tbuckley/cabot-search huggingface dataset:
Human cardiac inwardly rectifying current IKir2.2 is upregulated by activation of protein kinase A
Authors: E ZITRON
Journal: Cardiovascular Research (2004)

The cardiac inwardly rectifying potassium current IK1 and its molecular correlates Kir2.1 and Kir2.2 play an important role in cardiac repolarisation and in the pathogenesis of hereditary long-QT syndrome (LQTS-7). Protein kinases A (PKA) and C (PKC) are key enzymes in adrenergic signal transduction, inducing arrhythmias in heart disease. This study investigated the regulation of Kir2.2 (KCNJ12) by PKA.Cloned Kir2.2 channels were expressed heterologously in Xenopus oocytes and currents were measured with the double-electrode voltage-clamp technique.After activation of PKA by forskolin (100 micromol/l) or Ro-20-1724 (100 micromol/l), wild type currents at -120 mV were increased by 93.7% and 79.0%, respectively. Coapplication of the PKA inhibitor KT-5720 (2.5 micromol/l) attenuated this effect. No significant changes were apparent after mutation of the single PKA consensus site S430. In addition, removal of all four PKC consensus sites in Kir2.2 induced a phorbolester-mediated current increase which could be suppressed by PKA inhibitors H-89 (50 micromol/l) and KT-5720 (2.5 micromol/l).This study demonstrates antagonistic effects of PKA and PKC in the regulation of Kir2.2. Phosphorylation by PKC has been shown to cause an inhibition of Kir2.2 currents, whereas activation of PKA leads to current upregulation.
Distinguishing Ménétrier's disease from its mimics
Authors: Amy Rich, Tania Zuluaga Toro, Jarred Tanksley, William H Fiske, Christopher D Lind, Gregory D Ayers, Hubert Piessevaux, Mary K Washington, Robert J Coffey
Journal: Gut (2010)

<h3>ABSTRACT</h3> Autologous bone graft remains the gold standard by which bone graft substitutes are compared in spine fusion surgery. The utilization of bone graft substitutes, either as (1) an extender for spinal fusion constructs or (2) an alternative to minimize morbidity while maximizing outcomes, is changing. Moreover, current procedural technology (CPT) code 20939 became effective in 2018 defining bone marrow aspirate for bone grafting, spine surgery only. Changes in the complex landscape of grafting materials have prompted ISASS to provide category guidance for bone graft substitutes by comparing and contrasting US regulatory pathways, mechanisms of action, and supportive clinical evidence for these bone grafting materials.
A naturally occurring soluble isoform of murine Fas generated by alternative splicing.
Authors: D P Hughes, I N Crispe
Journal: The Journal of Experimental Medicine (1995)

We report a soluble isoform of mouse Fas, which is generated by alternative splicing of Fas mRNA to a newly identified exon located between exons 2 and 3 of the previously published Fas sequence. This splicing event creates a novel Fas transcript, Fas beta, with the potential to encode a truncated form of the extracellular domain, termed Fas B. In vitro, P815 mastocytoma cells transfected with Fas B become resistant to Fas ligand-induced apoptosis, and the resistance is mediated by a secreted product of the transfected cells. In vivo, Fas beta mRNA expression is correlated inversely with apoptosis among subsets of intrahepatic T lymphocytes, a cell population in which activation-induced T cell apoptosis occurs. We propose that Fas B is a new cytokine that acts physiologically to limit apoptosis induced by Fas ligand.
The safety and feasibility of the inhaled mannitol challenge test in young children: Table 1–
Authors: Afaf S. Alblooshi, Shannon J. Simpson, Stephen M. Stick, Graham L. Hall
Journal: European Respiratory Journal (2013)

To the Editor :

The mannitol challenge is an indirect challenge that increases airway surface liquid osmolality resulting in bronchoconstriction [1, 2]. Mannitol challenge tests are used clinically to diagnose asthma and, in particular, exercise-induced broncoconstriction (EIB) in adults and children above 6 years of age [3]. To date, mannitol has not been used as a challenge agent in children under 6 years of age and the feasibility and safety of its use in this age group is unknown.

