Neuroimaging predictors of onset and course of depression in childhood and adolescence: A systematic review of longitudinal studies.
Major depressive disorder (MDD) often emerges during adolescence with detrimental effects on development as well as lifetime consequences. Identifying neurobiological markers that are associated with the onset or course of this disorder in childhood and adolescence is important for early recognition and intervention and, potentially, for the prevention of illness onset. In this systematic review, 68 longitudinal neuroimaging studies, from 34 unique samples, that examined the association of neuroimaging markers with onset or changes in paediatric depression published up to 1 February 2019 were examined. These studies employed different imaging modalities at baseline; structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), functional MRI (fMRI) or electroencephalography (EEG). Most consistent evidence across studies was found for blunted reward-related (striatal) activity (fMRI and EEG) as a potential biological marker for both MDD onset and course. With regard to structural brain measures, the results were highly inconsistent, likely caused by insufficient power to detect complex mediating effects of genetic and environmental factors in small sample sizes. Overall, there were a limited number of samples, and confounding factors such as sex and pubertal development were often not considered, whereas these factors are likely to be relevant especially in this age range.


Multiple Object Tracking While Walking: Similarities and Differences Between Young, Young-Old, and Old-Old Adults.
Walking while simultaneously engaged in another activity becomes more difficult as one grows older. Here, we address the issue of changes in dual-task behavior at different stages of life, particularly in the latter stages. We developed a dual task that combined walking along an 8-m walkway with a multiple object tracking (MOT) task of increasing difficulty. This secondary cognitive task imitates visuospatial daily activities and provides reliable quantitative measurements. Our dual-task paradigm was tested on 27 young adults (23.85 ± 2.09 years old) and two groups of older adults (18 young-old and 18 old-old adults, aged 63.89 ± 3.32 and 80.83 ± 3.84 years, respectively). Significant decrease in tracking performance with increasing complexity of the MOT task was found in all three groups. An age-related decrease in MOT and gait performance was also found. However, young-old adults performed as well as young adults under low attentional load conditions (in the MOT task and simple walking), whereas their performance was as impaired as those of old-old adults under high attentional load conditions (in the MOT task and walking under dual-task condition). These different profiles between the two groups of older participants could be explained in terms of compensation strategies and risk of falling.


Bayesian spatial modelling of geostatistical data using INLA and SPDE methods: A case study predicting malaria risk in Mozambique.
Bayesian spatial models are widely used to analyse data that arise in scientific disciplines such as health, ecology, and the environment. Traditionally, Markov chain Monte Carlo (MCMC) methods have been used to fit these type of models. However, these are highly computationally intensive methods that present a wide range of issues in terms of convergence and can become infeasible in big data problems. The integrated nested Laplace approximation (INLA) method is a computational less-intensive alternative to MCMC that allows us to perform approximate Bayesian inference in latent Gaussian models such as generalised linear mixed models and spatial and spatio-temporal models. This approach can be used in combination with the stochastic partial differential equation (SPDE) approach to analyse geostatistical data that have been collected at particular sites to predict the spatial process underlying the data as well as to assess the effect of covariates and model other sources of variability. Here we demonstrate how to fit a Bayesian spatial model using the INLA and SPDE approaches applied to freely available data of malaria prevalence and risk factors in Mozambique. We show how to fit and interpret the model to predict malaria risk and assess the effect of covariates using the R-INLA package, and provide the R code necessary to reproduce the results or to use it in other spatial applications.


Use of mobile technology to identify behavioral mechanisms linked to mental health outcomes in Kenya: protocol for development and validation of a predictive model.
This study proposes to identify and validate weighted sensor stream signatures that predict near-term risk of a major depressive episode and future mood among healthcare workers in Kenya. The study will deploy a mobile application (app) platform and use novel data science analytic approaches (Artificial Intelligence and Machine Learning) to identifying predictors of mental health disorders among 500 randomly sampled healthcare workers from five healthcare facilities in Nairobi, Kenya. This study will lay the basis for creating agile and scalable systems for rapid diagnostics that could inform precise interventions for mitigating depression and ensure a healthy, resilient healthcare workforce to develop sustainable economic growth in Kenya, East Africa, and ultimately neighboring countries in sub-Saharan Africa. This protocol paper provides an opportunity to share the planned study implementation methods and approaches. A mobile technology platform that is scalable and can be used to understand and improve mental health outcomes is of critical importance.


Study of factors governing oil-water separation process using TiO₂ films prepared by spray deposition of nanoparticle dispersions.
Surfaces which possess extraordinary water attraction or repellency depend on surface energy, surface chemistry, and nano- and microscale surface roughness. Synergistic superhydrophilic-underwater superoleophobic surfaces were fabricated by spray deposition of nanostructured TiO2 on stainless steel mesh substrates. The coated meshes were then used to study gravity driven oil-water separation, where only the water from the oil-water mixture is allowed to permeate through the mesh. Oil-water separation efficiencies of up to 99% could be achieved through the coated mesh of pore sizes 50 and 100 μm, compared to no separation at all, that was observed in the case of uncoated meshes of the same material and pore sizes. An adsorbed water on the TiO2 coated surface, formation of a water-film between the wires that form the mesh and the underwater superoleophobicity of the structured surface are the key factors that contribute to the enhanced efficiency observed in oil-water separation. The nature of the oil-water separation process using this coated mesh (in which the mesh allows water to pass through the porous structure but resists wetting by the oil phase) minimizes the fouling of mesh so that the need for frequent replacement of the separating medium is reduced. The fabrication approach presented here can be applied for coating large surface areas and to develop a large-scale oil-water separation facility for oil-field applications and petroleum industries.


Hippocampus volume and episodic memory in schizophrenia.
Previous studies of schizophrenia have suggested a linkage between neuropsychological (NP) deficits and hippocampus abnormality. The relationship between hippocampus volume and NP functioning was investigated in 24 patients with chronic schizophrenia and 24 matched healthy controls. Overall intracranial, white and gray matter, and anterior (AH) and posterior (PH) hippocampus volumes were assessed from magnetic resonance images (MRI). NP domains of IQ, attention, and executive function were also evaluated with respect to volumetric measures. It was hypothesized that AH and PH volumes and episodic memory scores would be positively associated in controls and that the schizophrenia group would depart from this normative pattern. NP functioning was impaired overall and AH volume was smaller in the schizophrenia group. In the controls, the hippocampus-memory relationships involved AH and PH, and correlations were significant for verbal memory measures. In the schizophrenia group, positive correlations were constrained to PH. Negative correlations emerged between AH and verbal and visual memory measures. For both groups, cortical volume negatively correlated with age, but a negative correlation between age and hippocampus volume was found only in the schizophrenia group. In this sample of adults with schizophrenia, atypical relationships between regional hippocampus volumes and episodic memory ability were found, as was an atypical negative association between hippocampus volume and age.


Medical record and imaging evaluation to identify arterial tortuosity phenotype in populations at risk for intracranial aneurysms.
High arterial tortuosity may signify early arterial pathology which may precede development of intracranial aneurysms. We measured arterial tortuosity of intracranial vessels and reviewed the medical records of three groups of patients: with intracranial aneurysms, without aneurysms but at increased clinical risk, and controls without aneurysms or associated risk factors. There was significant but inconsistent evidence of increased arterial tortuosity in aneurysm cases and high-risk cases across different arteries. Medical records review identified that a subset of aneurysm cases carried a diagnosis of Loeys-Dietz syndrome that is often misdiagnosed as Marfan syndrome. We found increased arterial tortuosity in the Loeys-Dietz syndrome cases. A combination of medical record screening for Marfan syndrome or Loeys-Dietz symptoms such as aneurysms and evaluation of arterial tortuosity by a curve of scores from medical images may identify previously undiagnosed cases of Loeys-Dietz syndrome.


Residualizing iodine markedly improved tumor targeting using bispecific antibody-based pretargeting.
Previous studies have shown that pretargeting allows rapid visualization of renal cell carcinomas (RCC) with an (111)In-labeled bivalent peptide. For radioimmunotherapy, a beta-emitting radionuclide labeled to a bivalent peptide is required. Therapeutic efficacy of these radionuclides depends on the E(max), physical half-life, and residence time of the radiolabel in the tumor. The (131)I radiolabel generally clears rapidly from the tumor after internalization and subsequent degradation of the bivalent l-amino acid peptide (l-a.a. peptide) in the tumor cells. To improve the residence time of the iodine label in the tumor, a new bivalent peptide was synthesized that is peptidase resistant and consists of 4 d-amino acids (d-a.a. peptide). Here we investigated the characteristics of the residualizing iodine label in SK-RC-52 RCC tumors. The d-a.a. peptide was manually synthesized according to standard solid-phase Fmoc/HBTU (2-[1H-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate) chemistry. The uptake and retention in the tumor of (111)In-/(125)I-labeled bivalent peptides (l-a.a. peptide and d-a.a. peptide) were studied in female BALB/c athymic mice with subcutaneous SK-RC-52 RCC tumors. Tumors were pretargeted with the bispecific monoclonal antibody (bs-mAb) G250xDTIn-1 and, 72 h later, mice were injected intravenously with one of both radiolabeled peptides. The effect of bs-mAb-diDTPA-bs-mAb (DTPA is diethylenetriaminepentaacetic acid) bridging at the tumor cell surface on the internalization of the bs-mAb-diDTPA complex was investigated in SK-RC-52 tumor-bearing mice. The maximum uptake and retention of (125)I-labeled l-a.a. peptide in the tumor were significantly lower compared with that of the (111)In-labeled l-a.a. peptide. In contrast, the tumor uptake and retention of the (125)I-labeled d-a.a. peptide) were similar to that of the (111)In-labeled l-a.a. peptide but were superior at later time points. The biodistribution of the radioiodinated d-a.a. peptide was highly similar to that of the (111)In-labeled d-a.a. peptide, and both radiolabeled peptides were retained significantly better in the tumor than the (111)In-labeled l-a.a. peptide. bs-mAb-diDTPA-bs-mAb bridge formation did not affect internalization of the bs-mAb-diDTPA complex. Uptake and retention in the tumor of the iodinated peptide after pretargeting with a bs-mAb can be significantly improved using d-a.a. peptides. Accordingly, the radiation dose to the tumor, correlating with the therapeutic efficacy of pretargeted RCC, can be enhanced substantially.


