inhibitor, spironolactone and a beta-blocker. He had reduced his intake of food and water due to an intercurrent illness the days before admission. He was admitted to our coronary care unit due to bradycardia and hypotension. On arrival his blood pressure was 60/40 mm Hg, and he was in a cardiogenic shock. The electrocardiogram showed broad QRS-complexes and large T waves. Serum-potassium was 9.1 mmol/L and he had acute renal failure with oliguria, probably caused by reduced cardiac output due to hypovolemia combined with taking an ACE inhibitor and spironolactone. Haemodialysis was started and during dialysis QRS complexes became more narrow and heart rate and blood pressure normalized. The patient was discharged 10 days later with normal potassium and creatinine levels. Patients treated with ACE-inhibitors and spironolactone should be monitored closely. During intercurrent illness dehydration may occur and this can lead to renal failure and hyperkalemia which can be life-threatening. The condition should be recognized and addressed promptly, and if indicated haemodialysis should be performed.


Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19.
Extensive migration has led to the necessity of knowledge regarding the treatment of migrants with different ethnical backgrounds. This is especially relevant for pharmacological treatment, because of the significant variation between migrant groups in their capacity to metabolize drugs. For psychiatric medications, CYP2D6 and CYP2C19 enzymes are clinically relevant. The aim of this meta-analysis was to analyze studies reporting clinically useful information regarding CYP2D6 and CYP2C19 genotype frequencies, across populations and ethnic groups worldwide. To that end, we conducted a comprehensive meta-analysis using Embase, PubMed, Web of Science, and PsycINFO (>336,000 subjects, 318 reports). A non-normal metabolizer (non-NM) probability estimate was introduced as the equivalent of the sum-prevalence of predicted poor, intermediate, and ultrarapid metabolizer CYP2D6 and CYP2C19 phenotypes. The probability of having a CYP2D6 non-NM predicted phenotype was highest in Algeria (61%) and lowest in Gambia (2.7%) while the probability for CYP2C19 was highest in India (80%) and lowest in countries in the Americas, particularly Mexico (32%). The mean total probability estimates of having a non-NM predicted phenotype worldwide were 36.4% and 61.9% for CYP2D6 and CYP2C19, respectively. We provide detailed tables and world maps summarizing clinically relevant data regarding the prevalence of CYP2D6 and CYP2C19 predicted phenotypes and demonstrating large inter-ethnic differences. Based on the documented probability estimates, pre-emptive pharmacogenetic testing is encouraged for every patient who will undergo therapy with a drug(s) that is metabolized by CYP2D6 and/or CYP2C19 pathways and should be considered in case of treatment resistance or serious side effects.


When pretesting fails to enhance learning concepts from reading texts.
Prior research suggests that people can learn more from reading a text when they attempt to answer pretest questions first. Specifically, pretests on factual information explicitly stated in a text increases the likelihood that participants can answer identical questions after reading than if they had not answered pretest questions. Yet, a central goal of education is to develop deep conceptual understanding. The present experiments investigated whether conceptual pretests facilitate learning concepts from reading texts. In Experiment 1, participants were given factual or conceptual pretest questions; a control group was not given a pretest. Participants then read a passage and took a final test consisting of both factual and conceptual questions. Some of the final test questions were repeated from the pretest and some were new. Although factual pretesting improved learning for identical factual questions, conceptual pretesting did not enhance conceptual learning. Conceptual pretest errors were significantly more likely to be repeated on the final test than factual pretest errors. Providing correct answers (Experiment 2) or correct/incorrect feedback (Experiment 3) following pretest questions enhanced performance on repeated conceptual test items, although these benefits likely reflect memorization and not conceptual understanding. Thus, pretesting appears to provide little benefit for learning conceptual information. (PsycINFO Database Record


