tbuckley/cabot-search huggingface dataset:
VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells
Authors: Tilman Schneider-Hohendorf, Jan Rossaint, Hema Mohan, Daniel Böning, Johanna Breuer, Tanja Kuhlmann, Catharina C. Gross, Ken Flanagan, Lydia Sorokin, Dietmar Vestweber, Alexander Zarbock, Nicholas Schwab, Heinz Wiendl
Journal: The Journal of Experimental Medicine (2014)

The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients' T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM(+)/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM(+) cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier.
Bradykinin contribution to renal blood flow effect of angiotensin converting enzyme inhibitor in the conscious sodium-restricted dog.
Authors: B G Zimmerman, P C Raich, R J Vavrek, J M Stewart
Journal: Circulation Research (1990)

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)
Conservation and Diversification of Msx Protein in Metazoan Evolution
Authors: H. Takahashi, A. Kamiya, A. Ishiguro, A. C. Suzuki, N. Saitou, A. Toyoda, J. Aruga
Journal: Molecular Biology and Evolution (2007)

Msx (/msh) family genes encode homeodomain (HD) proteins that control ontogeny in many animal species. We compared the structures of Msx genes from a wide range of Metazoa (Porifera, Cnidaria, Nematoda, Arthropoda, Tardigrada, Platyhelminthes, Mollusca, Brachiopoda, Annelida, Echiura, Echinodermata, Hemichordata, and Chordata) to gain an understanding of the role of these genes in phylogeny. Exon-intron boundary analysis suggested that the position of the intron located N-terminally to the HDs was widely conserved in all the genes examined, including those of cnidarians. Amino acid (aa) sequence comparison revealed 3 new evolutionarily conserved domains, as well as very strong conservation of the HDs. Two of the three domains were associated with Groucho-like protein binding in both a vertebrate and a cnidarian Msx homolog, suggesting that the interaction between Groucho-like proteins and Msx proteins was established in eumetazoan ancestors. Pairwise comparison among the collected HDs and their C-flanking aa sequences revealed that the degree of sequence conservation varied depending on the animal taxa from which the sequences were derived. Highly conserved Msx genes were identified in the Vertebrata, Cephalochordata, Hemichordata, Echinodermata, Mollusca, Brachiopoda, and Anthozoa. The wide distribution of the conserved sequences in the animal phylogenetic tree suggested that metazoan ancestors had already acquired a set of conserved domains of the current Msx family genes. Interestingly, although strongly conserved sequences were recovered from the Vertebrata, Cephalochordata, and Anthozoa, the sequences from the Urochordata and Hydrozoa showed weak conservation. Because the Vertebrata-Cephalochordata-Urochordata and Anthozoa-Hydrozoa represent sister groups in the Chordata and Cnidaria, respectively, Msx sequence diversification may have occurred differentially in the course of evolution. We speculate that selective loss of the conserved domains in Msx family proteins contributed to the diversification of animal body organization.
Phylogenetic inference: how much evolutionary history is knowable?
Authors: J A Lake
Journal: Molecular Biology and Evolution (1997)

In order to reconstruct phylogenetic trees from extremely dissimilar sequences it is necessary to estimate accurately the extent of sequence divergence. In this paper a new method of sequence analysis, Markov triple analysis, is developed for determining the relative frequencies of nucleotide substitutions within the three branches of a three-taxon dendrogram. Assuming that nucleotide sites are independently and identically distributed and assuming a Markov model for nucleotide (or protein) evolution, it is shown that the unique Markov matrices can be reconstructed given only the joint probability distribution relating three taxa. (In the much simpler case involving only two taxa and two character states, Markov matrices can also be reconstructed, provided symmetry assumptions are placed on the elements of the matrices.) The method is illustrated using sequence data from the combined first and second codon positions derived from complete human, mouse, and cow mitochondrial sequences.
Serum levels of trimethylpsoralen after oral administration
Authors: L. STOLK, A.H. SIDDIQUI, R.H. CORMANE
Journal: British Journal of Dermatology (1981)

