Percutaneous central venous catheters versus peripheral cannulae for delivery of parenteral nutrition in neonates.
Neonatal parenteral nutrition may be delivered via peripheral cannulas or central venous catheters (umbilical or percutaneous). As the result of complications associated with umbilical catheters, many neonatal units prefer to use percutaneous catheters after initial stabilisation. Although they can be difficult to place, these catheters may be more stable than peripheral cannulae and require less frequent replacement. These delivery methods may be associated with different risks of adverse events, including acquired invasive infection and extravasation injury. To determine the effects of infusion of parenteral nutrition via percutaneous central venous catheters versus peripheral cannulae on nutrient input, growth and development and complications among hospitalised neonates receiving parenteral nutrition in terms of adverse consequences such as bacteraemia or invasive fungal infection, cardiac tamponade or other extravasation injuries. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 5), MEDLINE (1966 to June 2015) and EMBASE (1980 to June 2015), as well as conference proceedings and previous reviews. Randomised controlled trials that compared delivery of intravenous fluids (primarily parenteral nutrition) via percutaneous central venous catheters versus peripheral cannulae in hospitalised neonates. We extracted data using standard methods of the Cochrane Neonatal Group, with separate evaluation of trial quality and data extraction by two review authors. We found six trials recruiting a total of 549 infants. One trial showed that use of a percutaneous central venous catheter was associated with a smaller deficit between prescribed and actual nutrient intake during the trial period (mean difference (MD) -7.1%, 95% confidence interval (CI) -11.02 to -3.2). Infants in the percutaneous central venous catheter group needed significantly fewer catheters/cannulae (MD -4.3, 95% CI -5.24, -3.43). Meta-analysis of data from all trials revealed no evidence of an effect on the incidence of invasive infection (typical risk ratio (RR) 0.95, 95% CI 0.72 to 1.25; typical risk difference (RD) -0.01, 95% CI -0.08 to 0.06). Data from one small trial suggest that use of percutaneous central venous catheters to deliver parenteral nutrition increases nutrient input. The significance of this in relation to long-term growth and developmental outcomes is unclear. Three trials suggest that use of percutaneous central venous catheters decreases the number of catheters/cannulae needed to deliver nutrition. No evidence suggests that percutaneous central venous catheter use increases risks of adverse events, particularly invasive infection, although none of the included trials was large enough to rule out an effect on uncommon severe adverse events such as pericardial effusion.


Lived Experience among Patients Newly Diagnosed with Lung Adenocarcinoma Stage IV within One Year.
lung cancer (LC) is the fifth of the 10 leading causes of death in the world. LC is in first place for cancer-related mortality for both males and females in Taiwan. It is one of the most difficult cancers to treat and is often diagnosed at a late stage. Patients with stage IV are often unprepared for the diagnosis. To explore lived experience among patients newly diagnosed with lung adenocarcinoma stage IV within one year. Twelve participants were recruited in this study. Content analysis of the interviews revealed four themes: (1) emotional roller coaster, (2) trying to find out causes, (3) adjusting my lifestyle, and (4) cancer fighter. This study provides new insight into the experiences of lung cancer patients y with newly diagnosed lung adenocarcinoma stage 4. These results will inform future supportive care service development and intervention research for patients with advanced stage cancer.


Altered resting-state cerebral blood flow and functional connectivity mediate suicidal ideation in major depressive disorder.
The relationships among cerebral blood flow (CBF), functional connectivity (FC) and suicidal ideation (SI) in major depressive disorder (MDD) patients have remained elusive. In this study, we characterized the changes in CBF and FC among 175 individuals including 47 MDD without SI (MDDNSI), 59 MDD with SI (MDDSI), and 69 healthy control (HC) who underwent arterial spin labeling and resting-state functional MRI scans. Then the voxel-wise CBF, seed-based FC and partial correlation analyses were measured. Mediation analysis was carried out to reveal the effects of FC on the association between CBF and behavioral performances in both subgroups. Results showed that CBF was higher in MDDSI patients in the bilateral precuneus compared to HC and MDDNSI participants. MDDSI patients exhibited enhanced FC in the prefrontal-limbic system and decreased FC in the sensorimotor cortex (SMC) relative to MDDNSI patients. CBF and FC were significantly correlated with clinical variables. More importantly, exploratory mediation analyses identified that abnormal FC can mediate the association between regional CBF and behavioral performances. These results highlight the potential role of precuneus gyrus, prefrontal-limbic system as well as SMC in the process of suicide and provide new insights into the neural mechanism underlying suicide in MDD patients.


Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells.
Acute kidney injury (AKI) is characterized by tubular cell death and interstitial inflammation. TWEAK promotes experimental kidney injury and activates the transcription factor NF-κB, a key regulator of genes involved in cell survival and inflammatory response. In search of potential therapeutic targets for AKI, we compared a transcriptomics database of NF-κB-related genes from murine AKI-kidneys with a transcriptomics database of TWEAK-stimulated cultured tubular cells. Four out of twenty-four (17%) genes were significantly upregulated (false discovery rate, FDR<0.05), while nine out of twenty-four (37%) genes were significantly upregulated at FDR <0.1 in both databases. Bcl3 was the top upregulated NF-κB-related gene in experimental AKI and one of the most upregulated genes in TWEAK-stimulated tubular cells. Quantitative reverse transcription PCR (qRT-PCR), western blot and immunohistochemistry confirmed Bcl3 upregulation in both experimental conditions and localized increased Bcl3 expression to tubular cells in AKI. Transcriptomics database analysis revealed increased Bcl3 expression in numerous experimental and human kidney conditions. Furthermore, systemic TWEAK administration increased kidney Bcl3 expression. In cultured tubular cells, targeting Bcl3 by siRNA resulted in the magnification of TWEAK-induced NF-κB transcriptional activity, chemokine upregulation and Klotho downregulation, and in the sensitization to cell death induced by TWEAK/TNFα/interferon-γ. In contrast, Bcl3 overexpression decreased NF-κB transcriptional activity, inflammatory response and cell death while dampening the decrease in Klotho expression. In conclusion, Bcl3 expressed in response to TWEAK stimulation decreases TWEAK-induced inflammatory and lethal responses. Therefore, therapeutic upregulation of Bcl3 activity should be explored in kidney disease because it has advantages over chemical inhibitors of NF-κB that are known to prevent inflammatory responses but can also sensitize the cells to apoptosis.


Overexpression of cloned genes using recombinant Escherichia coli regulated by a T7 promoter: I. Batch cultures and kinetic modeling.
A novel Eschericha coli expression system directed by bacteriophage T7 RNA Polymerase utilized for overexpression of the cloned gene. The recombinant cell contains the plasmid with a bacteriophage promoter, the T7 promoter, to regulate the expression of the target gene. This promoter is recognized only by T7 RNA polymerase, whose gene has been fused into the host chromosome and is under control of the lacUV5 promoter. Therefore, the target gene on the plasmid can be expressed only in the presence of T7 RNA polymerase, which is induced by isopropyl-beta-D-thiogalactopyranoside (IPTG). The batch cultures were performed to investigate the effect of induction on kinetics of cell growth and foreign protein formation and to determine the optimal induction strategy. It was observed that the specific growth rates of the recombinant cells dramatically decrease after induction, and that there is an optimal induction time for maximizing the accumulated intracellular foreign protein. This optimal induction time varies significantly with inducer concentration. To better understand the optimal behavior, a lumped mechanistic model was constructed to analyze the induced cell growth and foreign protein formation rates.


Mesh size analysis of cellulose nanofibril hydrogels using solute exclusion and PFG-NMR spectroscopy.
The pore structure of TEMPO-mediated oxidized CNF hydrogels, chemically cross-linked with water-soluble diamines, is studied. A solute exclusion method and pulsed-field-gradient NMR are used to estimate the mesh size distribution in the gel network in its hydrated state. Dextran fractions with the nominal molecular weights in the range of 10-2000 kDa are used as probes. The results show a nonuniform network structure, consisting of a group of large openings that contain ∼50% of water, and regions with a more compact structure and smaller mesh units that restrict the diffusivity of the dextran molecules. A biexponential model is proposed for the NMR echo amplitude decay due to the probe diffusion into the gel network. A typical single exponential model does not fit the experimental data when the probe molecular size is comparable to the network mesh size. The results obtained with NMR, using the proposed biexponential model, are in very good agreement with those determined with solute exclusion. Precise mesh size estimation with solute exclusion using pore models is subject to restrictions, and vary with the assumed pore geometry. The average mesh size obtained using a spherical pore model, ∼35 nm, in the compact regions of the hydrogel, is in good agreement with the theoretical value in a network of rodlike particles. Neglecting the wall effects leads to underestimation of the mesh size with both techniques.


Capacity of the store-regulator in maintaining iron balance.
There is evidence that iron stores alter iron absorption to meet body iron needs. In this study, quantitative aspects of this regulation of iron balance are examined. Two male subjects, one with low and one with average iron stores, were given additional dietary iron over 500 days. Changes in iron stores were monitored by plasma ferritin measurements, and the ferritin estimate of stores was validated at the end of the study by bleeding to the point of iron deficiency. The subject with low iron stores increased his ferritin by 39 micrograms/L or 0.8 mg/day, whereas the subject with average iron stores had no significant change. It is concluded that the mechanism by which stores regulate food iron absorption has a capacity of about 1 mg/day, sufficient to meet usual physiological needs, with the exception of pregnancy, as well as the ability to resist increase in stores above normal despite an iron rich diet.


Concertina Effect.
Accordion effect or concertina effect - also known as "crumpled coronary" - is an uncommon occurrence during coronary angioplasty. It usually has no major clinical sequelae and should be differentiated from spasm, dissection, and thrombosis, which require special management.


Lability of IgE Levels Early in Life.
We report a case of a very fast and intriguing decrease in IgE concentrations after exclusion from the diet of any CM lysate in an unusual clinical presentation of cow's milk allergy in an infant. Analysis of IgE kinetics after allergen elimination suggests rapid cessation of IgE biosynthesis and a short IgE half-life.


