tbuckley/cabot-search huggingface dataset:
Genetics and Early Detection in Idiopathic Pulmonary Fibrosis
Authors: Rachel K. Putman, Ivan O. Rosas, Gary M. Hunninghake
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Genetic studies hold promise in helping to identify patients with early idiopathic pulmonary fibrosis (IPF). Recent studies using chest computed tomograms (CTs) in smokers and in the general population have demonstrated that imaging abnormalities suggestive of an early stage of pulmonary fibrosis are not uncommon and are associated with respiratory symptoms, physical examination abnormalities, and physiologic decrements expected, but less severe than those noted in patients with IPF. Similarly, recent genetic studies have demonstrated strong and replicable associations between a common promoter polymorphism in the mucin 5B gene (MUC5B) and both IPF and the presence of abnormal imaging findings in the general population. Despite these findings, it is important to note that the definition of early-stage IPF remains unclear, limited data exist to definitively connect abnormal imaging findings to IPF, and genetic studies assessing early-stage pulmonary fibrosis remain in their infancy. In this perspective we provide updated information on interstitial lung abnormalities and their connection to IPF. We summarize information on the genetics of pulmonary fibrosis by focusing on the recent genetic findings of MUC5B. Finally, we discuss the implications of these findings and suggest a roadmap for the use of genetics in the detection of early IPF.
Rare finding of a gastrojejuno appendicular fistula during a laparotomy for roux-en-y conversion
Authors: Cunnigaiper Dhanasekaran Narayanan, Achi Ranganath Bhaskarapprakash, Balakumar Vijay, Shanthi Vijayaraghavan, Varadachari Srinivasan
Journal: International Journal of Surgery (2007)
Adult hippocampal neurogenesis and its role in Alzheimer's disease
Authors: Yangling Mu, Fred H Gage
Journal: Molecular Neurodegeneration (2011)

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.
Somatically mutated Ig VH3-21 genes characterize a new subset of chronic lymphocytic leukemia
Authors: Gerard Tobin, Ulf Thunberg, Anna Johnson, Ingrid Thörn, Ola Söderberg, Magnus Hultdin, Johan Botling, Gunilla Enblad, Jan Sällström, Christer Sundström, Göran Roos, Richard Rosenquist
Journal: Blood (2002)
Escalating incidence of eosinophilic esophagitis: A 20-year prospective, population-based study in Olten County, Switzerland
Authors: Petr Hruz, Alex Straumann, Christian Bussmann, Pius Heer, Hans-Uwe Simon, Marcel Zwahlen, Christoph Beglinger, Alain M. Schoepfer
Journal: Journal of Allergy and Clinical Immunology (2011)
Involvement of BK α subunit tyrosine phosphorylation in vascular hyporesponsiveness of superior mesenteric artery following hemorrhagic shock in rats
Authors: R ZHOU, L LIU, D HU
Journal: Cardiovascular Research (2005)

Vascular hyporesponsiveness is a major complication following severe trauma and shock. It plays important roles in the development of shock and seriously interferes with the treatment of shock. The mechanism responsible for the occurrence of vascular hyporesponsiveness has not been fully understood. The purpose of this study was to determine whether the alpha subunit tyrosine sites of large conductance calcium-activated potassium channel (BK(Ca)) could be phosphorylated and whether the phosphorylation of BK(Ca) was closely associated with the activation of BK(Ca) and the development of vascular hyporesponsiveness following hemorrhagic shock in rats.A hemorrhagic shock (30 mm Hg for 0.5, 2, 4 h) model of Wistar rats was established. Phosphorylation of tyrosine residues of the BK(Ca) alpha subunit from vascular smooth muscle cells (VSMC) in superior mesenteric arteries (SMA) was detected by immunoprecipitation and Western blotting. BK(Ca) activity was evaluated by cell-attached patch clamping. The vascular responsiveness of SMA to norepinephrine was measured with an isolated organ perfusion system.The level of BK(Ca) alpha subunit tyrosine phosphorylation was increased in a time-dependent manner following hemorrhagic shock, which was mediated by protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP). The activation of VSMC BK(Ca) following hemorrhagic shock was inhibited by genistein (2x10(-5) mol/L), the permeable isoflavone PTK inhibitor, and was potentiated by the PTP inhibitor sodium orthovanadate (Na(3)VO(4), 10(-3) mol/L). The decreased vasoresponsiveness following hemorrhagic shock was partly restored by genistein (10(-5) mol/L) or by the BK(Ca)-selective inhibitor tetrabutylammonium chloride (0.1 mmol/L), while it was further decreased by Na(3)VO(4) (10(-5) mol/L).The tyrosine residues of BK(Ca) alpha subunit of SMA were phosphorylated following hemorrhagic shock, which was regulated by PTK and PTP and appeared to be related to the activation of BK(Ca) and the development of vascular hyporesponsiveness following hemorrhagic shock.
Ultraviolet B but not Ultraviolet A Radiation Initiates Melanoma
Authors: Edward C. De Fabo, Frances P. Noonan, Thomas Fears, Glenn Merlino
Journal: Cancer Research (2004)