Serum concentrations of trimethylpsoralen were determined for up to 5 h after oral administration in four patients with vitiligo. Measureable amounts of trimethylpsoralen were found in the serum only after administration of high oral doses (100 to 400 mg TMP).
Serum Protein-Bound Carbohydrates in Rheumatic Disease: I. RESULTS OF DIFFERENTIATED ANALYSES IN VARIOUS RHEUMATIC DISORDERS
Authors: L.E. Böttiger, Eva Malmquist, B. Olhagen
Journal: Annals of the Rheumatic Diseases (1964)

The differential diagnosis between rheumatoid arthritis (RA) with severe general symptoms and systemic lupus erythematosus (SLE) with marked articular involvement may be very difficult, as is sometimes the differentiation between other rheu- matic disorders.The possibility of using the diphenylamine reaction (test for sialic acid) as an aid in differential diagnosis has been discussed by Adam, Malecek, and Kuftova (1957).Stidworthy, Payne, Shetlar, and Shetlar (1957) recommended the deter- mination of protein-bound hexoses as a sign of activity and Bollet (1957) analysed protein-bound hexosamines, but we know no series wherein all these components have been analysed by chemical methods.We have studied a group of nearly 200 patients with rheumatic diseases to find out whether detailed analyses of serum protein-bound carbo- hydrates were of value in differential diagnosis.The protein-bound carbohydrates (hexoses, hexo- samines, and sialic acid) were analysed in whole serum and after zone electrophoretic separation in polyvinyl chloride. MaterialThe series comprised 187 in-and out-patients from the Department of Rheumatology, Karolinska Sjukhuset.The diagnostic criteria used were as follows:Rheumatoid Arthritis (RA).-All 61patients in this group fulfilled the diagnostic criteria of Ropes, Bennett, Cobb, Jacox, and Jessar (1959).The rheumatoid factor test was positive in 53 of them.Systemic Lupus Erythematosus (SLE).-Tenpatients had arthralgia or arthritis, signs of visceral involvement, increased serum gamma globulin levels, and a positive L.E.-cell test at some time or other.Only one patient in this group had a positive haemagglutination test for rheumatoid factor.method.Paper Electrophoresis.-In barbital buffer of pH 8-6 and ionic strength 0-1.489
UK doctors and equal opportunities in the NHS: national questionnaire surveys of views on gender, ethnicity and disability
Authors: Trevor Lambert, Geraldine Surman, Michael Goldacre
Journal: Journal of the Royal Society of Medicine (2014)

Objectives To seek doctors’ views about the NHS as an employer, our surveys about doctors’ career intentions and progression, undertaken between 1999 and 2013, also asked whether the NHS was, in their view, a good ‘equal opportunities’ employer for women doctors, doctors from ethnic minority groups and doctors with disabilities. Design and Setting Surveys undertaken in the UK by mail and Internet. Participants UK medical graduates in selected graduation years between 1993 and 2012. Main outcome measures Respondents were asked to rate their level of agreement with three statements starting ‘The NHS is a good equal opportunities employer for…’ and ending ‘women doctors’, ‘doctors from ethnic minorities’ and ‘doctors with disabilities’. Results Of first-year doctors surveyed in 2013, 3.6% (78/2158) disagreed that the NHS is a good equal opportunities employer for women doctors (1.7% of the men and 4.7% of the women); 2.2% (44/1968) disagreed for doctors from ethnic minorities (0.9% of white doctors and 5.8% of non-white doctors) and 12.6% (175/1387) disagreed for doctors with disabilities. Favourable perceptions of the NHS in these respects improved substantially between 1999 and 2013; among first-year doctors of 2000–2003, combined, the corresponding percentages of disagreement were 23.5% for women doctors, 23.1% for doctors from ethnic minorities and 50.6% for doctors with disabilities. Conclusions Positive views about the NHS as an equal opportunities employer have increased in recent years, but the remaining gap in perception of this between women and men, and between ethnic minority and white doctors, is a concern.
Resistance and Cross-Resistance of Cultured Leukemia P388 Cells to Vincristine, Adriamycin, Adriamycin Analogs, and Actinomycin D&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Lee J. Wilkoff, Elizabeth A. Dulmadge
Journal: JNCI Journal of the National Cancer Institute (1978)

