Disposition of the cholesterol absorption inhibitor ezetimibe in mdr1a/b (-/-) mice.
The lipid lowering agent ezetimibe (EZ) and its intestinally formed glucuronide (GLUC) were shown to be substrates of the efflux transporters P-glycoprotein (P-gp) and the multidrug resistance associated protein 2 (MRP2) which markedly influences the disposition and efficacy of EZ in man. This study aims to elucidate the unique meaning of P-gp in the pharmacokinetics of EZ in mice. In brief, serum concentrations, organ distribution and elimination of EZ were determined in 10 male wild-type and mdr1a/b (-/-) mice after oral treatment with EZ (10 mg/kg, 10 days). EZ and GLUC were quantified in serum, urine, feces and various tissues using a validated LC-MS/MS method. Compared to wild-type mice, mdr1a/b knockout was associated with significantly increased serum concentrations of GLUC (5.58 +/- 2.07 versus 2.09 +/- 0.83 ng/ml, p < 0.001) but not of EZ (0.92 +/- 0.73 versus 0.55 +/- 0.40 ng/ml, n.s.). Consequently, urinary excretion of GLUC was about three-fold increased (9.96 +/- 0.27 versus 3.10 +/- 1.37 microg/day, p = 0.049) whereas renal clearance and the amount excreted via feces remained unchanged. Both EZ and GLUC were not over-proportionally distributed into investigated organs. P-glycoprotein primary influences the oral absorption of ezetimibe in mice. Distribution, renal and fecal excretion of the drug seems not to be markedly affected by P-glycoprotein.


Increased platelet size and release reaction in essential hypertension.
Basal platelet function was measured in 35 40-year-old men with untreated mild essential hypertension and compared with 44 age-matched normotensive men. The groups differed significantly with respect to platelet size in venous blood (hypertensive, 7.46 +/- 0.10 X 10(-15) l versus normotensive, 7.11 +/- 0.09 X 10(-15) l; P = 0.01) and arterial concentration of the platelet-specific protein beta-thromboglobulin (hypertensive, 1.11 +/- 0.23 nmol/l versus normotensive, 0.59 +/- 0.04 nmol/l; P = 0.02). The normotensive subjects had significantly higher beta-thromboglobulin (BTG) in venous than in arterial blood (P less than 0.01). The hypertensive men showed no such difference. In contrast to the normotensive subjects, the hypertensive group had reduced arterial compared with venous platelet count (P less than 0.01). This may reflect an increased liability in the hypertensive subjects to lose platelets through adherence to the cannula during arterial blood sampling. The above findings point to increased platelet activity in essential hypertension, particularly in arterial blood.


Factors associated with exacerbation of newly diagnosed mild ulcerative colitis based on a nationwide registry in Japan.
The exacerbation of disease in patients with ulcerative colitis (UC) can greatly affect quality of life and can impose economic burdens. In Japan, a large nationwide registry for the medical reimbursement of UC patients has existed since 1975. We aimed to examine factors associated with UC exacerbation among patients newly diagnosed with mild UC using electronic data from the registry. We retrospectively reviewed the clinical data of patients (n = 8120) newly diagnosed with mild UC between 2003 and 2011, and examined the association of patient background, medications, clinical symptoms and laboratory data, and pathological findings with exacerbation of UC, using the Cox proportional hazards model. The incidence of UC exacerbation was 94.6 per 1000 person-years (mean follow-up of 2.1 years). We found that male sex, age <17 years, an extensive lesion (left-sided colitis or pancolitis), overweight or obesity, hematochezia (mild or moderate-to-severe), mushy stools, frequency of bowel movements, and crypt architectural distortion were positively associated with UC exacerbation. On the other hand, age >40 years, high hemoglobin concentration, and high serum albumin levels were inversely associated with UC exacerbation among patients with mild UC in Japan. Using data from the Japanese nationwide registry, we identified several factors, including body mass index and pathological findings, associated with disease exacerbation among patients with newly diagnosed mild UC. Our findings may lead to earlier recognition of exacerbation in patients with mild UC, thus enabling optimal care.


m-Carboranylphosphinate as Versatile Building Blocks To Design all Inorganic Coordination Polymers.
The first examples of coordination polymers of manganese(II) and a nickel(II) complex with a purely inorganic carboranylphosphinate ligand are reported, together with its exhaustive characterization. X-ray analysis revealed 1D polymeric chains with carboranylphosphinate ligands bridging two manganese(II) centers. The reactivity of polymer 1 with water and Lewis bases has also been studied.


Comparative study on immediate versus delayed meniscus allograft transplantation: 4- to 6-year follow-up.
Meniscus allograft transplantation (MAT) is generally used for patients who sustain symptoms after meniscectomy, which could be called delayed MAT. Meniscus allograft transplantation for patients immediately after meniscectomy has not been reported. Compared with the conventional delayed MAT, immediate MAT might provide better clinical results and reduce joint degeneration. Cohort study; Level of evidence, 3. The study was performed with 18 transplanted menisci (6 medial, 12 lateral) from 16 patients. Eight menisci were transplanted immediately after meniscectomy (IM group); 10 menisci, from patients who complained of knee symptoms at a mean time of 35 months (range, 9-92 months) after total meniscectomy, underwent delayed transplantation (DE group). Fourteen patients undergoing meniscectomy during the same period were included as controls (ME group). Degenerative changes in knee joints were evaluated by plain radiographs and magnetic resonance imaging (MRI). Allograft extrusion and relative percentage of extrusion were measured on MRI. Other outcome assessments included preoperative and postoperative International Knee Documentation Committee (IKDC), Tegner, and Lysholm scores; visual analog scale (VAS) for pain; and range of motion and isokinetic muscle strength evaluation. The mean length of follow-up was 50.8 months (range, 44-62 months) for the IM group, 72.0 months (range, 44-94 months) for the DE group, and 54.3 months (range, 45-62 months) for the ME group. A statistically significant difference in favor of the IM and ME groups was found on the VAS (0.4 [IM group] vs 1.1 [ME group] vs 2.5 [DE group]) and muscle strength (P < .05). The mean IKDC score in the IM group was significantly higher than that in the DE group (93 [range, 85-99] vs 74 [range, 38-95], respectively; P < .05). The IM group showed significantly less preoperative to postoperative cartilage degeneration changes on radiographs and MRI when compared with the DE and ME groups (Kellgren-Lawrence score changes: 0.25 [IM group] vs 1.0 [DE group] vs 1.7 [ME group]; Yulish score changes: 0.25 [IM group] vs 1.0 [DE group] vs 1.1 [ME group]; P < .05). Extrusion of the allograft was observed in the body of the menisci in all patients. No significant difference was found in terms of the Lysholm score, Tegner score, joint narrowing, or meniscus extrusion (P > .05). Compared with delayed MAT, immediate MAT led to more satisfactory subjective results, less joint degeneration, and less muscle strength deficits. The short-term results of delayed meniscus transplantation were close to those of meniscectomy.


Clinical and bacteriological outcomes in hospitalised patients with community-acquired pneumonia treated with azithromycin plus ceftriaxone, or ceftriaxone plus clarithromycin or erythromycin: a prospective, randomised, multicentre study.
This study compared patients with moderate-to-severe community-acquired pneumonia (CAP) requiring hospitalisation, who received initial therapy with either intravenous ceftriaxone plus intravenous azithromycin, followed by step-down to oral azithromycin (n = 135), with patients who received intravenous ceftriaxone combined with either intravenous clarithromycin or erythromycin, followed by step-down to either oral clarithromycin or erythromycin (n = 143). Clinical and bacteriological outcomes were evaluated at the end of therapy (EOT; day 12-16) or at the end of study (EOS; day 28-35). At baseline, mean APACHE II scores were 13.3 and 12.6, respectively, with >50% of patients classified as Fine Pneumonia Severity Index (PSI) category IV or V. Clinical success rates (cure or improvement) in the modified intent-to-treat (MITT) population at EOT were 84.3% in the ceftriaxone/azithromycin group and 82.7% in the ceftriaxone/clarithromycin or erythromycin group. At EOS, MITT success rates (cure only) were 81.7% and 75.0%, respectively. Equivalent success rates in the clinically evaluable population were 83% and 87%, respectively, at EOT, and 79% and 78%, respectively, at EOS. MITT bacteriological eradication rates were 73.2% and 67.4%, respectively, at EOT, and 68.3% vs. 60.9%, respectively, at EOS. Mean length of hospital stay (LOS) was 10.7 and 12.6 days, and the mean duration of therapy was 9.5 and 10.5 days, respectively. The incidence of infusion-related adverse events was 16.3% and 25.2% (p 0.04), respectively. An intravenous-to-oral regimen of ceftriaxone/azithromycin was at least equivalent in efficacy and safety to the comparator regimen and appeared to be a suitable treatment option for hospitalised patients with CAP.


Multivalency: influence of the residence time and the retraction rate on rupture forces measured by AFM.
The Bell-Evans theory relative to rupture forces between non-covalently interacting molecules predicts that the rupture force increases linearly with the logarithm of the force loading rate. Here we investigate by force spectroscopy performed with an atomic force microscope (AFM) the rupture forces between surfaces covered by β-cyclodextrin (β-CD) molecules and AFM tips coated with adamantane (AD) groups. The β-CD molecules are either deposited through a self-assembled monolayer (SAM) or grafted on poly(allylamine hydrochloride) chains (PAH-CD) that are adsorbed on the substrate. The AD groups are fixed covalently on the AFM tip through either a one-AD or a four-AD platform linked to the tip though a PEO chain. It is found that while the rupture forces between AFM tips covered with tetravalent AD molecules and SAM-CD surfaces do not exceed twice those found with tips covered by monovalent AD molecules, the rupture forces increase by a factor of 20 on PAH-CD substrates for a tetravalent AD covered tip compared to a monovalent one. Thus, there seems to exist a synergistic effect between the molecule multivalence and the polymeric nature of the CD-covered substrate. As found in the literature, we observe an increase of the intensity of the rupture forces between the AD-covered AFM tip and the β-CD covered substrate with the contact time over timescales up to several seconds. Finally, we find that when the host-guest system involves the multivalency of the AD guest and/or the polymeric nature of the host the mean rupture force decreases with the loading rate in contrast to what is predicted by the Bell-Evans theory. We tentatively explain this "anti-Bell-Evans" behavior by the possibility of rebinding during the rupture process. This effect should have important implications in the understanding of forces at the cellular level.


