Succession of biofilm communities responsible for biofouling of membrane bio-reactors (MBRs).
Biofilm formation is one of the main factors associated with membrane biofouling in membrane bioreactors (MBRs). As such, it is important to identify the responsible organisms to develop targeted strategies to control biofouling. This study investigated the composition and changes in the microbial communities fouling MBR membranes over time and correlated those changes with an increase in transmembrane pressure (TMP). Based on qPCR data, bacteria were the dominant taxa of the biofilm (92.9-98.4%) relative to fungi (1.5-6.9%) and archaea (0.03-0.07%). NMDS analysis indicated that during the initial stages of operation, the biofilm communities were indistinguishable from those found in the sludge. However, the biofilm community significantly diverged from the sludge over time and ultimately showed a unique biofilm profile. This suggested that there was strong selection for a group of organisms that were biofilm specialists. This pattern of succession and selection was correlated with the rapid increase in TMP, where bacteria including Rhodospirillales, Sphingomonadales and Rhizobiales dominated the biofilm at this time. While most of the identified fungal OTUs matched Candida sp., the majority of fungal communities were unclassified by 18S rRNA gene sequencing. Collectively, the data suggests that bacteria, primarily, along with fungi may play an important role in the rapid TMP increase and loss of system performance.


Prodrug design targeting intestinal PepT1 for improved oral absorption: design and performance.
Oligopeptide transporter 1 (PepT1) plays an essential role in the oral absorption of di-and tripeptides from the digestion of ingested protein. PepT1 has become a striking prodrug-designing target recently, since some poorly absorbed drugs can be modified as peptidomimetic prodrugs targeting intestinal PepT1 to improve membrane permeability, and eventually oral absorption of the parent drug. However, little and no comprehensive attempts have been made to especially focus on the recent developments of prodrugs targeting intestinal PepT1. This article summarized biology, transport mechanism, structure-transport requirements for PepT1 and significant advances on the PepT1-targeted prodrugs within the two decades. The article also aimed to highlight some inspirations and knowledge on the multifunctional PepT1-targeted design, which are necessary for obtaining optimal prodrug candidates. That is the requirements of multifunctional rational PepT1 prodrugs include enough binding affinity for PepT1, controlled or targeted release of parent drug, escapement from P-gp mediated efflux and enhanced chemical/metabolic stability. Several types of peptidomimetic prodrugs reported recently were discussed in detail in this review.


Sildenafil does not improve performance in 16.1 km cycle exercise time-trial in acute hypoxia.
Sildenafil is a pulmonary vasodilator that has potential to mitigate the decrement in endurance performance caused by hypoxic pulmonary vasoconstriction. The purpose of this study was to determine the effects of sildenafil on pulmonary artery pressure, cardiac output, pulse oxygen saturation, and exercise performance at moderate simulated altitude. We hypothesized that sildenafil would reduce the decline in exercise performance in hypoxia by blunting the rise in pulmonary artery pressure and causing a relative increase in cardiac output and oxygen saturation. Twelve endurance trained men performed three experimental cycling trials at sea level and simulated moderate altitude of 3,000m (FIO2 = 0.147) after ingesting either a placebo or sildenafil 50 mg capsule in a double blinded fashion. Each test consisted of a warmup period, a 15-minute steady state period at 60% of peak power output, and a 16.1 km time-trial. All subjects experienced a decline in maximal exercise capacity in hypoxia that ranged from 6% to 24%. This decline was correlated with the reduction in pulse oxygen saturation in hypoxic maximal exercise. Sildenafil had no effect on pulmonary artery pressure, cardiac output, or pulse oxygen saturation measured during steady state exercise. There was no effect of sildenafil on mean power output during the time-trial. During high intensity cycle exercise in acute, moderate hypoxia pulmonary artery pressure is unaffected by sildenafil and does not appear to influence cardiovascular function or exercise performance.


Cancer-testis specific gene OIP5: a downstream gene of E2F1 that promotes tumorigenesis and metastasis in glioblastoma by stabilizing E2F1 signaling.
The cancer-testis specific gene Opa interacting protein 5 (OIP5) is reactivated in many human cancers, but its functions in glioblastoma remain unclear. Here, we assessed the significance of OIP5 in the tumorigenesis and metastasis of glioblastoma for the first time. An immunohistochemistry assay was performed to detect OIP5 expression changes in glioblastoma patients. Overall survival analysis was performed to evaluate the prognostic significance of OIP5. Growth curve, colony formation, and transwell assays were used to analyze cell proliferation and metastasis. Tumorigenicity potential was investigated in orthotopic tumor models, and immunoprecipitation, chromatin immunoprecipitation, and luciferase assays were employed to explore the mechanisms underlying the activation of OIP5 expression by E2F transcription factor 1 (E2F1) to stabilize and maintain E2F1 signaling. OIP5 was found to be upregulated in glioblastoma patients and to impair patient survival, and the increased expression of OIP5 was positively correlated with tumor stage. Compared with short hairpin green fluorescent protein cells, cells in which OIP5 was knocked down exhibited significantly reduced proliferation, metastasis, colony formation, and tumorigenicity abilities, whereas OIP5 recovery enhanced these abilities. OIP5 was highly correlated with cell cycle progression but had no obvious effects on apoptosis. Notably, we demonstrated a feedback loop in which E2F1 activates the expression of OIP5 to stabilize and maintain E2F1 signaling and promote the E2F1-regulated gene expression that is required for aggressive tumor biology. Collectively, our findings demonstrate that OIP5 promotes glioblastoma progression and metastasis, suggesting that OIP5 is a potential target for anticancer therapy.


Cloaking from surface plasmon polaritons by a circular array of point scatterers.
In recent years it has been demonstrated both theoretically and experimentally that it is possible to cloak a predefined region of space from interaction with external volume electromagnetic waves, rendering an arbitrary object inside this region invisible to an outside observer. The several strategies that have been developed for achieving such cloaking cannot be applied directly to the cloaking of a surface feature from surface plasmon polaritons propagating on that surface. Here we demonstrate that it is possible to generate an arrangement of two concentric rings of point scatterers on a metal surface that significantly reduces the scattering of surface plasmon polaritons from an object enclosed within this circular structure.


Clinical and echocardiographic characteristics after six months of sacubitril/valsartan in Chagas heart disease - A case series.
Chagas cardiomyopathy is the most prevalent non-ischaemic cardiomyopathy in Latin America, with high morbidity and mortality even today. Treatment of these patients is based on the use of medications for heart failure. This study evaluated a case series of patients with Chagas heart disease who used sacubitril/valsartan at a referral hospital for this disease in Brazil. After 6 months, there was a symptomatic improvement in these individuals assessed by the New York Heart Association (NYHA) functional class, with a 44.3% reduction in the absolute number of patients classified as III-IV in the period (P = 0.035), but without changes in the parameters on the echocardiogram for reverse ventricular remodelling. There was a high mortality rate and number of hospitalizations. These results emphasize the importance of studying the use of sacubitril/valsartan in Chagas heart disease to better describe its effectiveness considering the particularities of these individuals.


Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 2-year randomized, double-blind, placebo-controlled study.
To evaluate in a 24-month, prospective, randomized, double-blind, placebo-controlled study whether pure administration of the phytoestrogen genistein (54 mg/d) might reduce the number and severity of hot flushes in postmenopausal women, with no adverse effect on the endometrium and vagina. A total of 389 participants met the parent study criteria and were randomly assigned to receive the phytoestrogen genistein (n = 198) or placebo (n = 191). About 40% of participants in both groups did not experience hot flushes, and the evaluation was performed in a subgroup of 236 participants (genistein, n = 119; placebo, n = 117). Reductions from the baseline in the frequency and severity of hot flushes were the principal criteria of efficacy. Endometrial thickness was evaluated by ultrasonography. The maturation value was also used to determine hormonal action on the vaginal cells. There were no significant differences in vasomotor symptoms between groups at the baseline (4.4 +/- 0.33 hot flushes per day in the genistein group and 4.2 +/- 0.35 hot flushes per day in the control group). After 12 months of genistein therapy, there was a significant reduction (-56.4%) in the mean number of hot flushes, with a significant difference compared with the control group. After 24 months, there was no further decrease in the number of hot flushes in both groups. No significant difference was found in mean endometrial thickness and the maturation value score between the two groups, either at the baseline or after 24 months. The phytoestrogen genistein has been shown to be effective on vasomotor symptoms without an adverse effect on the endometrium and vagina, but after the first year, there was no further improvement in the decrease in hot flushes.


Life After the Event: A Review of Basic Life Support Training for Parents Following Apparent Life-Threatening Events and Their Experience and Practices Following Discharge.
Apparent Life-Threatening Events (ALTEs) are a common presentation to paediatric hospitals and represent a significant cause of parental anxiety. Basic Life Support (BLS) training is recommended for all caregivers following ALTEs. This study aimed to assess the rate of caregiver BLS training and reviewed parents experience following discharge. Parents were interviewed by phone following discharge. Over the study period 25 children attended the Emergency Department with ALTE, 17/25 (68%) were trained and 13/17 (76%) were contactable for interview. All parents found training decreased their anxiety level and were interested in attending for re-training. BLS resuscitation was subsequently required by 2/13 (15%) of children. Non-medical grade monitors were in use by 10/13 (77%) of caregivers following discharge. Caregivers are eager to engage in BLS training and it effectively reduces their caregiver anxiety. We recommend an increase in instructor staff and use of group re-training post discharge.


