Pharmacological and Safety Profile of Dexlansoprazole: A New Proton Pump Inhibitor - Implications for Treatment of Gastroesophageal Reflux Disease in the Asia Pacific Region.
Although gastroesophageal reflux disease is not as common in Asia as in western countries, the prevalence has increased substantially during the past decade. Gastroesophageal reflux disease is associated with considerable reductions in subjective well-being and work productivity, as well as increased healthcare use. Proton pump inhibitors (PPIs) are currently the most effective treatment for gastroesophageal reflux disease. However, there are limitations associated with these drugs in terms of partial and non-response. Dexlansoprazole is the first PPI with a dual delayed release formulation designed to provide 2 separate releases of medication to extend the duration of effective plasma drug concentration. Dexlansoprazole has been shown to be effective for healing of erosive esophagitis, and to improve subjective well-being by controlling 24-hour symptoms. Dexlansoprazole has also been shown to achieve good plasma concentration regardless of administration with food, providing flexible dosing. Studies in healthy volunteers showed no clinically important effects on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition, with no dose adjustment of clopidogrel necessary when coprescribed. This review discusses the role of the new generation PPI, dexlansoprazole, in the treatment of gastroesophageal reflux disease in Asia.


Trends on integrating technologies for mobile and personalized care. Findings from the section on health and clinical management.
Summarize current excellent research and trends in the field of Health and Clinical Management. Synopsis of the articles selected for the IMIA Yearbook 2013. Five papers from international peer-reviewed journals have been selected for the section of Health and Clinical Management. The selected articles illustrate current research regarding the Health and Clinical Management and showed that it is impacted by the importance of personalizing the care and integrating the use of mobile and connected technologies.


Spatial prediction of childhood malnutrition across space in Nigeria based on point-referenced data: an SPDE approach.
Malnutrition remains a leading cause of child mortality in Nigeria. The spatial analysis based on areal level approaches could, in reality, conceal variations at smaller units. Using point-referenced data from Nigeria Demographic and Health Survey, we quantify the prevalence of malnutrition among under-five children in Nigeria at 1.63 by 1.63 km spatial resolution, and compute the exceedance probability maps for stunting, wasting and underweight at 20% threshold level using the stochastic partial differential equation approach with Bayesian inference based on integrated nested Laplace approximation. Results show divergence prevalence of the malnutrition indicators among children living in neighbouring locations and that the prevalence of stunting and underweight increase with age. The prevalence of stunting was uneven among children living in Kebbi, Zamfara, Sokoto, Kaduna, Kano, Katsina, Bauchi, Gombe and Taraba states with more concentrations in the northern fringes of some of the states. Except for few locations in about three states, the probability is more than 90% that the prevalence of stunting in all parts of the country exceeds 20% but this was not the case for wasting. The findings can assist in location-specific policy formulation and implementations.


Effect of peptichemio upon localization of injected radiolabelled lymphocytes in the lymphatic organs of antigen-stimulated mice.
Increased localization (trapping) of lymphocytes occurs in lymphoid organs following antigenic challenge. The effect of peptichemio (PTC) upon lymphocyte trapping in lymph nodes and spleen was investigated: the results demonstrate that the drug diminishes trapping in lymphatic organs. The depression of lymphocyte trapping may provide at least one mechanism whereby PTC achieves it immunosuppressive effects.


Antibody repertoire development in fetal and neonatal piglets. XIV. Highly restricted IGKV gene usage parallels the pattern seen with IGLV and IGHV.
Kappa transcripts from fetal piglets were compared to the recently reported kappa genome. Although five IGKV gene families are present in the genome, only IGKV1 and IGKV2 family genes are transcribed; the latter comprises >95% of the repertoire, in which two genes account for ~80%. We provisionally identified a new sequence allele of IGKV2-10 and two new IGKV genes that were not present in the genome of a single Duroc sow. One of these (IGKV2-1) accounted for 39% of the total pre-immune repertoire. The discovery of new IGKV genes and alleles in only 90 transcripts from mixed breeds, suggests considerable polymorphism and polygeny in the kappa locus of swine. Similar to lambda rearrangements, CDR3 length and diversity is restricted. The somatic mutation frequency is low and accumulates in especially CDR1. This transcriptional analysis of the pre-immune kappa repertoire completes a comparative study of all three Ig loci which has allowed the potential and actual combinatorial repertoire to be determined. Calculations show that combinatorial diversity in all three loci contribute comparatively little to the swine pre-immune antibody repertoire. Compared to humans that can potentially generate a million binding site variants, only 16-48 variant comprise 70% of the swine repertoire and 224 account for 95-100%. The frequency of somatic mutation does not differ among rearrangements from all three loci and the CDR3 diversity index shows that swine overwhelmingly generate their pre-immune repertoire by junctional diversity in heavy chain rearrangements.


Factors affecting sleep quality in patients with systemic lupus erythematosus.
This study aimed to assess the sleep quality and the factors affecting the sleep quality in patients with systemic lupus erythematosus (SLE). This was a descriptive and cross-sectional study conducted in 105 patients with SLE who were admitted to the rheumatology polyclinic of a university hospital between May and July 2017. The data were collected using a "Patient Description Form" and the "Pittsburgh Sleep Quality Index (PSQI)." The total mean (standard deviation) PSQI score of the patients was 7.81 (3.11). Duration of disease, presence of comorbid diseases, side effects of drugs, and sleep disruption and related problems were identified as factors affecting sleep quality. The model of the regression showed that side effects of drugs, sleep disruption, and trouble falling asleep suffered higher PSQI score (bad sleep quality). Results of this study showed that the sleep quality was generally poor in patients with SLE. Sleep quality was affected by some disease and sleep variables. Therefore, comprehensive sleep evaluation is necessary in the planning of treatment and care of SLE patients and to implement initiatives to improve sleep patterns in these patients.


ImPact test-retest reliability: reliably unreliable?
Computerized neuropsychological testing is commonly used in the assessment and management of sport-related concussion. Even though computerized testing is widespread, psychometric evidence for test-retest reliability is somewhat limited. Additional evidence for test-retest reliability is needed to optimize clinical decision making after concussion. To document test-retest reliability for a commercially available computerized neuropsychological test battery (ImPACT) using 2 different clinically relevant time intervals. Cross-sectional study. Two research laboratories. Group 1 (n = 46) consisted of 25 men and 21 women (age = 22.4 ± 1.89 years). Group 2 (n = 45) consisted of 17 men and 28 women (age = 20.9 ± 1.72 years). Both groups completed ImPACT forms 1, 2, and 3, which were delivered sequentially either at 1-week intervals (group 1) or at baseline, day 45, and day 50 (group 2). Group 2 also completed the Green Word Memory Test (WMT) as a measure of effort. Intraclass correlation coefficients (ICCs) were calculated for the composite scores of ImPACT between time points. Repeated-measures analysis of variance was used to evaluate changes in ImPACT and WMT results over time. The ICC values for group 1 ranged from 0.26 to 0.88 for the 4 ImPACT composite scores. The ICC values for group 2 ranged from 0.37 to 0.76. In group 1, ImPACT classified 37.0% and 46.0% of healthy participants as impaired at time points 2 and 3, respectively. In group 2, ImPACT classified 22.2% and 28.9% of healthy participants as impaired at time points 2 and 3, respectively. We found variable test-retest reliability for ImPACT metrics. Visual motor speed and reaction time demonstrated greater reliability than verbal and visual memory. Our current data support a multifaceted approach to concussion assessment using clinical examinations, symptom reports, cognitive testing, and balance assessment.


Preliminary estimation of the realistic optimum temperature for vegetation growth in China.
The estimation of optimum temperature of vegetation growth is very useful for a wide range of applications such as agriculture and climate change studies. Thermal conditions substantially affect vegetation growth. In this study, the normalized difference vegetation index (NDVI) and daily temperature data set from 1982 to 2006 for China were used to examine optimum temperature of vegetation growth. Based on a simple analysis of ecological amplitude and Shelford's law of tolerance, a scientific framework for calculating the optimum temperature was constructed. The optimum temperature range and referenced optimum temperature (ROT) of terrestrial vegetation were obtained and explored over different eco-geographical regions of China. The results showed that the relationship between NDVI and air temperature was significant over almost all of China, indicating that terrestrial vegetation growth was closely related to thermal conditions. ROTs were different in various regions. The lowest ROT, about 7.0 °C, occurred in the Qinghai-Tibet Plateau, while the highest ROT, more than 22.0 °C, occurred in the middle and lower reaches of the Yangtze River and the Southern China region.


A Ketamine Protocol and Intubation Rates for Psychiatric Air Medical Retrieval.
The air medical transfer of psychiatric patients with acute agitation is a regular requirement in only a few countries, with ours (Australia) being one of them. The optimal strategy has yet to be well described, ranging from physical restraints to general anesthesia with endotracheal intubation. In an Australian air medical service, Royal Flying Doctor Service (Queensland Section) rates of endotracheal intubation required for patient management were retrospectively compared before and after implementation of a ketamine sedation protocol for this patient population. A systematic retrospective review was performed using 9 years of data included in the Royal Flying Doctor Service (Queensland Section) electronic database (2004-2013). Coding for mental health as the primary diagnosis and intubation were the search criteria. A total of 1,478 patients were transferred during the study period, with 44 requiring intubation. This equates to intubation rates of 3.5% before protocol use compared with 2.3% after protocol implementation. In an Australian air medical service, the implementation of a ketamine sedation protocol for the management of the acutely agitated patient requiring air transfer has reduced the number of intubations in this patient group.


Whole-cell catalysis by surface display of fluorinase on Escherichia coli using N-terminal domain of ice nucleation protein.
Fluorinases play a unique role in the production of fluorine-containing organic molecules by biological methods. Whole-cell catalysis is a better choice in the large-scale fermentation processes, and over 60% of industrial biocatalysis uses this method. However, the in vivo catalytic efficiency of fluorinases is stuck with the mass transfer of the substrates. A gene sequence encoding a protein with fluorinase function was fused to the N-terminal of ice nucleation protein, and the fused fluorinase was expressed in Escherichia coli BL21(DE3) cells. SDS-PAGE and immunofluorescence microscopy were used to demonstrate the surface localization of the fusion protein. The fluorinase displayed on the surface showed good stability while retaining the catalytic activity. The engineered E.coli with surface-displayed fluorinase could be cultured to obtain a larger cell density, which was beneficial for industrial application. And 55% yield of 5'-fluorodeoxyadenosine (5'-FDA) from S-adenosyl-L-methionine (SAM) was achieved by using the whole-cell catalyst. Here, we created the fluorinase-containing surface display system on E.coli cells for the first time. The fluorinase was successfully displayed on the surface of E.coli and maintained its catalytic activity. The surface display provides a new solution for the industrial application of biological fluorination.