Medical spending differences in the United States and Canada: the role of prices, procedures, and administrative expenses.
The United States far outspends Canada on health care, but the sources of additional spending are unclear. We evaluated the importance of incomes, administration, and medical interventions in this difference. Pooling various sources, we calculated medical personnel incomes, administrative expenses, and procedure volume and intensity for the United States and Canada. We found that Canada spent $1589 per capita less on physicians and hospitals in 2002. Administration accounted for the largest share of this difference (39%), followed by incomes (31%), and more intensive provision of medical services (14%). Whether this additional spending is wasteful or warranted is unknown.


Acute mania. Clinical and genetic study of responders and nonresponders to treatments.
We examined the relationships among family history of psychiatric illness, demographic and historical variables, clinical course and presentation, and treatment response for 58 patients satisfying research criteria for mania. Nearly two thirds of the group had excellent responses to somatic treatment, particularly lithium ion, while one third had poor responses to lithium carbonate, neuroleptics, or electric convulsive therapy. Responders frequently exhibited euphoric moods, grandiose delusions, and tended to have cyclothymic premorbid personalities. Nonresponders were rarely euphoric, frequently exhibited incomplete auditory hallucinations, and tended to hve formal thought disorder and depressive-withdrawn premorbid personalities. Responders tended (nonsignificant) to have greater genetic loading for affective illness and alcoholism. We could not distinguish the two groups by their age at illness onset, duration of illness, or number of illness episodes per ill patient year.


Prospective study on prevalence, intensity, type, and therapy of acute pain in a second-level urban emergency department.
Pain represents the most frequent cause for patient admission to emergency departments (EDs). Oligoanalgesia is a common problem in this field. The aims of this study were to assess prevalence and intensity of pain in patients who visited a second-level urban ED and to evaluate the efficacy of pharmacological treatment administered subsequent to variations in pain intensity. A 4-week prospective observational study was carried out on 2,838 patients who visited a second-level urban ED. Pain intensity was evaluated using the Numeric Rating Scale at the moment of triage. The efficacy of prescribed analgesic therapy was evaluated at 30 and 60 minutes, and at discharge. Data concerning pain intensity were classified as absent, slight, mild, or severe. Pain was evaluated in relation to the prescribed therapy. Pain prevalence was 70.7%. Traumatic events were the primary cause in most cases (40.44%), followed by pain linked to urologic problems (13.52%), abdominal pain (13.39%), and nontraumatic musculoskeletal pain (7.10%). Only 32.46% of patients were given pharmacological therapy. Of these, 76% reported severe pain, 19% moderate, and 5% slight, and 66% received nonsteroidal anti-inflammatory drugs or paracetamol, 4% opioids, and 30% other therapies. A difference of at least 2 points on the Numerical Rating Scale was observed in 84% of patients on reevaluation following initial analgesic therapy. Pain represents one of the primary reasons for visits to EDs. Although a notable reduction in pain intensity has been highlighted in patients who received painkillers, results show that inadequate treatment of pain in ED continues to be a problem.


Understanding Psychosocial Wellbeing in the Context of Complex and Multidimensional Problems.
This Special Issue deals with the topic of how people and social groups face problems in an increasingly complex and globalized society. The topics included in the call for papers were the interaction of psychosocial well-being and mental health with economic, gender, racial and ethnic inequalities, migration and demographic change and conflict and war, as well as the effects of stigma on people discriminated against because of their differential characteristics, whether they are of a sexual, disability or other minority. We made this proposal because we believed that, despite the introduction of the biopsychosocial model in the late 1970s as a paradigm of the integration of different disciplinary views, research in mental health and psychosocial well-being is still highly fragmented. For decades, we have tried to advance by emphasizing a part of the equation, with results that are at least modest. Therefore, in this Special Issue, we prioritized works aiming at disciplinary and methodological integration. The Special Issue was open to any subject area related to the impacts of social issues on mental health and psychosocial well-being. We were interested in empirical and theoretical enquiries at all ecological levels, from the psychosocial impact of social dynamics on individuals, to the analysis of how sociocultural and geopolitical factors influence health and collective psychosocial well-being.


GB virus C (GBV-C) infection in hepatitis C virus (HCV)/HIV-coinfected patients receiving HCV treatment: importance of the GBV-C genotype.
Persistent GB virus C (GBV-C) coinfection leads to slower human immunodeficiency virus (HIV) progression. Despite the existence of multiple GBV-C genotypes, their relevance to the progression of HIV disease is unknown. We therefore investigated (1) the prevalence and genotype of GBV-C in hepatitis C virus (HCV)/HIV-coinfected patients and (2) the impact of HCV treatment on GBV-C RNA clearance. We retrospectively studied 130 HCV/HIV-coinfected patients initiating HCV therapy. Anti-E2 enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction (PCR), and real-time PCR were used to detect and quantify GBV-C infection. GBV-C genotype was determined by sequencing the 5' untranslated region. GBV-C infection (past or current) was identified in 111 (85%) of the patients. Ongoing GBV-C replication was detected in 40 patients. Coinfection with GBV-C genotype 2 was associated with significantly higher CD4(+) cell counts. After 24 weeks of HCV therapy, GBV-C RNA clearance was observed in 50% of patients, although this was not associated with changes in HIV load or with CD4(+) cell counts. Sustained GBV-C RNA clearance was observed in 31% of patients with GBV-C RNA detected at baseline. GBV-C coinfection was extremely common. GBV-C RNA clearance with HCV therapy was associated with neither short-term loss of HIV control nor impaired immune status. The association of GBV-C genotype 2 with higher CD4(+) cell counts merits further study.


Assessing Hydration in Children: From Science to Practice.
Raising children's awareness about their hydration status could be done through a noninvasive biomarker. Urine color (UC) has been validated as a biomarker of hydration in adults and children aged 8-14 years. The aim of this survey was to design and to evaluate the level of understanding and attractiveness of a self-assessment, UC-based hydration tool for children aged 6-11 years. The first phase of the survey consisted of face-to-face interviews during which 84 children identified those graphical elements necessary to understand the hydration message from 6 illustration-based designs containing the UC chart. The graphic elements selected were the basis to create 3 new designs. During the 2nd phase, the level of understanding and attractiveness of these 3 new designs was then evaluated via an online questionnaire by a total of 1,231 children in 3 countries. The design with the highest level of understanding was totally or partially understood by 76% of the participants, independent of age and gender. The levels of understanding, however, differed in the countries. In Indonesia, the levels of understanding of the 3 designs were comparable; whereas in both France (74%) and Mexico (78%), significantly more participants totally and partially understood one of the 3 designs. The levels of attractiveness of the 3 designs were comparable, independent of country, age, and gender. On average, 80% of all participants liked the 3 designs a bit or a lot. Only 14% did not like the designs, and 5% of participants had no opinion regarding attractiveness. These results indicated that three out of four children like and understand the correct hydration message from a strictly illustration-based tool containing the eight-point UC scale.


The effect of free diabetes care on metabolic control and on health-related quality of life among youths with type 1 diabetes in Cameroon.
To assess the effect of free diabetes care on metabolic control and on health-related quality of life (HRQoL) of youths living with type 1 diabetes in Cameroon. We conducted a clinical audit of a multicenter prospective cohort, performed in three of the nine clinics of the 'Changing Diabetes in Children' (CDiC) project in Cameroon. We collected data on demography, glycemic control, diabetes acute complications, and patients' HRQoL at baseline and after 1 year of follow-up. One hundred and four patients (51 female) were included. The mean age was 16±2 years (min-max: 9-18), the mean duration of diabetes was 5±3 years, and the mean HbA1C level was 11.4%±2.7%. A significant reduction in HbA1c (11.4%±2.7% vs 8.7±2.4%), episodes of severe hypoglycemia (27/104 vs 15/104), and episodes of ketoacidosis (31/104 vs 7/104) were observed after 1 year (p<0.05). We did not observe any significant difference in the total HRQoL score (p=0.66). However, we observed a significant decrease in diabetes-associated symptoms (p<0.05). Age, level of education, duration of diabetes, glycemic control, and the presence or absence of diabetes complications did not significantly affect the total HRQoL score. One year after free diabetes care offered through the CDiC project, a significant improvement was observed in glycemic control and acute complications of diabetes, but not in the total score of HRQoL of youths living with type 1 diabetes enrolled in the project.


Mechanisms of DNA methylation regulatory function and crosstalk with histone lysine methylation.
DNA methylation is a well-studied epigenetic modification that has key roles in regulating gene expression, maintaining genome integrity, and determining cell fate. Precisely how DNA methylation patterns are established and maintained in specific cell types at key developmental stages is still being elucidated. However, research over the last two decades has contributed to our understanding of DNA methylation regulation by other epigenetic processes. Specifically, lysine methylation on key residues of histone proteins has been shown to contribute to the allosteric regulation of DNA methyltransferase (DNMT) activities. In this review, we discuss the dynamic interplay between DNA methylation and histone lysine methylation as epigenetic regulators of genome function by synthesizing key recent studies in the field. With a focus on DNMT3 enzymes, we discuss mechanisms of DNA methylation and histone lysine methylation crosstalk in the regulation of gene expression and the maintenance of genome integrity. Further, we discuss how alterations to the balance of various sites of histone lysine methylation and DNA methylation contribute to human developmental disorders and cancers. Finally, we provide perspectives on the current direction of the field and highlight areas for continued research and development.


