ATF3 Sustains IL-22-Induced STAT3 Phosphorylation to Maintain Mucosal Immunity Through Inhibiting Phosphatases.
In gut epithelium, IL-22 transmits signals through STAT3 phosphorylation (pSTAT3) which provides intestinal immunity. Many components in the IL-22-pSTAT3 pathway have been identified as risk factors for inflammatory bowel disease (IBD) and some of them are considered as promising therapeutic targets. However, new perspectives are still needed to understand IL-22-pSTAT3 signaling for effective clinical interventions in IBD patients. Here, we revealed activating transcription factor 3 (ATF3), recently identified to be upregulated in patients with active IBD, as a crucial player in the epithelial IL-22-pSTAT3 signaling cascade. We found ATF3 is central to intestinal homeostasis and provides protection during colitis. Loss of ATF3 led to decreased crypt numbers, more shortened colon length, impaired ileal fucosylation at the steady state, and lethal disease activity during DSS-induced colitis which can be effectively ameliorated by rectal transplantation of wild-type colonic organoids. Epithelial stem cells and Paneth cells form a niche to orchestrate epithelial regeneration and host-microbe interactions, and IL-22-pSTAT3 signaling is a key guardian for this niche. We found ATF3 is critical for niche maintenance as ATF3 deficiency caused compromised stem cell growth and regeneration, as well as Paneth cell degeneration and loss of anti-microbial peptide (AMP)-producing granules, indicative of malfunction of Paneth/stem cell network. Mechanistically, we found IL-22 upregulates ATF3, which is required to relay IL-22 signaling leading to STAT3 phosphorylation and subsequent AMP induction. Intriguingly, ATF3 itself does not act on STAT3 directly, instead ATF3 regulates pSTAT3 by negatively targeting protein tyrosine phosphatases (PTPs) including SHP2 and PTP-Meg2. Furthermore, we identified ATF3 is also involved in IL-6-mediated STAT3 activation in T cells and loss of ATF3 leads to reduced capacity of Th17 cells to produce their signature cytokine IL-22 and IL-17A. Collectively, our results suggest that via IL-22-pSTAT3 signaling in the epithelium and IL-6-pSTAT3 signaling in Th17 cells, ATF3 mediates a cross-regulation in the barrier to maintain mucosal homeostasis and immunity.


Within- and between-cohort variation in measured macronutrient intakes, taking account of measurement errors, in the European Prospective Investigation into Cancer and Nutrition study.
Multicenter epidemiologic studies provide a unique opportunity to evaluate the association between exposure and disease at the individual and the aggregate levels. The two components can eventually be pooled to corroborate each other, using weights proportional to the intraclass correlation coefficient (ICC), which expresses the amount of between-cohort variability in the exposure variable compared with the total. The greater the ICC, the more the overall estimate will reflect the between-cohort component. Dietary measurements are affected by measurement errors, particularly within a cohort. In 1992-2000, the variability of macronutrient intake distribution before and after calibration for measurement error in the European Prospective Investigation into Cancer and Nutrition was evaluated. A two-level, random-effects model was used. Evaluation of macronutrient densities revealed that energy has a considerable effect on the calibration model, leading to ICC values larger than those for the absolute intakes. Given the shrinkage of the within-center variability, a sizable increase in the ICC was observed for protein in men and women (0.48 and 0.54, respectively) and carbohydrates in men (0.41). Results suggest that the effect of calibration on macronutrient intake variability is greater for the within-cohort component, thus increasing the relative importance of the between-cohort component. After calibration, the two components had a similar weight. This observation has important implications for the analysis of multicenter studies because the between-cohort component provides a large part of the overall heterogeneity.


A novel oxygen-sensitive potassium current in rat carotid body type I cells.
1. Hypoxic stimuli depolarize carotid body type I cells causing voltage-gated calcium influx. This study investigates the cause of this membrane depolarization. Isolated type I cells from neonatal (11-16 day) rat carotid bodies were used in the experiments. 2. Tetraethylammonium (TEA; 10 mM), 1 and 5 mM 4-aminopyridine (4-AP) and 20 nM charybdotoxin all failed to evoke a significant rise in [Ca2+]i. Similarly, in perforated patch whole-cell recordings, a combination of 10 mM TEA and 5 mM 4-AP failed to depolarize type I cells. 3. In type I cells voltage clamped at -70 mV, anoxia evoked a small inward current under control conditions, but had no effect in the absence of pipette and extracellular K+. 4. Anoxia decreased resting membrane conductance from 322 to 131 pS. The anoxia-sensitive current (measured using voltage ramps from -100 to -40 mV) had a reversal potential of -89 mV in 4.5 mM Ko+ and -66 mV in 20 mM Ko+, indicating that this current was carried principally by potassium ions. In contrast, 10 mM TEA + 5 mM 4-AP had little effect on the current-voltage relationship of the cells over the same range. 5. This O2-sensitive K+ conductance showed only mild outward rectification over the range -90 to +30 mV, which could be approximated by the Goldman-Hodgkin-Katz current equation. In addition, there was no time-dependent activation or inactivation of membrane currents elicited by voltage steps in the range -100 to -30 mV. 6. The O2-sensitive K+ conductance was inhibited by graded reductions in PO2 to 40 Torr and below, with a K1/2 of about 12 Torr. 7. The data suggest that hypoxia depolarizes type I cells principally through the inhibition of a small voltage-insensitive resting (or background) K+ conductance, and not through the inhibition of voltage-gated TEA and 4-AP-sensitive K+ channels (e.g. maxi-K or KO2 channels), as has been previously suggested.


Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system.
In our search for genes associated with gastric cancer progression, we identified macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, as an overexpressed gene in gastric tumor tissues. Expression analysis of MIC-1 in gastric tumor tissues revealed a specific expression in gastric cancer cells, and this expression level was well correlated with invasive potential in various human gastric cancer cell lines. Stable transfection of MIC-1 into SNU-216, a human gastric cancer cell line, significantly increased its invasiveness. The overexpression of MIC-1 into SNU-216 cells significantly increased the activity of urokinase-type plasminogen activator (uPA), and the expressions of uPA and urokinase-type plasminogen activator receptor (uPAR). Similarly, the stimulation of gastric cancer cell lines with purified recombinant MIC-1 dose-dependently increased cell invasiveness, uPA activity, and uPA and uPAR expression. However, MIC-1 did not significantly suppress the proliferation of gastric cancer cell lines. We also found that the stimulation of human gastric cell lines with recombinant MIC-1 strongly induced activation of mitogen-activated protein kinase kinase-1/2 and extracellular signal-regulated kinase-1/2. Additional analysis revealed that PD98059, a selective inhibitor of mitogen-activated protein kinase kinase-1/2, suppressed not only gastric cancer cell invasiveness and uPA activity, but also the mRNA expressions of uPA and uPAR, as induced by recombinant MIC-1. Our results indicate that MIC-1 may contribute to the malignant progression of gastric cancer cells by inducing tumor cell invasion through the up-regulation of the uPA activation system via extracellular signal-regulated kinase-1/2-dependent pathway.


Today's Mistakes and Tomorrow's Wisdom in Endoscopic Imaging of Barrett's Esophagus.
Esophageal adenocarcinoma (EAC) is one of the main causes of cancer-related deaths worldwide and its incidence is rising. Barrett's esophagus (BE) can develop low- and high-grade dysplasia which can progress to EAC overtime. The golden standard to detect dysplastic BE (DBE) or EAC is surveillance with high-definition white-light endoscopy (HD-WLE) and random biopsies according to the Seattle protocol. However, this method is time-consuming and associated with a remarkable miss rate. Therefore, there is great need for the development of novel reliable techniques to optimize surveillance strategies and improve detection rates. Optical chromoendoscopy (OC) techniques like narrow-band imaging have shown improved detection of DBE and EAC compared to HD-WLE and random biopsies. Most recent OC techniques, including the iSCAN optical enhancement system and linked color imaging, showed improved characterization of DBE and EAC retrospectively. Fluorescence molecular endoscopy (FME) presented promising results to highlight DBE and EAC. Moreover, with the establishment of well-performing delineation computer-aided detection (CAD) algorithms and the first real-time CAD system for EAC, we expect clinical application of CAD in the near future. Despite impressive progress made in the development of advanced endoscopic techniques, combined HD-WLE/OC followed by random biopsies remains the golden standard for BE surveillance. Surveillance depends on appropriate mucosal cleansing, sufficient inspection time, and competence of the performing gastroenterologist to improve detection of EAC. In addition, to facilitate the clinical implementation of advanced endoscopic techniques, multicenter prospective clinical studies are demanded for OC and FME. Meanwhile, further optimization of CAD algorithms, the education of gastroenterologists, and analysis of the interaction between the clinician and the computer should be performed.


GEMBASSY: an EMBOSS associated software package for comprehensive genome analyses.
The popular European Molecular Biology Open Software Suite (EMBOSS) currently contains over 400 tools used in various bioinformatics researches, equipped with sophisticated development frameworks for interoperability and tool discoverability as well as rich documentations and various user interfaces. In order to further strengthen EMBOSS in the fields of genomics, we here present a novel EMBOSS associated software (EMBASSY) package named GEMBASSY, which adds more than 50 analysis tools from the G-language Genome Analysis Environment and its Representational State Transfer (REST) and SOAP web services. GEMBASSY basically contains wrapper programs of G-language REST/SOAP web services to provide intuitive and easy access to various annotations within complete genome flatfiles, as well as tools for analyzing nucleic composition, calculating codon usage, and visualizing genomic information. For example, analysis methods such as for calculating distance between sequences by genomic signatures and for predicting gene expression levels from codon usage bias are effective in the interpretation of meta-genomic and meta-transcriptomic data. GEMBASSY tools can be used seamlessly with other EMBOSS tools and UNIX command line tools. The source code written in C is available from GitHub (https://github.com/celery-kotone/GEMBASSY/) and the distribution package is freely available from the GEMBASSY web site (http://www.g-language.org/gembassy/).