Effect of TiO2 as an additive on the sintering performance of Sm-doped CeO2-based electrolyte for solid oxide fuel cells.
In this work, TiO2 was selected as an additive to the Sm0.2Ce0.8O2-δ (SDC) electrolyte and its influence on the electrolyte properties were investigated. The tetrabutyl titanate hydrolysis product was introduced into the SDC samples as a source of TiO2. The lattice contraction of SDC was observed by XRD when the smaller ionic radius Ti4+ (0.605Å) were substituted for Ce4+ (0.97 Å). XRD analysis shows that the doping content of the TiO2 in SDC should be limited to 1 wt% to maintain the single-phase cubic fluorite structure of the SDC and avoid impurity phases. SEM characterizations suggest that the addition of TiO2 significantly promoted the grain growth and the sintering activity, especially when doping with 0.5 wt% of TiO2. The electrochemical measurements reveal that the addition of TiO2 had little effect on the conductivity of SDC samples, which was 0.0306 S cm-1 at 700°C. This study shows that 0.5 wt% TiO2 doping can effectively improve the sintering activity without reducing the SDC performance.


A patient data storage and retrieval system.
A patient data storage and retrieval system has been developed for a microcomputer used in a nuclear medicine department. The advantages of coding clinical information and the problems encountered in coding are highlighted. The application of the stored patient data is briefly discussed.


[Analysis of risk factors for delayed bleeding after endoscopic submucosal dissection of gastric epithelial neoplasm].
Objective: To determine the potential risk factors of delayed hemorrhage after endoscopic submucosal dissection (ESD) in patients with early gastric carcinomas or precancerous lesions. Methods: The clinical data of 637 patients with early gastric carcinomas (EGC) who treated with ESD in Department of Endoscopy at Cancer Hospital, Chinese Academy of Medical Sciences, from August 2013 to August 2019, were retrospectively analyzed. Univariate analysis and multivariate logistic analysis were conducted to evaluate the risk factors associated with delayed bleeding. Results: A total of 699 lesions in 637 patients, of which 696 lesions were resected enbloc, the curative resection rate was 92.1% (644/699). The pathological diagnosis after ESD showed that 46 cases were low-grade intraepithelial neoplasia, 71 were high-grade intraepithelial neoplasia, and 582 were cancer. Delayed bleeding occurred in 74 lesions, while other 625 lesions without postoperative bleeding. The incidence was 10.6%. Compared with the non-bleeding group, there were statistically significant differences in the maximum length of the lesion, the gross shape of the lesion, the control of intra operative bleeding, and the operation time in the delayed bleeding group (P<0.05). Multivariate logistic regression analysis showed that the maximum length of the lesion and the gross shape of the lesion were independent factors of delayed bleeding after ESD. Delayed bleeding was inclined to occur in patients with lesion size ≥3.0 cm (OR=1.958, 95% CI: 1.162-3.299) and the superficial and flat lesion (OR=10.598, 95% CI: 1.313-85.532) after ESD. Conclusions: The maximum length of the lesion and the gross shape of the lesion are independent impact factors of delayed bleeding occurring in patients with EGC and precancerous lesions after ESD. Patients with lesion size≥3 cm, or superficial flat lesion should be paid attention after ESD operation. It needs to take timely measures to prevent the very likely bleeding in order to ensure postoperative recovery and improve the quality of life for postoperative patients.


Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease.
Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease.


Harnessing the power of conversations with virtual humans to change health behaviors.
Skillful, collaborative conversations are powerful tools to improve physical and mental health. Whether you are a parent talking with your child about the dangers of substance abuse, an educator concerned about a student's signs of psychological distress, a veteran worried about a buddy who is contemplating suicide, or a healthcare professional wanting to better engage patients to increase treatment compliance, having the skill, confidence and motivation to engage in conversations can truly transform the health and well-being of those you interact with. Kognito develops role-play simulations that prepare individuals to effectively lead real-life conversations that measurably improve social, emotional, and physical health. The behavior change model that drives the simulations draws upon components of game mechanics, virtual human simulation technology and integrates evidence-based instructional design components as well as principles of social-cognitive theory and neuroscience such as motivational interviewing, emotional regulation, empathy and mindfulness. In the simulations, users or enter a risk-free practice environment and engage in a conversation with intelligent, fully animated, and emotionally responsive virtual characters that model human behavior. It is in practicing these conversations, and receiving feedback from a virtual coach, that users learn to better lead conversations in real life. Numerous longitudinal studies have shown that users who complete Kognito simulations demonstrate statistically significant and sustained increases in attitudinal variables that predict behavior change including preparedness, likelihood, and self-efficacy to better manage conversations. Pending the target population, each online or mobile simulation resulted in desired behavior changes ranging from increased referrals of students, patients or veterans in psychological distress to mental health support services, or increasing physician patient-centered communication or patient self-confidence and active involved in the decision-making processes. These simulations have demonstrated a capability to address major health and public health concerns where effective conversations are necessary to bring about changes in attitudes and behaviors.


True and false memories, parietal cortex, and confidence judgments.
Recent studies have asked whether activity in the medial temporal lobe (MTL) and the neocortex can distinguish true memory from false memory. A frequent complication has been that the confidence associated with correct memory judgments (true memory) is typically higher than the confidence associated with incorrect memory judgments (false memory). Accordingly, it has often been difficult to know whether a finding is related to memory confidence or memory accuracy. In the current study, participants made recognition memory judgments with confidence ratings in response to previously studied scenes and novel scenes. The left hippocampus and 16 other brain regions distinguished true and false memories when confidence ratings were different for the two conditions. Only three regions (all in the parietal cortex) distinguished true and false memories when confidence ratings were equated. These findings illustrate the utility of taking confidence ratings into account when identifying brain regions associated with true and false memories. Neural correlates of true and false memories are most easily interpreted when confidence ratings are similar for the two kinds of memories.


Military personnel and dependents in population analysis and projection.
"Concentrations of [U.S.] armed forces and their dependents create some unusual (and little recognized) problems for applied demographers, both in analysis and projection.... Their presence complicates both the collection and interpretation of data, and has special impact on the preparation of projections." The authors discuss possible ways of resolving these problems.


Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease.
Although plasma globotriaosylsphingosine (lyso-Gb3) is a promising biomarker of Fabry disease (FD), few studies have assessed the impact of lyso-Gb3 in patients with FD. A total of 38 patients diagnosed with FD at Ruijin Hospital between January 2012 and December 2014 were recruited in the current study. An additional 120 unrelated healthy individuals were selected as healthy controls. A simplified liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was performed to determine lyso-Gb3 levels in plasma. Protein precipitation and glycolipid extraction were conducted using acetone/methanol. Clinical performance, including diagnostic value and disease surveillance, were compared between plasma lyso-Gb3 levels and α-galactosidase A (α-gal A) enzyme activity. The overall coefficient of variation values between inter- and intra-days varied between 2.8 and 18.9% and linearity correlation coefficients were ≥0.99 for all assays. Therefore, the effectiveness of the LC-MS/MS method was validated. Furthermore, a cut-off value of 0.81 ng/ml plasma lyso-Gb3 was able to separate patients with FD from healthy individuals. The sensitivity of this cut-off was 94.7% and the specificity was 100%. Compared with α-gal A enzyme activity, the diagnostic rate of patients assessed using plasma lyso-Gb3 levels was similar; however, there was a tighter correlation between plasma lyso-Gb3 levels and the mainz severity score index score in male patients (r=0.711 vs. r=-0.687). The sensitivity of plasma lyso-Gb3 in diagnosing female patients with FD was higher than α-gal A enzyme activity (82.4 vs. 23.5%). To the best of our knowledge, the present study is the first to report the effectiveness of plasma lyso-Gb3 levels in diagnosing Chinese patients with FD. Using α-gal A activity as a reference, the results of current study indicated that plasma lyso-Gb3 levels are more useful at diagnosing female patients with FD. Furthermore, plasma lyso-Gb3 levels are more suitable at determining overall disease severity in male patients.


Down-Klinefelter syndrome (48,XXY,+21) in a child with congenital heart disease: case report and literature review.
Congenital heart disease (CHD) is extremely rarely reported in 48, XYY, +21 karyotype. Herein, we reported one case of 48,XYY,+21 karyotype with CHD and reviewed the available literature. The phenotypic characteristics of the 4-month-old child showed the presence of features typical of mongoloid slant. X-ray detection showed the form of heart was corpulent and the bilateral mediastinum was broad. Doppler echocardiogram detection showed atrial septal and ventricular septal defects with patent ductus arteriosus, pulmonary hypertension and mild tricuspid regurgitation. Including this case, 63 cases of 48, XYY, +21 chromosome pattern have been reported. However, only 9 cases have CHD.


A pool of Y2 neuropeptide Y receptors activated by modifiers of membrane sulfhydryl or cholesterol balance.
The cloned guinea-pig Y2 neuropeptide Y (NPY) receptors expressed in Chinese hamster ovary (CHO) cells, as well as the Y2 receptors natively expressed in rat forebrain, are distributed in two populations. A smaller population that is readily accessed by agonist peptides on the surface of intact cells constitutes less than 30% of Y2 receptors detected in particulates after cell homogenization. A much larger fraction of cell surface Y2 sites can be activated by sulfhydryl modifiers. A fast and large activation of these masked or cryptic sites could be obtained with membrane-permeating, vicinal cysteine-bridging arsenical phenylarsine oxide. A lower activation is effected by N-ethylmaleimide, an alkylator that slowly penetrates lipid bilayers. The restricted-access alkylator, 2-[(trimethylammonium)ethyl]methanethiosulfonate, was not effective in unmasking these sites. Some of the hidden cell surface Y2 sites could be activated by polyene filipin III through complexing of membrane cholesterol. The results are consistent with the presence of a large Y2 reserve in a compartment that can be accessed by alteration of sulfhydryl balance or fluidity of the cell membrane, and by treatments that affect the anchoring and aggregation of membrane proteins.