The assessment of bronchial responsiveness in young children is difficult and limited by the cooperation of the child. The standardisation of lung function tests suitable for use in young children, such as the interrupter technique or the forced oscillation technique (FOT), provide an opportunity to assist in the assessment of bronchial responsiveness in young children and a variety of challenge tests using FOT have been reported in young children [4].

The aim of this preliminary study was to assess the feasibility and safety of the mannitol challenge test in young children using the FOT as the objective outcome measure.

20 children aged 3–7 years were recruited; 10 of these children were healthy and 10 children had a history of parentally reported exercise-induced symptoms (EIS) in the past year. The mannitol challenge test (Aridol; Pharmaxis, Frenchs Forest, Australia) was performed as previously published [2], with the exceptions that the respiratory resistance at 8 Hz ( R rs8) from the FOT was used as the primary outcome and the definition of a positive response was altered, as detailed below.

Prior to …
The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis
Authors: C. F. Wright, H. Burton
Journal: Human Reproduction Update (2008)

BACKGROUNDCell-free fetal nucleic acids (cffNA) can be detected in the maternal circulation during pregnancy, potentially offering an excellent method for early non-invasive prenatal diagnosis (NIPD) of the genetic status of a fetus. Using molecular techniques, fetal DNA and RNA can be detected from 5 weeks gestation and are rapidly cleared from the circulation following birth.
Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure
Authors: Anne L. Taylor, Susan Ziesche, Clyde Yancy, Peter Carson, Ralph D'Agostino, Keith Ferdinand, Malcolm Taylor, Kirkwood Adams, Michael Sabolinski, Manuel Worcel, Jay N. Cohn
Journal: New England Journal of Medicine (2004)

We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously noted to have a favorable response to this therapy.A total of 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life.The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (-0.1+/-1.9 vs. -0.5+/-2.0, P=0.01; range of possible values, -6 to +2), as were its individual components (43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life [change in score, -5.6+/-20.6 vs. -2.7+/-21.2, with lower scores indicating better quality of life; P=0.02; range of possible values, 0 to 105]).The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.
Thalidomide, semen distribution, teratogenicity… and cost: reply from authors
Authors: J.J. Wu, D.B. Huang, S. Hsu, S.K. Tyring
Journal: British Journal of Dermatology (2006)

Conflicts of interest none declared. Sir, Unfortunately, due to space limitations we could not address all possible issues concerning thalidomide use.1 However, we agree about the two concerns of the potential risk of thalidomide in male patients and of cost. It was demonstrated that thalidomide causes loss of elongating and round spermatids and degeneration of testicular germinal epithelium in the rabbit model.2 Further, thalidomide has been shown to be distributed into rabbit semen3 and human semen.4 Although one study showed congenital defects in newborn rabbits whose fathers were treated with thalidomide,3 a more recent study showed that males treated with thalidomide which were bred with untreated females resulted in no significant fetal alterations attributable to thalidomide.2 Thus, there is conflicting evidence in the rabbit model. There is no reported literature that human males treated with thalidomide may cause teratogenicity in an untreated female. However, as the threshold dose of thalidomide exposure causing birth defects is not known, it may be wise to err on the safe side and encourage males who are on thalidomide to use barrier contraception during and after 3 months of thalidomide therapy and to avoid sperm donation.
Pretreatment Nomogram for Prostate-Specific Antigen Recurrence After Radical Prostatectomy or External-Beam Radiation Therapy for Clinically Localized Prostate Cancer
Authors: Anthony V. D'Amico, Richard Whittington, S. Bruce Malkowicz, Julie Fondurulia, Ming-Hui Chen, Irving Kaplan, Clair J. Beard, John E. Tomaszewski, Andrew A. Renshaw, Alan Wein, C. Norman Coleman
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To present nomograms providing estimates of prostate-specific antigen (PSA) failure–free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT. RESULTS: Pretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P &lt; .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality. CONCLUSION: Men at high risk (&gt; 50%) for early (≤ 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.
DOTS PLUS versus non DOTS PLUS outcomes in MDRTB patients
Authors: Adriana Sorete Arbore, Violeta Cojocariu, Rodica Sorete Arbore
Journal: European Respiratory Journal (2012)