Gene regulation of alpha4beta2 nicotinic receptors: microarray analysis of nicotine-induced receptor up-regulation and anti-inflammatory effects.
alpha4beta2 Nicotinic acetylcholine receptors play an important role in the reward pathways for nicotine. We investigated whether receptor up-regulation of alpha4beta2 nicotinic acetylcholine receptors involves expression changes for non-receptor genes. In a microarray analysis, 10 muM nicotine altered expression of 41 genes at 0.25, 1, 8 and 24 h in halpha4beta2 SH-EP1 cells. The maximum number of gene changes occurred at 8 h, around the initial increase in (3)[H]-cytisine binding. Quantitative RT-PCR corroborated gene induction of endoplasmic reticulum proteins CRELD2, PDIA6, and HERPUD1, and suppression of the pro-inflammatory cytokines IL-1beta and IL-6. Nicotine suppresses IL-1beta and IL-6 expression at least in part by inhibiting NFkappaB activation. Antagonists dihydro-beta-erythroidine and mecamylamine blocked these nicotine-induced changes showing that receptor activation is required. Antagonists alone or in combination with nicotine suppressed CRELD2 message while increasing alpha4beta2 binding. Additionally, small interfering RNA knockdown of CRELD2 increased basal alpha4beta2 receptor expression, and antagonists decreased CRELD2 expression even in the absence of alpha4beta2 receptors. These data suggest that endoplasmic reticulum proteins such as CRELD2 can regulate alpha4beta2 expression, and may explain antagonist actions in nicotine-induced receptor up-regulation. Further, the unexpected finding that nicotine suppresses inflammatory cytokines suggests that nicotinic alpha4beta2 receptor activation promotes anti-inflammatory effects similar to alpha7 receptor activation.


Specificity of IgE antibodies to sequential epitopes of hen's egg ovomucoid as a marker for persistence of egg allergy.
Approximately two-thirds of egg-allergic infants become tolerant within the first 5 years of life. We sought (1) to compare the recognition of sequential (linear) and conformational binding sites of ovomucoid, ovalbumin and ovotransferrin, by IgE antibodies of children with persistent and transient egg allergy, (2) to identify immunodominant IgE-and IgG-binding epitopes of ovomucoid, and (3) to compare epitope-specificity of IgE antibodies between patients with differing natural histories of egg allergy. Using immunodot-blots or ImmunoCAPs, IgE-antibodies against conformational (native) and sequential (reduced and alkylated) egg proteins were determined at the time of clinical reactivity in patients who retained their allergy and in those who developed clinical tolerance. IgE- and IgG-binding epitopes were mapped for ovomucoid using overlapping decapeptides on SPOTs membranes. Recognition of the major IgE-binding epitopes were compared between patients with differing natural histories of egg allergy. The patients with long-lasting egg allergy had a higher concentrations of IgE antibodies against sequential and native ovomucoid and ovalbumin than the children who subsequently gained tolerance (P < 0.01). Four major IgE-binding epitopes were identified in ovomucoid at amino acid 1-10, 9-20, 47-56, and 113-124. IgE antibodies of all seven patients with persistent egg allergy recognized these epitopes whereas none of the 11 children who outgrew their egg allergy did so. Patients with persistent egg allergy develop IgE antibodies against more sequential and conformational epitopes of ovomucoid and ovalbumin. The presence of serum IgE antibodies to specific sequential epitopes of ovomucoid may be used as a screening instrument for persistent egg allergy.


Plasma carotenoids and prostate cancer: a population-based case-control study in Arkansas.
Carotenoids possess antioxidant properties and thus may protect against prostate cancer. Epidemiological studies of dietary carotenoids and this malignancy were inconsistent, partially due to dietary assessment error. In this study, we aimed to investigate the relation between plasma concentrations of carotenoids and the risk of prostate cancer in a population-based case-control study in Arkansas. Cases (n = 193) were men with prostate cancer diagnosed in 3 major hospitals, and controls (n = 197) were matched to cases by age, race, and county of residence. After adjustment for confounders, plasma levels of lycopene, lutein/zeaxanthin, and beta-cryptoxanthin were inversely associated with prostate cancer risk. Subjects in the highest quartile of plasma lycopene (513.7 microg/l) had a 55% lower risk of prostate cancer than those in the lowest quartile (140.5 microg/l; P trend = 0.042). No apparent association was observed for plasma alpha-carotene and beta-carotene. Further adjustment for the other 4 carotenoids did not materially alter the risk estimates for plasma lycopene, lutein/zeaxanthin, and beta-cryptoxanthin but appeared to result in an elevated risk with high levels of plasma alpha-carotene and beta-carotene. The results of all analyses did not vary substantially by age, race, and smoking status. This study added to the emerging evidence that high circulating levels of lycopene, lutein/zeaxanthin, and beta-cryptoxanthin are associated with a low risk of prostate cancer.


Titration of sodium channels in canine gastric mucosa.
Net Na+ flux from mucosa to lumen, potential difference, and volume and plasma protein outputs were measured in vagally denervated, separated pouches of the dog's oxyntic or pyloric glandular mucosa when the pouches were irrigated with Na+-free solutions whose pH ranged from 1.5 to 12.2. The apparent permeability to Na+(P'Na) was calculated. P'Na is lowest when the mucosa is bathed with acid and increases 2- to 3-fold when the pH is raised to 10. In the range of pH 10.0--11.2 P'Na is greater by an order of magnitude, but volume output is small, and no plasma proteins are shed. When the pH is above 11.2 there is an abrupt increase in P'Na, and the mucosa sheds a large volume of fluid containing plasma proteins. The change effected by raising the pH to the range of 10.0--11.2 occurs within 10 sec, and it is reversible. The change effected by raising the pH above 11.2 also occurs within 10 sec, and it is partly reversible.


Beneficial effects of conjugated linoleic acid and exercise on bone of middle-aged female mice.
Conjugated linoleic acids (CLA) are a group of polyunsaturated fatty acids that has recently been shown to have several beneficial effects on different diseases, including prevention of bone loss. The important feature of CLA is to reduce fat mass, thereby reducing body weight significantly. Although loss of body weight is known to increase bone loss, there is increasing evidence that CLA maybe beneficial to bone. Another factor that can reduce body weight is exercise (EX). It is well established that moderate EX stimulates bone formation. In this study, we analyzed the changes in bone using pQCT densitometry in middle-aged C57Bl/6 mice fed CLA (0.5%) and/or exercised. Twelve-month-old mice were divided into the following groups: group 1, corn oil, sedentary (CO SED); group 2, corn oil, exercise (CO EX); group 3, CLA, sedentary (CLA SED); and group 4, CLA, exercise (CLA EX). Mice were maintained in the respective experimental regimens for 10 weeks, after which mice were scanned using DEXA and killed. The lumbar vertebrae, femur, and tibia were analyzed using pQCT densitometry. CLA, when given alone or in combination with EX, significantly reduced body weight and increased lean mass. CLA treatment also significantly increased bone mass. Further, additional increase in bone mass was observed in mice treated with a combination of CLA and EX in almost all the bone sites analyzed. We conclude that CLA, when consumed as a dietary supplement along with moderate treadmill EX, significantly increases bone mass in middle-aged female mice.


Predictors of maternal language to infants during a picture book task in the home: Family SES, child characteristics and the parenting environment.
This study investigated the contribution of child characteristics and parenting environment to the relationship between family SES/demographic characteristics and maternal language to infants.1157 children were drawn from a representative sample of 1292 infants born to mothers in rural Appalachian counties and rural counties in southern minority U.S. communities. Mothers and their 6-8 month old babies were videotaped at home while talking about a wordless picture book. Mothers' language output and complexity were analyzed. Child temperament, age, and parenting environment (knowledge of child development and observed mother-child engagement) were predictors of maternal language. Furthermore, their inclusion reduced the magnitude of the association between demographic characteristics and maternal language. Tests of mediation suggested that the parenting environment partially mediates the relationship between SES/demographic characteristics and maternal language. Findings are discussed with respect to identifying proximal processes that explain how SES may exert its influence on the language of young children.


Secondary failure of platelet recovery after hematopoietic stem cell transplantation.
After primary recovery of platelet counts after transplantation, there can be a late persistent decline called secondary failure of platelet recovery (SFPR), which may occur although the counts of other cell lineages remain within the normal range. SFPR was defined as a decline of platelet counts below 20,000/microL for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts > or = 50,000/microL without transfusions for 7 consecutive days after hematopoietic stem cell transplantation (HSCT). The study population consisted of 2871 consecutive patients receiving transplants from January 1990 to March 1997. After primary recovery of platelet counts, SFPR not due to relapse of the underlying disease was observed in 285 of 1401 (20%) patients undergoing allogeneic transplantation and 36 (8%) of 444 patients undergoing autologous transplantation, with a median time of onset after transplantation at day 63 (range, day 21-156) and day 44 (range, day 24-89), respectively. Concomitant neutropenia was seen in 57 (20%) of 285 patients undergoing allogeneic HSCT and 7 (19%) of 36 patients undergoing autologous HSCT with SFPR. By multivariable analysis, the following were factors significantly associated with SFPR after allogeneic HSCT: a transplant from an unrelated donor; a graft-versus-host disease (GVHD) prophylaxis other than methotrexate and cyclosporine; development of grade 2 through 4 acute GVHD; impaired renal or liver function; conditioning with the combination of busulfan, cyclophosphamide, and total body irradiation; stem cell dose; and infections. Cytomegalovirus infection after engraftment and source of stem cells were the only significant risk factors after autologous HSCT. The hazard rate of death was significantly higher in patients who experienced SFPR (hazard ratio = 2.6 for allogeneic HSCT; hazard ratio = 2.2 for autologous HSCT). SFPR was associated with serious complications and poor outcome after transplantation. The identification of the characteristics and risk factors for SFPR could improve patient counseling and management and lead to the design of effective treatment strategies.


Extensive ribosomal DNA amplification during Andean common bean (Phaseolus vulgaris L.) evolution.
The extent of 5S and 45S ribosomal DNA (rDNA) variation was investigated in wild and domesticated common beans (Phaseolus vulgaris) chosen to represent the known genetic diversity of the species. 5S and 45S rDNA probes were localized on mitotic chromosomes of 37 accessions by fluorescent in situ hybridization (FISH). The two 5S rDNA loci were largely conserved within the species, whereas a high variation in the number of 45S rDNA loci and changes in position of loci and number of repeats per locus were observed. Domesticated accessions from the Mesoamerican gene pool frequently had three 45S rDNA loci per haploid genome, and rarely four. Domesticated accessions from Andean gene pool, particularly from the race Peru, showed six, seven, eight or nine loci, but seven loci were found in all three races of this gene pool. Between three and eight loci were observed in accessions resulting from crosses between Andean and Mesoamerican genotypes. The presence of two to eight 45S rDNA loci in wild common beans from different geographic locations indicates that the 45S rDNA amplification observed in the Andean lineage took place before domestication. Our data suggest that ectopic recombination between terminal chromosomal regions might be the mechanism responsible for this variation.