Chitosan and platelet-derived growth factor synergistically stimulate cell proliferation in gingival fibroblasts.
Chitosan is a naturally derived polymer that may be applied in periodontal therapy for tissue-reconstruction purposes. Previous studies have shown that chitosan may stimulate tissue healing. However, reports exploring the cellular responses stimulated by chitosan are lacking. In the present study we analyzed whether chitosan may promote cell proliferation in primary cultures of human gingival fibroblasts. Chitosan particles were generated, and their size, zeta potential and morphology were characterized using transmission and scanning electron microscopy and zetasizer analysis. The biocompatibility of chitosan particles was analyzed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell-viability assay and by detecting the release of lactate dehydrogenase into the cell-culture medium. The total number of cells was estimated by staining with crystal violet followed by measurement of the absorbance at 560 nm on a microplate reader. Cell proliferation was studied by detecting proliferating cell nuclear antigen protein levels, immunofluorescence for Ki67 and incorporation of 5'-bromo-2'-deoxyuridine. The sizes of the chitosan particles generated were in the micrometer and nanometer ranges. Cell viability was increased in the presence of chitosan. Moreover, the combination of chitosan and platelet-derived growth factor (PDGF-BB) potently stimulated cell viability, cell proliferation and activation of the ERK1/2 pathway involved in cell proliferation. The present study shows that chitosan is well tolerated by gingival fibroblasts and is able to stimulate cell proliferation through the ERK1/2 signaling pathway. A synergistic response between chitosan and growth factors (such as PDGF-BB) may stimulate cell proliferation in gingival fibroblasts exposed to this biomaterial.


Human upper-airway respiratory airflow: In vivo comparison of computational fluid dynamics simulations and hyperpolarized 129Xe phase contrast MRI velocimetry.
Computational fluid dynamics (CFD) simulations of respiratory airflow have the potential to change the clinical assessment of regional airway function in health and disease, in pulmonary medicine and otolaryngology. For example, in diseases where multiple sites of airway obstruction occur, such as obstructive sleep apnea (OSA), CFD simulations can identify which sites of obstruction contribute most to airway resistance and may therefore be candidate sites for airway surgery. The main barrier to clinical uptake of respiratory CFD to date has been the difficulty in validating CFD results against a clinical gold standard. Invasive instrumentation of the upper airway to measure respiratory airflow velocity or pressure can disrupt the airflow and alter the subject's natural breathing patterns. Therefore, in this study, we instead propose phase contrast (PC) velocimetry magnetic resonance imaging (MRI) of inhaled hyperpolarized 129Xe gas as a non-invasive reference to which airflow velocities calculated via CFD can be compared. To that end, we performed subject-specific CFD simulations in airway models derived from 1H MRI, and using respiratory flowrate measurements acquired synchronously with MRI. Airflow velocity vectors calculated by CFD simulations were then qualitatively and quantitatively compared to velocity maps derived from PC velocimetry MRI of inhaled hyperpolarized 129Xe gas. The results show both techniques produce similar spatial distributions of high velocity regions in the anterior-posterior and foot-head directions, indicating good qualitative agreement. Statistically significant correlations and low Bland-Altman bias between the local velocity values produced by the two techniques indicates quantitative agreement. This preliminary in vivo comparison of respiratory airway CFD and PC MRI of hyperpolarized 129Xe gas demonstrates the feasibility of PC MRI as a technique to validate respiratory CFD and forms the basis for further comprehensive validation studies. This study is therefore a first step in the pathway towards clinical adoption of respiratory CFD.


Complications after Living Donor Hepatectomy: Analysis of 176 Cases at a Single Center.
Living liver donation is one of the most selfless and humane acts a person can perform. Few single-center reports have been published specifically evaluating complications and quality of life post-donation. We conducted a retrospective analysis of outcomes of 176 living liver donors at our center to determine the incidence, type, and Clavien grade of complications, as well as long-term quality of life. Of 176 living donors, 154 underwent right hepatectomy, 4 underwent left hepatectomy lobectomy, and 18 underwent left lateral segmentectomy. Mean follow-up time was 4.8 years. Complications were more frequent among right-lobe donors than left-lateral segmentectomy and left-lobe donors (p = 0.003). Of note, 82% of complications were Clavien grade 1 or 2. Of the 154 right-lobe donors, 3 had Clavien grade 3a complications, 9 had grade 3b complications (4 had bile leaks, 3 had intra-abdominal bleeding, and 2 had pleural effusions). No donor had complications that were Clavien grade 4 or higher. Per multivariate regression, resected graft volume (p = 0.0498) and post-donation international normalized ratio >2 (p = 0.00499) were significantly associated with a higher risk of Clavien grade 3 complications; however, sex, age, previous abdominal operation, post-donation bilirubin >6 mg/dL, and aspartate transaminase >650 IU/L were not. Per our 36-item Short-Form Health Survey results, donors (mean 8.3 years post-donation) reported above-average quality of life compared with standard US population. In a liver donation survey sent between 1 and 15 years post-donation, the most frequently reported problems were incisional discomfort and intolerance to fatty meals. In our single-center study, early complication rates were comparable with those of multicenter reports. Most complications (82%) were Clavien grade 1 or 2. During a long follow-up period, our donors continue to have improved quality of life.


[Effect of comprehensive control and prevention for chronic disease in demonstration plot of Chongqing].
To evaluate the effect of comprehensive control and prevention for chronic diseases in demonstration plot of Chongqing. Residents were enrolled through multi-stage stratified random sampling method from 17 districts or counties which had successfully established demonstration plots and 21 districts or counties which had not established demonstration plots (non-demonstration plot for short) yet on May, 2012. Questionnaire was designed to survey awareness of health knowledge, health behaviors and utilization of health supportive tools. The results were analyzed by SPSS 15.0 software. We investigated 15 108 residents, 6156 of which were in demonstration plot and others (8951) were not. The findings revealed the percentage of the people who were aware the national action of health lifestyle in demonstration plot and in non-demonstration plot were 44.4% (2734/6157) and 40.2% (3598/8951), respectively, and the awareness of the hypertension risk of too much sodium were 72.4% (4458/6156) and 67.5% (6042/8951), respectively, and the awareness of the cardinal vascular disease (CVD) risk of obesity and overweight were 77.2% (4753/6157) and 69.6% (6230/8951), respectively. About the residents' health behaviors in demonstration plot and in non-demonstration plot, the utilization rates of salt restriction scoop or pot were 23.5% (1447/6157) and 17.9% (1602/8951), and the utilization rates of oil restriction pot were 16.7% (1028/6157) and 11.8% (1064/8951), respectively. Totally, 33 of the 37 indexes were shown higher in demonstration plot than that in non-demonstration plot (P < 0.05). The chronic diseases comprehensive control and prevention in demonstration plot was more effective, and the remarkable improvement of health knowledge and behaviors level had been achieved in demonstration plot.


Ultrasonographic Assessment of the Femoral Cartilage Thickness in Patients with Pes Planus: A Multicenter Study by TURK-MUSCULUS.
The aims of this study were to measure the distal femoral cartilage thicknesses of patients with pes planus by using ultrasound imaging and to explore whether ultrasound measurements are associated with degree of pes planus. One hundred seven patients (61 men, 46 women; aged 18-45 yrs) with pes planus and 107 age- and sex-matched as well as body mass index-matched healthy controls were enrolled in this study. After clinical assessment of the patients, measurements for pes planus were done on the radiographs, and ultrasound imaging of the distal femoral cartilage was performed from the right medial condyle, the right lateral condyle, the right intercondylar area, the left medial condyle, the left lateral condyle, and the left intercondylar area. Femoral cartilage values were thicker than those of the control group at all measurement sites (except for the right lateral condyle) (P's < 0.05). In a subgroup analysis regarding the sex difference, right medial condyle and left medial condyle values in the male subjects as well as right lateral condyle, right intercondylar area, left lateral condyle, and left intercondylar area values in the female subjects were found to be thicker (all P < 0.05). The distal femoral cartilages of the pes planus patients seem to be thicker, and this finding could possibly stem from excessive mechanical stress on the knee joint caused by impaired lower extremity biomechanics.


Vascularized lymph node flap transfer and lymphovenous anastomosis for klippel-trenaunay syndrome with congenital lymphedema.
A female patient with Klippel-Trenaunay syndrome, including hypertrophic bone and soft tissue in the forelimbs, bilateral lower limbs lymphedema, port-wine stains, and superficial veins of Servelle, was presented. The diagnosis of lymphedema was confirmed by lymphoscintigraphy and indocyanine green lymphography. The novel treatments consisted of vascularized lymph node transplantation to the left lymphedematous extremity and lymphovenous anastomosis to the right lymphedematous extremity. Significant improvements in subjective and objective clinical outcome were observed early in the postoperative period with continued improvements during the follow-up period.


Effect of precooling on pain during local anesthesia administration in children: a systematic review.
This study was conducted to determine how precooling reduces the subjective reported pain and objective pain and to evaluate the effectiveness of precooling the injection site before administration of local anesthesia in children. Electronic databases (PubMed, Ovid SP, Cochrane Central Register of Controlled Trials) were searched for publications from 1980 to 2020. Studies were screened for titles and abstracts, followed by full-text evaluation of included reports. Six studies were included in this systematic review. The primary outcome evaluated was the pain perception or the subjective pain reported by the child receiving the injection. The secondary outcome evaluated was objective pain evaluated in each study. Among 5 studies that evaluated child reported pain scores on a visual analogue scale (VAS), 4 studies reported lower scores in the precooling group and one study reported a higher VAS score in the precooling group than in children treated with 20% benzocaine topical anesthesia. Among 6 studies that evaluated the pain reaction of children by Sound Eye Motor (SEM) score, 4 studies reported a lower SEM score in the precooling group, one study reported no significant difference between the precooling and control groups, and one study reported higher SEM scores in the precooling group than in children treated with 20% benzocaine topical anesthesia. Within the limits of this systematic review, evidence suggests that precooling the injection site with ice can be an effective adjunct to topical anesthesia in reducing both subjective and objective pain during local anesthesia administration in children.