Abstract Cutaneous malignant melanoma is one of the fastest increasing cancers with an incidence that has more than doubled in the last 25 years. Sunlight exposure is strongly implicated in the etiology of cutaneous malignant melanoma and the UV portion of the sunlight spectrum is considered responsible. Data are, however, conflicting on the roles of ultraviolet B [UVB; 280–320 nanometers (nm)] and ultraviolet A (UVA; 320–400 nm), which differ in their ability to initiate DNA damage, cell signaling pathways and immune alterations. To address this issue, we have used specialized optical sources, emitting isolated or combined UVB or UVA wavebands or solar simulating radiation, together with our hepatocyte growth factor/scatter factor-transgenic mouse model of UV-induced melanoma that uniquely recapitulates human disease. Only UVB-containing sources initiated melanoma. These were the isolated UVB waveband (&amp;gt;96% 280–320 nm), the unfiltered F40 sunlamp (250–800 nm) and the solar simulator (290–800 nm). Kaplan-Meier survival analysis indicated that the isolated UVB waveband was more effective in initiating melanoma than either the F40 sunlamp or the solar simulator (modified log rank P &amp;lt; 0.02). The latter two sources showed similar melanoma effectiveness (P = 0.38). In contrast, transgenic mice irradiated with either the isolated UVA waveband (&amp;gt;99.9% 320–400 nm, 150 kJ/m2), or an F40 sunlamp filtered to remove &amp;gt; 96% of the UVB, responded like unirradiated control animals. We conclude that, within the constraints of this animal model, UVB is responsible for the induction of mammalian cutaneous malignant melanoma whereas UVA is ineffective even at doses considered physiologically relevant. This finding may have major implications with respect both to risk assessment from exposure to solar and artificial UVB, and to development of effective protection strategies against melanoma induction by UVB. Moreover, these differences in wavelength effectiveness can now be exploited to identify UV pathways relevant to melanomagenesis.
The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema
Authors: E. Wauters, D. Smeets, J. Coolen, J. Verschakelen, P. De Leyn, M. Decramer, J. Vansteenkiste, W. Janssens, D. Lambrechts
Journal: European Respiratory Journal (2011)

Clinical studies suggest that bronchial obstruction and emphysema increase susceptibility to lung cancer. We assessed the possibility of a common genetic origin and investigated whether the lung cancer susceptibility locus on chromosome 5p15.33 increases the risk for bronchial obstruction and emphysema. Three variants in the 5p15.33 locus encompassing the TERT and CLPTM1L genes were genotyped in 777 heavy smokers and 212 lung cancer patients. Participants underwent pulmonary function tests and computed tomography of the chest, and completed questionnaires assessing smoking behaviour. The rs31489 C-allele correlated with reduced forced expiratory volume in 1 s (p=0.006). Homozygous carriers of the rs31489 C-allele exhibited increased susceptibility to bronchial obstruction (OR 1.82, 95% CI 1.24–2.69; p=0.002). A similar association was observed for diffusing capacity of the lung for carbon monoxide (p=0.004). Consistent with this, CC-carriers had an increased risk of emphysema (OR 2.04, 95% CI 1.41–2.94; p=1.73×10 −4 ) and displayed greater alveolar destruction. Finally, CC-carriers also had an increased risk for lung cancer (OR 1.90, 95% CI 1.21–2.99; p=0.005), and were more susceptible to developing both lung cancer and bronchial obstruction than lung cancer alone (OR 2.11, 95% CI 1.04–4.26; p=0.038). The rs31489 variant on 5p15.33 is associated with bronchial obstruction, presence and severity of emphysema, and lung cancer.
Beneficial Effects of Combined Colestipol-Niacin Therapy on Coronary Atherosclerosis and Coronary Venous Bypass Grafts
Authors: David H. Blankenhorn
Journal: JAMA (1987)