Romania is confronted with an important number of MDRTB cases.  2007, DOTS PLUS strategy was applied in the management of selected MDRTB cases.  Aim: to assess the impact of DOTS PLUS strategy on cases registered in Iasi, Romania in 2007-2010.  Method: comparative analysis of MDRTB characteristics, treatment regimens and outcomes in 2 groups of MDRTB patients; first with 21 cases treated using DOTS PLUS strategy, second: 48 cases not included in DOTS PLUS cohort.  Results: first group (9F/12M) 11 new TB cases, 10 relapses.  Second group (11F/37M) 20 new TB cases, 25 relapses, 2 treatments after default, 1 chronic, previously treated with second line drugs.  First group received treatment according to WHO guidelines, with 6-7 drugs: Z, E,1 injectable, Ofx, Pto, Cs, PAS.  Second group received individualized treatment depending on intermittent drug supply of different aminoglicosides and fluoroquinolones, without PAS.  Median number of doses for injectable drugs was 196 in DOTS PLUS group/102 in the second group and of 330 doses /225 doses for Ofloxacin.  There were significant differences between number of doses both in fluoroquinolones and aminoglicosides (p  Final treatment outcomes: success 57.1% in DOTS PLUS group/ 31.2% in the second group and death rate 9.5% versus 35.4%.  Comparative analysis revealed significant differences regarding success rate (p  Conclusions:  Treatment outcomes in DOTS PLUS group were significantly better;  Weak points in the non DOTS PLUS group were identified (e.g: insufficient doses of injectable drugs);  DOTS PLUS ensures both correct regimens with access to all active second line drugs and regular drug supply; it is an opportunity for proper management of MDRTB cases.
Inhibition of Methylcholanthrene-induced Carcinogenesis by an Interferon γ Receptor–dependent Foreign Body Reaction
Authors: Zhihai Qin, Hye-Jung Kim, Jens Hemme, Thomas Blankenstein
Journal: The Journal of Experimental Medicine (2002)

The foreign body reaction is one of the oldest host defense mechanisms against tissue damage which involves inflammation, scarring, and encapsulation. The chemical carcinogen methylcholanthrene (MCA) induces fibrosarcoma and tissue damage in parallel at the injection site. Tumor development induced by MCA but not due to p53-deficiency is increased in interferon-gamma receptor (IFN-gammaR)-deficient mice. In the absence of IFN-gammaR, MCA diffusion and DNA damage of surrounding cells is increased. Locally produced IFN-gamma induces the formation of a fibrotic capsule. Encapsulated MCA can persist virtually life-long in mice without inducing tumors. Together, the foreign body reaction against MCA prevents malignant transformation, probably by reducing DNA damage. This mechanism is more efficient in the presence of IFN-gammaR. Our results indicates that inflammation and scarring, both suspected to contribute to malignancy, prevent cancer in certain situations.
Peritubular Ischemia Contributes More to Tubular Damage than Proteinuria in Immune-Mediated Glomerulonephritis
Authors: Muh Geot Wong, Yusuke Suzuki, Chiaki Tanifuji, Hisaya Akiba, Ko Okumura, Takeshi Sugaya, Tokunori Yamamoto, Satoshi Horikoshi, Si Yen Tan, Carol Pollock, Yasuhiko Tomino
Journal: Journal of the American Society of Nephrology (2007)

Proteinuria is a key factor in the progression of tubulointerstitial injury. Recently, tubular ischemia as a result of loss of peritubular capillaries has been identified as another major contributor to disease progression, but the relative contribution of these insults on tubulointerstitial damage
Fetal Liver-Sparing Cardiovascular Adaptations Linked to Mother’s Slimness and Diet
Authors: Guttorm Haugen, Mark Hanson, Torvid Kiserud, Sarah Crozier, Hazel Inskip, Keith M. Godfrey
Journal: Circulation Research (2004)