Endoscopic hemoclip placement and epinephrine injection for Mallory-Weiss syndrome with active bleeding.
Mallory-Weiss syndrome with active bleeding requires effective hemostasis. This is an investigation of the respective efficacy and safety of endoscopic hemoclip placement and endoscopic epinephrine injection in Mallory-Weiss syndrome. Thirty-five patients with Mallory-Weiss syndrome with spurting vessels or oozing in a university hospital were enrolled prospectively and randomly assigned to endoscopic hemoclip placement (18 patients) or endoscopic epinephrine injection (17 patients) performed by 4 endoscopists with similar clinical experiences. Demographic characteristics, endoscopic variables, and outcome parameters as well as rates of hemostasis and recurrent bleeding were analyzed. The mean (SD) number of hemoclips applied was 2.5 (1.2) and the mean volume of injection was 7.9 (4.3) mL. Primary hemostasis was achieved in all 35 patients. In each group there was 1 case of recurrent bleeding. Secondary hemostasis was achieved by repeating the same procedures as at randomization in both cases. There were no significant differences in age, gender, prior ingestion of alcohol, presenting symptoms, hemoglobin level, shock, comorbid diseases, bleeding stigmata, tear location, blood transfusion, or hospitalization between the groups. There were no procedure-related complications in either group; surgery was not required in any patient. For both groups, there were no second episodes of recurrent bleeding, procedure-related complication, or need of operation. Endoscopic hemoclip placement and endoscopic epinephrine injection are equally effective and safe for the management of active bleeding in Mallory-Weiss syndrome, even in patients with shock or comorbid diseases.


[A new method for visual SARS DNA sequences analysis].
Traditional DNA sequence analysis is based on sequence alignment, while a new DNA visual sequence analysis is proposed in this paper. Based on S. Wolfram's cellular automation theory, the method transfers one-dimensional DNA sequence into two-demensional visual image. Applying this method to SARS DNA sequence analysis, a characteristic of SARS-CoV differing from non-SARS is discovered. Compared with all known coronaviruses' images, It is found that this is a unique characteristic of SARS virus, and it is helpful to clinical identification of SARS.


Potential markers of disease behavior in acromegaly and gigantism.
Introduction: Acromegaly and gigantism entail increased morbidity and mortality if left untreated, due to the systemic effects of chronic GH and IGF-1 excess. Guidelines for the diagnosis and treatment of patients with GH excess are well established; however, the presentation, clinical behavior and response to treatment greatly vary among patients. Numerous markers of disease behavior are routinely used in medical practice, but additional biomarkers have been recently identified as a result of basic and clinical research studies.Areas covered: This review focuses on genetic, molecular and genomic features of patients with GH excess that have recently been linked to disease progression and response to treatment. A PubMed search was conducted to identify markers of disease behavior in acromegaly and gigantism. Markers already considered as part of routine studies in clinical care guidelines were excluded. Literature search was expanded for each marker identified. Novel markers not included or only partially covered in previously published reviews on the subject were prioritized.Expert opinion: Recognizing the most relevant markers of disease behavior may help the medical team tailoring the strategies for approaching each case of acromegaly and gigantism. This customized plan should make the evaluation, treatment and follow up process more efficient, greatly improving the patients' outcomes.


Effect of hot-etching treatment duration on the shear bond strength of zirconia-to-resin cement.
The surface of zirconia was treated with hot-acid etching of different durations to improve its shear bond strength to resin. Zirconia discs were subjected to untreated, sand-blasting, and hot-etching treatments for 10, 30 and 60 min. The discs were bonded to the surface of bovine enamel specimens using RelyX Ultimate resin cement. The bonded specimens were divided into immediate and thermocyling aging groups according to whether they underwent thermal cycling. A universal mechanical testing machine was used to measure the shear bond strength of the specimens. One-way analysis of variance was used to determine the effect of hot-etching time on the shear bond strength. In the immediate and thermocyling aging groups, 60 min of hot-etching provided significantly higher shear bond strength than the other conditions (p<0.05).


H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.
The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis. Inhibition of aerobic glycolysis enzyme LDHA and G6PD had no significant effects on tumor cell survival. Ablation of G6PD had no significant effect on human mesothelioma and colon carcinoma xenograft growth in athymic mice. However, activation of G6PD with the G6PD-selective activator AG1 induced tumor cell death. AG1 increased tumor cell ROS production and the resultant extrinsic and intrinsic death pathways, mitochondrial processes, and unfolded protein response in tumor cells. Consistent with increased tumor cell death in vitro, AG1 suppressed human mesothelioma xenograft growth in a dose-dependent manner in vivo. Furthermore, AG1 treatment significantly increased tumor-bearing mouse survival in an intra-peritoneum xenograft athymic mouse model. Therefore, in human mesothelioma and colon carcinoma, G6PD is not essential for tumor growth. G6PD acts as a metabolic checkpoint to control metabolic flux towards the PPP to promote tumor cell apoptosis, and its expression is repressed by its promotor H3K9me3 deposition.


Adoptive immunotherapy against sarcomas.
Conventional treatments reached an unsatisfactory therapeutic plateau in the treatment of advanced unresectable bone and soft tissue sarcomas that remain an unsolved medical need. Several evidences support the concept that adoptive immunotherapy may effectively integrate within the complex and multidisciplinary treatment of sarcomas. In this work we reviewed adoptive immunotherapy strategies that have been explored in sarcoma settings, with specific focus on issues related to their clinic transferability. We schematically divided approaches based on T lymphocytes specific for MHC-restricted tumor-associated antigens or relying on MHC-independent immune effectors such as natural killer (NK), cytokine-induced killer (CIK) or γδ T cells. Preclinical findings and initial clinical reports showed the potentialities and drawbacks of different adoptive immunotherapy strategies. The expansion of tumor infiltrating lymphocytes is difficult to be reproduced outside melanoma. Genetically redirected T cells appear to be a promising option and initial reports are encouraging against patients with sarcomas. Adoptive immunotherapy with MHC-unrestricted effectors such as NK, CIK or γδ T cells has recently shown great preclinical potential in sarcoma setting and biologic features that may favor clinical transferability. Combination of different immunotherapy approaches and integration with conventional treatments appear to be key issues for successful designing of next clinical trials.


Are Various σ-Hole Bonds Steered by the Same Mechanisms?
Representative Lewis acid-Lewis base complexes linked by tetrel, pnicogen, chalcogen, and halogen bonds have been studied within the quantum theory of atoms in molecules (QTAIM) approach and the hybrid variation-perturbation theory (HVPT) to analyze possible relationships between these σ-hole dimers. Results obtained at the MP2/aug-cc-pVTZ level indicate numerous correlations similar to hydrogen-bonded systems.


Detection of bladder cancer with feature fusion, transfer learning and CapsNets.
This paper confronts two approaches to classify bladder lesions shown in white light cystoscopy images when using small datasets: the classical one, where handcrafted-based features feed pattern recognition systems and the modern deep learning-based (DL) approach. In between, there are alternative DL models that had not received wide attention from the scientific community, even though they can be more appropriate for small datasets such as the human brain motivated capsule neural networks (CapsNets). However, CapsNets have not yet matured hence presenting lower performances than the most classic DL models. These models require higher computational resources, more computational skills from the physician and are more prone to overfitting, making them sometimes prohibitive in the routine of clinical practice. This paper shows that carefully handcrafted features used with more robust models can reach similar performances to the conventional DL-based models and deep CapsNets, making them more useful for clinical applications. Concerning feature extraction, it is proposed a new feature fusion approach for Ta and T1 bladder tumor detection by using decision fusion from multiple classifiers in a scheme known as stacking of classifiers. Three Neural Networks perform classification on three different feature sets, namely: Covariance of Color Histogram of Oriented Gradients, proposed in the ambit of this paper; Local Binary Patterns and Wavelet Coefficients taken from lower scales. Data diversity is ensured by a fourth Neural Network, which is used for decision fusion by combining the outputs of the ensemble elements to produce the classifier output. Both Feed Forward Neural Networks and Radial Basis Functions are used in the experiments. Contrarily, DL-based models extract automatically the best features at the cost of requiring huge amounts of training data, which in turn can be alleviated by using the Transfer Learning (TL) strategy. In this paper VGG16 and ResNet-34 pretrained in ImageNet were used for TL, slightly outperforming the proposed ensemble. CapsNets may overcome CNNs given their ability to deal with objects rotational invariance and spatial relationships. Therefore, they can be trained from scratch in applications using small amounts of data, which was beneficial for the current case, improving accuracy from 94.6% to 96.9%.


Nitric oxide expression by interleukin-10 in the endoscopic and open methods of vein harvesting in coronary artery bypass surgery.
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that suppresses lymphocyte functions, regulates production of proinflammatory cytokines, and suppresses nitric oxide production by activated macrophages. We examined IL-10 expression and its value as a surrogate index for nitric oxide (NO) production in endothelial cultures obtained from saphenous vein samples. Using 2 different techniques (the open and endoscopic), we harvested samples of human saphenous veins from 90 randomly selected patients undergoing coronary artery bypass surgery (CABG). Endothelial cells collected from the vein samples retrieved through both techniques were cultured for 72 hours. Using a solid phase enzyme linked-immuno-sorbent assay (ELISA), we analyzed pre- and postoperative sera, in addition to the supernatants from the cultures, for IL-10. Mean preoperative levels of IL-10 (0.09 +/- 0.04 pg/mL) did not differ significantly from that for postoperative sera (0.14 +/- 0.17 pg/mL) (P = 0.54). Mean IL-10 levels for endothelial cell culture supernatants did not differ significantly between the endoscopic (0.32 +/- 0.39 pg/mL) and the open method (0.46 +/- 0.80 pg/mL) (P= 0.30). Our findings indicate that endoscopic and open saphenectomies are technically comparable with respect to their effects on IL-10 release during saphenous vein harvesting for CABG. We recommend the endoscopic method for its low morbidity and earlier hospital discharge.


Preparation of nanoformulation of 5-fluorouracil to improve anticancer efficacy: integrated spectroscopic, docking, and MD simulation approaches.
Nanoformulations (NFs) can be used as a novel drug delivery system to treat all cancer types. One of the major drawbacks of conventional anticancer drugs is that they have poor specificity and higher toxicity towards normal cells. 5-fluorouracil (5-FU) is a well-studied anticancer drug that has a significant role in various cancers, specifically colorectal cancer therapy. This study was performed to determine the functional groups, particle size, surface charge, heterogeneity, and stability of the NF. The NFs of 5-FU were prepared through the ultrasonication technique by increasing the surfactant (Tween-80) concentrations. Among all three NFs, nanoformulated 5-FU (n5-FU) showed the most effective particle size (10.72 nm) with a zeta potential of (-4.57 mV). The cytotoxicity and apoptosis profiles confirmed that n5-FU enhanced the anticancer effect of the pure drug in HCT-116 cells, as evident from MTT assay, fluorescence microscopy, and FACS analysis. In HCT-116 cells, the IC50 values of pure and n5-FU were obtained as 41.3 μM and 18.8 μM, respectively, indicating that n5-FU was more effective against the cancer cell line. The cellular uptake study was performed to check the intake of NF in cancer cells. However, the microtubule-affinity regulating kinase-4 (MARK-4), a cancer-target protein, was purified to study the inhibition and interaction studies. The inhibition assay confirmed the inhibitory potential of 5-FU against MARK-4 protein. the multi-spectroscopic, molecular docking and MD simulation studies were performed to analyse the conformational changes, binding studies, intermolecular interactions, and stability of MARK-4 protein upon binding 5-FU. This demonstrates that NF can enhance the effectiveness of anticancer drugs.Communicated by Ramaswamy H. Sarma.