PLAGL2 increases adriamycin resistance and EMT in breast cancer cells by activating the Wnt pathway.
Adriamycin (ADR) is an effective treatment for breast cancer; nevertheless, it is often linked with acquired resistance in breast cancer cells, reducing ADR's therapeutic efficacy and increasing the risk of recurrence and poor prognosis. It has been revealed that the zinc-finger transcription factor pleomorphic adenoma gene like-2 (PLAGL2) is required for epithelial to mesenchymal transition (EMT) in cancer cells. Recent data indicates that PLAGL2 is also involved in regulating chemotherapeutic drug resistance, albeit the exact mechanism by which this happens remains unknown. This study examines the effect of PLAGL2 on adriamycin resistance and EMT in breast cancer cells. The small interfering RNA (siRNA) targeting PLAGL2 was transfected to breast cancer cells to alter PLAGL2 expression. Cell counting kit-8 (CCK-8) and colony formation assay detected cell growth and proliferation rate. Moreover, wound-healing and transwell assays were conducted to evaluate migration and invasion. Western blot (WB) checked the apoptosis and EMT-associated proteins. PLAGL2 expression is associated with breast cancer cells' acquired resistance to ADR in this investigation. Additionally, deletion of PLAGL2 was associated with enhanced sensitivity to ADR, reduced proliferation, migration, and invasion capabilities, increased E-cadherin levels, and reduced Wnt6, β-catenin, and DVL1 levels in ADR-resistant breast cancer cells (MCF-7/ADR and MDA-MB-231/ADR cells). PLAGL2 could bind to the promoter region of Wnt6 and promote its expression. Additionally, the results of this research established that Wnt signaling is implicated in breast cancer cells' resistance to ADR since BML-284, a Wnt signaling activator partly restored the sensitivity of MCF-7/ADR and MDA-MB-231/ADR cells to ADR. PLAGL2 promotes adriamycin resistance and cell aggressiveness in breast cancer cells via activating the Wnt signaling pathway.


Estimation of traversed distance in level walking using a single inertial measurement unit attached to the waist.
A method for estimating step length during level walking using a single inertial measurement unit is proposed. A combination of an optimally filtered direct and reverse integration technique and a velocity update technique for the initial velocity values identification was implemented to reduce the effects of the acceleration signals drift. The method takes advantage of the cyclic nature of gait. The inertial measurement unit was placed at waist level on the right side and the method was validated on eight subjects walking for 75 m while varying their speed. The traversed distance was estimated with an average error equal to 0.8% of the total walking distance.


Implicit learning: A way to improve visual search in spatial neglect?
Studies have shown that neglect patients are able to use stimulus regularities to orient faster toward the neglected side, without necessarily being aware of that information, or at the very least without being able to verbalize their knowledge. In order to better control for the involvement of explicit processes, the present study sought to test neglect patients' ability to detect more complex associations between stimuli using tasks similar to those used in implicit learning studies. Our results demonstrate that neglect patients had difficulties implicitly learning complex associations, contrary to what we found with controls. The possible influence of attentional and working memory impairments are discussed.


Kinetics of Mu DNA synthesis.
Mu specific DNA synthesis starts at 10 min after infection. All essentail amber mutants of Mu were tested for the ability to replicate in a non permissive host. Except for the amber mutants A and B, which were already known to be blocked in Mu DNA synthesis (Wijffelman et al., 1974), all the other mutants showed normal Mu DNA replication. Using mitomycin C-treated cells Mu DNA synthesis was found to start at about 20 min after induction. However using the much more sensitive method of DNA-RNA hybridization, it was found that the DNA synthesis starts already at 10 min after induction, and that at 20 min after induction about 7 copies of the Mu DNA are present per cell.


Frequency, pattern, and risk factors of postoperative recurrence of Crohn's disease after resection different from ileo-colonic.
The frequency of recurrence in Crohn's disease (CD) patients after curative resection different from the ileo-colonic is undefined. We aimed to assess the frequency, pattern, outcome, and risk factors of postoperative recurrence in CD patients under regular follow-up after anastomosis different from ileo-colonic. In a retrospective study, clinical records of 537 CD patients under regular follow-up from January 2001 to August 2007 were reviewed. The outcome after surgery was assessed on the basis of clinical records prospectively recorded. Previous resection was observed in 183 of 537 (34%) patients, including the ileo-colon in 145 (79%) and other gastrointestinal (GI) segments in 38 (21%). Recurrence was detected in 16 of 38 (42%) patients (all symptomatic) including five of 14 (35%) with ileostomy, five of five (100%) with ileo-rectal, three of 11 (27%) with ileo-ileal, one or four (25%) with colorectal, and two of three (33%) with duodenum-jejunal anastomosis. Ileo-colonic resection was reported in 145 of 183 (79%) patients, showing recurrence in 128 (88.3%) and symptomatic in 47 (36.7%) patients. The frequency of recurrence was higher in patients with ileo-colonic resection than in patients with other types of resection (128/145, 88% vs 16/38, 42%, p < 0.001). The frequency of symptomatic recurrence was lower in patients with ileo-colonic resection than in those with other resections (47/128, 37% vs 16/16, 100%; p < 0.001). Risk factors for recurrence were comparable in the two subgroups (smoke, odds ratio, OR 1.5 vs 1.4; appendectomy, OR 0.32 vs 0.33; familial inflammatory bowel disease, OR 0.43 vs 1.26). Postoperative recurrence is observed in a high proportion of CD patients after resection different from ileo-colon (including ileostomy), although at a lower frequency than observed after ileo-colonic resection.


Aprotic polar solvents inducing chromosomal malsegregation in yeast interfere with the assembly of porcine brain tubulin in vitro.
A number of aprotic solvents which had previously been found to induce mitotic aneuploidy in yeast were tested for their effects on re-assembly of twice recycled tubulin from pig brain. Some of the solvents which were strong aneuploidy-inducing mutagens in yeast slowed down tubulin assembly in vitro at concentrations lower than those required for aneuploidy induction. Ethyl acetate, methyl acetate, diethyl ketone and acetonitrile fell into this category. Other strong aneuploidy-inducing agents like acetone and 2-methoxyethyl acetate accelerated tubulin assembly. Non-genetically active methyl isopropyl ketone and isopropyl acetate both accelerated assembly, whereas methyl n-propyl ketone and n-propyl acetate were weak inducers of aneuploidy and slowed down the rate and extent of assembly. Those chemicals which slowed down the assembly rate also reduced the extent of assembly. Most chemicals which accelerated assembly also led to an increased extent of assembly, with the exception of isopropyl acetate. At the higher concentrations, however, a maximum assembly rate was reached which was followed by a slow decline. Although a perfect correlation between effects on the induction of chromosomal malsegregation and the interference with tubulin assembly in vitro was not seen, the experiments with tubulin were carried out using this class of chemicals because some of them strongly induced mitotic aneuploidy under conditions which suggested tubulin to be the prime target. The lack of a perfect coincidence might be due to species differences between the porcine brain and the yeast spindle tubulin, or the test for aneuploidy induction may have been negative because the concentrations required for an effect on yeast tubulin may be greater than the general lethal toxicity limit. Bearing this reservation in mind, the results suggest that the yeast aneuploidy test has a considerable predictive value for mammalian mutagenicity.


Studies of human germinal mutations by deoxyribonucleic acid hybridization.
Spontaneous mutations that occur in human germ cells contribute significantly to clinical disorders and result in premature mortality, incurable morbidity, mental handicap, and infertility. We have used molecular analysis of deoxyribonucleic acid to study the occurrence of spontaneous human germinal mutations. We examined 458 offspring and parents in 60 multigeneration human families. Probes for hypervariable loci were dispersed throughout all chromosomes to note the occurrence of new mutations. We found that both point mutations and insertion-deletion mutations occur frequently enough to be directly quantitated. The rates of occurrence detected at the molecular level are much greater than the rates detected with other modalities. The mutational rates at some loci approach 1% in live-born children. Such mutations appear to be sequence specific and related to the processes of meiosis or mitosis as they occur in the production of human gametes.


Determination of aglycone conjugated metabolites of scutellarin in rat plasma by HPLC.
A specific, precise and accurate high-performance liquid chromatography (HPLC) method for the determination of aglycone conjugated metabolites of scutellarin in plasma after enzymolysis to scutellarein (the aglycone of scutellarin) was developed and validated. The chromatographic separation was performed on a Lunar C18(2) reversed-phase column at a column temperature of 40 degrees C. The mobile phase, delivered at 1.0 ml/min, consisted of acetonitrile-KH2PO4 buffer (40 mM, pH 2.5) (33:67, v/v). The detection wavelength was set at 335 nm. Scutellarein and I.S. (quercetin) were isolated by a liquid-liquid extraction after incubating the plasma samples with beta-glucuronidase/sulfatase. The method was validated using scutellarin spiked plasma as standards. Linearity was confirmed in the concentration range of 0.2165-4.329 nmol/ml, R.S.D.s were within 8.32%, and the recoveries of scutellarein ranged from 101.2 to 108.6%. The method is applicable to the pharmacokinetic study of aglycone conjugated metabolites of scutellarin in rats after oral administration of scutellarin.


