Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study.
Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis. This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6. Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial. There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).


Auditory resting-state functional connectivity in tinnitus and modulation with transcranial direct current stimulation.
The functional connectivity (FC) between the right and left auditory cortex is weak in tinnitus patients. Transcranial direct current stimulation (tDCS) over the auditory cortex has potential as a tool to modulate auditory-based FC. This study investigated the effects of applying tDCS in tinnitus patients, and searched for modulation of brain networks in resting-state functional magnetic resonance imaging (rs-fMRI) through an analysis of FC with the stimulated brain region. Nine male patients with chronic tinnitus and 10 male volunteers with normal hearing were enrolled. The subjects were evaluated with rs-fMRI immediately before and after tDCS. The tinnitus patients filled out the self-evaluation questionnaires designed to measure tinnitus conditions before tDCS treatment and 1 week afterwards. The FC between the right and left auditory cortex was significantly weaker in tinnitus patients than in controls. After tDCS treatment, in the tinnitus group, the primary auditory cortex showed a reduction in the amount of statistically significant connectivity with the somatosensory area and motor area, but maintained strong significant connectivity (p < 0.005) with the auditory area and insular cortex. In contrast, in the control group, there remained strong significant connectivity between the primary auditory cortex and the somatosensory area, motor area, insular cortex, and auditory area.


Effect of repeated sodium phosphate loading on cycling time-trial performance and VO2peak.
Research into supplementation with sodium phosphate has not investigated the effects of a repeated supplementation phase. Therefore, this study examined the potential additive effects of repeated sodium phosphate (SP) supplementation on cycling time-trial performance and peak oxygen uptake (VO2peak). Trained male cyclists (N = 9, M ± SD VO2peak = 65.2 ± 4.8 ml · kg-1 · min-1) completed baseline 1,000-kJ time-trial and VO2peak tests separated by 48 hr, then ingested either 50 mg · kg fat-free mass-1 · d-1 of tribasic SP or a combined glucose and NaCl placebo for 6 d before performing these tests again. A 14-d washout period separated the end of one loading phase and the start of the next, with 2 SP and 1 placebo phase completed in a counterbalanced order. Although time-trial performance (55.3-56.5 min) was shorter in SP1 and SP2 (~60-70 s), effect sizes and smallest-worthwhile-change values did not differ in comparison with baseline and placebo. However, mean power output was greater than placebo during time-trial performance at the 250-kJ and 500-kJ time points (p < .05) after the second SP phase. Furthermore, mean VO2peak values (p < .01) were greater after the SP1 (3.5-4.3%), with further improvements (p < .01) found in SP2 (7.1-7.7%), compared with baseline and placebo. In summary, repeated SP supplementation, ingested either 15 or 35 d after initial loading, can have an additive effect on VO2peak and possibly time-trial performance.


Serum oxidized protein and prostate cancer risk within the Prostate Cancer Prevention Trial.
To evaluate the role of oxidative stress in prostate cancer risk, we analyzed serum levels of protein carbonyl groups in 1,808 prostate cancer cases and 1,805 controls, nested in the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial that found finasteride decreased prostate cancer risk. There were no significant differences in protein carbonyl levels in baseline samples between those later diagnosed with prostate cancer and those without at the end of study biopsy. Adjusted odds ratios and 95% confidence intervals (95% CI) for the 4th quartile of protein carbonyl level for the combined, placebo, and finasteride arms were 1.03 (95% CI, 0.85-1.24), 0.88 (95% CI, 0.69-1.12), and 1.27 (95% CI, 0.94-1.71), respectively. There were no significant associations between carbonyl level and risk when analyzing high-grade and low-grade disease separately, nor did finasteride affect protein oxidation levels. The results of this large nested case-control study do not support the hypothesis that oxidative stress, at least as measured by protein carbonyl level, plays a role in prostate cancer.


Impedimetric real-time monitoring of neural pluripotent stem cell differentiation process on microelectrode arrays.
In today's neurodevelopment and -disease research, human neural stem/progenitor cell-derived networks represent the sole accessible in vitro model possessing a primary phenotype. However, cultivation and moreover, differentiation as well as maturation of human neural stem/progenitor cells are very complex and time-consuming processes. Therefore, techniques for the sensitive non-invasive, real-time monitoring of neuronal differentiation and maturation are highly demanded. Using impedance spectroscopy, the differentiation of several human neural stem/progenitor cell lines was analyzed in detail. After development of an optimum microelectrode array for reliable and sensitive long-term monitoring, distinct cell-dependent impedimetric parameters that could specifically be associated with the progress and quality of neuronal differentiation were identified. Cellular impedance changes correlated well with the temporal regulation of biomolecular progenitor versus mature neural marker expression as well as cellular structure changes accompanying neuronal differentiation. More strikingly, the capability of the impedimetric differentiation monitoring system for the use as a screening tool was demonstrated by applying compounds that are known to promote neuronal differentiation such as the γ-secretase inhibitor DAPT. The non-invasive impedance spectroscopy-based measurement system can be used for sensitive and quantitative monitoring of neuronal differentiation processes. Therefore, this technique could be a very useful tool for quality control of neuronal differentiation and moreover, for neurogenic compound identification and industrial high-content screening demands in the field of safety assessment as well as drug development.


Percutaneous Venoplasty for Central Venous Stenosis: Effect on Patient's Symptoms and Patency of Arteriovenous Accesses.
To determine symptomatic relief and patency rate of arteriovenous (AV) fistulae and grafts after venoplasty in patients with central venous stenosis (CVS) on hemodialysis. Case series. The Aga Khan University Hospital, Karachi, from January 2012 to December 2017. The data of patients who had one session of successful venoplasty for CVS were reviewed. The outcomes measured were symptomatic recovery and improvement in the patency of AV accesses. Symptomatic recovery was termed 'complete', when there was complete symptomatic relief after venoplasty; and 'partial' when the procedure was technically successful, but symptoms were not resolved. Primary patency of AV access was the duration from first intervention till further intervention. Cumulative patency was the total duration of time fistula remains patent with multiple interventions. Events, considered end points to functional access status, were placement of new access site, ligation of access site, dialysis catheter placement or the patient death. Thirty-five patients had technically successful venoplasty with mean age of 56.86 ±14.6 years. Twenty-one (60%) were female patients. All patients tolerated the procedure well. Twenty-one (60%) patients had complete relief of symptoms. Fourteen patients (40%) had partial relief of symptoms. Twenty-one patients required repeat angioplasties. The mean follow-up was 18.6 ±9.02 months. Primary patency was 40%, 24%, 24% at 6, 12 and 24 months. Cumulative patency was 69%, 66% and 59% at 6, 12 and 24 months. Percutaneous venoplasty provided symptomatic relief to the patients and improved the short-term patency of AV accesses.


Self-reference in psychosis and depression: a language marker of illness.
Language use is of increasing interest in the study of mental illness. Analytical approaches range from phenomenological and qualitative to formal computational quantitative methods. Practically, the approach may have utility in predicting clinical outcomes. We harnessed a real-world sample (blog entries) from groups with psychosis, strong beliefs, odd beliefs, illness, mental illness and/or social isolation to validate and extend laboratory findings about lexical differences between psychosis and control subjects. We describe the results of two experiments using Linguistic Inquiry and Word Count software to assess word category frequencies. In experiment 1, we compared word use in psychosis and control subjects in the laboratory (23 per group), and related results to subject symptoms. In experiment 2, we examined lexical patterns in blog entries written by people with psychosis and eight comparison groups. In addition to between-group comparisons, we used factor analysis followed by clustering to discern the contributions of strong belief, odd belief and illness identity to lexical patterns. Consistent with others' work, we found that first-person pronouns, biological process words and negative emotion words were more frequent in psychosis language. We tested lexical differences between bloggers with psychosis and multiple relevant comparison groups. Clustering analysis revealed that word use frequencies did not group individuals with strong or odd beliefs, but instead grouped individuals with any illness (mental or physical). Pairing of laboratory and real-world samples reveals that lexical markers previously identified as specific language changes in depression and psychosis are probably markers of illness in general.


A Wnt- and beta -catenin-dependent pathway for mammalian cardiac myogenesis.
Acquisition of a cardiac fate by embryonic mesodermal cells is a fundamental step in heart formation. Heart development in frogs and avians requires positive signals from adjacent endoderm, including bone morphogenic proteins, and is antagonized by a second secreted signal, Wnt proteins, from neural tube. By contrast, mechanisms of mesodermal commitment to create heart muscle in mammals are largely unknown. In addition, Wnt-dependent signals can involve either a canonical beta-catenin pathway or other, alternative mediators. Here, we tested the involvement of Wnts and beta-catenin in mammalian cardiac myogenesis by using a pluripotent mouse cell line (P19CL6) that recapitulates early steps for cardiac specification. In this system, early and late cardiac genes are up-regulated by 1% DMSO, and spontaneous beating occurs. Notably, Wnt3A and Wnt8A were induced days before even the earliest cardiogenic transcription factors. DMSO induced biochemical mediators of Wnt signaling (decreased phosphorylation and increased levels of beta-catenin), which were suppressed by Frizzled-8Fc, a soluble Wnt antagonist. DMSO provoked T cell factor-dependent transcriptional activity; thus, induction of Wnt proteins by DMSO was functionally coupled. Frizzled-8Fc inhibited the induction of cardiogenic transcription factors, cardiogenic growth factors, and sarcomeric myosin heavy chains. Likewise, differentiation was blocked by constitutively active glycogen synthase kinase 3beta, an intracellular inhibitor of the Wntbeta-catenin pathway. Conversely, lithium chloride, which inhibits glycogen synthase kinase 3beta, and Wnt3A-conditioned medium up-regulated early cardiac markers and the proportion of differentiated cells. Thus, Wntbeta-catenin signaling is activated at the inception of mammalian cardiac myogenesis and is indispensable for cardiac differentiation, at least in this pluripotent model system.