The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol hydrochloride and niacin therapy in 162 nonsmoking men aged 40 to 59 years with previous coronary bypass surgery. During two years of treatment there was a 26% reduction in total plasma cholesterol, a 43% reduction in low-density lipoprotein cholesterol, plus a simultaneous 37% elevation of high-density lipoprotein cholesterol. This resulted in a significant reduction in the average number of lesions per subject that progressed (<i>P</i>&lt;.03) and the percentage of subjects with new atheroma formation (<i>P</i>&lt;.03) in native coronary arteries. Also, the percentage of subjects with new lesions (<i>P</i>&lt;.04) or any adverse change in bypass grafts (<i>P</i>&lt;.03) was significantly reduced. Deterioration in overall coronary status was significantly less in drug-treated subjects than placebo-treated subjects (<i>P</i>&lt;.001). Atherosclerosis regression, as indicated by perceptible improvement in overall coronary status, occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated (<i>P</i>=.002). (<i>JAMA</i>1987;257:3233-3240)
Regulation of IgG memory responses by helper and suppressor T cells activated by the type 2 antigen, polyvinylpyrrolidone.
Authors: H Braley-Mullen
Journal: The Journal of Experimental Medicine (1985)

T cells from CAF1 mice immunized with various amounts of the type 2 antigen polyvinylpyrrolidone (PVP) were assessed for their ability to provide help to PVP-specific memory B cells for the production of IgG. Low doses (0.0025 micrograms) of PVP consistently activated helper T cells (Th), which were required for the production of IgG by primed B cells. In contrast, T cells from mice primed with higher amounts (0.25 or 25 micrograms) of PVP did not provide significant help to the same B cells for IgG production. Moreover, when mixed with B cells and low-dose PVP-primed Th, T cells from mice primed with 0.25 or 25 micrograms PVP suppressed PVP-specific IgG, but not IgM antibody responses. The suppressor cells induced by higher amounts of PVP were eliminated either by injecting cyclophosphamide (CY) before priming with PVP, or by treating the primed T cells with anti-Lyt-2.2 and C before transfer. Pretreatment of suppressor T cell (Ts) donors with CY or removal of Lyt-2+ T cells not only eliminated Ts activity, but also unmasked significant Th activity in the T cells from high-dose PVP-primed mice. Thus, both low and high amounts of PVP can activate Th, although high amounts of PVP also induce Ts, the activity of which predominates in a normal unfractionated T cell population. The amount of PVP (0.0025 micrograms) that induces dominant help for IgG memory responses was only marginally immunogenic for induction of primary PVP-specific IgM responses, while 0.25 and 25 micrograms PVP, which induce dominant suppression for IgG memory responses, are optimally immunogenic for primary IgM responses. These results are discussed in the context of the inability of most type 2 antigens to elicit primary IgG responses or to prime memory B cells for production of IgG, responses which are dependent on the function of antigen-specific Th.
Calcium and potassium are important regulators of barrier homeostasis in murine epidermis.
Authors: S H Lee, P M Elias, E Proksch, G K Menon, M Mao-Quiang, K R Feingold
Journal: Journal of Clinical Investigation (1992)