Effectiveness of manual therapy or pulsed shortwave diathermy in addition to advice and exercise for neck disorders: a pragmatic randomized controlled trial in physical therapy clinics.
To determine whether manual therapy or pulsed shortwave diathermy, in addition to advice and exercise, provide better clinical outcome at 6 months than advice and exercise alone in primary care patients with nonspecific neck disorders. This was a multicenter, 3-arm randomized controlled trial in 15 physical therapy departments. Of the 735 screened patients, 350 were recruited to the study (mean age 51 years) from July 2000 to June 2002. Participants were randomized to advice and exercise plus manual therapy, advice and exercise plus pulsed shortwave, or advice and exercise alone. Assessments were undertaken at baseline, 6 weeks, and 6 months. The primary outcome was the Northwick Park Neck Pain Questionnaire. Analysis was by intention to treat. Of the participants, 115 were allocated to advice and exercise, 114 to advice and exercise plus manual therapy, and 121 to advice and exercise plus pulsed shortwave; 98% received the allocated treatment. There was 93% followup at 6 months. The mean +/- SD fall in Northwick Park score at 6 months was 11.5 +/- 15.7 for advice and exercise alone, 10.2 +/- 14.1 for advice and exercise plus manual therapy, and 10.3 +/- 15.0 for advice and exercise plus pulsed shortwave. There were no statistically significant differences in mean changes between groups. The addition of pulsed shortwave or manual therapy to advice and exercise did not provide any additional benefits in the physical therapy treatment of neck disorders.


Psychosocial outcomes of antiepileptic drug discontinuation. The Medical Research Council Antiepileptic Drug Withdrawal Study Group.
The MRC Antiepileptic Drug Withdrawal Study compared seizure control and the risk of relapse resulting from policies of slow discontinuation and routine maintenance of antiepileptic drug (AED) treatment in patients seizure-free for > or = 2 years. Because the decision to discontinue AEDs can have important psychosocial as well as medical consequences, we also sought to examine the psychosocial outcomes of the alternative policies Questionnaires were sent to eligible adults 2 years after their randomization. The response rate was 85%. There was little evidence of substantial effects of treatment policy on psychosocial outcomes, but seizure recurrence since randomization was associated with increased distress on several measures. However, receiving AEDs to control seizures was also associated with increased distress. Among patients for whom the risk of relapse after discontinuation appears low, the psychosocial benefits of discontinuation may be considerable.


Technetium Tc 99m dimercaptosuccinic acid renal scintigraphy in children with acute pyelonephritis: correlation with other imaging tests.
INTRODUCTION. Urinary tract infection is the most common serious bacterial infection in children. The aim of this study was to compare the value of different laboratory and imaging techniques in detecting renal involvement in acute pyelonephritis. MATERIALS AND METHODS. In a cross-sectional study of patients 1 month to 14 years of age diagnosed with urinary tract infection were examined with systemic inflammatory markers, renal ultrasonography, voiding cystourethrography (VCUG), and technetium Tc 99m dimercaptosuccinic acid ((99m)Tc-DMSA) renal scintigraphy. A total of 1467 pediatric patients were eligible for treatment of pyelonephritis. Evaluations included a complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinalysis, urine culture, and measurement of serum blood urea nitrogen and creatinine levels. RESULTS. The results of (99m)Tc-DMSA scans were normal in 20.2%, mild decreased cortical uptake in 45.0%, moderate decreased cortical uptake in 12.3%, severe decreased cortical uptake in 12.0%, and decreased cortical function plus irregularity or scar formation in 10.5%. Voiding cystourethrography showed vesicoureteral reflux in 25.9%. The sensitivity of (99m)Tc-DMSA for prediction of vesicoureteral reflux was 84.1% with a negative predictive value of 80.6%. Significant differences were found in the level of blood leukocyte count (P = .03), urine leukocyte count (P = .003), ESR (P = .008), and age (P = .04) between patients with normal and abnormal (99m)Tc-DMSA scan results. CONCLUSIONS. We found that in patient with clinical signs of pyelonephritis, (99m)Tc-DMSA renal scintigraphy can detect pyelonephritis more accurately than the other inflammatory and imaging tests.


