The IL-33:ST2 axis is unlikely to play a central fibrogenic role in idiopathic pulmonary fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with limited treatment options. Interleukin-33 (IL-33) is proposed to play a role in the development of IPF however the exclusive use of prophylactic dosing regimens means that the therapeutic benefit of targeting this cytokine in IPF is unclear. METHODS: IL-33 expression was assessed in ILD lung sections and human lung fibroblasts (HLFs) by immunohistochemistry and gene/protein expression and responses of HLFs to IL-33 stimulation measured by qPCR. In vivo, the fibrotic potential of IL-33:ST2 signalling was assessed using a murine model of bleomycin (BLM)-induced pulmonary fibrosis and therapeutic dosing with an ST2-Fc fusion protein. Lung and bronchoalveolar lavage fluid were collected for measurement of inflammatory and fibrotic endpoints. Human precision-cut lung slices (PCLS) were stimulated with transforming growth factor-β (TGFβ) or IL-33 and fibrotic readouts assessed. RESULTS: IL-33 was expressed by fibrotic fibroblasts in situ and was increased by TGFβ treatment in vitro. IL-33 treatment of HLFs did not induce IL6, CXCL8, ACTA2 and COL1A1 mRNA expression with these cells found to lack the IL-33 receptor ST2. Similarly, IL-33 stimulation had no effect on ACTA2, COL1A1, FN1 and fibronectin expression by PCLS. Despite having effects on inflammation suggestive of target engagement, therapeutic dosing with the ST2-Fc fusion protein failed to reduce BLM-induced fibrosis measured by hydroxyproline content or Ashcroft score. CONCLUSIONS: Together these findings suggest the IL-33:ST2 axis does not play a central fibrogenic role in the lungs with therapeutic blockade of this pathway unlikely to surpass the current standard of care for IPF

An Australian longitudinal pilot study examining health determinants of cardiac outcomes 12 months post percutaneous coronary intervention

Background Percutaneous coronary intervention (PCI) is a very common revascularisation procedure for coronary artery disease (CAD). The purpose of this study was to evaluate cardiac outcomes, health related quality of life (HRQoL), resilience and adherence behaviours in patients who have undergone a PCI at two time points (6 and 12 months) following their procedure. Methods A longitudinal pilot study was conducted to observe the cardiac outcomes across a cohort of patients who had undergone a percutaneous coronary intervention (PCI). Participants who had undergone PCI 6 months prior were invited. Those participants who met the inclusion criteria and provided consent then completed a telephone survey (time point 1). These participants were then contacted 6 months later (i.e. 12 months post-intervention, time point 2) and the measures were repeated. Results All patients (n = 51) were recorded as being alive at time point 1. The multiple model indicated that controlling for other factors, gender was significantly associated with a linear combination of outcome measures (p = 0.004). The effect was moderate in magnitude (partial-η2 = 0.303), where males performed significantly better than females 6 months after the PCI procedure physically and with mood. Follow-up univariate ANOVAs indicated that gender differences were grounded in the scale measuring depression (PHQ9) (p = 0.005) and the physical component score of the short form measuring HRQoL (SF12-PCS) (p = 0.003). Thirteen patients were lost to follow-up between time points 1 and 2. One patient was confirmed to have passed away. The pattern of correlations between outcome measures at time point 2 revealed statistically significant negative correlation between the PHQ instrument and the resilience scale (CD-RISC) (r = -0.611; p < 0.001); and the physical component score of the SF-12 instrument (r = -0.437; p = 0.054). Conclusions Men were performing better than women in the 6 months post-PCI, particularly in the areas of mood (depression) and physical health. This pilot results indicate gender-sensitive practices are recommended particularly up to 6 months post-PCI. Any gender differences observed at 6 month appear to disappear at 12 months post-PCI. Further research into the management of mood particularly for women post-PCI is warranted. A more detailed inquiry related to access/attendance to secondary prevention is also warranted

Why do women invest in pre-pregnancy health and care? A qualitative investigation with women attending maternity services

Background Despite the importance attributed to good pre-pregnancy care and its potential to improve pregnancy and child health outcomes, relatively little is known about why women invest in pre-pregnancy health and care. We sought to gain insight into why women invested in pre-pregnancy health and care. Methods We carried out 20 qualitative in-depth interviews with pregnant or recently pregnant women who were drawn from a survey of antenatal clinic attendees in London, UK. Interviewees were purposively sampled to include high and low investors in pre-pregnancy health and care, with variation in age, partnership status, ethnicity and pre-existing medical conditions. Data analysis was conducted using the Framework method. Results We identified three groups in relation to pre-pregnancy health and care: 1) The “prepared” group, who had high levels of pregnancy planning and mostly positive attitudes to micronutrient supplementation outside of pregnancy, carried out pre-pregnancy activities such as taking folic acid and making changes to diet and lifestyle. 2) The “poor knowledge” group, who also had high levels of pregnancy planning, did not carry out pre-pregnancy activities and described themselves as having poor knowledge. Elsewhere in their interviews they expressed a strong dislike of micronutrient supplementation. 3) The “absent pre-pregnancy period” group, had the lowest levels of pregnancy planning and also expressed anti-supplement views. Even discussing the pre-pregnancy period with this group was difficult as responses to questions quickly shifted to focus on pregnancy itself. Knowledge of folic acid was poor in all groups. Conclusion Different pre-pregnancy care approaches are likely to be needed for each of the groups. Among the “prepared” group, who were proactive and receptive to health messages, greater availability of information and better response from health professionals could improve the range of pre-pregnancy activities carried out. Among the “poor knowledge” group, better response from health professionals might yield greater uptake of pre-pregnancy information. A different, general health strategy might be more appropriate for the “absent pre-pregnancy period” group. The fact that general attitudes to micronutrient supplementation were closely related to whether or not women invested in pre-pregnancy health and care was an unanticipated finding and warrants further investigation.This report is independent research commissioned and funded by the Department of Health Policy Research Programme Pre-Pregnancy Health and Care in England: Exploring Implementation and Public Health Impact, 006/0068