Abciximab-induced delayed profound thrombocytopaenia.
Abciximab, the first approved glycoprotein (GP IIb/IIIa) inhibitor, is being widely used during acute coronary syndromes and offers the promising approach to antithrombotic therapy. We present a case of a young woman who initially received abciximab infusion for undergoing percutaneous coronary intervention of left anterior descending artery and was eventually diagnosed with abciximab-induced delayed thrombocytopaenia. This case outlines the importance of close follow-up of these patients to prevent serious adverse events.


Deformation Behaviour and Damage Evolution of Carbonaceous Phyllite under Cyclic Triaxial Loading.
Rocks present complex deformation behaviours and damage processes under triaxial cyclic loading-a subject not yet sufficiently researched. This paper performed triaxial multistage constant-amplitude cyclic loading experiments under different confining stresses on carbonaceous phyllite. The degradation process is analysed by investigating the variation of elastic modulus ES, Poisson's ratio υ, irreversible strain εirr and energy. Moreover, the rock's failure mode is explored from both macro and micro perspectives. The results showed that the increase in stress level caused the decrease of ES in a step-like form, and the constant-amplitude cyclic loading in each stress level caused a slow decrease of ES, while the υ increased with stress level and constant-amplitude cycles in a similar form. εirr accumulated rapidly at first and then slowly at each stress level; the stress level and irreversible axial strain are related by an exponential function. In terms of energy evolution analysis, the damage to rock can be represented by the cumulative damage energy, there were deceleration accumulations and stability accumulation stages of damage at all stress levels, and an acceleration accumulation stage occurred when the rock was close to failure. The failures of rock under cyclic loading are mainly shear failures, accompanied by grain crushing.


Myeloid-derived suppressor cells: their role in the pathophysiology of hematologic malignancies and potential as therapeutic targets.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells at various stages of differentiation/maturation that have a role in cancer induction and progression. They function as vasculogenic and immunosuppressive cells, utilizing multiple mechanisms to block both innate and adaptive anti-tumor immunity. Recently, their mechanism of action and clinical importance have been defined, and the cross-talk between myeloid cells and cancer cells has been shown to contribute to tumor induction, progression, metastasis and tolerance. In this review, we focus on the role of MDSCs in hematologic malignancies and the therapeutic approaches targeting MDSCs that are currently in clinical studies.


Association of N-terminal pro-brain natriuretic peptide with contrast-induced acute kidney injury and long-term mortality in patients with heart failure and mid-range ejection fraction: An observation study.
The potential value of N-terminal pro-brain natriuretic peptide (NT-proBNP) for contrast-induced acute kidney injury (CI-AKI) in patients with heart failure and mid-range ejection fraction (HFmrEF) is unclear. We investigated whether NT-proBNP is associated with CI-AKI and long-term mortality following elective cardiac catheterization in patients with HFmrEF.A total of 174 consecutive patients with HFmrEF undergoing elective coronary angiography or intervention were enrolled. The primary endpoint was the development of CI-AKI, defined as an absolute increase of ≥0.3 mg/dL or ≥ 50% from baseline serum creatinine with 48 hours after contrast medium exposure. Receiver-operating characteristic curve analysis was conducted, and Youden index was used to determine the best cutoff NT-proBNP value. Multivariable logistic regression and Cox proportional hazards regression analyses were performed to identify the independent risk factors for CI-AKI and long-term mortality, respectively.The incidence of CI-AKI was 12.1%. Patients with CI-AKI had higher NT-proBNP values than those without (4373[1561.9-7470.5] vs 1303[625.2-2482.3], P = 0.003). Receiver-operating characteristic curve revealed that NT-proBNP was not significantly different from the Mehran risk score in predicting CI-AKI (area under the curve [AUC] = 0.723 vs 0.767, P = 0.516). The best cutoff NT-proBNP value for CI-AKI was 3299 pg/mL, with 70.6% sensitivity and 83.1% specificity. Multivariable analysis demonstrated that NT-proBNP ≥3299 pg/mL is significantly related to CI-AKI (odds ratio = 12.79; 95% confidence interval, 3.18-51.49; P < 0.001). Cox regression analysis showed that NT-proBNP ≥3299 pg/mL is associated with long-term mortality (adjusted hazard ratio = 11.91; 95%CI, 2.16-65.70; P = 0.004) during follow-up.In patients with HFmrEF, NT-proBNP ≥3299 pg/mL is associated with CI-AKI and long-term mortality following elective coronary angiography or intervention.


Carbohydrate Intake Practices and Determinants of Food Choices During Training in Recreational, Amateur, and Professional Endurance Athletes: A Survey Analysis.
Carbohydrate (CHO) intake during exercise can optimize endurance performance. However, there is limited information regarding fueling practices of endurance athletes during training. Accordingly, an anonymous German-language online survey was circulated examining the determinants of CHO choices, and intake practices among runners, triathletes, and cyclists during training. Survey questions included predefined answers, and a Likert scale with response of CHO food choice intakes from 1 = never to 5 = always. 1,081 endurance participants (58.0% male, 68.6% aged 18-39 years) of varying competitive levels were included in the analysis. Overall, most participants consumed a combination of commercial sport nutrition products and everyday foods (67.4%, n = 729) with their primary reason that food-first was preferred, but in some exercise scenarios, commercial sport nutrition products were deemed more convenient (61.3%, n = 447). Participants consuming commercial sport nutrition products only (19.3%, n = 209) most often valued their ease of intake during exercise (85.2%, n = 178). Among those consuming everyday foods only (13.2%, n = 143), the most common reason was the perceived importance of eating wholesome foods/natural ingredients (84.6%, n = 121). Between the most frequently consumed CHO sources during training at low-to-moderate intensities (n = 1032), sports drinks (mean ± SD; 2.56 ± 1.33) were consumed significantly more often than bananas (2.27 ± 1.14, p < 0.001), with no significant difference in intake frequency between bananas and traditional muesli/fruit/energy bars (2.25 ± 1.14, p = 0.616). Whereas during high intensities (n = 1,077), sports drinks (3.31 ± 1.51) were significantly more often consumed than gels (2.79 ± 1.37), and gels significantly more often than energy bars (2.43 ± 1.28), all commercial sport nutrition products (all, p < 0.001). Overall, 95.1% (n = 1028) of all participants consumed CHO during training at all exercise intensities, with males (n = 602; 2.35 ± 0.70) consuming significantly more often commercial sport nutrition products than females (n = 424; 2.14 ± 0.79, p < 0.001); females consumed significantly more often everyday foods than males (1.66 ± 0.47 vs. 1.54 ± 0.42, p < 0.001). Most participants used mixed CHO forms during low-to-moderate (87.9%), and high exercise intensities (94.7%). 67.6% (n = 731) of all participants reported guiding their CHO intake rates during training by gut feeling. These large-scale survey findings suggest a preference of endurance participants' CHO intake during training in liquid form independent of exercise intensities and offer novel insights into CHO intake practices to guide sports nutrition strategies and education.


Independent estimation of T*2 for water and fat for improved accuracy of fat quantification.
Noninvasive biomarkers of intracellular accumulation of fat within the liver (hepatic steatosis) are urgently needed for detection and quantitative grading of nonalcoholic fatty liver disease, the most common cause of chronic liver disease in the United States. Accurate quantification of fat with MRI is challenging due the presence of several confounding factors, including T*(2) decay. The specific purpose of this work is to quantify the impact of T*(2) decay and develop a multiexponential T*(2) correction method for improved accuracy of fat quantification, relaxing assumptions made by previous T*(2) correction methods. A modified Gauss-Newton algorithm is used to estimate the T*(2) for water and fat independently. Improved quantification of fat is demonstrated, with independent estimation of T*(2) for water and fat using phantom experiments. The tradeoffs in algorithm stability and accuracy between multiexponential and single exponential techniques are discussed.


A graph extension of the positional Burrows-Wheeler transform and its applications.
We present a generalization of the positional Burrows-Wheeler transform, or PBWT, to genome graphs, which we call the gPBWT. A genome graph is a collapsed representation of a set of genomes described as a graph. In a genome graph, a haplotype corresponds to a restricted form of walk. The gPBWT is a compressible representation of a set of these graph-encoded haplotypes that allows for efficient subhaplotype match queries. We give efficient algorithms for gPBWT construction and query operations. As a demonstration, we use the gPBWT to quickly count the number of haplotypes consistent with random walks in a genome graph, and with the paths taken by mapped reads; results suggest that haplotype consistency information can be practically incorporated into graph-based read mappers. We estimate that with the gPBWT of the order of 100,000 diploid genomes, including all forms structural variation, could be stored and made searchable for haplotype queries using a single large compute node.


Transcranial direct current stimulation in obsessive-compulsive disorder: an update in electric field modeling and investigations for optimal electrode montage.
Introduction: Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation intervention that has been investigated for several psychiatric disorders, including Obsessive-Compulsive Disorder (OCD). As there are several candidate brain regions for targeting OCD relevant networks, clinical studies using tDCS have considerably varied in terms of the electrode montages used. Computer modeling of electric field currents induced by tDCS can help guiding the research of relevant targets for OCD. In this review, the authors used this tool to investigate targeted brain areas from previous studies of tDCS in OCD. Areas covered: A literature search for articles with the keywords 'tDCS', 'Transcranial Direct Current Stimulation' and 'Obsessive Compulsive Disorder' was conducted to identify relevant publications. For comparing different electrode montages, electric field (EF) models were performed using high-resolution brain scan templates. Authors found 13 studies mostly showing an improvement in OCD symptoms. The electrode montages varied considerably between studies. Nonetheless, two main patterns of EFs could be identified: 'focal montages', with EFs concentrated in the prefrontal cortex, and 'diffuse montages', with widespread EFs over cortical areas. Expert opinion: Electric field simulation can guide future clinical trials in psychiatry, using personalized tDCS montages with distinct electrode positioning according to clusters of symptoms.