Sedation and analgesia in gastrointestinal endoscopy: what's new?
Various types of sedation and analgesia technique have been used during gastrointestinal endoscopy procedures. The best methods for analgesia and sedation during gastrointestinal endoscopy are still debated. Providing an adequate regimen of sedation/analgesia might be considered an art, influencing several aspects of endoscopic procedures: the quality of the examination, the patient's cooperation and the patient's and physician's satisfaction with the sedation. The properties of a model sedative agent for endoscopy would include rapid onset and offset of action, analgesic and anxiolytic effects, ease of titration to desired level of sedation, rapid recovery and an excellent safety profile. Therefore there is an impulse for development of new approaches to endoscopic sedation. This article provides an update on the methods of sedation today available and future directions in endoscopic sedation.


Newer antibacterial agents and their potential role in cystic fibrosis pulmonary exacerbation management.
Pulmonary exacerbations in cystic fibrosis (CF) are frequent events and account for a substantial proportion of the burden of morbidity and mortality in this disease. Antibacterial therapies to treat pulmonary exacerbations are instituted empirically and are individualized based on both patient factors (severity of exacerbation, frequency of exacerbation, recent courses of anti-infectives) and pathogen factors (previously isolated pathogens and in vitro predicted susceptibilities). However, the epidemiology of pathogens infecting CF airways is changing, with increased incidence of methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Pseudomonas aeruginosa and other Gram-negative non-fermenters such as Stenotrophomonas maltophilia and Achromobacter xylosoxidans. Accordingly, a great need for new and novel agents for the management of acute exacerbations in CF exists. While several antibiotics have recently been approved or are close to approval for clinical use, frequently their emphasis has been for Gram-positive, and specifically MRSA-related, disease. Despite this, these agents may have a role in CF-related exacerbations. This article reviews the spectrum of activity, pharmacokinetics and clinical and theoretical evidence for the use of newer agents including tigecycline, doripenem and ceftobiprole in the management of CF pulmonary exacerbations. Appropriate use of these agents in CF will require detailed CF-specific pharmacokinetic and pharmacodynamic data.


Mammalian single-stranded DNA binding protein UP I is derived from the hnRNP core protein A1.
Antibodies induced against mammalian single-stranded DNA binding protein (ssDBP) UP I were shown to be cross-reactive with most of the basic hnRNP core proteins, the main constituents of 40S hnRNP particles. This suggested a structural relationship between both groups of proteins. Using the anti-ssDBP antibodies, a cDNA clone (pRP10) was isolated from a human liver cDNA library in plasmid expression vector pEX1. By DNA sequencing this clone was shown to encode in its 949 bp insert the last 72 carboxy terminal amino acids of the ssDBP UP I. Thereafter, an open reading frame continued for another 124 amino acids followed by a UAA (ochre) stop codon. Direct amino acid sequencing of a V8 protease peptide from hnRNP core protein A1 showed that this peptide contained at its amino terminus the last 11 amino acids of UP I followed by 19 amino acids which are encoded by the open reading frame of cDNA clone pRP10 immediately following the UP I sequence. This proves that ssDBP UP I arises by proteolysis from hnRNP core protein A1. This finding must lead to a re-evaluation of the possible physiological role of UP I and related ssDBPs. The formerly assumed function in DNA replication, although not completely ruled out, should be reconsidered in the light of a possible alternative or complementary function in hnRNA processing where UP I could either be a simple degradation product of core protein A1 (as a consequence of controlling the levels of active A1) or may continue to function as an RNA binding protein which has lost the ability to interact with the other core proteins.(ABSTRACT TRUNCATED AT 250 WORDS)


Reversing how to think about ambiguous figure reversals: spontaneous alternating by uninformed observers.
Ambiguous figures are a special class of images that can give rise to multiple interpretations. Traditionally, switching between the possible interpretations of an ambiguous figure, or reversing one's interpretation, has been attributed either to top-down or to bottom-up processes (e.g. attributed to having knowledge of the nature of the ambiguity, or to a form of neuronal fatigue). Here we present evidence that is incompatible with both forms of explanations. Observers aged 5-9 years can reverse ambiguous figures when uninformed about the ambiguity, negating purely top-down explanations. Further, those children who make these 'spontaneous' reversals are more likely to succeed on a high-order theory-of-mind task, negating purely bottom-up explanations.


Evaluation of the effects of coal fly ash amendments on the toxicity of a contaminated marine sediment.
Approaches for cleaning up contaminated sediments range from dredging to in situ treatment. In this study, we discuss the effects of amending reference and contaminated sediments with coal fly ash to reduce the bioavailability and toxicity of a field sediment contaminated with polycyclic aromatic hydrocarbons (PAHs). Six fly ashes and a coconut charcoal were evaluated in 7-d whole sediment toxicity tests with a marine amphipod (Ampelisca abdita) and mysid (Americamysis bahia). Fly ashes with high carbon content and the coconut charcoal showed proficiency at reducing toxicity. Some of the fly ashes demonstrated toxicity in the reference treatments. It is suspected that some of this toxicity is related to the presence of ammonia associated with fly ashes as a result of postoxidation treatment to reduce nitrous oxide emissions. Relatively simple methods exist to remove ammonia from fly ash before use, and fly ashes with low ammonia content are available. Fly ashes were also shown to effectively reduce overlying water concentrations of several PAHs. No evidence was seen of the release of the metals cadmium, copper, nickel, or lead from the fly ashes. A preliminary 28-d polychaete bioaccumulation study with one of the high-carbon fly ashes and a reference sediment was also performed. Although preliminary, no evidence was seen of adverse effects to worm growth or lipid content or of accumulation of PAHs or mercury from exposure to the fly ash. These data show fly ashes with high carbon content could represent viable remedial materials for reducing the bioavailability of organic contaminants in sediments.


Enhancing magnetic resonance imaging-driven Alzheimer's disease classification performance using generative adversarial learning.
Generative adversarial networks (GAN) can produce images of improved quality but their ability to augment image-based classification is not fully explored. We evaluated if a modified GAN can learn from magnetic resonance imaging (MRI) scans of multiple magnetic field strengths to enhance Alzheimer's disease (AD) classification performance. T1-weighted brain MRI scans from 151 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI), who underwent both 1.5-Tesla (1.5-T) and 3-Tesla imaging at the same time were selected to construct a GAN model. This model was trained along with a three-dimensional fully convolutional network (FCN) using the generated images (3T*) as inputs to predict AD status. Quality of the generated images was evaluated using signal to noise ratio (SNR), Blind/Referenceless Image Spatial Quality Evaluator (BRISQUE) and Natural Image Quality Evaluator (NIQE). Cases from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL, n = 107) and the National Alzheimer's Coordinating Center (NACC, n = 565) were used for model validation. The 3T*-based FCN classifier performed better than the FCN model trained using the 1.5-T scans. Specifically, the mean area under curve increased from 0.907 to 0.932, from 0.934 to 0.940, and from 0.870 to 0.907 on the ADNI test, AIBL, and NACC datasets, respectively. Additionally, we found that the mean quality of the generated (3T*) images was consistently higher than the 1.5-T images, as measured using SNR, BRISQUE, and NIQE on the validation datasets. This study demonstrates a proof of principle that GAN frameworks can be constructed to augment AD classification performance and improve image quality.


Glutathione S-transferase Yc cDNA from Syrian hamster kidney.
A cDNA encoding alpha-class glutathione S-transferase Yc (GSTYc) has been isolated from a Syrian hamster kidney library, and its nucleotide sequence (968 bp) has been determined. Analysis of the deduced amino acid sequence revealed a high level of identity between Syrian hamster GSTYc, rat GST Yc1 and Yc2 and mouse GSTYc. Northern-blot experiments demonstrated that Syrian hamster GSTYc expression is tissue-specific. A GSTYc mRNA of approx. 1 kb is expressed in liver, kidney, vas deferens and epididymis. Expression of the GSTYc transcript was not detected in testis or uterus.


Association of vaccine-related attitudes and beliefs between parents and health care providers.
Health care providers influence parental vaccination decisions. Over 90% of parents report receiving vaccine information from their child's health care provider. The majority of parents of vaccinated children and children exempt from school immunization requirements report their child's primary provider is a good source for vaccine information. The role of health care providers in influencing parents who refuse vaccines has not been fully explored. The objective of the study was to determine the association between vaccine-related attitudes and beliefs of health care providers and parents. We surveyed parents and primary care providers of vaccinated and unvaccinated school age children in four states in 2002-2003 and 2005. We measured key immunization beliefs including perceived risks and benefits of vaccination. Odds ratios for associations between parental and provider responses were calculated using logistic regression. Surveys were completed by 1367 parents (56.1% response rate) and 551 providers (84.3% response rate). Parents with high confidence in vaccine safety were more likely to have providers with similar beliefs, however viewpoints regarding disease susceptibility and severity and vaccine efficacy were not associated. Parents whose providers believed that children get more immunizations than are good for them had 4.6 higher odds of holding that same belief compared to parents whose providers did not have that belief. The beliefs of children's health care providers and parents, including those regarding vaccine safety, are similar. Provider beliefs may contribute to parental decisions to accept, delay or forgo vaccinations. Parents may selectively choose providers who have similar beliefs to their own.


Multiple paradigm shifts in multiple sclerosis.
The present article reviews the currently ongoing scientific debate of our changing views on the pathogenesis of multiple sclerosis and the therapeutic strategies currently available for multiple sclerosis. The most important observations include that (a) axonal loss accounts for permanent disability in multiple sclerosis, (b) remyelination should be possible in theory but fails for unknown reasons in the multiple sclerosis lesion, (c) inflammation can be beneficial, (d) treatment should be initiated early, and (e) immunosuppressive strategies exhibit beneficial effects in progressive forms of the disease. Our current understanding of the immunopathogenesis of multiple sclerosis has changed in the past. Whereas demyelination was originally thought to be relevant for the lasting neurological deficit, it is nowadays commonly accepted that the extent of axonal loss dictates the degree of permanent clinical disability. How axonal damage can be prevented remains elusive. The interaction between the myelinating cell and the neuron gains increasing attention, however the evolving knowledge has not yet yielded new treatment concepts. Hence for the time being, it seems prudent to make optimal use of current approved therapies. Recent trials underlined the need for early initiation of treatment with immunomodulatory drugs. The superiority of one of the interferons is still a matter of debate, and a conclusive answer cannot be given at present. Finally, with mitoxantrone we have a drug at hand which can be used in progressive forms of multiple sclerosis, especially when other disease modifying drugs are not or no longer effective.