Role of the PAS sensor domains in the Bacillus subtilis sporulation kinase KinA

Histidine kinases are sophisticated molecular sensors that are used by bacteria to detect and respond to a multitude of environmental signals. KinA is the major histidine kinase required for initiation of sporulation upon nutrient deprivation in Bacillus subtilis. KinA has a large N-terminal region (residues 1 to 382) that is uniquely composed of three tandem Per-ARNT-Sim (PAS) domains that have been proposed to constitute a sensor module. To further enhance our understanding of this "sensor" region, we defined the boundaries that give rise to the minimal autonomously folded PAS domains and analyzed their homo- and heteroassociation properties using analytical ultracentrifugation, nuclear magnetic resonance (NMR) spectroscopy, and multiangle laser light scattering. We show that PAS(A) self-associates very weakly, while PAS(C) is primarily a monomer. In contrast, PAS(B) forms a stable dimer (K-d [dissociation constant] o

Characterization of mixed lymphocyte reaction blocking antibodies (MLR-Bf) in human pregnancy

BACKGROUND: It is known that during normal pregnancy and after immunotherapy blocking antibodies are developed, these antibodies inhibit mixed lymphocyte reaction and are also anti-mitogenic in nature. Mixed lymphocyte reaction blocking antibodies are specific to the husband's lymphocytes. In the present study an attempt has been made to characterize the mixed lymphocyte reaction blocking antibodies in normal pregnancy and in women with recurrent spontaneous abortion after immunotherapy. METHODS: Serum was obtained from women of different gestational windows of pregnancy (Ist, IInd, IIIrd trimesters and post delivery period of normal pregnancy), recurrent spontaneous aborters from pre and post immunization. Healthy (male and females) controls were screened for the presence of mixed lymphocyte reaction blocking antibodies. The standard mixed lymphocyte reaction technique was used to evaluate the inhibitory effect of serum in the mixed lymphocyte reaction. Each serum was tested for cytotoxic antibodies. Immunoglobulin G and its isotypes were isolated according to the standard protocol. RESULTS: In the present study we have observed that there was significant inhibition of proliferation response when immunoglobulin G from different trimesters of pregnancy were added to one way mixed lymphocyte reaction or to phytohemagglutinin activated lymphocyte proliferation assay. Similar pattern was seen when immunoglobulin G isolated from adequately immunized women with recurrent spontaneous abortion was used. It was further confirmed that amongst all the isotypes of immunoglobulin G, only immunoglobulin G-3 was found to be positive for the inhibitory effect. CONCLUSIONS: Present study indicates that mixed lymphocyte reaction blocking antibodies are immunoglobulin G-3 in nature. It is developed during pregnancy and also after immunotherapy in women with recurrent spontaneous abortion who subsequently have the successful pregnancy

Post-emergence selectivity of metribuzin to carrot.

The objective of this study was to evaluate the selectivity of the herbicide metribuzin to carrot plants as a function of genotype, dose, and plant growth stage at the time of application. Two experiments were carried out, one in a greenhouse and another in the field

Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control.

BACKGROUND: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed. METHODS: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms. RESULTS: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms. CONCLUSIONS: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status

The Effect of the CO32- to Ca2+ Ion activity ratio on calcite precipitation kinetics and Sr2+ partitioning