[HIV infection in intravenous drug dependent patients--Vienna 1988 results].
The rapid spread of HIV infection among intravenous drug abusers plays an increasing role in the AIDS epidemic. In this context the Austrian government changed politics and introduced a methadone maintenance program 1987, to reach more intravenous drug addicts and to stop intravenous drug abuse of this clients. 119 intravenous drug users were anonymously tested for HIV antibodies between April 18 and May 17, 1988 at the out-patient clinic of the Psychiatric University clinic of Vienna and were examined by means of a standardized questionnaire. The data are discussed in respect of the benefits of a methadone maintenance program to decrease HIV-infection among intravenous drug abusers in Vienna.


Mental health comorbidity in youth with atopic dermatitis: A narrative review of possible mechanisms.
The presence of atopic dermatitis (AD) in youth has been linked to a variety of mental health concerns including disruptive behavior, symptoms of anxiety and depression, and diagnoses of attention deficit/hyperactivity disorder and autism spectrum disorder. However, the factors accounting for these relationships are not well understood. The current review summarizes possible mechanisms identified in previous research and highlights areas for future investigation. Among the primary mechanisms studied to date, child sleep is the only factor that has been characterized in relative detail, with findings generally supporting the mediating role of sleep problems in the relationship between AD and psychological symptoms. There is substantial evidence suggesting a negative impact of child AD on parent mental health and the impact of parent mental health on child psychological functioning, although the latter has not been assessed specifically in populations of children with AD. There is also preliminary support for other mechanisms, including pruritus and pain, atopic comorbidities, social functioning, and systemic antihistamine use, in the development of mental health concerns in pediatric AD. Furthermore, research suggests the presence of bidirectional relationships between AD and psychological functioning via inflammatory responses to stress and impaired treatment adherence. Overall, significant additional research is needed to better characterize the nature and magnitude of the relationships among these multiple mechanisms and various psychosocial outcomes. Nevertheless, the findings to date support routine screening of psychological health in patients with AD as well as screening for potential risk factors, which may also serve as targets of therapeutic intervention.


Kinetic theoretical approach to turbulence in variable-density incompressible, statistically inhomogeneous fluids.
The kinetic theory is developed for the mass mixing of two incompressible immiscible fluids due to Rayleigh-Taylor instability (as an example for turbulence in variable-density statistically inhomogeneous incompressible fluids). An expression is derived for the fine grain force in terms of the mass-density and velocity fields. This expression enables the conversion of the Navier-Stokes equation into an exact explicit conservation equation in phase space. The equation is a generalization, to the variable-density case, of the Lundgren equation [T. S. Lundgren, Phys. Fluids 10, 969 (1967)]. The conserved quantity is the fine grain density-velocity distribution (FGDVD). The fine grain mass-density and fluid velocity fields are the two lowest moments of the FGDVD. The joint density-velocity probability density function (DVPDF) is the ensemble average of the FGDVD. Using detailed numerical solutions of the Navier-Stokes equation, it is found that the correlation between the acceleration and the FGDVD is weak. This result identifies a small parameter which enables the derivation, by controlled approximations, of closed equations for the DVPDFs. The lowest order yields the mean-field approximation. It is shown by a numerical solution of the closed kinetic equation in the mean-field approximation that it properly describes the time evolution of the system for periods shorter than the relaxation time. Closure schemes beyond the mean field are discussed.


Effect of endomorphin on somatostatin secretion in the isolated perfused rat stomach.
Recently the two peptides endomorphin-1 and -2 were isolated from bovine brain, which are postulated to be endogenous agonists for mu-opiate receptors in the CNS. Since exogenous and endogenous opioids have been shown to influence gastric functions, it was of interest to examine the effects of endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2), EM-1) and -2 (Tyr-Pro-Phe-Phe-NH(2), EM-2) in the isolated perfused rat stomach. EM-1 10(-8) M and 10(-6) M inhibited somatostatin (SLI) levels from a mean of 79 +/- 2.7 pg/min and 73 +/- 2.7 pg/min to 52 +/- 4.0 pg/min (n = 5, n.s.) and 27 +/- 3.0 pg/min (n = 5, P < 0.05), respectively. To characterize the effect on stimulated SLI-secretion, it was prestimulated for 30 min with gastric inhibitory polypeptide (GIP, 10(-9) M). EM-1 decreased prestimulated SLI-secretion in a concentration-dependent manner from a mean of 469 +/- 64.9 pg/min during the immediately preceding 15 minutes to 184 +/- 12.1 pg/min (67 +/- 4.0 %) at 10(-7) M and from a mean of 1146 +/- 269.6 pg/min to 111 +/- 14.1 pg/min (94 +/- 2.2 %) at 10(-6) M (each n = 6, each P < 0.05). In addition EM-2 was also examined at a concentration of 10(-6) M, which inhibited prestimulated SLI-secretion from a mean of 514 +/- 14.9 pg/min to a nadir of 204 +/- 44.7 pg/min (42 +/- 5 %, n = 6, P < 0.05). Application of the specific mu-opiate receptor antagonist CTOP in doses of 10(-7) to 10(-5) M significantly attenuated the inhibitory effect of EM-1 10(-7) M from 67 +/- 4.0 % to 34 +/- 4.7 % (10(-7) M), 33 +/- 3.0 % (10(-6) M) or 30 +/- 8.6 % (10(-5) M), respectively. This residual inhibition, however, was still significantly different from the preceding perfusion period. On the other hand, naloxone 10(-6) M completely abolished the inhibitory effect of EM-1 10(-7) M. Similarly, the inhibitory effect of 10(-6) M EM-1 was also significantly reduced by CTOP from 94 +/- 2.2 % to 60 +/- 10.9 % (10(-7) M), 61 +/- 5.5 % (10(-6) M) or 51 +/- 12.5 % (10(-5) M), respectively, and the residual effect was significantly different from the preceding perfusion period as well. At this higher dose of EM-1 (10(-6) M) naloxone 10(-6) M reduced the effect to 35 +/- 8.2 %, but there was still a significant difference of SLI levels compared to the preceding stimulation period (P < 0.05). Naloxone 10(-6) M reduced the inhibitory effect of EM-2 10(-6) M from 42 +/- 5.0 % to 20 +/- 5.0 % (P < 0.05), which was still significantly different compared to the preceding stimulation period. EM-1 at the doses of 10(-12) M, 10(-10) M, 10(-8) M and 10(-6) M had no significant effect neither on basal gastrin, bombesin (BLI) and vasoactive intestinal polypeptide (VIP) release nor during concomitant infusion of GIP. EM-1 and -2 inhibit basal and prestimulated SLI secretion in the isolated perfused rat stomach, which is in part attenuated by the mu-receptor antagonist CTOP. The greater inhibitory effect of naloxone, which can be demonstrated at least during the lower dose of EM-1, indicates that other opiate receptors contribute as well. The failure of naloxone to completely antagonize the effect of the higher concentration of EM-1 or EM-2 could be due to insufficient dosage or might indicate the involvement of non-opiate receptor mechanisms.


Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene.
By extending previous studies of the phenobarbital (PB)-responsive 132-base pair (bp) enhancer sequence in the CYP2B10 gene, we have delimited a 51-bp enhancer element that is fully inducible by PB in mouse primary hepatocytes. Sixteen structurally unrelated phenobarbital-type inducers activated the 51-bp enhancer element in transient transfection assays. The results thus indicate that most PB-type inducers, if not all inducers, increase the transcription of the CYP2B10 gene by activating this 51-bp element, now designated PB-responsive enhancer module or PBREM.


The role of patient advocacy organizations in shaping genomic science.
Patient advocacy organizations (PAOs) are nonprofit groups that represent patients and families affected by a significant medical condition or disease. We review some of the different approaches that humanities and social researchers use to study PAOs. Drawing on this recent scholarship, we describe some contemporary patient groups and explore how PAOs can collaborate with biomedical researchers to advance genomic science. We highlight research that aims to describe how PAOs are contributing to multiple aspects of biomedical research, including study design, definition of research goals, data collection and analysis, dissemination of results, and research funding. We also describe several challenges that genomic researchers may encounter in collaborations with PAOs. Throughout our review, we focus on the manner in which new PAO roles challenge traditional boundaries between researchers and subjects, thereby redefining the relationship of patients to science. We consider how this shift may affect our view of scientific collaborations and impact genomic researchers in the future.


A Rare Case of Adult Autoimmune Neutropenia Successfully Treated with Prednisolone.
Autoimmune neutropenia (AIN) is a rare disorder that may cause life-threatening infections. In adults, most cases are secondary to other pathological conditions, and primary AIN is extremely rare. We herein report a case involving a 57-year-old woman diagnosed with AIN. A granulocyte immunofluorescence test detected autoantibodies against human neutrophil antigens in her serum, while various examinations revealed no other causes of neutropenia, suggesting her AIN was primary. She was refractory to granulocyte-colony-stimulating factor but responded to prednisolone. Her neutrophil count remained normal after gradual discontinuation of prednisolone. Diagnostic procedures and optimal treatments for this disorder need to be established.


Restriction fragment length polymorphism analysis of HLA-DR, DQ, DP and C4 alleles in Caucasians with systemic lupus erythematosus.
HLA-DR, DQ, DP and C4 null alleles were determined by restriction fragment length polymorphism (RFLP) analysis in 60 Caucasian patients with systemic lupus erythematosus (SLE) and 66 controls. DR3 (DRw17) and DQw2.1 were increased in frequency in the patients with SLE associated with the presence of C4A null genes. HLA-DP alleles determined by RFLP analysis of genomic DNA as well as of PCR amplified DNA were not associated with SLE or any clinical or autoantibody subset thereof. No DR, DQ, or C4 null gene association was found with renal or neuropsychiatric involvement or nDNA antibodies (or levels thereof). These data suggest that the primary predisposition to SLE lies with HLA-DR or C4 null alleles, and not with HLA-DP.