Fetal adaptations to impaired maternoplacental nutrient supply include altered regional blood flow. Whether such responses operate within the normal range of maternal body composition or diet is unknown, but any change in fetal liver perfusion could alter hepatic development, with long-term consequences for the risk of cardiovascular and metabolic disease. In 381 low-risk pregnancies, we found that the fetuses of slimmer mothers with lower body fat stores and those eating an unbalanced diet had greater liver blood flow and shunted less blood away from the liver through the ductus venosus at 36 weeks gestation. Consequences of such “liver-sparing” may underlie the increased cardiovascular risk of people whose mothers were slimmer and had lower body fat stores in pregnancy.
CD1-restricted adaptive immune responses to <i>Mycobacteria</i> in human group 1 CD1 transgenic mice
Authors: Kyrie Felio, Hanh Nguyen, Christopher C. Dascher, Hak-Jong Choi, Sha Li, Michael I. Zimmer, Angela Colmone, D. Branch Moody, Michael B. Brenner, Chyung-Ru Wang
Journal: The Journal of Experimental Medicine (2009)

Group 1 CD1 (CD1a, CD1b, and CD1c)–restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)–infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human group 1 CD1 transgenic (hCD1Tg) mice that express all three human group 1 CD1 isoforms and support the development of group 1 CD1–restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit group 1 CD1–restricted Mtb lipid–specific T cell responses in hCD1Tg mice. In contrast to CD1d-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon reexposure, group 1 CD1–restricted T cells exhibit delayed primary responses and more rapid secondary responses, similar to conventional T cells. Collectively, our data demonstrate that group 1 CD1–restricted T cells participate in adaptive immune responses upon mycobacterial infection and could serve as targets for the development of novel Mtb vaccines.
Overexpression of the Zinc Uptake Transporter hZIP1 Inhibits Nuclear Factor-κB and Reduces the Malignant Potential of Prostate Cancer Cells<i>In vitro</i>and<i>In vivo</i>
Authors: Konstantin Golovine, Peter Makhov, Robert G. Uzzo, Tavis Shaw, David Kunkle, Vladimir M. Kolenko
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Intracellular zinc levels and expression of the zinc uptake transporter, hZIP1, are markedly down-regulated in prostate adenocarcinomatous tissue compared with normal prostate tissue. Our previous studies have shown that zinc inhibits nuclear factor-κB (NF-κB) activity and reduces the malignant potential of prostate cancer cells in vitro. In this study, we investigate the functional effect of hZIP1 overexpression on NF-κB activity and tumorigenic potential in human prostate cancer cells in vitro and in vivo. Experimental Design: NF-κB activity in PC-3 prostate cancer cells was examined by Western blotting and luciferase assay. ELISA was used to examine the expression of tumorigenic cytokines. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, adhesion, and invasiveness assays were used to assess the malignant potential of tumor cells. The effect of hZIP1 overexpression on prostate tumor progression in vivo was assessed using a xenograft model. Results: Overexpression of the hZIP1 transporter in PC-3 cells results in significant inhibition of NF-κB activity in the presence of physiologic levels of zinc. NF-κB inhibition coincides with a reduction in expression of several NF-κB controlled prometastatic and antiapoptotic factors as well as sensitization of the cells to etoposide and tumor necrosis factor-mediated apoptosis-inducing ligand-mediated cell death. Moreover, overexpression of the hZIP1 transporter induces regression of prostate tumor growth in a xenograft model. Conclusions: Our results show that hZIP1 overexpression has a functional effect on the malignant potential of prostate cancer cells via inhibition of NF-κB-dependent pathways and support the concept that hZIP1 may function as a tumor suppressor gene in prostate cancer.
Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells
Authors: Heather A Himburg, Garrett G Muramoto, Pamela Daher, Sarah K Meadows, J Lauren Russell, Phuong Doan, Jen-Tsan Chi, Alice B Salter, William E Lento, Tannishtha Reya, Nelson J Chao, John P Chute
Journal: Nature Medicine (2010)
The QA2 subregion controls the expression of two antigens recognized by H-2- unrestricted cytotoxic T cells
Authors: J Forman, J Trial, S Tonkonogy, L Flaherty
Journal: The Journal of Experimental Medicine (1982)