Paeoniflorin inhibited nod-like receptor protein-3 inflammasome and NF-κB-mediated inflammatory reactions in diabetic foot ulcer by inhibiting the chemokine receptor CXCR2.
Diabetic foot ulcer (DFU) is an invariably common complication of diabetes, characterized by delayed wound healing process and increased inflammation. Evidence has indicated that paeoniflorin exerts an anti-inflammatory effect in diabetic retinopathy. The current work was aimed to investigate the effect of paeoniflorin on inflammation and wound healing in DFU. DFU rat models by streptozotocin and skin biopsy punch, as well as high glucose-treated human immortalized keratinocytes (HaCaT) were established. Levels of blood glucose, wound contraction and proinflammatory cytokine were detected after paeoniflorin administration. Several essential targets associated with the NF-κB and Nod-like receptor protein-3 (NLRP3) signaling pathways were examined. Results showed markedly down-regulation of interleukin (IL)-1β, IL-18 and tumor necrosis factor-alpha in paeoniflorin-treated DFU rats. Paeoniflorin decreased the expression levels of chemokine receptor CXCR2, nuclear NF-κB and p-IκB (Ser36), as well as increased IκB level. Histological analysis and immunostaining showed lower inflammatory cells with decreased NLRP3 and cleaved caspase-1 levels following paeoniflorin treatment. Further in vitro evidence confirmed that paeoniflorin efficiently inhibited NLRP3 and NF-κB-mediated inflammation in DFU by inhibiting CXCR2. These findings are suggestive of greatly attenuated wound inflammation and better wound healing in paeoniflorin-treated DFU rats. Our study demonstrates that paeoniflorin is a potential therapeutic agent for DFU.


Mapping and analysis of quantitative trait loci in experimental populations.
Simple statistical methods for the study of quantitative trait loci (QTL), such as analysis of variance, have given way to methods that involve several markers and high-resolution genetic maps. As a result, the mapping community has been provided with statistical and computational tools that have much greater power than ever before for studying and locating multiple and interacting QTL. Apart from their immediate practical applications, the lessons learnt from this evolution of QTL methodology might also be generally relevant to other types of functional genomics approach that are aimed at the dissection of complex phenotypes, such as microarray assessment of gene expression.


Assembly Processes and Biogeographical Characteristics of Soil Bacterial Sub-communities of Different Habitats in Urban Green Spaces.
The process of urbanization is one of the most important human-driven activities that reshape the natural distribution of soil microorganisms. However, it is still unclear about the effects of urbanization on the different taxonomic soil bacterial community dynamics. In this study, we collected soil samples from highly urbanized the regions of Yangtze River Delta, Beijing-Tianjin-Hebei in China, to explore the bio-geographic patterns, assembly processes, and symbiotic patterns of abundant, moderate, and rare bacterial communities. We found that the number of moderate and rare taxa species were lower than that of abundant taxa, but their α-diversity index was higher than abundant taxa. Proteobacteria, Acidobacteria, Actinobacteria, Bacterioidetes, and Chloroflexi were the dominant phylum across all three sub-communities. And the β-diversity value of rare taxa was significantly higher than those of moderate and abundant taxa. Abundant, moderate, and rare sub-communities showed a weak distance-decay relationship, and the moderate taxa had the highest turnover rate of microbial geography in the context of urbanization. Diffusion limitation was the dominant process of soil bacterial community assembly. The co-occurrence networks of abundant, moderate, and rare taxa were dominated by positive correlations. The network of moderate taxa had the highest modularity, followed by abundant taxa. The main functions of the abundant, moderate, and rare taxa were related to Chemoheterotrophy and N transformations. Redundancy analysis showed that the dispersal limitation, climate, and soil properties were the main factors dominating bio-geographic differences in soil bacterial community diversity. We conclude that human-dominated urbanization processes have generated more uncertain survival pressures on soil bacteria, which resulted in a stronger linkage but weak bio-geographic variation for soil bacteria. In the future urban planning process, we suggest that such maintenance of native vegetation and soil types should be considered to maintain the long-term stability of local microbial ecosystem functions.


Drug Development for the Therapy of Mitochondrial Diseases.
Mitochondrial diseases are a heterogeneous group of inherited or acquired devastating disorders that affect the energy metabolism of the body. Many strategies have been investigated, but currently there is no FDA-approved drug that can alleviate disease symptoms or slow disease progression. This review analyzes to what extent growing knowledge over the past two decades about the etiology and pathogenesis of mitochondrial diseases is reflected in the design and development of new experimental drugs for the therapy of these disorders. All currently registered clinical trials involving new experimental drug entities are reviewed to evaluate how far away we are from the first FDA-approved drug therapy for mitochondrial disease.


A novel denoising method for low-dose CT images based on transformer and CNN.
Computed Tomography (CT) has become a mainstream imaging tool in medical diagnosis. However, the issue of increased cancer risk due to radiation exposure has raised public concern. Low-dose computed tomography (LDCT) technique is a CT scan with lower radiation dose than conventional scans. LDCT is used to make a diagnosis of lesions with the smallest dose of x-rays, and is currently mainly used for early lung cancer screening. However, LDCT has severe image noise, and these noises affect adversely the quality of medical images and thus the diagnosis of lesions. In this paper, we propose a novel LDCT image denoising method based on transformer combined with convolutional neural network (CNN). The encoder part of the network is based on CNN, which is mainly used to extract the image detail information. In the decoder part, we propose a dual-path transformer block (DPTB), which extracts the features of input of the skip connection and the features of input of the previous level through two paths respectively. DPTB can better restore the detail and structure information of the denoised image. In order to pay more attention to the key regions of the feature images extracted at the shallow level of the network, we also propose a multi-feature spatial attention block (MSAB) in the skip connection part. Experimental studies are conducted, and comparisons with the state-of-the-art networks are made, and the results demonstrate that the developed method can effectively remove the noise in CT images and improve the image quality in the evaluation metrics of peak signal to noise ratio (PSNR), structural similarity (SSIM), and root mean square error (RMSE) and is superior to the state-of-the-art models. Our method achieved 28.9720 of PSNR, 0.8595 of SSIM and 14.8657 of RMSE on the Mayo Clinic LDCT Grand Challenge dataset. For different noise level σ (15, 35, and 55) on the QIN_LUNG_CT dataset, our proposed also achieved better performances.


The genome of Acorus deciphers insights into early monocot evolution.
Acorales is the sister lineage to all the other extant monocot plants. Genomic resource enhancement of this genus can help to reveal early monocot genomic architecture and evolution. Here, we assemble the genome of Acorus gramineus and reveal that it has ~45% fewer genes than the majority of monocots, although they have similar genome size. Phylogenetic analyses based on both chloroplast and nuclear genes consistently support that A. gramineus is the sister to the remaining monocots. In addition, we assemble a 2.2 Mb mitochondrial genome and observe many genes exhibit higher mutation rates than that of most angiosperms, which could be the reason leading to the controversies of nuclear genes- and mitochondrial genes-based phylogenetic trees existing in the literature. Further, Acorales did not experience tau (τ) whole-genome duplication, unlike majority of monocot clades, and no large-scale gene expansion is observed. Moreover, we identify gene contractions and expansions likely linking to plant architecture, stress resistance, light harvesting, and essential oil metabolism. These findings shed light on the evolution of early monocots and genomic footprints of wetland plant adaptations.


Role of capping agents in the application of nanoparticles in biomedicine and environmental remediation: recent trends and future prospects.
Capping agents are of utmost importance as stabilizers that inhibit the over-growth of nanoparticles and prevent their aggregation/coagulation in colloidal synthesis. The capping ligands stabilize the interface where nanoparticles interact with their medium of preparation. Specific structural features of nanoparticles are attributed to capping on their surface. These stabilizing agents play a key role in altering the biological activities and environmental perspective. Stearic effects of capping agents adsorbed on the surface of nanoparticles are responsible for such changing physico-chemical and biological characteristics. Firstly, this novel review article introduces few frequently used capping agents in the fabrication of nanoparticles. Next, recent advancements in biomedicine and environmental remediation approaches of capped nanoparticles have been elaborated. Lastly, future directions of the huge impact of capping agents on the biological environment have been summarized.


UCP1 alleviates renal interstitial fibrosis progression through oxidative stress pathway mediated by SIRT3 protein stability.
Renal interstitial fibrosis is a common pathway for the progressive development of chronic renal diseases (CKD) with different etiology, and is the main pathological basis leading to end-stage renal disease. Although the current research on renal interstitial fibrosis is gradually deepening, the diagnosis and treatment methods are still very lacking. Uncoupling protein 1 (UCP1) is a nuclear encoded protein in mitochondria inner membrane and plays an important role in regulating energy metabolism and mitochondrial homeostasis. However, the biological significance of UCP1 and potential regulatory mechanisms in the development of CKD remain unclear. Unilateral ureteral obstruction (UUO) model was used to construct the animal model of renal fibrosis, and TGF-β1 stimulation of HK2 cells was used to construct the vitro model of renal fibrosis. UCP1 expression was detected by Western blot, immunoblot analysis and immunohistochemistry. UCP1 was upregulated by UCP1 overexpressing lentivirus and UCP1 agonist CL316243. Western blot and immunofluorescence were used to detect epithelial mesenchymal transition (EMT)-related markers, such as collagen I, fibronectin, antioxidant enzyme SOD2 and CAT. Reactive oxygen species (ROS) production was detected by ROS detection kit. SIRT3 knockdown was performed by siRNA. This study presents that UCP1 is significantly downregulated in patients with renal fibrosis and UUO model. Further studies discover that UCP1 overexpression and CL316243 treatments (UCP1 agonists) reversed EMT and extracellular matrix (ECM) accumulation in renal fibrosis models in vivo and in vitro. Simultaneously, UCP1 reduced the ROS production by increasing the stability of SIRT3. When SIRT3 was knocked down, the production of ROS decreased. Elevating the expression of UCP1 can inhibit the occurrence of oxidative stress by stabilizing SIRT3, thereby reducing EMT and ECM accumulation, and ultimately alleviating renal interstitial fibrosis. It will provide new instructions and targets for the treatment of CKD.


Fungi associated with rice at entre rios province, Argentina. toxigenic capacity offusarium graminearum andmicrodochium nivale isolates.
A mycological survey was carried out on rice samples harvested in 1997 and 1998 from Entre Ríos province, belonging to the main production area of Argentina. The relative density and isolation frequency of the prevalent fungi were statistically compared between locations and harvest seasons. The genusAlternaria was the most prevalent component of the internal seedborne mycoflora in the two harvest seasons. Fungi belonging to the generaPhoma, Fusarium, Microdochium, Penicillium andAspergillus were also isolated. The predominant species of these genera wereAlternaria alternata, Phoma glomerata, Fusarium graminearum, Microdochium nivale, Penicillium citrinum and Aspergillus flavus.


