tbuckley/cabot-search huggingface dataset:
Protein kinase C inhibits human hair follicle growth and hair fibre production in organ culture
Authors: C.S. HARMON, T.D. NEVINS, W.B. BOLLAG
Journal: British Journal of Dermatology (2006)

In this study we have used a human hair follicle whole-organ culture system to examine the effects of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a potent activator of protein kinase C (PKC), on hair follicle growth and hair fibre production. Anagen hair follicles were isolated from human facial skin by microdissection and placed in suspension culture in supplemented Williams E medium. Hair follicle and hair fibre lengths were measured daily using an inverted microscope and cumulative growth values were calculated. Treatment with TPA resulted in a potent, dose-dependent inhibition of total cumulative hair follicle growth (IC50 = 1 nM). Hair follicles grew at a comparable rate for 4 days in the presence or absence of 10 nM TPA, after which growth of TPA-treated follicles ceased while control follicles grew by a further 0.8 mm over the subsequent 6 days. In contrast, 10 nM TPA treatment did not affect hair fibre elongation for a period of 8 days, after which TPA-treated fibre production ceased while control fibres grew by a further 0.79 mm over the subsequent 7 days. Incubation of hair follicles with TPA resulted in a 41% inhibition of hair fibre protein synthesis, as measured biochemically from the incorporation of 3H-leucine using a differential akali extraction method. The inhibitory effect of TPA on follicle growth was partially prevented by preincubation with the selective PKC inhibitor H-7, and almost completely prevented by preincubation with the more potent PKC inhibitor Ro 31-7549. Neither agent alone significantly affected follicle growth at concentrations that reversed the TPA response. These findings indicate that PKC is a negative regulator of hair follicle growth, and suggest that PKC may play a part in the transduction of follicular growth-inhibitory signals.
Risk Profile and Prediction of Long-Term Ischemic Stroke Mortality
Authors: David Tanne, Shlomit Yaari, Uri Goldbourt
Journal: Circulation (1998)

Background —Multinational comparisons demonstrate marked ethnic and regional variation in stroke mortality and risk-factor distribution. We assessed the role of ethnicity and estimated the cumulative effect of multiple risk factors on long-term ischemic stroke mortality. Methods and Results —Civil servants and municipal employees in Israel (n=9734 men; age, ≥42 years), chosen by stratified sampling in 6 prespecified areas of birth (those born in Israel and those who were immigrants from 5 other regional-ethnic strata), were included in the Israeli Ischemic Heart Disease (IIHD) Project. Over a 21-year follow-up period, age-adjusted mortality rates per 10 000 person-years attributed to ischemic stroke (n=282; International Classification of Diseases [ICD]-9 codes 433 to 438) were higher among immigrants to Israel from northern Africa and the Mideast (17.1 to 19.0), than from 3 parts of Europe (11.3 to 12.4). Crude rates per 1000 subjects observed in those born in Asia or Africa (29.4 to 31.2) exceeded rates predicted by risk-factor profiles (21.4 to 24.9). Adjusted hazard ratios were 3.00 for age (per 10 years), 2.15 for left ventricular hypertrophy, 1.69 for systolic blood pressure (BP, per 20 mm Hg), 1.86 for diabetes mellitus, 1.83 for peripheral vascular disease, 1.79 for smoking (&gt;20 cigarettes per day), 1.51 for coronary heart disease, 1.16 for percent cholesterol contained in the HDL fraction (%HDL, per 5% decrease), and 1.88 for diastolic BP (per 12 mm Hg; assessed in an alternative model). Accounting for regression dilution bias and assessed from repeat measurements, we found that hazard ratio estimates associated with diastolic BP, systolic BP, and percent HDL (per increments described) increased to 3.22, 2.23, and 1.23, respectively. Ischemic stroke mortality rates were 30-fold greater among subjects at the highest versus the lowest quintile of predicted probability according to risk-factor profiles (81.2 versus 2.6 per 1000 subjects). Conclusions —Assessment of multiple risk factors provides useful quantitative prediction of long-term ischemic stroke mortality risk. Regional-ethnic variations are consistent with a hypothesis that other, undetermined inherent genetic or sociocultural factors act to increase ischemic stroke mortality rates in immigrants to Israel from the Mideast and northern Africa over that predicted by conventional risk factors.
Ethanol dilates coronary arteries and increases coronary flow via transient receptor potential vanilloid 1 and calcitonin gene-related peptide
Authors: D GAZZIERI, M TREVISANI, F TARANTINI, P BECHI, G MASOTTI, G GENSINI, S CASTELLANI, N MARCHIONNI, P GEPPETTI, S HARRISON
Journal: Cardiovascular Research (2006)

