tbuckley/cabot-search huggingface dataset:
Pharmacological approach to smoking cessation
Authors: J Prignot
Journal: European Respiratory Journal (1989)

At present, the possibilities of pharmacological intervention in smoking cessation remain limited. Some products, like smoking deterrants, lobeline, amphetamine and sedatives, definitely seem to have been rejected. The efficiency of other drugs aiming to treat the withdrawal syndrome (e.g. clonidine) or to eradicate the smoking habit (e.g. mecamylamine) must still be confirmed in large controlled trials. The same is true of the "cigarette substitutes" which have appeared recently. The only effective substitute treatment currently available is nicotine, presented as nicotine gum; other modalities of administration of nicotine are in preparation. Even if it has not fulfilled all the expectations of its promoters and of the smokers who hoped for a panacea, nicotine gum, when administered to highly dependent smokers motivated to stop, with the appropriate technique, effects a moderate increase not only in the cessation rate but also in the long-term abstention rate, in so far as the necessary psychological support is provided, either by the physician in medical settings, or by other health professionals, in smoking-cessation clinics or in industrial and community settings. The addiction to psychoactive nicotine presents only one facet of the smoking process in chronic smokers. They must also be helped to face the behavioural components of their habits, so individualized counselling remains essential, in addition to the prescription of the gum, in order to achieve satisfactory rates of long-term smoking cessation.
Recognition of YKL-39, a human cartilage related protein, as a target antigen in patients with rheumatoid arthritis
Authors: T Sekine
Journal: Annals of the Rheumatic Diseases (2001)

To investigate whether autoimmunity to YKL-39, a recently cloned cartilage protein, occurs in patients with rheumatoid arthritis (RA).Autoantibody to YKL-39 was assayed by enzyme linked immunosorbent assay (ELISA) and western blotting in serum samples from patients with RA, systemic lupus erythematosus (SLE), and healthy donors, using recombinant YKL-39 protein. This reactivity was compared with that against a YKL-39 homologue, YKL-40 (human cartilage gp-39/chondrex), which has been reported to be an autoantigen in RA.Autoantibody to YKL-39 was detected in seven of 87 patients with RA (8%), but not in serum samples from patients with SLE or healthy donors. YKL-40 reactivity was found in only one of 87 RA serum samples (1%), with no cross reactivity to YKL-39.The existence of anti-YKL-39 antibody in a subset of patients with RA is reported here for the first time. Further, it was shown that the immune response to YKL-39 was independent of that to YKL-40. Clarification of the antibody and T cell responses to autoantigens derived from chondrocyte, cartilage, or other joint components may lead to a better understanding of the pathophysiology of joint destruction in patients with RA.
Long‐term outcome in diabetic heart failure patients treated with cardiac resynchronization therapy
Authors: Cecilia Fantoni, François Regoli, Ali Ghanem, Santi Raffa, Catherine Klersy, Antonio Sorgente, Francesco Faletra, Massimo Baravelli, Luigi Inglese, Jorge A. Salerno‐Uriarte, Helmut U. Klein, Tiziano Moccetti, Angelo Auricchio
Journal: European Journal of Heart Failure (2008)
Pulmonary tuberculosis in the differential diagnosis of community-acquired pneumonia
Authors: Oscar M.P. Jolobe
Journal: European Respiratory Journal (2012)

To the Editors:

Especially in view of the need to maintain a high index of suspicion for tuberculosis (TB) in elderly patients and in patients with HIV infection, I would like to add to the reservations expressed about the guidelines for the management of adults lower respiratory tract infections [1, 2] by voicing concern about another aspect of the guidelines. In this instance, I would like to draw attention to the omission of any mention of the role of Mycobacterium tuberculosis either as an alternative aetiology for radiographic and clinical stigmata simulating community-acquired pneumonia (CAP) [3, 4] …
Quantifying the Effect of Metformin Treatment and Dose on Glycemic Control
Authors: Jennifer A. Hirst, Andrew J. Farmer, Raghib Ali, Nia W. Roberts, Richard J. Stevens
Journal: Diabetes Care (2012)