Obesity in patients with bipolar disorder: a biopsychosocial-behavioral model.
We provide a model to explicate how factors representing different levels of analysis (i.e., biology, psychology, sociodemographics, and behavior) interact to influence the onset and maintenance of obesity in bipolar disorder. We conducted MEDLINE (1966-2005) and PsycInfo (1872-2005) searches of all English-language articles using the keywords obesity, body weight, weight gain, and metabolic syndrome combined with bipolar disorder, depression, atypical depression, binge eating, and pharmacotherapy. Studies were selected if they provided data regarding (1) the prevalence of obesity in patients with bipolar disorder, (2) correlates of obesity in patients with bipolar disorder, or (3) evidence that a clinical feature(s) or correlate(s) of bipolar disorder is associated with obesity. Ninety-two studies were reviewed. Obesity is prevalent in patients with bipolar disorder and is associated with increased medical morbidity and poorer psychiatric outcome. Variables that may interact to influence the onset and maintenance of obesity in bipolar disorder include genetic factors, neurotransmitter abnormalities, atypical depression, eating behaviors, pharmacotherapy, age, gender, socioeconomic status, and physical inactivity. Although the exact causes of obesity in bipolar disorder undoubtedly vary across patients, the etiologic cascade, which includes biological, psychological, and sociodemographic variables, ultimately directly or indirectly affects levels of physical activity and eating behavior, leading to obesity in this population. Behavioral interventions aimed at targeting physical inactivity and overeating in bipolar disorder patients are needed, as are better screening and treatment for binge eating. Finally, there is a clear need for ongoing research to explicate the causes and consequences of obesity across levels of analysis.


Study of the protective effect of calcium channel blockers against neuronal damage induced by glutamate in cultured hippocampal neurons.
The aim of this study was to examine the putative protective effect of calcium channel blockers on hippocampal neurons in the experimental model of excitotoxic damage. Seven-day old primary dissociated cultures of rat hippocampal neural cells containing one of the following calcium channel blockers: cinnarizine, flunarizine or nimodipine were exposed to glutamate-induced injury. Quantitative assessments of neuronal injury were accomplished by measuring lactate dehydrogenase (LDH) activity in the media 24 h after exposure to glutamate and by counting and establishing the apoptotic and necrotic cells in flow cytometry with Annexin V-FITC/PI staining. In our experiment, glutamate induced a 339% elevation of apoptotic cells and a 289% increase of necrotic cells in hippocampal neurons as compared to control cultures without drugs. In cultures containing flunarizine, glutamate-induced cell apoptosis was suppressed by 62% while necrosis showed no significant alternation. Cinnarizine exerted no anti-apoptotic effects on glutamate-injured cultured hippocampal neurons, while nimodipine intensified the apoptotic pathway of cell death and promoted an increase in the number of apoptotic neurons by 26%. When cinnarizine or nimodipine were used, the percentage of necrotic cells was significantly lower when compared with glutamate-injured cultures and it amounted to 44% and 24% for cinnarizine and nimodipine, respectively. The obtained results suggest the beneficial anti-apoptotic potential of flunarizine and the anti-necrotic potential of cinnarizine against glutamate-induced death of cultured hippocampal neurons. Nimodipine can protect neurons against necrosis, but has an intensified adverse pro-apoptotic effect on cultured neurons in the experimental model of excitotoxic injury.


Measurement of anti-D intrinsic affinity with unlabeled antibodies.
The method most commonly used for measuring the affinity of MoAbs specific for the D antigen is a binding assay using 125I-labeled MoAb. Although the method is relatively simple, there are several drawbacks that can lead to inaccurate results. The objective of the present work was to develop a method for the determination of the affinity of anti-D MoAb using unlabelled antibodies. Rh-positive RBCs were sensitized with varying amounts of unlabeled anti-D MoAb, and, at equilibrium, the amount of anti-D bound to the RBCs was measured by ELISA. The affinity and the number of antigenic sites were determined with the Scatchard and Langmuir equations. The method was applied to determine the affinity of several MoAbs specific for the D antigen on RBCs of different Rh-positive phenotypes. Similar results were observed with both equations. The affinity constant (Ka) for 3 MoAbs specific for the D antigen on group O R1r RBCs ranged from 1.3 to 7.4 108 M-1, depending on the antibody. When measured by a binding assay with 125I-labeled anti-D MoAbs, the Ka were significantly lower, indicating that 125I-labeling diminishes anti-D affinity, even when the labeling is at a low level. A simple ELISA method was developed for the measurement of the affinity of anti-D MoAbs for the D antigen and for the number of antigenic sites per RBC. As a result, the affinity of anti-D can be estimated accurately, thus avoiding the drawbacks inherent in modification of the antibody by 125I-labeling.


Reproductive performance of early- and late-calving dairy cows artificially inseminated after ovulation synchronization and estrous resynchronization or artificially inseminated after observed estrus.
Within seasonal dairy systems, cows that calve late in the calving season are less likely to become pregnant and maintain a yearly calving interval. Very few studies have examined effective strategies for reproductive management of these late-calving cows. The objectives were to evaluate the reproductive performance of early- and late-calving dairy cows that were either inseminated after observed estrus (control) or enrolled in a timed AI and resynchronization protocol [progesterone (P4) Ovsynch Resynch)]. Early-calving cows calved during the first week of the calving season, whereas late-calving cows calved after 6 wk but were at least 10 d in milk at study commencement. Three dairy herds participated in the study with 391 cows total. Within each calving group, cows were randomly assigned to P4 Ovsynch Resynch or control (no treatment) in a 2 × 2 experimental design. Artificial insemination continued for 6 wk after mating start date (MSD) and was followed by 6 wk of natural service. The interval from MSD to AI was shorter (11.7 vs. 14.7 d) and the 3-wk pregnancy rate (49.5 vs. 21.2%) and the 6-wk pregnancy rate (60.8 vs. 42.4%) were greater in the early-calving compared with the late-calving control cows. By design, synchronized cows received timed AI on MSD and were not included in the statistical analysis of submission rate and interval from MSD to AI. The proportion of cows that received a second AI was not increased by the progesterone-based resynchronization strategy but was greater in early-calving compared with late-calving cows. The 12-wk pregnancy rate was greater (64.5 vs. 45.0%) in the early-calving synchronized cows compared with the late-calving synchronized cows. The interval from MSD to pregnancy was 6 and 12.6 d shorter for synchronized compared with control cows in the early- and late-calving groups, respectively. The results demonstrated reduced reproductive performance of late-calving cows compared with early-calving cows. Nonetheless, a major improvement to reproductive performance was achieved by targeting late-calving cows with a synchronization program, even when cows were only 20 to 50 DIM at first AI. Resynchronization of estrus with a progesterone device only, however, was not sufficient to increase the proportion of nonpregnant cows that received a second AI.


Parkinsonism and ataxia.
Ataxia is not a common feature in Parkinson's disease. Nevertheless, some rare forms of parkinsonism have ataxia as one of the main features in their clinical picture, especially those with juvenile or early-onset. On the other side, in cerebellar degenerative diseases, parkinsonism might accompany the typical symptoms and even become predominant in some cases. Many disorders involving different neurological systems present with a movement phenomenology reflecting the underlying pattern of pathological involvement, such as neurodegeneration with brain iron accumulation, neurodegeneration associated with calcium deposition, and metabolic and mitochondrial disorders. The prototype of sporadic disorders that present with a constellation of symptoms due to the involvement of multiple Central Nervous System regions is multiple system atrophy, whose motor symptoms at onset can be cerebellar ataxia or parkinsonism. Clinical syndromes encompassing both parkinsonian and cerebellar features might represent a diagnostic challenge for neurologists. Recognizing acquired and potentially treatable causes responsible for complex movement disorders is of paramount importance, since an early diagnosis is essential to prevent permanent consequences. The present review aims to provide a pragmatic overview of the most common diseases characterized by the coexistence of cerebellar and parkinsonism features and suggests a possible diagnostic approach for both inherited and sporadic disorders. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.


Competing mortality risk from second primary malignancy in bladder cancer patients following radical cystectomy: Implications for survivorship.
Muscle-invasive bladder cancer (BC) often occurs in patients with competing mortality risks, while also being associated with the highest rate of second primary nonurothelial cancers (SNUC) of all solid malignancies. We investigated the incidence, risk factors, and timing of SNUC as a competing mortality risk factor in patients with BC who were treated with curative intent radical cystectomy (RC). We performed a retrospective cohort study assessing patients who underwent RC for cT2-4 N0M0 BC from January 1, 2005 to December 31, 2018 at a single, high volume tertiary care referral center. The Fine-Gray multivariable regression model was used to evaluate predictive factors for SNUC. Cumulative incidence of mortality (CIM) was estimated with modified Kaplan-Meier analysis. The median follow-up time for the 693 patients who underwent RC was 3.7 years (interquartile range [IQR] 1.9-5.9 years). SNUC developed in 85 (12.3%) patients at a median 3.0 years post-RC (IQR 1.2-5.5 years). On multivariable analysis, the only significant predictor for developing SNUC was freedom from BC recurrence or metastasis (HR 1.54, 95% CI 1.12-1.76, P = 0.019). The most common SNUCs were primary lung cancer (24, 3.2% of cohort) and colon cancer (9, 1.3% of cohort). BC surveillance imaging diagnosed SNUC in 35/52 (67.3%) patients with solid-organ visceral primaries. The overall mortality rate for any SNUC was 38.8%, with the 3 most lethal cancer types being pancreatic, lung, and colon (62.5%, 54.2%, and 44.4% mortality, respectively). The incidence of SNUC uniformly increased postoperatively, with a cumulative incidence of 22.1% (95% CI, 16.8-27.9%) at 12-years post-RC. 163 patients (23.5%) died from BC, 33 patients (4.8%) died from SNUC, and 94 patients (13.6%) died from other causes. While the CIM for BC plateaued around 5-years post-RC at 24%, the incidence of other-cause mortality uniformly rose throughout the postoperative period. By post-RC year 9 there was no significant difference in CIM between BC (CIM 27.2%, 95% CI, 23.5-31.1%) and other-causes (CIM 20.0%, 95% CI, 15.8-24.6%). The cumulative incidence of SNUC at 12-years post-RC was 22%, with the majority identified on BC surveillance imaging. While BC mortality plateaued around 5-years post-RC, mortality related to SNUC or other causes rose steadily in the postoperative period. These data have clinical significance with regards to patient counseling, survivorship and oncologic surveillance in the highly comorbid muscle-invasive BC population.