Profile of gantenerumab and its potential in the treatment of Alzheimer's disease.
Alzheimer's disease, which is characterized by gradual cognitive decline associated with deterioration of daily living activities and behavioral disturbances throughout the course of the disease, is estimated to affect 27 million people around the world. It is expected that the illness will affect about 63 million people by 2030, and 114 million by 2050, worldwide. Current Alzheimer's disease medications may ease symptoms for a time but are not capable of slowing down disease progression. Indeed, all currently available therapies, such as cholinesterase inhibitors (donepezil, galantamine, rivastigmine), are primarily considered symptomatic therapies, although recent data also suggest possible disease-modifying effects. Gantenerumab is an investigational fully human anti-amyloid beta monoclonal antibody with a high capacity to bind and remove beta-amyloid plaques in the brain. This compound, currently undergoing Phase II and III clinical trials represents a promising agent with a disease-modifying potential in Alzheimer's disease. Here, we present an overview of gantenerumab ranging from preclinical studies to human clinical trials.


A Normative Data Set for the Clinical Assessment of Achromatic and Chromatic Contrast Sensitivity Using a qCSF Approach.
The measurement of achromatic sensitivity has been an important tool for monitoring subtle changes in vision as the result of disease or response to therapy. In this study, we aimed to provide a normative data set for achromatic and chromatic contrast sensitivity functions within a common cone contrast space using an abbreviated measurement approach suitable for clinical practice. In addition, we aimed to provide comparisons of achromatic and chromatic binocular summation across spatial frequency. We estimated monocular cone contrast sensitivity functions (CCSFs) using a quick Contrast Sensitivity Function (qCSF) approach for achromatic as well as isoluminant, L/M cone opponent, and S cone opponent stimuli in a healthy population of 51 subjects. We determined the binocular CCSFs for achromatic and chromatic vision to evaluate the degree of binocular summation across spatial frequency for these three different mechanisms in a subset of 20 subjects. Each data set shows consistent contrast sensitivity across the population. They highlight the extremely high cone contrast sensitivity of L/M cone opponency compared with the S-cone and achromatic responses. We also find that the two chromatic sensitivities are correlated across the healthy population. In addition, binocular summation for all mechanisms depends strongly on stimulus spatial frequency. This study, using an approach well suited to the clinic, is the first to provide a comparative normative data set for the chromatic and achromatic contrast sensitivity functions, yielding quantitative comparisons of achromatic, L/M cone opponent, and S cone opponent chromatic sensitivities as a function of spatial frequency.


Bipyrrolidine salan alkoxide complexes of lanthanides: synthesis, characterisation, activity in the polymerisation of lactide and mechanistic investigation by DOSY NMR.
Four dimeric lanthanide alkoxide complexes bearing ONNO bipyrrolidine salan ligands (LMeH2/LtBuH2) have been prepared with Nd, Sm and Yb. Depending on the metal and substituents, these complexes adopt varying coordination geometries. While investigating the hydrolytic degradation of these complexes, three dimeric mixed alkoxide/hydroxide and bis-hydroxide products were also prepared, isolated and characterised. Despite paramagnetism, 1H NMR and diffusion ordered spectroscopy (DOSY) allowed additional characterisation alongside elemental and single-crystal X-ray diffraction analyses. These systems were very active for the controlled ring-opening polymerisation (ROP) of rac-lactide (LA), under industrially relevant melt conditions and in solution, yielding complete conversion within 5 minutes at [Ln] : [LA] ratios of up to 3000 : 1 in toluene, and at 80 °C, whilst retaining low dispersities (Đ = 1.1). 1H DOSY NMR spectroscopy was employed to monitor polymer growth from the metal centres in situ, and revealed a dinuclear catalytically active species.


VEXOR: an integrative environment for prioritization of functional variants in fine-mapping analysis.
The identification of the functional variants responsible for observed genome-wide association studies (GWAS) signals is one of the most challenging tasks of the post-GWAS research era. Several tools have been developed to annotate genetic variants by their genomic location and potential functional implications. Each of these tools has its own requirements and internal logic, which forces the user to become acquainted with each interface. From an awareness of the amount of work needed to analyze a single locus, we have built a flexible, versatile and easy-to-use web interface designed to help in prioritizing variants and predicting their potential functional implications. This interface acts as a single-point of entry linking association results with reference tools and relevant experiments. VEXOR is an integrative web application implemented through the Shiny framework and available at: http://romix.genome.ulaval.ca/vexor. email@example.com. Supplementary data are available at Bioinformatics online.


An association between plastic mattress covers and sheepskin underbedding use in infancy and house dust mite sensitization in childhood: a prospective study.
Higher house dust mite (HDM) allergen exposure during infancy has been associated with increased HDM sensitization. Infant bedding has been associated with the accumulation of varying levels of HDM. Prospective data on the relationship between infant bedding and the development of HDM sensitization has not been previously examined. To determine if particular types of bedding used in infancy are associated with increased risk of house dust mite sensitization in childhood. A population-based sample (n = 498) of children born in 1988 or 1989, and who were resident in Northern Tasmania in 1997, participated in this study. These children were part of a birth cohort study (1988-95), the Tasmanian Infant Health Survey. Data on infant underbedding and mattresses was available on 460 and 457 children, respectively. The main outcome measure was HDM sensitization defined as a skin prick test (SPT) reaction of 3 mm or more to the allergens of Dermatophagoides pteronyssinus and/or Dermatophagoides farinae. The use of either sheepskin underbedding or plastic mattress covers in infancy was associated with an increased risk of sensitization to HDM allergens at age 8 years. The adjusted risk ratio (RR) for sensitization to HDM with sheepskin in infancy was 2.27 (95% CI: 1.14, 4.55), P = 0.020. The adjusted RR for sensitization to HDM with the use of plastic mattress covers in infancy was 2.06 (95% CI: 1.22, 3.51), P = 0.007. The use of a foam mattress in infancy was not related to subsequent HDM sensitization. Infant's bedding plays a role in the development of HDM sensitization in childhood. Intervention studies to examine mite allergen levels and the role of underbedding on the development of HDM sensitization are required.


A MELAS syndrome family harboring two mutations in mitochondrial genome.
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous mitochondrial disorder with variable clinical symptoms. Here, from the sequencing of the entire mitochondrial genome, we report a Korean MELAS family harboring two homoplasmic missense mutations, which were reported 9957T>C (Phe251Leu) transition mutation in the cytochrome c oxidase subunit 3 (COX3) gene and a novel 13849A>C (Asn505His) transversion mutation in the NADH dehydrogenase subunit 5 (ND5) gene. Neither of these mutations was found in 205 normal controls. Both mutations were identified from the proband and his mother, but not his father. The patients showed cataract symptom in addition to MELAS phenotype. We believe that the 9957T>C mutation is pathogenic, however, the 13849A>C mutation is of unclear significance. It is likely that the 13849A>C mutation might function as the secondary mutation which increase the expressivity of overlapping phenotypes of MELAS and cataract. This study also demonstrates the importance of full sequencing of mtDNA for the molecular genetic understanding of mitochondrial disorders.


von Willebrand's disease diagnosed after menorrhagia worsened from levonorgestrel intrauterine system.
Adult females with menorrhagia may have unrecognized mild von Willebrand's disease. Most females with known von Willebrand's disease report menorrhagia. A 38-year-old healthy female desired contraception. She described heavy menses lasting 8 days since menarche. History included uncomplicated vaginal deliveries. Physical examination was normal. The levonorgestrel intrauterine system was placed. Her menorrhagia then worsened to 14 successive days each month. Evaluation revealed mild von Willebrand's disease. At 19 months of follow-up, she retained her levonorgestrel intrauterine system and avoided pregnancy. Her menses slowly improved to spotting for 8 days each month. Von Willebrand's disease is a likely cause of menorrhagia that goes unrecognized as well as a potential cause for "failed" conservative treatment for menorrhagia. Understanding the cause of menorrhagia is an important aspect of evaluating this common symptom.


Mindfulness as a Protective Factor for Dissatisfaction in HCWs: The Moderating Role of Mindful Attention between Climate Stress and Job Satisfaction.
With the aim of investigating the possible moderating effect of job control and dispositional mindfulness between different sources of organizational stress and job satisfaction, a correlational study was designed involving health care workers (HCWs). The following questionnaires were administered and completed by 237 HCWs: (1) Occupational Stress Indicator (OSI), to measure the sources of stress at work (managerial role, climate power, climate structure, internal relationships), and job satisfaction; (2) Mindfulness Attention Awareness Scale (MAAS) to assess the individual's level of attention to what is taking place in the present; (3) Job Control Scale (JCS) to assess the perceived control at work. Hierarchical regression analyses were used to test the hypothesized relationships between variables; the results showed that, between the different sources of stress, the organizational climate dimension was negatively associated with job satisfaction; moreover, mindfulness attention moderated the relationship between climate stress and job satisfaction; unexpectedly, the interaction between job control and the organizational climate dimension was not significant in affecting job satisfaction. This study can provide useful information for Human Resources Management (HRM) practices regarding job and mental control interventions and empowerment, and possibly offer a new interpretation of the role of attention to what is happening in the present moment and autonomy between climate stressors and occupational satisfaction.


GO-BEYOND: a real-world study of persistence of golimumab in patients with axial spondyloarthritis and rheumatoid arthritis in Turkey.
Aim: To evaluate the retention rate of golimumab (GLM) in patients with rheumatoid arthritis (RA) and axial spondyloarthritis (ax-SpA). Materials & methods: Patients had received/were receiving GLM as their first or second biological drug for at least 3 months. We recorded demographic and clinical data, data on drug continuation and disease activity. Patients were classified as biologic-naive and biologic-experienced. Results: The study included 60 RA and 269 ax-SpA patients. At month 24, the retention rates were 67.2 and 57.1% (biologic-naive and biologic-experienced RA) and 74.8 and 80.4% (anti-TNF-naive and -experienced ax-SpA). No significant differences in retention were observed between the biologic-naive and -experienced groups for either disease. Conclusion: The results of this study confirm the effectiveness of GLM in the treatment of RA and axSpA with good retention rates at 2 years in a real-world setting in Turkey.