The relationship of analogical distance to analogical function and preinventive structure: the case of engineering design.
Analogy was studied in real-world engineering design, using the in vivo method. Analogizing was found to occur frequently, entailing a roughly equal amount of within- and between-domain analogies. In partial support for theories of unconscious plagiarism (Brown & Murphy, 1989; Marsh, Landau, & Hicks, 1996) and Ward's (1994) path-of-least-resistance model, it was found that the reference to exemplars (in the form of prototypes) significantly reduced the number of between-domain analogies between source and target, as compared with using sketches or no external representational systems. Analogy served three functions in relation to novel design concepts: identifying problems, solving problems, and explaining concepts. Problem identifying analogies were mainly within domain, explanatory analogies were mainly between domain, and problem-solving analogies were a mixture of within- and between-domain analogies.


SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy.
Blood clots are a central feature of coronavirus disease-2019 (COVID-19) and can culminate in pulmonary embolism, stroke, and sudden death. However, it is not known how abnormal blood clots form in COVID-19 or why they occur even in asymptomatic and convalescent patients. Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19. SARS-CoV-2 spike induces structurally abnormal blood clots and thromboinflammation neutralized by a fibrin-targeting antibody.


Smooth pursuit eye movements: is perceived motion necessary?
It has recently been shown that perceived motion, in the absence of any appropriate retinal motion, is a sufficient stimulus to generate smooth pursuit eye motions. This raises the question of whether perceived motion is necessary for pursuit. In three experiments we obtained a negative answer to this question: retinal motion always governed pursuit.


Transsphenoidal hypophysectomy: postsurgical CT findings.
Transsphenoidal surgery produces changes in the paranasal sinuses and sella that should be familiar to radiologists in view of the frequency of this type of surgery. Some of these changes, such as soft-tissue-density debris in the sinuses, are transient. Fat and other packing material identifiable in the sinuses and sella after surgery is permanent. The procedure is associated with a variety of complications that are readily detectable by computed tomography (CT). These include bleeding, compression of parasellar structures by packing material, cerebrospinal fluid leaks, and pneumocephalus. After a transsphenoidal procedure, with or without follow-up radiation therapy, residual enhancing intrasellar and parasellar lesions may still be identified.


Caffeine Supplementation and Physical Performance, Muscle Damage and Perception of Fatigue in Soccer Players: A Systematic Review.
Soccer is a complex team sport and success in this discipline depends on different factors such as physical fitness, player technique and team tactics, among others. In the last few years, several studies have described the impact of caffeine intake on soccer physical performance, but the results of these investigations have not been properly reviewed and summarized. The main objective of this review was to evaluate critically the effectiveness of a moderate dose of caffeine on soccer physical performance. A structured search was carried out following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines in the Medline/PubMed and Web of Science databases from January 2007 to November 2018. The search included studies with a cross-over and randomized experimental design in which the intake of caffeine (either from caffeinated drinks or pills) was compared to an identical placebo situation. There were no filters applied to the soccer players' level, gender or age. This review included 17 articles that investigated the effects of caffeine on soccer-specific abilities (n = 12) or on muscle damage (n = 5). The review concluded that 5 investigations (100% of the number of investigations on this topic) had found ergogenic effects of caffeine on jump performance, 4 (100%) on repeated sprint ability and 2 (100%) on running distance during a simulated soccer game. However, only 1 investigation (25%) found as an effect of caffeine to increase serum markers of muscle damage, while no investigation reported an effect of caffeine to reduce perceived fatigue after soccer practice. In conclusion, a single and moderate dose of caffeine, ingested 5⁻60 min before a soccer practice, might produce valuable improvements in certain abilities related to enhanced soccer physical performance. However, caffeine does not seem to cause increased markers of muscle damage or changes in perceived exertion during soccer practice.


A visual-attention model using Earth Mover's Distance-based saliency measurement and nonlinear feature combination.
This paper introduces a new computational visual-attention model for static and dynamic saliency maps. First, we use the Earth Mover's Distance (EMD) to measure the center-surround difference in the receptive field, instead of using the Difference-of-Gaussian filter that is widely used in many previous visual-attention models. Second, we propose to take two steps of biologically inspired nonlinear operations for combining different features: combining subsets of basic features into a set of super features using the Lm-norm and then combining the super features using the Winner-Take-All mechanism. Third, we extend the proposed model to construct dynamic saliency maps from videos by using EMD for computing the center-surround difference in the spatiotemporal receptive field. We evaluate the performance of the proposed model on both static image data and video data. Comparison results show that the proposed model outperforms several existing models under a unified evaluation setting.


