tbuckley/cabot-search huggingface dataset:
Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells.
Authors: V Brinkmann, T Geiger, S Alkan, C H Heusser
Journal: The Journal of Experimental Medicine (1993)

An increased ratio of T helper type 2 (Th2)- vs Th1-like cells contributes to the immune dysregulation in allergic disease situations and in many chronic infections, including AIDS. Th2-type immune responses are characterized by Th cells that produce increased levels of interleukin-4 (IL-4) and decreased levels of interferon gamma (IFN-gamma). The induction of either a Th1- or a Th2-like phenotype may be critically controlled by the antigen-presenting cells and their cytokines, e.g., IFN-alpha. In this study we have determined the frequencies of potential IL-4- and/or IFN-gamma-producing T cells in the peripheral blood of randomly selected healthy individuals, and analyzed whether IFN-alpha controls IL-4 and/or IFN-gamma production. Purified CD4+ or CD8+ T cells were stimulated for 24 h via the T cell receptor/CD3 complex in the presence or absence of IFN-alpha, and single IL-4- and IFN-gamma-secreting cells were detected in enzyme-linked immunospot assays. In the absence of IFN-alpha, CD4 cells produced IFN-gamma at frequencies of 1:50-300, and produced IL-4 at frequencies of 1:110-&amp;lt;1:100,000. Addition of IFN-alpha during the activation of CD4 cells increased the levels of IFN-gamma mRNA. As a consequence, the numbers of IFN-gamma-producing CD4 cells and the amounts of secreted IFN-gamma increased 10-fold. In contrast, IFN-alpha did not increase the frequency of IL-4-secreting CD4 cells. In the absence of IFN-alpha, addition of exogenous IL-4 to cultures of CD4 cells suppressed IFN-gamma secretion by 70%. However, in the presence of IFN-alpha, IL-4 did not display any suppressive effect. Compared with CD4 cells, CD8 cells produced IFN-gamma more frequently (1:5-10) but IL-4 less frequently (1:5,300 to &amp;lt; 1:100,000). IFN-alpha did not display any effect on the frequency of either IFN-gamma or IL-4 production by CD8 cells. Taken together the results indicate that IFN-alpha increases the frequency of IFN-gamma-secreting CD4 Th cells and antagonizes the suppressive effect of IL-4 on IFN-gamma production. As a consequence, IFN-alpha may favor the induction and maintenance of Th1-like cells and thereby counteract Th2-driven allergic immune responses.
Bronchiectasis in Germany: a population-based estimation of disease prevalence
Authors: Felix C. Ringshausen, Andrés de Roux, Roland Diel, David Hohmann, Tobias Welte, Jessica Rademacher
Journal: European Respiratory Journal (2015)

Bronchiectasis is a chronic and progressive disease, which frequently is associated with a significant symptom burden and which may require intensive treatment. To date, epidemiological data on the prevalence of bronchiectasis in Europe are exceedingly scarce due to a great lack of research [1]. However, these data on disease burden are important in order to inform authorities and to allocate resources in healthcare [2], in particular as bronchiectasis is associated with high healthcare system usage as well as significant morbidity and mortality [3, 4]. The aim of the present study was to estimate the overall prevalence of bronchiectasis in Germany over a 1-year period from a representative sample of routine statutory health insurance claim data, with special attention paid to the distribution of age and sex, and the site of healthcare provision, as well as chronic obstructive pulmonary disease (COPD) as a concomitant condition. Robust evidence for the prevalence of bronchiectasis in Germany and its association with chronic airflow obstruction <http://ow.ly/QvSBo> Data adjustment and analysis were performed by the Health Risk Institute in coordination with Elsevier Health Analytics (both Berlin, Germany).
Enhancement of platelet response to immune complexes and IgG aggregates by lipid A-rich bacterial lipopolysaccharides.
Authors: M H Ginsberg, P M Henson
Journal: The Journal of Experimental Medicine (1978)