Evaluation of metagenetic community analysis of planktonic copepods using Illumina MiSeq: Comparisons with morphological classification and metagenetic analysis using Roche 454.
Metagenetics is a rapid and taxonomically comprehensive method for revealing community structures within environmental samples, based on large amounts of sequence data produced by high-throughput sequencers. Because community structures of planktonic copepods are important in the ocean owing to their high diversity and abundance, a metagenetic analysis of the 28S D2 region using Roche 454 was previously developed. However, the Illumina MiSeq platform with a high sequence output is being used more frequently in metagenetics, and non-calanoid copepods have not previously been fully evaluated. Here, we evaluated an Illumina MiSeq-based metagenetic analysis using a mock community and field-collected samples that were examined in a previous study using Roche 454, and the community structure, including non-calanoid copepods, was compared among morphological and metagenetic analyses. We removed a singleton read and applied an appropriate abundance threshold to remove erroneous Molecular Operational Taxonomic Units (MOTUs) with low-abundance sequences in the MiSeq-based analysis. Results showed that the copepod community was successfully characterized using Illumina MiSeq. Higher-quality sequences were obtained using MiSeq than by Roche 454, which reduced the overestimation of diversity, especially at a strict 99% similarity threshold for MOTU clustering. Taxonomic compositions in terms of both biomass and presence/absence of species, including non-calanoids, were more appropriately represented in the MiSeq- than in Roche 454-based analysis. Our data showed that metagenetic analysis using Illumina MiSeq is more useful for revealing copepod communities than Roche 454, owing to the lower cost and higher quality.


Effects of Ficus deltoidea aqueous extract on hematological and biochemical parameters in rats.
Aqueous extract of Ficus deltoidea var. agustifolia was examined for the subchronic toxicity effects in rats. Groups of 10 rats were given the extract daily by oral gavage for 90 days at 0 (control), 100 and 300mg/kg/body weight, respectively. Blood samples were collected upon sacrificed and analysed for haemogram and biochemistry. The results showed there were no significant changes of the blood parameters in all treated groups compared to the control.


Mirror-Image Thymidine Discriminates against Incorporation of Deoxyribonucleotide Triphosphate into DNA and Repairs Itself by DNA Polymerases.
DNA polymerases are known to recognize preferably d-nucleotides over l-nucleotides during DNA synthesis. Here, we report that several general DNA polymerases catalyze polymerization reactions of nucleotides directed by the DNA template containing an l-thymidine (l-T). The results display that the 5'-3' primer extension of natural nucleotides get to the end at chiral modification site with Taq and Phanta Max DNA polymerases, but the primer extension proceeds to the end of the template catalyzed by Deep Vent (exo-), Vent (exo-), and Therminator DNA polymerases. Furthermore, templating l-nucleoside displays a lag in the deoxyribonucleotide triphosphate (dNTP) incorporation rates relative to natural template by kinetics analysis, and polymerase chain reactions were inhibited with the DNA template containing two or three consecutive l-Ts. Most interestingly, no single base mutation or mismatch mixture corresponding to the location of l-T in the template was found, which is physiologically significant because they provide a theoretical basis on the involvement of DNA polymerase in the effective repair of l-T that may lead to cytotoxicity.


How the COVID-19 Overcomes the Battle? An Approach to Virus Structure.
Coronaviruses primarily cause zoonotic infections, however in the past few decades several interspecies transmissions have occurred, the last one by SARS-CoV-2, causing COVID-19 pandemic, posing serious threat to global health. The SARS-CoV-2 spike (S) protein plays an important role in viral attachment, fusion and entry. However, other structural and non-structural SARS-CoV-2 proteins are potential influencers in virus pathogenicity. Among these proteins; Orf3, Orf8, and Orf10 show the least homology to SARSCoV proteins and therefore should be further studied for their abilities to modulate antiviral and inflammatory responses. Here, we discuss how SARS-COV-2 interacts with our immune system.


Variational Bayesian Approach to Multiframe Image Restoration.
Image restoration is a fundamental problem in the field of image processing. The key objective of image restoration is to recover clean images from images degraded by noise and blur. Recently, a family of new statistical techniques called variational Bayes (VB) has been introduced to image restoration, which enables us to automatically tune parameters that control restoration. While information from one image is often insufficient for high-quality restoration, however, current state-of-the-art methods of image restoration via VB approaches use only a single-degraded image to recover a clean image. In this paper, we propose a novel method of multiframe image restoration via a VB approach, which can achieve higher image quality while tuning parameters automatically. Given multiple degraded images, this method jointly estimates a clean image and other parameters, including an image warping parameter introduced for the use of multiple images, through Bayesian inference that we enable by making full use of VB techniques. Through various experiments, we demonstrate the effectiveness of our multiframe method by comparing it with single-frame one, and also show the advantages of our VB approach over non-VB approaches.


Interaction of serotonin with Candida albicans selectively attenuates fungal virulence in vitro.
In this study we investigated whether the direct interaction between Candida albicans CBS 5982 and 5-hydroxytryptamine (5-HT) alters candidial virulence. Hyphae elongation, phospholipase activity and the production of secreted aspartyl proteinases (Saps) following 5-HT treatment were investigated. 5-HT treatment of C. albicans significantly (P < 0.05) affected hyphal extension, phospholipase activity and the production of Saps at concentrations of 118-0.46 mM. In conclusion, our findings suggest that the interaction between 5-HT and C. albicans may diminish the virulence properties of this fungal pathogen.


[Learning self-management for pain. Potentials and limits of an Internet website for low back pain].
This paper examines the role of an interactive website--named Oneself--on patients' chronic low back pain self-management in the Italian part of Switzerland. As part of a qualitative evaluation, we conducted semi-structured interviews with a purposive sample of 18 Oneself users. Results confirm that the Internet may promote attitudes and behaviors of self-management of chronic low back pain. However, it seems that individuals take advantage of this means differently, based on their profile (age, familiarization with the web) and stage of advancement in the self-management process. We conclude that information and support provided online should be tailored according to these different criteria.


IR-Driven Photocatalytic Water Splitting with WO2-NaxWO3 Hybrid Conductor Material.
An IR-driven photocatalytic water splitting system based on WO2-NaxWO3 (x > 0.25) hybrid conductor materials was established for the first time; this system can be directly applied in seawater. The WO2-NaxWO3 (x > 0.25) hybrid conductor material was readily prepared by a high-temperature reduction process of semiconductor NaxWO3 (x < 0.25) nanowire bundles. A novel ladder-type carrier transfer process is suggested for the established IR-driven photocatalytic water splitting system.


[MR imaging and arrhythmogenic right ventricular dysplasia (ARVD)].
Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy of unknown etiology responsible for 20% of cases of sudden death in young adults secondary to arrhythmia. It is characterized histologically by fatty or fibro-fatty infiltration of the right ventricular myocardium. Diagnostic criteria have been proposed for diagnosing ARVD. Imaging, especially MRI, plays an important role. MR imaging must be performed using cardiac gating, and should include both cine-MR sequences for evaluation of segmental and global right ventricular function or any morphological change of the right ventricular shape, and anatomic sequences to detect fatty or fibro-fatty infiltration of the right ventricular myocardium.


Hydrogen sulphide: biopharmacological roles in the cardiovascular system and pharmaceutical perspectives.
Hydrogen sulphide (H(2)S) is now viewed as an important endogenous gasotransmitter, which exhibits many beneficial effects on the cardiovascular system. H(2)S is biosynthesized in mammalian tissues by both non-enzymatic processes and several enzymatic pathways ensured by cystathionine-β-synthase and cystathionine-γ-lyase. H(2)S is endowed with the antioxidant properties of inorganic and organic sulphites, being a scavenger of reactive oxygen species. Furthermore, H(2)S triggers other important effects and the activation of ATP-sensitive potassium channels (KATP) accounts for its vasorelaxing and cardioprotective effects. H(2)S also inhibits smooth muscle proliferation and platelet aggregation. Conversely, the impairment of H(2)S contributes to the pathogenesis of hypertension and is involved in cardiovascular complications associated with diabetes mellitus. There is also evidence of a link between H(2)S and endothelial nitric oxide (NO). Recent observations indicate a possible pathogenic link between deficiencies of H(2)S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H(2)S led to consider this mediator as "the new NO" and to evaluate new attractive opportunities to develop innovative classes of drugs. In this review, the main roles played by H(2)S in the cardiovascular system and the first examples of H(2)S-donor drugs are discussed. Some hybrid drugs are also addressed in this review. In such compounds opportune H(2)S-releasing moieties are conjugated to well-known drugs to improve their pharmacodynamic profile or to reduce the potential for adverse effects.


Sexual surgery in late-nineteenth-century America.
This article describes how the tendency of post-Civil War medicine accorded with general social tendencies. Doctors' attitudes toward women reflected their anxiety about female emancipation and changing sex roles. The specialty of gynecology emerged in significant part as a reaction to female emancipation. The strong surgical emphasis in American gynecology practice has continued. The operations, clitoridectomy and female castration, were intended to reimpose the traditional sexual order (the term "castration" and "female circumcision" implied women had become men). The paper goes on to describe the beginnings of psychosomatic medicine, the circularity of gynecologists' treatment of women, and the effects of this treatment. The operations were in part the expression of a symbiotic relation between doctor and patient. Because they expressed widespread and deep-seated beliefs, they were difficult to challenge.