[Comparison of pulmonary perfusion imaging with pulmonary angiography in diagnosis of pulmonary involvement in Takayasu's arteritis].
To compare the diagnostic value of (99)Tc(m)-MAA pulmonary perfusion imaging with that of pulmonary angiography for pulmonary involvement in Takayasu's arteritis. Twenty-one patients (19 women, 2 men), with diagnosed Takayasu's arteritis and underwent both (99)Tc(m)-MAA pulmonary perfusion imaging and pulmonary angiography, were retrospectively analyzed. Out of the 21 patients, pulmonary angiography detected 11 patients with pulmonary artery involvement whereas 13 patients were revealed perfusion defects by pulmonary perfusion imaging. The agreement of diagnosis by pulmonary perfusion imaging with that by pulmonary angiography existed in 19 patients (90.5%, Kappa = 0.81, P < 0.0001). There were 331 pulmonary segments consistently diagnosed by pulmonary perfusion imaging and pulmonary angiography in 378 pulmonary segments (87.5%, Kappa = 0.74, P < 0.0001). Pulmonary perfusion imaging is highly accorded with pulmonary angiography in detecting the pulmonary involvement in Takayasu's arteritis. Therefore, pulmonary perfusion imaging could be used as a non-invasive screening test for the pulmonary artery involvement in Takayasu's arteritis.


Evaluation of Orbital Lymphoproliferative and Inflammatory Disorders by Gene Expression Analysis.
Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are often challenging to differentiate. Furthermore, it is still uncertain how chronic inflammation, such as IgG4-ROD, can lead to mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we aimed to evaluate the diagnostic value of gene expression analysis to differentiate orbital autoimmune diseases and elucidate genetic overlaps. First, we established a database of NSOI, relapsing NSOI, IgG4-ROD and MALT lymphoma patients of our orbital center (2000−2019). In a consensus process, three typical patients of the above mentioned three groups (mean age 56.4 ± 17 years) at similar locations were selected. Afterwards, RNA was isolated using the RNeasy FFPE kit (Qiagen) from archived paraffin-embedded tissues. The RNA of these 12 patients were then subjected to gene expression analysis (NanoString nCounter®), including a total of 1364 target genes. The most significantly upregulated and downregulated genes were used for a machine learning algorithm to distinguish entities. This was possible with a high probability (p < 0.0001). Interestingly, gene expression patterns showed a characteristic overlap of lymphoma with IgG4-ROD and NSOI. In contrast, IgG4-ROD shared only altered expression of one gene regarding NSOI. To validate our potential biomarker genes, we isolated the RNA of a further 48 patients (24 NSOI, 11 IgG4-ROD, 13 lymphoma patients). Then, gene expression pattern analysis of the 35 identified target genes was performed using a custom-designed CodeSet to assess the prediction accuracy of the multi-parameter scoring algorithms. They showed high accuracy and good performance (AUC ROC: IgG4-ROD 0.81, MALT 0.82, NSOI 0.67). To conclude, genetic expression analysis has the potential for faster and more secure differentiation between NSOI and IgG4-ROD. MALT-lymphoma and IgG4-ROD showed more genetic similarities, which points towards progression to lymphoma.


A previously unreported complication of the AO cannulated 4.0- and 4.5-mm screw systems: a review of three cases.
Cannulated screws are utilized widely in the management of periarticular fractures and osteotomies. Reports of complications related to these screws have increased as use has become more commonplace. A novel mode of mechanical failure of 4.0-mm and 4.5-mm A-O cannulated screws is described in three patients, as well as hypotheses regarding possible causes of the failure. It may be prudent to predrill and tap dense cortical bone when such devices are used in teenagers and young adults patients in an attempt to avoid similar damage to the screw during insertion.


Telomeres and telomerase in human cancer (review).
Telomerase has recently come into the limelight as one of the most prevalent tumour markers, due to its nearly ubiquitous presence in malignant tissues and absence from most somatic tissues. The essential role of telomeres in unlimited cell proliferation and that of the enzyme in telomere maintenance have suggested that telomerase inhibitors may be effective in cancer therapy. We provide here a compendium and an evaluation of the available data relating to this hypothesis.


[Changes in indicators of external and internal secretion of the pancreas during treatment of chronic pancreatitis of alcoholic etiology with somatostatin analogs].
To study somatostatin (SS) content in patients with chronic pancreatitis (CP) and effects of sandostatin (a synthetic analogue of SS) on endo- and exocrine pancreatic functions in CP patients. SS plasma levels were measured by radioimmunoassay in basal conditions in 32 CP patients. Sandostatin treatment was given to 20 patients with CP of alcohol etiology (twice a day subcutaneously for 5 days). In the course of the treatment the following indices were measured: serum trypsin, amilase, lipase, alpha 2-macroglobulin, general antitryptic activity, blood immunoreactive insulin in basal conditions and after intravenous injection of glucose. SS levels in peripheral blood were elevated in patients with complicated alcoholic CP. Sandostatin in CP used for 5 days had no significant impact on insulin secretion, levels of pancreatic enzymes, inhibiting system of blood. 90% patients with alcoholic CP experienced relief of pain which may relate to suppression of stimulated secretion of gastrointestinal hormones as well as to a favourable action of sandostatin on stabilization of membranes of acinar cells. Sandostatin administration in CP patients is justified and is especially recommended in the complicated course.


Virus-mediated export of chromosomal DNA in plants.
The propensity of viruses to acquire genetic material from relatives and possibly from infected hosts makes them excellent candidates as vectors for horizontal gene transfer. However, virus-mediated acquisition of host genetic material, as deduced from historical events, appears to be rare. Here, we report spontaneous and surprisingly efficient generation of hybrid virus/host DNA molecules in the form of minicircles during infection of Beta vulgaris by Beet curly top Iran virus (BCTIV), a single-stranded DNA virus. The hybrid minicircles replicate, become encapsidated into viral particles, and spread systemically throughout infected plants in parallel with the viral infection. Importantly, when co-infected with BCTIV, B. vulgaris DNA captured in minicircles replicates and is transcribed in other plant species that are sensitive to BCTIV infection. Thus, we have likely documented in real time the initial steps of a possible path of virus-mediated horizontal transfer of chromosomal DNA between plant species.


Identification of Host Factors Interacting with a γ-Shaped RNA Element from a Plant Virus-Associated Satellite RNA.
Previously, we identified a highly conserved, γ-shaped RNA element (γRE) from satellite RNAs of cucumber mosaic virus (CMV), and we determined γRE to be structurally required for satRNA survival and the inhibition of CMV replication. It remains unknown how γRE biologically functions. In this work, pull-down assays were used to screen candidates of host factors from Nicotiana benthamiana plants using biotin-labeled γRE as bait. Nine host factors were found to interact specifically with γRE. Then, all of these host factors were down-regulated individually in N. benthamiana plants via tobacco rattle virus-induced gene silencing and tested with infection by GFP-expressing CMV (CMV-gfp) and the isolate T1 of satRNA (sat-T1). Out of nine candidates, three host factors, namely histone H3, GTPase Ran3, and eukaryotic translation initiation factor 4A, were extremely important for infection by CMV-gfp and sat-T1. Moreover, we found that cytosolic glyceraldehyde-3-phosphate dehydrogenase 2 contributed to the replication of CMV and sat-T1, but also negatively regulated CMV 2b activity. Collectively, our work provides essential clues for uncovering the mechanism by which satRNAs inhibit CMV replication.


Endurance exercise training in orthostatic intolerance: a randomized, controlled trial.
Orthostatic intolerance is a syndrome characterized by chronic orthostatic symptoms of light-headedness, fatigue, nausea, orthostatic tachycardia, and aggravated norepinephrine levels while standing. The aim of this study was to assess the protective effect of exercise endurance training on orthostatic symptoms and to examine its usefulness in the treatment of orthostatic intolerance. 2768 military recruits were screened for orthostatic intolerance by questionnaire. Tilt-table testing identified 36 cases of orthostatic intolerance out of the 2768 soldiers. Subsequently, 31 of these subjects with orthostatic intolerance entered a randomized, controlled trial. The patients were allocated randomly to either a "training" (3 months jogging) or a "control" group. The influence of exercise training on orthostatic intolerance was assessed by determination of questionnaire scores and tilt-table testing before and after intervention. After training, only 6 individuals of 16 still had orthostatic intolerance compared with 10 of 11 in the control group. The Fisher exact test showed a highly significant difference in diagnosis between the 2 groups (P=0.008) at the end of the study. Analysis of the questionnaire-score showed significant interaction between time and group (P=0.001). The trained subjects showed an improvement in the average symptom score from 1.79+/-0.4 to 1.04+/-0.4, whereas the control subjects showed no significant change in average symptom score (2.09+/-0.6 and 2.14+/-0.5, respectively). Our data demonstrate that endurance exercise training leads to an improvement of symptoms in the majority of patients with orthostatic intolerance. Therefore, we suggest that endurance training should be considered in the treatment of orthostatic intolerance patients.