Objectives Consumption of alcoholic beverages reduces the risk of coronary artery disease (CAD), and epidemiological studies have shown that ethanol per se is protective. However, the mechanism by which ethanol exerts protection is not fully known. Ethanol can stimulate neuropeptide-containing primary sensory neurons via the activation of transient receptor potential vanilloid 1 (TRPV1). Here, we have studied whether ethanol-mediated TRPV1 activation causes the release of calcitonin gene-related peptide (CGRP) that, via dilatation of coronary arteries and other mechanisms, may protect the heart from CAD.
Participation and yield of colonoscopy versus non-cathartic CT colonography in population-based screening for colorectal cancer: a randomised controlled trial
Authors: Esther M Stoop, Margriet C de Haan, Thomas R de Wijkerslooth, Patrick M Bossuyt, Marjolein van Ballegooijen, C Yung Nio, Marc J van de Vijver, Katharina Biermann, Maarten Thomeer, Monique E van Leerdam, Paul Fockens, Jaap Stoker, Ernst J Kuipers, Evelien Dekker
Journal: The Lancet Oncology (2011)
Erythrocyte Adenosine Deaminase Deficiency without Immunodeficiency
Authors: Rochelle Hirschhorn, Vivien Roegner, Trefor Jenkins, Carol Seaman, Sergio Piomelli, William Borkowsky
Journal: Journal of Clinical Investigation (1979)

Inherited deficiency of the purine salvage enzyme adenosine deaminase (ADA) gives rise to a syndrome of severe combined immunodeficiency (SCID). We have studied a 2.5-yr-old immunologically normal child who had been found to lack ADA in his erythrocytes during New York State screening of normal newborns. His erythrocytes were not detectably less deficient in ADA than erythrocytes of ADA−-SCID patients. In contrast, his lymphocytes and cultured long-term lymphoid cells contained appreciably greater ADA activity than those from patients with ADA−-SCID. This residual ADA activity had a normal molecular weight and Km but was markedly unstable at 56°C. His residual erythrocytes-ADA activity also appeared to have diminished stability in vivo. ADA activity in lymphoid line cells of a previously reported erythrocyte-ADA-deficient!Kung tribesman was found to contain 50% of normal activity and to exhibit diminished stability at 56°C. ATP content of erythrocytes from both partially ADA-deficient individuals was detectably greater than normal (12.3 and 6.1 vs. normal of 2.6 nmol/ml packed erythrocytes). However, the dATP content was insignificant compared to that found in erythrocytes of ADA−-SCID patients (400-1,000 nmol/ml packed erythrocytes). The New York patient, in contrast to normals, excreted detectable amounts of deoxyadenosine, but this was <2% of deoxyadenosine excreted by ADA−-SCID patients. Thus, the residual enzyme in cells other than erythrocytes appears to be sufficient to almost totally prevent accumulation of toxic metabolites.
Public Health Implications of Recommendations to Individualize Glycemic Targets in Adults With Diabetes
Authors: Neda Laiteerapong, Priya M. John, Aviva G. Nathan, Elbert S. Huang
Journal: Diabetes Care (2012)

To estimate how many U.S. adults with diabetes would be eligible for individualized A1C targets based on 1) the 2012 American Diabetes Association (ADA) guideline and 2) a published approach for individualized target ranges.We studied adults with diabetes ≥20 years of age from the National Health and Nutrition Examination Survey 2007-2008 (n = 757). We assigned A1C targets based on duration, age, diabetes-related complications, and comorbid conditions according to 1) the ADA guideline and 2) a strategy by Ismail-Beigi focused on setting target ranges. We estimated the number and proportion of adults with each A1C target and compared individualized targets to measured levels.Using ADA guideline recommendations, 31% (95% CI 27-34%) of the U.S. adult diabetes population would have recommended A1C targets of <7.0%, and 69% (95% CI 66-73%) would have A1C targets less stringent than <7.0%. Using the Ismail-Beigi strategy, 56% (51-61%) would have an A1C target of ≤7.0%, and 44% (39-49%) would have A1C targets less stringent than <7.0%. If a universal A1C <7.0% target were applied, 47% (41-54%) of adults with diabetes would have inadequate glycemic control; this proportion declined to 30% (26-36%) with the ADA guideline and 31% (27-36%) with the Ismail-Beigi strategy.Using individualized glycemic targets, about half of U.S. adults with diabetes would have recommended A1C targets of ≥7.0% but one-third would still be considered inadequately controlled. Diabetes research and performance measurement goals will need to be revised in order to encourage the individualization of glycemic targets.
How do we choose a therapeutic regimen in cystic fibrosis?
Authors: C F Robertson
Journal: Thorax (2002)