The Pupil Evaluation Inventory. A sociometric technique for assessing children's social behavior.
The Pupil Evaluation Inventory was developed to assess peer ratings of the behavior of male and female children in grades one through nine. Three homogeneous and stable factors emerged from a factor analyss: Aggression, Withdrawal and Likeability. High interrater agreement between male and female raters, stability of factorial structure, high internal consistency, and moderate concurrent validity were found across sex and grade levels. Test-retest reliability was high for a separate sample of third and sixth graders. There was a tendency for higher internal consistency and teacher-peer correlations for the Aggression factor.


Comparison of the effects of Hepatic-Aid and a Casein modular diet on encephalopathy, plasma amino acids, and nitrogen balance in cirrhotic patients.
Hepatic-Aid is purported to ameliorate encephalopathy and promote positive nitrogen balance in protein-intolerant, cirrhotic patients by correcting their imbalanced amino acid profile. This study evaluated Hepatic-Acid by comparing a 50-g Casein diet with an identical diet with 20-g Casein/30-g Hepatic-Aid per day in a cross-over study. Four patients with biopsy-proven stable cirrhosis, encephalopathy, and under-nutrition were studied. Each study period included three days of equilibration and eight days of metabolic balance, with the following measured at baseline and on balance days 5 and 8: routine biochemistry, fasting ammonia, psychometric tests, EEG, and plasma amino acid profiles. There was no significant change in clinical status, routine biochemistry, fasting ammonia, psychometrics or EEG between the two study periods. Mean (+/-SD) nitrogen balance on the Casein diet at 1.5 +/- 1.5 g/day was not significantly different from that on the Hepatic-Aid diet at 1.5 +/- 1.2 g/day. Plasma amino acid profiles showed a significant fall (p less than 0.05) in fasting and intraprandial tyrosine (tyr) and phenylalanine (phe) on Hepatic-Aid, but only intraprandial leucine (leu), isoleucine (ile), and valine (val) were significantly increased (p less than 0.05) on Hepatic-Aid. The ratio leu + ile + val to tyr + phe was significantly increased (p less than 0.05) on Hepatic-Aid. It is concluded that Hepatic-Aid, as given in this study, maintains N balance similar to Casein, alters the amino acid profile towards normal, but does not ameliorate encephalopathy.


Calcium and/or Vitamin D Supplementation for the Prevention of Fragility Fractures: Who Needs It?
Vitamin D and calcium have different biological functions, so the need for supplementation, and its safety and efficacy, need to be evaluated for each separately. Vitamin D deficiency is usually the result of low sunlight exposure (e.g., in frail older people, those who are veiled, those with dark-skin living at higher latitudes) and is reversible with calciferol 400-800 IU/day. Calcium supplements produce a 1% increase in bone density in the first year of use, without further increases subsequently. Vitamin D supplements do not improve bone density in clinical trials except in analyses of subgroups with baseline levels of 25-hydroxyvitamin D <30 nmol/L. Supplementation with calcium, vitamin D, or their combination does not prevent fractures in community-dwelling adults, but a large study in vitamin D-deficient nursing home residents did demonstrate fracture prevention. When treating osteoporosis, co-administration of calcium with anti-resorptive drugs has not been shown to impact on treatment efficacy. Correction of severe vitamin D deficiency (<25 nmol/L) is necessary before use of potent anti-resorptive drugs to avoid hypocalcemia. Calcium supplements cause gastrointestinal side effects, particularly constipation, and increase the risk of kidney stones and, probably, heart attacks by about 20%. Low-dose vitamin D is safe, but doses >4000 IU/day have been associated with more falls and fractures. Current evidence does not support use of either calcium or vitamin D supplements in healthy community-dwelling adults.


Cryptic Speciation in the Genus Cryptoglena (Euglenaceae) Revealed by Nuclear and Plastid SSU and LSU rRNA Gene.
The photosynthetic euglenoid genus Cryptoglena is differentiated from other euglenoid genera by having a longitudinal sulcus, one chloroplast, two large trough-shaped paramylon plates positioned between the chloroplast and pellicle, and lack of metaboly. The genus contains only two species. To understand genetic diversity and taxonomy of Cryptoglena species, we analyzed molecular and morphological data from 25 strains. A combined data set of nuclear SSU and LSU and plastid SSU and LSU rRNA genes was analyzed using Bayesian, maximum likelihood, maximum parsimony, and distance (neighbor joining) methods. Although morphological data of all strains showed no significant species-specific pattern, molecular data segregated the taxa into five clades, two of which represented previously known species: C. skujae and C. pigra, and three of which were designated as the new species, C. soropigra, C. similis, and C. longisulca. Each species had unique molecular signatures that could be found in the plastid SSU rRNA Helix P23_1 and LSU rRNA H2 domain. The genetic similarity of intraspecies based on nr SSU rDNA ranged from 97.8% to 100% and interspecies ranged from 95.3% to 98.9%. Therefore, we propose three new species based on specific molecular signatures and gene divergence of the nr SSU rDNA sequences.


Unsaturated fatty acids and lipoxygenase products regulate phagocytic NADPH oxidase activity by a nondetergent mechanism.
Neutrophils produce reactive oxygen species (superoxide anion [O2-]) via activation of reduced nicotinamide dinucleotide phosphate oxidase. In the intact neutrophil, this enzyme can be activated by increases in cytosolic calcium, protein kinase C, and unsaturated fatty acids such as arachidonic acid, all of which are produced on stimulation by chemotactic peptides like N-formyl-methionyl-leucyl-phenylalanine. Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) do not stimulate the respiratory burst but instead prime the cell for an enhanced response by an appropriate stimulus. We examined the role and potential mechanisms of free fatty acids in stimulating or priming neutrophil O2- production. Except for arachidonic acid, the ability of an unsaturated fatty acid to stimulate O2- production was not correlated with its critical micellar concentration, suggesting that detergent action was not the primary mechanism. Eicosatetraynoic acid, which blocks further arachidonate metabolism by the 5- and 15-lipoxygenases, inhibited O2- production by arachidonic acid. However, eicosatetraenoic acid did not inhibit other unsaturated fatty acid or phorbol ester-induced O2- production, suggesting that the effects of arachidonic acid were mediated at least in part by a metabolite. The same negatively charged, unsaturated fatty acids that directly stimulated O2- production when used in micromolar concentrations also primed neutrophils when added in nanomolar concentrations. The amount of a priming response was independent of chain length or number of double bonds. The magnitude of priming observed in GM-CSF-treated cells could be reconstituted with combinations of arachidonic acid and its lipoxygenase products.(ABSTRACT TRUNCATED AT 250 WORDS)


Origin of high thermoelectric performance with a wide range of compositions for BixSb2-xTe3 single quintuple layers.
Composition regulation of semiconductors can engineer the band structures and hence optimize their properties for better applications. Herein, we report a BixSb2-xTe3 (BST) single QL with high ZT values (∼1.2 to ∼1.5) at 300 K across a wide range of compositions 0 < x≤ 1. The improved description of band structures by the unfold method reveals the multi-valley bands near the Fermi energy. The high power factor of a p-type BST single QL originates from the robust multi-valley character of valence bands. The wide composition range is ensured by the valence band maximum dominated by the antibonding states of Sb-Te2 bonds, which would be affected little by the disorder. The optimal composition for the BST single QL is attributed to the different contributions from Sb and Bi to the valence band edge. This work paves the way for the further combination of a large power factor and low thermal conductivity across a wide range of compositions.


Application of CRISPR-Cas9 Editing for Virus Engineering and the Development of Recombinant Viral Vaccines.
CRISPR-Cas technology, discovered originally as a bacterial defense system, has been extensively repurposed as a powerful tool for genome editing for multiple applications in biology. In the field of virology, CRISPR-Cas9 technology has been widely applied on genetic recombination and engineering of genomes of various viruses to ask some fundamental questions about virus-host interactions. Its high efficiency, specificity, versatility, and low cost have also provided great inspiration and hope in the field of vaccinology to solve a series of bottleneck problems in the development of recombinant viral vaccines. This review highlights the applications of CRISPR editing in the technological advances compared to the traditional approaches used for the construction of recombinant viral vaccines and vectors, the main factors affecting their application, and the challenges that need to be overcome for further streamlining their effective usage in the prevention and control of diseases. Factors affecting efficiency, target specificity, and fidelity of CRISPR-Cas editing in the context of viral genome editing and development of recombinant vaccines are also discussed.


Endogenous opiates modulate the pulsatile secretion of biologically active luteinizing hormone in man.
We studied the secretion of physiological pools of immunoreactive and biologically active luteinizing hormone in response to endogenous pulses of gonadotropin-releasing hormone (GNRH) in eugonadal men. Concentrations of immunoactive and bioactive luteinizing hormone (LH) were determined in blood drawn at 20-min intervals for 8 h in eight normal men under two conditions: (a) after placebo, in order to evaluate spontaneous LH pulsations in the basal state, and (b) after administration of the opiate-receptor antagonist, naltrexone, which is believed to amplify the pulsatile release of endogenous GNRH. Spontaneous and naltrexone-stimulated secretion of LH occurred in pulses of high biological activity, as measured in the RICT (rat interstitial cell testosterone bioassay), i.e., bioactive:immunoactive LH ratios within both spontaneous and naltrexone-stimulated LH pulses were higher than corresponding interpulse ratios (P less than 0.001). Quantitative characterization of the pulsatile release of bioactive LH revealed the following specific effects of opiate-receptor blockade: increased 8-h mean and integrated serum concentrations of bioactive LH (P less than 0.002), enhanced pulse frequency of bioactive LH release (P less than 0.001), and augmented peak amplitude of bio-LH pulses (P less than 0.01). Moreover, this increase in episodic secretion of bioactive LH was associated with increased 8-h mean and integrated serum testosterone concentrations in these men (P less than 0.05). We conclude the following: (a) LH is normally released in spontaneous pulses of high biological activity in men; (b) when the endogenous GNRH signal is amplified by opiate-receptor blockade, the pituitary gland releases more frequent bioactive LH pulses, which are of high amplitude and contain a high bioactive:immunoactive LH ratio. This increase in pulsatile release of bioactive LH quantitated in the RICT assay in vitro is reflected by acutely increased serum testosterone concentrations in vivo. We infer that modulation of the episodic GNRH signal by endogenous opiates provides another significant mechanism by which the hypothalamus can alter the biological activity of circulating gonadotropic hormone in man. Moreover, observed alterations in the pulsatile pattern of bioactive LH release were associated in turn with significant changes in testosterone concentrations. Thus, we hypothesize that alterations in the properties of the bioactive LH pulse signal can provide an important mechanism for regulating target-cell function within the gonad in states of health or disease.