Facile synthesis of sponge-like Ni3N/NC for electrocatalytic water oxidation.
Sponge-like Ni3N/NC was prepared through a facile approach and was examined as a catalyst for the oxygen evolution reaction (OER). This material can efficiently catalyze water oxidation to reach a current density of 10 mA cm-2 with a small overpotential of 310 mV in 1.0 M KOH aqueous solution. The high efficiency can be attributed to the good electronic conductivity, large specific surface area and fast mass diffusion ability of Ni3N/NC.


What leads to failure of joint-preserving surgery for ankle osteoarthritis?: when this surgery fails, what next?
This article discusses the lack of scientific evidence regarding the treatment of failed joint-preserving surgery. Most of the concepts of treatment derive from treatment modalities in trauma and orthopedic surgery. The main question for the foot and ankle specialist is whether the joint can be salvaged. The definition of failure is difficult. Therefore pain reported by the patient is the main symptom that dictates the course of treatment. Whenever possible the joint should be maintained. However, if pain is associated with global radiographic osteoarthritis, total ankle replacement or fusions are the only means to solve the problem.


SAMHD1's protein expression profile in humans.
The deoxynucleoside triphosphate triphosphohydrolase and 3' → 5' exonuclease SAMHD1 restricts HIV-1 infection in noncycling hematopoietic cells in vitro, and SAMHD1 mutations are associated with AGS. Little is known about the in vivo expression and functional regulation of this cellular factor. Here, we first assessed the SAMHD1 protein expression profile on a microarray of 25 human tissues from >210 donors and in purified primary cell populations. In vivo, SAMHD1 was expressed in the majority of nucleated cells of hematopoietic origin, including tissue-resident macrophages, DCs, pDCs, all developmental stages of thymic T cells, monocytes, NK cells, as well as at lower levels in B cells. Of note, SAMHD1 was abundantly expressed in HIV target cells residing in the anogenital mucosa, providing a basis for its evaluation as a cellular factor that may impact the efficiency of HIV transmission. Next, we examined the effect of the activation status and proinflammatory cytokine treatment of cells on expression and phosphorylation of SAMHD1. Activated, HIV-susceptible CD4(+) T cells carried pSAMHD1(T592), whereas resting CD4(+) T cells and macrophages expressed the unphosphorylated protein with HIV-restrictive activity. Surprisingly, stimulation of these primary cells with IFN-α, IFN-γ, IL-4, IL-6, IL-12, IL-18, IL-27, or TNF-α affected neither SAMHD1 expression levels nor threonine 592 phosphorylation. Only IL-1β moderately down-regulated SAMHD1 in activated CD4(+) T cells. Taken together, this study establishes the first cross-sectional protein expression profile of SAMHD1 in human tissues and provides insight into its cell cycle-dependent phosphorylation and unresponsiveness to multiple proinflammatory cytokines.


Positive Clinical Outcomes Are Synergistic With Positive Educational Outcomes When Using Telehealth Consulting in General Practice: A Mixed-Methods Study.
The use of telehealth technology to enable real-time consultations between patients and specialist services (to whom travel may be an impediment to the patient's care) has recently been encouraged in Australia through financial incentives. However, the uptake has been both fragmented and inconsistent. The potential benefits for patients include access to a broader range of specialist referral services, cost and time saving, and more rapid access to specialist services and a continuum of care through the triangulation of interaction between patient, primary health care providers (general practitioners and nurses), and specialists. Enhanced broadband connectivity and higher-grade encryption present an opportunity to trial the use of telehealth consulting as an intrinsic element of medical education for both medical students and doctors-in-training within rural practices and Aboriginal Medical Services. This paper discusses the reported, and varied, benefits of telehealth consulting arising from a multisite trial in New South Wales, Australia. The purpose of this study is to encourage the use of selected telehealth consultations between patients in a primary care setting with a specialist service as an integral aspect of medical education. The trial closely followed the protocol developed for this complex and multiaspect intervention. This paper discusses one aspect of the research protocol--using telehealth consultations for medical education--in detail. Qualitative and quantitative analyses were conducted. In the quantitative analysis, free-text comments were made on aspects of Telehealth Consulting for the patient, concerning the quality of the interactions, and the time and cost saving, and also on the leaning opportunities. Students commented that their involvement enhanced their learning. All respondents agreed or strongly agreed that that the interpersonal aspects were satisfactory, with some brief comments supporting their views. In the analysis of the qualitative data, five themes emerged from the analyses concerning the educational benefits of Telehealth Consulting for different levels of learners, while three themes were identified concerning clinical benefits. The results demonstrated strong synergies between the learning derived from the telehealth consulting and the clinical benefits to the patient and clinicians involved.


Notification of a family history of breast cancer: issues of privacy and confidentiality.
Little information is available about notifying individuals with a family history of cancer about their risk of cancer. With the recent identification of BRCA1, an important predisposition gene for breast and ovarian cancer, genetic testing is becoming available to high-risk women and their families. Some of these individuals, may not be aware of their family history and may be notified of their family history by medical personnel or biomedical investigators. This disclosure could be detrimental to the individual by changing their perception of risk, sense of privacy, or psychosocial well-being. Members of 544 breast cancer families are currently being contacted as part of an epidemiologic follow-up study at the University of Minnesota. Some family members were unaware of their relative's diagnosis and therefore, notification occurred when they were contacted by study personnel. To determine the impact of risk notification in this context, 376 male and female relatives of 160 breast cancer probands were surveyed to assess their prior knowledge of their family history of cancer, issues relating to study participation, and their concerns regarding the possibility of developing cancer. Following a telephone interview about family history, family members were administered a short, open-ended questionnaire. The majority of individuals (82%) were blood relatives of the proband and 71% were either first- or second-degree relatives. A proportion of blood relatives (24%) were not aware of their family history of breast cancer. More blood relatives (76%) than nonblood relatives (62%, P < 0.01) were aware of their family history. 43 respondents (12%) expressed specific concerns about participating in the large genetic follow-up study and 16 comments concerned privacy issues. Neither the reasons for participation nor an individual's concern about developing cancer was associated with gender of the respondent, relationship to the proband, or awareness of breast cancer in the family. Interestingly, individuals who were notified about their family history through the large follow-up study were no more likely than other family members to be more concerned about developing cancer. Understanding the privacy and psychosocial issues of family members who are informed about a family history of breast cancer may aid in developing appropriate guidelines for notification. Risk notification in this setting does not appear to have a significant impact on these family members.


Functional reinnervation and development of supersensitivity to NE after renal denervation in rats.
The time course for functional reinnervation and development of supersensitivity to norepinephrine (NE) in the denervated rat kidney was studied using an in situ kidney preparation perfused at constant flow. Changes in perfusion pressure were measured during renal nerve stimulation (RNS, 1-10 Hz) and after administration of NE (1-50 ng, ia) up to 8 wk after unilateral renal denervation or a sham operation. During the first 2 wk after denervation, supersensitivity to NE was present, but there was no response to RNS. Between 24 and 32 days after denervation, RNS produced responses averaging 40% of control in denervated kidneys and supersensitivity to NE was still present. A fluorescence assay was used to determine that the NE concentration in kidneys 24-32 days after denervation was less than 30% of that found in control kidneys. At 8 wk, average responses to RNS in denervated kidneys were not significantly different from innervated kidneys, while supersensitivity to NE was still present. These results indicate that functional reinnervation of the renal vasculature begins to occur between 14 and 24 days after denervation, and that complete return of function may occur by 8 wk. The response to RNS during reinnervation appears to be due to a combination of regeneration of nerve fibers and denervation supersensitivity to NE.


In vitro effect of arsenical compounds on glutathione-related enzymes.
The mechanism of arsenic toxicity is believed to be due to the ability of arsenite (As(III)) to bind protein thiols. Glutathione (GSH) is the most abundant cellular thiol, and both GSH and GSH-related enzymes are important antioxidants that play an important role in the detoxification of arsenic and other carcinogens. The effect of arsenic on the activity of a variety of enzymes that use GSH has been determined using purified preparations of glutathione reductase (GR) from yeast and bovine glutathione peroxidase (GPx) and equine glutathione S-transferase (GST). The effect on enzyme activity of increasing concentrations (from 1 microM to 100 mM) of commercial sodium arsenite (As(III)) and sodium arsenate (As(V)) and a prepared arsenic(III)-glutathione complex [As(III)(GS)(3)] and methylarsenous diiodide (CH(3)As(III)) has been examined. GR, GPx, and GST are not sensitive to As(V) (IC(50) > 50 mM), and none of the enzymes are inhibited or activated by physiologically relevant concentrations of As(III), As(III)(GS)(3), or CH(3)As(III), although CH(3)As(III) is the most potent inhibitor (0.3 mM < IC(50) < 1.5 mM). GPx is the most sensitive to arsenic treatment and GST the least. Our results do not implicate a direct interaction of As with the glutathione-related enzymes, GR, GPx, and GST, in the mechanism of arsenic toxicity. CH(3)As(III) is the most effective inhibitor, but it is unclear whether this product of arsenic metabolism is produced at a sufficiently high concentration in critical target tissues to play a major role in either arsenic toxicity or carcinogenesis.