Conservation of Brachyury, Mef2, and Snail in the myogenic lineage of jellyfish: a connection to the mesoderm of bilateria.
One major difference between simple metazoans such as cnidarians and all the bilaterian animals is thought to involve the invention of mesoderm. The terms diploblasts and triploblasts are therefore, often used to group prebilaterian and bilaterian animals, respectively. However, jellyfish contain well developed striated and smooth muscle tissues that derive from the entocodon, a mesoderm-like tissue formed during medusa development. We investigated the hypothesis, that the entocodon could be homologous to the third germ layer of bilaterians by analyzing the structures and expression patterns of the homologues of Brachyury, Mef2, and Snail in the jellyfish Podocoryne carnea. These are regulatory genes from the T-box, MADS-box and zinc finger families known to play important roles in bilaterian mesoderm patterning and muscle differentiation. The sequence and expression data demonstrate that the genes are structurally and functionally conserved and even more similar to humans or other deuterostomes than to protostome model organisms such as Drosophila or Caenorhabditis elegans. Based on these data we conclude that the common ancestor of the cnidarians and bilaterians not only shared genes that play a role in regulating myogenesis but already used them to develop and differentiate muscle systems similar to those of triploblasts.


Hepatitis C virus-specific T-cell gamma interferon and proliferative responses are more common in perihepatic lymph nodes than in peripheral blood or liver.
The activation state, differentiation state, and functions of liver lymphocytes and perihepatic lymph nodes during chronic hepatitis C virus (HCV) infection are not well understood. Here, we performed phenotypic and functional analyses of freshly prepared lymphocytes isolated from the livers, perihepatic lymph nodes, and peripheral blood compartments of chronic HCV-infected and disease control subjects with end-stage liver disease undergoing liver transplantation. We measured lymphocyte subset frequency and memory T-cell gamma interferon (IFN-gamma) and proliferative responses to HCV peptide and control viral antigens in direct ex vivo assays. We found higher frequencies of CD4 cells in the lymph node compartment than in the other compartments for both HCV-infected and disease control subjects. Lymph node CD4 and CD8 cells less commonly expressed the terminal differentiation marker CD57, a finding consistent with an earlier differentiation state. In HCV-infected subjects, HCV-specific IFN-gamma-producing and proliferative responses were commonly observed in the lymph node fraction, while they were uncommonly observed in the peripheral blood or liver fractions. In contrast, control viral CD4 protein antigen and CD8 peptide antigen-specific IFN-gamma responses were commonly observed in the periphery and uncommonly observed in the lymph nodes of these same subjects. These findings are consistent with a selective defect in HCV-specific T-cell effector function or distribution in patients with advanced chronic HCV infection. The high frequency of HCV-reactive T cells in perihepatic lymph nodes indicates that a failure to generate or sustain T-lymphocyte HCV reactivity is not responsible for the paucity of functional cells even in end-stage liver disease.


BAP31-Mediated miR-206/133b Cluster Promotes Transendothelial Migration and Metastasis of Colorectal Cancer.
Dysregulated B cell receptor-associated protein 31 (BAP31) plays a crucial role in tumor progression. This study aimed to investigate the functions and molecular mechanism of BAP31 on the miR-206/133b cluster in colorectal cancer (CRC). qPCR was conducted to detect miRNA and mRNA levels in tissues and cells. Western blot assays were used to assess the levels of biomarkers and targets, as well as the levels of BAP31 and HOXD10. Wound healing, coculture and transwell assays were conducted to assess the transendothelial migration abilities of CRC cells. A luciferase assay was employed to assess miRNA binding effects on targets, as well as the initiating transcription effect of genomic fragments. Tumor growth and lung metastatic models were established through an in vivo animal study. BAP31 overexpression in CRC cells led to a reduction in the expression of the miR-206/133b cluster. The expression of the miR-206/133b cluster was correlated with the transendothelial migration capability of CRC cells. The miR-206/133b cluster was found to directly regulate cell division cycle 42 (CDC42) and actin-related protein 2/3 complex subunit 5 (ARPC5) in the tight junction pathway (hsa04530). Moreover, a potential transcription regulator of the miR-206/133b cluster was also found to be Homeobox D10 (HOXD10). We further elucidated the molecular mechanisms and functional mechanisms of BAP31's regulatory role in the expression levels of the miR-206/133b cluster by inhibiting HOXD10 translocation from the cytoplasm to the nucleus. In conclusion, this study provides valuable insights into how BAP31 regulates the transcription of the miR-206/133b cluster and how BAP31-related lung metastases arise in CRC.


A double-blind, parallel, multicenter comparison of L-acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys.
Attention deficit hyperactivity disorder (ADHD) is a frequent behavioral problem in young boys with fragile X syndrome (FXS), and its treatment is critical for improving social ability. The short-term efficacy of stimulant medications like methylphenidate (MPH) is well established in children with ADHD. FXS boys treated with MPH have improved attention span and socialization skills; however their mood becomes unstable at higher doses. Therefore, alternative pharmacological treatment of ADHD symptoms is desirable. A recent study showed that carnitine has a beneficial effect on the hyperactive-impulsive behavior in boys with ADHD without side effects. Our previous placebo-controlled trial indicated that L-acetylcarnitine (LAC) reduces hyperactivity in FXS boys. The objective of this study was to determine the efficacy of LAC in a larger sample of FXS boys with ADHD. The study design was randomized, double blind placebo controlled, parallel, and multicenter (with eight centers involved in Italy, France, and Spain). Sixty-three FXS males with ADHD (aged 6-13 years) were enrolled; 7 patients dropped out, 56 completed the one-year treatment, and 51 were included in the statistical analysis. Both groups improved their behavior, showing that psychosocial intervention has a significant therapeutic effect. However, we observed a stronger reduction of hyperactivity and improvement of social behavior in patients treated with LAC, compared with the placebo group, as determined by the Conners' Global Index Parents and the Vineland Adaptive Behavior Scale. Our results show that LAC (20-50 mg/kg/day) represents a safe alternative to the use of stimulant drugs for the treatment of ADHD in FXS children.


Coordination of K+ transporters in neurospora: TRK1 is scarce and constitutive, while HAK1 is abundant and highly regulated.
Fungi, plants, and bacteria accumulate potassium via two distinct molecular machines not directly coupled to ATP hydrolysis. The first, designated TRK, HKT, or KTR, has eight transmembrane helices and is folded like known potassium channels, while the second, designated HAK, KT, or KUP, has 12 transmembrane helices and resembles MFS class proteins. One of each type functions in the model organism Neurospora crassa, where both are readily accessible for biochemical, genetic, and electrophysiological characterization. We have now determined the operating balance between Trk1p and Hak1p under several important conditions, including potassium limitation and carbon starvation. Growth measurements, epitope tagging, and quantitative Western blotting have shown the gene HAK1 to be much more highly regulated than is TRK1. This conclusion follows from three experimental results: (i) Trk1p is expressed constitutively but at low levels, and it is barely sensitive to extracellular [K(+)] and/or the coexpression of HAK1; (ii) Hak1p is abundant but is markedly depressed by elevated extracellular concentrations of K(+) and by coexpression of TRK1; and (iii) Carbon starvation slowly enhances Hak1p expression and depresses Trk1p expression, yielding steady-state Hak1p:Trk1p ratios of ∼500:1, viz., 10- to 50-fold larger than that in K(+)- and carbon-replete cells. Additionally, it appears that both potassium transporters can adjust kinetically to sustained low-K(+) stress by means of progressively increasing transporter affinity for extracellular K(+). The underlying observations are (iv) that K(+) influx via Trk1p remains nearly constant at ∼9 mM/h when extracellular K(+) is progressively depleted below 0.05 mM and (v) that K(+) influx via Hak1p remains at ∼3 mM/h when extracellular K(+) is depleted below 0.1 mM.


Online communication as a potential travel medicine research tool: analysis of messages posted on the TravelMed listserv.
Access to the Internet and electronic mail has created opportunities for online discussion that can facilitate medical education and clinical problem solving. Research into the use of these information technologies is increasing and the analysis of these tools can support and guide the activities of professional organizations, including educational endeavors. The initial objective was to analyze patterns of information exchange on the International Society of Travel Medicine's (ISTM) travel health electronic mailing list related to a specific area of society interest. Secondary objectives included the analysis of listserv use in relation to subscriber demographics and rates of participation to support travel health educational activities. This study examined the use of the ISTM TravelMed listserv over an 8-month period from January 1, 2006, to July 31, 2006. Descriptive data analysis included TravelMed user demographics, the type of posting, the topic and frequency of postings, and the source of information provided. During the study period, 911 (47%) of the eligible ISTM members subscribed to the TravelMed listserv. About 369 of these subscribers posted 1,710 individual messages. About 1,506 (88%) postings were educational; 207 (12%) postings were administrative. A total of 389 (26%) of the educational postings were primary queries and 1,120 (74%) were responses, with a mean string length of 2.9 responses per query (range: 1-51). Twenty participants contributed 40% of the educational postings. The topics with the most frequent postings were vaccines and vaccine-preventable diseases (473/31%) and malaria (258/17%). Postings focused on special populations, including pregnant women or immigrants, comprised a total of 14 postings (<1%). During the study period, a limited number of ISTM members (19%) authored postings on the listserv. Regular discussion centered on a limited number of recurring topics. The analysis provides several opportunities for the support of educational initiatives, clinical problem solving, and program evaluation.


The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner.
Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The β-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of β-catenin/Wnt-signaling pathway-inhibition by the β-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of β-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/β-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/β-catenin signaling-activity.


The recent decline of unionization in the United States.
The dramatic decline in unionization during the last decade is investigated with the use of survey data from 1977 and 1984. First, it is found that only a small fraction of the decline in unionization can be accounted for by shifts in labor force structure. Second, there has been a substantial drop in demand for union representation among nonunion workers that can be accounted for by an increase in the job satisfaction of nonunion workers and a decrease in nonunion workers' reports that unions improve wages and working conditions. Finally, there has been a substantial increase in employer resistance to unionization that is likely to have made it more difficult for unions to organize even those workers who desire union representation. Increased foreign and increased nonunion domestic competition (particularly in deregulated industries) may be key underlying causes of these changes.