Plankton microorganisms coinciding with two consecutive mass fish kills in a newly reconstructed lake.
Lake Karla, Greece, was dried up in 1962 and its refilling started in 2009. We examined the Cyanobacteria and unicellular eukaryotes found during two fish kill incidents, in March and April 2010, in order to detect possible causative agents. Both microscopic and molecular (16S/18S rRNA gene diversity) identification were applied. Potentially toxic Cyanobacteria included representatives of the Planktothrix and Anabaena groups. Known toxic eukaryotes or parasites related to fish kill events were Prymnesium parvum and Pfiesteria cf. piscicida, the latter being reported in an inland lake for the second time. Other potentially harmful microorganisms, for fish and other aquatic life, included representatives of Fungi, Mesomycetozoa, Alveolata, and Heterokontophyta (stramenopiles). In addition, Euglenophyta, Chlorophyta, and diatoms were represented by species indicative of hypertrophic conditions. The pioneers of L. Karla's plankton during the first months of its water refilling process included species that could cause the two observed fish kill events.


Chiari III malformation: a comprehensive review of this enigmatic anomaly.
Chiari III is one of the rarest of the Chiari malformations and is characterized by a high cervical or low occipital encephalocele and osseous defect with or without spinal cord involvement and may include many of the anatomical characteristics seen in the Chiari II malformation. Herein, we provide a comprehensive review of this rare anomaly as well as a translation of Chiari's original description. We review all reported cases of Chiari III malformation found in the extant literature. Out of 57 reported cases of Chiari III malformation, encephaloceles were in a high cervical/low occipital position in 23, 8 were in a high cervical position, 17 were in low occipital position, and the position in 9 cases was not reported. The pathogenesis of Chiari III malformation remains unclear. The majority of patients have concomitant hydrocephalus. Brain parts occurring in the sac from the most to least common include the following: cerebellum, occipital lobe, and parietal lobe. The severity of symptoms is correlated with the amount of brain structures within the encephalocele. Neurologic functional outcomes have been varied and depend on the neurological status of the patient before surgery.


Discovery of Intake Biomarkers of Lentils, Chickpeas, and White Beans by Untargeted LC-MS Metabolomics in Serum and Urine.
To identify reliable biomarkers of food intake (BFIs) of pulses. A randomized crossover postprandial intervention study is conducted on 11 volunteers who consumed lentils, chickpeas, and white beans. Urine and serum samples are collected at distinct postprandial time points up to 48 h, and analyzed by LC-HR-MS untargeted metabolomics. Hypaphorine, trigonelline, several small peptides, and polyphenol-derived metabolites prove to be the most discriminating urinary metabolites. Two arginine-related compounds, dopamine sulfate and epicatechin metabolites, with their microbial derivatives, are identified only after intake of lentils, whereas protocatechuic acid is identified only after consumption of chickpeas. Urinary hydroxyjasmonic and hydroxydihydrojasmonic acids, as well as serum pipecolic acid and methylcysteine, are found after white bean consumption. Most of the metabolites identified in the postprandial study are replicated as discriminants in 24 h urine samples, demonstrating that in this case the use of a single, noninvasive sample is suitable for revealing the consumption of pulses. The results of the present untargeted metabolomics work reveals a broad list of metabolites that are candidates for use as biomarkers of pulse intake. Further studies are needed to validate these BFIs and to find the best combinations of them to boost their specificity.


Ineffective and non-nodulating mutant strains of Rhizobium japonicum.
Mutant strains of Rhizobium japonicum that were unable to allow the Corsoy cultivar of soybean to reduce acetylene or fix N2 were isolated. These strains grow as well as the wild type in a variety of media. Mutant strains SM1 and SM2 did not form nodules on the host plant; however, they reduced acetylene in the nonsymbiotic assay. Strains SM3 and SM4 produced nodules that did not have the characteristic pink pigment caused by leghemoglobin. The nodules formed by these strains also were small. One mutant strain, SM5, produced large pink nodules. The lesion in this strain seems to be in the gene that specifies nitrogenase component II.