Can new, improvised Visual Prostate Symptom Score replace the International Prostate Symptom Score? Indian perspective.
Visual Prostate Symptom Score (VPSS) was introduced to overcome the drawbacks of the International Prostate Symptom Score (IPSS). However, this score also has potential for improvement. The primary objective of this study was to evaluate the utility of VPSS in patients with benign enlarged prostate (BEP) after uroflowmetric validation of the stream component. The secondary objective was to improve VPSS by adding a new severity grading and to assess if the "new upgraded VPSS" can replace IPSS in terms of ease of completion without assistance and the time taken. Of 115 patients, 42.60% of them were of the age group between 61-70 years; mean ± standard deviation age was 64.75 years ± 8.042 (range 48-90 years). Nineteen (16.52%) patients, who had education level ≥10th grade completed IPSS without assistance. One hundred and eight (93.91%) patients completed VPSS without assistance (P = 0.000). None of those (0/6) with no formal education (but able to read and write) could complete the IPSS without assistance, whereas 66.67% completed the VPSS without assistance. Six minutes and two minutes was the average time taken to complete IPSS (4-10 min) and VPSS (1-3 min), respectively. Responses to different variables of VPSS were statistically significant (P < 0.001) compared to the IPSS. Correlation between the severity grading of the two scores was statistically significant (P < 0.001), with a statistically significant positive correlation between VPSS and IPSS (r = +0.582, P < 0.001). The new severity grading system developed on par with the IPSS, improvising the existing VPSS, showed statistically significant positive correlation to the IPSS (r = +0.587, P < 0.001). VPSS correlated well with IPSS. The "new improvised VPSS" developed by incorporating severity grading is a potential tool that can replace IPSS by overcoming its limitations.


Ion pair and solvation dynamics of [Bmim][BF4 ] + water system.
In this work, 1-butyl-3-methylimidazolium tetrafluoroborate/water mixtures were analysed over the whole water composition (xw ) in order to study the rotational and translational behaviour of the ions. We employed a multinuclear NMR approach to determine anion/cation/water diffusion coefficients and longitudinal relaxation rates at different water content. In neat ionic liquids (IL), the cation diffuses faster than the anion, and at low xw , anions and cations share almost the same diffusion coefficient, but above a critical water concentration, the anion begins to diffuse faster than the cation. We identified this composition as approximately 10% xw where the ions share the same diffusion coefficient. We found that the water at this composition seems to have a much more dramatic effect in the rotational diffusion of the anion that decreases substantially and approaches that of the anion in the diluted IL. Translational and rotational dynamics of the ions suggest that water is first incorporated in pockets in the nanostructure of the IL allowing the ions to maintain most of the cation/anion interactions present in neat IL but already disrupting some anion/cation interactions due to preferential interaction with the anion. HOESY and NOESY data show that water displays contacts both with the cation and the anion in a positive NOE regime in contrary to the negative regime found for the cation/anion and cation/cation cross-relaxation. This is in accordance with the high relative diffusion coefficient of water and suggests that water molecules can exchange between preferential location sites that allow water to maintain contacts both with the anion and cation.


Fatty acid signals in Bacillus megaterium are attenuated by cytochrome P-450-mediated hydroxylation.
In previous publications [English, Hughes and Wolf (1994) J. Biol. Chem. 269, 26836-26841; English, Hughes and Wolf (1996) Biochem. J. 316, 279-283], we have demonstrated that peroxisome proliferators and non-steroidal anti-inflammatory drugs are inducers of the cytochrome P-450BM-3 gene in Bacillus megaterium ATCC14581. Their mechanism of action involves binding to and subsequent displacement of the transcriptional repressor, Bm3R1, from its operator site, which results in the activation of cytochrome P-450BM-3 gene transcription. We now present evidence that the branched-chain fatty acid, phytanic acid, is a potent inducer of cytochrome P-450BM-3. We have also observed that phytanic acid and peroxisome proliferators are inducers of Bm3R1 protein accumulation and associated DNA-binding activity. In contrast, several barbiturates, although capable of inducing cytochrome P-450BM-3 and Bm3R1 gene transcription, were unable to induce the Bm3R1 protein. We also demonstrate that cytochrome P-450BM-3 readily oxidizes phytanic acid, and provide evidence that, although the omega-1 hydroxy acid derivatives of phytanic acid can associate with Bm3R1, they do so with an affinity two orders of magnitude lower than the unmodified fatty acid. As a consequence, the ability of the hydroxylated product to induce cytochrome P-450BM-3 gene expression in vivo is markedly reduced. These data collectively suggest that metabolism of fatty acids by cytochrome P-450BM-3 leads to an attenuation of their ability to activate the transcription of the BM-3 operon. This work places the action of bacterial fatty acid hydroxylases in an autoregulatory loop where they may be responsible for the inactivation or clearance of the inducing fatty acid signal.


Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow.
Breast cancer cells frequently home to the bone marrow, where they may enter a dormant state before forming a bone metastasis. Several members of the interleukin-6 (IL-6) cytokine family are implicated in breast cancer bone colonization, but the role for the IL-6 cytokine leukaemia inhibitory factor (LIF) in this process is unknown. We tested the hypothesis that LIF provides a pro-dormancy signal to breast cancer cells in the bone. In breast cancer patients, LIF receptor (LIFR) levels are lower with bone metastases and are significantly and inversely correlated with patient outcome and hypoxia gene activity. Hypoxia also reduces the LIFR:STAT3:SOCS3 signalling pathway in breast cancer cells. Loss of the LIFR or STAT3 enables otherwise dormant breast cancer cells to downregulate dormancy-, quiescence- and cancer stem cell-associated genes, and to proliferate in and specifically colonize the bone, suggesting that LIFR:STAT3 signalling confers a dormancy phenotype in breast cancer cells disseminated to bone.


Low-density lipoprotein cholesterol reduction and goal achievement with ezetimibe/simvastatin versus atorvastatin or rosuvastatin in patients with diabetes, metabolic syndrome, or neither disease, stratified by National Cholesterol Education Program risk category.
Patients with diabetes mellitus (DM) and metabolic syndrome are at increased risk of coronary heart disease (CHD). Studies have shown differential statin efficacy on low-density lipid cholesterol (LDL-C) by CHD risk strata. The aim of this study was to evaluate the consistency of effect with ezetimibe/simvastatin (E/S) combination therapy, atorvastatin, or rosuvastatin in patients with DM, metabolic syndrome, or neither condition (No DM/metabolic syndrome), stratified by the National Cholesterol Education Panel Adult Treatment Panel III (NCEP ATP III) CHD risk group. Post hoc analyses of 2 multicenter, double-blind, randomized, 6-week studies comparing E/S 10/10, 10/20, 10/40, or 10/80 mg with either atorvastatin 10, 20, 40, or 80 mg, or rosuvastatin 10, 20, or 40 mg. Treatments were compared by pooling across all doses for LDL-C reduction and NCEP LDL-C goal attainment in patients with DM, metabolic syndrome without DM, or No DM/metabolic syndrome across NCEP CHD risk strata. NCEP LDL-C goal attainment was lowest in the high-risk group with atherosclerotic vascular disease (12-64%) and greatest in the moderate and low-risk groups (84-100%). In contrast, LDL-C reduction was generally similar irrespective of disease or risk subgroup. All treatments were generally well tolerated, with overall similar safety regardless of disease and risk level. In these studies, CHD risk strata were inversely related to the likelihood of attaining NCEP LDL-C goals, but did not appear to affect the percentage LDL-C change from baseline. This demonstrates the need for especially aggressive cholesterol lowering necessary to reach the lower LDL-C goal for high-risk patients.


Functional outcomes in children with osteonecrosis secondary to treatment of developmental dysplasia of the hip.
Osteonecrosis of the femoral head is a major potential complication following the treatment of developmental dysplasia of the hip. It remains unclear if the radiographic changes associated with osteonecrosis are clinically relevant. In the present cross-sectional study, we determined the relationship between morphological changes on radiographs (classified with use of the Bucholz-Ogden system) and health-related quality of life (assessed with the Health Utilities Index Mark 3 [HUI3]; maximum score, 1), physical function (assessed with the Activities Scale for Kids [ASK]; maximum score, 100), and hip function (assessed with the Children's Hospital Oakland Hip Evaluation Scale [CHOHES]; maximum score, 100). The study group included seventy-two children (mean age, 14 ± 2.5 years) with a diagnosis of osteonecrosis of the hip secondary to the treatment of developmental dysplasia of the hip. Patient assessments were standardized (intraclass correlation coefficient, ≥0.93). Radiographs were graded by three experts according to consensus. Analyses were adjusted for the number of previous surgical procedures on the hip and for the severity of residual hip dysplasia. The median ASK score was 97 (interquartile range, 93 to 100), the median CHOHES score was 86 (interquartile range, 77 to 96), and the median HUI3 score was 1 (interquartile range, 0.9 to 1). The ASK summary scores were nearly equal (median, >90) across all radiographic grades. Adjusted mean scores showed a downward shift with worse radiographic grades. The ASK scores (p = 0.004) and CHOHES scores (p = 0.006) differed across radiographic grades, with Bucholz-Ogden grade-I and II hips demonstrating significantly better scores than grade-III and IV hips. Osteonecrosis secondary to the treatment of developmental dysplasia of the hip is a relatively benign condition in children and teenagers. While it was associated with limited hip function, it was not associated with physical disability. However, we speculate that this function will decline with increasing age. With regard to clinical outcome, Bucholz-Ogden grade-I hips are similar to grade-II hips and grade-III hips are similar to grade-IV hips.


The role of hepatocyte growth factor in corneal wound healing.
Hepatocyte growth factor (HGF) is a glycoprotein produced by mesenchymal cells and operates as a key molecule for tissue generation and renewal. During corneal injury, HGF is primarily secreted by stromal fibroblasts and promotes epithelial wound healing in a paracrine manner. While this mesenchymal-epithelial interaction is well characterized in various organs and the cornea, the role of HGF in corneal stromal and endothelial wound healing is understudied. In addition, HGF has been shown to play an anti-fibrotic role by inhibiting myofibroblast generation and subsequent production of a disorganized extracellular matrix and tissue fibrosis. Therefore, HGF represents a potential therapeutic tool in numerous organs in which myofibroblasts are responsible for tissue scarring. Corneal fibrosis can be a devastating sequela of injury and can result in corneal opacification and retrocorneal membrane formation leading to severe vision loss. In this article, we concisely review the available literature regarding the role of HGF in corneal wound healing. We highlight the influence of HGF on cellular behaviors in each corneal layer. Additionally, we suggest the possibility that HGF may represent a therapeutic tool for interrupting dysregulated corneal repair processes to improve patient outcomes.


