tbuckley/cabot-search huggingface dataset:
Mediation Analysis of Aortic Stiffness and Renal Microvascular Function
Authors: Todd Woodard, Sigurdur Sigurdsson, John D. Gotal, Alyssa A. Torjesen, Lesley A. Inker, Thor Aspelund, Gudny Eiriksdottir, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Andrew S. Levey, Gary F. Mitchell
Journal: Journal of the American Society of Nephrology (2014)

Aortic stiffening, assessed by carotid-femoral pulse wave velocity, is associated with CKD. Transmission of excessive flow pulsatility into the low-impedance renal microvasculature may mediate this association. However, direct analyses of macrovascular-microvascular relations in the kidney are limited. Using arterial tonometry, iohexol clearance, and magnetic resonance imaging, we related arterial stiffness, GFR, urinary albumin excretion, and potential mediators, including renal artery pulsatility index, renal vascular resistance, and arterial volume in the cortex, in 367 older adults (ages 72-92 years) participating in the Age, Gene/Environment Susceptibility-Reykjavik Study. In a model adjusted for age, sex, heart rate, and body size, aortic stiffness was related to GFR (Slope of regression B=-2.28±0.85 ml/min per SD, P=0.008) but not urine albumin (P=0.09). After accounting for pulsatility index, the relation between aortic stiffness and GFR was no longer significant (P=0.10). Mediation analysis showed that 34% of the relation between aortic stiffness and GFR was mediated by pulsatility index (95% confidence interval of indirect effect, -1.35 to -0.29). An additional 20% or 36% of the relation was mediated by lower arterial volume in the cortex or higher renal vascular resistance, respectively, when offered as mediators downstream from higher pulsatility index (95% confidence interval of indirect effect including arterial volume in the cortex, -2.22 to -0.40; 95% confidence interval of indirect effect including renal vascular resistance, -2.51 to -0.76). These analyses provide the first evidence that aortic stiffness may contribute to lower GFR by transferring excessive flow pulsatility into the susceptible renal microvasculature, leading to dynamic constriction or vessel loss.
Lymph Node Status and <i>TS</i> Gene Expression Are Prognostic Markers in Stage II/III Rectal Cancer After Neoadjuvant Fluorouracil-Based Chemoradiotherapy
Authors: Torsten Liersch, Claus Langer, B. Michael Ghadimi, Bettina Kulle, Daniela E. Aust, Gustavo B. Baretton, Wolfgang Schwabe, Peter Häusler, Heinz Becker, Christiane Jakob
Journal: Journal of Clinical Oncology (2006)

According to the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group, preoperative combined fluorouracil (FU) -based long-term chemoradiotherapy (CT/RT) is recommended for patients with International Union Against Cancer (UICC) stage II/III rectal cancer. However, despite the local benefit of neoadjuvant treatment, the overall prognostic value remains uncertain in comparison with adjuvant CT/RT. Furthermore, the prognostic value of molecular biomarkers, such as thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), all of which are involved in the FU metabolism, is unknown in neoadjuvant settings. We assessed the impact of standardized preoperative CT/RT and intratumoral TS, TP, and DPD levels on patient outcome.Forty patients with rectal cancer pretherapeutic UICC stage II/III, receiving preoperative FU-based CT/RT (CAO/ARO/AIO-94 trial) followed by standardized surgery, including total mesorectal excision, were investigated. Downsizing, downstaging, tumor regression, as well as TS, TP, and DPD gene expression of post-treatment surgical specimens were correlated with disease-free survival (DFS) and overall survival (OS).Significant downsizing (P < .001) and downstaging (P = .001) were achieved with preoperative CT/RT. During a median follow-up of 49 months (95% CI, 43 to 58 months), the cancer recurrence rate was 28.2%. DFS and OS were significantly increased in patients with downstaging (P < .001 and P = .003, respectively), compared with patients without downstaging. All patients who developed cancer recurrence had a persistent positive lymph node status after preoperative CT/RT (P < .001) and a significantly higher TS gene expression (P = .035) compared with those patients without recurrence.Persistent positive lymph node status and high intratumoral TS expression after preoperative CT/RT are predictive of an unfavorable prognosis in rectal cancer UICC stage II/III.
Atriopeptin III. A potent natriuretic, diuretic, and hypotensive agent in rats with chronic renal failure.
Authors: B R Cole, M A Kuhnline, P Needleman
Journal: Journal of Clinical Investigation (1985)