Use of an elliptical machine for improving functional walking capacity in individuals with chronic stroke: a case series.
Decreased functional walking capacity is a common consequence of stroke. Identifying practical and cost-effective methods to improve walking in individuals with stroke is an important goal of rehabilitation professionals. Participants were 3 men with chronic (>6 month) stroke, who could walk on level surfaces either without an assistive device or with a single-point cane. Participants trained 2 to 3 times per week for 8 weeks, using an elliptical machine. The training target was 20 minutes of uninterrupted training, while maintaining predetermined parameters of heart rate and perceived exertion. Outcome measures assessed before and after training included habitual and fast gait speed, 6-minute walk test (6MWT), Timed "Up & Go" test, and Berg Balance Scale. Following training there was no change in walking speed. There was no change in 6MWT performance for participants 1 and 2. While participant 3 showed a 25% improvement in 6MWT, this change did not meet the minimal detectable change for walking speed in individuals with stroke. All participants demonstrated improved Berg Balance Scale performance (9%-28%), with participant 1 exceeding the minimal detectable change in this measure. Timed Up & Go test performance improved by 5% to 15% in all participants. Elliptical training appears to be a safe and feasible training alternative for ambulatory individuals with chronic stroke. Training 2 to 3 days per week resulted in no improvements in walking speed; however, participants did demonstrate variable improvements in endurance, balance, and functional mobility. It is possible that a higher training frequency and/or training speed are required to influence walking performance in individuals who are ambulatory. Equipment design, principles of exercise prescription, and participant characteristics should be considered when selecting elliptical training as an intervention.


Patient-important outcomes in registered diabetes trials.
Concerns about the safety and efficacy of diabetes interventions persist, in part because randomized clinical trials (RCTs) have not measured their effect on patient-important outcomes, ie, death and quality of life (morbidity, pain, function). To systematically determine the extent to which ongoing and future RCTs in diabetes will ascertain patient-important outcomes. On November 10, 2007, we searched primary RCT registries ClinicalTrials.gov (http://www.clinicaltrials.gov), International Standard Randomized Controlled Trial Number Register (http://isrctn.org), and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). We identified phase 2 through 4 RCTs enrolling patients with diabetes. Of 2019 RCTs, 1054 proved eligible. We randomly sampled 50% of the eligible RCTs (527 of 1054) and selected 436 registered since registration became mandatory (2004). Pairs of reviewers working independently collected study characteristics and determined the outcomes measured and their type (physiological outcomes, surrogate outcomes thought to reflect an increased risk for patient-important outcomes, and patient-important outcomes). Of the 436 registered RCTs included in this analysis, 24 (6%) had not started enrollment, 109 (25%) were actively enrolling, and 303 (69%) had completed enrollment. Primary outcomes were patient-important outcomes in only 78 of 436 RCTs (18%; 95% confidence interval [CI], 14%-22%), physiological and laboratory outcomes in 69 of 436 (16%; 95% CI, 13%-20%), and surrogate outcomes in 268 of 436 (61%; 95% CI, 57%-66%). Patient-important outcomes were reported as primary or secondary outcomes in 201 of 436 (46%; 95% CI, 41%-51%). In multivariate analysis, large trials (odds ratio [OR], 1.10; 95% CI, 1.02-1.19 for every additional 100 patients) and trials of longer duration (OR, 1.03; 95% CI, 1.01-1.06 for every additional 30 days) were more likely while parallel design RCTs (OR, 0.15; 95% CI, 0.05-0.44) and type 2 diabetes trials (OR, 0.23; 95% CI, 0.09-0.61) were less likely to assess patient-important outcomes as a primary outcome. In this sample of registered ongoing RCTs in diabetes, only 18% included patient-important outcomes as primary outcomes.


Nanotechnology of emerging targeting systems.
Recent developments in the design and testing of complex nanoscale payload-carrying systems (i.e. systems with payloads that do not exceed 100 nm in size) are the focus of this brief review. Emerging systems include targeted single-walled nanotubes, viral capsids, dendrimers, gold nanoparticles, milled boron carbide nanoparticles, and protein nucleic acid assemblies. Significant advances are emerging with each of these bionanotechnological approaches to cellular targeting.


Prostate-specific antigen screening in the United States vs in the European Randomized Study of Screening for Prostate Cancer-Rotterdam.
Dissemination of prostate-specific antigen (PSA) testing in the United States coincided with an increasing incidence of prostate cancer, a shift to earlier stage disease at diagnosis, and decreasing prostate cancer mortality. We compared PSA screening performance with respect to prostate cancer detection in the US population vs in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC-Rotterdam). We developed a simulation model for prostate cancer and PSA screening for ERSPC-Rotterdam. This model was then adapted to the US population by replacing demography parameters with US-specific ones and the screening protocol with the frequency of PSA tests in the US population. We assumed that the natural progression of prostate cancer and the sensitivity of a PSA test followed by a biopsy were the same in the United States as in ERSPC-Rotterdam. The predicted prostate cancer incidence peak in the United States was then substantially higher than the observed prostate cancer incidence peak (13.3 vs 8.1 cases per 1000 man-years). However, the actual observed incidence was reproduced by assuming a substantially lower PSA test sensitivity in the United States than in ERSPC-Rotterdam. For example, for nonpalpable local- or regional-stage cancers (ie, stage T1M0), the estimates of PSA test sensitivity were 0.26 in the United States vs 0.94 in ERSPC-Rotterdam. We conclude that the efficacy of PSA screening in detecting prostate cancer was lower in the United States than in ERSPC-Rotterdam.


Relevance of Shear Transformations in the Relaxation of Supercooled Liquids.
While deeply supercooled liquids exhibit divergent viscosity and increasingly heterogeneous dynamics as the temperature drops, their structure shows only seemingly marginal changes. Understanding the nature of relaxation processes in this dramatic slowdown is key for understanding the glass transition. Here, we show by atomistic simulations that the heterogeneous dynamics of glass-forming liquids strongly correlate with the local residual plastic strengths along soft directions computed in the initial inherent structures. The correlation increases with decreasing temperature and is maximum in the vicinity of the relaxation time. For the lowest temperature investigated, this maximum is comparable with the best values from the literature dealing with the structure-property relationship. However, the nonlinear probe of the local shear resistance in soft directions provides here a real-space picture of relaxation processes. Our detection method of thermal rearrangements allows us to investigate the first passage time statistics and to study the scaling between the activation energy barriers and the residual plastic strengths. These results shed new light on the nature of relaxations of glassy systems by emphasizing the analogy between the thermal relaxations in viscous liquids and the plastic shear transformation in amorphous solids.


ACR Appropriateness Criteria® postoperative adjuvant therapy in non-small cell lung cancer.
Therapeutic options for postoperative adjuvant treatment for patients with non-small cell lung cancer (NSCLC) continue to evolve, and may include postoperative radiotherapy (PORT) and chemotherapy, alone or in combination. The use of platinum-based adjuvant chemotherapy has been demonstrated to confer an improvement in overall survival in patients with completely resected, stage N1 or N2 NSCLC, in several randomized trials and 2 meta-analyses. Consideration may also be given to adjuvant chemotherapy in patients with node-negative NSCLC, when the primary tumor is >4 cm, based on subset analyses of recent prospective studies. The precise role of PORT is less well defined. Older randomized studies indicated that the toxicity of PORT outweighed the potential improvement in local control, but studies using more modern radiation techniques show significantly reduced toxicity, inferring that select patients may benefit. Relative indications for PORT include the presence of mediastinal lymph nodes, positive surgical margins, and considerations with regard to the extent and type of resection. This study by the lung cancer expert panel of the American College of Radiology summarizes the recent evidence-based literature that addresses the use of postoperative adjuvant radiotherapy and chemotherapy in patients with NSCLC, illustrated with clinical scenarios. The sequencing of radiotherapy and chemotherapy is discussed, along with issues regarding radiotherapy dose and fractionation, and the appropriate use of intensity modulated radiation therapy and particle therapy.


Population density equations for stochastic processes with memory kernels.
We present a method for solving population density equations (PDEs)--a mean-field technique describing homogeneous populations of uncoupled neurons-where the populations can be subject to non-Markov noise for arbitrary distributions of jump sizes. The method combines recent developments in two different disciplines that traditionally have had limited interaction: computational neuroscience and the theory of random networks. The method uses a geometric binning scheme, based on the method of characteristics, to capture the deterministic neurodynamics of the population, separating the deterministic and stochastic process cleanly. We can independently vary the choice of the deterministic model and the model for the stochastic process, leading to a highly modular numerical solution strategy. We demonstrate this by replacing the master equation implicit in many formulations of the PDE formalism by a generalization called the generalized Montroll-Weiss equation-a recent result from random network theory-describing a random walker subject to transitions realized by a non-Markovian process. We demonstrate the method for leaky- and quadratic-integrate and fire neurons subject to spike trains with Poisson and gamma-distributed interspike intervals. We are able to model jump responses for both models accurately to both excitatory and inhibitory input under the assumption that all inputs are generated by one renewal process.


Optimization and validation of FePro cell labeling method.
Current method to magnetically label cells using ferumoxides (Fe)-protamine (Pro) sulfate (FePro) is based on generating FePro complexes in a serum free media that are then incubated overnight with cells for the efficient labeling. However, this labeling technique requires long (>12-16 hours) incubation time and uses relatively high dose of Pro (5-6 microg/ml) that makes large extracellular FePro complexes. These complexes can be difficult to clean with simple cell washes and may create low signal intensity on T2* weighted MRI that is not desirable. The purpose of this study was to revise the current labeling method by using low dose of Pro and adding Fe and Pro directly to the cells before generating any FePro complexes. Human tumor glioma (U251) and human monocytic leukemia cell (THP-1) lines were used as model systems for attached and suspension cell types, respectively and dose dependent (Fe 25 to 100 microg/ml and Pro 0.75 to 3 microg/ml) and time dependent (2 to 48 h) labeling experiments were performed. Labeling efficiency and cell viability of these cells were assessed. Prussian blue staining revealed that more than 95% of cells were labeled. Intracellular iron concentration in U251 cells reached approximately 30-35 pg-iron/cell at 24 h when labeled with 100 microg/ml of Fe and 3 microg/ml of Pro. However, comparable labeling was observed after 4 h across the described FePro concentrations. Similarly, THP-1 cells achieved approximately 10 pg-iron/cell at 48 h when labeled with 100 microg/ml of Fe and 3 microg/ml of Pro. Again, comparable labeling was observed after 4 h for the described FePro concentrations. FePro labeling did not significantly affect cell viability. There was almost no extracellular FePro complexes observed after simple cell washes. To validate and to determine the effectiveness of the revised technique, human T-cells, human hematopoietic stem cells (hHSC), human bone marrow stromal cells (hMSC) and mouse neuronal stem cells (mNSC C17.2) were labeled. Labeling for 4 hours using 100 microg/ml of Fe and 3 microg/ml of Pro resulted in very efficient labeling of these cells, without impairing their viability and functional capability. The new technique with short incubation time using 100 microg/ml of Fe and 3 microg/ml of Pro is effective in labeling cells for cellular MRI.


Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation.
Cap-dependent protein synthesis in animal cells is inhibited by heat shock, serum deprivation, metaphase arrest, and infection with certain viruses such as adenovirus (Ad). At a mechanistic level, translation of capped mRNAs is inhibited by dephosphorylation of eukaryotic initiation factor 4E (eIF-4E) (cap-binding protein) and its physical sequestration with the translation repressor protein BP-1 (PHAS-I). Dephosphorylation of BP-I blocks cap-dependent translation by promoting sequestration of eIF-4E. Here we show that heat shock inhibits translation of capped mRNAs by simultaneously inducing dephosphorylation of eIF-4E and BP-1, suggesting that cells might coordinately regulate translation of capped mRNAs by impairing both the activity and the availability of eIF-4E. Like heat shock, late Ad infection is shown to induce dephosphorylation of eIF-4E. However, in contrast to heat shock, Ad also induces phosphorylation of BP-1 and release of eIF-4E. BP-1 and eIF-4E can therefore act on cap-dependent translation in either a mutually antagonistic or cooperative manner. Three sets of experiments further underscore this point: (i) rapamycin is shown to block phosphorylation of BP-1 without inhibiting dephosphorylation of eIF-4E induced by heat shock or Ad infection, (ii) eIF-4E is efficiently dephosphorylated during heat shock or Ad infection regardless of whether it is in a complex with BP-1, and (iii) BP-1 is associated with eIF-4E in vivo regardless of the state of eIF-4E phosphorylation. These and other studies establish that inhibition of cap-dependent translation does not obligatorily involve sequestration of eIF-4E by BP-1. Rather, translation is independently regulated by the phosphorylation states of eIF-4E and the 4E-binding protein, BP-1. In addition, these results demonstrate that BP-1 and eIF-4E can act either in concert or in opposition to independently regulate cap-dependent translation. We suggest that independent regulation of eIF-4E and BP-1 might finely regulate the efficiency of translation initiation or possibly control cap-dependent translation for fundamentally different purposes.


Science for Competition among Powers: Geographical Knowledge, Colonial-Diplomatic Networks, and the Scramble for Africa*.
Historical studies on the relationship between science and diplomacy tend to focus on events since World War II and on initiatives for the maintenance of peace or to achieve cooperation over contentious matters. This article presents the case of José Vicente Barbosa du Bocage (1823-1907), a Portuguese zoologist who had formal diplomatic responsibilities in a context of competition for the colonization of Africa in the nineteenth century. He used his knowledge in African geography to implement colonial and diplomatic strategies that aimed at outcompeting rival powers. The development of a network of actors with scientific, colonial, and diplomatic expertise was crucial for the negotiations that involved the partition of the Congo basin, which resulted in victories for Portugal that surpassed the country's marginal political relevance at the international level and had long-lasting consequences.


Getting meaningful informed consent from older adults: a structured literature review of empirical research.
To perform a structured literature review of the published empirical research on informed consent with older adults in order to make recommendations to improve the informed consent process and to highlight areas needing further examination. Relevant literature was identified by searching electronic databases (AGELINE, BIOETHICSLINE, CancerLit, Ethics Index, Health, LegalTrac, MEDLINE, PAIS International, PsycInfo, and Sociofile). Studies were included if they were reports of primary research data about informed consent and, if patients or other subjects were used, older subjects were included in the sample. Data related to the aspect of informed consent under study (recruitment, decision-making capacity, voluntariness, disclosure of information, understanding of information, consent forms, authorization, and policies and procedures) were abstracted and entered into a specially designed database. Characterization of the population, age of subjects, setting, whether informed consent was being studied in the context of research or treatment, study design, the nature of outcome or dependent variables, independent variables (e.g., experimental conditions in a randomized controlled trial or patient/subject characteristics in a nonrandomized comparison), and results according to the aspect of informed consent under study. A total of 99 articles met all the inclusion criteria and posed 289 unique research questions covering a wide range of aspects of informed consent: recruitment (60); decision making capacity (21); voluntariness (6); disclosure (30); understanding (139); consent forms (7); authorization (11); policies (13); and other (2). In the secondary analyses of numerous studies, diminished understanding of informed consent information was associated with older age and fewer years of education. Older age was also sometimes associated with decreased participation in research. Studies of disclosure of informed consent information suggest strategies to improve understanding and include a variety of novel formats (e.g., simplified, storybook, video) and procedures (e.g., use of health educators, quizzing subjects, multiple disclosure sessions). A systematic review of the published literature on informed consent reveals evidence for impaired understanding of informed consent information in older subjects and those with less formal education. Effective strategies to improve the understanding of informed consent information should be considered when designing materials, forms, policies, and procedures for obtaining informed consent. Other than empirical research that has investigated disclosure and understanding of informed consent information, little systematic research has examined other aspects of the informed consent process. This deficit should be rectified to ensure that the rights and interests of patients and of human subjects who participate in research are adequately protected.


Replication in a superficial epithelial cell niche explains the lack of pathogenicity of primate foamy virus infections.
Foamy viruses (FVs) are ancient retroviruses that are ubiquitous in nonhuman primates (NHPs). While FVs share many features with pathogenic retroviruses, such as human immunodeficiency virus, FV infections of their primate hosts have no apparent pathological consequences. Paradoxically, FV infections of many cell types in vitro are rapidly cytopathic. Previous work has shown that low levels of proviral DNA are found in most tissues of naturally infected rhesus macaques, but these proviruses are primarily latent. In contrast, viral RNA, indicative of viral replication, is restricted to tissues of the oral mucosa, where it is abundant. Here, we perform in situ hybridization on tissues from rhesus macaques naturally infected with simian FV (SFV). We show that superficial differentiated epithelial cells of the oral mucosa, many of which appear to be shedding from the tissue, are the major cell type in which SFV replicates. Thus, the innocuous nature of SFV infection can be explained by replication that is limited to differentiated superficial cells that are short-lived and shed into saliva. This finding can also explain the highly efficient transmission of FVs among NHPs.


A Polyphenol-Enriched Fraction of Rose Oil Distillation Wastewater Inhibits Cell Proliferation, Migration and TNF-α-Induced VEGF Secretion in Human Immortalized Keratinocytes.
Water steam distillation of rose flowers separates the essential oil from the polyphenol-containing rose oil distillation wastewater. Recently, a strategy was developed to separate rose oil distillation wastewater into a polyphenol depleted water fraction and a polyphenol-enriched fraction [RF20-(SP-207)]. The objective of the present study was to investigate RF20-(SP-207) and fraction F(IV), augmented in quercetin and ellagic acid, for possible antiproliferative effects in immortalized human keratinocytes (HaCaT) since rose petals are known to contain compounds with potential antiproliferative activity.RF20-(SP-207) revealed dose-dependent antiproliferative activity (IC50 of 9.78 µg/mL). In a nontoxic concentration of 10 µg/mL, this effect was stronger than that of the two positive controls LY294002 (10 µM, PI3 K-inhibitor, 30 % inhibition) and NVP-BEZ235 (100 nM, dual PI3 K/mTOR inhibitor, 30 % inhibition) and clearly exceeded the antiproliferative action of quercetin (50 µM, 25 % inhibition) and ellagic acid (1 µM, 15 % inhibition). Time-lapse microscopy detected a significant impairment of cell migration of RF20-(SP-207) and F(IV). At concentrations of 10 µg/mL of both, extract and fraction, cell migration was strongly suppressed (51 % and 28 % gap closure, respectively, compared to 95 % gap closure 24 hours after control treatment). The suppression of cell migration was comparable to the positive controls LY294002, NVP-BEZ235, and quercetin. Furthermore, basal and TNF-α-stimulated VEGF-secretion was significantly reduced by RF20-(SP-207) and F(IV) at 10 µg/mL (44 % vs. untreated control).In conclusion, RF20-(SP-207) showed promising antiproliferative and antimigratory effects and could be developed as a supportive, therapy against hyperproliferation-involved skin diseases.


The ameliorative effect of black tea extract and quercetin on bisphenol A-induced cytotoxicity.
The purpose of our study was, to explore the possible ameliorating effects of black tea extract and quercetin, against bisphenol A-induced cytotoxicity. For this, human red blood corpuscles (RBC) were taken as the model. Blood samples collected in EDTA vials from healthy adults were used for preparation of RBC suspension. This suspension was treated with bisphenol A (0-150 microg/mL) with and without black tea extract or quercetin (0-200 microg/mL). The results showed that addition of bisphenol A causes concentration-dependent increase in rate of hemolysis. Addition of black tea extract or quercetin alone to RBC suspension did not cause any significant reduction. However, concurrent addition of bisphenol A (0-150 microg/mL) and black tea extract or quercetin caused concentration-dependent amelioration in bisphenol A-induced cytotoxicity.