The effect of the common lipid moiety of bacterial LPS on secretion from washed human platelets has been studied. The lipid A-rich LPS of S. minnesota R595 and a lipid A preparation both potentiated platelet serotonin secretion in response to IgG aggregates or immune complexes up to 50-fold but had little effect in the absence of IgG. Lipid A has been shown to bind immune aggregates, raising the possibility that its mechanism of action involved effective enlargement or insolubilization of the aggregates. IgG aggregates of dimer to tetramer size were shown to be platelet simuli, equivalent on a weight basis to larger soluble aggregates. The effect of both sizes of aggregates on platelets were equally enhanced by the LPS, indicating that increased size of aggregates alone could not account for the effect of LPS. Similarly, because lipid A-rich LPS enhanced platelet response to already insoluble immune complexes, its mechanism of action cannot simply be insolubilization of immune aggregates. These LPS did not enhance platelet stimulation by antiplatelet antibody, monosodium urate crystals, or thrombin and only slightly enhanced stimulation by insoluble human skin collagen. This indicates some stimulus specificity in the ability of LPS to increase platelet secretion. The enhancement of cell response to immune complexes by the common lipid region of LPS may represent a mechanism for the diverse effects of LPS in vivo and in vitro.
Recurrent diabetic ketoacidosis after changing pen devices for insulin injection
Authors: Vishal Rai Bhardwaj, Neil Metcalfe, Emma Innes, Esther Harrison, David Jenkins
Journal: BMJ (2006)

Diabetic ketoacidosis is a state of severe uncontrolled diabetes mellitus caused by severe insulin deficiency. It is characterised by hyperglycaemia, hyperketonaemia, and metabolic acidosis.1 Diabetic ketoacidosis is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus,2 and in Western countries the overall mortality is 5-10%.1–3 Common precipitating causes include infection and inadequate dose of insulin resulting from non-adherence, failure to follow “sick day” rules (advice on increasing insulin during intercurrent illness), and poor injection technique.4 We have recently encountered two patients with recurrent diabetic ketoacidosis caused by unrecognised difficulty in switching from one type of prefilled insulin injection device to another.



Fig 2 
To administer insulin with the FlexPen, the dose is measured by dialling the appropriate number of units on the dose selector. The button is pushed to expel insulin via a needle attached to the clear barrel of the device. “Reverse dialling” of the dose selector does not expel insulin



### Case 1

A 68 year old man with type 1 diabetes mellitus was admitted to hospital with critically ischaemic feet. A vascular opinion deemed the right foot to be unsalvageable and an emergency below knee amputation was performed. Postoperatively the patient was stable and …
PTU-136 Does A Normal Igg Indicate Histological Remission In Autoimmune Hepatitis (aih)?
Authors: VM Gordon, E McFarlane, A Dube, D Gleeson
Journal: Gut (2014)