As the range of treatments for cystic fibrosis increases and the costs rise, the clinician is faced with an increasingly complex dilemma to develop a treatment schedule that provides optimal benefit, given financial restraints and the impact of an increasingly complex therapeutic regimen on patient adherence.

Over the past 20 years there has been an exponential increase in research to develop new treatments for the management of cystic fibrosis—particularly following the identification of the CFTR protein and its impact on the composition and function of the surface epithelial cell airway surface liquid. While early progress was achieved in gene therapy, it is the pharmacological modulation of function of the CFTR protein and the airway surface liquid that is more likely to be translated into treatment.

One of the major consequences of the defect in CFTR production is alteration of the airway surface liquid to impair mucociliary clearance and promote infection. There have been several attempts to alter the properties of the airway surface liquid and to reduce the viscosity of the mucus to improve mucociliary clearance. Agents investigated include recombinant human rhDNase,1 hypertonic saline,2 dry powder mannitol,3 amiloride,2 and 5′-uridine triphosphate.4 Each has shown a modest …
Fulvestrant, Formerly ICI 182,780, Is as Effective as Anastrozole in Postmenopausal Women With Advanced Breast Cancer Progressing After Prior Endocrine Treatment
Authors: A. Howell, J.F.R. Robertson, J. Quaresma Albano, A. Aschermannova, L. Mauriac, U.R. Kleeberg, I. Vergote, B. Erikstein, A. Webster, C. Morris
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) and anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. PATIENTS AND METHODS: Patients (n = 451) with advanced breast cancer were randomized to receive fulvestrant 250 mg as a once-monthly (one × 5 mL) intramuscular injection or an oral dose of anastrozole 1 mg in this open, parallel-group, multicenter trial. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rates, defined as complete response (CR) or partial response (PR), duration of response (DOR), and tolerability. RESULTS: Patients were followed for a median period of 14.4 months. In terms of TTP, fulvestrant was as effective as anastrozole (hazard ratio, 0.98; confidence interval [CI], 0.80 to 1.21; P = .84). Median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole. OR rates showed a numerical advantage for fulvestrant (20.7%) over anastrozole (15.7%) (odds ratio, 1.38; CI, 0.84 to 2.29; P = .20). Clinical benefit rates (CR + PR + stable disease ≥ 24 weeks) were 44.6% for fulvestrant and 45.0% for anastrozole. Median DOR was 15.0 months for fulvestrant and 14.5 months for anastrozole. Both treatments were well tolerated, with 3.2% and 1.3% of fulvestrant- and anastrozole-treated patients, respectively, withdrawn from treatment because of an adverse event. CONCLUSION: Fulvestrant was as effective as anastrozole. These data confirm that fulvestrant is an additional, effective, and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy.
A Placental Growth Factor Variant Unable to Recognize Vascular Endothelial Growth Factor (VEGF) Receptor-1 Inhibits VEGF-Dependent Tumor Angiogenesis via Heterodimerization
Authors: Valeria Tarallo, Loredana Vesci, Onofrio Capasso, Maria Teresa Esposito, Teresa Riccioni, Lucio Pastore, Augusto Orlandi, Claudio Pisano, Sandro De Falco
Journal: Cancer Research (2010)