Droplets formation and merging in two-phase flow microfluidics.
Two-phase flow microfluidics is emerging as a popular technology for a wide range of applications involving high throughput such as encapsulation, chemical synthesis and biochemical assays. Within this platform, the formation and merging of droplets inside an immiscible carrier fluid are two key procedures: (i) the emulsification step should lead to a very well controlled drop size (distribution); and (ii) the use of droplet as micro-reactors requires a reliable merging. A novel trend within this field is the use of additional active means of control besides the commonly used hydrodynamic manipulation. Electric fields are especially suitable for this, due to quantitative control over the amplitude and time dependence of the signals, and the flexibility in designing micro-electrode geometries. With this, the formation and merging of droplets can be achieved on-demand and with high precision. In this review on two-phase flow microfluidics, particular emphasis is given on these aspects. Also recent innovations in microfabrication technologies used for this purpose will be discussed.


Cardiovascular event rates in the MOSAIC trial: 2-year follow-up data.
The Multicentre Obstructive Sleep Apnoea Intervention Cardiovascular (MOSAIC) trial investigated the effect of continuous positive airway pressure (CPAP) on both sleepiness and predicted cardiovascular risk over 6 months in minimally symptomatic patients with obstructive sleep apnoea. Although there was clear benefit in terms of Epworth Sleepiness Score, there was no improvement in blood pressure and predicted vascular risk score. In order to calculate the required size of future trials, with real vascular events as the endpoint, the rate of such events in this population is needed. 188 patients from the original trial were followed for 2 years. The overall number of new vascular events over the 2 years was 25, and all-cause mortality was 4. There was a weak statistically significant reduction in vascular events in the CPAP group (p=0.049). Large-scale randomised trials are needed to determine if CPAP causes a real reduction in vascular events in minimally symptomatic patients. Based on our figures, future trials of CPAP versus no treatment would need to randomise approximately 2540 patients to not miss a real reduction in vascular events and over 6000 for mortality.


Epidemiology of pleural empyema in English hospitals and the impact of influenza.
Pleural empyema represents a significant healthcare burden due to extended hospital admissions and potential requirement for surgical intervention. This study aimed to assess changes in incidence and management of pleural empyema in England over the past 10 years and the potential impact of influenza on rates.Hospital Episode Statistics data were used to identify patients admitted to English hospitals with pleural empyema between 2008 and 2018. Linear regression was used to analyse the relationship between empyema rates and influenza incidence recorded by Public Health England. The relationship between influenza and empyema was further explored using serological data from a prospective cohort study of patients presenting with pleural empyema.Between April 2008 and March 2018 there were 55 530 patients admitted with pleural empyema. There was male predominance (67% versus 33%), which increased with age. Cases have increased significantly from 4447 in 2008 to 7268 in 2017. Peaks of incidence correlated moderately with rates of laboratory-confirmed influenza in children and young adults (r=0.30). For nine of the 10 years studied, the highest annual point incidence of influenza coincided with the highest admission rate for empyema (with a 2-week lag). In a cohort study of patients presenting to a single UK hospital with pleural empyema/infection, 24% (17 out of 72) had serological evidence of recent influenza infection, compared to 7% in seasonally matched controls with simple parapneumonic or cardiogenic effusions (p<0.001).Rates of empyema admissions in England have increased steadily with a seasonal variation that is temporally related to influenza incidence. Patient-level serological data from a prospective study support the hypothesis that influenza may play a pathogenic role in empyema development.


Mathematical Modeling of Cancer Immunotherapy and Its Synergy with Radiotherapy.
Combining radiotherapy with immune checkpoint blockade may offer considerable therapeutic impact if the immunosuppressive nature of the tumor microenvironment (TME) can be relieved. In this study, we used mathematical models, which can illustrate the potential synergism between immune checkpoint inhibitors and radiotherapy. A discrete-time pharmacodynamic model of the combination of radiotherapy with inhibitors of the PD1-PDL1 axis and/or the CTLA4 pathway is described. This mathematical framework describes how a growing tumor first elicits and then inhibits an antitumor immune response. This antitumor immune response is described by a primary and a secondary (or memory) response. The primary immune response appears first and is inhibited by the PD1-PDL1 axis, whereas the secondary immune response happens next and is inhibited by the CTLA4 pathway. The effects of irradiation are described by a modified version of the linear-quadratic model. This modeling offers an explanation for the reported biphasic relationship between the size of a tumor and its immunogenicity, as measured by the abscopal effect (an off-target immune response). Furthermore, it explains why discontinuing immunotherapy may result in either tumor recurrence or a durably sustained response. Finally, it describes how synchronizing immunotherapy and radiotherapy can produce synergies. The ability of the model to forecast pharmacodynamic endpoints was validated retrospectively by checking that it could describe data from experimental studies, which investigated the combination of radiotherapy with immune checkpoint inhibitors. In summary, a model such as this could be further used as a simulation tool to facilitate decision making about optimal scheduling of immunotherapy with radiotherapy and perhaps other types of anticancer therapies. Cancer Res; 76(17); 4931-40. ©2016 AACR.


The Role of Prion Protein Expression in Predicting Gastric Cancer Prognosis.
Previous reports indicated that prion protein (PrP) is involved in gastric cancer (GC) development and progression, but its role in GC prognosis has been poorly characterized. A total of 480 GC patients were recruited in this retrospective study. PrP expression in cancerous and non-cancerous gastric tissues was detected by using the tissue microarray and immunohistochemical staining techniques. Our results showed that the PrP expression in GC was significantly less frequent than that in the non-cancerous gastric tissue (44.4% vs 66.4%, P < 0.001). Cox regression analysis revealed that PrP expression was associated with TNM stage, survival status and survival time. GC patients with higher TNM stages (stages II, III and IV) had significantly lower PrP expression levels in tumors than those with lower TNM stages (stages 0 and I). Kaplan-Meier survival curves revealed that negative PrP expression was associated with poor overall survival (log-rank test: P < 0.001). The mean survival time for patients with negative PrP expression was significant lower than those with positive PrP expression (43.0±28.5m vs. 53.9±31.1m, P<0.001). In multivariate Cox hazard regression, PrP expression was an independent prognostic factor for GC survival, with a HR (hazard ratio) of 0.687 (95%CI:0.520-0.907, P=0.008). Our results revealed that negative PrP expression could independently predict worse outcome in GC and thereby could be used to guide the clinical practice.


Stem cell and niche regulation in human short bowel syndrome.
Loss of functional small bowel surface area following surgical resection for disorders such as Crohn's disease, intestinal ischemic injury, radiation enteritis, and in children, necrotizing enterocolitis, atresia, and gastroschisis, may result in short bowel syndrome, with attendant high morbidity, mortality, and health care costs in the United States. Following resection, the remaining small bowel epithelium mounts an adaptive response, resulting in increased crypt cell proliferation, increased villus height, increased crypt depth, and enhanced nutrient and electrolyte absorption. Although these morphologic and functional changes are well described in animal models, the adaptive response in humans is less well understood. Clinically the response is unpredictable and often inadequate. Here we address the hypotheses that human intestinal stem cell populations are expanded and that the stem cell niche is regulated following massive gut resection in short bowel syndrome (SBS). We use intestinal enteroid cultures from patients with SBS to show that the magnitude and phenotype of the adaptive stem cell response are both regulated by stromal niche cells, including intestinal subepithelial myofibroblasts, which are activated by intestinal resection to enhance epithelial stem and proliferative cell responses. Our data suggest that myofibroblast regulation of bone morphogenetic protein signaling pathways plays a role in the gut adaptive response after resection.


Quantification of lipid peroxidation in tissue extracts based on Fe(III)xylenol orange complex formation.
Commonly used spectrophotometric methods for determining the extent of lipid peroxidation in animal tissue extracts, such as measurements of diene conjugation and thiobarbituric acid reactive substances (TBARS), have been criticized for their lack of specificity. This study shows that lipid hydroperoxides can be effectively quantified in animal tissue extracts using an assay based on the formation of a Fe(III)xylenol orange complex. Addition of H2O2, cumene hydroperoxides, or methanolic tissue extracts to an acidic reaction mixture containing 0.25 mM Fe(II) and 0.1 mM xylenol orange caused the formation of a broad Fe(III)xylenol orange complex absorbance peak at 560-580 nm with a corresponding decrease in the xylenol orange peak at 440 nm. Complex formation measured at 580 nm was saturable with both xylenol orange and Fe (II) concentration. Addition of ascorbic acid, GSH, and cysteine (0.3-5 mM) caused a saturable reduction of the Fe(III)xylenol orange complex. Formation of the Fe(III)xylenol orange complex was linear with the amount of tissue extract added. A significant correlation (r = 0.88, p < 0.005) existed between the xylenol orange method of estimating lipid peroxidation and the conventional TBARS assay in a series of animal tissues tested. The time course of increase in A580nm in tests using tissue extracts was typical of a free radical reaction; a lag phase was followed by a log phase. No increase in A580nm was observed up to 24 h when highly peroxidizable arachidonic acid was assayed. These results indicate that the formation of the Fe(III)xylenol orange complex reflects a chemical amplification of the original level of lipid hydroperoxides present in tissue extracts and that peroxidizable lipids do not influence the assay. The potential usefulness of the xylenol orange assay for comparative biochemical and toxicological studies of oxidative stress is discussed.


Artesunate and sulfadoxine-pyrimethamine combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Uganda: a randomized, double-blind, placebo-controlled trial.
Drug-resistant malaria is spreading in Africa. The few available drugs might be safeguarded if combined with an artemisinin derivative. We investigated the efficacy, safety, and tolerability of 2 combinations of artesunate with sulfadoxine-pyrimethamine (SP) in a mesoendemic region in Uganda with SP resistance, from September 1999 to June 2000. In a randomized, double-blind, placebo-controlled trial, 420 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were assigned SP alone (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine) or combined with artesunate (AS; 4 mg/kg/d) for either 1 d (SPAS1) or 3 d (SPAS3). Children were followed-up for 28 d. Day 14 cure rates were 84.6% (99/117) with SPAS3 and 61.9% (73/118) with SPAS1 compared with 55.8% (86/154) with SP. Corresponding day 28 results were 74.4% (87/117) and 45.2% (52/115) compared with 40.5% (62/153). A significant improvement was obtained with the addition of 3 d, but not 1 d, of artesunate (risk ratio [RR] = 1.5, 95% CI 1.3-1.8 at 14 d and RR = 1.8, 95% CI 1.5-2.3 at 28 d). Both AS regimens achieved significantly faster parasite clearance and lower gametocyte carriage. All drug regimens were well tolerated, but SP alone was ineffective. Treatment efficacy improved with SPAS3 but the cure rate at day 28 was modest. The combinations were well tolerated and safe. In areas where SP resistance is prevalent other combinations should be considered.