OBJECTIVE Metformin is the first-line oral medication recommended for glycemic control in patients with type 2 diabetes. We reviewed the literature to quantify the effect of metformin treatment on glycated hemoglobin (HbA1c) levels in all types of diabetes and examine the impact of differing doses on glycemic control. RESEARCH DESIGN AND METHODS MEDLINE, EMBASE, and the Cochrane Library were searched from 1950 to June 2010 for trials of at least 12 weeks’ duration in which diabetic patients were treated with either metformin monotherapy or as an add-on therapy. Data on change in HbA1c were pooled in a meta-analysis. Data from dose-comparison trials were separately pooled. RESULTS A total of 35 trials were identified for the main analysis and 7 for the dose-comparison analysis. Metformin monotherapy lowered HbA1c by 1.12% (95% CI 0.92–1.32; I2 = 80%) versus placebo, metformin added to oral therapy lowered HbA1c by 0.95% (0.77–1.13; I2 = 77%) versus placebo added to oral therapy, and metformin added to insulin therapy lowered HbA1c by 0.60% (0.30–0.91; I2 = 79.8%) versus insulin only. There was a significantly greater reduction in HbA1c using higher doses of metformin compared with lower doses of metformin with no significant increase in side effects. CONCLUSIONS Evidence supports the effectiveness of metformin therapy in a clinically important lowering of HbA1c used as monotherapy and in combination with other therapeutic agents. There is potential for using higher doses of metformin to maximize glycemic control in diabetic patients without increasing gastrointestinal effects.
Allergen specific induction of proinflammatory cytokines and chemokines in peripheral blood mononuclear cells of latex allergic patients
Authors: M. Lehto, K. Palosuo, A. Kotovuori, E. Varjonen, S. Lehtimäki, M. Majuri, T. Reunala, N. Kalkkinen, T. Palosuo, H. Alenius
Journal: Journal of Allergy and Clinical Immunology (2005)
Smooth Muscle Cells and Myofibroblasts Use Distinct Transcriptional Mechanisms for Smooth Muscle α-Actin Expression
Authors: Qiong Gan, Tadashi Yoshida, Jian Li, Gary K. Owens
Journal: Circulation Research (2007)

There has been considerable controversy regarding the lineage relationship between smooth muscle cells (SMCs) and myofibroblasts, because they express a number of common cell-selective markers including smooth muscle (SM) alpha-actin. We have shown previously that MCAT elements within the SM alpha-actin promoter confer differential activity in cultured SMCs versus myofibroblasts. In the present study, to determine the role of MCAT elements in vivo, we generated transgenic mice harboring an SM alpha-actin promoter-enhancer-LacZ reporter gene containing MCAT element mutations and compared transgene expression patterns with wild-type SM alpha-actin promoter-enhancer-LacZ transgenic mice. Results showed no differences in LacZ expression patterns in adult SMC-containing tissues. However, of interest, mutations of MCAT elements selectively abolished transgene expression in myofibroblasts within granulation tissue of skin wounds. In addition, mutations of MCAT elements caused a delay in the induction of transgene expression in SMCs, as well as loss of expression in cardiac and skeletal muscles during embryogenesis. Results of small interfering RNA-induced knockdown experiments showed that RTEF-1 regulated SM alpha-actin transcription in myofibroblasts, but not in differentiated SMCs. Moreover, quantitative chromatin immunoprecipitation assays revealed that RTEF-1 bound to the MCAT element-containing region within the SM alpha-actin promoter in myofibroblasts, whereas transcriptional enhancer factor (TEF)-1 was bound to the same region in differentiated SMCs. These results provide novel evidence that, although both SMCs and myofibroblasts express SM alpha-actin, they use distinct transcriptional control mechanisms for regulating its expression. Results also indicate that the MCAT element-mutated SM alpha-actin promoter-enhancer is a useful tool to direct gene expression selectively in differentiated SMCs.
Authors' response to editorial by Levy and colleagues on treating ACL injuries in young moderately active adults
Authors: L. S. Lohmander, H. P. Roos, E. M. Roos, J. Ranstam, R. B. Frobell
Journal: BMJ (2013)

Levy and colleagues misinterpreted our report on the five year outcome of treatment for rupture of the anterior cruciate ligament (ACL).1 2

We assessed whether structured rehabilitation plus early ACL reconstructive surgery was superior to structured rehabilitation with optional delayed reconstruction.3 We found no significant differences in primary or secondary outcomes between the two treatment strategies at …
Ciprofloxacin or Tamsulosin in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Authors: Richard B. Alexander
Journal: Annals of Internal Medicine (2004)