Cultured P388 cells derived from leukemia P388 passaged in vivo in (C57BL X DBA/2)F1 mice were approximately one-tenth less sensitive to N-trifluoroacetyladriamycin-14-valerate (AD32) and cinerubin A, inasmuch as the concentrations of these agents had to be increased tenfold to produce a reduction in cell viability of the same order of magnitude as that produced by adriamycin, daunomycin, or actinomycin D. Cultured P388 cells derived from resistant cell populations developed in vivo retained their resistance to vincristine. These resistant cells exhibited cross-resistance to actinomycin D, adriamycin, daunomycin, and AD32, but cross-resistance to cinerubin A could not be detected. Data also showed that the vincristine-resistant cells were more sensitive to AD32 (2.8 x 10(-6) M) than to adriamycin (3.4 x 10(-6) M) during a 6-hour exposure of cells to agents.
MPF2-Like-A MADS-Box Genes Control the Inflated Calyx Syndrome in Withania (Solanaceae): Roles of Darwinian Selection
Authors: M. R. Khan, J.-Y. Hu, S. Riss, C. He, H. saedler
Journal: Molecular Biology and Evolution (2009)

The Chinese lantern, which is the inflated calyx syndrome (ICS) of Physalis, is formed by MPF2 in the presence of the plant hormones, cytokinin and gibberellin. MPF2 knockdown mutants of Physalis have small leaves, no ICS, and are male sterile, thus, revealing three MPF2-related functions. Of the close relatives of Physalis, Tubocapsicum has only a rudimentary calyx, whereas others, like the Withania species, have ICS. From all Withania samples tested, two classes of MPF2-like orthologs, MPF2-like-A and MPF2-like-B, were isolated, whereas only the latter class was obtained from tetraploid Tubocapsicum. Though distinct differences can be observed between MPF2-like-A and MPF2-like-B proteins, that is MPF2-like-A proteins have an aberrant structure in that they have a three amino acid deletion in their C-domain and an eight amino acid extension at the C-terminal end, MPF2-like-A genes are phylogenetically closer to the PhysalisMPF2-like genes. Unlike MPF2-like-B, the overexpression of MPF2-like-A in Arabidopsis revealed extra large sepals thus suggesting that MPF2-like-A genes are very likely responsible for the ICS formation in Withania. This correlated with the expression pattern of MPF2-like-A in vegetative and flower tissues, whereas MPF2-like-B is expressed only in vegetative tissues of Withania. In Tubocapsicum, however, MPF2-like-B RNA is detectable in all tissues tested. Finally, positive Darwinian selection was observed in the branch leading to Physalis MPF2-like and Withania MPF2-like-A proteins, followed by purifying selection once the trait had evolved. By contrast, purifying selection was detected for all other MPF2-like proteins tested. The contribution of the MPF2-like gene duplication to subfunctionalization is discussed.
Recent Declines in Hormone Therapy Utilization and Breast Cancer Incidence: Clinical and Population-Based Evidence
Authors: Christina A. Clarke, Sally L. Glaser, Connie S. Uratsu, Joseph V. Selby, Larry H. Kushi, Lisa J. Herrinton
Journal: Journal of Clinical Oncology (2006)