Development of a Mobile Laboratory for Sudden Onset Disasters.
Clinical diagnostics in sudden onset disasters have historically been limited. We set out to design, implement, and evaluate a mobile diagnostic laboratory accompanying a type 2 emergency medical team (EMT) field hospital. Available diagnostic platforms were reviewed and selected against in field need. Platforms included HemoCue301/WBC DIFF, i-STAT, BIOFIRE FILMARRAY multiplex rt-PCR, Olympus BX53 microscopy, ABO/Rh grouping, and specific rapid diagnostic tests. This equipment was trialed in Katherine, Australia, and Dili, Timor-Leste. During the initial deployment, an evaluation of FilmArray tests was successful using blood culture identification, gastrointestinal, and respiratory panels. HemoCue301 (n = 20) hemoglobin values were compared on Sysmex XN 550 (r = 0.94). HemoCue WBC DIFF had some variation, dependent on the cell, when compared with Sysmex XN 550 (r = 0.88-0.16). i-STAT showed nonsignificant differences against Vitros 250. Further evaluation of FilmArray in Dili, Timor-Leste, diagnosed 117 pathogens on 168 FilmArray pouches, including 25 separate organisms on blood culture and 4 separate cerebrospinal fluid pathogens. This mobile laboratory represents a major advance in sudden onset disaster. Setup of the service was quick (< 24 hr) and transport to site rapid. Future deployment in fragmented health systems after sudden onset disasters with EMT2 will now allow broader diagnostic capability.


Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.
Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.


Influence of the oxazole ring connection on the fluorescence of oxazoyl-triphenylamine biphotonic DNA probes.
On the basis of our previous work on DNA fluorophores derived from vinylpyridinium-triphenylamine, we explored the structure space around the electron-rich triphenylamine (TP) core by changing the vinyl bond to an oxazole ring. As 2,5-diaryloxazoles are known to be highly fluorescent and efficient two photon absorbers, we synthesized analogues with two different connections of the oxazole to the triphenylamine core: TP-Ox2Py and TP-Ox5Py sets. Since the benzimidazolium group was proven to be more effective in the TP series than the pyridinium, we also synthesized a TP-Ox5Bzim set. The TP-Ox5Py series retains the TP-Py properties: on/off behavior on DNA, good two-photon cross-section and bright staining of nuclear DNA by microscopy under both one or two-photon excitation. On the other hand, the TP-Ox2Py series does not display fluorescence upon binding to DNA. The TP-Ox5Bzim set is fluorescent even in the absence of DNA and displays lower affinity than the corresponding TP-Ox5Py. CD experiments and docking were performed to understand these different behaviors.


Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort.
Although methotrexate (MTX) is the consensual first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), substantial heterogeneity remains with its prescription and dosage, which are often not optimal. To evaluate the symptomatic and structural impact of optimal MTX dose in patients with early RA in daily clinical practice over 2 years. Patients included in the early arthritis ESPOIR cohort who fulfilled the ACR-EULAR (American College of Rheumatology/European League against Rheumatism) criteria for RA and received MTX as a first DMARD were assessed. Optimal MTX dose was defined as ≥10 mg/week during the first 3 months, with escalation to ≥20 mg/week or 0.3 mg/kg/week at 6 months without Disease Activity Score in 28 joints remission. Symptomatic and structural efficacy with and without optimal MTX dose was assessed by generalised logistic regression with adjustment for appropriate variables. Within the first year of follow-up, 314 patients (53%) with RA received MTX as a first DMARD (mean dose 12.2±3.8 mg/week). Only 26.4% (n=76) had optimal MTX dose. After adjustment, optimal versus non-optimal MTX dose was more efficient in achieving ACR-EULAR remission at 1 year (OR 4.28 (95% CI 1.86 to 9.86)) and normal functioning (Health Assessment Questionnaire ≤0.5; OR at 1 year 4.36 (95% CI 2.03 to 9.39)), with no effect on radiological progression. Results were similar during the second year. Optimal MTX dose is more efficacious than non-optimal dose for remission and function in early arthritis in daily practice, with no impact on radiological progression over 2 years.


Phylogeography and support vector machine classification of colour variation in panther chameleons.
Lizards and snakes exhibit colour variation of adaptive value for thermoregulation, camouflage, predator avoidance, sexual selection and speciation. Furcifer pardalis, the panther chameleon, is one of the most spectacular reptilian endemic species in Madagascar, with pronounced sexual dimorphism and exceptionally large intraspecific variation in male coloration. We perform here an integrative analysis of molecular phylogeography and colour variation after collecting high-resolution colour photographs and blood samples from 324 F. pardalis individuals in locations spanning the whole species distribution. First, mitochondrial and nuclear DNA sequence analyses uncover strong genetic structure among geographically restricted haplogroups, revealing limited gene flow among populations. Bayesian coalescent modelling suggests that most of the mitochondrial haplogroups could be considered as separate species. Second, using a supervised multiclass support vector machine approach on five anatomical components, we identify patterns in 3D colour space that efficiently predict assignment of male individuals to mitochondrial haplogroups. We converted the results of this analysis into a simple visual classification key that can assist trade managers to avoid local population overharvesting.


Neuroprotective Effect of Lacosamide on Hypoxic-Ischemic Brain Injury in Neonatal Rats.
Lacosamide (LCM) is an antiepileptic drug that enhances the slow inactivation of sodium channels and modulates collapsin response mediator protein-2. LCM was recently demonstrated to exert a neuroprotective effect in a murine model of traumatic brain injury and status epilepticus. Assuming the same underlying excitotoxicity-related brain injury mechanism, we hypothesized that LCM would have a neuroprotective effect in hypoxic-ischemic brain injury. We divided rats into three groups at each testing session: pre- or postfed with LCM, fed with normal saline, and sham. A hypoxic-ischemic brain injury was induced by subjecting 7-day-old rats to right carotid artery coagulation followed by 2.5 h of exposure to 8% oxygen. The animals were killed on postnatal day 12 to evaluate the severity of brain damage. Open field testing was also performed between week 2 and week 6, and the Morris water maze test was performed in week 7 after hypoxia-ischemia. The incidence of liquefactive cerebral infarction was lower in rats prefed with LCM at 100 mg/kg/dose, with the mortality rate being higher at higher doses (200 and 300 mg/kg/dose). The infarct areas were smaller in LCM-prefed rats in several brain regions including the hemisphere, hippocampus, cortex, and striatum. Spatial learning and memory function were better in LCM-prefed rats (p<0.05). No effect was observed in postfed rats. This study suggests that LCM pretreatment exerts a neuroprotective effect on hypoxia-ischemia in neonatal rats. The obtained results suggest that LCM pretreatment could be used as an effective neuroprotective method for neonates under hypoxic-ischemic conditions including heart surgery.


Evaluation of the effect of topical application of lavender oil on autonomic nerve activity in dogs.
To investigate the effect of topical application of undiluted lavender oil on sympathovagal activity in dogs. 5 healthy adult male Beagles. An ambulatory ECG monitor (Holter recorder) was placed on each dog (day0), and 48-hour ECGs were recorded, beginning at 8:00 the next day (day 1). Lavender oil (0.18 mL) or saline (0.9% NaCl) solution (0.18 mL) was topically applied to the inner pinnas of both ears of all dogs at 8:30, 12:00, 15:30, and 19:00 on day 2. Each trial was duplicated in each dog, with an interval of 3 to 4 days between trials. Spectral indices of heart rate variability, power in the high-frequency range, and the ratio of low-frequency to high-frequency power were calculated as an indirect estimate of autonomic nerve activity. When dogs were treated with lavender oil, the mean heart rate was significantly lower during the period of 19:00 to 22:30 on day 2, compared with the mean heart rate during the same period when dogs were treated with saline solution. On the other hand, high-frequency power during the period of 15:30 to 19:00 was significantly higher when dogs were treated with lavender oil, compared with the high-frequency power during the same period when dogs were treated with saline solution. The study revealed some evidence that topical application of lavender oil affected vagal activity in dogs. However, whether such an effect exists and whether lavender oil has a calming effect on dogs remains equivocal and requires additional investigation.


The Ins and Outs of Anthrax Toxin.
Anthrax is a severe, although rather rare, infectious disease that is caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. The infectious form is the spore and the major virulence factors of the bacterium are its poly-γ-D-glutamic acid capsule and the tripartite anthrax toxin. The discovery of the anthrax toxin receptors in the early 2000s has allowed in-depth studies on the mechanisms of anthrax toxin cellular entry and translocation from the endocytic compartment to the cytoplasm. The toxin generally hijacks the endocytic pathway of CMG2 and TEM8, the two anthrax toxin receptors, in order to reach the endosomes. From there, the pore-forming subunit of the toxin inserts into endosomal membranes and enables translocation of the two catalytic subunits. Insertion of the pore-forming unit preferentially occurs in intraluminal vesicles rather than the limiting membrane of the endosome, leading to the translocation of the enzymatic subunits in the lumen of these vesicles. This has important consequences that will be discussed. Ultimately, the toxins reach the cytosol where they act on their respective targets. Target modification has severe consequences on cell behavior, in particular on cells of the immune system, allowing the spread of the bacterium, in severe cases leading to host death. Here we will review the literature on anthrax disease with a focus on the structure of the toxin, how it enters cells and its immunological effects.


Best method in clinical practice and in research studies to determine left atrial size.
Although the anteroposterior dimension of the left atrium is universally used in clinical practice and research, we hypothesized that it may be an inaccurate surrogate for volume because its use is based on the unlikely assumption that there is a constant relation among atrial dimensions. The following measurements of the left atrium were made at end ventricular systole: (1) M-mode-derived anteroposterior linear dimension from the parasternal long-axis view; (2) digitized planimetry of the left atrial (LA) cavity from the apical 4-chamber view; and (3) digitized planimetry of the LA cavity from the apical 2-chamber view. The following volume calculations were obtained from these digital measurements: (1) volume derived from the M-mode dimension assuming a spherical shape; (2) volume derived from the single plane area-length of apical 4-chamber view, which assumes that LA geometry can be generalized from a single 2-dimensional plane; and (3) volume derived from the biplane method of discs. The correlation coefficient between the M-mode and biplane methods of determining LA volume was r = 0.76. The mean difference (+/-2 SDs) between these methods is -25 +/- 33 ml. The correlation coefficient between the single plane apical 4-chamber and biplane methods of determining LA volume is r = 0.97. The mean difference (+/-2 SDs) between these methods was -5.0 +/- 12 ml, indicating good agreement. The M-mode measure of the left atrium is an inaccurate representation of its size. Two-dimensional-derived LA volumes provide a more accurate measure of the true size of the left atrium and are more sensitive to changes in LA size. When an echocardiographic measure of LA size is made either in an individual patient or as a variable in a research study, the M-mode measure should be avoided.