<h3>Introduction</h3> Response to immunosuppressive treatment in AIH is often monitored by measurement of serum immunoglobulin G (IgG) as well as ALT. It is commonly assumed that serum IgG level correlates with histological activity (or Ishak necroinflammatory score: NIS) on liver biopsy, the historical “gold standard”. However, only one group (Luth <i>et al</i> 2008; J of Clin 42(8):926–930.) have examined this relationship, finding that normalisation of both serum ALT and IgG reliably predicted a NIS of &lt;6 but not a NIS of &lt;4 (corresponding to minimal hepatitis, seen in less than half of the patients presumed to be in remission). Here, we aimed to reassess how well serum IgG correlated with NIS in treated patients with AIH undergoing follow-up biopsy for confirmation of disease remission. <h3>Methods</h3> We assessed 31 follow-up biopsies, performed to confirm histological remission in 28 patients with AIH (International Group criteria; Alvarez J Hepatol 1999; 31:929) on immunosuppressive treatment and an accompanying serum IgG (measured within 6 weeks of biopsy). <h3>Results</h3> For 29 of the 31 follow-up biopsies, accompanying serum IgG was in the normal range (≤16 gm/L). However, only 13 of these 31 biopsies showed NIS &lt;4 (minimal hepatitis). On ROC analysis, area under the curve (AUC) for IgG in predicting a NIS of ≥4 (n = 31) was 0.596 (p = 0.368). Sensitivity and specificity of IgG (cut off &gt;16 grm/L) in predicting a NIS of ≥4 was 5.5% and 57% respectively. Corresponding positive (PPV) and negative (NPV) predictive values were only 50% and 59% respectively. AUC for change in IgG (∆IgG: baseline values minus values accompanying follow up biopsy; n = 29) in predicting NIS &gt;4 was 0.551 (p = 0.642). Defining histological remission instead as minimal or mild hepatitis- NIS &lt;6 (as Luth’s group did because they found that such patients did not develop fibrosis progression), there were still 4/29 (14%) patients with normal serum IgG who were not in histological remission. On ROC analysis, AUC for IgG in prediction of NIS &gt;6 on follow-up biopsy (n = 31) was 0.62 (p = 0.39). PPV and NPV for serum IgG (cut off &gt;16 grm/L) in predicting of NIS ≥6) was 50% and 86% respectively. AUC for ∆IgG in prediction of NIS ≥6 was 0.608 (p = 0.453). <h3>Conclusion</h3> Normalisation of serum IgG values in patients with AIH following treatment is not predicative of histological remission. At present, this requires a liver biopsy. <h3>Disclosure of Interest</h3> None Declared.
Gas exchange after pulmonary thromboemoblization in dogs.
Authors: D R Dantzker, P D Wagner, V W Tornabene, N P Alazraki, J B West
Journal: Circulation Research (1978)

Gas exchange following experimental pulmonary thromboembolization was studied with an inert gas elimination technique in 17 dogs. Pulmonary arterial, systemic arterial, and expired gas concentrations of six gases infused intravenously were measured before embolization and 5, 10, 15, 30, 60, and 120 minutes after embolization. Distributions of ventilation-perfusion (VA/Q) ratios were derived from the measured concentrations. In all dogs, embolization caused an increase in blood flow and ventilation to VA/Q ratios less than 1. There were no lung units with VA/Q ratios between 10 and 100 before embolization, but, in two-thirds of the dogs, such regions developed after embolization. Ventilation to unperfused lung showed a transient increase of 2-6%. Radioisotope studies of lobes removed post-mortem indicated that thromboemboli rarely caused complete abolition of lobar blood flow. Pulmonary embolization did not cause arteriovenous shunts to appear. The hypoxemia caused by embolization could be accounted for by the changes in VA/Q distributions. Over the 2-hour period after embolization, lung function improved as the distributions partially returned toward the preembolization patterns.
HBsAG POSITIVE REACTIVITY IN MAN NOT DUE TO HEPATITIS B VIRUS
Authors: P. Coursaget, C. Bourdil, P. Adamowicz, J. Chotard, I.Diop Mar, B. Yvonnet, M.N. Mevelec, J.L. Barrès, R. N'Doye, J.P. Chiron
Journal: The Lancet (1987)
Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene regulatory protein.
Authors: L K Olson, J B Redmon, H C Towle, R P Robertson
Journal: Journal of Clinical Investigation (1993)

Chronically culturing HIT-T15 cells in media containing high glucose concentrations leads to decreased insulin mRNA levels, insulin content, and insulin secretion.These changes can be prevented by culturing the cells in media containing lower glu- cose levels (Robertson, R. P., H.
Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines
Authors: R. H. McMahan
Journal: Journal of Clinical Investigation (2006)

