Cellular Mechanisms Underlying the Laxative Effect of Flavonol Naringenin on Rat Constipation Model

BACKGROUND & AIMS: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively. METHODS/PRINCIPAL FINDINGS: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group. CONCLUSIONS: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Depression in multicultural Australia: Policies, research and services

BACKGROUND: Depression is one of the leading causes of disability in Australia. The cultural and linguistic diversity of the Australian population poses a significant challenge to health policy development, service provision, professional education, and research. The purpose of this study is to explore the extent to which the fact of cultural and linguistic diversity has influenced the formulation of mental health policy, the conduct of mental health research and the development of mental health services for people with depression from ethnic minority communities. METHODS: The methods used for the different components of the study included surveys and document-based content and thematic analyses. RESULTS: Policy is comprehensive but its translation into programs is inadequate. Across Australia, there were few specific programs on depression in ethnic minority communities and they are confronted with a variety of implementation difficulties. The scope and scale of research on depression in Ethnic minority communities is extremely limited. CONCLUSION: A key problem is that the research that is necessary to provide evidence for policy and service delivery is lacking. If depression in Ethnic minority communities is to be addressed effectively the gaps between policy intentions and policy implementation, and between information needs for policies and practice and the actual research that is being done, have to be narrowed

Do International Health Partnerships contribute to reverse innovation? a mixed methods study of THET-supported partnerships in the UK

Background International health partnerships (IHPs) are changing, with an increased emphasis on mutual accountability and joint agenda setting for both the high- and the low- or middle-income country (LMIC) partners. There is now an important focus on the bi-directionality of learning however for the UK partners, this typically focuses on learning at the individual level, through personal and professional development. We sought to evaluate whether this learning also takes the shape of ‘Reverse Innovation’ –when an idea conceived in a low-income country is subsequently adopted in a higher-income country. Methods This mixed methods study used an initial scoping survey of all the UK-leads of the Tropical Health Education Trust (THET)-supported International Health Partnerships (n = 114) to ascertain the extent to which the IHPs are or have been vehicles for Reverse Innovation. The survey formed the sampling frame for further deep-dive interviews to focus on volunteers’ experiences and attitudes to learning from LMICs. Interviews of IHP leads (n = 12) were audio-recorded and transcribed verbatim. Survey data was analysed descriptively. Interview transcripts were coded thematically, using an inductive approach. Results Survey response rate was 27% (n = 34). The majority (70%) strongly agreed that supporting LMIC partners best described the mission of the partnership but only 13% of respondents strongly agreed that learning about new innovations and models was a primary mission of their partnership. Although more than half of respondents reported having observed innovative practice in the LMIC, only one IHP respondent indicated that this has led to Reverse Innovation. Interviews with a sample of survey respondents revealed themes primarily around how learning is conceptualised, but also a central power imbalance between the UK and LMIC partners. Paternalistic notions of knowledge could be traced to partnership power dynamics and latent attitudes to LMICs. Conclusions Given the global flow of innovation, if High-income countries (HICs) are to benefit from LMIC practices, it is paramount to keep an open mind about where such learning can come from. Making the potential for learning more explicit and facilitating innovation dissemination upon return will ultimately underpin the success of adoption

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038

Lack of trade-offs between the male and female sexual functions in the gynodioecious herb Geranium sylvaticum

Resource allocation trade-offs between sexual functions are predicted, but these are usually measured only at the whole plant level. In some gynodioecious species, individuals with partially restored male fertility exist providing an opportunity to investigate whether the costs associated with male fertility restoration are linked to seed production. In this study, we examined whether there is a relationship between the numbers of stamens and seeds produced both at the flower level and at the plant level in the gynodioecious herb Geranium sylvaticum. We individually marked flowers in plants varying in the degree of male sterility in the field and counted the number of seeds produced. There was no significant correlation between the numbers of stamens and seeds produced at the flower level suggesting an absence of resource trade-off between female and male functions. Furthermore, the numbers of stamens and seeds were positively correlated at the plant level. The lack of trade-offs between the two sexual functions in this species indicates that relative sex allocation was not affected by resources within a single season and/or that the male costs were relatively small

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Combined measurement of differential and total cross sections in the H → γγ and the H → ZZ* → 4ℓ decay channels at s=13 TeV with the ATLAS detector

A combined measurement of differential and inclusive total cross sections of Higgs boson production is performed using 36.1 fb−1 of 13 TeV proton–proton collision data produced by the LHC and recorded by the ATLAS detector in 2015 and 2016. Cross sections are obtained from measured H→γγ and H→ZZ*(→4ℓ event yields, which are combined taking into account detector efficiencies, resolution, acceptances and branching fractions. The total Higgs boson production cross section is measured to be 57.0−5.9 +6.0 (stat.) −3.3 +4.0 (syst.) pb, in agreement with the Standard Model prediction. Differential cross-section measurements are presented for the Higgs boson transverse momentum distribution, Higgs boson rapidity, number of jets produced together with the Higgs boson, and the transverse momentum of the leading jet. The results from the two decay channels are found to be compatible, and their combination agrees with the Standard Model predictions

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta