Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature.

BACKGROUND: Electrophysiological data suggest that cardiac KATP channels consist of Kir6.2 and SUR2A subunits, but the distribution of these (and other KATP channel subunits) is poorly defined. We examined the localization of each of the KATP channel subunits in the mouse and rat heart. RESULTS: Immunohistochemistry of cardiac cryosections demonstrate Kir6.1 protein to be expressed in ventricular myocytes, as well as in the smooth muscle and endothelial cells of coronary resistance vessels. Endothelial capillaries also stained positive for Kir6.1 protein. Kir6.2 protein expression was found predominantly in ventricular myocytes and also in endothelial cells, but not in smooth muscle cells. SUR1 subunits are strongly expressed at the sarcolemmal surface of ventricular myocytes (but not in the coronary vasculature), whereas SUR2 protein was found to be localized predominantly in cardiac myocytes and coronary vessels (mostly in smaller vessels). Immunocytochemistry of isolated ventricular myocytes shows co-localization of Kir6.2 and SUR2 proteins in a striated sarcomeric pattern, suggesting t-tubular expression of these proteins. Both Kir6.1 and SUR1 subunits were found to express strongly at the sarcolemma. The role(s) of these subunits in cardiomyocytes remain to be defined and may require a reassessment of the molecular nature of ventricular KATP channels. CONCLUSIONS: Collectively, our data demonstrate unique cellular and subcellular KATP channel subunit expression patterns in the heart. These results suggest distinct roles for KATP channel subunits in diverse cardiac structures

A Study of Wall-Crossing: Flavored Kinks in D=2 QED

We study spectrum of D=2 N=(2,2) QED with N+1 massive charged chiral multiplets, with care given to precise supermultiplet countings. In the infrared the theory flows to CP^N model with twisted masses, where we construct generic flavored kink solitons for the large mass regime, and study their quantum degeneracies. These kinks are qualitatively different and far more numerous than those of small mass regime, with features reminiscent of multi-pronged (p,q) string web, complete with the wall-crossing behavior. It has been also conjectured that spectrum of this theory is equivalent to the hypermultiplet spectrum of a certain D=4 Seiberg-Witten theory. We find that the correspondence actually extends beyond hypermultiplets in D=4, and that many of the relevant indices match. However, a D=2 BPS state is typically mapped to several different kind of dyons whose individual supermultiplets are rather complicated; the match of index comes about only after summing over indices of these different dyons. We note general wall-crossing behavior of flavored BPS kink states, and compare it to those of D=4 dyons.Comment: 47 pages, 5 figures; typos fixed; references adde

Protective effect of Dendrobium officinale polysaccharides on experimental Sjogren's syndrome

Sjogren's syndrome (SS), usually described as a chronic inflammation which results in xerostomia (dry mouth) and xerophthalmia (dry eyes). According to the theory of traditional Chinese medicine, body fluid impairment causes the dryness, inducing water secretion deficiency. Discovery of a family of water-specific membrane channel proteins, the aquaporins, provides an interesting molecular mechanism of water permeability and transportation which were found abnormal in tissues of SS patients. Thus, this dryness may lead to the dysfunction in organs as various systematic manifestations. We established an autoallergic mouse model in vivo, and human salivary gland cell line A-253 in vitro. Polysaccharides of Dendrobium officinale (DP) were administrated as treatment, which was described to nourish yin and promote the body fluid. Results showed that immunization with SG autoantigen induced decrease of body weight and increased water intake, decreased AQP5 expression in a series of organs related to body fluid. Sera from model mice induced apoptosis of A-253 cells with activation of caspase-3. Administration of DP could reverse these pathological changes in both the animal and cell model. Thus, DP may be a promising candidate for the treatment of SS by up-regulating the expression of AQP-5 and protecting cells from apoptosis. © 2010 The Berkeley Electronic Press. All rights reserved.published_or_final_versio

Protective effect of Dendrobium officinale polysaccharides on experimental Sjogren's syndrome

Sjogren's syndrome (SS), usually described as a chronic inflammation which results in xerostomia (dry mouth) and xerophthalmia (dry eyes). According to the theory of traditional Chinese medicine, body fluid impairment causes the dryness, inducing water secretion deficiency. Discovery of a family of water-specific membrane channel proteins, the aquaporins, provides an interesting molecular mechanism of water permeability and transportation which were found abnormal in tissues of SS patients. Thus, this dryness may lead to the dysfunction in organs as various systematic manifestations. We established an autoallergic mouse model in vivo, and human salivary gland cell line A-253 in vitro. Polysaccharides of Dendrobium officinale (DP) were administrated as treatment, which was described to nourish yin and promote the body fluid. Results showed that immunization with SG autoantigen induced decrease of body weight and increased water intake, decreased AQP5 expression in a series of organs related to body fluid. Sera from model mice induced apoptosis of A-253 cells with activation of caspase-3. Administration of DP could reverse these pathological changes in both the animal and cell model. Thus, DP may be a promising candidate for the treatment of SS by up-regulating the expression of AQP-5 and protecting cells from apoptosis. © 2010 The Berkeley Electronic Press. All rights reserved.published_or_final_versio

Novel Branches of (0,2) Theories

We show that recently proposed linear sigma models with torsion can be obtained from unconventional branches of conventional gauge theories. This observation puts models with log interactions on firm footing. If non-anomalous multiplets are integrated out, the resulting low-energy theory involves log interactions of neutral fields. For these cases, we find a sigma model geometry which is both non-toric and includes brane sources. These are heterotic sigma models with branes. Surprisingly, there are massive models with compact complex non-Kahler target spaces, which include brane/anti-brane sources. The simplest conformal models describe wrapped heterotic NS5-branes. We present examples of both types.Comment: 36 pages, LaTeX, 2 figures; typo in Appendix fixed; references added and additional minor change