Chronic renal failure is frequently associated with volume overload, resulting in hypertension and, in some cases, congestive heart failure. Atriopeptin III (AP III), a 24-amino acid atrial peptide, is a potent vasodilator and natriuretic/diuretic agent in normal rats. An infusion of AP III at 0.2 microgram/kg per min for 60 min produced dramatic responses in animals with chronic renal failure (5/6 nephrectomy 4 wk before study). Systemic blood pressure fell 20% by the end of infusion. A pronounced rise in glomerular filtration rate (24%) was maintained during the infusion period when urine flow rate was stable (35-60 min), even though renal blood flow was unchanged from base line. Urinary volume increased 4.4-fold and sodium excretion increased 9 to 12-fold during the infusion. Fractional excretion of sodium ranged between 9 and 15% in those animals whose initial GFR values were lower than 0.5 ml/min. We conclude that AP III is a potent natriuretic/diuretic agent in rats with reduced renal mass, presumably exerting that effect predominantly through increases in GFR. This agent may well be useful in the treatment of volume overload in patients with chronic renal failure.
Interrupting antiretroviral treatment needs particular care
Authors: W A C Sewell
Journal: BMJ (2001)

EDITOR—Noble and Kehlet raise an important issue in their editorial about the interruption of drug treatment during the postoperative period.1 We would emphasise the particular problems of drug interruptions in HIV infected patients receiving combination antiretroviral treatment; in these patients the general rule that some drugs are better than none does not apply.

Efavirenz and nevirapine are both non-nucleoside reverse transcriptase inhibitors with long plasma half …
LIM kinase1 modulates function of membrane type matrix metalloproteinase 1: implication in invasion of prostate cancer cells
Authors: Tenekua Tapia, Richard Ottman, Ratna Chakrabarti
Journal: Molecular Cancer (2011)

Abstract Background LIM kinase 1 (LIMK1) is an actin and microtubule cytoskeleton modulatory protein that is overexpressed in a number of cancerous tissues and cells and also promotes invasion and metastasis of prostate and breast cancer cells. Membrane type matrix metalloproteinase 1 (MT1-MMP) is a critical modulator of extracellular matrix (ECM) turnover through pericellular proteolysis and thus plays crucial roles in neoplastic cell invasion and metastasis. MT1-MMP and its substrates pro-MMP-2 and pro-MMP-9 are often overexpressed in a variety of cancers including prostate cancer and the expression levels correlate with the grade of malignancy in prostate cancer cells. The purpose of this study is to determine any functional relation between LIMK1 and MT1-MMP and its implication in cell invasion. Results Our results showed that treatment with the hydroxamate inhibitor of MT1-MMP, MMP-2 and MMP-9 ilomastat inhibited LIMK1-induced invasion of benign prostate epithelial cells. Over expression of LIMK1 resulted in increased collagenolytic activity of MMP-2, and secretion of pro-MMP2 and pro-MMP-9. Cells over expressing LIMK1 also exhibited increased expression of MT1-MMP, transcriptional activation and its localization to the plasma membrane. LIMK1 physically associates with MT1-MMP and is colocalized with it to the Golgi vesicles. We also noted increased expression of both MT1-MMP and LIMK1 in prostate tumor tissues. Conclusion Our results provide new information on regulation of MT1-MMP function by LIMK1 and showed for the first time, involvement of MMPs in LIMK1 induced cell invasion.
Guidelines on the radical management of patients with lung cancer
Authors: E. Lim, D. Baldwin, M. Beckles, J. Duffy, J. Entwisle, C. Faivre-Finn, K. Kerr, A. Macfie, J. McGuigan, S. Padley, S. Popat, N. Screaton, M. Snee, D. Waller, C. Warburton, T. Win
Journal: Thorax (2010)

A joint initiative by the British Thoracic Society and the Society for Cardiothoracic Surgery in Great Britain and Ireland was undertaken to update the 2001 guidelines for the selection and assessment of patients with lung cancer who can potentially be managed by radical treatment.
Tolerance of Human and Rat Atrial Muscle to Hypothermia and Anoxia
Authors: GEORGE NOREN, DAVID GOLDRING, WILLIAM SLEATOR
Journal: Circulation Research (1961)

Evidence is presented which strongly suggests the preservation of contractility of human atrial muscle when hypothermia of 25 to 31 C. is used during anoxia. Parallel studies were carried out on albino rat atria which gave results similar to that of the human tissue. This report adds further evidence that hypothermia is valuable in open-heart surgery when anoxic is indicated for the repair of cardiac malformations.
Conducting clinical trials over the internet: feasibility study
Authors: T. McAlindon
Journal: BMJ (2003)