[Limits of quantitative evaluation methods].
Technical considerations limit the arrhythmias quantifiable by Holter monitoring to atrial and ventricular extrasystoles. However, benign atrial extrasystoles are often neglected and are not considered a target of importance for the study of antiarrhythmic drugs. As regards quantification of ventricular extrasystoles, possible causes of bias should be recognised: the exclusion of patients with dominant irregular and/or wide QRS rhythms, the failure to take global heart rate into account, the qualitative approach to assessment of important parameters such as QRS morphology, coupling interval, grouping which are only considered statistically in terms of prevalence. As a result of these limitations major arrhythmias both at atrial level (salvos of extrasystoles, atrial tachycardia, flutter, fibrillation) and junctional (paroxysmal reciprocating tachycardia) and ventricular levels (ventricular tachycardias of differing origins and types) are systematically disregarded by quantitative standardised protocols, although modern antiarrhythmic agents have been introduced precisely for their treatment. To consider minor arrhythmias more reliable models for study than serious ones because they are easier to quantity, is an error which has been well demonstrated, as in many respects we still do not know how to quantify relatively important parameters. A good example of this situation is the confusion and contradictions in the literature about the long-term prognosis of myocardial infarction evaluated by methods of counting ventricular extrasystoles: the most formal conclusions are drawn from reports containing the least and most qualitative data and which include bias unrelated to the techniques, chosen consciously or not by the authors.


Dynamics of embryonic stem cell differentiation inferred from single-cell transcriptomics show a series of transitions through discrete cell states.
The complexity of gene regulatory networks that lead multipotent cells to acquire different cell fates makes a quantitative understanding of differentiation challenging. Using a statistical framework to analyze single-cell transcriptomics data, we infer the gene expression dynamics of early mouse embryonic stem (mES) cell differentiation, uncovering discrete transitions across nine cell states. We validate the predicted transitions across discrete states using flow cytometry. Moreover, using live-cell microscopy, we show that individual cells undergo abrupt transitions from a naïve to primed pluripotent state. Using the inferred discrete cell states to build a probabilistic model for the underlying gene regulatory network, we further predict and experimentally verify that these states have unique response to perturbations, thus defining them functionally. Our study provides a framework to infer the dynamics of differentiation from single cell transcriptomics data and to build predictive models of the gene regulatory networks that drive the sequence of cell fate decisions during development.


Extramammary Paget's disease of the vulva: An annotated review of the current literature.
Extramammary Paget's disease is a rare and unusual neoplastic entity that presents mainly on apocrine gland-bearing skin. The vulva is the most common site of involvement but any area of the anogenital skin can be affected. Due to its rarity, variable clinical course and deceptive histological appearance it has a high misdiagnosis rate and both gynaecologists and dermatologists have limited experience in its management. The significance of the disease lies in its association with underlying malignancy as well as its inherent ability to invade the dermis and metastasise. The management is notoriously complicated and recurrence rates are high despite aggressive surgeries. Several alternative modalities are being explored, with results that are often variable and unpredictable. This review summarises the histopathological, clinical and therapeutic features of extramammary Paget's disease of the vulva reported in recent years.


Pancreatic polypeptide response to secretin in obesity: effects of glucose intolerance.
Pancreatic polypeptide (PP) may function as a regulator of satiety. Its secretion is impaired in certain animal models of obesity and the administration of PP may improve the hyperphagia and hyperinsulinism seen in these animals. In obese humans, decreased, normal or increased, basal and stimulated concentrations of PP in plasma have been reported. However the advent of diabetes confounds the picture since PP levels in diabetes are generally raised. We have therefore examined the PP responses to intravenous secretin, a known PP secretagogue, in 23 obese subjects, 12 with normal and 11 with abnormal glucose tolerance, and compared the results with those in 23 age and sex-matched healthy controls. The mean maximum PP level in obese subjects with normal glucose tolerance (98 +/- 13 pg/ml) was significantly less than that in normal subjects (218 +/- 23 pg/ml) but in obese subjects with abnormal glucose tolerance, it was significantly greater (578 +/- 115 pg/ml). Within each of the 3 study groups taken separately, PP response to secretin was not correlated with glucose or insulin levels, or with the degree of obesity. Thus, obesity per se appears to be associated with impaired PP responses, which may be masked by abnormalities in glucose tolerance.


Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer.
Because some studies have linked polymorphic variants of the estrogen-metabolizing genes CYP17 and catechol O-methyl transferase (COMT) with risk for hormonally related cancers, we sought to determine whether selected polymorphisms of these genes differed between women with and without ovarian cancer. From a population-based study of ovarian cancer, we analyzed DNA from a total of 480 cases and controls. PCR amplification was performed using primers that amplify restriction sites for MspAI (A2 polymorphism-CYP17) and NlaIII (Val/Met polymorphism-COMT). Digestion of the PCR products was performed. Genotypes identified by gel electrophoresis were assigned as homozygous wild type (WW), heterozygous variant (Wv), and homozygous variant (vv). Frequencies were compared using chi(2) or Fisher's exact tests. Logistic regression was used to calculate crude and adjusted relative risks (RRs) for ovarian cancer associated with possession of any variant allele overall, and within demographic, weight, and smoking history categories, and by histological subtype of ovarian cancer. A portion (68.9%) of cases either carried or was homozygous for the A2 variant of CYP17 compared with 53.9% of controls, for a RR (and 95% confidence interval) of 1.86 (1.26, 2.75; P = 0.003), adjusted for age, parity, oral contraceptive use, site of study, and family history of breast or ovarian cancer. The increased risk was most apparent for women >50 and women with invasive serous cancers. A portion (71.9%) of cases either carried or was homozygous for the Val/Met variant of COMT, compared with 76.9% of controls (P = 0.27). Although the inverse association of ovarian cancer with possession of a Val/Met variant was not significant overall, it was for mucinous tumors of the ovary, with an adjusted RR of 0.28 (0.13, 0.61; P = 0.0012). Possession of the A2 variant of CYP17 appears to increase risk for ovarian cancer, whereas possession of the Val/Met variant of COMT decreases the risk for mucinous tumors. Confirmation in other populations and further exploration of potential pathogenetic mechanisms will be necessary.


Alkaline phosphatase activity of polymorphonuclear leucocytes and lymphocytes separated from normal human blood.
Suspensions of polymorphonuclear leucocytes and lymphocytes were prepared from normal human blood by the glass bead column method of Rabinowitz (1964). The alkaline phosphatase activity of the separated cells was determined by biochemical and cytochemical techniques. Lymphocytes were found to contain an enzyme catalysing the hydrolysis of beta-glycerophosphate at alkaline pH but not of p-nitrophenylphosphate at the same pH and in the same buffer system. The alkaline phosphatase in polymorphonuclear leucocytes catalysed the hydrolysis of both substrates equally. The importance of this finding to the interpretation of clinical data is discussed.


Fluorescent properties of spinach leaf plasma membranes and chloroplast envelopes.
Plasma membranes and chloroplast envelopes were isolated from green spinach leaves, and emission and excitation spectra recorded in aqueous solution at 25 degrees C. Chloroplast envelopes excited by 420 nm showed strong emission peaks at 635 and 680 nm that came from chlorophyll precursors present only in these membranes. Upon UV excitation, both plasma membranes and chloroplast envelopes exhibited emission peak at 420 nm originating from pterins and 520 nm due to flavins. Oxidation of the membranes increased both the emission and excitation fluorescence intensity.


Clinical Evaluation of a Skin Protectant for the Management of Incontinence-Associated Dermatitis: An Open-Label, Nonrandomized, Prospective Study.
The purpose of this study was to evaluate the efficacy of an investigational skin protectant product at managing severe skin breakdown associated with incontinence. Open-label, nonrandomized, prospective study. The sample comprised 16 patients; inclusion criteria were: patients older than 18 years, cared for in the intensive care unit of a level I trauma center hospital or in long-term care facilities in the northeast region of the United States, and had incontinence-associated dermatitis (IAD). Twelve of the patients had epidermal skin loss and 4 had severe redness. The investigational product is a formulation based on acrylate chemistry. The skin protectant application schedule was twice weekly for up to 3 weeks for a maximum of 6 applications during the study period. The skin was evaluated via a skin assessment instrument specifically designed for use in this study; this instrument has not undergone validation studies. The main outcome measure was changes in the instrument score over time. In addition, complete reepithelialization was recorded when observed, and pain scores (associated with IAD) were noted in participants who were able to report pain. The IAD score improved in 13 of 16 patients, remained unchanged in 1 patient, and deteriorated in 2 patients. The median percent improvement in the skin assessment instrument was 96% (P = .013). Four of the patients with epidermal skin loss had complete reepithelialization of the skin surface with 4 to 6 applications of the skin protectant, and 5 had substantial improvement. The 4 patients with severe red skin returned to healthy normal skin with 2 to 4 skin protectant applications. Substantial pain reduction was reported by all 9 patients who reported pain at enrollment. No adverse events associated with the skin protectant application were reported during data collection. Results of this study suggest that an acrylate-based product, evaluated here for the first time in patients, may be effective as a protective barrier in the presence of continued incontinence. Additional research is needed to confirm these findings.


Treatment of sleep apnoea with continuous positive airway pressure in children with craniofacial malformations.
We conducted sleep studies in a consecutive series of 21 children with craniofacial malformations and suspected obstructive sleep apnoea. Thirteen had sleep apnoea, and one patient with a tracheostomy could not be tested. Twelve children were admitted for initiation of treatment with nasal continuous positive airway pressure (nCPAP). Ten patients accepted nCPAP, two did not. Seven children use home treatment successfully. Obstructive sleep apnoea in most children is completely eliminated with nCPAP. The treatment is safe, effective, and leads to a reduction in the number of operations done for children with craniofacial malformations. Aesthetic operations can be delayed until facial growth is complete.