Preferred reporting items for studies mapping onto preference-based outcome measures: The MAPS statement

'Mapping' onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. The primary audiences for the MAPS statement are researchers reporting mapping studies, the funders of the research, and peer reviewers and editors involved in assessing mapping studies for publication. A de novo list of 29 candidate reporting items and accompanying explanations was created by a working group comprised of six health economists and one Delphi methodologist. Following a two-round, modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community, a final set of 23 items deemed essential for transparent reporting, and accompanying explanations, was developed. The items are contained in a user friendly 23 item checklist. They are presented numerically and categorised within six sections, namely: (i) title and abstract; (ii) introduction; (iii) methods; (iv) results; (v) discussion; and (vi) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document. It is anticipated that the MAPS statement will improve the clarity, transparency and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co-published by eight health economics and quality of life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in five years' time. This statement was published jointly in Applied Health Economics and Health Policy, Health and Quality of Life Outcomes, International Journal of Technology Assessment in Health Care, Journal of Medical Economics, Medical Decision Making, PharmacoEconomics, and Quality of Life Research

Shoulder pain due to cervical radiculopathy: an underestimated long-term complication of herpes zoster virus reactivation?

Purpose To evaluate if herpes zoster virus (HZV) reactivation may be considered in the aetiology of cervical radiculopathy. Methods The study group was composed of 110 patients (52 M-58F;mean age ± SD:46.5 ± 6.12; range:40-73) with a clinical diagnosis of cervical radiculopathy. Patients with signs of chronic damage on neurophysiological studies were submitted to an X-ray and to an MRI of the cervical spine in order to clarify the cause of the cervical radiculopathy and were investigated for a possible reactivation of HZV; HZV reactivation was considered as “recent” or “antique” if it occurs within or after 24 months from the onset of symptoms, respectively. Data were submitted to statistics. Results Thirty-eight patients (34,5%,16 M-22F) had a history of HZV reactivation: four (2 M-2F) were “recent” and 34 (14 M-20F) were “antique”. In 68 of 110 participants (61,8%,30 M-38F), pathological signs on X-ray and/or MRI of the cervical spine appeared; in the remaining 42 (38,2%,22 M-20F) X-ray and MRI resulted as negative. Among patients with HZV reactivation, seven (18,4%) had a “positive” X-ray-MRI while in 31 (81,6%) the instrumental exams were considered as negative. The prevalence of “antique” HZV reactivations was statistically greater in the group of patients with no pathological signs on X-ray/MRI of the cervical spine with respect to the group with a pathological instrumental exam (p < 0.01). Conclusions It may be useful to investigate the presence of a positive history of HZV reactivation and to consider it as a long-term complication of a cervical root inflammation especially in patients in which X-ray and MRI of the cervical spine did not show pathological findings

Synthetic nuclear diagnostics for inferring plasma properties of inertial confinement fusion implosions

A suite of synthetic nuclear diagnostics has been developed to post-process radiation hydrodynamics simulations performed with the code Chimera. These provide experimental observables based on simulated capsule properties and are used to assess alternative experimental and data analysis techniques. These diagnostics include neutron spectroscopy, primary and scattered neutron imaging, neutron activation, γ-ray time histories and carbon γ-ray imaging. Novel features of the neutron spectrum have been analysed to infer plasma parameters. The nT and nD backscatter edges have been shown to provide a shell velocity measurement. Areal density asymmetries created by low mode perturbations have been inferred from the slope of the downscatter spectrum down to 10 MeV. Neutron activation diagnostics showed significant aliasing of high mode areal density asymmetries when observing a capsule implosion with 3D multimode perturbations applied. Carbon γ-ray imaging could be used to image the ablator at a high convergence ratio. Time histories of both the fusion and carbon γ signals showed a greater time difference between peak intensities for the perturbed case when compared to a symmetric simulation

Role of Operon aaoSo-mutT in Antioxidant Defense in Streptococcus oligofermentans

Previously, we have found that an insertional inactivation of aaoSo, a gene encoding L-amino acid oxidase (LAAO), causes marked repression of the growth of Streptococcus oligofermentans. Here, we found that aaoSo and mutT, a homolog of pyrophosphohydrolase gene of Escherichia coli, constituted an operon. Deletion of either gene did not impair the growth of S. oligofermentans, but double deletion of both aaoSo and mutT was lethal. Quantitative PCR showed that the transcript abundance of mutT was reduced for 13-fold in the aaoSo insertional mutant, indicating that gene polarity derived from the inactivation of aaoSo attenuated the expression of mutT. Enzymatic assays were conducted to determine the biochemical functions of LAAO and MutT of S. oligofermentans. The results indicated that LAAO functioned as an aminoacetone oxidase [47.75 nmol H2O2 (min·mg protein)–1]; and MutT showed the pyrophosphohydrolase activity, which removed mutagens such as 8-oxo-dGTP. Like paraquat, aaoSo mutations increased the expression of SOD, and addition of aminoacetone (final concentration, 5 mM) decreased the mutant’s growth by 11%, indicating that the aaoSo mutants are under ROS stress. HPLC did reveal elevated levels of cytoplasmic aminoacetone in both the deletion and insertional gene mutants of aaoSo. Electron spin resonance spectroscopy showed increased hydroxyl radicals in both types of aaoSo mutant. This demonstrated that inactivation of aaoSo caused the elevation of the prooxidant aminoacetone, resulting the cellular ROS stress. Our study indicates that the presence of both LAAO and MutT can prevent endogenous metabolites-generated ROS and mutagens. In this way, we were able to determine the role of the aaoSo-mutT operon in antioxidant defense in S. oligofermentans

Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research