Widening the landscape of transcriptional regulation of green algal photoprotection.
Availability of light and CO2, substrates of microalgae photosynthesis, is frequently far from optimal. Microalgae activate photoprotection under strong light, to prevent oxidative damage, and the CO2 Concentrating Mechanism (CCM) under low CO2, to raise intracellular CO2 levels. The two processes are interconnected; yet, the underlying transcriptional regulators remain largely unknown. Employing a large transcriptomic data compendium of Chlamydomonas reinhardtii's responses to different light and carbon supply, we reconstruct a consensus genome-scale gene regulatory network from complementary inference approaches and use it to elucidate transcriptional regulators of photoprotection. We show that the CCM regulator LCR1 also controls photoprotection, and that QER7, a Squamosa Binding Protein, suppresses photoprotection- and CCM-gene expression under the control of the blue light photoreceptor Phototropin. By demonstrating the existence of regulatory hubs that channel light- and CO2-mediated signals into a common response, our study provides an accessible resource to dissect gene expression regulation in this microalga.


Carbamazepine hypersensitivity and rickettsiosis mimicking Kawasaki disease.
We report on two patients whose clinical presentation resembled that of Kawasaki disease. The first patient was a boy with epilepsy, whose symptoms first appeared following treatment with carbamazepine. The second boy had Mediterranean Spotted Fever. The significance of medical history in avoiding overdiagnosis of Kawasaki disease is emphasized.


No evidence of increased ocular involvement in candidemic patients initially treated with echinocandins.
Candins are commonly used as initial therapy in patients with candidemia and are known to diffuse poorly into ocular tissue. The aim of our multicenter study was to assess whether eye involvement was more common in patients initially treated with echinocandins. We performed a post hoc analysis of a prospective, multicenter, population-based candidemic surveillance program implemented in Spain during 2010-2011 (CANDIPOP project). Eye involvement was detected in 13 of 168 patients with candidemia (7.7%) who underwent ophthalmoscopy. Two patients had endophthalmitis, while the remaining patients had chorioretinitis. The frequency of ocular candidiasis was similar in patients receiving initial therapy with candins (3/56; 5.4%) or with other regimens (10/112; 8.9%). At multivariate analysis, risk conditions for eye involvement were dialysis after candidemia (OR, 19.4; 95% CI, 1.7-218.4) and involvement of organs other than the eye (OR, 5.4; 95% CI, 1.1-25.7). In conclusion, eye involvement was not found to be more frequent in patients receiving initial therapy with echinocandins than in patients receiving other drugs.


Deoxyinosine repair in nuclear extracts of human cells.
Deamination of adenine can occur spontaneously under physiological conditions generating the highly mutagenic lesion, hypoxanthine. This process is enhanced by ROS from exposure of DNA to ionizing radiation, UV light, nitrous acid, or heat. Hypoxanthine in DNA can pair with cytosine which results in A:T to G:C transition mutations after DNA replication. In Escherichia coli, deoxyinosine (hypoxanthine deoxyribonucleotide, dI) is removed through an alternative excision repair pathway initiated by endonuclease V. However, the correction of dI in mammalian cells appears more complex and was not fully understood. All four possible dI-containing heteroduplex DNAs, including A-I, C-I, G-I, and T-I were introduced to repair reactions containing extracts from human cells. The repair reaction requires magnesium, dNTPs, and ATP as cofactors. We found G-I was the best substrate followed by T-I, A-I and C-I, respectively. Moreover, judging from the repair requirements and sensitivity to specific polymerase inhibitors, there were overlapping repair activities in processing of dI in DNA. Indeed, a hereditable non-polyposis colorectal cancer cell line (HCT116) demonstrated lower dI repair activity that was partially attributed to lack of mismatch repair. A plasmid-based convenient and non-radioisotopic method was created to study dI repair in human cells. Mutagenic dI lesions processed in vitro can be scored by restriction enzyme cleavage to evaluate the repair. The repair assay described in this study provides a good platform for further investigation of human repair pathways involved in dI processing and their biological significance in mutation prevention.


Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats.
Studies showed that the metabolic unlike the neuroendocrine effects of ghrelin could be abrogated by co-administered unacylated ghrelin. The aim was to investigate the interaction between ghrelin and desacyl ghrelin administered intraperitoneally on food intake and neuronal activity (c-Fos) in the arcuate nucleus in non-fasted rats. Ghrelin (13 microg/kg) significantly increased food intake within the first 30 min post-injection. Desacyl ghrelin at 64 and 127 microg/kg injected simultaneously with ghrelin abolished the stimulatory effect of ghrelin on food intake. Desacyl ghrelin alone at both doses did not alter food intake. Both doses of desacyl ghrelin injected separately in the light phase had no effects on food intake when rats were fasted for 12h. Ghrelin and desacyl ghrelin (64 microg/kg) injected alone increased the number of Fos positive neurons in the arcuate nucleus compared to vehicle. The effect on neuronal activity induced by ghrelin was significantly reduced when injected simultaneously with desacyl ghrelin. Double labeling revealed that nesfatin-1 immunoreactive neurons in the arcuate nucleus are activated by simultaneous injection of ghrelin and desacyl ghrelin. These results suggest that desacyl ghrelin suppresses ghrelin-induced food intake by curbing ghrelin-induced increased neuronal activity in the arcuate nucleus and recruiting nesfatin-1 immunopositive neurons.


Lysosomal storage disorder 4+1 multiplex assay for newborn screening using tandem mass spectrometry: application to a small-scale population study for five lysosomal storage disorders.
We sought to modify a previously published tandem mass spectrometry method of screening for 5 lysosomal storage disorders (LSDs) in order to make it better suited for high-throughput newborn screening. Two 3-mm dried blood spot (DBS) punches were incubated, each with a different assay solution. The quadruplex solution was used for screening for Gaucher, Pompe, Krabbe and Fabry diseases, while a separate solution was used for Niemann-Pick A/B disease. The mean activities of acid-β-glucocerebrosidase (ABG), acid sphingomyelinase (ASM), acid glucosidase (GAA), galactocerebroside-β-galactosidase (GALC) and acid-galactosidase A (GLA) were measured on 5055 unidentified newborns. The mean activities (compared with their disease controls) were, 15.1 (0.35), 22.2 (1.34), 16.8 (0.51), 3.61 (0.23), and 20.7 (1.43) (μmol/L/h), respectively. The number of specimens that fell below our retest level cutoff of <20% daily mean activity (DMA) for each analyte is: ABG (6), ASM (0), GAA (5), GALC (17), and GLA (2). This method provides a simplified and reliable assay for screening for five LSDs with clear distinction between activities from normal and disease samples. Advantages of this new method include significant decreases in processing time and the number of required assay solutions and overall decreased complexity.


The impact of neuropsychiatric disease on fetal growth: a case-control study.
To determine the impact of depression, epilepsy and drug abuse during pregnancy on delivery and fetal outcome. Due to the worldwide increasing prevalence of neurological and psychiatric diseases and drug abuse, the number of affected pregnant women is increasing. A large-scale retrospective case-control analysis of pregnancies affected by depression, epilepsy or drug abuse with and without medication was conducted in two German perinatal centres between 2013 and 2017. The case group consisted of 706 pregnant women who had a diagnosis of depression, epilepsy or drug abuse vs. 12,574 pregnant women without neuropsychiatric diagnosis (control group). The analysis included the rate of intrauterine growth restriction, birth weight and length, neonatal head circumference. Significant differences in the subgroups were found in the parameters intrauterine growth restriction, birth weight, length and head circumference. Women with epilepsy were affected less often than women with depression and substance abuse. Major differences were found in the group of women with substance abuse. Negative associations were found within the non-pharmacologically managed disease group itself compared to women exposed to medication. The present results demonstrated a negative association between maternal neurological or psychiatric disease and pregnancy outcome in the examined parameters. However, the non-pharmacologically treated maternal disease was identified as a risk factor itself.


Enzymes involved in adenine nucleotide metabolism of developing chick embryo liver.
1. This paper describes the changes in the activity of adenylate deaminase, adenylate and inosinate phosphatase, and adenosine deaminase in the developing chick embryo liver. 2. The adenylate and inosinate phosphatase and adenosine deaminase activity appears considerably higher in chick embryo liver with respect to other chick embryo tissues previously examined. 3. During development the control exerted by ATP on AMP breakdown undergoes variations. Consequently, in the first period of incubation AMP is degraded by the direct pathway (AMP-IMP) and in the last period of incubation by the indirect pathway (AMP-adenosine). In the intermediate period (from the 12th to the 15th day of incubation) both pathways may be followed. 4. The ability to synthesize purine nucleotides through "salvage pathway" seems to be acquired by embryonic liver at least at the 15th day.


Evidence of diversity and recombination in Arsenophonus symbionts of the Bemisia tabaci species complex.
Maternally inherited bacterial symbionts infecting arthropods have major implications on host ecology and evolution. Among them, the genus Arsenophonus is particularly characterized by a large host spectrum and a wide range of symbiotic relationships (from mutualism to parasitism), making it a good model to study the evolution of host-symbiont associations. However, few data are available on the diversity and distribution of Arsenophonus within host lineages. Here, we propose a survey on Arsenophonus diversity in whitefly species (Hemiptera), in particular the Bemisia tabaci species complex. This polyphagous insect pest is composed of genetic groups that differ in many ecological aspects. They harbor specific bacterial communities, among them several lineages of Arsenophonus, enabling a study of the evolutionary history of these bacteria at a fine host taxonomic level, in association to host geographical range and ecology. Among 152 individuals, our analysis identified 19 allelic profiles and 6 phylogenetic groups, demonstrating this bacterium's high diversity. These groups, based on Arsenophonus phylogeny, correlated with B. tabaci genetic groups with two exceptions reflecting horizontal transfers. None of three genes analyzed provided evidence of intragenic recombination, but intergenic recombination events were detected. A mutation inducing a STOP codon on one gene in a strain infecting one B. tabaci genetic group was also found. Phylogenetic analyses of the three concatenated loci revealed the existence of two clades of Arsenophonus. One, composed of strains found in other Hemiptera, could be the ancestral clade in whiteflies. The other, which regroups strains found in Hymenoptera and Diptera, may have been acquired more recently by whiteflies through lateral transfers. This analysis of the genus Arsenophonus revealed a diversity within the B. tabaci species complex which resembles that reported on the larger scale of insect taxonomy. We also provide evidence for recombination events within the Arsenophonus genome and horizontal transmission of strains among insect taxa. This work provides further insight into the evolution of the Arsenophonus genome, the infection dynamics of this bacterium and its influence on its insect host's ecology.