Nationwide Trends in Incidence and Mortality of Stroke Among Younger and Older Adults in Denmark.
To investigate the extent to which the incidence and mortality of a first-time stroke among younger and older adults changed from 2005 to 2018 in Denmark using nationwide registries. We used the Danish Stroke Registry and the Danish National Patient Registry to identify patients 18 to 49 years of age (younger adults) and those ≥50 years of age (older adults) with a first-time ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. We computed age-standardized incidence rates and 30-day and 1-year mortality risks separately for younger and older adults and according to smaller age groups, stroke subtype, sex, and severity (Scandinavian Stroke Scale score). Average annual percentage changes (AAPCs) were computed to assess temporal trends. We identified 8,680 younger adults and 105,240 older adults with an ischemic stroke or intracerebral hemorrhage. The incidence rate per 100,000 person-years of ischemic stroke (20.8 in 2005 and 21.9 in 2018, AAPC -0.6 [95% confidence interval (CI) -1.5 to 0.3]) and intracerebral hemorrhage (2.2 in 2005 and 2.5 in 2018, AAPC 0.6 [95% CI -1.0 to 2.3]) remained steady in younger adults. In older adults, rates of ischemic stroke and intracerebral hemorrhage declined, particularly in those ≥70 years of age. Rates of subarachnoid hemorrhage declined, but more so in younger than older adults. Stroke mortality declined over time in both age groups, attributable largely to declines in the mortality after severe strokes. Most trends were similar for men and women. The incidence of ischemic stroke and intracerebral hemorrhage was steady in younger adults from 2005 to 2018, while it dropped in adults >70 years of age. Stroke mortality declined during this time.


Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain.
We tested the hypothesis that treatment of embolic stroke with recombinant human tissue plasminogen activator (rhtPA) alters cerebral expression of adhesion molecules. Male Wistar rats were subjected to middle cerebral artery occlusion by a single fibrin-rich clot. P-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) immunoreactivity was measured at 6 or 24 hours after embolic stroke in control rats and in rats treated with rhtPA at 1 or 4 hours after stroke. To examine the therapeutic efficacy of combined rhtPA and anti-ICAM-1 antibody treatment at 4 hours after embolization, ischemic lesion volumes were measured in rats treated with rhtPA alone, rats treated with rhtPA and anti-ICAM-1 antibody, and nontreated rats. Administration of rhtPA at 1 hour after embolization resulted in a significant reduction of adhesion molecule vascular immunoreactivity after embolization in the ipsilateral hemisphere compared with corresponding control rats. However, when rhtPA was administered to rats at 4 hours after embolization, significant increases of adhesion molecule immunoreactivity in the ipsilateral hemisphere were detected. A significant increase of ICAM-1 immunoreactivity was also detected in the contralateral hemisphere at 24 hours after ischemia. A significant reduction in lesion volume was found in rats treated with the combination of rhtPA and anti-ICAM-1 antibody compared with rats treated only with rhtPA. The present study suggests that the time of initiation of thrombolytic therapy alters vascular immunoreactivity of inflammatory adhesion molecules in the ischemic brain and that therapeutic benefit can be obtained by combining rhtPA and anti-ICAM-1 antibody treatment 4 hours after stroke.


Sex-linked genetic diversity and differentiation in a globally distributed avian species complex.
Sex chromosomes often bear distinct patterns of genetic variation due to unique patterns of inheritance and demography. The processes of mutation, recombination, genetic drift and selection also influence rates of evolution on sex chromosomes differently than autosomes. Measuring such differences provides information about how these processes shape genomic variation and their roles in the origin of species. To test hypotheses and predictions about patterns of autosomal and sex-linked genomic diversity and differentiation, we measured population genetic statistics within and between populations and subspecies of the barn swallow (Hirundo rustica) and performed explicit comparisons between autosomal and Z-linked genomic regions. We first tested for evidence of low Z-linked genetic diversity and high Z-linked population differentiation relative to autosomes, then for evidence that the Z chromosome bears greater ancestry information due to faster lineage sorting. Finally, we investigated geographical clines across hybrid zones for evidence that the Z chromosome is resistant to introgression due to selection against hybrids. We found evidence that the barn swallow mating system, demographic history and linked selection each contribute to low Z-linked diversity and high Z-linked differentiation. While incomplete lineage sorting is rampant across the genome, our results indicate faster sorting of ancestral polymorphism on the Z. Finally, hybrid zone analyses indicate barriers to introgression on the Z chromosome, suggesting that sex-linked traits are important in reproductive isolation, especially in migratory divide regions. Our study highlights how selection, gene flow and demography shape sex-linked genetic diversity and underlines the relevance of the Z chromosome in speciation.


Molecular Impact of Conventional and Electronic Cigarettes on Pulmonary Surfactant.
The alveolar epithelium is covered by a non-cellular layer consisting of an aqueous hypophase topped by pulmonary surfactant, a lipo-protein mixture with surface-active properties. Exposure to cigarette smoke (CS) affects lung physiology and is linked to the development of several diseases. The macroscopic effects of CS are determined by several types of cell and molecular dysfunction, which, among other consequences, lead to surfactant alterations. The purpose of this review is to summarize the published studies aimed at uncovering the effects of CS on both the lipid and protein constituents of surfactant, discussing the molecular mechanisms involved in surfactant homeostasis that are altered by CS. Although surfactant homeostasis has been the topic of several studies and some molecular pathways can be deduced from an analysis of the literature, it remains evident that many aspects of the mechanisms of action of CS on surfactant homeostasis deserve further investigation.


[Superparamagnetic iron oxide particles: what value has the T1 effect in the MR diagnosis of focal liver lesions?].
To evaluate the T1 effect of superparamagnetic iron oxide (SPIO) in MR imaging of focal hepatic lesions. 21 patients with 34 liver lesions (18 benign) were examined before and immediately after infusion of SPIO particles (Endorem) with a T1-weighted GRE- and SE sequence and a double echo SE sequence at 1.5T. Changes of lesion signal intensity and contrast-to-noise (C/N) ratio were measured in addition to a qualitative analysis of changes in liver vessel signal. In all cases a marked increase of liver vessel signal intensity was observed on T1-weighted images after SPIO infusion. In contrast to malignant lesions, haemangiomas and adenomas showed significant signal changes (p < 0.05) on T1-and T2-weighted images. Highest signal changes were achieved for haemangiomas on T1-GRE images (+80%) followed by T1-SE (+41%) and T2-SE (-42%). Malignant liver lesions exhibited highest C/Ns on T2-weighted postcontrast images. The T1-effect of Endorem offers no benefits in respect of detectability of malignant liver lesions. However, it is helpful in characterising haemangiomas and their differentiation from liver tumours.


The effects of sodium channel ligands on muscarinic receptor binding in mouse forebrain.
The neurotoxins veratridine and aconitine are best known for their abilities to open action potential sodium channels in neuronal and muscle cells. These neurotoxins were tested for their abilities to influence the binding of 3H-QNB in mouse forebrain employing a glass-fiber filtration assay. Veratridine and aconitine produced approximately 95% and 77% inhibition of muscarinic receptor specific 3H-QNB binding with IC50 values of 11 and 20 microM, respectively. Further analysis revealed that both veratridine and aconitine were competitive inhibitors of 3H-QNB binding. Tetrodotoxin, an antagonist of the actions of veratridine and aconitine on sodium channels, at 10 microM inhibited the binding of 3H-QNB by 9% in the presence of 10 microM veratridine while having no effect when used in combination with aconitine. These data indicate that there may be a relationship between muscarinic receptors and action potential sodium channels.


Cylindrical quasi-cavity waveguide for static wide angle pattern projection.
Beam deflection methods such as rotary mirrors and motorized turning optical heads suffer from a variety of electro-mechanical related problems which affect laser scanning performance. These include wobble, jitter, wear, windage and synchronization issues. A novel optical structure consisting of two concentric and cylindrical interfaces with unique optical coating properties for the static projection of a laser spot array over a wide angle is demonstrated. The resulting ray trajectory through the waveguide is modeled using linear equations. Spot size growth is modeled using previously defined ray transfer matrices for tilted optical elements. The model is validated by comparison with experimental spot size measurements for 20 transmitted beams. This novel form of spot projection can be used as the projection unit in optical sensing devices which range to multiple laser footprints.


Effect of glycemic control on microvascular complications in patients with type I diabetes mellitus.
The relation between the control of blood glucose levels and the progression of early diabetic retinopathy and the width of skeletal muscle capillary basement membrane was studied in 54 insulin-dependent diabetic patients. After initial ophthalmologic evaluation including seven-field fundus photography and fluorescein angiography and measurement of levels of glycosylated hemoglobin and width of skeletal muscle capillary basement membrane, the patients were divided into two groups: an experimental group of 30 patients who were treated with continuous subcutaneous insulin infusion and a control group of 24 patients who continued to receive conventional treatment--usually two injections of insulin daily. After a mean follow-up period of 31.4 months, the experimental group had a significant decrease in glycosylated hemoglobin levels as compared with baseline values (mean +/- SEM, 7.2 +/- 0.3 percent versus 10.1 +/- 0.4 percent), reflecting improved control of blood glucose levels. The conventional treatment group had no change in glycosylated hemoglobin levels after a mean of 33.5 months of follow-up. With use of either a modified Early Treatment Diabetic Retinopathy Study grading system or macular microaneurysm counts, the experimental treatment group showed significantly less progression of retinopathy (p less than 0.05). The skeletal muscle capillary basement membrane width was significantly reduced only in the experimental treatment group with stable or improved retinopathy and was unchanged in the control group. There was a tendency for skeletal muscle capillary basement membrane width to increase in thickness over time in those patients whose retinopathy worsened irrespective of treatment. It is concluded that meticulous diabetic control may slow the progression of early diabetic retinopathy. Changes in skeletal muscle capillary basement membrane width may reflect the course of diabetic retinopathy.