<p>Abstract</p> <p>Background</p> <p>A proposed strategy for immobilizing trace metals in the subsurface is to stimulate calcium carbonate precipitation and incorporate contaminants by co-precipitation. Such an approach will require injecting chemical amendments into the subsurface to generate supersaturated conditions that promote mineral precipitation. However, the formation of reactant mixing zones will create gradients in both the saturation state and ion activity ratios (i.e., <inline-formula><m:math name="1467-4866-13-1-i1" xmlns:m="http://www.w3.org/1998/Math/MathML"><m:msub><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mi>C</m:mi><m:msup><m:mrow><m:msub><m:mrow><m:mi>O</m:mi></m:mrow><m:mrow><m:mn>3</m:mn></m:mrow></m:msub></m:mrow><m:mrow><m:mn>2</m:mn><m:mo class="MathClass-bin">-</m:mo></m:mrow></m:msup></m:mrow></m:msub><m:mo class="MathClass-bin">/</m:mo><m:msub><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mi>C</m:mi><m:msup><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mn>2</m:mn><m:mo class="MathClass-bin">+</m:mo></m:mrow></m:msup></m:mrow></m:msub></m:math></inline-formula>). To better understand the effect of ion activity ratios on CaCO₃precipitation kinetics and Sr²⁺co-precipitation, experiments were conducted under constant composition conditions where the supersaturation state (Ω) for calcite was held constant at 9.4, but the ion activity ratio <inline-formula><m:math name="1467-4866-13-1-i2" xmlns:m="http://www.w3.org/1998/Math/MathML"><m:mrow><m:mo class="MathClass-open">(</m:mo><m:mrow><m:mi>r</m:mi><m:mo class="MathClass-rel">=</m:mo><m:msub><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mi>C</m:mi><m:msup><m:mrow><m:msub><m:mrow><m:mi>O</m:mi></m:mrow><m:mrow><m:mn>3</m:mn></m:mrow></m:msub></m:mrow><m:mrow><m:mn>2</m:mn><m:mo class="MathClass-bin">-</m:mo></m:mrow></m:msup></m:mrow></m:msub><m:mo class="MathClass-bin">/</m:mo><m:msub><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mi>C</m:mi><m:msup><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mn>2</m:mn><m:mo class="MathClass-bin">+</m:mo></m:mrow></m:msup></m:mrow></m:msub></m:mrow><m:mo class="MathClass-close">)</m:mo></m:mrow></m:math></inline-formula> was varied between 0.0032 and 4.15.</p> <p>Results</p> <p>Calcite was the only phase observed, by XRD, at the end of the experiments. Precipitation rates increased from 41.3 ± 3.4 μmol m^-2min^-1at <it>r = </it>0.0315 to a maximum rate of 74.5 ± 4.8 μmol m^-2min^-1at <it>r = </it>0.306 followed by a decrease to 46.3 ± 9.6 μmol m^-2min^-1at <it>r </it>= 1.822. The trend was simulated using a simple mass transfer model for solute uptake at the calcite surface. However, precipitation rates at fixed saturation states also evolved with time. Precipitation rates accelerated for low <it>r </it>values but slowed for high <it>r </it>values. These trends may be related to changes in effective reactive surface area. The <inline-formula><m:math xmlns:m="http://www.w3.org/1998/Math/MathML" name="1467-4866-13-1-i1"><m:msub><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mi>C</m:mi><m:msup><m:mrow><m:msub><m:mrow><m:mi>O</m:mi></m:mrow><m:mrow><m:mn>3</m:mn></m:mrow></m:msub></m:mrow><m:mrow><m:mn>2</m:mn><m:mo class="MathClass-bin">-</m:mo></m:mrow></m:msup></m:mrow></m:msub><m:mo class="MathClass-bin">/</m:mo><m:msub><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mi>C</m:mi><m:msup><m:mrow><m:mi>a</m:mi></m:mrow><m:mrow><m:mn>2</m:mn><m:mo class="MathClass-bin">+</m:mo></m:mrow></m:msup></m:mrow></m:msub></m:math></inline-formula> ratios did not affect the distribution coefficient for Sr in calcite (D^P_Sr²⁺), apart from the indirect effect associated with the established positive correlation between D^P_Sr²⁺and calcite precipitation rate.</p> <p>Conclusion</p> <p>At a constant supersaturation state (Ω = 9.4), varying the ion activity ratio affects the calcite precipitation rate. This behavior is not predicted by affinity-based rate models. Furthermore, at the highest ion ratio tested, no precipitation was observed, while at the lowest ion ratio precipitation occurred immediately and valid rate measurements could not be made. The maximum measured precipitation rate was 2-fold greater than the minima, and occurred at a carbonate to calcium ion activity ratio of 0.306. These findings have implications for predicting the progress and cost of remediation operations involving enhanced calcite precipitation where mineral precipitation rates, and the spatial/temporal distribution of those rates, can have significant impacts on the mobility of contaminants.</p

Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders

Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations

A survey of people with foot problems related to rheumatoid arthritis and their educational needs

Background Up to 50% of people with rheumatoid arthritis (RA) have foot symptoms at diagnosis, hence early foot health intervention is recommended and this should include patient education. This study identifies, for the first time, the foot health education (FHE) needs of people with RA. Methods An online survey of people with RA (n = 543) captured quantitative data in relation to the aims, methods of delivery, content, timing and accessibility of FHE. Results The majority concurred about the aims of FHE. Verbal delivery and websites were the most common methods. Written and verbal FHE were perceived to be the most effective methods. The point of diagnosis was the preferred time to receive it. Lack of access to FHE included minimal focus on foot health during consultations by both health practitioners and patients with RA. Participant gender, age, disease duration and living situation had a statistically significant influence on the results. Conclusion Foot health education is rarely considered within the medical consultation. There is a lack of patient and/or health professional awareness of this need with a detrimental impact on foot health. Patients require health professionals to identify their foot education health needs. Tailored foot health education should begin at initial diagnosis