Palliative Management of Nonoperative Femoral Neck Fractures With Continuous Peripheral Pain Catheters: 20 Patient Case Series.
To identify the success of pain catheters in the management of pain in nonoperatively treated femoral neck fractures (FNFs) in supplement to current multimodal protocols for end-of-life pain management. Twenty patients aged older than 50 years with FNFs were selected in a retrospective fashion at a level 1 trauma center. These patients were treated nonoperatively with indwelling continuous peripheral pain catheters to palliate pain. Adjunctive pain control for patients undergoing nonoperative management of FNFs was provided with an indwelling continuous intra-articular/peripheral nerve ropivacaine pain catheters. Pain scores 24 hours before/after continuous pain catheter placement, ambulation status before/after continuous pain catheter placement, mortality at 30 days/1 year, and length of hospital stay were measured. Twenty patients were identified with an average age of 84.55 years. The average length of stay was 4.85 days with a decrease of 4.45 points on the visual analog scale and an improvement of 90% in ambulation status. Thirty-day and one-year mortality were 65% and 95%, respectively. This case series provides orthopedic surgeons with an option for and data on the success of this adjunct to palliate patients who elect to undergo nonoperative management of FNFs. This study also helps define which patients may be candidates for nonoperative management of geriatric hip fractures.


EGFRAP encodes a new negative regulator of the EGFR acting in both normal and oncogenic EGFR/Ras-driven tissue morphogenesis.
Activation of Ras signaling occurs in ~30% of human cancers. However, activated Ras alone is insufficient to produce malignancy. Thus, it is imperative to identify those genes cooperating with activated Ras in driving tumoral growth. In this work, we have identified a novel EGFR inhibitor, which we have named EGFRAP, for EGFR adaptor protein. Elimination of EGFRAP potentiates activated Ras-induced overgrowth in the Drosophila wing imaginal disc. We show that EGFRAP interacts physically with the phosphorylated form of EGFR via its SH2 domain. EGFRAP is expressed at high levels in regions of maximal EGFR/Ras pathway activity, such as at the presumptive wing margin. In addition, EGFRAP expression is up-regulated in conditions of oncogenic EGFR/Ras activation. Normal and oncogenic EGFR/Ras-mediated upregulation of EGRAP levels depend on the Notch pathway. We also find that elimination of EGFRAP does not affect overall organogenesis or viability. However, simultaneous downregulation of EGFRAP and its ortholog PVRAP results in defects associated with increased EGFR function. Based on these results, we propose that EGFRAP is a new negative regulator of the EGFR/Ras pathway, which, while being required redundantly for normal morphogenesis, behaves as an important modulator of EGFR/Ras-driven tissue hyperplasia. We suggest that the ability of EGFRAP to functionally inhibit the EGFR pathway in oncogenic cells results from the activation of a feedback loop leading to increase EGFRAP expression. This could act as a surveillance mechanism to prevent excessive EGFR activity and uncontrolled cell growth.


"Looking for children": the search for fertility among the Sara of southern Chad.
Despite the long history of infertility and childlessness in Central Africa, and the ongoing demand for treatment of fertility-related problems, the interpretations and experiences of the men and women living in the region vis-à vis the inability to have children remain largely unrecorded. In this paper I examine what the Sara, one of Chad's largest ethnic groups, have to say about fertility problems, and how these views are linked to changes in the social, cultural, and economic landscape of southern Chad in the 20th century. I describe the iterative and inductive process, commonly referred to by the Sara as "doing research," that the Sara use to explore the reasons for the inability to conceive or bear children in the face of multiple reproductive threats. The Sara's causal constructions convey a holistic and multifaceted perspective on this demographic anomaly--a perspective that is missing from most demo graphic and epidemiologic accounts and that has important implications for public health policy and practice.


2-Deoxyglucose and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells.
Cancer cells consume more glucose than normal cells, mainly due to their increased rate of glycolysis. 2-Deoxy-d-glucose (2DG) is an analogue of glucose, and sorafenib is a kinase inhibitor and molecular agent used to treat hepatocellular carcinoma (HCC). The present study aimed to demonstrate whether combining 2DG and sorafenib suppresses tumor cell proliferation and motility more effectively than either drug alone. HLF and PLC/PRF/5 HCC cells were incubated with sorafenib with or without 1 µM 2DG, and subjected to a proliferation assay. A scratch assay was then performed to analyze cell motility following the addition of 2DG and sorafenib in combination, and each agent alone. RNA was isolated and subjected to reverse transcription-quantitative polymerase chain reaction to analyze the expression of cyclin D1 and matrix metalloproteinase-9 (MMP9) following the addition of 2DG and sorafenib in combination and each agent alone. Proliferation was markedly suppressed in cells cultured with 1 µM 2DG and 30 µM sorafenib compared with cells cultured with either agent alone (P<0.05). In addition, levels of Cyclin D1 expression decreased in cells exposed to 3 µM sorafenib and 1 µM 2DG compared with cells exposed to 2DG or sorafenib alone (P<0.05). Scratch assay demonstrated that the distance between the growing edge of the cell sheet and the scratched line was shorter in cells cultured with sorafenib and 2DG than in cells cultured with 2DG or sorafenib alone (P<0.05). Levels of MMP9 expression decreased more in cells treated with both sorafenib and 2DG than in cells treated with 2DG or sorafenib alone (P<0.05). Therefore, 2DG and sorafenib in combination suppressed the proliferation and motility of HCC cells more effectively than 2DG or sorafenib alone, and a cancer treatment combining both drugs may be more effective than sorafenib alone.


Escalation in the relative prevalence of ciprofloxacin-resistant gonorrhoea among men with urethral discharge in two South African cities: association with HIV seropositivity.
The objectives of this study were to assess the prevalence of ciprofloxacin-resistant gonorrhoea in two South African cities and to investigate the association between the isolation of ciprofloxacin-resistant Neisseria gonorrhoeae and the HIV serostatus of patients. Gonococci were cultured from endourethral swabs taken from consecutive men with urethritis attending clinics in Johannesburg and Cape Town. Minimum inhibitory concentrations (MIC) for ciprofloxacin and ceftriaxone were determined with E-tests. Isolates with a ciprofloxacin MIC of 1 mg/l or greater were defined as resistant and isolates with a ceftriaxone MIC of 0.25 mg/l or less were defined as susceptible. Rapid tests were used to screen and confirm the presence of HIV antibodies. Survey data from 2004 were used as a baseline to assess trends in gonococcal resistance to ciprofloxacin. In 2004, the prevalence of ciprofloxacin resistance was 7% in Cape Town and 11% in Johannesburg. In 2007, 37/139 (27%) Cape Town isolates and 47/149 (32%) Johannesburg isolates were resistant to ciprofloxacin; in comparison with 2004 data, this represents 2.9-fold and 1.9-fold increases, respectively. All isolates were fully susceptible to ceftriaxone. There was a significant association between HIV seropositivity and the presence of ciprofloxacin-resistant gonorrhoea among patients (p = 0.034). Johannesburg and Cape Town have witnessed significant rises in the prevalence of ciprofloxacin-resistant gonorrhoea among men with urethritis. The resistant phenotype is linked to HIV seropositivity. There is now an urgent need to change national first-line therapy for presumptive gonococcal infections within South Africa.


Resident microglia die and infiltrated neutrophils and monocytes become major inflammatory cells in lipopolysaccharide-injected brain.
Generally, it has been accepted that microglia play important roles in brain inflammation. However, recently several studies suggested possible infiltration of blood neutrophils and monocytes into the brain. To understand contribution of microglia and blood inflammatory cells to brain inflammation, the behavior of microglia, neutrophils, and monocytes was investigated in LPS (lipopolysaccharide)-injected substantia nigra pars compacta, cortex, and hippocampus of normal and/or leukopenic rats using specific markers of neutrophils (myeloperoxidase, MPO), and microglia and monocytes (ionized calcium binding adaptor molecule-1, Iba-1), as well as a general marker for these inflammatory cells (CD11b). CD11b-immunopositive (CD11b(+)) cells and Iba-1(+) cells displayed similar behavior in intact and LPS-injected brain at 6 h after the injection. Interestingly, however, CD11b(+) cells and Iba-1(+) cells displayed significantly different behavior at 12 h: Iba-1(+) cells disappeared while CD11b(+) cells became round in shape. We found that CD11b/Iba-1-double positive (CD11b(+)/Iba-1(+)) ramified microglia died within 6 h after LPS injection. The round CD11b(+) cells detected at 12 h were MPO(+). These CD11b(+)/MPO(+) cells were not found in leukopenic rats, suggestive of neutrophil infiltration. MPO(+) neutrophils expressed inducible nitric oxide synthase, interleukin-1beta, cyclooxygenase-2, and monocyte chemoattractant protein-1, but died within 18 h. CD11b(+) cells detected at 24 h appeared to be infiltrated monocytes, since these cells were once labeled with Iba-1 and were not found in leukopenic rats. Furthermore, transplanted monocytes were detectable in LPS-injected brain. These results suggest that at least a part of neutrophils and monocytes could have been misinterpreted as activated microglia in inflamed brain.


Effect of contraction type at varying angular velocities on isokinetic muscle strength training.
The aim of this study is to determine whether concentric and eccentric isokinetic training performed at certain angular velocities in sedentary individuals is effective only in the angular velocities and contraction type where the training is performed, or at other angular velocities and contraction types that are not being trained. Twenty-eight sedentary individuals (matched according to weight, age and gender) volunteered to participate in this case study. The study was conducted on a total of 56 extremities belonging to 28 individuals (14 women, 14 men) aged between 24 and 60 years. Concentric and eccentric strength tests were performed at 30-60-90-120-150-180°/sec. The participants were randomly divided into two groups as concentric training group and eccentric training group, through stratified randomization matching. The training was done 3 days a week for a total of 6 weeks. At the end of the study, no difference was found between the pre- and posttraining measurements in the concentric training group (P>0.05). In the eccentric training group, the eccentric muscle strength of the knee flexors and extensors at angular velocity of 90°/sec, the eccentric strength of the knee extensors at angular velocity of 120°/sec, and the eccentric muscle strength of the knee flexors at angular velocity of 180°/sec were found to be different and an increase was seen after the training (P=0.032, P=0.049, P=0.041, P=0.032). These results demonstrate that eccentric training may be preferred in cases where muscle strength increase is needed in short time.