One approach to enhancing the T cell response to tumors is vaccination with mimotopes, mimics of tumor epitopes. While mimotopes can stimulate proliferation of T cells that recognize tumor-associated antigens (TAAs), this expansion does not always correlate with control of tumor growth. We hypothesized that vaccination with mimotopes of optimal affinity in this interaction will improve antitumor immunity. Using a combinatorial peptide library and a cytotoxic T lymphocyte clone that recognizes a TAA, we identified a panel of mimotopes that, when complexed with MHC, bound the TAA-specific TCR with a range of affinities. As expected, in vitro assays showed that the affinity of the TCR-peptide-MHC (TCR-pMHC) interaction correlated with activity of the T cell clone. However, only vaccination with mimotopes in the intermediate-affinity range elicited functional T cells and provided protection against tumor growth in vivo. Vaccination with mimotopes with the highest-affinity TCR-pMHC interactions elicited TAA-specific T cells to the tumor, but did not control tumor growth at any of the peptide concentrations tested. Further analysis of these T cells showed functional defects in response to the TAA. Thus, stimulation of an antitumor response by mimotopes may be optimal with peptides that increase but do not maximize the affinity of the TCR-pMHC interaction.
High Glucose Concentrations Increase Endothelial Cell Permeability via Activation of Protein Kinase Cα
Authors: Albrecht Hempel, Christian Maasch, Ute Heintze, Carsten Lindschau, Rainer Dietz, Friedrich C. Luft, Hermann Haller
Journal: Circulation Research (1997)

Abstract Endothelial cell permeability is impaired in diabetes mellitus and may be increased by high extracellular glucose concentrations. High glucose activates protein kinase C (PKC), a family of kinases vital to intracellular signaling. We tested the hypothesis that high glucose concentration activates PKC in endothelial cells and leads to an increase in endothelial cell permeability via distinct PKC isoforms. Porcine aortic endothelial cells were used, and the PKC isoforms α, δ, ε, ζ, and θ were identified in these cells. Glucose caused a rapid dose-dependent increase in endothelial cell permeability, with an EC 50 of 17.5 mmol/L. Phorbol 12-myristate 13-acetate (TPA) induced an increase in permeability very similar to that elicited by glucose. The effect of glucose and TPA was totally reversed by preincubating the cells with the PKC inhibitors staurosporine (10 −8 mol/L) and Goe 6976 (10 −8 mol/L). Downregulation of PKC by preincubation with TPA for 24 hours also abolished the effect of glucose and TPA on endothelial cell permeability. High glucose (20 mmol/L) caused an increase in PKC activity at 2, 10, and 30 minutes. Cell fractionation and Western blot analysis showed a glucose-induced translocation of PKCα and PKCε. Confocal microscopy confirmed the translocation and showed an association of PKCα and PKCε with nuclear structures and the cell membrane. Specific antisense oligodesoxynucleotides (ODNs) against PKCα reduced the expression of the isoform, abolished the effects of glucose on endothelial cell permeability completely, and reduced the TPA effect significantly. In contrast, specific antisense ODNs against PKCε had no effect on glucose-induced permeability and only a minor effect on the TPA-induced increase in permeability. We conclude that an increase in extracellular glucose leads to a rapid dose-dependent increase in endothelial cell permeability via the activiation of PKC and that this effect is mediated by the PKC isoform α.
Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome.
Authors: R Rebar, H L Judd, S S Yen, J Rakoff, G Vandenberg, F Naftolin
Journal: Journal of Clinical Investigation (1976)