Galectin-3 (MAC-2) controls phagocytosis and macropinocytosis through intracellular and extracellular mechanisms.
Galectin-3 (Gal-3; formally named MAC-2) is a β-galactoside-binding lectin. Various cell types produce Gal-3 under either normal conditions and/or pathological conditions. Gal-3 can be present in cells' nuclei and cytoplasm, secreted from producing cells, and associated with cells' plasma membranes. This review focuses on how Gal-3 controls phagocytosis and macropinocytosis. Intracellular and extracellular Gal-3 promotes the phagocytosis of phagocytic targets/cargo (e.g., tissue debris and apoptotic cells) in "professional phagocytes" (e.g., microglia and macrophages) and "non-professional phagocytes" (e.g., Schwann cells and astrocytes). Intracellularly, Gal-3 promotes phagocytosis by controlling the "eat me" signaling pathways that phagocytic receptors generate, directing the cytoskeleton to produce the mechanical forces that drive the structural changes on which phagocytosis depends, protrusion and then retraction of filopodia and lamellipodia as they, respectively, engulf and then internalize phagocytic targets. Extracellularly, Gal-3 promotes phagocytosis by functioning as an opsonin, linking phagocytic targets to phagocytic receptors, activating them to generate the "eat me" signaling pathways. Macropinocytosis is a non-selective endocytic mechanism that various cells use to internalize the bulk of extracellular fluid and included materials/cargo (e.g., dissolved nutrients, proteins, and pathogens). Extracellular and intracellular Gal-3 control macropinocytosis in some types of cancer. Phagocytosed and macropinocytosed targets/cargo that reach lysosomes for degradation may rupture lysosomal membranes. Damaged lysosomal membranes undergo either repair or removal by selective autophagy (i.e., lysophagy) that intracellular Gal-3 controls.


Rising food accessibility contributed to the increasing dietary diversity in rural and urban China.
China has undergone a dramatic transition in food consumption in the past few decades. Diet composition has changed significantly because of an increase in food accessibility and lifestyle changes. To investigate dietary changes in China from the perspective of dietary diversity, we assessed the trend of dietary diversity in China by using the following 4 indicators: count index, dietary diversity score, entropy, and Simpson index. Data of 24,542 adults (age >=18 y) were obtained from the China Health and Nutrition Survey (CHNS) conducted in 2004, 2006, 2009, and 2011. Furthermore, the association between dietary diversity and the number of food facilities was investigated using multivariable regression and local polynomial regression. Results indicate that dietary diversity increased over time and was unequally distributed among regions and families. Urban residents had a significantly more diverse diet compared with their rural counterparts (p<0.01). Moreover, dietary diversity was positively associated with food accessibility (p<0.01), and it was affected by socioeconomic factors such as the family income, household size, gender, age, education, and region. Taken together, these data suggest that the increase in dietary diversity in China in the past decade can be partially attributed to the increase in food accessibility.


[Effects of glucocorticoid on tissue remodeling of nasal mucosa of chronic rhinosinusitis with nasal polyposis after endoscopic surgery].
To evaluate the effects of glucocorticoid on tissue remodeling of nasal mucosa from patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) after endoscopic surgery. Nasal mucosa obtained from 30 cases of CRSwNP during nasal endoscopic surgery were considered as preoperation group. These patients were equally divided into two groups after surgery, ie. glucocorticoid group and contrast group. Uncinate process mucosa samples from 6 patients during septoplasty were considered as normal control group. Epithelial damage and expressions of transforming growth factor-beta1 (TGF-beta1) and collagen III were studied by light microscopy and immunohistochemistry. In nasal mucosa samples of preoperation group, epithelial damage showed 90% (27/30) of stage 3 and 10% (3/30) of stage 2; TGF-beta1 positive cells and collagen III positive basement membrane with more than 20 microm were seen in 87% (26/30) and 97% (29/30) of samples, respectively. No significant difference was observed in morphology of nasal mucosa and expressions of TGF-beta1 and collagen III between glucocorticoid group and contrast group at 1th month after surgery. At 3th month after surgery, epithelial damage displayed 53% (8/15) of stage 3, 33% (5/15) of stage 2 and 14% (2/15) of stage 1 in contrast group; however, 93% (14/15) of stage 0 and 7% (1/15) of stage 1 in glucocorticoid group. The difference of epithelial damage between two groups was significant (Uc = 4.481, P < 0.05). The amount of TGF-beta1 positive cell was markedly higher in contrast group than in glucocorticoid group (t = 2.32, P < 0.05). The thickness of basement membrane was above 20 microm in 67% of contrast group (10 cases) and 27% of glucocorticoid group (4 cases); the difference between the two groups was significant (P < 0.05). Tissue remodeling is present in nasal mucosa of CRSwNP after endoscopic surgery. Early and appropriate administration of glucocorticoid plays an important role in inhibition of tissue remodeling and prevention of relapse. Postoperative follow-up should not be less than 3 month.


[The possibility of monitoring of bronchial hyperresponsiveness].
The aim of this review was to present the evidence of the role of the measurement of bronchial hyperresponsiveness in monitoring of asthma. Airway hyperresponsiveness can be assessed during regular clinic visit and it is related to the severity of asthma and airway inflammation. The indirect markers of airway hyperresponsiveness, such as AMP or hypertonic saline may more accurately reflect airway inflammation and remodelling than routine symptoms and lung function monitoring. Monitoring of patients with asthma is a key aspect of optimal asthma management and the measurement of airway hyperresponsiveness may improve asthma control.


Depth-resolved optical imaging of transmural electrical propagation in perfused heart.
We present a study of the 3-dimensional (3D) propagation of electrical waves in the heart wall using Laminar Optical Tomography (LOT). Optical imaging contrast is provided by a voltage sensitive dye whose fluorescence reports changes in membrane potential. We examined the transmural propagation dynamics of electrical waves in the right ventricle of Langendorf perfused rat hearts, initiated either by endo-cardial or epi-cardial pacing. 3D images were acquired at an effective frame rate of 667Hz. We compare our experimental results to a mathematical model of electrical transmural propagation. We demonstrate that LOT can clearly resolve the direction of propagation of electrical waves within the cardiac wall, and that the dynamics observed agree well with the model of electrical propagation in rat ventricular tissue.


Fabrication of a plasmonic modulator incorporating an overlaid grating coupler.
The fabrication of a novel plasmonic reflection modulator is presented and described. The modulator includes plasmon excitation using a diffraction grating coupler and is based on a metal-insulator-semiconductor structure on silicon. Fabrication includes a thin thermal oxide, a plasmonic metal surface defined by optical lithography, a metal grating coupler defined by overlaid e-beam lithography, a passivation layer with metalized vias, and electrical contacts. Physical characterization of intermediate structures is provided along with modulation measurements at λ0 ∼ 1550 nm which verify the concept.


In vitro antimicrobial activity of plant-derived diterpenes against bovine mastitis bacteria.
We evaluated the antibacterial activity of three diterpenes isolated from natural sources against a panel of microorganisms responsible for bovine mastitis. ent-Copalic acid (CA) was the most active metabolite, with promising MIC values (from 1.56 to 6.25 µg mL-1) against Staphylococcus aureus (ATCC and clinical isolate), Staphylococcus epidermidis, Streptococcus agalactiae, and Streptococcus dysgalactiae. We conducted time-kill assays of CA against S. aureus, a commensal organism considered to be a ubiquitous etiological agent of bovine mastitis in dairy farms worldwide. In the first 12 h, CA only inhibited the growth of the inoculums (bacteriostatic effect), but its bactericidal effect was clearly noted thereafter (between 12 and 24 h). In conclusion, CA should be considered for the control of several Gram-positive bacteria related to bovine mastitis.


Different additional risk factors for cerebral infarctions associated with the factor V Leiden mutation in a family.
Several cases with cerebral infarctions associated with the factor V Leiden mutation have been reported. However, bearing in mind the large number of asymptomatic individuals with the factor V Leiden mutation, additional risk factors for cerebral infarctions should be considered. In this report, two siblings with cerebral infarctions associated with a combination of heterozygous factor V Leiden mutation and different additional exogenous and endogenous thrombogenic risk factors are described. Respiratory problems in the perinatal period and increased lipoprotein (a) concentrations in the first patient and an episode of gastroenteritis from Shigella infection and persistent high titers of serum anticardiolipin and beta(2)-glycoprotein I antibodies in the second patient were recorded as additional thrombogenic risk factors. Furthermore, both patients were found to be heterozygous for the methylenetetrahydrofolate reductase gene C677T mutation. These findings suggest that even in the same family, different additional thrombogenic risk factors can be present in infants with cerebral infarctions associated with the factor V Leiden mutation. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of these infants with cerebral infarctions associated with the factor V Leiden mutation and of their related family members. To our knowledge, the second patient in this study is the first patient reported to have cerebral infarctions associated with the combination of the factor V Leiden mutation and persistent high titers of serum beta(2)-glycoprotein I antibodies.


Sleep during Transcendental Meditation.
Electroencephalograms (EEGs) and DC electrooculograms (EOGs) were recorded during Transcendental Meditation periods for 8 experienced Ss. The records, scored blind showed that all but 2 Ss spent considerable portions of their meditation periods in unambiguous physiological sleep.


Proarrhythmic effects of an oxygen-derived free radical generating system on action potentials recorded from guinea pig ventricular myocardium: a possible cause of reperfusion-induced arrhythmias.
Standard microelectrode techniques were used to study the effects of a free radical generating system on action potentials recorded from guinea pig ventricular myocardium. Free radicals were generated by mixing xanthine oxidase (0.02-0.04 mu/ml) with the superfusate-modified Locke's solution containing purine 2.3 mM. The system was validated by demonstrating that it could reduce cytochrome C at a rate of 15.9 +/- 1.5 mol/l/min. This rate was decreased to 3.0 +/- 0.3 (p less than 0.001) in the presence of superoxide dismutase (12 mg/100 ml), and the reaction was absent if xanthine oxidase and purine were premixed for 60 minutes prior to adding cytochrome C. Superfusion of guinea pig ventricular strips with the free radical generating system (20-30 minutes) resulted in a highly significant reduction in resting potential from -79.3 +/- 1.8 mV to -70.9 +/- 1.4 mV (p less than 0.0001, n = 6) and in action potential amplitude from 110.9 +/- 2.2 mV to 101.7 +/- 4.0 mV (p less than 0.0001). There was an accompanying fall in maximum rate of depolarization (Vmax) from 254.1 +/- 17.7 V/sec to 207.1 +/- 18.6 V/sec (p less than 0.01) and no significant change in action potential duration. These changes were accompanied by spontaneous activity in 3 of 6 preparations and reversed after 20-30 minutes washing in Locke's solution. They were largely abolished by adding superoxide dismutase (12 mg/100 ml) to the superfusate and completely absent if the xanthine oxidase and purine were premixed for 60 minutes before superfusing the myocardium. We conclude that the phenomena observed may contribute to the genesis of reperfusion arrhythmias.