Evaluation of different strategies for real-time RT-PCR expression analysis of corticotropin-releasing hormone and related proteins in human gestational tissues.
In this article real-time quantitative RT-PCR strategies for investigation of mRNA distribution in stress-related corticotropin-releasing hormone (CRH), CRH-binding protein (CRH-BP), and CRH receptors (CRH-R1, CRH-R2) in human gestational tissues are described. The effect of sample and RNA preparation, reverse transcription, and the quantitation strategy were investigated. Both thawing of the sample before homogenization and the RT reaction were identified as critical steps. In contrast, the time-lag from the biopsy until snap-freezing and the homogenization procedure had little effect. The "housekeeping" gene cyclophilin was found to be differently expressed in gestational tissues, compromising its use as internal reference. For relative quantitation of mRNA levels by TaqMan PCR the standard curve method and the comparative C (T) method (DeltaDeltaC (T) or DeltaC (T)' method) were compared. Both calculation strategies delivered similar relative mRNA amounts in identifying the placenta as the main source of CRH and CRH-BP mRNA compared with myometrium and decidua. Consistent results were also obtained for CRH-R1 and CRH-R2 by both methods of calculation. We conclude that the simpler comparative C (T) method is adequate for assessing the mRNA levels of CRH, CRH-BP, and CRH receptors in human gestational tissues.


Clinicopathological differences between variants of the NAB2-STAT6 fusion gene in solitary fibrous tumors of the meninges and extra-central nervous system.
Investigations on the NAB2-STAT6 fusion gene in solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) have increased since its discovery in 2013. Although several SFTs reported without NAB2-STAT6 fusion gene analysis, we reviewed 546 SFTs/HPCs with NAB2-STAT6 fusion gene analysis in this study and investigated differences between the gene variants. In total, 452 cases tested positive for the NAB2-STAT6 fusion gene, with more than 40 variants being detected. The most frequent of these were NAB2 exon 6-STAT6 exon 16/17/18 and NAB2 exon 4-STAT6 exon 2/3, with the former occurring most frequently in SFTs in meninges, soft tissues, and head and neck; the latter predominated in SFTs in the pleura and lung. There was no difference between the histology of SFTs and fusion gene variants. A follow-up analysis of SFTs showed that 51 of 202 cases had a recurrence, with 18 of 53 meningeal SFTs having a local recurrence and/or metastasis within 0-19 years. In meninges and soft tissue, SFTs with the NAB2 exon 6-STAT6 exon 16/17/18 tended to recur more frequently than SFTs with the NAB2 exon 4-STAT6 exon 2/3. Clinicopathological data, including yearly follow-ups, are required for meningeal SFTs/HPCs to define the correlation of variants of NAB2-STAT6 fusion gene.


Relaxation electrodynamics of superinsulators.
Superinsulators offer a unique laboratory realizing strong interaction phenomena like confinement and asymptotic freedom in quantum materials. Recent experiments evidenced that superinsulators are the mirror-twins of superconductors with reversed electric and magnetic field effects. Cooper pairs and Cooper holes in the superinsulator are confined into neutral electric pions by electric strings, with the Cooper pairs playing the role of quarks. Here we report the non-equilibrium relaxation of the electric pions in superinsulating films. We find that the time delay [Formula: see text] of the current passage in the superinsulator is related to the applied voltage V via the power law, [Formula: see text], where [Formula: see text] is the effective threshold voltage. Two distinct critical exponents, [Formula: see text] and [Formula: see text], correspond to jumps from the electric Meissner state to the mixed state and to the superinsulating resistive state with broken charge confinement, respectively. The [Formula: see text] value establishes a direct experimental evidence for the electric strings' linear potential confining the charges of opposite signs in the electric Meissner state and effectively rules out disorder-induced localization as a mechanism for superinsulation. We further report the memory effects and their corresponding dynamic critical exponents arising upon the sudden reversal of the applied voltage. Our observations open routes for exploring fundamental strong interaction charge confinement via desktop experiments.


Recent advances in fluorescent probes for extracellular pH detection and imaging.
Extracellular pH plays vital roles in physiological and pathological processes including tumor metastasis and chemotherapy resistance. Abnormal extracellular pH is known to be associated with various pathological states, such as those in tumors, ischemic stroke, infection, and inflammation. Specifically, dysregulated pH is regarded as a hallmark of cancer because enhanced glycolysis and poor perfusion in most solid malignant tumors create an acidic extracellular environment, which enhances tumor growth, invasion, and metastasis. Close connection between the cell functions with extracellular pH means that precise and real-time measurement of the dynamic change of extracellular pH can provide critical information for not only studying physiological and pathological processes but also diagnosis of cancer and other diseases. This review highlights the recent development of based fluorescent probes for extracellular pH measurement, including design strategies, reaction mechanism and applications for the detection and imaging of extracellular pH.


Structural lung disease in preschool children with cystic fibrosis: An 18 month natural history study.
This study was performed to describe the natural history of CF lung disease in young children over an 18 month period to assess the use of CT scanning as an outcome measure for intervention trials. Chest CT scans were obtained at baseline and after 18 months in 42 two- to six-year-old children with CF. CT scans were scored by 2 experienced radiologists for the presence and severity of bronchiectasis, mucous plugging, and air trapping. Mean age at baseline 3.5 (1.3) (mean, sd) years. One or more findings of CF lung disease was seen on the first CT in 27 (64%) and at 18 months in 30 (75%). From baseline to 18 months bronchiectasis, mucous plugging, and air trapping increased from 50% to 53%, 14% to 28%, and 48% to 58% respectively. There was marked variability in the rate of progression, with subjects commonly showing improvement in lung disease. Bronchiectasis worsened in 14 (33%) and improved in 13 (31%). Single subjects with F508del/class III and F508del/class V demonstrated greater worsening and improvement respectively than F508del homozygous and class I genotypes. The natural history of CF lung disease over 18 months varies widely between subjects. Factors including genotype may affect natural history as well as the effectiveness of mediators and could be an important confounder if not recognized. These findings suggest that the use of CT scanning as an outcome surrogate for CF lung disease in young children may be more challenging than has been previously recognized.


Oncostatin M is a FIP1L1/PDGFRA-dependent mediator of cytokine production in chronic eosinophilic leukemia.
Chronic eosinophilic leukemia (CEL) is a myeloproliferative neoplasm characterized by expansion of neoplastic eosinophils, tissue infiltration, and organ damage. In a subset of these patients, the FIP1L1/PDGFRA (F/P) oncoprotein is detectable. F/P exhibits constitutive tyrosine kinase activity and activates a number of signaling pathways. So far, however, little is known about the role of F/P-dependent proteins in the pathogenesis of CEL. A screen for F/P-dependent cytokines was performed in growth factor-dependent human cell lines lentivirally transduced with F/P. Signal transduction pathways were characterized in Ba/F3 cells with doxycycline-inducible expression of F/P and in EOL-1 cells. Cytokine expression was confirmed in patients' material by immunohistochemistry, immunofluorescence, and confocal microscopy. Gene expression analysis, proliferation assays, and chemotaxis assays were used to elucidate paracrine interactions between neoplastic eosinophils and stromal cells. We show that F/P upregulates expression of oncostatin M (OSM) in various cell line models in a STAT5-dependent manner. Correspondingly, neoplastic eosinophils in the bone marrow were found to overexpress OSM. OSM derived from F/P + cells stimulated proliferation of stromal cells. Moreover, OSM-containing supernatants from F/P + cells were found to upregulate production of stromal cell-derived factor-1 (SDF-1)/CXCL12 in human fibroblasts. SDF-1, in turn, induced migration of EOL-1 cells in a dose-dependent manner. We have identified a F/P-driven paracrine interaction between neoplastic eosinophils and stromal cells that may contribute to tissue fibrosis and accumulation of neoplastic eosinophils in CEL.


Corrigendum: Duration of Humoral and Cellular Immunity 8 Years After Administration of Reduced Doses of the 17DD-Yellow Fever Vaccine.
[This corrects the article DOI: 10.3389/fimmu.2019.01211.].


Metabolic Improvements and Remission of Prediabetes and Type 2 Diabetes: Results From a Multidomain Lifestyle Intervention Clinic.
Although lifestyle interventions are first-line treatment for individuals living with prediabetes and type 2 diabetes (T2D), they are rarely implemented effectively in routine clinical care. We present a retrospective analysis of a 12-month, single-centre, structured multidomain lifestyle intervention clinic offered to individuals living with prediabetes and type 2 diabetes. The intervention consisted of expert-guided educational and nutritional counselling combined with a personalized physical exercise prescription, with the main goal of improving metabolic health and reaching remission. Anthropometric parameters, glucose, basal insulin, glycated hemoglobin (A1C), and lipid levels were measured at baseline and at 3, 6, and 12 months after the lifestyle intervention initiation. Remission of prediabetes and T2D were defined as a return of A1C at 6 months to <6.5% (or <5.7% for prediabetes) and persisting for at least 3 months in the absence of glucose-lowering pharmacotherapy. After a multidomain, expert-guided lifestyle intervention, 117 individuals living with prediabetes and T2D had significantly improved metabolic profiles: Mean weight change at 12 months was -4.9 kg (95% confidence interval [CI], -4.0 to -5.7; p<0.001), and mean change in A1C at 12 months was -0.6% (95% CI, -0.4 to -0.7; p<0.001). A substantial proportion of individuals reached the criteria for remission (20% among participants with prediabetes and 12% among those with T2D). The results of this study suggest that prioritizing lifestyle changes in a multifaceted, progressive, 12-month intervention in this population improves anthropometric and insulin resistance measures, and has the potential to normalize metabolic values, even to the point of reaching the criteria of remission.