Staphylococcus lugdunensis infective endocarditis: a literature review and analysis of risk factors.
Infective endocarditis caused by Staphylococcus lugdunensis is a rare disease. Since its first description in 1988, there have only been a few reports of this disease and the causative organism. These publications were primarily case reports and brief case series. We conducted a literature review to identify the nature of the disease and its risk factors. We retrospectively reviewed the cases reported between 1988 and 2008 by searching the relevant literature using the keywords "endocarditis" and "Staphylococcus lugdunensis" in the Medline database. All cases included met the definition of the modified Duke criteria. For the period 1988-2008, 67 cases from 27 articles were reviewed. The mean age of individuals was 53.9 years. Left-sided valvular endocarditis represented 52 (82.5%) of cases and native-valve endocarditis was evident in 48 (78.7%) of cases. A large proportion (82%) of 50 S. lugdunensis strains were susceptible to penicillin. Valve replacement operations were performed in 42 (66.7%) patients and the mortality rate was 38.8%. Univariate analysis showed a higher mortality rate in patients aged more than 50 years, those treated before 1995, those treated with antibiotics alone, and those with growth not detected by echocardiography. Medical treatment alone was the independent risk factor for mortality by multivariate analysis. S. lugdunensis endocarditis led to substantial morbidity and mortality. Detailed microbiological identification, echocardiography evaluation, and valve replacement may improve the clinical outcome of individuals with S. lugdunensis endocarditis.


Weak, strong, and coherent regimes of Fröhlich condensation and their applications to terahertz medicine and quantum consciousness.
In 1968, Fröhlich showed that a driven set of oscillators can condense with nearly all of the supplied energy activating the vibrational mode of lowest frequency. This is a remarkable property usually compared with Bose-Einstein condensation, superconductivity, lasing, and other unique phenomena involving macroscopic quantum coherence. However, despite intense research, no unambiguous example has been documented. We determine the most likely experimental signatures of Fröhlich condensation and show that they are significant features remote from the extraordinary properties normally envisaged. Fröhlich condensates are classified into 3 types: weak condensates in which profound effects on chemical kinetics are possible, strong condensates in which an extremely large amount of energy is channeled into 1 vibrational mode, and coherent condensates in which this energy is placed in a single quantum state. Coherent condensates are shown to involve extremely large energies, to not be produced by the Wu-Austin dynamical Hamiltonian that provides the simplest depiction of Fröhlich condensates formed using mechanically supplied energy, and to be extremely fragile. They are inaccessible in a biological environment. Hence the Penrose-Hameroff orchestrated objective-reduction model and related theories for cognitive function that embody coherent Fröhlich condensation as an essential element are untenable. Weak condensates, however, may have profound effects on chemical and enzyme kinetics, and may be produced from biochemical energy or from radio frequency, microwave, or terahertz radiation. Pokorný's observed 8.085-MHz microtubulin resonance is identified as a possible candidate, with microwave reactors (green chemistry) and terahertz medicine appearing as other feasible sources.


High efficiency THz generation in DSTMS, DAST and OH1 pumped by Cr:forsterite laser.
We investigated Terahertz generation in organic crystals DSTMS, DAST and OH1 directly pumped by a Cr:forsterite laser at central wavelength of 1.25 μm. This pump laser technology provides a laser-to-THz energy conversion efficiency higher than 3 percent. Phase-matching is demonstrated over a broad 0.1-8 THz frequency range. In our simple setup we achieved hundred μJ pulses in tight focus resulting in electric and magnetic field larger than 10 MV/cm and 3 Tesla.


Loss-of-function analysis of EphA receptors in retinotectal mapping.
EphA tyrosine kinases are thought to act as topographically specific receptors in the well-characterized projection map from the retina to the tectum. Here, we describe a loss-of-function analysis of EphA receptors in retinotectal mapping. Expressing patches of a cytoplasmically truncated EphA3 receptor in chick retina caused temporal axons to have reduced responsiveness to posterior tectal repellent activity in vitro and to shift more posteriorly within the map in vivo. A gene disruption of mouse EphA5, replacing the intracellular domain with beta-galactosidase, reduced in vitro responsiveness of temporal axons to posterior target membranes. It also caused map abnormalities in vivo, with temporal axons shifted posteriorly and nasal axons anteriorly, but with the entire target still filled by retinal axons. The anterior shift of nasal axons was not accompanied by increased responsiveness to tectal repellent activity, in contrast to the comparable anterior shift in ephrin-A knock-outs, helping to resolve a previous ambiguity in interpreting the ephrin gene knock-outs. The results show the functional requirement for endogenous EphA receptors in retinotectal mapping, show that the receptor intracellular domain is required for a forward signaling response to topographic cues, and provide new evidence for a role of axon competition in topographic mapping.


Crucial effects of fibroblasts and keratinocyte growth factor on morphogenesis of reconstituted human oral epithelium.
The connective tissue is known to have a general supportive effect for the development of the overlying epithelium; however, the more specific effects of fibroblasts and the involvement of their product, keratinocyte growth factor, on oral epithelial morphogenesis have not yet been addressed. Therefore, the purpose of this study was to investigate the effects of fibroblasts and keratinocyte growth factor on human oral epithelial morphogenesis in vitro. Reconstituted human oral epithelium was generated from primary human oral keratinocytes and fibroblasts by use of an organotypic cell culture model in a defined medium. Addition of fibroblasts to the collagen biomatrix increased total epithelial thickness from 28.0+/-5.0 microm to 66.1+/-8.6 microm (p=0.028), and basal cell proliferation from 3.6+/-0.7% to 16.6+/-1.1% (p=0.025). Presence of fibroblasts profoundly influenced the pattern of epithelial differentiation, and induced a switch in the pattern of cell death, from a predominance of spontaneous cell death in the basal cell layer (from 4.7+/-0.6% to 1.8+/-0.3%, p=0.029) to a more prevalent cell death due to terminal differentiation in the suprabasal cell layer (from 4.0+/- 0.1% to 5.4+/-0.1%, p=0.034). Keratinocyte growth factor promoted epithelial growth, but did not significantly enhance epithelial differentiation, demonstrating that fibroblasts possess additional mechanisms to keratinocyte growth factor synthesis that can modulate differentiation of reconstituted human oral epithelium.


Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.
Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.


Founding weaver ant queens (Oecophylla longinoda) increase production and nanitic worker size when adopting non-nestmate pupae.
Weaver ants (Oecophylla longinoda Latreille) are used commercially to control pest insects and for protein production. In this respect fast colony growth is desirable for managed colonies. Transplantation of non-nestmate pupae to incipient colonies has been shown to boost colony growth. Our objectives were to find the maximum number of pupae a founding queen can handle, and to measure the associated colony growth. Secondly, we tested if transplantation of pupae led to production of larger nanitic workers (defined as unusually small worker ants produced by founding queens in their first batch of offspring). Forty-five fertilized queens were divided into three treatments: 0 (control), 100 or 300 non-nestmate pupae transplanted to each colony. Pupae transplantation resulted in highly increased growth rates, as pupae were readily adopted by the queens and showed high proportions of surviving (mean = 76%). However, survival was significantly higher when 100 pupae were transplanted compared to transplantation of 300 pupae, indicating that queens were unable to handle 300 pupae adequately and that pupae require some amount of nursing. Nevertheless, within the 60-day experiment the transplantation of 300 pupae increased total colony size more than 10-fold whereas 100 pupae increased the size 5.6 fold, compared to control. This increase was due not only to the individuals added in the form of pupae but also to an increased per capita brood production by the resident queen, triggered by the adopted pupae. The size of hatching pupae produced by the resident queen also increased with the number of pupae transplanted, leading to larger nanitic workers in colonies adopting pupae. In conclusion, pupae transplantation may be used to produce larger colonies with larger worker ants and may thus reduce the time to produce weaver ant colonies for commercial purposes. This in turn may facilitate the implementation of the use of weaver ants.


Understanding beverage taxation: Perspective on the Philadelphia Beverage Tax's novel approach.
Despite the growing global trend of sugar-sweetened beverage (SSB) taxes for their potential as an untapped source of revenue and as a public health boon, these legislative efforts remain controversial. Multiple articles have reviewed this trend in recent years from modeling of long-term impacts to short-term empirical studies, yet most comprehensive, long-term health impact assessments remain forthcoming. These multi-faceted efficacy studies combined with case-based assessments of the policy process, descriptive pieces highlighting unique features of the policy and reflective perspectives targeting unanswered questions create a comprehensive body of literature to help inform present and future legislative efforts. The passage of the Philadelphia Beverage tax required a mix of political entrepreneurs, timing and context; while uniquely employing a nonpublic health frame, specific earmarking and a broadened scope with the inclusion of diet beverages. This perspective on the Philadelphia Beverage Tax will describe the passage and novel features of the Philadelphia Beverage Tax with a discussion of the ethical questions unique to this case.