Structure, function, and cortical representation of the rat submandibular whisker trident.
Although the neurobiology of rodent facial whiskers has been studied intensively, little is known about sensing in other vibrissae. Here we describe the under-investigated submandibular "whisker trident" on the rat's chin. In this three-whisker array, a unique unpaired midline whisker is laterally flanked by two slightly shorter whiskers. All three whiskers point to the ground and are curved backwards. Unlike other whiskers, the trident is not located on an exposed body part. Trident vibrissae are not whisked and do not touch anything over long stretches of time. However, trident whiskers engage in sustained ground contact during head-down running while the animal is exploring or foraging. In biomechanical experiments, trident whiskers follow caudal ground movement more smoothly than facial whiskers. Remarkably, deflection angles decrease with increasing ground velocity. We identified one putative trident barrel in the left somatosensory cortex and two barrels in the right somatosensory cortex. The elongated putative trident-midline barrel is the longest and largest whisker barrel, suggesting that the midline trident whisker is of great functional significance. Cortical postsynaptic air-puff responses in the trident representation show much less temporal precision than facial whisker responses. Trident whiskers do not provide as much high-resolution information about object contacts as facial whiskers. Instead, our observations suggest an idiothetic function: their biomechanics allow trident whiskers to derive continuous measurements about ego motion from ground contacts. The midline position offers unique advantages in sensing heading direction in a laterally symmetric manner. The changes in trident deflection angle with velocity suggest that trident whiskers might function as a tactile speedometer.


Evaluation of graphene as an advantageous adsorbent for solid-phase extraction with chlorophenols as model analytes.
Graphene, a novel class of carbon nanostructures, possesses an ultrahigh specific surface area, and thus has great potentials for the use as sorbent materials. We herein demonstrate the use of graphene as a novel adsorbent for solid-phase extraction (SPE). Eight chlorophenols (CPs) as model analytes were extracted on a graphene-packed SPE cartridge, and then eluted with alkaline methanol. The concentrations in the eluate were determined by HPLC with multi-wavelength UV detection. Under the optimized conditions, high sensitivity (detection limits 0.1-0.4 ng/mL) and good reproducibility of CPs (RSDs 2.2-7.7% for run-to-run assays) were achieved. Comparative studies showed that graphene was superior to other adsorbents including C18 silica, graphitic carbon, single- and multi-walled carbon nanotubes for the extraction of CPs. Some other advantages of graphene as SPE adsorbent, such as good compatibility with various organic solvents, good reusability and no impact of sorbent drying, have also been demonstrated. The proposed method was successfully applied to the analysis of tap and river water samples with recoveries ranging from 77.2 to 116.6%. This work not only proposes a useful method for environmental water sample pretreatment, but also reveals great potentials of graphene as an excellent sorbent material in analytical processes.


Experimental evidence for gradient length-driven electron transport in tokamaks.
Energy transport by the electrons in a tokamak is examined in steady-state and power modulation experiments using electron cyclotron heating. The results are consistent with the assumption that temperature profiles are limited by a critical gradient length, leading to "stiff" profiles. The modulation experiments show that the stiffness factor increases with temperature. They strongly suggest that turbulence driven by the electron temperature gradient may be a dominant mechanism of electron transport. Although possibly not universal, these results are valid under various plasma conditions.


Restriction mapping and close relationship of the DNA of Streptomyces erythraeus phages 121 and SE-5.
The biological properties and genome structure of two actinophages, 121 and SE-5, infecting Streptomyces erythraeus were characterized. They had the same host range (limited to S. erythraeus) and similar DNA G + C contents (around 60 mol %). Restriction maps of their genomes also showed many similarities. The close relationship between the two phages was confirmed by DNA hybridization experiments: large parts of their genomes were homologous, except for a segment in the middle of the map, where no hybridization was detected.


[Features of pregnant women with diabetes mellitus].
It is about a quantitative study aimed at knowing the features of 105 pregnant women attended at Hospital de Clínicas de Porto Alegre, Brazil, from January 2000 to January 2001. The results allowed the analysis of the delivery as well as baby conditions in addition to the values of the glycemia profile during the gestation. Moreover, they supplied information regarding the completion of the gestations of diabetic women that have made their pre-natal care at the hospital. These results provide significant input for the health team that attend this group of pregnant women and safety for the team performance and, as a result, for the pregnant women.


Intrauterine-like growth rates can be achieved with premixed parenteral nutrition solution in preterm infants.
Growth failure in neonatal intensive care units is a major challenge for pediatricians and neonatologists. The use of early "aggressive" parenteral nutrition (PN), with >2.5 g/(kg ·d) of amino acids and at least 40 kcal/(kg ·d) of energy from the first day of life, has been shown to provide nutritional intakes in the range recommended by international guidelines, reducing nutritional deficit and the incidence of postnatal growth restriction in preterm infants. However, nutritional practices and adherence to recommendations may vary in different hospitals. Two ready-to-use (RTU), premixed parenteral solutions (PSs) designed for preterm infants have been prospectively evaluated: a binary RTU premixed PS from our hospital pharmacy and a commercially premixed 3-chamber bag (Baxter Healthcare). These premixed PSs provide nitrogen and energy intakes in the range of the most recent recommendations, reducing or eliminating the early cumulative nutritional deficit in very-low-birth-weight infants, and avoiding the development of postnatal growth restriction. A further rationale for RTU premixed PSs is that preterm infants require balanced PN that contains not only amino acids and energy but also minerals and electrolytes from the first day of life in order to reduce the incidence of metabolic disorders frequently reported in extremely-low-birth-weight infants during the early weeks of life.


Selenium in Cancer Rehabilitation-A Retrospective Study from a Specialized Clinic.
Micronutrient deficiencies are common at the time of cancer diagnosis and are associated with worse prognosis. Little is known about them in cancer rehabilitation. Data from routine health-related quality of life (HRQOL) were analyzed at an inpatient cancer rehabilitation center. Rehabilitation patients completed the EORTC QLQ-C30 questionnaire before and after multidisciplinary rehabilitation treatment and three months after discharge. Selenium and zinc status were measured in whole blood at these three time points. In case of selenium deficiency, up to 600 µg selenium per day as sodium selenite was supplemented for three weeks during and for three months after rehabilitation. A total of 271 patients (breast, colon, and pancreatic cancer) were included in the analysis. There was clinically meaningful improvement in many domains of the EORTC QLQ-C30 during rehabilitation. However, the effect often waned in the three months after. Prevalence for selenium deficiency varied between 34 to 90% depending on cancer type (breast < colon < pancreas). In contrast, zinc deficiency was rare. Daily selenium supplementation of 600 µg was more efficient to correct selenium deficiency compared to 300 µg selenium per day. Rehabilitation and increasing selenium status after rehabilitation were associated with improved global quality of life, physical and emotional functioning, and fatigue. In cancer patients with decreasing selenium status, values of global quality of life, physical and emotional functioning, and fatigue were back to the values at the beginning of rehabilitation. Selenium deficiency is common in cancer patients admitted to a cancer rehabilitation clinic. Selenium supplementation during rehabilitation effectively corrected selenium deficiency in most cases. The positive effects of rehabilitation persisted longer when selenium status did not decrease after rehabilitation.


[Treatment of type 2 diabetes mellitus with the alpha-glucosidase inhibitor Miglitol in the doctor's office].
In an observational study carried out in accordance with paragraph 67 (6) of the AMG and beginning in May 1998, 846 patients with type 2 diabetes mellitus were followed for a period of three months by general practitioners and internists. The aim was to acquire data on the efficacy and tolerability of the alpha-glucosidase inhibitor, Miglitol, used in the doctor's office setting. A major point of interest was to determine the feasibility of using a regimen of gradually increasing doses in daily practice. The parameters investigated were HbA1c, fasting blood glucose and changes in the patient's weight. Any side effects were recorded by the care-providing physician and evaluated in the global tolerability analysis. The demographic data showed a balanced distribution of male and female patients. The average age of the men was 62 years, of the women 65 years. At the start of the observation, 62% of the patients had polyneuropathy, 35% retinopathy, and 25% nephropathy. 620 patients (73.3%) had received prior antidiabetic treatment. Depending on tolerability, the dose of Miglitol was increased individually from an initial 3 x 50 mg to 3 x 100 mg. 63.8% of the patients remained at the initial dose of 3 x 50 mg. A clear decrease in both HbA1c and fasting blood glucose was observed under treatment. During the course of the three months, the BMI decreased slightly by an average of 0.4 kg/m2, a desirable side effect in this patient group. Adverse reactions occurred in 39 ofthe 846 patients in the form of flatulence, diarrhea and enterospasm. Treatment with the alpha-glucosidase inhibitor Miglitol proved to be highly effective and readily combinable with other antidiabetics. Its efficacy was assessed to be "very good" or "good" by 86.5% of the physicians, and more than 90% assessed its tolerability to be "very good" or "good".


Identification of novel Nrf2/Keap1 pathway mutations in pediatric acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells, characterized by a wide range of biological and clinical heterogeneity. Oxidative stress is a common problem observed in carcinogenesis and it is involved in developing treatment resistance. Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor is the main regulator of antioxidant responses. The levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nrf2 and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Recently, many studies have shown that most of the genes in the Nrf2/Keap1/nuclear factor kappa-B (NF-κB)/phosphotyrosine-independent ligand for the Lck SH2 domain Of 62 KDa (p62) pathway show abnormally high mutational variations in cancer. However, variations in the Nrf2/Keap1/NF-κB1/p62 pathway in pediatric ALL have not been thoroughly investigated, yet. Thirty children, who were diagnosed with pediatirc ALL were included in the study. The Nrf2/Keap1/NF-κB1/p62 pathway variants were analyzed by DNA sequencing analysis. The PolyPhen-2 program was used for identifying pathogenic mutations. Our study examined the molecular dynamics (MD) perspectives of the effect of A159T and E121K mutations on protein stability for the first time in the literature by using the GROMACS45 software package utilizing the OPSLAA force field. Of the detected 17 nucleotide changes, 6 were novel. The study predicted the potential pathological effect of two mutations p. A159T and p.E121K in the Keap1 gene. The MD perspectives revealed that the E121K mutant's observed structural behavior accounted for the key role of His-129 and E121K, where E121K exhibited much higher drift compared to His-129. For a future perspective, it would be meaningful to study the protein-small molecule interactions of the Keap1 protein to elaborate on the drug effects in patients carrying these mutations.