Effectiveness and safety of chest pain assessment to prevent emergency admissions: ESCAPE cluster randomised trial.
To determine whether introducing chest pain unit care reduces emergency admissions without increasing reattendances and admissions over the next 30 days. Cluster randomised before and after intervention trial. 14 diverse acute hospitals in the United Kingdom. Patients attending the emergency department with acute chest pain during the year before and the year after the intervention started. Establishment of chest pain unit care compared with continuation of routine care. Proportion of chest pain attendances resulting in admission; reattendances and admissions over the next 30 days; daily emergency medical admissions (all causes); and proportion of emergency department attendances with chest pain. The introduction of chest pain unit care was associated with weak evidence of an increase in emergency department attendances with chest pain (16% v 3.5%; P=0.08); no change in the proportion of chest pain attendances resulting in admission (odds ratio 0.998, 95% confidence interval 0.940 to 1.059; P=0.945); small increases in the proportion reattending (odds ratio 1.10, 1.00 to 1.21; P=0.036) or being admitted (1.30, 0.97 to 1.74; P=0.083) over the next 30 days; and evidence of increased daily medical admissions (1.7 per day, 95% confidence interval 0.8 to 2.5; P<0.001). However, this last finding was highly sensitive to changes in the method used to handle missing data. The introduction of chest pain unit care did not reduce the proportion of patients with chest pain admitted and may have been associated with increased emergency department attendances with chest pain. Current Controlled Trials ISRCTN55318418.


Whispering gallery mode single nanoparticle detection and sizing: the validity of the dipole approximation.
Interactions between whispering gallery modes (WGMs) and small nanoparticles are commonly modeled by treating the particle as a point dipole scatterer. This approach is assumed to be accurate as long as the nanoparticle radius, a, is small compared to the WGM wavelength λ. In this Letter, however, we show that the large field gradients associated with the evanescent decay of a WGM causes the dipole theory to significantly underestimate the interaction strength and, hence, the induced WGM resonance shift, even for particles as small as a∼λ/10. To mitigate this issue, we employ a renormalized Born approximation to more accurately determine nanoparticle-induced resonance shifts and, hence, enable improved particle sizing. The domain of validity of this approximation is investigated, and supporting experimental results are presented.


Association of brain-derived neurotrophic factor and nerve growth factor gene polymorphisms with susceptibility to migraine.
Migraine is one of the most common neurological diseases worldwide. Migraine pathophysiology is very complex. Genetic factors play a major role in migraine. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), play an important role in central nervous system functioning, development, and modulation of pain. This study investigates whether polymorphisms in the BDNF and NGF genes are associated with migraine disease in a Turkish case-control population. Overall, 576 subjects were investigated (288 patients with migraine and 288 healthy controls) for the following polymorphisms: rs6265(G/A), rs8192466(C/T), rs925946(G/T), rs2049046(A/T), and rs12273363(T/C) in the BDNF gene, and rs6330(C/T), rs11466112(C/T), rs11102930(C/A), and rs4839435(G/A) in the NGF gene using 5'-exonuclease allelic discrimination assays. We found no differences in frequency of the analyzed eight polymorphisms between migraine and control groups. However, the frequency of minor A alleles of rs6265 in BDNF gene was borderline significant in the patients compared with the healthy controls (P=0.049; odds ratios [ORs] [95% confidence intervals {CIs}] =0.723 [0.523-0.999]). Moreover, when the migraine patients were divided into two subgroups, migraine with aura (MA) and migraine without aura (MO), the minor TT genotype of rs6330 in NGF was significantly higher in MA patients than in MO patients (P=0.036) or healthy controls (P=0.026), and this disappeared after correction for multiple testing. Also, the rs6330*T minor allele was more common in the MA group than in the MO group or controls (P=0.011, ORs [95% CIs] =1.626 [1.117-2.365] or P=0.007, ORs [95% CIs] =1.610 [1.140-2.274], respectively). In conclusion, this is the first clinical study to evaluate the association between BDNF and NGF polymorphisms in migraine patients compared with health controls. Our findings suggest that the NGF rs6330*T minor allele might be nominated as a risk factor for developing aura in migraine disease. Our results should be considered as preliminary, and they need to be confirmed by future studies.


The graded predictive pre-activation in Chinese sentence reading: evidence from eye movements.
Previous research has revealed that graded pre-activation rather than specific lexical prediction is more likely to be the mechanism for the word predictability effect in English. However, whether graded pre-activation underlies the predictability effect in Chinese reading is unknown. Accordingly, the present study tested the generality of the graded pre-activation account in Chinese reading. We manipulated the contextual constraint of sentences and the predictability of target words as independent variables. Readers' eye movement behaviors were recorded via an eye tracker. We examined whether processing an unpredictable word in a solid constraining context incurs a prediction error cost when this unpredictable word has a predictable alternative. The results showed no cues of prediction error cost on the early eye movement measures, supported by the Bayes Factor analyses. The current research indicates that graded predictive pre-activation underlies the predictability effect in Chinese reading.


Empowerment in breastfeeding as viewed by women: A qualitative study.
The positive effect of breastfeeding on health is globally accepted. However, breastfeeding has not yet practiced at a favorite level. Empowerment of mothers is an important factor for continuing breastfeeding. This study was conducted to explore women's perception of empowerment in breastfeeding. The present qualitative study was conducted in conventional content analysis method. Thirty-four semi-structured deep interviews were conducted with 18 mothers, four key family members, and 12 other personnel involved in breastfeeding counseling services. Analysis of participants' descriptions led to the emergence of five main categories: Enough knowledge and skill for breastfeeding, feeling adequacy in breastfeeding, overcoming breastfeeding problems, informed belief in the value of breastfeeding, and perceiving comprehensive support for breastfeeding. In participants' point of view, empowerment in breastfeeding can be formed through an acquisition of "Enough knowledge and skill for breastfeeding" as well as assurance about the proper quality and quantity of mother's milk. As well as overcoming breastfeeding problems will lead to stabilization empowerment in breastfeeding. In addition, data analysis showed that informed belief in the value of breastfeeding strengthens the empowerment in breastfeeding and presence of perceived comprehensive support for breastfeeding facilitates empowerment in breastfeeding continuance. Thus, comprehensive plans should be designing for promoting breastfeeding.


Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome.
Drug rash with eosinophilia and systemic symptoms syndrome is a severe idiosyncratic drug reaction with a long latency period. It has been described using many terms; however, drug rash with eosinophilia and systemic symptoms syndrome appears to be the most appropriate. This syndrome causes a diverse array of clinical symptoms, anywhere from 2 to 8 weeks after initiating the offending drug. Standardized criteria for the diagnosis have been developed; however, their utility remains to be validated. Unfortunately, the management of drug rash with eosinophilia and systemic symptoms syndrome is not well supported by strong evidence-based data.


Contralateral botulinum toxin injection to improve facial asymmetry after acute facial paralysis.
The application of botulinum toxin to the healthy side of the face in patients with long-standing facial paralysis has been shown to be a minimally invasive technique that improves facial symmetry at rest and during facial motion, but our experience using botulinum toxin therapy for facial sequelae prompted the idea that botulinum toxin might be useful in acute cases of facial paralysis, leading to improve facial asymmetry. In cases in which medical or surgical treatment options are limited because of existing medical problems or advanced age, most patients with acute facial palsy are advised to await spontaneous recovery or are informed that no effective intervention exists. The purpose of this study was to evaluate the effect of botulinum toxin treatment for facial asymmetry in 18 patients after acute facial palsy who could not be optimally treated by medical or surgical management because of severe medical or other problems. From 2009 to 2011, nine patients with Bell's palsy, 5 with herpes zoster oticus and 4 with traumatic facial palsy (10 men and 8 women; age range, 22-82 yr; mean, 50.8 yr) participated in this study. Botulinum toxin A (Botox; Allergan Incorporated, Irvine, CA, USA) was injected using a tuberculin syringe with a 27-gauge needle. The amount injected per site varied from 2.5 to 3 U, and the total dose used per patient was 32 to 68 U (mean, 47.5 +/- 8.4 U). After administration of a single dose of botulinum toxin A on the nonparalyzed side of 18 patients with acute facial paralysis, marked relief of facial asymmetry was observed in 8 patients within 1 month of injection. Decreased facial asymmetry and strengthened facial function on the paralyzed side led to an increased HB and SB grade within 6 months after injection. Use of botulinum toxin after acute facial palsy cases is of great value. Such therapy decreases the relative hyperkinesis contralateral to the paralysis, leading to greater symmetric function. Especially in patients with medical problems that limit the medical or surgical treatment options, botulinum toxin therapy represents a useful alternative.


Correlation and transport properties for mixtures at constant pressure and temperature.
Transport properties of mixtures of elements in the dense plasma regime play an important role in natural astrophysical and experimental systems, e.g., inertial confinement fusion. We present a series of orbital-free molecular dynamics simulations on dense plasma mixtures with comparison to a global pseudo ion in jellium model. Hydrogen is mixed with elements of increasingly high atomic number (lithium, carbon, aluminum, copper, and silver) at a fixed temperature of 100 eV and constant pressure set by pure hydrogen at 2g/cm^{3}, namely, 370 Mbars. We compute ionic transport coefficients, such as self-diffusion, mutual diffusion, and viscosity for various concentrations. Small concentrations of the heavy atoms significantly change the density of the plasma and decrease the transport coefficients. The structure of the mixture evidences a strong Coulomb coupling between heavy ions and the appearance of a broad correlation peak at short distances between hydrogen atoms. The concept of an effective one component plasma is used to quantify the overcorrelation of the light element induced by the admixture of a heavy element.


MLPA-based genotype-phenotype analysis in 1053 Chinese patients with DMD/BMD.
Large-scale analysis of the transmission, mutation characteristics and the relationship between the reading frame and phenotype of the DMD gene has previously been performed in several countries, however, analogous studies have yet to be performed in Chinese populations. Clinical data from 1053 Chinese patients with DMD/BMD were collected, and the DMD gene was tested by MLPA in all patients and 400 proband mothers. In 20 patients with negative MLPA, sequencing was also performed. We found that 27.50% of cases had a family medical history of DMD/BMD, and large rearrangements were identified in 70.56% of the probands, of which 59.35% and 11.21% were deletions or duplications, respectively. The carrier status of the mothers in the study was determined to be 50.75%, and it was established that the DMD mutation was inherited from the mother in 51.72% of the probands. Exons 45-54 and 3-22 were the most frequently deleted regions, and exons 3-11 and 21-37 were the most prevalently duplicated regions of the gene. Breakpoints mainly occurred in introns 43-55 for deletion mutations and in introns 2 and 7 for duplication mutations. No breakpoints were found at the 5' or 3' end of introns 31, 35, 36, 40, 65, 68, and 74-78 in any of the deletion or duplication mutations. The reading frame rule held true for 86.4% of the DMD patients and 74.55% of the BMD patients. It is essential to increase physicians' understanding of DMD/BMD, to promote scientific information, and to increase awareness in regards to genetic counseling and prenatal diagnosis in pedigrees with a family history of the disease, particularly in families with small DMD lesions in China. In addition, such a large-scale analysis will prove to be instructive for leading translational studies between basic science and clinical medicine.