The impact of diabetes on the labour force participation and income poverty of workers aged 45-64 years in Australia.
To quantify the poverty status and level of disadvantage experienced by Australians aged 45-64 years who have left the labour force due to diabetes in 2010. A purpose-built microsimulation model, Health&WealthMOD2030, was used to estimate the poverty status and level of disadvantage of those aged 45-64 years who prematurely retire from the workforce due to diabetes. A multiple regression model was used to identify significant differences in rates of income poverty and the degree of disadvantage between those out of the labour force due to diabetes and those employed full- or part-time with no diabetes. 63.9% of people aged 45-64 years who were out of the labour force due to diabetes were in poverty in 2010. The odds of being in poverty for those with no diabetes and employed full-time (OR of being in poverty 0.02 95%CI: 0.01-0.04) or part-time (OR of being in poverty 0.10 95%CI: 0.05-0.23) are significantly lower than those for persons not in the labour force due to diabetes. Amongst those with diabetes, those who were able to stay in either full- or part-time employment were as much as 97% less likely to be in poverty than those who had to retire early because of the condition. Sensitivity analysis was used to assess impacts of different poverty line thresholds and key socioeconomic predictors of poverty. This study has shown that having diabetes and not being in the labour force because of this condition significantly increases the chances of living in poverty. Intervening to prevent or delay the onset of diabetes is likely to improve their living standards.


Human DNA polymerase kappa bypasses and extends beyond thymine glycols during translesion synthesis in vitro, preferentially incorporating correct nucleotides.
Human polymerase kappa (polkappa), the product of the human POLK (DINB1) gene, is a member of the Y superfamily of DNA polymerases that support replicative bypass of chemically modified DNA bases (Ohmori, H., Friedberg, E. C., Fuchs, R. P., Goodman, M. F., Hanaoka, F., Hinkle, D., Kunkel, T. A., Lawrence, C. W., Livneh, Z., Nohmi, T., Prakash, L., Prakash, S., Todo, T., Walker, G. C., Wang, Z., and Woodgate, R. (2001) Mol. Cell 8, 7-8; Gerlach, V. L., Aravind, L., Gotway, G., Schultz, R. A., Koonin, E. V., and Friedberg, E. C. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 11922-11927). Polkappa is shown here to bypass 5,6-dihydro-5,6-dihydroxythymine (thymine glycol) generated in two different DNA substrate preparations. Polkappa inserts the correct base adenine opposite thymine glycol in preference to the other three bases. Additionally, the enzyme correctly extends beyond the site of the thymine glycol lesion when presented with adenine opposite thymine glycol at the primer terminus. However, steady state kinetic analysis of nucleotides incorporated opposite thymine glycol demonstrates different misincorporation rates for guanine with each of the two DNA substrates. The two substrates differ only in the relative proportions of thymine glycol stereoisomers, suggesting that polkappa distinguishes among stereoisomers and exhibits reduced discrimination between purines when incorporating a base opposite a 5R thymine glycol stereoisomer. When extending beyond the site of the lesion, the misincorporation rate of polkappa for each of the three incorrect nucleotides (adenine, guanine, and thymine) is dramatically increased. Our findings suggest a role for polkappa in both nonmutagenic and mutagenic bypass of oxidative damage.


Identifying effective intervention components for smoking cessation: a factorial screening experiment.
To identify promising intervention components intended to help smokers to attain and maintain abstinence in their quit smoking attempts. A fully crossed, six-factor randomized fractional factorial experiment. Eleven primary care clinics in southern Wisconsin, USA. A total of 637 adult smokers (55% women, 88% white) motivated to quit smoking who visited primary care clinics. Six intervention components designed to prepare smokers to quit, and achieve and maintain abstinence (i.e. for the preparation, cessation and maintenance phases of smoking treatment): (1) preparation nicotine patch versus none; (2) preparation nicotine gum versus none; (3) preparation counseling versus none; (4) intensive cessation in-person counseling versus minimal; (5) intensive cessation telephone counseling versus minimal; and (6) 16 versus 8 weeks of combination nicotine replacement therapy (nicotine patch + nicotine gum). Seven-day self-reported point-prevalence abstinence at 16 weeks. Preparation counseling significantly improved week 16 abstinence rates (P = .04), while both forms of preparation nicotine replacement therapy interacted synergistically with intensive cessation in-person counseling (P < 0.05). Conversely, intensive cessation phone counseling and intensive cessation in-person counseling interacted antagonistically (P < 0.05)-these components produced higher abstinence rates by themselves than in combination. Preparation counseling and the combination of intensive cessation in-person counseling with preparation nicotine gum or patch are promising intervention components for smoking and should be evaluated as an integrated treatment package.


Absence of epidermal growth factor receptor mutations in cervical cancer.
Epidermal growth factor receptor (EGFR) is overexpressed in the majority of cervical cancers (CCs). Somatic mutations of EGFR have been associated with clinical response to tyrosine kinase inhibitors (TKIs) in lung cancer patients. This study was designed to establish the frequency of EGFR point mutations in patients diagnosed with high-grade squamous intraepithelial lesions (HSIL) and CC. Nine cell lines derived from CC were screened for EGFR mutations in exons 18 through 21. Eighty-nine patient samples derived from invasive CC (n = 80) and HSIL (n = 9) were analyzed for the presence of EGFR mutations in exons 19 and 21. We found no mutations affecting the EGFR kinase domain in exons 18 through 21 in all cell lines tested, and no EGFR mutations were detected in exons 19 and 21 in all 89 human neoplastic samples analyzed. These data indicate that mutations in the EGFR kinase domain are very rare in CC and HSIL. Our results suggest, therefore, that treatment of CC patients with TKIs may not have the same efficacy as seen in patients with lung cancer, and that targeting the EGFR with other inhibitors may be more appropriate.


Use of fibrin glue in the treatment of pilonidal sinus disease: a pilot study.
Pilonidal sinus (PS) disease of the sacrococcigeal region is an acquired condition resulting from penetration of shed hair shafts through the skin. Different types of operations have been described in the letterature. More recently fibrin glue has been used with succesfull. Aim of this study was to assess the effectiveness of fibrin glue for the treatment of pilonidal sinus. Eight patients age ranged 21,8 +/- 6,5 affected by PS disease of sacrococcigeal region were included in this study. All patients undergoing surgical operation under local anaesthesia. Following administration of 1% methylene blue through the main opening, a small vertical elliptical incision is maked including the entire sinus opening and an excision of PS was performed without entering the sinus cavity, removing a minimal amount of subcutaneous tissue. Afterwards the highly concentrated fibrin glue, containing 1,000 U/ml of thrombin was applied to cover the wound. Post-operative pain, analgesic consumption, duration of hospital stay, failure healing, the rate and time of recurrence, time to healing, time to return to work and post-operative complications were recordered. All patients expressed satisfaction with the procedure. Mean hospital stay was 5.4 +/- 2.1 hours. Healing was achieved after 25.8 +/- 13.2 days. The post-operative pain mean score was 3.8 +/- 2.1 in first day, 2,9 +/- 1,8 in third day and 1,3 +/- 0,8 in the seventh day. The mean analgesic consumption per week was 5,6 +/- 3,2 medications. Mean time to return to work was 5,3 +/- 2,1 days. The minimal excision of PS and application of fibrin glue is a non-invasive effective treatment, easy and simple to performe and not associated to recurrences. For these reasons this procedure in our opinion as the first line treatment for pilonidal sinus disease.


HIV risks among injecting drug users in Vietnam: a review of the research evidence.
Injecting drug use plays a critical role in the transmission of HIV in Vietnam. This paper provides a comprehensive review of studies on risks of HIV infection among injecting drug users (IDUs) in Vietnam. Current research evidence shows that the age at which drug initiation starts is becoming younger and the transition time between non-injecting to injecting drug use becoming shorter. The practice of needle sharing and unprotected sex was quite common among the IDUs. Although most of the IDUs generally had good knowledge of HIV transmission routes, most IDUs were not aware of their infection status. Data from a national surveillance programme shows that a third of the IDUs were HIV positive. Amongst all HIV positive cases, almost two-thirds had a history of intravenous drug use. A number of studies have identified a range of risk factors and barriers to minimize the risk of HIV infection in IDUs. This paper discusses these issues and makes recommendations for changes to HIV/AIDS policies, programme interventions as well as future research on the topic.


Contributions of Adaptive Plant Architecture to Transgressive Salinity Tolerance in Recombinant Inbred Lines of Rice: Molecular Mechanisms Based on Transcriptional Networks.
Genetic novelties are important nucleators of adaptive speciation. Transgressive segregation is a major mechanism that creates genetic novelties with morphological and developmental attributes that confer adaptive advantages in certain environments. This study examined the morpho-developmental and physiological profiles of recombinant inbred lines (RILs) from the salt-sensitive IR29 and salt-tolerant Pokkali rice, representing the total range of salt tolerance including the outliers at both ends of the spectrum. Morpho-developmental and physiological profiles were integrated with a hypothesis-driven interrogation of mRNA and miRNA transcriptomes to uncover the critical genetic networks that have been rewired for novel adaptive architecture. The transgressive super-tolerant FL510 had a characteristic small tiller angle and wider, more erect, sturdier, and darker green leaves. This unique morphology resulted in lower transpiration rate, which also conferred a special ability to retain water more efficiently for osmotic avoidance. The unique ability for water retention conferred by such adaptive morphology appeared to enhance the efficacy of defenses mediated by Na+ exclusion mechanism (SalTol-effects) inherited from Pokkali. The super-tolerant FL510 and super-sensitive FL499 had the smallest proportions of differentially expressed genes with little overlaps. Genes that were steadily upregulated in FL510 comprised a putative cytokinin-regulated genetic network that appeared to maintain robust growth under salt stress through well-orchestrated cell wall biogenesis and cell expansion, likely through major regulatory (OsRR23, OsHK5) and biosynthetic (OsIPT9) genes in the cytokinin signaling pathway. Meanwhile, a constitutively expressed cluster in FL510 prominently featured two transcription factors (OsIBH1, TAC3) that control tiller angle and growth habit through the brassinosteroid signaling pathway. Both the putative cytokinin-mediated and brassinosteroid-mediated clusters appeared to function as highly coordinated network synergies in FL510. In contrast, both networks appeared to be sub-optimal and inferior in the other RILs and parents as they were disjointed and highly fragmented. Transgressively expressed miRNAs (miR169, miR397, miR827) were also identified as prominent signatures of FL510, with functional implications to mechanisms that support robust growth, homeostasis, and osmotic stress avoidance. Results of this study demonstrate how genetic recombination creates novel morphology that complements inducible defenses hence transgressive adaptive phenotypes.