[Antibacterial activity of cefotiam against clinical isolates in the field of obstetrics and gynecology].
Antibacterial activity of cefotiam (CTM) against clinically isolated organisms in the field of obstetrics and gynecology was discussed as follows: In the point of view of the MICs peak, CTM was 1-fold worse than CEZ against Gram-positive bacteria, while, in the case of the concentration of CTM required to inhibit the growth of 80% or 90% of the total number of tested Gram-positive organism, antibacterial activity of CTM was approximately identical with that of CEZ, CMZ or SBPC. CTM against E. coli, K, pneumoniae, P. Mirabilis was 16-32-fold more effective than CEZ and 4-16-fold than CMZ. Against indole-positive organisms with CEZ was no effective, CTM was considerably effective. But antibacterial activity of CTM against B. fragilis was insufficient. However, in the case that no spore forming anaerobic organism involved in infectious disease, it is said that existence of aerobic organism is important. As E. coli is representative of aerobic organism, CTM with potent antibacterial activity against this organism is seemed to be effective antibiotic for the gynecological infection.


The use of selective serotonin receptor inhibitors (SSRIs) is not associated with increased risk of endoscopy-refractory bleeding, rebleeding or mortality in peptic ulcer bleeding.
Observational studies have consistently shown an increased risk of upper gastrointestinal bleeding in users of selective serotonin receptor inhibitors (SSRIs), probably explained by their inhibition of platelet aggregation. Therefore, treatment with SSRIs is often temporarily withheld in patients with peptic ulcer bleeding. However, abrupt discontinuation of SSRIs is associated with development of withdrawal symptoms in one-third of patients. Further data are needed to clarify whether treatment with SSRIs is associated with poor outcomes, which would support temporary discontinuation of treatment. To identify if treatment with SSRIs is associated with increased risk of: (1) endoscopy-refractory bleeding, (2) rebleeding or (3) 30-day mortality due to peptic ulcer bleeding. A nationwide cohort study. Analyses were performed on prospectively collected data on consecutive patients admitted to hospital with peptic ulcer bleeding in Denmark in the period 2006-2014. Logistic regression analyses were used to investigate the association between treatment with SSRIs and outcome following adjustment for pre-defined confounders. Sensitivity and subgroup analyses were performed to evaluate the validity of the findings. A total of 14 343 patients were included. Following adjustment, treatment with SSRIs was not associated with increased risk of endoscopy-refractory bleeding (odds ratio [OR] [95% Confidence Interval (CI)]: 1.03 [0.79-1.33]), rebleeding (OR [95% CI]: 0.96 [0.83-1.11]) or 30-day mortality (OR [95% CI]: 1.01 [0.85-1.19]. These findings were supported by sensitivity and subgroup analyses. According to our data, treatment with SSRIs does not influence the risk of endoscopy-refractory bleeding, rebleeding or 30-day mortality in peptic ulcer bleeding.


Percutaneous balloon dilation of severe pulmonary valve stenosis in patients with cyanosis and congestive heart failure.
This article reports outcomes of percutaneous balloon dilation in patients with severe pulmonary valve stenosis, in particular in those treated late with cyanosis, congestive heart failure, and pericardial effusion. Percutaneous balloon dilation is the treatment of choice for pulmonary valve stenosis. Although earlier intervention may produce better results, patients may present late with congestive heart failure and cyanosis. Fifty-five patients who underwent pulmonary valve balloon dilation, were grouped into two groups, based on the presence or absence of congestive right heart failure and/or central cyanosis. Group I included 33 patients with severe pulmonary valve stenosis, but without clinical evidence of congestive right heart failure in the form of liver enlargement, raised jugular venous pressure, and peripheral edema and/or central cyanosis and group II included 22 patients with severe pulmonary valve stenosis and congestive right heart failure and/or central cyanosis. Their outcomes were compared. Doppler measured transvalvar pressure gradient decreased from 110.2 ± 34.0 mm Hg before to 52.5 ± 28.7 mm Hg in group I after dilation (P < 0.001), and from 138.4 ± 32.3 mm Hg to 53.9 ± 19.3 mm Hg in group II, (P < 0.001). Complications included ventricular tachycardia/fibrillation in three patients and severe bradycardia in one patient in group II. Twelve patients in group II developed clinical and radiologic evidence of reperfusion injury/pulmonary edema within the first 24 hr of intervention and needed ventilation for 2-9 days. Three of these patients died from intractable pulmonary edema. On follow up, clinical and echocardiographic improvement parameters were similar in the two groups. Those patients with severe pulmonary valve stenosis with congestive right heart failure, especially those with pericardial effusion, ascites and cyanosis, represent an important technical and clinical challenge. They are a high-risk group with or without treatment. If they survive the procedure, they may still remain at a high risk in the first few days afterward. Maintaining their ventilator and inotropic support after balloon dilation may increase survival. However, excellent results can be obtained.


[Infusion of high doses of platidiam in the treatment of patients with germ cell testicular tumors].
Sixteen patients with metastases of germ cell tumours were given VAB-6 combination chemotherapy including vinblastine, actinomycin-D, cyclophosphamide, bleomycin and platidiam (cis-platin). To intensify treatment 150 mg/m2 platidiam was administered by 24--hour infusion. Complete remission was observed in eight (50%) patients after chemotherapy alone; additional three (18.8%) cases were rendered tumor--free by surgery. At 20-26 months posttreatment, two cases were in relapse, and ten patients were alive. Toxicity was moderate. Infusion of high-dose platidiam assures a high complete remission rate, particularly, in cases of advanced germ cell tumours.


Paleodietary analysis on the prehistoric population of El Hierro (Canary Islands).
In order to deepen our knowledge of the dietary habits of the prehispanic inhabitants of El Hierro, we have determined bone strontium (Sr), manganese (Mn), magnesium (Mg), copper (Cu), zinc (Zn), and calcium (Ca) in 52 human tibiae (23 belonging to males and 20 to females individuals) buried in a single burial cave; in 21 modern individuals who served as controls; and in 11 bones of herbivores found at archeological sites of the Canary Islands. Results suggest that females consumed a more vegetarian diet, although site-corrected Sr/Ca ratio of both males and females speaks for a mixed-diet consumption.


[Higher levels of urokinase plasminogen activator system components in the airways of chronic obstructive pulmonary disease patients].
To investigate the state and the pathophysiologic significances of urinary plasminogen activator system components in airways of patients with chronic obstructive pulmonary disease (COPD). (1) Assay of induced sputum: 56 patients with COPD in stable clinical conditions (COPD group), aged (51 +/- 11) years with forced expiratory volume in one second of predicted % (FEV1% predicted) (53.5 +/- 14.4)% predicted, and 26 healthy control subjects (control group), aged (46 +/- 9) years; FEV1% predicted (85.1 +/- 1.0)% were studied. Levels of urokinase plasminogen activator system components in induced sputum, urokinase plasminogen activator (u-PA), urokinase plasminogen activator receptor (u-PAR), plasminogen activator inhibitor-1 (PAI-1) and interleukin-8 (IL-8), interferon-gamma (IFN-gamma), tumor necrosis factor (TNF-alpha), and interleukin-10 (IL-10) were determined by enzyme linked immunosorbent assay. (2) Pathological section of resected lung tissue: The study subjects included 11 patients receiving lung lobectomy for COPD with emphysematous bullae, aged (53 +/- 7) years, FEV1% predicted (58.3 +/- 6.6)%; as well as 10 non-COPD patients receiving lung lobectomy for local lesions with normal lung function, aged (47 +/- 12) years, FEV1% predicted (84.3 +/- 1.6)%, of which 3 were inflammatory pseudotumor, 5 were hamartoma, and 2 tuberculoma as the control. Cell expression of u-PA, u-PAR, PAI-1 in the pulmonary pathologic sections was investigated by immunohistochemistry. Induced sputum of COPD patients showed significant increase in u-PAR, PAI-1, and IL-8 compared to the control subjects, (570 +/- 614) ng/L vs (97 +/- 74) ng/L (t = 5.629, P < 0.01), (6162 +/- 9247) ng/L vs (574 +/- 731) ng/L (t = 4.346, P < 0.01) and (12,370 +/- 17,292) ng/L vs (1868 +/- 1905) ng/L (t = 4.486, all P < 0.01); and there were no differences in u-PA, IFN-gamma, TNF-alpha, and IL-10. Correlation analysis showed that u-PAR and PAI were positively correlated with IL-8 in COPD patients (r = 0.483, 0.770, all P < 0.01), while PAI negatively correlated with FEV1% (r = -0.272, P < 0.05). No correlation was found in healthy control subjects. u-PAR was localized in alveolar epithelial cells, macrophages, neutrophils and lymphocytes in COPD subjects, while u-PAR was mainly localized in alveolar epithelial cells in the control subjects. The ratio of positive expression in alveolar epithelial cells of control subjects was significantly lower than in that of COPD subjects (33 +/- 18)% vs (49 +/- 16)% (t = 2.213, P < 0.05), while the detectable intensity of expression in these cells of control subjects was also weaker than that of COPD subjects. PAI-1 was localized in fibroblasts, macrophages and neutrophils in COPD subjects, while mainly localized in fibroblasts in control subjects; the ratio of positive expression in fibroblasts in control subjects was also significantly lower than that in COPD subjects (37 +/- 16)% vs (61 +/- 16)% (t = 3.419, P < 0.05), meanwhile the detectable intensity of expression in these cells of control subjects was weaker than that of COPD one. u-PA system components are important inflammatory mediators in airways of COPD. PAI-1 is most likely to play a significant role in airway remodelling of COPD.


Oxidation mechanism of aliphatic ethers: theoretical insights on the main reaction channels.
This paper presents a quantum chemical study on oxidation process of a series of aliphatic ethers. On the basis of a detailed theoretical work on diethyl ether oxidation, the mechanism has been reduced at three competing reactions: the β-scission of the alkyl radical (R(I)OR(II)(•)) issued from the initiation step, the isomerization of the peroxy radical (R(I)OR(II)OO(•)) produced by reaction of the alkyl radical with molecular oxygen, and the hydroperoxide production, a bimolecular reaction between the peroxy radical and an ether molecule that also regenerates a R(I)OR(II)(•) radical. Results obtained from DFT calculations, including thermochemistry and rate constant evaluations, have been reported and discussed. The influence of the presence of the oxygen atom in the ether skeleton has been evaluated by making a comparison between some ethers and parent hydrocarbons. In particular, it has been found that oxygen increases the reactivity of vicinal sites by lowering activation barriers and favors the stabilization of radicals. Direct proportionality relationships have been searched between activation and reaction enthalpies of each class of competing reactions, but one has been found only for the isomerization reaction.