Topical solvent treatment removes lipids from the stratum corneum leading to a marked increase in transepidermal water loss (TEWL). This disturbance stimulates a variety of metabolic changes in the epidermis leading to rapid repair of the barrier defect. Using an immersion system we explored the nature of the signal leading to barrier repair in intact mice. Initial experiments using hypotonic to hypertonic solutions showed that water transit per se was not the crucial signal. However, addition of calcium at concentrations as low as 0.01 mM inhibited barrier repair. Moreover, both verapamil and nifedipine, which block calcium transport into cells, prevented the calcium-induced inhibition of TEWL recovery. Additionally, trifluoroperazine or N-6-aminohexyl-5-chloro-1-naphthalenesulfonamide, which inhibit calmodulin, prevented the calcium-induced inhibition of TEWL recovery. Although these results suggest an important role for calcium in barrier homeostasis, calcium alone was only modestly effective in inhibiting TEWL recovery. Potassium alone (10 mM) and phosphate alone (5 mM) also produced a modest inhibition of barrier repair. Together, however, calcium and potassium produced a synergistic inhibition of barrier repair (control 50% recovery vs. calcium + potassium 0-11% recovery in 2.5 h). Furthermore, in addition to inhibiting TEWL recovery, calcium and potassium also prevented the characteristic increase in 3-hydroxy-3-glutaryl CoA reductase activity that occurs after barrier disruption. Finally, the return of lipids to the stratum corneum was also blocked by calcium and potassium. These results demonstrate that the repair of the epidermal permeability barrier after solvent disruption can be prevented by calcium, potassium, and phosphate. The repair process may be signalled by a decrease in the concentrations of these ions in the upper epidermis resulting from increased water flux leading to passive loss of these ions.
Antiplectin autoantibodies in subepidermal blistering diseases
Authors: J.J.A. Buijsrogge, M.C.J.M. de Jong, G.J. Kloosterhuis, M.H. Vermeer, J. Koster, A. Sonnenberg, M.F. Jonkman, H.H. Pas
Journal: British Journal of Dermatology (2009)

Hemidesmosomal proteins may become targets of autoimmunity in subepidermal blistering diseases. Well-known recognized autoantigens are the intracellular plaque protein BP230, the transmembrane BP180 and its shed ectodomain LAD-1.To establish the prevalence of autoimmunity against plectin, another intracellular plaque protein, and to investigate its antigenic sites.Two hundred and eighty-two patients with subepidermal blistering diseases, investigated by routine immunoblot analysis for possible antiplectin antibodies, were included in the study. Epitope mapping was performed using recombinantly produced overlapping plectin domains from the actin-binding domain to the rod domain. The COOH-terminal region of plectin was not included in the study.In 11 of 282 (3.9%) patients an immunoblot staining pattern identical to that of antiplectin monoclonal antibody HD121 was found. Affinity-purified antibodies bound back to normal human skin in a pattern typical for plectin, i.e. to the epidermal basement membrane zone as well as to keratinocytes in the epidermis, and to myocytes. No binding was seen to plectin-deficient skin of a patient with epidermolysis bullosa simplex with muscular dystrophy. Epitope mapping of the plectin molecule showed that the central coiled-coil rod domain is an immunodominant hotspot as 92% of the sera with antiplectin antibodies reacted with it. Most patients with antiplectin antibodies also had antibodies to other pemphigoid antigens.Plectin is a minor pemphigoid antigen with an immunodominant epitope located on the central rod domain.
Influence of guideline adherence on outcome in a randomised controlled trial on the efficacy of methotrexate with folate supplementation in rheumatoid arthritis
Authors: J Fransen
Journal: Annals of the Rheumatic Diseases (2004)