Does hepatobiliary phase sequence qualitatively outperform unenhanced T1-weighted imaging in assessment of the ablation margin 24 hours after thermal ablation of hepatocellular carcinomas?
To retrospectively determine whether hepatobiliary phase (HBP) sequence outperforms unenhanced T1-weighted imaging (uT1wI) in distinguishing the ablation margin (AM) from hepatocellular carcinoma (HCC) 24 h after thermoablation. Ninety-one patients [mean age, 65.7 years; 68 M/23F] with 138 HCCs (>6 months follow-up) underwent pre- and postablation gadoxetate disodium-enhanced MRI. AM showed a hyperintense middle zone (MZ) surrounding central hypo- or hyperintense HCCs on uT1wI, and an intermediate-intense MZ encompassing central hypo- or hyperintense HCCs during HBP. The visible AM was defined as persistent MZ around HCCs, which were demarcated from MZ, or peripherally band encompassing MZ, which were not demarcated from HCC. The indefinite AM was defined as no demarcating HCCs from MZ. The ability to distinguish AM from HCC was classified as visible or indefinite on axial (ax)-uT1wI, ax-HBP, coronal (cor)-HBP, and combined all images. To investigate the AM visibility during HBP, significance of differences upon comparison of ax-uT1wI with combined images was analyzed. Preablation liver-tumor contrast ratio (LTCR) on ax-uT1wI and ax-HBP sequence is compared between the visible and indefinite AM. The McNemar test demonstrated a significant increase (p < 0.05) in visible AM from ax-uT1wI (60), to ax-HBP (70), cor-HBP (79), and combined images (83). TLCR with visible AM was significantly higher than that with indefinite AM on ax-uT1wI (0.4 vs. 0.2, p = 0.001) and ax-HBP sequence (0.9 vs. 0.6, p = 0.004). HBP sequence might have higher feasibility to distinguish AM from tumor than ax-uT1wI. The TLCR value in visible AM was higher than that in indefinite AM on both ax-uT1wI and ax-HBP sequences.


Three-dimensional assessment of bilateral symmetry of the radius and ulna for planning corrective surgeries.
The contralateral unaffected side is often used as a reference in planning a corrective osteotomy of a malunited distal radius. Two-dimensional radiographs have proven unreliable in assessing bilateral symmetry, so we assessed 3-dimensional configurations to assess bilateral symmetry. We investigated bilateral symmetry using 3-dimensional imaging techniques. A total of 20 healthy volunteers without previous wrist injury underwent a volumetric computed tomography of both forearms. The left radius and ulna were segmented to create virtual 3-dimensional models of these bones. We selected a distal part and a larger proximal part from these bones and matched them with a mirrored computed tomographic image of the contralateral side. This allowed us to calculate the relative displacements (Δx, Δy, Δz) and rotations (Δφx, Δφy, Δφz) for aligning the left bone with the right bone segments. We investigated the relation between longitudinal length differences in radiuses and ulnas. Relative differences of the radiuses were (Δx, Δy, Δz): -0.81 ± 1.22 mm, -0.01 ± 0.64 mm, and 2.63 ± 2.03 mm; and (Δφx, Δφy, Δφz): 0.13° ± 1.00°, -0.60° ± 1.35°, and 0.53° ± 5.00°. The same parameters for the ulna were (Δx, Δy, Δz): -0.22 ± 0.82 mm, 0.52 ± 0.99 mm, 2.08 ± 2.33 mm; and (Δφx, Δφy, Δφz): -0.56° ± 0.96°, -0.71° ± 1.51°, and -2.61° ± 5.58°. There is a strong relation between absolute length differences (Δz) between the radiuses and ulnas of individuals. We observed substantial length and rotational differences around the longitudinal bone axis in healthy individuals. Surgical planning using the unaffected side as a reference may not be as useful as previously assumed. However, including the length difference of the adjacent forearm bones can be useful in improving length correction in computer-assisted planning of radius or ulna osteotomies and in other reconstructive surgery procedures. Bilateral symmetry is important in reconstructive surgery procedures where the contralateral unaffected side is often used as a reference for planning and evaluation.


Bilateral Mycobacterium abscessus keratitis after laser in situ keratomileusis.
A 35-year-old man was diagnosed with Mycobacterium abscessus keratitis in the left eye 3 weeks after bilateral laser in situ keratomileusis (LASIK). Infection in the right eye developed 6 weeks after surgery. Despite aggressive treatment with topical amikacin and clarithromycin and oral clarithromycin, the infection progressed in both eyes. To improve antibiotic penetration, the LASIK flap was removed in both eyes. Culture positivity was prolonged; however, after 8 weeks of intensive topical antibiotics, the infection was eradicated. The final best corrected visual acuity was 20/30 in both eyes.


Undesired light images associated with ovoid intraocular lenses.
Ovoid intraocular lenses (IOLs) accounted for approximately 35% of the lenses implanted in 1991. Despite their popularity among surgeons, patient observations and complaints suggest that ovoid lenses are associated with undesired optical images postoperatively. A pilot clinical study was carried out to test that hypothesis. A multicentered investigation of 289 cases with well-centered IOLs determined that 45% of 168 patients with ovoid lenses observed unwanted optical phenomena at some time after surgery, whereas 17% of 121 patients with round IOLs had similar complaints. Based upon the preliminary clinical study a laboratory investigation was designed to assess optical performance differences between ovoid and round IOLs. One testing system used scatterometry and a second, ray tracing analysis. Both methods determined that the truncated, thickened edge of ovoid lenses was associated with significant light scattering, possibly accounting for the extraneous light images observed by some patients. The results of the clinical and laboratory investigations suggest that undesired optical images produced by ovoid IOLs are due to lens shape rather than to the reduced dimension of the optic.


Accuracy of core needle biopsy for the diagnosis of osteosarcoma: A retrospective analysis of 73 patients.
The goals of this retrospective study were to evaluate the accuracy of core needle biopsy (CNB) for the diagnosis of osteosarcoma and to identify criteria that may predict failed CNB. From 2002 to 2012, 73patients with a total of 73osteosarcomas underwent CNB. Patients demographics and procedure details were recorded, including tumor size, tumor characteristics (hemorrhagic or not, lytic, sclerotic [>50% bone condensation], or mixed), the type of anesthesia, the number of tissue samples, the size of the biopsy needle and pathology report. Procedures were analyzed in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A diagnosis was not made in 5/73patients (6.8%) with an overall sensitivity of 93.1%, a specificity of 100%, a PPV of 100% and a NPV of 99.9%. No complications due to CNB were observed. No criteria were identified as predictors of CNB failure. Even in the presence of sclerotic tumors, CNB should be the first line diagnostic test for suspected osteosarcomas, pending performance by a well-trained radiologist and reading by a specialized pathologist. IV.


Spectral Karyotyping for identification of constitutional chromosomal abnormalities at a national reference laboratory.
Spectral karyotyping is a diagnostic tool that allows visualization of chromosomes in different colors using the FISH technology and a spectral imaging system. To assess the value of spectral karyotyping analysis for identifying constitutional supernumerary marker chromosomes or derivative chromosomes at a national reference laboratory, we reviewed the results of 179 consecutive clinical samples (31 prenatal and 148 postnatal) submitted for spectral karyotyping. Over 90% of the cases were requested to identify either small supernumerary marker chromosomes (sSMCs) or chromosomal exchange material detected by G-banded chromosome analysis. We also reviewed clinical indications of those cases with marker chromosomes in which chromosomal origin was identified by spectral karyotyping. Our results showed that spectral karyotyping identified the chromosomal origin of marker chromosomes or the source of derivative chromosomal material in 158 (88%) of the 179 clinical cases; the identification rate was slightly higher for postnatal (89%) compared to prenatal (84%) cases. Cases in which the origin could not be identified had either a small marker chromosome present at a very low level of mosaicism (< 10%), or contained very little euchromatic material. Supplemental FISH analysis confirmed the spectral karyotyping results in all 158 cases. Clinical indications for prenatal cases were mainly for marker identification after amniocentesis. For postnatal cases, the primary indications were developmental delay and multiple congenital anomalies (MCA). The most frequently encountered markers were of chromosome 15 origin for satellited chromosomes, and chromosomes 2 and 16 for non-satellited chromosomes. We were able to obtain pertinent clinical information for 47% (41/88) of cases with an identified abnormal chromosome. We conclude that spectral karyotyping is sufficiently reliable for use and provides a valuable diagnostic tool for establishing the origin of supernumerary marker chromosomes or derivative chromosomal material that cannot be identified with standard cytogenetic techniques.


Effects of antikaliuretic agents on cardiac electrophysiology--measurements in papillary heart muscle and in purkinje fibers.
Electrophysiological parameters of myocardial excitability of heart muscle in vitro were studied under the influence of antikaliuretic diuretics. Potassium canrenoate, amiloride and triamterene were added in final concentrations of 5-440 mug/ml incubation medium. Resting and action potentials as well as refractory periods of single muscle cells and Purkinje fibers were measured by the microelectrode technique.--The antikaliuretic substances potassium canrenoate, amiloride and triamterene led to a significant concentration-dependent prolongation of action potential duration and, correspondingly, to a lengthening of the refractory period. Glycoside-induced shortening of the refractory period could be demonstrated to be antagonized by triamterene.--Results suggest that aldosterone antagonists, amiloride and triamterene may exhibit antiarrhythmic properties in the ventricular myocardium as well as in the conducting tissue. Drugs are equally effective when compared in molar concentrations. The application of antikaliuretic diuretics seems to be useful in the therapy of congestive heart failure with respect to their extrarenal cardiac effects, too.


Genomic integrity and the ageing brain.
DNA damage is correlated with and may drive the ageing process. Neurons in the brain are postmitotic and are excluded from many forms of DNA repair; therefore, neurons are vulnerable to various neurodegenerative diseases. The challenges facing the field are to understand how and when neuronal DNA damage accumulates, how this loss of genomic integrity might serve as a 'time keeper' of nerve cell ageing and why this process manifests itself as different diseases in different individuals.


Chromogranin A and its derived peptides: potential regulators of cholesterol homeostasis.
Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by its proteolytic cleavage and by their wide anatomical distribution. These peptides are emerging as novel modulators of cardiometabolic diseases that are often linked to high blood cholesterol levels. However, their impact on cholesterol homeostasis is poorly understood. The dynamic nature of cholesterol and its multitudinous roles in almost every aspect of normal body function makes it an integral component of metabolic physiology. A tightly regulated coordination of cholesterol homeostasis is imperative for proper functioning of cellular and metabolic processes. The deregulation of cholesterol levels can result in several pathophysiological states. Although studies till date suggest regulatory roles for CHGA and its derived peptides on cholesterol levels, the mechanisms by which this is achieved still remain unclear. This review aims to aggregate and consolidate the available evidence linking CHGA with cholesterol homeostasis in health and disease. In addition, we also look at common molecular regulatory factors (viz., transcription factors and microRNAs) which could govern the expression of CHGA and genes involved in cholesterol homeostasis under basal and pathological conditions. In order to gain further insights into the pathways mediating cholesterol regulation by CHGA/its derived peptides, a few prospective signaling pathways are explored, which could act as primers for future studies.