B6.KI mice were immunized with spleen cells from B6.K2, a Qa2-subregion congenic strain. Cytotoxic T cells were generated that recognize two target antigens controlled by this region. One of the target antigens is Qa-2. This was demonstrated by the findings that pretreatment of target cells with monoclonal anti-Qa-2 antibody blocked lysis of target cells, and Qa-2 target antigens and serological determinants had a concordant distribution on a panel of B10.W (wild) mice. The gene controlling the Qa-2 target antigen is not polymorphic because B6.K2 and three strains of Qa-2(+) B10.W mice express the same antigens, as determined by a CTL cold target competition assay. Anti-Qa-2 CTL were H-2 unrestricted because effector cells lysed Qa-2(+) targets irrespective of their H-2 haplotype, including five B 10.W strains, and lysis was not inhibited by pretreating target cells with anti-H-2 sera. The Qa2 subregion does not act as a restricting locus for anti-minor-H antigen CTL. A second target antigen was detected that was associated with the expression of the Qa-5 determinant. However, CTL activity could not be blocked by pretreating target cells with monoclonal anti-Qa-5. Therefore, the CTL target antigen may be expressed on a Qa-5(-) molecule. Although the Qa-5 associated CTL specificity is only detected on H-2D(b) strains, it is unlikely that CTL recognition is H-2 restricted because anti-H-2(b) sera has no effect in blocking this reactivity. Qa-2 and H-2 class I antigens share a similar structure and serve as target antigens for unrestricted CTL. However, unlike class I H-2 genes, Qa-2 neither restricts antigen-specific CTL nor is polymorphie. Therefore, it is likely that Qa-2 and H-2 are derived from a common ancestral gene and have evolved to serve different functions.
A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor
Authors: Florian Blaschke, Yasunori Takata, Evren Caglayan, Alan Collins, Peter Tontonoz, Willa A. Hsueh, Rajendra K. Tangirala
Journal: Circulation Research (2006)

C-reactive protein (CRP), the prototypical human acute phase protein, is an independent risk predictor of future cardiovascular events, both in healthy individuals and in patients with known cardiovascular disease. In addition, previous studies indicate that CRP might have direct proatherogenic properties. Ligand activation of the liver X receptor (LXR), a member of the nuclear hormone receptor superfamily, inhibits inflammatory gene expression in macrophages and attenuates the development of atherosclerosis in various animal models. We demonstrate herein that 2 synthetic LXR ligands, T0901317 and GW3965, inhibit interleukin-1β/interleukin-6–induced CRP mRNA and protein expression in human hepatocytes. Knockdown of LXRα/β by short interfering RNAs completely abolished the inhibitory effect of the LXR agonist T0901317 on cytokine-induced CRP gene transcription. Transient transfection experiments with 5′-deletion CRP promoter constructs identified a region from −125 to −256 relative to the initiation site that mediated the inhibitory effect of LXR ligands on CRP gene transcription. Depletion of the nuclear receptor corepressor by specific short interfering RNA increased cytokine-inducible CRP mRNA expression and promoter activity and reversed LXR ligand–mediated repression of CRP gene transcription. Chromatin immunoprecipitation assays indicated that nuclear receptor corepressor is present on the endogenous CRP promoter under basal conditions. Cytokine-induced clearance of nuclear receptor corepressor complexes was inhibited by LXR ligand treatment, maintaining the CRP gene in a repressed state. Finally, treatment of C57Bl6/J mice with LXR ligands attenuated lipopolysaccharide-induced mouse CRP and serum amyloid P component gene expression in the liver, whereas no effect was observed in LXRαβ knockout mice. Our observations identify a novel mechanism of inflammatory gene regulation by LXR ligands. Thus, inhibition of CRP expression by LXR agonists may provide a promising approach to impact initiation and progression of atherosclerosis.