Can randomised controlled trials be successfully conducted over the internet?The authors report a feasibility study of such a trial in patients with osteoarthritis of the kneeThe possibility of conducting clinical trials entirely on line is an enticing but relatively unexplored medical application of the internet.The penetrance of the internet in the population offers the possibility of rapid recruitment of participants, and technological advances enable instant collection of data in a secure and confidential manner. 1 These attributes could theoretically accelerate the evaluation of many compounds by cutting costs and reducing the duration of each study.Many components of an online trial, such as recruitment websites and electronic data capture technologies, have been separately described, 2-4 but few attempts have been made to integrate these into a single process, and no study has evaluated the performance of such an endeavour.
Carbonic Anhydrase IX Is Not an Independent Predictor of Outcome for Patients With Clear Cell Renal Cell Carcinoma
Authors: Bradley C. Leibovich, Yuri Sheinin, Christine M. Lohse, R. Houston Thompson, John C. Cheville, Jan Zavada, Eugene D. Kwon
Journal: Journal of Clinical Oncology (2007)

Purpose Expression of carbonic anhydrase IX (CAIX) has been reported to be an independent predictor of outcome and is being investigated as a therapeutic target for patients with clear cell renal cell carcinoma (ccRCC). We attempted to validate the prognostic utility of CAIX expression using a large cohort of ccRCC patients with long-term follow-up. Patients and Methods We identified 730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999. Anti-CAIX monoclonal antibody (clone M75) was used, and tumor specimens were blindly scored for expression levels. Associations of CAIX expression with RCC death were evaluated using Cox proportional hazards regression models. Results There were 241 RCC deaths and a median of 9.4 years of follow-up for patients still under observation. CAIX was expressed in 708 (97.0%) of the specimens; 163 tumors (22.3%) exhibited low (≤ 85% tumor cells positive) expression, and 567 (77.7%) exhibited high (&gt; 85% tumor cells positive) expression. Univariately, low CAIX expression was associated with increased risk of RCC death relative to high expression (risk ratio = 1.65; P &lt; .001). However, low CAIX expression was not associated with RCC death after adjusting for nuclear grade or coagulative tumor necrosis. Additionally, we observed CAIX expression in a number of extrarenal organs. Conclusion CAIX is strongly expressed by ccRCC. Although CAIX is associated with outcome in patients with ccRCC, it is not an independent prognostic marker. Furthermore, CAIX expression is apparent in extrarenal organs. As such, exploitation of CAIX as a prognostic marker and therapeutic target merits additional consideration.
Influence of diet on occult blood tests.
Authors: D G Illingworth
Journal: Gut (1965)

EDITORIAL SYNOPSIS The importance of dietary control is brought out by this study of orthotolidine (Ames) tests.Forty-three per cent of normal people passed positive stools when the Occultest method was employed with an unrestricted diet compared with 21 % for the Hematest method.There is a dearth of experiment on the human subject.Test-tube experiments on foodstuffs are helpful, but are not sufficient to allow of dogmatic statements about their dietary influences.To advise an unrestricted diet and give significance only to strongly positive reactions is an approach with a superficial appeal (Ratnoff, 1923;
Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic.
Authors: M Amagai, S Karpati, R Prussick, V Klaus-Kovtun, J R Stanley
Journal: Journal of Clinical Investigation (1992)

Complementary DNA cloning of the 130-kD pemphigus vulgaris (PV) autoantigen (PVA) has indicated that it is a member of the cadherin family of Ca(2+)-dependent cell adhesion molecules. By homology with typical cadherins, PVA has five extracellular domains (EC1 through EC5). To localize immunogenic domains and to determine whether antibodies against them might be pathogenic, we produced beta-galactosidase fusion proteins with cDNA encoding different portions of the extracellular domains of PVA (EC1-2, EC3-5, and each individual domain). Immunoblot analysis of these fusion proteins with 23 PV patients' sera demonstrated that major immunogenic regions of PVA are located on the EC1, EC2, and EC4 domains. IgG was affinity-purified from PV sera on fusion proteins representing the amino (EC1-2) and carboxy (EC3-5) terminus of the extracellular PVA, and injected into neonatal mice. PV IgG affinity-purified on the EC1-2 fusion protein caused suprabasilar acantholysis, the typical histological finding of PV, but IgG affinity-purified on the EC3-5 fusion protein or beta-galactosidase alone did not. These results indicate that at least one pathogenic epitope, which is sufficient to cause suprabasilar acantholysis in neonatal mice, is located on the amino-terminal region of PVA, an area thought to be important in cadherin homophilic adhesion.
Functional analysis of keratin components in the mouse hair follicle inner root sheath
Authors: R.M. Porter, M. Gandhi, N.J. Wilson, P. Wood, W.H.I. McLean, E.B. Lane
Journal: British Journal of Dermatology (2004)