TO THE EDITOR: Long-term use of estrogen- or progestincontaining hormone therapies (HT) is well recognized to be associated with increased risk of breast cancer both in observational studies and the Women’s Health Initiative (WHI) randomized trial. 1 After the early termination of the trial in July 2002 and the subsequent media coverage, reports from clinical series indicated immediate declines of 28% to 46% in prevalences of HT and estrogen-only (ET) use. 2,3 The population-level impact of these declines on breast cancer are uncertain given the 2- to 3-year lag time between diagnosis and data availability in cancer registries. To better understand the possible impact from changes in HT on breast cancer in larger populations, we compared recent secular trends in HT use and breast cancer incidence in available clinical and population-based data resources, including recently released cancer registry data for the year 2004. We calculated the annual prevalence of HT use and the annual incidence of invasive breast cancer for the period from 1994 to 2003 for women ages 50 to 74 years in Kaiser Permanente’s (Oakland, CA) Northern California region (KPNC), a large integrated health-delivery system from which computerized pharmacy, membership, and hospital cancer registry data were obtained. Women filling at least two prescriptions (generally constituting 90 days per prescription) of HT or ET in any calendar year were considered users for that year. First primary invasive breast cancer (International Classification of Disease–Oncology, 3rd edition [ICDO-3] 4 site 50.0-50.9) diagnoses were identified, with histologic subtypes defined as ductal (ICD-O-3 codes 8500), or “with lobular component” (ICD-O-3 codes 8520, 8522, 8524). Yearly denominators included women who were KPNC members for at least 11 months of
The treatment of atopic dermatitis with adjunctive high-dose intravenous immunoglobulin: a report of three patients and review of the literature
Authors: S. Jolles, J. Hughes, M. Rustin
Journal: British Journal of Dermatology (2000)

There are few reports of the use of high-dose intravenous immunoglobulin (hdIVIg) in the treatment of atopic dermatitis (AD). We describe our experience using this therapy in three patients with severe AD, all of whom had steroid-related side-effects. These patients received either Alphaglobin(R) or Sandoglobulin(R) 2 g/kg monthly: all had improved skin scores, allowing reduction of their steroid dose. Total IgE fell in one of three patients. We discuss the side-effects of hdIVIg and their management, and detail the differences between the available immunoglobulin products available in the U.K. There are several proposed mechanisms of action of this therapy which may be operative, and those most important in AD are discussed. In view of the time and expense involved in the treatment of patients with hdIVIg, careful patient assessment is vital. We describe dose reduction strategies and methods for cost containment. In addition, one of the patients has embarked on IVIg home therapy training. This will be the first time this has been attempted for a dermatological indication. Training of this type may be available through an immunotherapy service such as exists for patients with primary immunodeficiencies.
Thymus-mediated immune tolerance to renal allograft is donor but not tissue specific.
Authors: N Perico, M Rossini, O Imberti, G Remuzzi
Journal: Journal of the American Society of Nephrology (1991)

Studies were conducted in Lewis (RT1l) rats to determine whether the process of unresponsiveness to kidney graft induced by the intrathymic glomerular transplantation were donor-strain specific as suggested by previous studies (Remuzzi et al., Lancet 1991;337:750-752). When glomeruli from Sprague-Dawley rats were injected in the thymus of Lewis rats, the subsequent kidney graft from a "third party" Brown-Norway (RT1n) rejected within 9 to 14 days. Moreover, an alternative site for glomerular antigen inoculation, such as i.p. administration, failed to induce a state of unresponsiveness to renal allograft. Whether tolerance was tissue specific was investigated by intrathymic injection of a preparation of donor blood cells that only included white cells. Such a maneuver, followed 10 days later by a kidney transplant, allowed indefinite renal graft survival in all animals, whereas all rats injected intrathymically with blood cell medium alone rejected the kidney graft in 8 to 11 days. Shortening the time interval between intrathymic injection of blood cells and kidney transplantation still allowed the graft to survive indefinitely. Finally, Lewis (RT1l) rats with chronic renal failure injected intrathymically with blood cells from Brown-Norway (RT1n) rats tolerated indefinitely a subsequent kidney graft from the same donor. These findings indicate that (1) the induction of immune tolerance to renal allograft induced by intrathymic injection of antigens is donor but not tissue specific; (2) the time interval between intrathymic injection of donor cells and the subsequent kidney transplantation can be reduced to 24 h; and (3) uremia does not preclude the possibility of renal allograft tolerance after the thymus procedure.
iNOS depletion completely diminishes reactive nitrogen-species formation after an allergic response
Authors: A. Koarai, M. Ichinose, H. Sugiura, M. Tomaki, M. Watanabe, S. Yamagata, Y. Komaki, K. Shirato, T. Hattori
Journal: European Respiratory Journal (2002)