Partitioning the fitness components of RNA populations evolving in vitro.
All individuals in an evolving population compete for resources, and their performance is measured by a fitness metric. The performance of the individuals is relative to their abilities and to the biotic surroundings--the conditions under which they are competing--and involves many components. Molecules evolving in a test tube can also face complex environments and dynamics, and their fitness measurements should reflect the complexity of various contributing factors as well. Here, the fitnesses of a set of ligase ribozymes evolved by the continuous in vitro evolution system were measured. During these evolution cycles there are three different catalytic steps, ligation, reverse transcription, and forward transcription, each with a potential differential influence on the total fitness of each ligase. For six distinct ligase ribozyme genotypes that resulted from continuous evolution experiments, the rates of reaction were measured for each catalytic step by tracking the kinetics of enzymes reacting with their substrates. The reaction products were analyzed for the amount of product formed per time. Each catalytic step of the evolution cycle was found to have a differential incidence in the total fitness of the ligases, and therefore the total fitness of any ligase cannot be inferred from only one catalytic step of the evolution cycle. Generally, the ribozyme-directed ligation step tends to impart the largest effect on overall fitness. Yet it was found that the ligase genotypes have different absolute fitness values, and that they exploit different stages of the overall cycle to gain a net advantage. This is a new example of molecular niche partitioning that may allow for coexistence of more than one species in a population. The dissection of molecular events into multiple components of fitness provides new insights into molecular evolutionary studies in the laboratory, and has the potential to explain heretofore counterintuitive findings.


Burden, spectrum and outcomes of children with tuberculosis diagnosed at a district-level hospital in South Africa.
The Khayelitsha subdistrict has the highest burden of reported tuberculosis (TB) cases in Cape Town, Western Cape Province, South Africa. To characterise the TB burden, spectrum and treatment outcomes among children managed at a district-level hospital, the Khayelitsha District Hospital. Retrospective medical record review of all children (age <13 years) diagnosed with TB in January-July 2014. A lay health care worker completed daily surveillance and supported linkage to TB care. Symptoms and investigations at presentation, TB disease spectrum, referral pathways and outcomes were reported. Most children were aged 2 years (84/99, 85%), 18/96 (19%) were infected with the human immunodeficiency virus, 31/91 (34%) were malnourished and 80/99 (81%) had pulmonary TB only. The majority of the children (63/80, 79%) presented with cough of acute onset (<2 weeks). Only 5/36 (14%) eligible child contacts had documentation of receiving isoniazid preventive therapy. Twelve (13%) children had bacteriologically confirmed pulmonary TB. Overall, 93/97 (96%) children successfully continued TB care after hospital discharge. Favourable TB treatment outcomes were recorded in only 77 (78%) children. Children with TB managed at this district-level hospital were young, and frequently had acute symptoms and substantial comorbidities. Missed opportunities for TB prevention were identified. Linkage to care support resulted in excellent continuation of TB care; however, treatment outcomes could be further improved.


Miniaturized Ion Mobility Spectrometer with a Dual-Compression Tristate Ion Shutter for On-Site Rapid Screening of Fentanyl Drug Mixtures.
The hidden presence of fentanyl and new psychoactive substances in established illicit drugs has led to a great number of unintentional fatal overdoses, justifying the urgent need for portable tools for the rapid screening of various drugs. Ion mobility spectrometry, as a rapid detection technique, has been widely used in detecting illicit drugs, whereas it is insufficiently sensitive for bigger ions due to the mobility discrimination of an ion shutter. In this work, a miniaturized ion mobility spectrometer with an inner diameter of 14 mm and a drift length of 38.9 mm and equipped with a novel dual-compression tristate ion shutter has been developed, which could greatly reduce the mobility discrimination by compressing the ion packet twice during the injection process. The best gating performance of the dual-compression tristate ion shutter was about three times as high as that of the tristate ion shutter and twice as high as that of the Tyndall-Powell shutter. For example, the peak height was increased by 150 or 40% when the resolving power was the same, whereas the resolution of two neighboring peaks was improved by 46 or 19% when the peak heights were the same. In screening of fentanyl drug mixtures, the new shutter enhanced the identification accuracy of constituents by making peaks of slow dimer ions and complex ions observable. Besides, the new shutter helped to achieve high sensitivity for drug ions spreading a wide ion mobility range from 0.644 to 2.032 cm2 s-1 V-1, demonstrating its potential use in the analysis of other mixtures and the detection of large ions.


[Diabetes, hypothyroidism and celiac disease in Down's syndrome. A case report].
It is well known that Down's syndrome patients frequently suffer from immune system diseases leading to the production of autoantibodies and the onset of correlated pathologies. These disorders become increasingly frequent as the patients grow older and the onset of one autoimmune disease often predisposes the development of others. Autoimmune thyroiditis is the most frequent disorder and appears to affect 39% of adult patients. Over the past years a number of reports have been published regarding the coexistence of various autoimmune diseases in DS patients, but little is still known about the relationship between these pathologies and celiac disease. In order to contribute to knowledge regarding the prevalence of this association, the authors report a case of a DS patient who developed diabetes mellitus, hypothyroidism and celiac disease at different times. This case provides further confirmation of the association between Down's syndrome and autoimmune pathologies. The authors feel that follow-up programmes for DS patients should include an evaluation of thyroid function and antithyroid antibodies given that the onset of glandular hypofunction may be very subtle. Furthermore, they should also include tests to assay glycemia, anti-pancreatic insula and anti-insulin antibodies for diabetes and AGA and EMA for celiac disease.


[Relationship between catalytic properties, fixed charge concentration and electrostatic potential of polyelectrolyte-bound enzymes].
An equation for the calculation of the electrostatic potentials of polyelectrolyte-enzyme supports from electrostatic parameters has been derived by relating two different theories which describe the catalytic behaviour of polyelectrolyte-bound enzymes. The electrostatic potentials of polyionic supports have been determined by use of experimental results, on the one hand, from the fixed charge concentration and the ionic strength, on the other hand, from pH- and Km-shifts of immobilized enzymes. The accordance of potentials calculated from electrostatic and kinetic parameters confirms the macroscopic carrier-enzyme model.


Nematicidal activities of 4-quinolone alkaloids isolated from the aerial part of Triumfetta grandidens against Meloidogyne incognita.
The methanol extract of the aerial part of Triumfetta grandidens (Tiliaceae) was highly active against Meloidogyne incognita, with second-stage juveniles (J2s) mortality of 100% at 500 μg/mL at 48 h post-exposure. Two 4-quinolone alkaloids, waltherione E (1), a new alkaloid, and waltherione A (2), were isolated and identified as nematicidal compounds through bioassay-guided fractionation and instrumental analysis. The nematicidal activities of the isolated compounds against M. incognita were evaluated on the basis of mortality and effect on egg hatching. Compounds 1 and 2 exhibited high mortalities against J2s of M. incognita, with EC50 values of 0.09 and 0.27 μg/mL at 48 h, respectively. Compounds 1 and 2 also exhibited a considerable inhibitory effect on egg hatching, which inhibited 91.9 and 87.4% of egg hatching, respectively, after 7 days of exposure at a concentration of 1.25 μg/mL. The biological activities of the two 4-quinolone alkaloids were comparable to those of abamectin. In addition, pot experiments using the crude extract of the aerial part of T. grandidens showed that it completely suppressed the formation of gall on roots of plants at a concentration of 1000 μg/mL. These results suggest that T. grandidens and its bioactive 4-quinolone alkaloids can be used as a potent botanical nematicide in organic agriculture.


Actin depolymerization under force is governed by lysine 113:glutamic acid 195-mediated catch-slip bonds.
As a key element in the cytoskeleton, actin filaments are highly dynamic structures that constantly sustain forces. However, the fundamental question of how force regulates actin dynamics is unclear. Using atomic force microscopy force-clamp experiments, we show that tensile force regulates G-actin/G-actin and G-actin/F-actin dissociation kinetics by prolonging bond lifetimes (catch bonds) at a low force range and by shortening bond lifetimes (slip bonds) beyond a threshold. Steered molecular dynamics simulations reveal force-induced formation of new interactions that include a lysine 113(K113):glutamic acid 195 (E195) salt bridge between actin subunits, thus suggesting a molecular basis for actin catch-slip bonds. This structural mechanism is supported by the suppression of the catch bonds by the single-residue replacements K113 to serine (K113S) and E195 to serine (E195S) on yeast actin. These results demonstrate and provide a structural explanation for actin catch-slip bonds, which may provide a mechanoregulatory mechanism to control cell functions by regulating the depolymerization kinetics of force-bearing actin filaments throughout the cytoskeleton.


Toxoplasma gondii antibodies in HIV and non-HIV infected Thai pregnant women.
Serological evidence for Toxoplasma gondii infection in Thai pregnant women was investigated. One thousand six hundred and sixty-nine blood specimens were collected from 838 HIV-seropositive and 831 HIV-seronegative pregnant women attending the antenatal-care clinic at Siriraj Hospital, Bangkok, Thailand, during a two-year period. Toxoplasma IgG antibody was detected, using a solid-phase enzyme-linked immunosorbent assay in which the membrane protein p-30 was the predominant antigen. IgG positive sera were subsequently examined for IgM antibody by the capture antibody enzyme immunoassay. The IgG antibody was found in 450 (53.7%) HIV seropositive women and 44 (5.3%) non-HIV infected women, with a statistically significant difference (p < 0.0001). Three of the 450 HIV-seropositive and 2 of the 44 HIV-seronegative sera with IgG antibody were positive for IgM antibody against T. gondii. This result suggested that HIV seropositive pregnant women had a higher risk of Toxoplasma infection with increase exposure to their offspring.