Recently, a family of novel type I keratins of the inner root sheath of the hair follicle were discovered, increasing the number of keratins known to be expressed in the hair follicle. The mouse database shows three keratins that are possible orthologues of these inner root sheath keratins. The sequences of these keratins include rather unusual changes to a highly conserved motif at the end of the alpha-helical rod domain of the proteins, thought to be important in filament assembly.To investigate whether these keratins are expressed in the inner root sheath and to determine whether they assemble normally.To investigate this, polyclonal antibodies were raised for immunolocalization of the keratins and their cDNAs were cloned for transfection into cultured cells.At least two of these keratins were expressed in the inner root sheath but the timing of expression of the different keratins was variable. Transfection of the relevant cDNAs into cells in culture indicated that these keratins were capable of integrating into existing keratin networks without disruption, but that de novo filament assembly with the type II inner root sheath keratin, mK6irs, was poor.These results provide further evidence of the complexity of keratin expression in the three concentric layers of the inner root sheath.
Randomized Double-Blind Trial of Combined Modality Treatment With or Without Amifostine in Unresectable Stage III Non–Small-Cell Lung Cancer
Authors: Swan Swan Leong, Eng Huat Tan, Kam Weng Fong, Einar Wilder-Smith, Yew Kwang Ong, Bee Choo Tai, Lita Chew, Shih Hui Lim, Joseph Wee, Khai Mun Lee, Kian Fong Foo, Peter Ang, Peng Tiam Ang
Journal: Journal of Clinical Oncology (2003)

Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy.Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity.There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of -27% (95% confidence limit = -50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms.Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.
Exploiting the Redundancy in the Immune System
Authors: Arturo Casadevall, Liise-anne Pirofski
Journal: The Journal of Experimental Medicine (2003)

The fields of vaccinology and immunology have had a long-standing and complicated relationship. The view that vaccinology is a branch of immunology is more perception than reality. Vaccinology is older, practical, and often idiosyncratic, with its prime focus on the development of functional vaccines that protect a host against a particular microbe. Immunology is younger, conceptual, and strives to explain how a remarkably complex system recognizes and protects against internal and external threats without committing suicide. Vaccinology has been largely microbe-centered, clinically successful, and mostly empirical, whereas immunology has been largely host-centered, having struggled to translate its theoretical success and potential into clinical applicability. In this commentary, we examine the divide between vaccinology and immunology and put forth the view that vaccines often protect against infectious diseases by eliciting ‘unnatural’ immunity: immune responses that differ from and may even counteract those that arise during the development of natural immunity to
Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases
Authors: Akiharu Kubo, Keisuke Nagao, Masayuki Amagai
Journal: Journal of Clinical Investigation (2012)

Classic atopic dermatitis is complicated by asthma, allergic rhinitis, and food allergies, cumulatively referred to as atopic diseases. Recent discoveries of mutations in the filaggrin gene as predisposing factors for atopic diseases have refocused investigators’ attention on epidermal barrier dysfunction as a causative mechanism. The skin’s barrier function has three elements: the stratum corneum (air-liquid barrier), tight junctions (liquid-liquid barrier), and the Langerhans cell network (immunological barrier). Clarification of the molecular events underpinning epidermal barrier function and dysfunction should lead to a better understanding of the pathophysiological mechanisms of atopic diseases.
EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics
Authors: G Bertsias, J P A Ioannidis, J Boletis, S Bombardieri, R Cervera, C Dostal, J Font, I M Gilboe, F Houssiau, T Huizinga, D Isenberg, C G M Kallenberg, M Khamashta, J C Piette, M Schneider, J Smolen, G Sturfelt, A Tincani, R van Vollenhoven, C Gordon, D T Boumpas
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE. <h3>Methods:</h3> The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries' strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence, and agreement on the statements was measured across the 19 specialists. <h3>Results:</h3> Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10. <h3>Conclusion:</h3> Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.