Phylogenetic analysis of partial sequences of elongation factor 1alpha identifies major groups of lice (Insecta: Phthiraptera).
As a first attempt to use molecular data to resolve the relationships between the four suborders of lice and within the suborder Ischnocera, we sequenced a 347-bp fragment of the elongation factor 1alpha gene of 127 lice (Insecta: Phthiraptera) as well as outgroup taxa from the order Psocoptera. A number of well-supported monophyletic groups were found but the relationships among many of these groups could not be resolved. While it is probable that multiple substitutions at high divergences and ancient radiation over a short period of time have contributed to the problem, we attribute most of this lack of resolution to the high ratio of taxa to characters. Nevertheless, the sequence data unequivocally support a number of important relationships that are at variance with the conclusions of morphological taxonomy. These include the sister group relationship of Chelopistes and Oxylipeurus, two lice occupying different ecological niches on the same host, which have previously been assigned to different families. These results provide evidence in support of the hypothesis that lice have speciated in situ on the host in response to niche specialization and that this has given rise to convergent morphologies in the lice of different host groups which share similar ecological niches. We discuss our attempts to overcome the limitations of this large data set, including the use of leaf stability analysis, a new method for analyzing the stability of taxa in a phylogenetic tree, and examine a number of hypotheses of relationships based on both traditional taxonomy and host associations.


Healing activity of laser InGaAlP (660nm) in rats.
To evaluate the effect the healing activity of diode laser Indium Gallium Aluminum Phosphorus (InGaAlP) ë660nm on healing of surgical wounds in rats. Fifty-four female Wistar rats were used, divided into three groups (n=18) and subdivided into three subgroups (n=6) to be studied in 5, 10 and 15(th) days after surgical procedures. The wound was induced in the dorsal-cervical using punch. The lesions were irradiated on alternate days with InGaAlP laser, the energy densities of 3J/cm(2) (L3) or 6J/cm(2) (L6). The control group received no irradiation. At 5, 10 and 15(th) days after surgery the animals were euthanized and the repair area was removed and histological sections were stained with hematoxylin-eosin and picrossírius. We evaluated macroscopic and histological lesions in the times cited, as well as morphometric analysis of angiogenesis and collagen content. The wound healing activity InGaAlP laser was evidenced by increased angiogenesis group L3 and L6 in relation to control group (CG) at the 5(th) day (p=0.0001) and decreased polymorphonuclear infiltrate and hemorrhage (p=0.045 and p=0.07 respectively) in the groups L3 and L6 in relation to control group (GC). On the 10 and 15(th) days was also observed in groups treated with laser L3 and L6 stimulation was pronounced fibroplasia (p=0.0003 and p=0.034 respectively) when compared with the control group (CG). The InGaAlP laser acted positively on the healing of skin wounds in rats.


Lead bone toxicity in growing rats exposed to chronic intermittent hypoxia.
Lead chronic intoxication under hypoxic conditions revealed growth retardation in growing rats and damages on femoral and mandibular bones that predispose to fractures. These findings aimed us to investigate if bone material and geometric properties, bone mass in terms of histomorphometry or antioxidant capacity are also impaired in such experimental model. Combined treatments significantly reduced hemimandible cross sectional geometry and intrinsic stiffness (-16% and -34%); tibia and hemimandible bone volume (-45% and -40%) and growth plate cartilage thickness (-19%). These results show a previously unreported toxic effect of lead on mandible however, longer studies should be necessary to evaluate if an adaptation of bone architecture to maintain structural properties may occur and if the oxidative stress can be identified as the primary contributory agent in the pathogenesis of lead poisoning.


Effect on appetite control of minor cereal and pseudocereal products.
Recent findings suggest that Western diets based on highly palatable foods are likely to be much less satiating than more traditional diets or those typical of less developed countries. In particular, some alternative crops (for example, buckwheat, oat, barley, spelt, rye, quinoa, amaranth) seem to be of great nutritional interest and to represent important recipes for healthier and typical regional foods. The objective of the present study was to investigate the effect on subsequent food intake and feelings of satiety of alternative oat bread, oat and buckwheat pasta and of quinoa as compared with their wheat counterparts and rice, respectively. Three different experiments (one specific for each alternative crop food) were conducted, all with a within-subjects design. The preloading paradigm strategy was used. Results showed that preload energy level influenced total energy intake (preload plus ad libitum test meal intake), larger preloads inducing more eating than smaller preloads. No effect of formulation was observed on energy intake, as the consumption of alternative crop formulations did not decrease the total energy intake as compared with that of the counterparts. Satiating efficiency indices (SEI) for alternative crop foods were higher with respect to traditional cereal foods. In particular, white bread was the least satisfying food (SEI =0.2) and the different time of consumption (for lunch or as a snack) did not affect energy intake. In conclusion, oat or buckwheat formulations, and also quinoa, may be exploited for their potential impact on eating behaviour, particularly considering they are good sources of functional substances.


Hyperosmolar reconstituted lyophilized plasma is an effective low-volume hemostatic resuscitation fluid for trauma.
We performed this study to optimize reconstituted lyophilized plasma (LP) into a minimal volume fluid that provides effective hemostatic resuscitation for trauma while minimizing logistical limitations. We performed a prospective, blinded animal study. Plasma was lyophilized following whole blood collection from anesthetized swine. The minimal volume needed for reconstitution was determined, and this solution was evaluated for safe infusion into the swine. Reconstituted LP was analyzed for electrolyte content, osmolarity, and coagulation factor activity. Twenty swine were anesthetized and subjected to a validated model of polytrauma and hemorrhagic shock (including a Grade V liver injury), then randomized to resuscitation with LP reconstituted to either 100% of the original plasma volume (100%LP) or the minimal volume LP fluid. Physiologic data were monitored, and blood loss and hematocrit were measured. Coagulation status was evaluated using thrombelastography. The minimal volume of reconstituted LP safe for infusion in swine was 50% of the original plasma volume (50%LP). The 50%LP had higher electrolyte concentrations, osmolarity, and increased coagulation factor activity levels by volume compared with 100%LP (p < 0.05). Blood loss, hematocrit, mean arterial pressure, and heart rate did not differ between animals receiving 100%LP (n = 10) or 50%LP (n = 10) at any time point (p > 0.05). International normalized ratio and thrombelastography parameters were not different between groups (R time, α angle, or maximal amplitude, p > 0.05). Resuscitation with 50%LP fluid was well tolerated and equally effective compared with 100%LP, with respect to physiologic and hemostatic properties. The smaller volume of fluid necessary to reconstitute hypertonic LP makes it logistically superior to 100%LP for first responders and may reduce adverse effects of large-volume resuscitation.


Should we screen for occult coronary artery disease among asymptomatic patients with diabetes?
Diabetes mellitus predisposes people to premature atherosclerotic coronary artery disease (CAD). The risk of a myocardial infarction in diabetics without overt evidence of obstructive CAD matches that of patients without diabetes who have had a previous myocardial infarction. The available data suggest that occult CAD is a common finding among asymptomatic diabetics, ranging from 20% to >50%. The diagnostic accuracy of myocardial perfusion single-photon emission computed tomography (SPECT) in diabetics appears to be comparable to that observed in nondiabetic individuals. As shown in other patient groups, the ischemic burden assessed by stress SPECT in subjects with diabetes is also linked to their increased risk of adverse cardiovascular events. Among patients with normal stress SPECT, however, those with diabetes are at significantly greater risk than non-diabetics. Testing diabetics with an abnormal resting electrocardiogram or with evidence of peripheral or carotid occlusive arterial disease appears to result in an excellent yield of abnormal SPECT findings, as does testing in the setting of dyspnea. However, recent evidence suggests that achieving an adequate yield in asymptomatic diabetics without overt evidence of CAD is a greater challenge. Further investigation of sequential testing strategies is needed in order to identify an efficient means for screening asymptomatic patients with diabetes.


Heterogeneous nuclear ribonucleoprotein K and nucleolin as transcriptional activators of the vascular endothelial growth factor promoter through interaction with secondary DNA structures.
The human vascular endothelial growth factor (VEGF) promoter contains a polypurine/polypyrimidine (pPu/pPy) tract that is known to play a critical role in its transcriptional regulation. This pPu/pPy tract undergoes a conformational transition between B-DNA, single-stranded DNA, and atypical secondary DNA structures such as G-quadruplexes and i-motifs. We studied the interaction of the cytosine-rich (C-rich) and guanine-rich (G-rich) strands of this tract with transcription factors heterogeneous nuclear ribonucleoprotein (hnRNP) K and nucleolin, respectively, both in vitro and in vivo and their potential role in the transcriptional control of VEGF. Using chromatin immunoprecipitation (ChIP) assay for our in vivo studies and electrophoretic mobility shift assay (EMSA) for our in vitro studies, we demonstrated that both nucleolin and hnRNP K bind selectively to the G- and C-rich sequences, respectively, in the pPu/pPy tract of the VEGF promoter. The small interfering RNA (siRNA)-mediated silencing of either nucleolin or hnRNP K resulted in the down-regulation of basal VEGF gene, suggesting that they act as activators of VEGF transcription. Taken together, the identification of transcription factors that can recognize and bind to atypical DNA structures within the pPu/pPy tract will provide new insight into mechanisms of transcriptional regulation of the VEGF gene.


Molecular signature of human embryonic stem cells and its comparison with the mouse.
The molecular mechanism underlying pluripotency is largely unknown. Here, we provide the first global transcriptional profile of the state of "stemness" in human embryonic stem cells (HESCs). We have identified a set of 918 genes enriched in undifferentiated HESCs compared with their differentiated counterparts. These include ligand/receptor pairs and secreted inhibitors of the FGF, TGFbeta/BMP, and Wnt pathways, highlighting a prevalent role for these pathways in HESCs. Importantly, a significant number of HESCs-enriched genes, including several signaling components, are found to be intersected with published mouse embryonic stem cell data, indicating that a "core molecular program" is shared between the two pluripotent stem cells.