Subjective ratings of prospective memory deficits in chronic heavy alcohol users.
Chronic alcohol abuse has a detrimental effect on retrospective memory. Less is known about its putative effects on everyday memory. This study looked at self-ratings of prospective memory (PM) (memory for future events). After controlling for other drug and strategy use, chronic heavy alcohol users showed global impairments in PM, when compared to matched controls. The underlying mechanisms are discussed.


Nitric oxide modulates ventilatory responses to hypoxia in the developing rat.
Nitric oxide (NO) is an important excitatory neurotransmitter in the central nervous system. In the adult rat, both selective and nonselective blockers of constitutive nitric oxide synthase (NOS) induce marked ventilatory reductions during sustained hypoxia, thereby enhancing ventilatory roll-off. Since hypoxic ventilatory depression is greater in developing mammals during the late phases of hypoxic exposure, we hypothesized that limited NOS activity may play a role in the late arm of the ventilatory response. To test our hypothesis, 5-d-, 10-d-, and 15-d-old rat pups underwent a 30-min hypoxic challenge (10% O2) before and after administration of 100 mg/kg N-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Minute ventilation (VE) was measured using whole-body plethysmography. In 5-d-old pups, early VE hypoxic responses were enhanced, and late VE were similar after administration of L-NAME. In contrast, in 15-d-old hypoxic pups, L-NAME administration was associated with smaller early VE increments and significantly larger VE reductions when compared with pretreatment conditions. The role of central nervous system NO in the development of these ventilatory changes was further assessed by Western blots of protein equivalents from the nucleus tractus solitarius (NTS), the first central relay for peripheral chemoreceptor afferent input, which revealed increasing neuronal NOS expression with age. Furthermore, NADPH-diaphorase immunohistochemical staining of neurons in the NTS revealed increased positively labeled neuronal populations within subnuclei of this structure with advancing postnatal age. Current findings suggest that NOS activity mediates both excitatory and inhibitory components of the hypoxic ventilatory response. Furthermore, in brainstem respiratory regions, NO may play a role in modulating the prominent second phase of the biphasic response to hypoxia typically seen in early postnatal life.


Therapeutic complement inhibition – from experimental to clinical medicine.
Internationally, the use of the C5-inhibiting monoclonal antibody eculizumab has in the course of just a few years become the first choice of treatment of atypical haemolytic uraemic syndrome and the most severe phenotypes of paroxysmal nocturnal haemoglobinuria. At present eculizumab is the only complement inhibitor in ordinary clinical use. This despite the fact that there only exists one randomised, placebo-controlled trial of eculizumab for paroxysmal nocturnal haemoglobinuria and none for atypical haemolytic uraemic syndrome, and that the therapy is very costly. There is reason to believe that complement inhibition as therapy will increase in the future, and that other drugs will also prove to be effective.


Oxidized phospholipids facilitate calcific aortic valve disease by elevating ATF4 through the PERK/eIF2α axis.
In this study we sought to analyze the critical role of oxidized phospholipid (OxPL) in the progression of calcific aortic valve disease (CAVD) with the involvement of activating transcription factor 4 (ATF4). Differentially expressed genes related to CAVD were identified using bioinformatics analysis. Expression of ATF4 was examined in mouse models of aortic valve calcification (AVC) induced by the high cholesterol (HC) diet. Valvular interstitial cells (VICs) were then isolated from mouse non-calcified valve tissues, induced by osteogenic induction medium (OIM) and co-cultured with OxPAPC-stimulated macrophages. The effect of OxPLs regulating ATF4 on the macrophage polarization and osteogenic differentiation of VICs was examined with gain- and loss-of-function experiments in VICs and in vivo. In aortic valve tissues and OIM-induced VICs, ATF4 was highly expressed. ATF4 knockdown alleviated the osteogenic differentiation of VICs, as evidenced by reduced expression of bone morphogenetic protein-2 (BMP2), osteopontin (OPN), and osteocalcin. In addition, knockdown of ATF4 arrested the AVC in vivo. Meanwhile, OxPL promoted M1 polarization of macrophages and mediated osteogenic differentiation of VICs. Furthermore, OxPL up-regulated ATF4 expression through protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 subunit alpha (eIF2α) pathway. In conclusion, OxPL can potentially up-regulate the expression of ATF4, inducing macrophages polarized to M1 phenotype, osteogenic differentiation of VICs and AVC, thus accelerating the progression of CAVD.


Beyond Visual Acuity: Development of a Simple Test of the Slow-To-See Phenomenon in Children with Infantile Nystagmus Syndrome.
Conventional static visual acuity testing profoundly underestimates the impact of infantile nystagmus on functional vision. The slow-to-see phenomenon explains why many patients with nystagmus perform well in non-time restricted acuity tests but experience difficulty in certain situations. This is often observed by parents when their child struggles to recognise familiar faces in crowded scenes. A test measuring more than visual acuity could permit a more real-world assessment of visual impact and provide a robust outcome measure for clinical trials. Children with nystagmus and, age and acuity matched controls attending Southampton General Hospital were recruited for two tasks. In the first, eye-tracking measured the time participants spent looking at an image of their mother when alongside a stranger, this was then repeated with a sine grating and a homogenous grey box. Next, a tablet-based app was developed where participants had to find and press either their mother or a target face from up to 16 faces. Here, the response time was measured. The tablet task was refined over multiple iterations. In the eye-tracking task, controls spent significantly longer looking at their mother and the grating (P < .05). Interestingly, children with nystagmus looked significantly longer at the grating (P < .05) but not their mother (P > .05). This confirmed a facial target was key to further development. The tablet-based task demonstrated that children with nystagmus take significantly longer to identify the target; this was most pronounced using a 3-min test with 12-face displays. This study has shown a facial target is key to identifying the time-to-see deficit in infantile nystagmus and provides the basis for an outcome measure for use in clinical treatment trials.


Effect of combined axial compressive and anterior tibial loads on in situ forces in the anterior cruciate ligament: a porcine study.
This study investigated the impact of a combination of axial compressive and anterior-posterior tibial loads on the in situ forces in the anterior cruciate ligament. An axial compressive load is believed to contribute to increased stability of the knee joint; however, its effect on in situ forces in the anterior cruciate ligament has not been clearly defined, to our knowledge. It was hypothesized that the application of an axial compressive load, when combined with an anterior tibial load, would result in larger in situ forces in the anterior cruciate ligament than those caused by an isolated anterior tibial load. With use of a porcine knee model, the results confirmed this hypothesis; the addition of a 200 N axial compressive load to a 100 N anterior tibial load increased knee stability by reducing anterior-posterior tibial translation and internal-external tibial rotation and also caused a significant increase in in situ forces in the anterior cruciate ligament (p < 0.05). Specifically, there was a 34% increase in the in situ force at 30 degrees of flexion, a 68% increase at 60 degrees of flexion, and an 84% increase at 90 degrees of flexion compared with those for an isolated anterior tibial load of 100 N. Additionally, there was a statistically significant increase of the in situ forces in the anterior cruciate ligament at 60 and 90 degrees as compared with those at 30 degrees. These results suggest that axial compressive loads on the knee may play a role in injury of the anterior cruciate ligament when the knee is flexed.


The role of Candida albicans NOT5 in virulence depends upon diverse host factors in vivo.
We previously identified Candida albicans Not5p as an immunogenic protein expressed during oropharyngeal candidiasis (OPC). In this study, we demonstrate that C. albicans NOT5 reverses the growth defects of a Saccharomyces cerevisiae not5 mutant strain at 37 degrees C, suggesting that the genes share at least some functional equivalence. We implicate C. albicans NOT5 in the pathogenesis of disseminated candidiasis (DC) induced by intravenous infection among neutropenic and nonimmunosuppressed mice, as well as in that of OPC in mice immunosuppressed with corticosteroids. We find no role in virulence, however, among neutropenic and corticosteroid-suppressed mice with DC resulting from gastrointestinal translocation, nor do we implicate the gene in vulvovaginal candidiasis among mice in pseudoestrus. These findings suggest that the role of NOT5 in virulence depends on the specific in vivo environment and is influenced by diverse factors such as tissue site, portal of entry, and the status of host defenses. NOT5 is necessary for normal adherence to colonic and cervical epithelial cells in vitro, demonstrating that such assays cannot fully replicate disease processes in vivo. Lastly, antibody responses against Not5p do not differ in the sera of patients with OPC, patients with DC, and healthy controls, suggesting that the protein is associated with both commensalism and the pathogenesis of disease.


HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.
Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques. In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred. Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide. HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.


Viral safety of coagulation factor concentrates: memoirs from an insider.
The purpose of this essay is to recall the actions taken globally to improve the viral safety of coagulation factor concentrates, mainly in the years 1985-1990, at a time of confusing and often contradictory information on bloodborne viral infections in multitransfused patients with hemophilia (PWHs). I shall first recall the problem of the transmission and control of the hepatitis viruses, and then that of HIV: not only for temporal reasons, but also because understanding the progress of knowledge on hepatitis and the poor success of the early measures taken to tackle this problem in PWHs is essential to understand how the problem of HIV transmission was ultimately dealt with successfully.