N-cadherin (Cdh2) Maintains Migration and Postmitotic Survival of Cortical Interneuron Precursors in a Cell-Type-Specific Manner.
The multiplex role of cadherin-based adhesion complexes during development of pallial excitatory neurons has been thoroughly characterized. In contrast, much less is known about their function during interneuron development. Here, we report that conditional removal of N-cadherin (Cdh2) from postmitotic neuroblasts of the subpallium results in a decreased number of Gad65-GFP-positive interneurons in the adult cortex. We also found that interneuron precursor migration into the pallium was already delayed at E14. Using immunohistochemistry and TUNEL assay in the embryonic subpallium, we excluded decreased mitosis and elevated cell death as possible sources of this defect. Moreover, by analyzing the interneuron composition of the adult somatosensory cortex, we uncovered an unexpected interneuron-type-specific defect caused by Cdh2-loss. This was not due to a fate-switch between interneuron populations or altered target selection during migration. Instead, potentially due to the migration delay, part of the precursors failed to enter the cortical plate and consequently got eliminated at early postnatal stages. In summary, our results indicate that Cdh2-mediated interactions are necessary for migration and survival during the postmitotic phase of interneuron development. Furthermore, we also propose that unlike in pallial glutamatergic cells, Cdh2 is not universal, rather a cell type-specific factor during this process.


STITCH 3: zooming in on protein-chemical interactions.
To facilitate the study of interactions between proteins and chemicals, we have created STITCH, an aggregated database of interactions connecting over 300,000 chemicals and 2.6 million proteins from 1133 organisms. Compared to the previous version, the number of chemicals with interactions and the number of high-confidence interactions both increase 4-fold. The database can be accessed interactively through a web interface, displaying interactions in an integrated network view. It is also available for computational studies through downloadable files and an API. As an extension in the current version, we offer the option to switch between two levels of detail, namely whether stereoisomers of a given compound are shown as a merged entity or as separate entities. Separate display of stereoisomers is necessary, for example, for carbohydrates and chiral drugs. Combining the isomers increases the coverage, as interaction databases and publications found through text mining will often refer to compounds without specifying the stereoisomer. The database is accessible at http://stitch.embl.de/.


UHPLC method for the simultaneous determination of β-blockers, isoflavones, and flavonoids in human urine.
A simple method using solid-phase extraction (SPE) and ultra high-performance liquid chromatography (UHPLC) for the simultaneous determination of β-blockers, isoflavones, and flavonoids in human urine is developed. A statistical central composite design and response surface analysis is used to optimize the separation of the analytes. These multivariate procedures are efficient in determining the optimal separation condition using resolutions and retention time as responses. A gradient elution using a mobile phase consisting of 0.05% trifluoroacetic acid in water and acetonitrile is applied on a Hypersil GOLD column within a short analysis time of 4.5 min. UV detection was used to monitor the analytes. The suggested method was linear in a concentration range from 0.04-20.00 μg/mL, depending on the compound. The limits of detection ranged from 8.9 to 66.2 ng/mL. The precision was lower than 2.74%, and the accuracy was between 0.01-3.65%. The Oasis HLB column, with the highest recoveries, is selected for the pre-concentration step. This present paper reports, for the first time, a method for the simultaneous determination of β-blockers, isoflavones, and flavonoids in human urine samples. Furthermore, the developed method can also be applied to the routine determination of examined compounds concentrations in human urine.


Spinal Cord Stimulation for Complex Regional Pain Syndrome: A Case Study of a Pregnant Female.
Spinal cord stimulation (SCS) is a form of neuromodulation, used to treat chronic neuropathic pain refractory to conventional medical management. Spinal cord stimulators are treatment options when intractable chronic pain has not responded to more conventional treatment modalities. Currently, the use of SCS is contraindicated in pregnancy. Nevertheless, many SCS/neuromodulation recipients are women of child bearing age who may become pregnant. There are no published reports that focus on the possible side effects of SCS or neuromodulation therapy on human fertility, fetal development, pregnancy, delivery, or lactation. The purpose of this current report is to present a case study on the use of SCS/neuromodulation during pregnancy. Presentation of the case of a 24 year old female who became pregnant after receiving an SCS implantation for pain control secondary to complex regional pain syndrome (CRPS). The SCS was in use at the time of conception but deactivated when patient became aware of her pregnancy and intermittently reactivated for five minute intervals throughout the entire pregnancy. Currently very little documented evidence is available regarding the safety of using a SCS/neuromodulator during pregnancy; therefore its use during pregnancy is contraindicated. Available literature suggests that, women who have chosen to keep the SCS/neuromodulator activated during pregnancy have delivered healthy babies without any life threatening complications. Case presentations do not provide conclusive evidence of treatment effectiveness. This data is only preliminary and future studies should be used to assess outcomes and measures to provide quantification of the SCS implantation during pregnancy. Women of child bearing age who are recipients of SCS/neuromodulation implantation should be informed of the limited knowledge available regarding the impact of SCS/neuromodulation use during pregnancy. For current recipients, decisions about ongoing use during pregnancy should be an individual decision based on the potential risks and benefits.


The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1).
The tumor suppressor gene hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor, is epigenetically silenced in many human tumors. Here, we show that ectopic expression of HIC1 in the highly malignant MDA-MB-231 breast cancer cell line severely impairs cell proliferation, migration, and invasion in vitro. In parallel, infection of breast cancer cell lines with a retrovirus expressing HIC1 also induces decreased mRNA and protein expression of the tyrosine kinase receptor EphA2. Moreover, chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. Taken together, our results identify EphA2 as a new direct target gene of HIC1. Finally, we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. To conclude, our results involve the tumor suppressor HIC1 in the transcriptional regulation of the tyrosine kinase receptor EphA2, whose ligand ephrin-A1 is also a HIC1 target gene. Thus, loss of the regulation of this Eph pathway through HIC1 epigenetic silencing could be an important mechanism in the pathogenesis of epithelial cancers.


The clinical and translational research activities at the INT - IRCCS "Fondazione Pascale" cancer center (Naples, Italy) during the COVID-19 pandemic.
COVID-19 pandemic following the outbreak in China and Western Europe, where it finally lost the momentum, is now devastating North and South America. It has not been identified the reason and the molecular mechanisms of the two different patterns of the pulmonary host responses to the virus from a minimal disease in young subjects to a severe distress syndrome (ARDS) in older subjects, particularly those with previous chronic diseases (including diabetes) and cancer. The Management of the Istituto Nazionale Tumori - IRCCS "Fondazione Pascale" in Naples (INT-Pascale), along with all Health professionals decided not to interrupt the treatment of those hospitalized and to continue, even if after a careful triage in order not to allow SARS-CoV-2 positive subjects to access, to take care of cancer patients with serious conditions. Although very few (n = 3) patients developed a symptomatic COVID-19 and required the transfer to a COVID-19 area of the Institute, no patients died during the hospitalization and completed their oncology treatment. Besides monitoring of the patients, all employees of the Institute (physicians, nurses, researchers, lawyers, accountants, gatekeepers, guardians, janitors) have been tested for a possible exposure. Personnel identified as positive, has been promptly subjected to home quarantine and subdued to health surveillance. One severe case of respiratory distress has been reported in a positive employees and one death of a family member. Further steps to home monitoring of COVID-19 clinical course have been taken with the development of remote Wi-Fi connected digital devices for the detection of early signs of respiratory distress, including heart rate and oxygen saturation.In conclusion cancer care has been performed and continued safely also during COVID-19 pandemic and further remote home strategies are in progress to ensure the appropriate monitoring of cancer patients.


Rehospitalization with respiratory syncytial virus after neonatal intensive care unit discharge: A 3-year follow-up.
This study sought to determine 1) the incidence of rehospitalization with respiratory syncytial virus (RSV) infection within a 3-year follow-up among infants discharged from the neonatal intensive care unit (NICU), and 2) to examine associations between age at readmission and medical and sociodemographic characteristics among infants rehospitalized with RSV. A 3-year retrospective review of NICU discharges at a tertiary care center identified 2506 infants. Using medical record numbers linked with International Classification of Diseases, 9th ed, diagnostic codes for RSV infection, bronchiolitis, or respiratory distress, 67 NICU graduates were identified as having been readmitted from November to April (RSV season). Bivariate analyses and logistic regression modeling were applied to determine the association between a series of predictor variables and age at readmission with RSV by 90 days, 125 days, and 180 days after discharge from the NICU. The 3-year incidence of readmission with RSV infection after NICU discharge was 2.7%. During the 3-year follow-up, 6.4% of very low birth weight infants, 2.8% of low birth weight infants, and 1.7% of normal weight infants were readmitted with RSV. Crude results revealed that the presence of bacteremia, intraventricular hemorrhage, and necrotizing enterocolitis, as well as ventilation use, were associated with younger age at readmission with RSV. Simultaneous consideration of the effects of all of these medical predictors and birth weight on age at readmission revealed that normal birth weight was the only significant factor associated with younger age at readmission with RSV. This study found significantly lower rates of RSV readmission among NICU graduates than those reported previously in the literature. Based on these data, prophylactic treatment of all preterm infants may not be warranted.


The Roles of Carbohydrate Response Element Binding Protein in the Relationship between Carbohydrate Intake and Diseases.
Carbohydrates are macronutrients that serve as energy sources. Many studies have shown that carbohydrate intake is nonlinearly associated with mortality. Moreover, high-fructose corn syrup (HFCS) consumption is positively associated with obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Accordingly, products with equal amounts of glucose and fructose have the worst effects on caloric intake, body weight gain, and glucose intolerance, suggesting that carbohydrate amount, kind, and form determine mortality. Understanding the role of carbohydrate response element binding protein (ChREBP) in glucose and lipid metabolism will be beneficial for elucidating the harmful effects of high-fructose corn syrup (HFCS), as this glucose-activated transcription factor regulates glycolytic and lipogenic gene expression. Glucose and fructose coordinately supply the metabolites necessary for ChREBP activation and de novo lipogenesis. Chrebp overexpression causes fatty liver and lower plasma glucose levels, and ChREBP deletion prevents obesity and fatty liver. Intestinal ChREBP regulates fructose absorption and catabolism, and adipose-specific Chrebp-knockout mice show insulin resistance. ChREBP also regulates the appetite for sweets by controlling fibroblast growth factor 21, which promotes energy expenditure. Thus, ChREBP partly mimics the effects of carbohydrate, especially HFCS. The relationship between carbohydrate intake and diseases partly resembles those between ChREBP activity and diseases.