Pathology and epidemiology of phocid herpesvirus-1 in wild and rehabilitating harbor seals (Phoca vitulina richardsi) in the northeastern Pacific.
Phocid herpesvirus-1 (PhHV-1, subfamily Alphaherpesvirinae) was isolated from harbor seals (Phoca vitulina vitulina) in the Netherlands in 1985, and was subsequently identified in Pacific harbor seals (Phoca vitulina richardsi) from California, USA in the 1990s. PhHV-1-associated pathology was first recognized in harbor seal carcasses submitted to a veterinary diagnostic laboratory in Abbotsford, British Columbia, Canada in 2000, and 63 cases were identified by 2008. A review of these cases indicated that PhHV-1-associated disease is widespread in harbor seals in the wild and within rehabilitation facilities in the coastal northeastern Pacific (including British Columbia, Canada, and Washington, USA). Morbidity and mortality occurred primarily in neonatal and weanling seal pups, and was due to PhHV-1 alone, or in combination with other disease processes. All cases occurred between July and October, corresponding to the pupping and weaning seasons in this area. Although previous publications have described the prevalence of antibody to PhHV-1 in harbor seals from British Columbia, Canada and Washington, USA this is the first study to focus on the epidemiology and pathology of the virus in this region.


Hepatoprotective benefits of vitamin C against perfluorooctane sulfonate-induced liver damage in mice through suppressing inflammatory reaction and ER stress.
Our previous studies show that vitamin C (VC) plays promising hepatoprotection in mice. Intrahepatic exposure of perfluorooctane sulfonate (PFOS) can induce dose-dependent cytotoxicity. However, pharmacology-based assessment of VC on PFOS remains uninvestigated. This study aimed to evaluate the therapeutic benefits of VC on inhibiting PFOS-induced liver steatosis in mice, followed by representative biochemical analysis and immunoassay. As results, VC was beneficial for reduced PFOS-induced liver damages, as showed in reductions of serological levels of transaminases (ALT and AST), lipids (TG and TC), fasting glucose and insulin, inflammatory cytokines (TNF-α and IL6), while content of fibroblast growth factor 21 (FGF21) in serum was increased. In addition, VC reduced histiocytic changes of PFOS-lesioned livers, as revealed in reduced TNF-α-labeled cells and increased FGF21-labeled cells in immunofluorescence assay. Further, intrahepatic expressions of endoplasmic reticulum (ER) stress-based ATF6, eIF2α, GRP78, XBP1 proteins were down-regulated by treatments of VC. Taken together, our preliminary findings set forth that VC exerts pharmacological benefits against PFOS-induced liver steatosis in mice, and the underlying biological mechanism may be linked to suppressing hepatocellular inflammatory reaction and ER stress.


Simulating emergence of novelties using agent-based models.
Understanding the growth and evolution of social networks is an important area of study, as these networks form the foundation for many popular online services such as social networking sites (SNS) and online games. However, previous models developed to explain the growth mechanisms of these networks have struggled to accurately reproduce certain behaviors that are frequently observed in real data, such as waves of novelty, in which new individuals or topics receive more attention than existing ones for a short period of time. In this study, we introduce a new model that incorporates context information into existing agent-based models in order to more accurately capture the structure and growth dynamics of these networks. Context information is introduced through labels based on the timing of appearance and relationships with antecedent agents. New agents are first added to the network when they are called by existing agents, and at this time they are also given a label. Agents added to the network at the same time by the same agent will have the same label. These labels are used to classify agents and give them different selection probabilities. This newly introduced selection probability creates a mechanism in which new agents receive attention beyond preferential attachment. By comparing the results of our model with real data on ten metrics, we demonstrate that it is able to produce behavior that more closely resembles real data. This improved understanding of the dynamics of social networks has important implications for designing effective interventions, including strategies for user acquisition and retention.


Peritoneal macrophages and infertility: the association between cell number and pelvic pathology.
Increased numbers of peritoneal macrophages have been repeatedly associated with infertility. Because the factors contributing to this intraperitoneal exudate are unknown, this study was carried out to determine which anatomic or endocrinologic abnormalities in infertile women might be associated with an increase in leukocyte numbers. The peritoneal fluid from 103 women was analyzed. Nonparametric data analysis demonstrated significantly greater cell counts in infertile women with endometriosis, compared with other infertile women (P less than 0.01) or fertile control subjects (P less than 0.005). Multiple regression analysis was then used to determine the relationship of individual variables to cell number without the influence of confounding factors. These data demonstrate that the best correlation with elevated macrophage number is in women who have infertility and no mechanical fertility factors (of which mild endometriosis is a subgroup). Thus, an increase in peritoneal macrophage number is not restricted to women with endometriosis but, rather, is seen in a subset of infertile women generally without mechanical or endocrinologic infertility factors.


Life span and distribution of Onchocerca volvulus microfilariae in mice.
Microfilariae of Onchocerca volvulus obtained from onchocercomas were inoculated subcutaneously into the inguinal region of mice. Microfilariae disseminated rapidly, invading the tail and lungs within 1 hr and the ears within 3 hr postinoculation. During the early period of infection microfilariae appeared in the eyes, ears, viscera, pelt, carcass, and tail; later, the microfilariae tended to accumulate in the tail. Liver microfilariae were recovered up to 12 wk postinoculation. Intraperitoneal inoculation and subcutaneous inoculation into the inguinal region resulted in the concentration of microfilariae in the tail, whereas inoculation into the scalp caused microfilarial accumulation in the ears.


[Prophylaxis of neurological manifestations of lumbar osteochondrosis: intermediate results, unsolved problems and some methodologic aspects].
Issues of prophylaxis and rehabilitation are considered as regards neurologic manifestations of spinal osteochondrosis (NMSO). NMSO primary prophylaxis requires investigation and quantitative evaluation of the disease risk factors, epidemiologic determination of both incidence and prevalence in different groups of population in various periods of time. The standard risk group of NMSO in Byelorussian consists of population of 40-49-year-olds. Some professions may be risk factors for both onset and relapse of NMSO. Secondary prophylaxis of NMSO concerns elevated relapse risk, screening for individuals with either subclinic or early clinic manifestations of the disease. The computer screening-system has been created to identify a group at high risk of NMSO onset or relapse, to keep records, to print documents. It also gives chance to carry out individual prophylaxis of the high risk in the course of mass examination of employees.


A homology model of the pore region of HCN channels.
HCN channels are activated by membrane hyperpolarization and regulated by cyclic nucleotides, such as cyclic adenosine-mono-phosphate (cAMP). Here we present structural models of the pore region of these channels obtained by using homology modeling and validated against spatial constraints derived from electrophysiological experiments. For the construction of the models we make two major assumptions, justified by electrophysiological observations: i), in the closed state, the topology of the inner pore of HCN channels is similar to that of K(+) channels. In particular, the orientation of the S5 and S6 helices of HCN channels is very similar to that of the corresponding helices of the K(+) KcsA and K(+) KirBac1.1 channels. Thus, we use as templates the x-ray structure of these K(+) channels. ii), In the open state, the S6 helix is bent further than it is in the closed state, as suggested (but not proven) by experimental data. For this reason, the template of the open conformation is the x-ray structure of the MthK channel. The structural models of the closed state turn out to be consistent with all the available electrophysiological data. The model of the open state turned out to be consistent with all the available electrophysiological data in the filter region, including additional experimental data performed in this work. However, it required the introduction of an appropriate, experimentally derived constraint for the S6 helix. Our modeling provides a structural framework for understanding several functional properties of HCN channels: i), the cysteine ring at the inner mouth of the pore may act as a sensor of the intracellular oxidizing/reducing conditions; ii), the bending amplitude of the S6 helix upon gating appears to be significantly smaller than that found in MthK channels; iii), the reduced ionic selectivity of HCN channels, relative to that of K(+) channels, may be caused, at least in part, by the larger flexibility of the inner pore of HCN channels.


[Cognitive-behavioral therapy for auditory hallucinations resistant to neuroleptic treatment].
The aim of this study is to test the feasibility and the efficacy of a cognitive and behavior therapy manual for auditory hallucinations with persons suffering from schizophrenia in a French-speaking environment and under natural clinical conditions. Eight patients met ICD-10 criteria for paranoid schizophrenia, 2 for hebephrenic schizophrenia and 1 for schizoaffective disorder. All were hearing voices daily. Patients followed the intervention for 3 to 6 months according to their individual rhythms. Participants filled up questionnaires at pre-test, post-test and three months follow-up. The instruments were the Belief About Voice Questionnaire--Revised and two seven points scales about frequency of hallucinations and attribution of the source of the voices. Results show a decrease of voices' frequency and improvement in attributing the voices rather to an internal than to an external source. Malevolent or benevolent beliefs about voices are significantly decreased at follow-up as well as efforts at coping with hallucinations. Results should be interpreted with caution because of the small number of subjects. The sample may not be representative of patients with persistent symptoms since there is an over representation of patients with benevolent voices and an under representation of patients with substance misuse.


Illusory spirals and loops in crystal growth.
The theory of dislocation-controlled crystal growth identifies a continuous spiral step with an emergent lattice displacement on a crystal surface; a mechanistic corollary is that closely spaced, oppositely winding spirals merge to form concentric loops. In situ atomic force microscopy of step propagation on pathological L-cystine crystals did indeed show spirals and islands with step heights of one lattice displacement. We show by analysis of the rates of growth of smaller steps only one molecule high that the major morphological spirals and loops are actually consequences of the bunching of the smaller steps. The morphology of the bunched steps actually inverts the predictions of the theory: Spirals arise from pairs of dislocations, loops from single dislocations. Only through numerical simulation of the growth is it revealed how normal growth of anisotropic layers of molecules within the highly symmetrical crystals can conspire to create features in apparent violation of the classic theory.