Anaesthesia for abnormally invasive placenta: a single-institution case series.
Abnormally invasive placenta describes a spectrum of disorders resulting in pathological placental implantation. It is associated with the potential for severe maternal haemorrhage and poor fetal outcome. Increasing numbers of women are at risk owing to the rising incidence of uterine surgery and increasing maternal age. We report data over a five-year period describing anaesthetic management of cases of abnormally invasive placenta in a UK tertiary-referral maternity unit and assess how management has developed. Surgically confirmed cases of abnormally invasive placenta were identified from January 2011 to January 2016. Cases were identified using standard ICD-10 codes and by review of departmental records, with surgically-confirmed cases included following review of medical records. Forty cases of abnormally invasive placenta were identified. Eighteen (40%) women had significant medical co-morbidity. All parturients were delivered by caesarean delivery. Caesarean hysterectomy occurred in 24 (60%) cases, delayed hysterectomy in two (5%) and the uterus was preserved in the remaining 14 (35%). Thirty-eight (95%) caesarean deliveries were commenced under neuraxial anaesthesia with 17 (45%) converted to general anaesthesia intraoperatively. Interventional radiology was undertaken in 23 (58%) cases. Median [range] estimated blood loss was 1700mL [500-12000mL]. Intraoperative transfusion of packed red cells occurred in 14 (35%) cases. Intraoperative cell salvage was used in 26 (65%) cases. Four (10%) women were admitted to critical care postoperatively. There were no maternal deaths. Our data illustrate the burden on healthcare resources associated with management of abnormally invasive placenta, underlining the continued need for centralised services for treatment of these complex cases. An integrated multidisciplinary approach to case planning, case management and service provision is key to a successful outcome in these cases.


MPTP and MPP+ target specific aminergic cell populations in larval zebrafish.
Larval zebrafish offers a good model to approach brain disease mechanisms, as structural abnormalities of their small brains can be correlated to quantifiable behavior. In this study, the structural alterations in one diencephalic dopaminergic nucleus induced by 1-methyl-4-phenylpyridinium (MPP+), a toxin inducing Parkinson's disease in humans, and those found in several neuronal groups after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the pretoxin, were associated with decreased swimming speed. Detailed cell counts of dopaminergic groups indicated a transient decline of tyrosine hydroxylase expressing neurons up to about 50% after MPTP. The MPTP effect was partly sensitive to monoamine oxidase inhibitor deprenyl. Detailed analysis of the developing catecholaminergic cell groups suggests that the cell groups emerged at their final positions and no obvious significant migration from the original positions was seen. One 5-HT neuron group was also affected by MPTP treatment, whereas other groups remained intact, suggesting that the effect is selective. New nomenclature for developing catecholaminergic cell groups corresponding to adult groups is introduced. The diencephalic cell population consisting of groups 5,6 and 11 was sensitive to both MPTP and MPP+ and in this respect resembles mammalian substantia nigra. The results suggest that MPTP and MPP+ induce a transient functional deficit and motility disorder in larval zebrafish.


Genetics of ultrasonographic carotid atherosclerosis.
The search for genes related to the cause of common complex disorders such as cardiovascular disease has been frustrating, partly because of the many factors known to contribute to cardiovascular disease and the potential "distance" of cardiovascular disease as a phenotype from genes and gene products. Linkage and association studies for phenotypes more proximal in the pathway from DNA sequence variation to overt clinical disease, such as ultrasound-defined carotid atherosclerosis, may potentially be more enlightening. Only one genetic variant previously reported to be associated with atherosclerosis or clinically evident cardiovascular disease, matrix metalloproteinase (MMP) 3, has shown consistently positive associations with carotid disease, although it has not been studied widely. Another, PON1 L55M, is weakly associated in subgroups only, and 2, ApoE and MTHFR, are equivocal. Genetic variants reported to be associated with clinical cardiovascular disease show weak or no relationship to carotid atherosclerosis. This may reflect the known inconsistency in associations of genetic variants with clinical cardiovascular disease itself. Alternatively, genetic determinants of ultrasound-defined carotid atherosclerosis may differ from those of clinically manifest cardiovascular disease and may require pursuit through large-scale genomic studies of carotid atherosclerosis as a distinct phenotype. Only 1 genetic variant, MMP 3, has shown consistently positive associations with ultrasonographic carotid disease, although it has not been studied widely. Another, PON1 L55 mol/L, is weakly associated in subgroups only. Genetic variants reported to be associated with clinical cardiovascular disease show weak or no relationship to carotid atherosclerosis.


A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway.
Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/β-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/β-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and β-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/β-catenin pathway, but induces a classical WNT/PCP phenotype in vivo. Our study shows for the first time that LRRK2 activates the WNT/PCP signaling pathway through its interaction to multiple WNT/PCP components. We suggest that LRRK2 regulates the balance between WNT/β-catenin and WNT/PCP signaling, depending on the binding partners. Since this balance is crucial for homeostasis of midbrain dopaminergic neurons, we hypothesize that its alteration may contribute to the pathophysiology of Parkinson's disease.


Elevated lactate suppresses neuronal firing in vivo and inhibits glucose metabolism in hippocampal slice cultures.
Glucose is well accepted as the major fuel for neuronal activity, while it remains controversial whether lactate also supports neural activity. In hippocampal slice cultures, synaptic transmission supported by glucose was reversibly suppressed by lactate. To test whether lactate had a similar inhibitory effect in vivo, lactate was perfused into the hippocampi of unanesthetized rats while recording the firing of nearby pyramidal cells. Lactate perfusion suppressed pyramidal cell firing by 87.5+/-8.3% (n=6). Firing suppression was slow in onset and fully reversible and was associated with increased lactate concentration at the site of the recording electrode. In vivo suppression of neural activity by lactate occurred in the presence of glucose; therefore we tested whether suppression of neural firing was due to lactate interference with glucose metabolism. Competition between glucose and lactate was measured in hippocampal slice cultures. Lactate had no effect on glucose uptake. Lactate suppressed glucose oxidation when applied at an elevated, pathological concentration (10 mM), but not at its physiological concentration (1 mM). Pyruvate (10 mM) also inhibited glucose oxidation but was significantly less effective than lactate. The greater suppressive effect of lactate as compared to pyruvate suggests that alteration of the NAD(+)/NADH ratio underlies the suppression of glucose oxidation by lactate. ATP in slice culture was unchanged in glucose (1 mM), but significantly reduced in lactate (1 mM). ATP in slice culture was significantly increased by combination of glucose (1 mM) and lactate (1 mM). These data suggest that alteration of redox ratio underlies the suppression of neural discharge and glucose metabolism by lactate.


Selective Uptake and Refolding of Globular Proteins in Coacervate Microdroplets.
Intrinsic differences in the molecular sequestration of folded and unfolded proteins within poly(diallyldimethylammonium) (PDDA)/poly(acrylate) (PAA) coacervate microdroplets are exploited to establish membrane-free microcompartments that support protein refolding, facilitate the recovery of secondary structure and enzyme activity, and enable the selective uptake and exclusion of folded and unfolded biomolecules, respectively. Native bovine serum albumin, carbonic anhydrase, and α-chymotrypsin are preferentially sequestered within positively charged coacervate microdroplets, and the unfolding of these proteins in the presence of increasing amounts of urea results in an exponential decrease in the equilibrium partition constants as well as the kinetic release of unfolded molecules from the droplets into the surrounding continuous phase. Slow refolding in the presence of positively charged microdroplets leads to the resequestration of functional proteins and the restoration of enzymatic activity; however, fast refolding results in protein aggregation at the droplet surface. In contrast, slow and fast refolding in the presence of negatively charged PDDA/PAA droplets gives rise to reduced protein aggregation and misfolding by interactions at the droplet surface to give increased levels of protein renaturation. Together, our observations provide new insights into the bottom-up design and construction of self-assembling microcompartments capable of supporting the selective uptake and refolding of globular proteins.


Elevation of serum and urine levels of TIMP-1 and tenascin in patients with renal disease.
Chronic kidney disease is characterized by increased synthesis and inhibited destruction of collagenous and non-collagenous matrix proteins. Elevation of collagen fragments has been demonstrated in the serum and urine of patients with renal disease, but the dynamics of renal matrix deposition remain difficult to determine. To obtain a further insight into renal matrix metabolism we have assessed whether serum and urine concentrations of the non-collagenous protein, tenascin, and of the tissue inhibitor of metalloproteinases 1 (TIMP-1) are altered in association with renal disease. Serum and urine concentrations of both proteins were determined using a newly developed magnetic particle enzyme immunoassay and were compared with levels of N-terminal procollagen III-peptide (PIIINP) and related to the degree of renal failure and proteinuria. Circulating levels of tenascin and TIMP-1 were moderately, but significantly, higher in patients with chronic renal disease (n=54; mean creatinine clearance, 62 ml/min) than in healthy controls (n=176). Urine concentrations per mg creatinine of tenascin and TIMP-1 were significantly lower than serum levels, but were on average six- and 18-fold higher, respectively, in patients with renal disease than in controls. Urinary concentrations increased with progressive reduction in renal function, but were unrelated to proteinuria. TIMP-1 concentrations in urine correlated with tenascin, which is compatible with the impact of TIMP-1 on the accumulation of matrix proteins. The concentrations of proteins measured did not differ depending on the aetiology of renal disease. Urinary concentrations of tenascin and TIMP-1 are elevated in association with renal disease and may reflect specific aspects of renal fibrosis.