Disease burden of respiratory syncytial virus infection in the pediatric population in Japan.
Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections in children aged <5 years and is associated with long-term respiratory morbidities such as recurrent wheezing and asthma, decreased lung function, and allergic sensitization. The objective of this review was to evaluate the epidemiology and burden of RSV infection in the pediatric population in Japan. Studies indexed in PubMed and ICHUSHI databases during January 2010-December 2020 were manually reviewed. Data on proportion of RSV infections, seasonality, length of stay (LoS), mortality, medical expenses, and palivizumab use were extracted from the selected articles. Ninety-three articles were included (PubMed, 64; ICHUSHI, 29). The proportion of patients/samples with an RSV infection was 5.5%-66.7%, and 6.0%-29.9% in the inpatient and outpatient departments, respectively. RSV infections generally occurred during autumn/winter; however, recently the peak has shifted to summer. The LoS was variable and depended on factors such as age, infection severity, wheezing, and RSV subgroups. Mortality rates varied from <1% to 19% depending on the infection severity. The average daily hospitalization and intensive care unit cost was JPY 34,548 while intensive care unit incurred an additional cost of JPY 541,293. Palivizumab was indicated for high-risk infants and 0%-3% of patients required hospitalization despite palivizumab use. RSV imposes a significant burden on the Japanese healthcare system, suggesting a need to create awareness among caregivers of children, pregnant women and healthcare professionals to ensure early recognition of infection and adequate treatment or prophylaxis.


Hotline update of clinical trials and registries presented at the at the European Society of Cardiology Congress in Paris 2011.
This article provides information and commentaries on trials which were presented at the Hotline and Clinical Trial Update Sessions during the Late Breaking Clinical Trial Sessions European Society of Cardiology Congress, held in Paris, France, from 27th to 31st August 2011. This article gives an overview on a number of novel clinical trials in the field of cardiovascular medicine, which were presented. The data have been presented by leading experts in the accordant field with relevant positions in the trials. Unpublished reports should be considered as preliminary data as the analysis may change in the final publications. The comprehensive summaries have been generated from the oral presentation and the webcasts of the European Society of Cardiology, similar as previously reported (Lenski et al. in Clin Res Cardiol Off J Ger Card Soc 99: 679-692, 2010) and should provide the readers with the most comprehensive information of relevant publications. The data were presented by leading experts in the field with relevant positions in the trials.


Zanthoxylum capense constituents with antimycobacterial activity against Mycobacterium tuberculosis in vitro and ex vivo within human macrophages.
Zanthoxylum capense Thunb. (Rutaceae) is a medicinal plant traditionally used in Mozambique to treat tuberculosis. The main aim of the study was to find antimycobacterial lead compounds from Zanthoxylum capense. Another goal was to provide scientific validation for the use of this plant in traditional medicine. By bioassay-guided fractionation, 16 compounds were isolated and screened for their in vitro antimycobacterial activity against two different strains of Mycobacterium tuberculosis. Their in vitro cytotoxicity to human THP-1 macrophages was also assessed. The compounds with favourable selectivity index values (SI>10) were further investigated for their ability to inhibit the growth of Mycobacterium tuberculosis H37Rv in an intracellular macrophage model of infection. The best results were obtained for a benzophenanthridine alkaloid, decarine (1), and an N-isobutylamide, N-isobutyl-(2E,4E)-2,4-tetradecadienamide (15), which showed high activity against Mycobacterium tuberculosis H37Rv (MIC of 1.6 μg/ml), and a low macrophage cytotoxicity (IC50>60 μg/ml), indicating considerable selective activity. The benzophenanthridine alkaloid 6-acetonyldihydronitidine (6) revealed cytotoxicity (IC50 1.7 μg/ml), despite the determined MIC of 6.2-12.5 μg/ml. In infected macrophages, decarine (1) was able to reduce bacterial survival by almost two log units at a concentration of 6.2 μg/ml 5 days post-drug exposure. Compound 15 exhibited an intermediate activity at drug concentrations ranging from 6.2 to 25 μg/ml. The high antimycobacterial activity of decarine found, both in vitro and ex vivo against mycobacteria, and the low cytotoxicity towards human macrophages indicate that it may be valuable as a lead scaffold for the development of anti-TB drugs.


Time to treatment disruption in children with HIV-1 randomized to initial antiretroviral therapy with protease inhibitors versus non-nucleoside reverse transcriptase inhibitors.
Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy. We performed a secondary analysis of a multicenter phase 2/3, randomized, open-label trial in Europe, North and South America from 2002 to 2009. Children aged 31 days to <18 years, who were living with HIV-1 and treatment-naive, were randomized to antiretroviral therapy with two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Time to first documented treatment disruption to any component of antiretroviral therapy, derived from treatment records and adherence questionnaires, was analyzed using Kaplan-Meier estimators and Cox proportional hazards models. The modified intention-to-treat analysis included 263 participants. Seventy-two percent (n = 190) of participants experienced at least one treatment disruption during study. At 4 years, treatment disruption probabilities were 70% (protease inhibitor) vs. 63% (non-nucleoside reverse transcriptase inhibitor). The unadjusted hazard ratio (HR) for treatment disruptions comparing protease inhibitor vs. non-nucleoside reverse transcriptase inhibitor-based regimens was 1.19, 95% confidence interval [CI] 0.88-1.61 (adjusted HR 1.24, 95% CI 0.91-1.68). By study end, treatment disruption probabilities converged (protease inhibitor 81%, non-nucleoside reverse transcriptase inhibitor 84%) with unadjusted HR 1.11, 95% CI 0.84-1.48 (adjusted HR 1.13, 95% CI 0.84-1.50). Reported reasons for treatment disruptions suggested that participants on protease inhibitors experienced greater tolerability problems. Children had similar time to treatment disruption for initial protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, despite greater reported tolerability problems with protease inhibitor regimens. Initial pediatric antiretroviral therapy with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor may be acceptable for maintaining optimal, continuous therapy.


Unravelling the ultrastructure and mineralogical composition of fireworm stinging bristles.
Amphinomid fireworms are notorious for their stinging dorsal bristles (notochaetae), but it is still unclear whether the irritation they cause is merely mechanical or if the notochaetae contain toxins. Furthermore, although fireworm chaetae have always been described as calcareous, their composition has never been investigated to date and strong debates are ongoing on their internal structure. Unravelling the native ultrastructure and composition of fireworm chaetae is the first crucial step to assess whether the hypothesis of toxin vehiculation could be fully considered. We examined for the first time the chemical and mineralogical composition, the ultrastructure and the external structure of the dorsal and ventral chaetae of the large species Hermodice carunculata. All the measurements were carried out on samples prepared without the use of chemical reagents, except for those targeted to investigate if decalcification altered the ultrastructure of the chaetae. A crystal-chemical strategy, combining chemical, diffraction and thermal analyses clearly showed the occurrence of crystalline calcium carbonate and clusters of phosphatic amorphous material. Scanning electron micrographs and energy dispersive X-ray measurements showed that the dorsal chaetae have an extremely shallow insertion point in the body respect to the ventral chaetae, that could facilitate the release of the notochaetae in the environment. Their proximal part is characterized by canals with a hexagonal pattern rich in Ca and P, followed by a large cavity upwards. The harpoon-shaped ends and the central canals of the notochaetae completely disappeared after exposure to EDTA. The notochaetae are hollow and may be able to vehicle toxins. The absence of the honeycomb pattern in the distal part of the notochaetae and their slenderness probably contribute to their brittleness and high sensitivity to breakage on contact. These observations constitute keystone understandings to shed light on fireworm defensive and offensive capacities and their ecological success.


Life-threatening bleeding from arterial-oesophageal fistula following oesophagectomy.
Oesophageal carcinoma remains one of the most common forms of cancer. Resection in the form of oesophagectomy and gastric interposition remains the standard surgical treatment and is associated with a high rate of post-operative morbidity. We report a case of a 71-year old male who underwent successful Ivor-Lewis oesophageal resection and developed life-threatening haemorrhage 2 weeks post-op, attributed to an arterial-oesophageal fistula. The patient was transferred to a specialist ENT centre with ligation of branches of the carotid artery, but intermittent bleeding continued. Following transfer to a specialist oesophago-gastric unit, repeated angiography was required to image the point of bleeding, which was embolised via percutaneous technique. The etiology, presentation, diagnosis and management of arterial-oesophageal fistulae are discussed, along with review of existing reports of similar complications and treatment options. A multidisciplinary approach, along with timely and often repeated imaging, is required in the management of arterial-oesophageal fistulae.


Long-term growth and puberty concerns in international adoptees.
Growth delay is one of the most common and persistent findings in children who have been adopted from abroad. Although the cause is not clearly understood, it may be related to the observed phenomenon of psychosocial short stature described in children from abusive and neglectful settings in western countries. Fortunately, adopted children generally experience significant improvement in growth after joining their new family, but this may put girls at risk for early and rapidly progressing puberty. This review should help the health care team to understand these issues and work better with the adoptive parents to ensure a child's smooth transition into family life.


Has green finance boosted regional electricity consumption? Based on nighttime light data.
Green finance is gradually becoming essential to enhancing regional electricity consumption. This paper uses panel data from 30 Chinese provinces and regions from 2011 to 2021 and develops a system Generalized Method of Moments (GMM) and a mediating effect model to test the effects of green finance on regional electricity consumption level and the mechanism of action. The results show that green finance significantly boosts regional electricity consumption level, which still holds after various robustness tests. In terms of heterogeneity, the promotion effect of green finance on electricity consumption is significantly more substantial in the Eastern regions than in the central and western regions; the regions with a higher level of urbanisation are more robust than those with a lower level of urbanisation, and the regions with a higher level of the advanced industrial structure are stronger than those with a lower level. In terms of impact mechanisms, both foreign direct investment and green technology innovation have partial mediating effects on the impact of green finance on regional electricity consumption level. Green finance raises the level of regional electricity consumption by increasing the level of green technology innovation. At the same time, foreign direct investment has a "substitution effect" on the impact of green finance on regional electricity consumption. Therefore, it is essential to increase green financial policy support to raise regional electricity consumption, help upgrade electricity consumption, and help achieve the "double carbon goal".