Direct administration in the respiratory tract improves efficacy of broadly neutralizing anti-influenza virus monoclonal antibodies.
The emergence of influenza virus strains resistant to approved neuraminidase inhibitors and the time constrains after infection when these drugs can be effective constitute major drawbacks for this class of drugs. This highlights a critical need to discover new therapeutic agents that can be used for the treatment of influenza virus-infected patients. The use of broadly neutralizing anti-influenza monoclonal antibodies (MAbs) has been sought as an alternative immunotherapy against influenza infection. Here, we tested in mice previously characterized broadly neutralizing anti-hemagglutinin (HA) stalk MAbs prophylactically and therapeutically using different routes of administration. The efficacy of treatment against an influenza H1N1 pandemic virus challenge was compared between two systemic routes of administration, intraperitoneal (i.p.) and intravenous (i.v.), and two local routes, intranasal (i.n.) and aerosol (a.e.). The dose of MAb required for prophylactic protection was reduced by 10-fold in animals treated locally (i.n. or a.e.) compared with those treated systemically (i.p. or i.v.). Improved therapeutic protection was observed in animals treated i.n. on day 5 postinfection (60% survival) compared with those treated via the i.p. route (20% survival). An increase in therapeutic efficacy against other influenza virus subtypes (H5N1) was also observed when a local route of administration was used. Our findings demonstrate that local administration significantly decreases the amount of broadly neutralizing monoclonal antibody required for protection against influenza, which highlights the potential use of MAbs as a therapeutic agent for influenza-associated disease.


Cellulose nanomaterials in water treatment technologies.
Cellulose nanomaterials are naturally occurring with unique structural, mechanical and optical properties. While the paper and packaging, automotive, personal care, construction, and textiles industries have recognized cellulose nanomaterials' potential, we suggest cellulose nanomaterials have great untapped potential in water treatment technologies. In this review, we gather evidence of cellulose nanomaterials' beneficial role in environmental remediation and membranes for water filtration, including their high surface area-to-volume ratio, low environmental impact, high strength, functionalizability, and sustainability. We make direct comparison between cellulose nanomaterials and carbon nanotubes (CNTs) in terms of physical and chemical properties, production costs, use and disposal in order to show the potential of cellulose nanomaterials as a sustainable replacement for CNTs in water treatment technologies. Finally, we comment on the need for improved communication and collaboration across the myriad industries invested in cellulose nanomaterials production and development to achieve an efficient means to commercialization.


Plant root hair in tap water: a potential cause for diagnostic confusion.
Plant root hairs are commonly found artifacts in parasitology specimens and may be confused with helminthes by an untrained eye. We report a case of brain tuberculoma where the tissue sample was contaminated with root hair derived from tap water; the presence of this root hair, which mimicked a larva, led to diagnostic confusion. Therefore, tap water should be considered a source of root hair and vegetable matter.


Microbiome Disturbances and Autism Spectrum Disorders.
Autism spectrum disorders (ASDs) are considered a heterogenous set of neurobehavioral diseases, with the rates of diagnosis dramatically increasing in the past few decades. As genetics alone does not explain the underlying cause in many cases, attention has turned to environmental factors as potential etiological agents. Gastrointestinal disorders are a common comorbidity in ASD patients. It was thus hypothesized that a gut-brain link may account for some autistic cases. With the characterization of the human microbiome, this concept has been expanded to include the microbiota-gut-brain axis. There are mounting reports in animal models and human epidemiologic studies linking disruptive alterations in the gut microbiota or dysbiosis and ASD symptomology. In this review, we will explore the current evidence that gut dysbiosis in animal models and ASD patients correlates with disease risk and severity. The studies to date have surveyed how gut microbiome changes may affect these neurobehavioral disorders. However, we harbor other microbiomes in the body that might impact brain function. We will consider microbial colonies residing in the oral cavity, vagina, and the most recently discovered one in the placenta. Based on the premise that gut microbiota alterations may be causative agents in ASD, several therapeutic options have been tested, such as diet modulations, prebiotics, probiotics, synbiotics, postbiotics, antibiotics, fecal transplantation, and activated charcoal. The potential benefits of these therapies will be considered. Finally, the possible mechanisms by which changes in the gut bacterial communities may result in ASD and related neurobehavioral disorders will be examined.


Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice.
Autophagy is a self-degradative process responsible for the clearance of damaged or unnecessary cellular components. We have previously found that persistence of dysfunctional organelles due to autophagy failure is a key event in the pathogenesis of COL6/collagen VI-related myopathies, and have demonstrated that reactivation of a proper autophagic flux rescues the muscle defects of Col6a1-null (col6a1(-/-)) mice. Here we show that treatment with spermidine, a naturally occurring nontoxic autophagy inducer, is beneficial for col6a1(-/-) mice. Systemic administration of spermidine in col6a1(-/-) mice reactivated autophagy in a dose-dependent manner, leading to a concurrent amelioration of the histological and ultrastructural muscle defects. The beneficial effects of spermidine, together with its being easy to administer and the lack of overt side effects, open the field for the design of novel nutraceutical strategies for the treatment of muscle diseases characterized by autophagy impairment.


Assessing the Impact of Food Assistance on Stigma Among People Living with HIV in Uganda Using the HIV/AIDS Stigma Instrument-PLWA (HASI-P).
HIV-related stigma among persons living with HIV/AIDS (PLHIV) is prevalent throughout sub-Saharan Africa. There is limited evidence, however, on which interventions are effective in reducing it. We used data from a prospective impact evaluation of a 12-month food assistance intervention among 904 antiretroviral therapy (ART)- naïve PLHIV in Uganda to examine the program impact on stigma. Stigma was measured using the comprehensive HASI-P scale, which demonstrated good internal consistency (Cronbach's alpha = 0.87) and was correlated with several related constructs including physical and mental health-related quality of life, disclosure, and physical health symptoms in the sample. Using quasi-experimental difference-in-difference matching methods to better infer causality, we tested whether the intervention improved the overall stigma scale and its subscales. The food assistance intervention had a significant effect on reported internalized (but not external) stigma of approximately 0.2 SD (p < 0.01). The HASI-P stigma scale is a useful tool for measuring and tracking stigma. Food assistance interventions, embedded in an HIV care program, can reduce internalized stigma.


Toward a general psychological model of tension and suspense.
Tension and suspense are powerful emotional experiences that occur in a wide variety of contexts (e.g., in music, film, literature, and everyday life). The omnipresence of tension and suspense suggests that they build on very basic cognitive and affective mechanisms. However, the psychological underpinnings of tension experiences remain largely unexplained, and tension and suspense are rarely discussed from a general, domain-independent perspective. In this paper, we argue that tension experiences in different contexts (e.g., musical tension or suspense in a movie) build on the same underlying psychological processes. We discuss key components of tension experiences and propose a domain-independent model of tension and suspense. According to this model, tension experiences originate from states of conflict, instability, dissonance, or uncertainty that trigger predictive processes directed at future events of emotional significance. We also discuss possible neural mechanisms underlying tension and suspense. The model provides a theoretical framework that can inform future empirical research on tension phenomena.


Dose-related effects of adenosine and bradykinin on microvascular permselectivity to macromolecules in the hamster cheek pouch.
The hamster cheek pouch preparation was used to assess microvascular permselectivity responses to three vasodilating agents: bradykinin, adenosine, and papaverine. Fluorescein isothiocyanate-dextran 150 was injected intravenously as a macromolecular tracer. To quantify changes in permeability, we calculated fluorochrome clearance values from the ratio of suffusate to plasma fluorescein isothiocyanate-dextran 150 concentration. The microcirculation was recorded on videotape, using epifluorescence and bright-field light microscopy. Topical application of bradykinin elicited dose-dependent increases in macromolecular permeability. Adenosine also augmented permeability in a dose-dependent fashion. The increases in tracer clearance, relative to control, were 9.4 nl/min for 10(-5) M adenosine and 39.4 nl/min for 10(-4) M adenosine. The standard error for these doses was 1.5 nl/min. Adenosine, 10(-6) M, did not alter permeability. The increment in clearance induced by 10(-4) M was comparable to that of bradykinin, 8 X 10(-7) M. Pretreatment with phenidone had no effect on the permeability response mediated by 10(-5) M adenosine. Topical application of papaverine enhanced the transvascular exchange of macromolecules in one-half of the preparations examined. Comparable doses of adenosine were approximately three times as effective. This study indicated that adenosine, like bradykinin, is capable of modifying microvascular permeability responses in the hamster cheek pouch. This modulatory effect appears to be due to a direct action on the postcapillary microvascular membrane.


Designer self-assembling peptide nanofiber scaffolds for adult mouse neural stem cell 3-dimensional cultures.
Biomedical researchers have become increasingly aware of the limitations of conventional 2-dimensional tissue cell culture systems, including coated Petri dishes, multi-well plates and slides, to fully address many critical issues in cell biology, cancer biology and neurobiology, such as the 3-D microenvironment, 3-D gradient diffusion, 3-D cell migration and 3-D cell-cell contact interactions. In order to fully understand how cells behave in the 3-D body, it is important to develop a well-controlled 3-D cell culture system where every single ingredient is known. Here we report the development of a 3-D cell culture system using a designer peptide nanofiber scaffold with mouse adult neural stem cells. We attached several functional motifs, including cell adhesion, differentiation and bone marrow homing motifs, to a self-assembling peptide RADA16 (Ac-RADARADARADARADA-COHN2). These functionalized peptides undergo self-assembly into a nanofiber structure similar to Matrigel. During cell culture, the cells were fully embedded in the 3-D environment of the scaffold. Two of the peptide scaffolds containing bone marrow homing motifs significantly enhanced the neural cell survival without extra soluble growth and neurotrophic factors to the routine cell culture media. In these designer scaffolds, the cell populations with beta-Tubulin(+), GFAP(+) and Nestin(+) markers are similar to those found in cell populations cultured on Matrigel. The gene expression profiling array experiments showed selective gene expression, possibly involved in neural stem cell adhesion and differentiation. Because the synthetic peptides are intrinsically pure and a number of desired function cellular motifs are easy to incorporate, these designer peptide nanofiber scaffolds provide a promising controlled 3-D culture system for diverse tissue cells, and are useful as well for general molecular and cell biology.