[A COMPARATIVE STUDY ON TWO FIXATION METHODS FOR BENIGN LONG BONE PATHOLOGICAL FRACTURES IN CHILDREN].
To compare the effectiveness of locking compression plate and elastic intramedullary nail for the treatment of benign long bone pathological fractures in children, so as to provide the evidence for clinical treatment. Seventy-two children with long bone pathological fractures who accorded with the inclusion criteria between January 2005 and July 2013 were randomly divided into 2 groups. Fracture was fixed with elastic intramedullary nail in 33 cases (group A) and with locking compression plate in 39 cases (group B). There was no significant difference in sex, age, body mass index, primary lesion, location of fracture, side of fracture, and interval between injury and operation between 2 groups (P > 0.05). Group A had shorter operation time, less intraoperative blood loss, and less overall costs than group B, showing significant differences (P < 0.05). Primary healing of incision was obtained. All the patients were followed up 1-7 years (mean, 3.4 years). Tumor lesions disappeared and the pathological fracture healed after operation by X-ray film observation, and group A had faster fracture healing time than group B (P < 0.05). There was no loosening and displacement of internal fixation, bone resorption, and bone defect nonunion in 2 groups. Recurrence was found in 2 cases (6.1%) of group A and 3 cases (7.7%) of group B, showing no significant difference (χ2 = 0.074, P = 0.580). Re-fracture was found in 1 patient with tibial bone cyst of group B after 3 months of operation, and healed after 1 year of open reduction and internal fixation. According to X-ray film and comprehensive function evaluation of shoulder, elbow, hip, knee, and ankle, the results were all excellent in 2 groups at last follow-up. Elastic intramedullary nail fixation should be the first choice, and locking compression plate should be the second choice for children with benign long bone pathological fractures.


Exploring the Pharmacological Mechanisms of Xihuang Pills Against Prostate Cancer via Integrating Network Pharmacology and Experimental Validation In Vitro and In Vivo.
Background: Drug resistance is the major cause of increasing mortality in prostate cancer (PCa). Therefore, it an urgent to develop more effective therapeutic agents for PCa treatment. Xihuang pills (XHP) have been recorded as the efficient anti-tumor formula in ancient Chinese medical literature, which has been utilized in several types of cancers nowadays. However, the effect protective role of XHP on the PCa and its underlying mechanisms are still unclear. Methods: The active ingredients of XHP were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and BATMAN-TCM. The potential targets of PCa were acquired from the Gene Cards and OMIM databases. R language and Perl language program were utilized to clarify the interaction between the PCa-related targets and the potential targets of XHP. The potential targets of XHP for prostate cancer were gathered from the Gene ontology and KEGG pathway. Furthermore, cell proliferation assays were verified by PC3 and LNCaP cells. The efficacy and potential mechanism tests were confirmed by the PCa PC3 cells and mice subcutaneous transplantation. The effects of PI3K/Akt/mTOR-related proteins on proliferation, apoptosis, and cell cycle of PCa cells were measured by the Cell Counting Kit-8(CCK8), TUNEL assay, real-time quantitative reverse transcription PCR (QRT-PCR), and Western Blotting, respectively. Results: The active components of four traditional Chinese medicines in XHP were searched on the TCMSP and Batman TCM database. The biological active components of XHP were obtained as OB ≥30% and DL ≥0.18. The analysis of gene ontology and KEGG pathway identified the PI3K/Akt/mTOR signaling pathway as the XHP-associated pathway. Collectively, the results of in vitro and in vivo experiments showed that XHP had the effect of inhibiting on the proliferation of PC3 and LNCaP cells. XHP promoted the apoptosis and restrained the cell cycle and invasion of the PC3 cells and subcutaneous transplantation. Meanwhile, the suppression of XHP on the level of expression of PI3K, Akt, and mTOR-pathway-related pathway proteins has been identified in a dose-dependent manner. Conclusion: PI3K/Akt/mTOR pathway-related pathway proteins were confirmed as the potential XHP-associated targets for PCa. XHP can suppress the proliferation of prostate cancer via inhibitions of the PI3K/Akt/mTOR pathway.


Host HDL biogenesis machinery is recruited to the inclusion of Chlamydia trachomatis-infected cells and regulates chlamydial growth.
Chlamydia trachomatis is an obligate intracellular bacterial pathogen that is the most common cause of sexually transmitted bacterial infections and is the etiological agent of trachoma, the leading cause of preventable blindness. The organism infects epithelial cells of the genital tract and eyelid resulting in a damaging inflammatory response. Chlamydia trachomatis grows within a vacuole termed the inclusion, and its growth depends on numerous host factors, including lipids. Although a variety of mechanisms are involved in the acquisition of host cell cholesterol and glycosphingolipids by C. trachomatis, none of the previously documented pathways for lipid acquisition are absolutely required for growth. Here we demonstrate that multiple components of the host high-density lipoprotein (HDL) biogenesis machinery including the lipid effluxers, ABCA1 and CLA 1, and their extracellular lipid acceptor, apoA-1, are recruited to the inclusion of C. trachomatis-infected cells. Furthermore, the apoA-1 that accumulates within the inclusion colocalizes with pools of phosphatidylcholine. Knockdown of ABCA1, which mediates the cellular efflux of cholesterol and phospholipids to initiate the formation of HDL in the serum, prevents the growth of C. trachomatis in infected HeLa cells. In addition, drugs that inhibit the lipid transport activities of ABCA1 and CLA 1 also inhibit the recruitment of phospholipids to the inclusion and prevent chlamydial growth.These results strongly suggest that C. trachomatis co-opts the host cell lipid transport system involved in the formation of HDL to acquire lipids, such as phosphatidylcholine, that are necessary for growth.


An original calibration technique for soft x-ray detectors and its use in the Tore Supra tomographic system.
This paper describes in detail the recent progresses which have been made in Tore Supra for developing a new technique of calibration of the soft x-ray (SXR) detectors in the range 1-30 keV. The diode response as a function of the flux of photons resulted accurately linear over almost three orders of magnitude. Apart from a limited number of deficient detectors, promptly replaced with new ones, the spread of the diode responses (84 detectors) is about 20% total of the average value. It allowed the derivation of the calibration factor for each detector of the tomography system. The effect of the environmental temperature, in the range 15 degrees-40 degrees, has also been studied, revealing that up to 35 degrees the linearity of diode response and these calibration factors remain constant. It demonstrates the capability of discriminating slight and localized changes in the two dimensional spatial distribution of the SXR intensity.


Astragaloside IV alleviates heart failure via activating PPARα to switch glycolysis to fatty acid β-oxidation.
In heart failure (HF), energy metabolism pathway in cardiac muscle changes from fatty acid β-oxidation to glycolysis. However, the exact mechanism is unknown. Sarcoendoplasmic reticulum Ca2+α ATPase (SERCA) expression is downregulated and mitochondrial function is reduced in HF, perhaps partly due to a substantially reduced energy supply for excitation-contraction coupling resulting from a lower fatty acid β-oxidation rate. We investigated whether Astragaloside IV can activate peroxisome proliferator-activated receptor alpha (PPARα) to stimulate fatty acid β-oxidation and increase cardiac energy production, improving mitochondrial function and the efficiency of SERCA in HF. In pressure overload-induced HF mice and isolated hypertrophic myocardial cells, fatty acid β-oxidation and heart function were substantially strengthened following Astragaloside IV treatment, as demonstrated by the increased expression of PPARα and SERCA2a. In vitro, Astragaloside IV regulated energy metabolism by increasing ATP production and enhancing mitochondrial function, attributable to increased oxygen consumption and slightly increased mitochondrial Ca2+ uptake. In HF, Astragaloside IV switched glycolysis to fatty acid β-oxidation, as confirmed by reduced anaerobic glycolysis and an increased oxygen consumption ratio. These results suggest that Astragaloside IV can stimulate fatty acid β-oxidation and improve mitochondrial function, which may present a novel cardioprotective treatment that inhibits the progress of HF.


Modulatory effects on axonal function after intravenous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy.
To investigate the immediate and longitudinal mechanisms of action of intravenous immunoglobulin (IVIg) on axonal function in chronic inflammatory demyelinating polyneuropathy (CIDP). Prospective single-center study. Hospitals and outpatient clinics. Clinical and functional assessment, nerve conduction studies, and 526 motor excitability studies were undertaken in 27 patients, matched before and immediately after infusion and followed up longitudinally. Axonal excitability variables were measured before and immediately after infusion and compared with matched studies and findings in healthy controls. Immediately after infusion, patients demonstrated decreased threshold, with significant reduction in strength-duration time constant (P = .003), reduction in accommodation to depolarization (P = .04), and reduced threshold change during hyperpolarization (P = .003), accompanied by significant decreases in superexcitability (P = .03) and subexcitability (P = .02). In contrast, changes were absent in disease controls, confirming a specific IVIg action in CIDP patients. Longitudinally, changes correlated with clinical improvement (mean [SE] increase in the Medical Research Council sum score, 2.7 [0.7]; P = .005). Increased compound muscle action potential amplitude was associated with reduction in terminal latency (correlation coefficient, -0.65; P = .02). In addition, these changes translated into improvement in functional assessment with the adjusted Inflammatory Neuropathy Cause and Treatment score, which demonstrated a significant correlation with nerve excitability variables longitudinally (P = .01). Findings from the present series establish a modulatory effect of IVIg on axonal function in CIDP patients, suggesting that IVIg stabilizes axonal membrane potential and promotes axonal recovery.


Caring for people with intellectual disabilities and life-limiting illness: merging person-centered planning and patient-centered, family-focused care.
The number of older people with intellectual disabilities (IDs) is increasing in parallel to the lengthening life expectancy of the overall population. Little is known about the needs of older people with IDs who are at life's end. Service providers who offer direct care to people with IDs have begun to develop partnerships with hospice and palliative care specialists to provide focused care that is more specialized for their clients or residents who are approaching the end of life. However, community-based programs utilize different philosophies of care that focus on the daily management of people with IDs compared to programs that focus on care at the end of life. Merging these two approaches to care in community-based residences or community-based programs for people with IDs brings challenges for both types of programs. This article compares person-centered planning and patient-focused, family-centered care and proposes means for merging the two seemingly disparate approaches to care.