Improving vaccine potency through intercellular spreading and enhanced MHC class I presentation of antigen.
The potency of naked DNA vaccines is limited by their inability to amplify and spread in vivo. VP22, a HSV-1 protein, has demonstrated the remarkable property of intercellular transport and may thus provide a unique approach for enhancing vaccine potency. Therefore, we created a novel fusion of VP22 with a model Ag, human papillomavirus type 16 E7, in a DNA vaccine that generated enhanced spreading and MHC class I presentation of AG: These properties led to a dramatic increase in the number of E7-specific CD8(+) T cell precursors in vaccinated mice (around 50-fold) and converted a less effective DNA vaccine into one with significant potency against E7-expressing tumors. In comparison, nonspreading VP22(1-267) mutants failed to enhance vaccine potency. Our data indicated that the potency of DNA vaccines may be dramatically improved through intercellular spreading and enhanced MHC class I presentation of Ag.


Addressing the need for repeat prostate biopsy: new technology and approaches.
No guidelines currently exist that address the need for rebiopsy in patients with a negative diagnosis of prostate cancer on initial biopsy sample analysis. Accurate diagnosis of prostate cancer in these patients is often complicated by continued elevation of serum PSA levels that are suggestive of prostate cancer, resulting in a distinct management challenge. Following negative initial findings of biopsy sample analysis, total serum PSA levels and serum PSA kinetics are ineffective indicators of a need for a repeat biopsy; therefore, patients suspected of having prostate cancer might undergo several unnecessary biopsy procedures. Several alternative strategies exist for identifying men who might be at risk of prostate cancer despite negative findings of biopsy sample analysis. Use of other serum PSA-related measurements enables more sensitive and specific diagnosis and can be combined with knowledge of clinicopathological features to improve outcomes. Other options include the FDA-approved Progensa(®) test and prostate imaging using MRI. Newer tissue-based assays that measure methylation changes in normal prostate tissue are currently being developed. A cost-effective strategy is proposed in order to address this challenging clinical scenario, and potential directions of future studies in this area are also described.


How do Norwegian adolescents experience the role of social media in relation to mental health and well-being: a qualitative study.
During the last decade, social media has permeated most parts of society. Adolescents are particularly active users of social media, and their use has been suggested as a contributing factor to mental health issues in this group. Quantitative studies have found associations between the frequency and/or duration of social media use and more mental health issues. However, most studies are cross-sectional and the identified associations are weak and of questionable practical significance. The aim of this study was to investigate adolescents' lived experiences of using social media, focusing on both negative and positive aspects, using a qualitative approach. Qualitative research enables in-depth explorations of the experiences of individuals, nuance quantitative findings, and offer the perspective of adolescents into policies regarding social media use. Experiences and perspectives of 27 adolescents from two senior high schools in Norway were gathered using focus group interviews (mean age 16.8, range 15-18). The data were analysed using thematic analysis. According to the participants, social media use catalyse changes to how people communicate and relate to each other (theme 1). Some changes were positive, in terms of facilitating social connectedness, while others were negative, such as people behaving worse than in face-to-face interactions. Further, social media use affected the participants at the individual level (theme 2); positively in terms of a sense of belonging and social support, and negatively in terms of perceived stress, body pressure, and displacing other activities such as sleep and homework. The motivations for using, or not using, social media were multifaceted (theme 3), reflecting the positive and negative aspects of social media in terms of interpersonal and personal consequences. Social media was described as an important part of the participants' everyday life, with both a positive and negative impact on their mental health and well-being. Considering the compelling nature of social media and adolescents' relatively limited self-regulatory capacities, efforts to modify social media use should avoid relying on self-regulation, while also recognizing the importance of social media as an arena for peer interaction.


Modeling the effect of exposure notification and non-pharmaceutical interventions on COVID-19 transmission in Washington state.
Contact tracing is increasingly used to combat COVID-19, and digital implementations are now being deployed, many based on Apple and Google's Exposure Notification System. These systems utilize non-traditional smartphone-based technology, presenting challenges in understanding possible outcomes. In this work, we create individual-based models of three Washington state counties to explore how digital exposure notifications combined with other non-pharmaceutical interventions influence COVID-19 disease spread under various adoption, compliance, and mobility scenarios. In a model with 15% participation, we found that exposure notification could reduce infections and deaths by approximately 8% and 6% and could effectively complement traditional contact tracing. We believe this can provide health authorities in Washington state and beyond with guidance on how exposure notification can complement traditional interventions to suppress the spread of COVID-19.


The design and synthesis of aryl hydroxamic acid inhibitors of MMPs and TACE.
Three different classes of aryl hydroxamic acid scaffolds have been explored and provided potent inhibitors of MMP-1, -2, -9, -13 and TACE. Structure-based design has allowed the evolution of these inhibitors from broad spectrum inhibitors into compounds that are more selective for MMPs relevant to particular disease states. Aryl hydroxamates selective for MMP-9, MMP-13 and TACE have been disclosed that may aid in the study of the physiological role of these enzymes. Furthermore, the different selectivity profiles offered by these MMP/TACE inhibitors may allow the determination of which metalloprotease, or group of metalloproteases, must be inhibited for the safe, long-term treatment of osteoarthritis, rheumatoid arthritis and cancer. Some of these compounds have demonstrated useful biological activity in efficacy models relevant to osteoarthritis and rheumatoid arthritis and are therefore potential clinical candidates.


Knowledge regarding risk factors of hypertension among entry year students of a medical university.
Hypertension in youth is increasing, but there is a dearth of data about the knowledge of risk factors in this age group. To assess the knowledge of risk factors of hypertension among university students and associate it with the blood pressure, physical activity, family history of cardiovascular disease (CVD), and sociodemographic variables. A cross-sectional survey among students enrolled in the first year, in the four academic programs, with the use of a validated, self-administered questionnaire on physical activity in the past 30 days and knowledge of risk factors of hypertension. A score of 6 on 11 was considered as good knowledge for modifiable risk factors. Blood pressure was also measured. The data was analyzed using PASW-17, Chi square test, and binary logistic regression analysis was done. Of the 110 participants, 69.2% were < 20 years of age, 76.4% were females, and 40% were Arabs. Stress, high cholesterol, obesity, and smoking were identified as risk factors by 75.5, 73.6, 77.6, and 71.8%, respectively; 69.1% considered high salt intake and 62.7% considered high calorie diet as risk factors. Energy drink was considered as a risk factor by 64.5%, coffee consumption 35.5%, physical inactivity 47%, and oral contraceptives 13.6%. Half the group did not consider a family history of CVD as a risk factor, 60% did not consider older age as a risk factor, and 88% did not think male gender was a risk factor. Knowledge of modifiable risk factors was better than that of non-modifiable risk factors. Although nationality, course of study, raised blood pressure, and history of diabetes showed significant association with good knowledge, their net effect was not significant by the Adjusted Odd's Ratio. The study identified some gaps in knowledge regarding both modifiable and non-modifiable risk factors of hypertension among students. A larger study would enable health promotion activities tailored to the needs of this age group.


Optimization of glutamine peptide production from soybean meal and analysis of molecular weight distribution of hydrolysates.
The process parameters of enzymatic hydrolysis and molecular weight distribution of glutamine (Gln) peptides from soybean meal were investigated. The Protamex(®) hydrolysis pH of 6.10, temperature of 56.78 °C, enzyme to substrate ratio (E/S) of 1.90 and hydrolysis time of 10.72 h were found to be the optimal conditions by response surface methodology (RSM) for a maximal degree of hydrolysis (DH) value of 16.63% and Gln peptides content at 5.95 mmol/L. The soybean meal was hydrolyzed by a combination of Protamex(®) and trypsinase so that DH and Gln peptides would reach 22.02% and 6.05 mmol/mL, respectively. The results of size exclusion chromatography indicated that the relative proportion of the molecular weight <1000 Da fraction increased with DH values from 6.76%, 11.13%, 17.89% to 22.02%, most notably the 132-500 Da fractions of hydrolysates were 42.14%, 46.57%, 58.44% and 69.65%. High DH values did not lead to high Gln peptides content of the hydrolysate but to the low molecular weight Gln peptides.


[Peculiarities of cosmonauts fauces flora].
In the course of the work done the specific and quantitative composition of the streptococcal autoflora of the fauces of the cosmonauts and the members of backup drew was investigated. In populations of isolated microorganisms the non-pathogenic streptococci have dominated among which S. salivarius prevailed. The same species has constantly been isolated in all the cosmonauts, pre- and postflight. Observation of the microflora state of the fauces at different stages of their professional activity made it possible to reveal the peculiarities of an individual dynamics in the number of nonpathogenic streptococci isolated from tampon depending on the participation of the test-subjects in the previous space missions. This is evidently a reflection of the effect of psychoemotional tension on the state of colonization resistance (CR) of the fauces mucosa and, as result of this, on its microflora. In turn, the occurrence of the individual species of conditionally-pathogenic streptococci after the mission points to a decrease in the CR under effect of unfavourable factors of space mission.