omega-3 oil intake during weight loss in obese women results in remodelling of plasma triglyceride and fatty acids.
Previous studies have shown that a combination of weight loss and fish oil supplementation reduce cardiovascular disease and diabetes risks by increasing adiponectin and reducing triacylglyceride concentrations, while weight loss alone significantly improves insulin sensitivity and reduces inflammation. Here, a metabolomic approach, using a combination of (1)H-Nuclear Magnetic Resonance spectroscopy, and gas and liquid chromatography and mass spectrometry, was employed to elucidate the metabolic changes in blood plasma following weight loss and fish oil supplementation. The intervention study was conducted over 24 weeks, with 93 female subjects randomised to one of three groups. Two groups followed a 12-week weight loss program, followed by a 12-week weight maintenance period and were randomised to fish or placebo oil capsules; a control group did not follow the weight loss program and were given placebo oil capsules. Lipid profiles changed dramatically upon fish oil intake and subtly across the two weight loss groups. While the fish oil supplementation increased the proportion of various phospholipid species, previously reported reductions in total triacylglycerides (TAGs) upon fish oil intake were shown to be driven by a reduction in a specific subset of the measured TAGs. This remodelling of triglycerides may represent further beneficial effects of fish oil supplementation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-009-0161-7) contains supplementary material, which is available to authorized users.


Sleep quality and the evolution of the COVID-19 pandemic in five European countries.
The COVID-19 pandemic has led to lifestyle changes across Europe with a likely impact on sleep quality. This investigation considers sleep quality in relation to the evolution of the COVID-19 pandemic in five European countries. Using panel regressions and keeping policy responses to COVID-19 constant, we show that an increase in the four-week average daily COVID-19 deaths/100,000 inhabitants (our proxy for the evolution of the pandemic) significantly reduced sleep quality in France, Germany, Italy, Spain, and Sweden between April 2020 and June 2021. Our results are robust to a battery of sensitivity tests and are larger for women, parents and young adults. Additionally, we show that about half of the reduction in sleep quality caused by the evolution of the pandemic can be attributed to changes in lifestyles, worsened mental health and negative attitudes toward COVID-19 and its management (lower degree of confidence in government, greater fear of being infected). In contrast, changes in one's own infection-status from the SARS-CoV-2 virus or sleep duration are not significant mediators of the relationship between COVID-19-related deaths and sleep quality.


Functionally Guided Retinal Protective Therapy for Dry Age-Related Macular and Inherited Retinal Degenerations: A Pilot Study.
To review the results of retinal function testing in eyes undergoing panmacular subthreshold diode micropulse laser (SDM) prophylaxis for chronic progressive retinal disease. The records of all patients undergoing prophylactic panmacular SDM for high-risk age-related macular degeneration (AMD) and inherited photoreceptor degenerations (IRDs) examined by pattern electroretinography (PERG), automated microperimetry (AMP), and Central Vision Analyzer (CVA) testing before and after treatment were reviewed. A total of 158 consecutive eyes of 108 patients with AMD and 10 consecutive eyes of 8 patients with IRDs, evaluated both before and after SDM by PERG, were eligible for study. The IRD diagnoses included rod-cone degeneration (four eyes), cone-rod degeneration (three eyes), and Stargardt's disease (three eyes). In AMD, AMP was performed in 40 consecutive eyes, and CVA in the subsequent 73 consecutive eyes concurrent with PERG. The SDM treatment consisted of 1800 to 3000 confluent spots throughout the retina circumscribed by the major vascular arcades, including the fovea ("panmacular"). Testing was performed 1 week before and by 1 month after treatment. Results indicated that 149/168 eyes were improved by primary PERG measures: 139/158 eyes with AMD by PERG low-contrast scan Magnitude D (MagD)(μV)/Magnitude (Mag)(μV) ratios (P = 0.0001) and 10/10 eyes with IRDs by 24⁰ concentric ring scan MagD(μV)/Mag(μV) ratios (P = 0.002). Snellen visual acuity (VA) was unchanged, but macular sensitivity by AMP (P = 0.0439) and mesopic contrast VA by CVA (P = 0.006) were improved. There were no adverse treatment effects. Our findings suggest a role for SDM as retinal protective therapy in chronic progressive retinal diseases. Pattern electroretinography enables (early, preventive) functionally guided, rather than (late, therapeutic) image-guided, disease management.


Food consumption patterns and associated factors among Vietnamese women of reproductive age.
Adequate nutrient intakes among women of reproductive age (WRA) are important determinants of maternal, neonatal and child health outcomes. However, data on dietary intake for WRA in Vietnam are lacking. This paper aimed to examine the adequacy and determinants of energy and macronutrient intakes among WRA enrolled in a study of preconceptual micronutrient supplementation (PRECONCEPT) being conducted in 20 rural communes in Thai Nguyen province, Vietnam. Dietary intakes were determined for 4983 WRA who participated in the baseline survey using a previously validated 107-item (semi-quantitative) food-frequency questionnaire that was administered by trained field workers. Multivariate linear and logistic regression analyses were used to examine factors associated with energy and macronutrient intakes. A disproportionate number of energy came from starches, primarily rice. Carbohydrate, fat and protein constituted 65.6%, 19.5% and 14.8% of total energy, respectively. Fat intake was below recommended levels in 56.5% of respondents, but carbohydrate intakes were above recommended level in 54.6%. Only 0.1% and 5.2% of WRA achieved adequate intake of n-3 and n-6 long-chain polyunsaturated fatty acids, respectively. Multivariate linear regression revealed that low education, low socioeconomic status, and food insecurity were significant predictors of reduced total energy intake, reduced energy from protein and fat, and greater energy from carbohydrates. Logistic regression confirmed that inadequate macronutrient intake was more common among the poor, food insecure, and less educated. Imbalanced dietary intakes among underprivileged women reflect lack of dietary diversity. Nutrition programs should be linked with social development, poverty reduction, education programs and behavior change counseling in order to improve the nutritional status of WRA in Vietnam.


Dynamic Life Cycle Assessments of a Conventional Green Building and a Net Zero Energy Building: Exploration of Static, Dynamic, Attributional, and Consequential Electricity Grid Models.
Our study assesses the differences between regional average- and marginal-electricity generation mixes as well as the variability between predicted and observed energy consumption of a "conventional green" Leadership in Energy and Environmental Design (LEED) building and a Net-Zero Energy Living Building (NZEB). The aim of our study was to evaluate the importance of using temporally resolved building-level data while capturing the dynamic effects a changing electrical grid has on the life cycle impacts of buildings. Two static and four dynamic life cycle assessment (LCA) models were evaluated for both buildings. Both buildings' results show that the most appropriate models ( hybrid consequential for the LEED Gold building, hourly consequential for the NZEB) significantly modified the use-phase global warming potential (GWP) impacts relative to the design static LCA (49% greater impact for the LEED Gold building; 45% greater reduction for the NZEB). In other words, a "standard" LCA would underestimate the use phase impacts of the LEED Gold building and the benefits of the NZEB in the GWP category. Although the results in this paper are specific to two case study buildings, the methods developed are scalable and can be implemented more widely to improve building life cycle impact estimates.


A medication assessment tool to evaluate prescribers' adherence to evidence-based guidelines in bipolar disorder.
Background The goal of evidence-based clinical practice has led to an increased interest in the development of tools to measure adherence to national guidelines in different diseases. This aids in detecting and measuring inappropriate prescribing to specific patient groups by using quality standards extracted from evidence-based guidelines, and ultimately provide the basis of consistent standardized prescribing. Objective To design and validate a medication assessment tool to assess prescribers' adherence to international guideline recommendations in the management of bipolar disorder (MATBD). Setting Outpatient psychiatry clinic at a secondary healthcare setting in Kuwait. Method International guidelines concerned with the management of bipolar disorder were reviewed in order to develop MATBD. Face and content validity of the developed tool (MATBD) was performed with a research and expert group. A 4-point Likert scale was used to assess the expert group's level of agreement to individual criterion. Content validity ratio (CVR) was calculated for each criterion (n = 54) and the content validity index (CVI) was calculated for each section (n = 5) of the MATBD. Finally, feasibility testing was performed on 19 patient records to confirm the tool's fitness for purpose. Main Outcomes Measure Perceived relevance, utility, and clarity of individual criteria, and reliability of their application to clinical settings. Results Face validity and content validity were achieved with a research and expert group (n = 14). Content validity ratio (CVR) was demonstrated for 54 criteria; criteria with a negative CVR were removed. This resulted in a draft MATBD comprising of 52 criteria (CVI: 0.814). Feasibility testing on 19 patients' records resulted in a final MATBD comprising of 49 criteria divided into 3 sections: initial assessment, acute management and monitoring. Conclusion A medication assessment tool was developed and validated to be used as a means of profiling potential opportunities for medication therapy management optimization, and improving therapeutic interventions regarding the management of bipolar disorder.


Generation of mice deficient for macrophage galactose- and N-acetylgalactosamine-specific lectin: limited role in lymphoid and erythroid homeostasis and evidence for multiple lectins.
Macrophage receptors function in pattern recognition for the induction of innate immunity, in cellular communication to mediate the regulation of adaptive immune responses, and in the clearance of some glycosylated cells or glycoproteins from the circulation. They also function in homeostasis by initiating the engulfment of apoptotic cells. Evidence has suggested that macrophage receptors function to recognize cells that are destined for programmed cell death but not yet overtly apoptotic. We have examined the function of a macrophage receptor specific for unsialylated glycoproteins, known as the mouse macrophage galactose- and N-acetylgalactosamine-specific lectin (mMGL) (Ii et al., J. Biol. Chem. 265:11295-11298, 1990; Sato et al., J. Biochem. [Tokyo] 111:331-336, 1992; Yamamoto et al., Biochemistry 33:8159-8166, 1994). With targeted disruption, we tested whether mMGL is necessary for macrophage function, controlled thymic development, the loss of activated CD8 T cells, and the turnover of red blood cells. Evidence indicates that mMGL may play a nonessential role in several of these macrophage functions. Experiments are presented that indicate the existence of another galactose- and N-acetylgalactosamine-recognizing lectin distinct from mMGL. This may explain the absence of a strong phenotype in mMGL-deficient mice.