Clinical Manifestations Associated With the N-Terminal-Acetyltransferase NAA10 Gene Mutation in a Girl: Ogden Syndrome.
Ogden syndrome is a rare X-linked disorder caused by pathogenic variants in the NAA10 gene. This syndrome, reported in just over 20 children, has been associated with dysmorphic features, failure to thrive, developmental impairments, hypotonia, and cardiac arrhythmias. We describe a 14-year-old girl who presented in infancy with hypotonia, global developmental delay, and dysmorphic features. She later developed autism spectrum disorder, epileptic encephalopathy, extrapyramidal signs, early morning lethargy with hypersomnolence, and hypertension with left ventricular hypertrophy. Magnetic resonance imaging showed a thin corpus callosum and progressive white matter loss. Whole exome sequencing identified a de novo pathogenic variant in the NAA10 gene (c.247C>T, p.R83C). Much of her early presentation was in keeping with what has been previously described with Ogden syndrome. We have identified additional evolving neurological impairments in this, to date, oldest documented girl with Ogden syndrome. We recommend screening patients with Ogden syndrome for these newly identified features of early life trajectories to guide management.


Neuraminidase inhibitors: zanamivir and oseltamivir.
To review the pharmacology, pharmacokinetics, efficacy, and safety of zanamivir and oseltamivir for the prophylaxis and treatment of influenza. A MEDLINE search restricted to English-language journals was conducted (1980-May 2000). All efficacy and safety trials were included if conducted in humans and published in a journal. Abstracts were included if no other data source was available. Zanamivir and oseltamivir block influenza neuraminidase and prevent the cleavage of sialic acid residues, thus interfering with progeny virus dispersement within the mucosal secretions and reducing viral infectivity. The neuraminidase trials for prophylaxis and treatment of influenza enrolled predominantly young (mean age 29-37 y), healthy, mostly unvaccinated individuals who were at the lowest risk of influenza and its complications. When zanamivir 10 mg inhaled twice daily or oseltamivir 75 mg orally twice daily were used for treatment, systemic symptoms such as myalgias, fever, and headache were reduced by approximately 0.7-1.5 days. Greater efficacy (symptom reduction by 1.5-2.0 d) was noted in proven cases of influenza infection, in febrile patients, and in patients who received the treatment medication within 30 hours of symptom onset. Clinical efficacy did not increase when doses higher than the treatment dose approved by the Food and Drug Administration were used. When given for prophylaxis, zanamivir 10 mg inhaled once daily or oseltamivir 75 mg orally once daily was used for four to six weeks and achieved protective clinical efficacy for laboratory-confirmed influenza ranging from 67% to 74%, depending on whether culture or serologic tests were performed. The most common adverse effects (usually < 5%) included upper respiratory tract symptoms. Patients with asthma or chronic obstructive pulmonary disease who received zanamivir had an increased incidence of a > 20% decline in forced expiratory volume in one second or peak expiratory flow rates. Headaches, nausea, and vomiting were more frequent in the oseltamivir groups than in placebo groups. The most common gastrointestinal adverse effects, nausea and vomiting, were reduced to approximately 10% by administering the medication with food. Zanamivir and oseltamivir are more effective in preventing culture-positive influenza or for treatment of culture-positive influenza in febrile (> or = 37.8 degrees C) individuals. Treatment is more effective if initiated within 30 hours of symptom onset in febrile individuals; however, it is difficult to meet these criteria. More realistically, clinical efficacy is closer to 60-70% and, for treatment started within 48 hours for laboratory-confirmed influenza, symptom reduction is approximately 0.7-1.5 days. If used appropriately to minimize the development of resistance, the neuraminidase inhibitors represent a new and unique class of antiinfluenza agents that can potentially reduce the morbidity associated with influenza.


Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal.
Severe malaria anemia is characterized by inhibited/altered erythropoiesis and presence of hemozoin-(HZ)-laden bone-marrow macrophages. HZ mediates peroxidation of unsaturated fatty acids and production of bioactive aldehydes such as 4-hydroxynonenal (HNE). HZ-laden human monocytes inhibited growth of cocultivated human erythroid cells and produced HNE that diffused to adjacent cells generating HNE-protein adducts. Cocultivation with HZ or treatment with low micromolar HNE inhibited growth of erythroid cells interfering with cell cycle without apoptosis. After HZ/HNE treatment, 2 critical proteins in cell-cycle regulation, p53 and p21, were increased and the retinoblastoma protein, central regulator of G₁-to-S-phase transition, was consequently hypophosphorylated, while GATA-1, master transcription factor in erythropoiesis was reduced. The resultant decreased expression of cyclin A and D2 retarded cell-cycle progression in erythroid cells and the K562 cell line. As a second major effect, HZ and HNE inhibited protein expression of crucial receptors (R): transferrinR1, stem cell factorR, interleukin-3R, and erythropoietinR. The reduced receptor expression and the impaired cell-cycle activity decreased the production of cells expressing glycophorin-A and hemoglobin. Present data confirm the inhibitory role of HZ, identify HNE as one HZ-generated inhibitory molecule and describe molecular targets of HNE in erythroid progenitors possibly involved in erythropoiesis inhibition in malaria anemia.


[Comparison of hemodynamic responses to orotracheal intubation between using GlideScope videolaryngoscope and fiberoptic bronchoscope].
To compare the hemodynamic responses to orotracheal intubation with GlideScope videolaryngoscope (GSVL) and with fiberoptic bronchoscope (FOB) after induction of general anesthesia. Totally 57 ASA physical status I - II adult patients undergoing elective plastic surgery and requiring orotracheal intubation were randomly allocated to either GSVL group (n = 29) or FOB group (n = 28). After a routine intravenous anesthetic induction, orotracheal intubation was performed. Noninvasive blood pressure (BP) and heart rate (HR) were recorded before and after anesthetic induction, at intubation and thereafter at 1 minute interval for 5 minutes. The intubation time was not significantly different between the two groups (P > 0.05). After intubation, BP and HR exhibited significant increases compared to the post-induction values in both groups, but the maximum values of BP did not exceed the pre-induction values while the maximum value of HR was higher than the pre-induction value. During the observation, BP and HR at all time points as well as the maximum values of BP and HR had no significant differences between the two groups (P > 0.05). The orotracheal intubations using FOB and GSVL result in similar hemodynamic responses.


PPAR-α Agonist Fenofibrate Upregulates Tetrahydrobiopterin Level through Increasing the Expression of Guanosine 5'-Triphosphate Cyclohydrolase-I in Human Umbilical Vein Endothelial Cells.
Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide (NO) synthase. Guanosine 5'-triphosphate cyclohydrolase-I (GTPCH-I) is a key limiting enzyme for BH4 synthesis. In the present in vitro study, we investigated whether peroxisome proliferator-activated receptor α (PPAR-α) agonist fenofibrate could recouple eNOS by reversing low-expression of intracellular BH4 in endothelial cells and discussed the potential mechanisms. After human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) for 24 hours, the levels of cellular eNOS, BH4 and cell supernatant NO were significantly reduced compared to control group. And the fluorescence intensity of intracellular ROS was significantly increased. But pretreated with fenofibrate (10 umol/L) for 2 hours before cells were induced by LPS, the levels of eNOS, NO, and BH4 were significantly raised compared to LPS treatment alone. ROS production was markedly reduced in fenofibrate group than LPS group. In addition, our results showed that the level of intracellular GTPCH-I detected by western blot was increased in a concentration-dependent manner after being treated with fenofibrate. These results suggested that fenofibrate might help protect endothelial function and against atherosclerosis by increasing level of BH4 and decreasing production of ROS through upregulating the level of intracellular GTPCH-I.


Wildfires Increase Concentrations of Hazardous Air Pollutants in Downwind Communities.
Due in part to climate change, wildfire activity is increasing, with the potential for greater public health impact from smoke in downwind communities. Studies examining the health effects of wildfire smoke have focused primarily on fine particulate matter (PM2.5), but there is a need to better characterize other constituents, such as hazardous air pollutants (HAPs). HAPs are chemicals known or suspected to cause cancer or other serious health effects that are regulated by the United States (US) Environmental Protection Agency. Here, we analyzed concentrations of 21 HAPs in wildfire smoke from 2006 to 2020 at 309 monitors across the western US. Additionally, we examined HAP concentrations measured in a major population center (San Jose, CA) affected by multiple fires from 2017 to 2020. We found that concentrations of select HAPs, namely acetaldehyde, acrolein, chloroform, formaldehyde, manganese, and tetrachloroethylene, were all significantly elevated on smoke-impacted versus nonsmoke days (P < 0.05). The largest median increase on smoke-impacted days was observed for formaldehyde, 1.3 μg/m3 (43%) higher than that on nonsmoke days. Acetaldehyde increased 0.73 μg/m3 (36%), and acrolein increased 0.14 μg/m3 (34%). By better characterizing these chemicals in wildfire smoke, we anticipate that this research will aid efforts to reduce exposures in downwind communities.


Principles of pharmacoeconomic analysis of drug therapy.
Economic analyses have become increasingly important in healthcare in general and with respect to pharmaceuticals in particular. If economic analyses are to play an important and useful role in the allocation of scarce healthcare resources, then such analyses must be performed properly and with care. This article outlines some of the basic principles of pharmacoeconomic analysis. Every analysis should have an explicitly stated perspective, which, unless otherwise justified, should be a societal perspective. Cost minimisation, cost-effectiveness, cost-utility and cost-benefit analyses are a family of techniques used in economic analyses. Cost minimisation analysis is appropriate when alternative therapies have identical outcomes, but differ in costs. Cost-effectiveness analysis is appropriate when alternative therapies differ in clinical effectiveness but can be examined from the same dimension of health outcome. Cost-utility analysis can be used when alternative therapies may be examined using multiple dimensions of health outcome, such as morbidity and mortality. Cost-benefit analysis requires the benefits of therapy to be described in monetary units and is not usually the technique of choice. The technique used in an analysis should be described and explicitly defended according to the problem being examined. For each technique, the method of determining costs is the same; direct, indirect, and intangible costs can be considered. The specific costs to be used depend on the analytical perspective; a societal perspective implies the use of both direct and indirect economic costs. A modelling framework such as a decision tree, influence diagram, Markov chain, or network simulation must be used to structure the analysis explicitly. Regardless of the choice of framework, all modelling assumptions should be described. The mechanism of data collection for model inputs must be detailed and defended. Models must undergo careful verification and validation procedures. Following baseline analysis of the model, further analyses should examine the role of uncertainty in model assumptions and data.