Comparison of Accelerated Solvent Extraction (ASE) and Energized Dispersive Guided Extraction (EDGE) for the analysis of pesticides in leaves.
Various techniques have been evaluated for the extraction and cleanup of pesticides from environmental samples. In this work, a Selective Pressurized Liquid Extraction (SPLE) method for pesticides was developed using a Thermo Fisher Scientific Accelerated Solvent Extraction (ASE) system. This instrument was compared to the newly introduced (2017) extraction instrument, the Energized Dispersive Guided Extraction (EDGE) system, which combines Pressurized Liquid Extraction (PLE) and dispersive Solid Phase Extraction (dSPE). We first optimized the SPLE method using the ASE instrument for pesticide extraction from alfalfa leaves using layers of Florisil and graphitized carbon black (GCB) downstream of the leaf homogenate in the extraction cell (Layered ASE method). We then compared results obtained for alfalfa and citrus leaves with the Layered ASE method to those from a method in which the leaf homogenate and sorbents were mixed (Mixed ASE method) and to similar methods modified for use with EDGE (Layered EDGE and Mixed EDGE methods). The ASE and EDGE methods led to clear, colorless extracts with low residual lipid weight. No significant differences in residual lipid masses were observed between the methods. The UV-Vis spectra showed that Florisil removed a significant quantity of the light-absorbing chemicals, but that GCB was required to produce colorless extracts. Recoveries of spiked analytes into leaf homogenates were generally similar among methods, but in several cases, significantly higher recoveries were observed in ASE extracts. Nonetheless, no significant differences were observed among pesticide concentrations in field samples when calculated with the isotope dilution method in which labelled surrogates were added to samples before extraction. The extraction time with the ASE methods was ~45 minutes, which was ~4.5 times longer than with the EDGE methods. The EDGE methods used ~10 mL more solvent than the ASE methods. Based on these results, the EDGE is an acceptable extraction instrument and, for most compounds, the EDGE had a similar extraction efficiency to the ASE methods.


Repeated Low-level Red-light Therapy: The Next Wave in Myopia Management?
Exposure to long-wavelength light has been proposed as a potential intervention to slow myopia progression in children. This article provides an evidence-based review of the safety and myopia control efficacy of red light and discusses the potential mechanisms by which red light may work to slow childhood myopia progression.The spectral composition of the ambient light in the visual environment has powerful effects on eye growth and refractive development. Studies in mammalian and primate animal models (macaque monkeys and tree shrews) have shown that daily exposure to long wavelength (red or amber) light promotes slower eye growth and hyperopia development and inhibits myopia induced by form deprivation or minus lens wear. Consistent with these results, several recent randomized controlled clinical trials in Chinese children have demonstrated that exposure to red light for three minutes twice a day significantly reduces myopia progression and axial elongation. These findings have collectively provided strong evidence for the potential of using red light as a myopia control intervention in clinical practice. However, several questions remain unanswered. In this article, we review the current evidence on the safety and efficacy of red light as a myopia control intervention, describe potential mechanisms, and discuss some key unresolved issues that require consideration before red light can be broadly translated into myopia control in children.


[Role of physical activity in the prevention of osteoporosis].
In recent years, osteoporosis has become a leading cause of morbidity and mortality in elderly women. Research has demonstrated that the prevention of osteoporosis and osteoporosis-related fractures may best be achieved by initiating sound health behaviors early in life and continuing them throughout life. Evidence suggests that osteoporosis is easier to prevent than to treat. In fact, healthy early life practices, including the adequate consumption of most nutrients, calcium in particular, and regular physical activity, contribute to greater bone mineral mass and optimal peak bone mass. Bone is living tissue that responds to exercise by becoming stronger. Two types of exercises are important for building and maintaining bone mass and density: Weight-bearing exercises, in which bones and muscles work against gravity and resistance training that use muscular strength to improve muscle mass and strengthen bone. Exercise can also improve gait, balance, coordination, proprioception, reaction time, and muscle strength, even in very old and frail elderly people. Overall, the evidence strongly suggests that regular physical activity, especially started in childhood and adolescence, is a cheap and safe way of both improving bone strength and reducing the risk to fall.


Use of Laser in Arteriovenous Malformation Surgery.
Arteriovenous malformation surgery is particularly demanding owing to the need to control bleeding of small, deep white matter vessels during and after removal of the nidus; this is probably one of the most critical moments of arteriovenous malformation surgery. The aim of this article is to describe a useful technique based on the use of tweezers to temporarily stop the blood flow followed by coagulation with the thulium laser. Surgery was performed in 20 patients with unruptured cerebral arteriovenous malformations. In each case, the superficial feeder vessels were easily coagulated with nonstick bipolar tips. The finer and deeper feeder vessels were coagulated with use of tweezers and thulium laser. All patients were treated successfully. Optimal intraoperative hemostasis was achieved. Results were good with no postoperative complications. Our results could encourage a more standardized use of the described technique.


Time trends and sociodemographic determinants of preterm births in pregnancy cohorts in Matlab, Bangladesh, 1990-2014.
Preterm birth is the major cause of under-five mortality. Population-based data on determinants and proportions of children born preterm are limited, especially from low-income countries. This study aimed at assessing time trends and social, reproductive and environmental determinants of preterm births based on a population-based pregnancy cohort over 25 years in rural Bangladesh. In this cohort study in Matlab, a rural area in Bangladesh, we used data from the Health and Demographic Surveillance System from 1990 to 2014. Gestational age at birth was based on the reported last menstrual period and verified by ultrasound assessments. Preterm birth proportions were assessed within strata of social and reproductive characteristics, and time series analysis was performed with decomposition for trend and seasonality. We also determined the prevented fractions of preterm birth reduction associated with social and demographic changes during the follow-up period. Analyses were based on 63 063 live births. Preterm birth decreased from 29% (95% CI 28.6 to 30.1) in 1990-1994 to 11% (95% CI 10.5 to 11.6) in 2010-2014. Low education, older age and multi-parity were associated with higher proportions of preterm births across the study period. Preterm births had a marked seasonal variation. A rapid increase in women's educational level and decrease in parity were associated with the decline in preterm births, and 27% of the reduction observed from 1990 to 2014 could be attributed to these educational and reproductive changes. The reduction in preterm birth was to a large extent associated with the sociodemographic transition, especially changes in maternal education and parity. The persistent seasonal variation in the proportion of preterm birth may reflect the environmental stressors for pregnant women across the study period. Continued investments in girls' education and family planning programmes may contribute to further reduction of preterm births in Bangladesh.


Sinonasal mucosal melanomas: defining profiles for better survival outcomes.
Sinonasal mucosal melanoma is an aggressive malignancy with a 5-year survival rate ranging from 20% to 39%. Despite the evolving surgical and radiotherapy techniques, and introduction of immune-checkpoint inhibitor therapy, overall survival rates remain poor. A retrospective cohort study was conducted at the Hospital Clinic de Barcelona and the Hospital de la Santa Creu i Sant Pau between 1984 and 2020; primary outcome measures were 3 and 5-year melanoma-specific survival (MSS). Kaplan-Meier survival analysis and Cox proportional hazards model were performed to identify predictors of survival. Fifty patients were included, the mean age was 70.4, MSS at 3 and 5 years was 51.2%, and 29.5%, respectively. The median follow-up was 39.6 months during which 46% presented locoregional recurrence and 36%, metastasis. The univariate and multivariate analyses found as survival predictors the N category, the treatment received, the surgical margins and the mitotic index. We found an overall 5-year MSS of 29.5%. Those patients with intention-to-cure (stages III and IVa) treated by surgery that were N0 at diagnosis, with < 10 mitoses per HPF showed a 5-year MSS rate of 74.1%. More studies will be needed to adequately define the patients' profiles that will benefit from a better survival outcome.


Modeling Truth Existence in Truth Discovery.
When integrating information from multiple sources, it is common to encounter conflicting answers to the same question. Truth discovery is to infer the most accurate and complete integrated answers from conflicting sources. In some cases, there exist questions for which the true answers are excluded from the candidate answers provided by all sources. Without any prior knowledge, these questions, named no-truth questions, are difficult to be distinguished from the questions that have true answers, named has-truth questions. In particular, these no-truth questions degrade the precision of the answer integration system. We address such a challenge by introducing source quality, which is made up of three fine-grained measures: silent rate, false spoken rate and true spoken rate. By incorporating these three measures, we propose a probabilistic graphical model, which simultaneously infers truth as well as source quality without any a priori training involving ground truth answers. Moreover, since inferring this graphical model requires parameter tuning of the prior of truth, we propose an initialization scheme based upon a quantity named truth existence score, which synthesizes two indicators, namely, participation rate and consistency rate. Compared with existing methods, our method can effectively filter out no-truth questions, which results in more accurate source quality estimation. Consequently, our method provides more accurate and complete answers to both has-truth and no-truth questions. Experiments on three real-world datasets illustrate the notable advantage of our method over existing state-of-the-art truth discovery methods.


Trophic Behavior and Species Diversity of the Anopheles barbirostris Complex (Diptera: Culicidae) in Thailand.
Species of the Anopheles barbirostris complex (Myzorhynchus Series of the subgenus Anopheles) are potential vectors of malaria and filariasis parasites. Owing to the lack of reliable identification methods, the biting activity and host preference of the species within this complex have not been previous described. In this study, the trophic behavior and host preferences of the species in the complex were determined in Thailand, and a map of their geographical distributions constructed. Adult female mosquitoes in Chanthaburi and Prachuap Khiri Khan provinces were collected using human landings (indoor and outdoor) and cow-bait. Morphological characters were used to initially identify the mosquitoes, and then, species were further separated by multiplex PCR. Four species were identified in the An. barbirostris complex: An. wejchoochotei Taai & Harbach (Diptera: Culicidae), An. saeungae Taai & Harbach (Diptera: Culicidae), An. dissidens Taai & Harbach (Diptera: Culicidae), and An. campestris Reid (Diptera: Culicidae). The species showed exophagic and zoophilic behavior, except An. wejchoochotei in Chanthaburi, which displayed slight endophilic behavior. Indoor and outdoor blood feeding behavior of An. wejchoochotei and An. saeungae peaked at 2000 h. An updated distribution map of the An. barbirostris complex in Thailand is presented. With a better understanding of the sibling vector species and their spatial distributions, more specific and effective control strategies for vectors of malaria and filariasis in Thailand can be achieved.