Nitric oxide (NO) shows proinflammatory actions mainly via reactive nitrogen species (RNS) formation through superoxide- and peroxidase-dependent mechanisms. The purpose of this study was to examine the role of inducible NO synthase (iNOS) in RNS production, airway hyperresponsiveness, and inflammation after allergen challenge. Ovalbumin (OVA)-sensitised, iNOS-deficient and wild-type mice were used. RNS production was assessed by nitrotyrosine (NT) immunoreactivity in the airways. Airway inflammation and responsiveness were evaluated by eosinophil accumulation and methacholine (i.v.) challenge, respectively. In wild-type mice, OVA-inhalation challenge increased iNOS immunoreactivity in airway epithelial cells as well as iNOS protein measured by Western blotting. The total amounts of nitrite and nitrate in bronchoalveolar lavage (BAL) fluid were increased, and NT immunoreactivity was also observed abundantly in airway inflammatory cells. In iNOS-deficient mice, both iNOS expression and NT formation were completely abolished, and the total amounts of nitrite and nitrate in BAL fluid were significantly decreased. In contrast, OVA-induced airway eosinophil recruitment and hyperresponsiveness were observed almost equally in wild-type and iNOS-deficient mice. These data suggest that reactive nitrogen species production after allergic reaction occurs totally via inducible nitric oxide synthase-dependent pathways. Allergen-mediated airway eosinophil recruitment and hyperresponsiveness appear to be independent of reactive nitrogen species production.
The Quality of Life in Hand Eczema Questionnaire (QOLHEQ): validation of the German version of a new disease-specific measure of quality of life for patients with hand eczema
Authors: R.F. Ofenloch, E. Weisshaar, A.-K. Dumke, S. Molin, T.L. Diepgen, C. Apfelbacher
Journal: British Journal of Dermatology (2014)

Health-related quality of life (HRQOL) is widely used as a patient-reported outcome to evaluate clinical trials. In routine care it can also be used to improve treatment strategies or to enhance patients' self-awareness and empowerment. Therefore a disease-specific instrument is needed that assesses in detail all the impairments caused by the disease of interest. For patients with hand eczema (HE) such an instrument was developed by an international expert group, but its measurement properties are unknown.To validate the German version of the Quality of Life in Hand Eczema Questionnaire (QOLHEQ), which covers the domains of (i) symptoms, (ii) emotions, (iii) functioning and (iv) treatment and prevention.The QOLHEQ was assessed up to three times in 316 patients with HE to test reliability and sensitivity to change. To test construct validity we also assessed several reference measures. The scale structure was analysed using the Rasch model for each subscale and a structural equation model was used to test the multi domain structure of the QOLHEQ.After minor adaptions of the scoring structure, all four subscales of the QOLHEQ did not significantly misfit the Rasch model (α > 0·05). The fit indices of the structural equation model showed a good fit of the multi domain construct with four subscales assessing HRQOL. Nearly all a priori-defined hypotheses relating to construct validity could be confirmed. The QOLHEQ showed a sensitivity to change that was superior compared with all reference measures.The QOLHEQ is ready to be used in its German version as a sensitive outcome measure in clinical trials and for routine monitoring. The treatment-relevant subscales enable its use to enhance patients' self-awareness and to monitor treatment decisions.