To study the influence of rheumatologists' adherence to a methotrexate guideline on efficacy and toxicity in the treatment of rheumatoid arthritis.In a 48 week randomised controlled trial of methotrexate, comparing folates with placebo, rheumatologists were advised on methotrexate dosage using a guideline reflecting daily practice. The influence of guideline non-adherence on outcome was analysed using generalised estimating equations and survival analysis.In 51% of the 411 study patients the guidelines were always followed. Non-adherence resulted in lower doses of methotrexate in 25% of cases, and higher doses in 24%. The reduction in the disease activity score was significantly greater (mean -0.4; p = 0.0085) in the adherent group than in the "low dose" group; the "high dose" group did not differ from the adherent group. Dropout caused by severe adverse events did not differ between the three groups.There is an indication that adherence to guidelines on methotrexate dosage may benefit patients with rheumatoid arthritis by improving disease activity without increasing toxicity. For definite proof, a randomised controlled trial comparing guideline supported dosing with usual care is needed.
Antisignal Recognition Particle Antibodies–Related Cardiomyopathy
Authors: Mathilde Thiébaut, Benjamin Terrier, Samia Menacer, Alice Berezne, Guillaume Bussone, Claire Goulvestre, Rémi Bellance, Loïc Guillevin, Olivier Vignaux, Luc Mouthon
Journal: Circulation (2013)
Urinary excretion of aquaporin-2 water channel protein in human and rat.
Authors: T Rai, K Sekine, K Kanno, K Hata, M Miura, A Mizushima, F Marumo, S Sasaki
Journal: Journal of the American Society of Nephrology (1997)

Previous studies by the authors demonstrated that the response of urinary aquaporin-2 (AQP2) excretion to dDAVP (deamino-8-D-arginine vasopressin) infusion is an index of vasopressin action on the kidney (N Engl J Med 332: 1540-1545, 1995). In the study presented here, the characteristics of urinary excretion of AQP2 were examined further. An RIA suitable for AQP2 in the urine was established. Relatively high concentrations of detergent and bovine serum albumin in the RIA buffer allowed analysis of urine samples with a wide range of concentrations and increased the sensitivity of the assay. AQP2 in the urine existed as a high molecular weight form of approximately 190 kD by HPLC analysis. The mean urinary AQP2 concentration corrected for creatinine in spot urine samples of healthy subjects who voided in the morning was 1081 +/- 699 fmol/mg creatinine (mean +/- SD, n = 208). The amount of daily excretion of AQP2 in the urine was the same in men and women. Urinary AQP2 content was not affected by age of the subjects and showed a positive correlation with urine osmolality. Finally, the fraction of AQP2 excreted in the urine compared with whole kidney content was determined in the rat. Approximately 3% of AQP2 in the kidney was excreted daily, and this fraction did not change when rats were dehydrated for 3 d. These data demonstrate the necessity of establishing well-designed protocols to use urinary AQP2 as a marker of AVP action.
Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone
Authors: Fernand Labrie, Van Luu-The, Claude Labrie, Alain Bélanger, Jacques Simard, Sheng-Xiang Lin, Georges Pelletier
Journal: Endocrine Reviews (2003)

Serum androgens as well as their precursors and metabolites decrease from the age of 30–40 yr in women, thus suggesting that a more physiological hormone replacement therapy at menopause should contain an androgenic compound. It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin. Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and characterization of most of the enzymes responsible for the transformation of DHEA and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids. The sex steroids made in peripheral tissues are then inactivated locally into more water-soluble compounds that diffuse into the general circulation where they can be measured. In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects. The advantage of DHEA over other androgenic compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side effects observed with androgens or estrogens administered systemically.
High-resolution MRI for assessment of middle meningeal artery involvement in giant cell arteritis
Authors: T A Bley, J Geiger, S Jacobsen, O Wieben, M Markl, P Vaith, T Grist, M Langer, M Uhl
Journal: Annals of the Rheumatic Diseases (2009)

Giant cell arteritis (GCA) typically involves the superficial cranial arteries, the aorta and its branches. It has been discussed to which extent the vasculitic changes of the cranial arteries continue into the intracranial region. Autopsy findings have indicated that the characteristic signs of arteritic inflammation of GCA end after crossing the dural border.1 In a recent review of several published cases it was concluded that intracranial/intradural involvement in GCA is rare and represents a small subset of GCA that is non-responsive to corticosteroids and has a fatal course.2

Contrast-enhanced, high-resolution MRI allows non-invasive assessment of mural inflammation in the extracranial, superficial arteries in giant cell arteritis.3 Here, we report MRI findings suggestive of intracranial vasculitic involvement in patients with GCA. High-resolution MRI of …