Perceived unfairness in working conditions: the case of public health services in Tanzania.
The focus on the determinants of the quality of health services in low-income countries is increasing. Health workers' motivation has emerged as a topic of substantial interest in this context. The main objective of this article is to explore health workers' experience of working conditions, linked to motivation to work. Working conditions have been pointed out as a key factor in ensuring a motivated and well performing staff. The empirical focus is on rural public health services in Tanzania. The study aims to situate the results in a broader historical context in order to enhance our understanding of the health worker discourse on working conditions. The study has a qualitative study design to elicit detailed information on health workers' experience of their working conditions. The data comprise focus group discussions (FGDs) and in-depth interviews (IDIs) with administrators, clinicians and nursing staff in the public health services in a rural district in Tanzania. The study has an ethnographic backdrop based on earlier long-term fieldwork in the same part of Tanzania. The article provides insights into health workers' understanding and assessment of their working conditions. An experience of unsatisfactory working conditions as well as a perceived lack of fundamental fairness dominated the FGDs and IDIs. Informants reported unfairness with reference to factors such as salary, promotion, recognition of work experience, allocation of allowances and access to training as well as to human resource management. The study also revealed that many health workers lack information or knowledge about factors that influence their working conditions. The article calls for attention to the importance of locating the discourse of unfairness related to working conditions in a broader historical/political context. Tanzanian history has been characterised by an ambiguous and shifting landscape of state regulation, economic reforms, decentralisation and emerging democratic sentiments. Such a historic contextualisation enhances our understanding of the strong sentiments of unfairness revealed in this study and assists us in considering potential ways forward.


Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues.
Exposure to environmental cues associated with food can evoke eating behavior in the absence of hunger. This capacity for reward cues to promote feeding behaviors under sated conditions can be examined in the laboratory using cue-potentiated feeding (CPF). The orexigenic neuropeptide Melanin Concentrating Hormone (MCH) is expressed throughout brain circuitry critical for CPF. We examined whether deletion of the MCH receptor, MCH-1R, would in KO mice disrupt overeating in the presence of a Pavlovian CS+ associated with sucrose delivery. While both wild-type controls and KO mice showed comparable food magazine approach responses during the CPF test, MCH-1R deletion significantly impaired the ability of the CS+ to evoke overeating of sucrose under satiety. Through the use of a refined analysis of meal intake, it was revealed that this disruption to overeating behavior in KO mice reflected a reduction in the capacity for the CS+ to initiate and maintain bursts of licking behavior. These findings suggest that overeating during CPF requires intact MCH-1R signaling and may be due to an influence of the CS+ on the palatability of food and on regulatory mechanisms of peripheral control. Thus, disruptions to MCH-1R signaling may be a useful pharmacological tool to inhibit this form of overeating behavior.


Modeling temporal interactions with interval temporal bayesian networks for complex activity recognition.
Complex activities typically consist of multiple primitive events happening in parallel or sequentially over a period of time. Understanding such activities requires recognizing not only each individual event but, more importantly, capturing their spatiotemporal dependencies over different time intervals. Most of the current graphical model-based approaches have several limitations. First, time--sliced graphical models such as hidden Markov models (HMMs) and dynamic Bayesian networks are typically based on points of time and they hence can only capture three temporal relations: precedes, follows, and equals. Second, HMMs are probabilistic finite-state machines that grow exponentially as the number of parallel events increases. Third, other approaches such as syntactic and description-based methods, while rich in modeling temporal relationships, do not have the expressive power to capture uncertainties. To address these issues, we introduce the interval temporal Bayesian network (ITBN), a novel graphical model that combines the Bayesian Network with the interval algebra to explicitly model the temporal dependencies over time intervals. Advanced machine learning methods are introduced to learn the ITBN model structure and parameters. Experimental results show that by reasoning with spatiotemporal dependencies, the proposed model leads to a significantly improved performance when modeling and recognizing complex activities involving both parallel and sequential events.


Validation of a Knowledge Transfer Tool According to the OMERACT Filter: Does Web-based Real-time Iterative Calibration Enhance the Evaluation of Bone Marrow Lesions in Hip Osteoarthritis?
To assess reliability and feasibility of using a Web-based interface and interactive online calibration tool for magnetic resonance imaging (MRI) scoring of bone marrow lesions (BML) in osteoarthritis (OA), applied to the Hip MR Inflammation Scoring System (HIMRISS). Seven readers new to HIMRISS (3 radiologists, 4 rheumatologists) scored coronal short-tau inversion recovery MRI from a hip OA observational study obtained pre- and 8-week poststeroid injection (n = 40 × 2 scans × 2 hips = 160 hips). By crossover design, Group B (4 readers) scored 20 patients (40 hips) using conventional spreadsheet-based methods and then another 20 using a Web-based interface and an online real-time iterative calibration (RETIC) training module. Group A (3 readers) reversed the order, scoring the first 20 subjects by the new method and the final 20 conventionally. Outcomes included ICC and reader survey. Interobserver reliability for BML status was high by both spreadsheet and Web-based methods (0.84-0.90), regardless of the order in which scoring was performed. Reliability of change scores was moderate and improved with training. Improvement was greater in readers who began with the spreadsheet method and then used the Web-based method than in those who began with the Web-based method, especially at the acetabulum. Readers found Web-based/RETIC scoring more user-friendly and nearly 50% faster than traditional spreadsheet methods. HIMRISS offers reliable BML scoring in OA, whether by conventional spreadsheet-based scoring or by a Web-based interface with interactive feedback. The new method allowed faster readings, provided a consistent training environment that helped inexperienced readers achieve reliability equivalent to that of conventional methods, and was preferred by the readers.


Constrained iterative Hirshfeld charges: A variational approach.
We develop a variational procedure for the iterative Hirshfeld (HI) partitioning scheme. The main practical advantage of having a variational framework is that it provides a formal and straightforward approach for imposing constraints (e.g., fixed charges on certain atoms or molecular fragments) when computing HI atoms and their properties. Unlike many other variants of the Hirshfeld partitioning scheme, HI charges do not arise naturally from the information-theoretic framework, but only as a reverse-engineered construction of the objective function. However, the procedure we use is quite general and could be applied to other problems as well. We also prove that there is always at least one solution to the HI equations, but we could not prove that its self-consistent equations would always converge for any given initial pro-atom charges. Our numerical assessment of the constrained iterative Hirshfeld method shows that it satisfies many desirable traits of atoms in molecules and has the potential to surpass existing approaches for adding constraints when computing atomic properties.


Achievement of Sustained Net Plasma Heating in a Fusion Experiment with the Optometrist Algorithm.
Many fields of basic and applied science require efficiently exploring complex systems with high dimensionality. An example of such a challenge is optimising the performance of plasma fusion experiments. The highly-nonlinear and temporally-varying interaction between the plasma, its environment and external controls presents a considerable complexity in these experiments. A further difficulty arises from the fact that there is no single objective metric that fully captures both plasma quality and equipment constraints. To efficiently optimise the system, we develop the Optometrist Algorithm, a stochastic perturbation method combined with human choice. Analogous to getting an eyeglass prescription, the Optometrist Algorithm confronts a human operator with two alternative experimental settings and associated outcomes. A human operator then chooses which experiment produces subjectively better results. This innovative technique led to the discovery of an unexpected record confinement regime with positive net heating power in a field-reversed configuration plasma, characterised by a >50% reduction in the energy loss rate and concomitant increase in ion temperature and total plasma energy.


Perceptions about genetic testing for the susceptibility to alcohol dependence and other multifactorial diseases.
Beliefs, attitudes, and preferences about the risk and benefits of genetic testing are important determinants of willingness to undergo testing. The purpose of this study was to evaluate the perceived importance of genetic testing for alcohol dependence compared with other multifactorial diseases among African Americans. Surveys were conducted with 258 participants using the Genetic Psycho-Social Implications (GPSI) questionnaire to evaluate several areas of hypothetical genetic testing for alcohol dependence. Respondents were divided into two groups: those who perceived testing for alcohol dependence to be equally important as testing for cancer and those who did not. Using chi-square, the groups' responses were compared for nine GPSI items measuring beliefs about the severity of alcohol dependence, general benefits of genetic testing, and specific benefits of genetic testing for diabetes, hypertension, or a disease affecting a family member. Nearly 86% of respondents believed that genetic testing for alcoholism was equally as important as testing for cancer. Those who reported parity of importance of alcohol dependence and cancer screening were more likely to believe that alcoholism is a deadly disease (p<0.001) and genetic testing influences health (p<0.001). African Americans reported favorable attitudes and beliefs in possible availability of susceptibility genetic testing for alcohol dependence. The perceived importance of testing for alcohol dependence was associated with beliefs about the severity of alcoholism and certain benefits of genetic testing in general.


Fabrication and characterization of subwavelength nanostructures on freestanding GaN slab.
We develop a novel way to fabricate subwavelength nanostructures on the freestanding GaN slab using a GaN-on-silicon system by combining self-assemble technique and backside thinning method. Silicon substrate beneath the GaN slab is removed by bulk silicon micromachining, generating the freestanding GaN slab and eliminating silicon absorption of the emitted light. Fast atom beam (FAB) etching is conducted to thin the freestanding GaN slab from the backside, reducing the number of confined modes inside the GaN slab. With self-assembled silica nanospheres acting as an etching mask, subwavelength nanostructures are realized on the GaN surface by FAB etching. The reflection losses at the GaN interfaces are thus suppressed. When the InGaN/GaN multiple quantum wells (MQWs) active layers are excited, the light extraction efficiency is significantly improved for the freestanding nanostructured GaN slab. This work provides a very practical approach to fabricate freestanding nanostructures on the GaN-on-silicon system for further improving the light extraction efficiency.