Abstract Angiogenesis is one of the crucial events for cancer development and growth. Two members of the vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF), which are able to heterodimerize if coexpressed in the same cell, are both required for pathologic angiogenesis. We have generated a PlGF1 variant, named PlGF1-DE in which the residues Asp72 and Glu73 were substituted with Ala, which is unable to bind and activate VEGF receptor-1 but is still able to heterodimerize with VEGF. Here, we show that overexpression in tumor cells by adenoviral delivery or stable transfection of PlGF1-DE variant significantly reduces the production of VEGF homodimer via heterodimerization, determining a strong inhibition of xenograft tumor growth and neoangiogenesis, as well as significant reduction of vessel lumen and stabilization, and monocyte-macrophage infiltration. Conversely, the overexpression of PlGF1wt, also reducing the VEGF homodimer production comparably with PlGF1-DE variant through the generation of VEGF/PlGF heterodimer, does not inhibit tumor growth and vessel density compared with controls but induces increase of vessel lumen, vessel stabilization, and monocyte-macrophage infiltration. The property of PlGF and VEGF-A to generate heterodimer represents a successful strategy to inhibit VEGF-dependent angiogenesis. The PlGF1-DE variant, and not PlGF1wt as previously reported, acts as a “dominant negative” of VEGF and is a new candidate for antiangiogenic gene therapy in cancer treatment. Cancer Res; 70(5); 1804–13
Effects of thapsigargin on aequorin-injected and skinned preparations of ferret ventricular muscles
Authors: T. Tanaka, K. Komukai, M. Kawai, E. Tanaka, S. Kurihara
Journal: Cardiovascular Research (1995)

We investigated the effects of thapsigargin (TG) (0.1-1 microM) on the relation between intracellular Ca2+ concentration and tension in ferret papillary muscles using aequorin-injected and skinned preparations.Aequorin was injected into the superficial cells of ferret papillary muscles; the Ca2+ signals of aequorin and tension in twitch and those with the application of 15 mM caffeine were simultaneously measured. The alteration of Ca2+ sensitivity of the contractile elements was examined by measuring the pCa-tension relation in Triton-X-treated skinned preparations.TG decreased the peak of the Ca2+ signal accompanied by a prolonged decay time. However, the tension was scarcely altered even at 1 microM TG. TG inhibited the caffeine-induced Ca2+ signal. Prolongation of decay of the Ca2+ signal by TG in twitch was further enhanced by isoprenaline (10 nM). The pCa-tension relation of the skinned preparation was slightly but significantly shifted to the right by TG.The apparent dissociation of the effects of TG on the Ca2+ signal and tension in intact preparations is not a result of alteration of the Ca2+ sensitivity of the myofilaments. The effects of TG in multicellular preparations are probably limited to the outer layer of the preparation. The slower time course of the Ca2+ signal induced by TG is due to the inhibition of Ca2+ uptake by sarcoplasmic reticulum, which is more significantly observed when the intracellular Ca2+ transient is increased by isoprenaline.
Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry
Authors: H. C. Leffers, M. Ostergaard, B. Glintborg, N. S. Krogh, H. Foged, U. Tarp, T. Lorenzen, A. Hansen, M. S. Hansen, M. S. Jacobsen, L. Dreyer, M. L. Hetland
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> To describe drug survival, disease activity and clinical response in patients with rheumatoid arthritis (RA) treated with abatacept or tocilizumab in routine care, based on prospectively registered observational data from the nationwide Danish DANBIO registry. <h3>Methods</h3> 150 Patients with RA treated with abatacept and 178 treated with tocilizumab were identified. Drug survival was investigated. Response data were available in 104 and 97 patients, respectively. Changes in 28-joint Disease Activity Score (DAS28) based on C-reactive protein (CRP) and European League Against Rheumatism (EULAR) response after 24 and 48 weeks were investigated. No direct comparison of drugs was made. <h3>Results</h3> Median (IQR) disease duration was 8.5 (3–14)/9 (3–12) years (abatacept/tocilizumab). 95%/93% of patients had previously received one or more tumour necrosis factor inhibitor (TNFi). After 48 weeks, 54%/64% of patients (abatacept/tocilizumab) maintained treatment. Among patients with available response data, DAS28 was 5.3 (4.7–6.1), 3.4 (2.7–4.9) and 3.3 (2.5–4.3) at baseline, weeks 24 and 48, respectively, in the abatacept group and 5.4 (4.7–6.2), 2.9 (2.3–4.0) and 2.5 (1.9–4.5) in the tocilizumab group. At weeks 24 and 48, the remission rates for abatacept/tocilizumab were 19%/39% and 26%/58%, respectively. EULAR good-or-moderate response rates were 70%/88% and 77%/84%, respectively. The decline in DAS28 variables over time appeared similar between drugs, except for CRP, which seemed to decline more rapidly among tocilizumab-treated patients. <h3>Conclusions</h3> In patients with RA (≥90% TNFi failures), a good-or-moderate EULAR response was achieved in ≥70% of patients treated with abatacept or tocilizumab for 24 weeks in routine care. Apparent declines in DAS28 variables over time were similar between drugs, except for the more rapid CRP decline among tocilizumab-treated patients, directly caused by interleukin 6 inhibition.
Ventricular Activation and the Vectorcardiogram in Bundle-Branch Blocks
Authors: DEMETRIO SODI-PALLARES, ABDO BJSTENI, MARIO R. TESTELLI, GUSTAVO A. MEDRAXO
Journal: Circulation Research (1961)