Islamic medical ethics in the 20th century.
While the practice of Western medicine is known today to doctors of all ethnic and religious groups, its standards are subject to the availability of resources. The medical ethics guiding each doctor is influenced by his/her religious or cultural background or affiliation, and that is where diversity exists. Much has been written about Jewish and Christian medical ethics. Islamic medical ethics has never been discussed as an independent field of ethics, although several selected topics, especially those concerning sexuality, birth control and abortions, have been more discussed than others. Islamic medical ethics in the 20th century will be characterised on the basis of Egyptian fatawa (legal opinions) issued by famous Muslim scholars and several doctors. Some of the issues discussed by Islamic medical ethics are universal: abortions, organ transplants, artificial insemination, cosmetic surgery, doctor-patient relations, etc. Other issues are typically Islamic, such as impediments to fasting in Ramadan, diseases and physical conditions that cause infringement of the state of purity, medicines containing alcohol, etc. Muslims' attitudes to both types of ethical issues often prove that pragmatism prevails and the aim is to seek a compromise between Islamic heritage and the achievements of modern medicine, as long as basic Islamic dogma is not violated.


15-deoxy-D12,14-prostaglandin J2 suppresses RANTES expression by inhibiting NADPH oxidase activation in Helicobacter pylori-infected gastric epithelial cells.
Peroxisome proliferators-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor. 15 deoxy-(12,14) prostaglandin J(2) (15d-PGJ(2)) is a potent PPAR-γ ligand and acts as an anti-inflammatory agent via PPAR-γ-dependent and independent mechanisms. Helicobacter pylori (H. pylori) induces gastric inflammation by inducing the activation of oxidant-sensitive transcription factor NF-κB and cytokine expression in gastric epithelial cells. Since 15d-PGJ(2) inhibits NF-κB activation in various cells, it may suppress H. pylori-induced inflammatory signaling and cytokine expression in gastric epithelial cells. The present study aims to determined the effect of 15d-PGJ(2) on the activation of inflammatory mediators Jak/Stat (Janus kinase/signal transducers and activators of transcription) and induction of cytokine RANTES in H. pylori-infected gastric epithelial AGS cells. Since NADPH oxidase is a candidate for the production of reactive oxygen species in H. pylori-infected gastric epithelial cells, we determined the effect of 15d-PGJ(2) on the activation of NADPH oxdase. AGS cells were cultured in the presence of H. pylori treated with or without 15d-PGJ(2). The activations of NADPH oxidase and Jak1/Stat3, the levels of H(2)O(2) and RANTES in the medium, and DNA binding activity of Stat3 were assessed. A Jak/Stat3 specific inhibitor AG490 and an inhibitor of NADPH oxidase diphenyleneiodonium (DPI) were treated to determine the direct involvement of Jak/Stat and NADPH oxidase on the production of H(2)O(2) and RANTES in H. pylori-infected cells. H. pylori induced the production of H(2)O(2) and RANTES as well as the activations of NADPH oxidase and Jak1/Stat3, which were inhibited by the treatment of 15d-PGJ(2). DPI suppressed H. pylori-induced alterations similar to 15d-PGJ(2). However, AG490 had no effect on NADPH oxidase activation, but reduced the level of RANTES in the medium released from H. pylori-infected cells. NADPH oxidase activation is an upstream signaling of Jak1/Stat3 activation and induction of RANTES in H. pylori-infected AGS cells. 15d-PGJ(2), inhibits the activations of NADPH oxidase and Jak1/Stat3 and RANTES expression, suggesting that 15d-PGJ(2) may be beneficial for the treatment of H. pylori-induced gastric inflammation.


Obstructive Jaundice Due to Hilar Bile Duct Compression with Encasement of the Right Hepatic Artery.
A 68-year-old woman had a solitary 12.0 cm hepatic cyst with a septum. The cyst was located near the hepatic hilum and she presented with obstructive jaundice caused by compression of the hilar bile duct. Stenosis of the common hepatic duct was detected at the porta hepatis on endoscopic retrograde cholangiography (ERC), and encasement of the right hepatic artery at the same level was revealed by abdominal angiography. Transpapillary cholangioscopy showed compression and mucosal erosions of the hilar bile duct. After transpapillary cholangioscopy, the hepatic cyst became infected, for which emergency percutaneous transhepatic drainage was performed. As a result, the patient's obstructive jaundice subsided. The mucosal erosions of the bile duct that existed at a site corresponding to the encasement of the right hepatic artery also improved. In conclusion, bile duct stenosis was considered to be caused by compression due to the hepatic cyst and the right hepatic artery.


Ultrasound's 'window on the womb' brings ethical challenges for balancing maternal and fetal health interests: obstetricians' experiences in Australia.
Obstetric ultrasound has become a significant tool in obstetric practice, however, it has been argued that its increasing use may have adverse implications for women's reproductive freedom. This study aimed to explore Australian obstetricians' experiences and views of the use of obstetric ultrasound both in relation to clinical management of complicated pregnancy, and in situations where maternal and fetal health interests conflict. A qualitative study was undertaken as part of the CROss-Country Ultrasound Study (CROCUS). Interviews were held in November 2012 with 14 obstetricians working in obstetric care in Victoria, Australia. Data were analysed using qualitative content analysis. One overall theme emerged from the analyses: The ethical challenge of balancing maternal and fetal health interests, built on four categories: First, Encountering maternal altruism' described how pregnant women's often 'altruistic' position in relation to the health and wellbeing of the fetus could create ethical challenges in obstetric management, particularly with an increasing imbalance between fetal benefits and maternal harms. Second, 'Facing shifting attitudes due to visualisation and medico-technical advances' illuminated views that ultrasound and other advances in care have contributed to a shift in what weight to give maternal versus fetal welfare, with increasing attention directed to the fetus. Third, 'Guiding expectant parents in decision-making' described the difficult task of facilitating informed decision-making in situations where maternal and fetal health interests were not aligned, or in situations characterised by uncertainty. Fourth, 'Separating private from professional views' illuminated divergent views on when the fetus can be regarded as a person. The narratives indicated that the fetus acquired more consideration in decision-making the further the gestation progressed. However, there was universal agreement that obstetricians could never act on fetal grounds without the pregnant woman's consent. This study suggests that medico-technical advances such as ultrasound have set the scene for increasing ethical dilemmas in obstetric practice. The obstetricians interviewed had experienced a shift in previously accepted views about what weight to give maternal versus fetal welfare. As fetal diagnostics and treatment continue to advance, how best to protect pregnant women's right to autonomy requires careful consideration and further investigation.


Large global variations in measured airborne metal concentrations driven by anthropogenic sources.
Globally consistent measurements of airborne metal concentrations in fine particulate matter (PM2.5) are important for understanding potential health impacts, prioritizing air pollution mitigation strategies, and enabling global chemical transport model development. PM2.5 filter samples (N ~ 800 from 19 locations) collected from a globally distributed surface particulate matter sampling network (SPARTAN) between January 2013 and April 2019 were analyzed for particulate mass and trace metals content. Metal concentrations exhibited pronounced spatial variation, primarily driven by anthropogenic activities. PM2.5 levels of lead, arsenic, chromium, and zinc were significantly enriched at some locations by factors of 100-3000 compared to crustal concentrations. Levels of metals in PM2.5 and PM10 exceeded health guidelines at multiple sites. For example, Dhaka and Kanpur sites exceeded the US National Ambient Air 3-month Quality Standard for lead (150 ng m-3). Kanpur, Hanoi, Beijing and Dhaka sites had annual mean arsenic concentrations that approached or exceeded the World Health Organization's risk level for arsenic (6.6 ng m-3). The high concentrations of several potentially harmful metals in densely populated cites worldwide motivates expanded measurements and analyses.


Histology of a Woolly Mammoth (Mammuthus primigenius) Preserved in Permafrost, Yamal Peninsula, Northwest Siberia.
In 2007, the baby woolly mammoth (Mammuthus primigenius) named Lyuba was found frozen in the Siberian tundra permafrost along the Yuribey River. She was proclaimed the best-preserved mammoth discovery. As part of the endoscopic examination of Lyuba, tissue samples of hair, muscle, and internal organs were taken. The sectioned biopsies were stained using standard and special histological stains. In general, the microscopic preservation of the tissue was good although no clearly identifiable cell nuclei were found by standard staining methods. Only a few cell nuclei could be identified in some samples when fluorescence stained with DAPI. The best-preserved structures were collagen fibers and muscle tissue, which gave some structural resemblance to the organs. In the hairs, evidence of pigmentation, a scaly surface, diagonal intra-hair structures, and a medulla were seen. Fat droplets could be identified with Sudan Red in the subcutaneous fat sample and in several organs. Bacteria were seen on the lumen side of the small intestine and caecum, and in the liver and lung tissue. In addition, fungi and pollen were seen in the lung sample. In the wall of the caecum and small intestine, blood vessels and nerves were visualized. Iron was identified in the vivianite sample. Some biopsies compared well structurally with the African elephant tissue sections. The histological findings support the theory that Lyuba drowned in muddy water. The microscopic tissue preservation and cell nuclei destruction indicate that Lyuba's body underwent at least one freeze-thaw cycle.


Exogenous leukemia inhibitory factor stimulates oligodendrocyte progenitor cell proliferation and enhances hippocampal remyelination.
New CNS neurons and glia are generated throughout adulthood from endogenous neural stem and progenitor cells. These progenitors can respond to injury, but their ability to proliferate, migrate, differentiate, and survive is usually insufficient to replace lost cells and restore normal function. Potentiating the progenitor response with exogenous factors is an attractive strategy for the treatment of nervous system injuries and neurodegenerative and demyelinating disorders. Previously, we reported that delivery of leukemia inhibitory factor (LIF) to the CNS stimulates the self-renewal of neural stem cells and the proliferation of parenchymal glial progenitors. Here we identify these parenchymal glia as oligodendrocyte (OL) progenitor cells (OPCs) and show that LIF delivery stimulates their proliferation through the activation of gp130 receptor signaling within these cells. Importantly, this effect of LIF on OPC proliferation can be harnessed to enhance the generation of OLs that express myelin proteins and reform nodes of Ranvier in the context of chronic demyelination in the adult mouse hippocampus. Our findings, considered together with the known beneficial effects of LIF on OL and neuron survival, suggest that LIF has both reparative and protective activities that make it a promising potential therapy for CNS demyelinating disorders and injuries.