To evaluate gonadotropin release in polycystic ovary syndrome (PCO), one or more of the following hypothalamic-pituitary function tests were performed on 24 patients with the syndrome. These tests included (a) the pulsatile pattern and day-to-day fluctuation of gonadotropin release; (b) effects of exogenous estrogen and antiestrogen (clomiphene) administration on gonadotropin release; and (c) pituitary responsiveness to maximal (150 mug) and submaximal (10 mug) luteinizing hormone-releasing factor (LRF) injections. In 10 of the 14 patients sampled frequently (15 min) for 6 h, luteinizing hormone (LH) levels were elevated above the concentration seen in normal cycling women (except the LH surge). These high LH concentrations appeared to be maintained by and temporally related to the presence of exaggerated pulsatile LH release, either in the form of enhanced amplitude or increased frequency. In all subjects, levels of follicle-stimulating hormone (FSH) were low or low normal, and a pulsatile pattern was not discernible. In four patients, daily sampling revealed marked day-to-day fluctuation of LH but not FSH. That the elevated LH levels were not related to a defect in the negative-feedback effect of estrogen was suggested by the appropriate fall of LH in four patients given an acute intravenous infusion of 17beta-estradiol. This infusion had no effect on FSH levels. In addition, clomiphene elicited rises of both LH and FSH that were comparable to the ones observed in normal women given the same treatment. The clomiphene study also suggested that the positive-feed-back mechanism of estrogen on LH release was intact when the preovulatory rises of 17beta-estradiol induced appropriate LH surges. The elevated LH levels appeared to be related to a heightened pituitary responsiveness to the LRF. This was found in the 11 and 2 patients given maximal (150 mug) and submaximal (10 mug) doses of LRF, respectively. The augmented pituitary sensitivity for LH release correlated with the basal levels of both estrone (P less than 0.025) and 17beta-estradiol (P less than 0.02). The net increase in FSH was significantly greater (P less than 0.001) in the PCO patients than the normal women with maximal doses of LRF. With the smaller dose study none of the injections had a discernible effect on FSH concentrations in either subject. The disparity between LH and FSH secretion could be explained by the preferential inhibitory action of estrogen on FSH release, coupled with a relative insensitivity of FSH release. These data indicate that in these PCO patients the abnormalities of the hypothalamic-pituitary regulation of gonadotropin secretion was not an inherent defect but represented a functional derangement consequent to inappropriate estrogen feedback, which led to a vicious cycle of chronic anovulation and inappropriate gonadotropin secretion.
Hormonochemotherapy in advanced breast cancer:: Authors' reply
Authors: M W Ghilchik, N A Shaikh, P A Beranek, M J Reed
Journal: BMJ (1987)

community services are provided.They may degenerate into a form of probation, with brief statutory home visits to supervise medication.In their favour, community treatment orders cut both ways.They both commit the patients to treatment and commit psychiatric teams to providing continuing care for these most disabled and challenging patients.
Pathogenic Role of Cyclic AMP in the Impairment of Urinary Concentrating Ability in Acute Hypercalcemia
Authors: Nama Beck, Harbans Singh, Sarah W. Reed, H. V. Murdaugh, Bernard B. Davis
Journal: Journal of Clinical Investigation (1974)

A possible association between the impairment of urinary concentrating ability and an impairment of the vasopressin-dependent cyclic AMP system in hypercalcemia was investigated in rat kidneys both in vivo and in vitro. The increases of urinary osmolality and negative free water clearance and the increase of urinary cyclic AMP excretion by vasopressin injection were significantly less in the hypercalcemic rats than in the control rats. The increase of cyclic AMP concentration by vasopressin in renal medullary tissue was significantly less in the slices obtained from the hypercalcem'c rats than in those obtained from the control rats. The activation of adenylate cyclase by vasopressin was significantly less in the group with an increased concentration of calcium in media than the control group, but phosphodiesterase activity was not affected by calcium concentration in the media. These data suggest that the impaired urinary concentrating ability in hypercalcemic kidneys is due at least in part to the direct inhibitory effect of calcium on the vasopressin-dependent cyclic AMP system at the level of adenylate cyclase in renal medulla.
A Pilot Trial of CTLA-4 Blockade with Human Anti-CTLA-4 in Patients with Hormone-Refractory Prostate Cancer
Authors: Eric J. Small, N. Simon Tchekmedyian, Brian I. Rini, Lawrence Fong, Israel Lowy, James P. Allison
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) augments and prolongs T-cell responses and is a strategy to elicit antitumor immunity. The objectives of this pilot study were to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of the anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with Ipilimumab. Experimental Design: Patients with metastatic hormone-refractory prostate cancer received a single 3 mg/kg i.v. dose of Ipilimumab. Serologic measures of autoimmunity were obtained, and T-cell activation was evaluated by flow cytometry. Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement, and diagnostic imaging were also undertaken. Results: Fourteen patients were treated: 12 patients received a single dose of Ipilimumab, and 2 patients were re-treated with a second dose upon PSA progression. Two patients showed PSA declines of ≥50%. Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritis requiring systemic corticosteroids. The mean ± SD Ipilimumab terminal elimination half-life was 12.5 ± 5.3 days. Conclusions: A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity. PSA-modulating effects observed warrant further investigation.