The relationship between the ventricular activation and the vectorcarcliogram was studied in clinical aucl experimental cases of bundle-branch blocks. The observations were limited to the methods of Frank ancl Grishman, taken as representatives of the two mail1 groups of vectorcardiographic methods in use. 111 clinical cases of right or left bundle-braticll block, the curves obtained with the method of Grisli~nan showed a better correlation with the electrocarcliographic trwit~gs and with our knowledge of the sequence of the ventriv-6l ular ;wtiratioil process. I11 clogs. after the production of either right or left bundle-branch blocli, the vectorcarcliogram~s accordiilg to the methods of Frank aucl Grishman did not reveal iniportant ventricular forces which were presrn t in the vectorcardiograms calculateci from the installtaneons apparent masiinn~u potential graclients. The concept of equivalent or single clipole as representing the electrical actirity of the heart was cliscussecl. The limitations of its application to rectorcarcliogral)l~y were pointed out. Comparing the diagnostic valuc of clcctrocardiography versus vectorcarcliograpliy, the conclusion was reachecl that a distant exploration ("moving away " from the heart) will never give as much information is a. proximal esploratioil (LL~novii~g close" to the heart). The apparent superiority of Grisliman's over Frank's method was attributed to the fact that Grishmm's methocl does not adjust to the clipole concept, which is closely aclhered to in Frank's method. By adhering to the clipole concept as closely as possil,le, the ~nowments of the many activation fronts of carcliac activity are lost, ;and a situation is created which is entirely artificial according to the understanding of the activation process of the heart. A possible solution to the problem of vectorcardiograph may lie in the development of lead tensors.
Nongastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas: Clinical and therapeutic features of 24 localized patients
Authors: P.L. Zinzani, M. Magagnoli, S. Ascani, P. Ricci, V. Poletti, F. Gherlinzoni, G. Frezza, M. Bendandi, C. Stefanetti, E. Merla, S. Pileri, S. Tura
Journal: Annals of Oncology (1997)

Peripheral B-cell lymphoma of the marginal zone (MALT, low-grade), presenting as localized, extranodal disease, usually affects the elderly. The gastrointestinal tract is the most frequently involved extranodal location, representing 70% of all MALT lymphomas. Recently, numerous other extranodal sites involved by MALT lymphomas have also been described.From January 1990 to October 1995, 24 patients with untreated nongastrointestinal low-grade MALT lymphoma were submitted to treatments ranging from the local approach of radiotherapy and local alpha-interferon (alpha-IFN) administration to chemotherapy. The tumours were located in the lung (seven cases), conjunctiva (four cases), lachrymal gland and orbital soft tissue (four cases), salivary glands (three cases), skin (three cases), breast (two cases), and thyroid (one case). All patients had low-grade stage IE tumours.Chemotherapy was administered in 11 patients (six with lung, three with salivary gland, one with breast, and one with thyroid locations); radiation therapy was employed in seven patients (three with lachrymal gland, three with skin, and one with breast locations); local alpha-IFN administration was administered in five patients (four with conjunctival, and one with lachrymal gland sites); and surgery was employed in one patient with a lung tumour. All patients achieved complete remissions; three local recurrences and two relapses in other sites were observed. The global five-year survival rate was 100% with a relapse-free survival rate of 79%.These data confirm the significant efficacy of different therapeutic approaches to specific sites inbes obtaining a good remission rate for nongastrointestinal localized low-grade MALT lymphomas.