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men is principally defined by pain in the pelvic region lasting more than 3 months. No cause of the disease has been established, and therapies are empirical and mostly untested. Antimicrobial agents and α-adrenergic receptor blockers are frequently used. Objective: To determine whether 6-week therapy with ciprofloxacin or tamsulosin is more effective than placebo at improving symptoms in men with refractory, long-standing CP/CPPS. Design: Randomized, double-blind trial with a 2 × 2 factorial design comparing 6 weeks of therapy with ciprofloxacin, tamsulosin, both drugs, or placebo. Setting: Urology outpatient clinics at 10 tertiary care medical centers in North America. Patients: Patients were identified from referral-based practices of urologists. One hundred ninety-six men with a National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score of at least 15 and a mean of 6.2 years of symptoms were enrolled. Patients had received substantial previous treatment. Measurements: The authors evaluated NIH-CPSI total score and subscores, patient-reported global response assessment, a generic measure of quality of life, and adverse events. Interventions: Ciprofloxacin, 500 mg twice daily; tamsulosin, 0.4 mg once daily; a combination of the 2 drugs; or placebo. Results: The NIH-CPSI total score decreased modestly in all treatment groups. No statistically significant difference in the primary outcome was seen for ciprofloxacin versus no ciprofloxacin (P = 0.15) or tamsulosin versus no tamsulosin (P > 0.2). Treatments also did not differ significantly for any of the secondary outcomes. Limitations: Treatment lasting longer than 6 weeks was not tested. Patients who had received less pretreatment may have responded differently. Conclusion: Ciprofloxacin and tamsulosin did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms. *For the members of the Chronic Prostatitis Collaborative Research Network, see the Appendix.
Binding Activities and Antitumor Properties of a New Mouse/Human Chimeric Antibody Specific for GD2 Ganglioside Antigen
Authors: Nidia Alvarez-Rueda, Stéphanie Leprieur, Béatrice Clémenceau, Stéphane Supiot, Véronique Sébille-Rivain, Alain Faivre-Chauvet, François Davodeau, François Paris, Jacques Barbet, Jacques Aubry, Stéphane Birklé
Journal: Clinical Cancer Research (2007)

We previously generated a mouse monoclonal antibody (mAb) specific for the tumor-associated GD2 ganglioside antigen. Here, we describe the development of a chimeric anti-GD2 mAb for more effective tumor immunotherapy.We cloned the cDNA encoding the immunoglobulin light and heavy chains of the 60C3 anti-GD2 mAb, and constructed chimeric genes by linking the cDNA fragments of the variable regions of the murine light and heavy chains to cDNA fragments of the human kappa and gamma1 constant regions, respectively.The resultant chimeric anti-GD2 mAb, c.60C3, showed identical binding affinity and specificity to that of its murine counterpart. Both c.60C3 and 60C3 were rapidly internalized by tumor cells at 37 degrees C. When human serum and human natural killer cells were used as effectors in complement-mediated cytotoxicity and antibody-dependent cell cytotoxicity, respectively, c.60C3 was more effective in killing GD2-expressing tumor cells. However, c.60C3 was ineffective at inducing cell death by apoptosis, although binding of 60C3 induced apoptotic death in vitro. In an in vivo, GD2-expressing, syngeneic tumor model, i.v. injection of c.60C3, but not of 60C3, significantly suppressed tumor growth in mice (P<0.0005).Immune effector functions mediated by this antibody and its potentially reduced immunogenicity make chimeric c.60C3 a promising therapeutic agent against neuroectodermic tumors.
Obesity, Insulin Resistance, and the Metabolic Syndrome
Authors: A.A. Lteif, K. Han, K.J. Mather
Journal: Circulation (2005)

Insulin resistance is strongly associated with obesity and other components of the metabolic syndrome (MS). The relative importance of these components in the determination of endothelial function is unknown. Furthermore, there is conflicting evidence about whether ethnic differences exist in the relative importance of these components in regard to other cardiovascular outcomes. We evaluated the contributions of insulin resistance, obesity, and the other components of the MS to impaired endothelial function.The relationships of the MS components (as defined according the National Cholesterol Education Program) and insulin resistance (estimated using the homeostasis model) with endothelium-dependent vasodilation were examined in 42 white and 55 black subjects. Endothelium-dependent vasodilation was assessed as the increment in leg blood flow (measured by thermodilution) after exposure to methacholine chloride. Waist circumference, glucose, blood pressure, and insulin resistance distributions did not differ between ethnic groups; blacks in our sample had higher HDL cholesterol (1.31 versus 1.09 mmol/L; P<0.001) and lower triglyceride levels (1.01 versus 1.37 mmol/L; P=0.005) than white subjects. In the absence of the MS, black subjects exhibited reduced endothelium-dependent vasodilation compared with white subjects (P=0.005), and both groups demonstrated significantly worse endothelial function when the MS was present (maximal increase in leg blood flow: blacks: 107+/-9% MS absent, 53+/-16% MS present; whites: 163+/-16% MS absent, 54+/-18% MS absent; P=0.007, MS absent versus present; P=NS for interaction of ethnicity and MS). Multivariable regression analysis examining relationships of endothelial function with the 5 MS components (analyzed as continuous variables) revealed independent relationships only with waist circumference (P=0.01) and systolic blood pressure (P=0.02). Waist circumference was no longer independently associated after adding insulin resistance to the modeling (P=0.02 for log of homeostasis model index of insulin resistance, P=0.02 for systolic blood pressure). Ethnicity still exerted an independent effect on endothelial function after accounting for the above components (P=0.04 for an additional effect of ethnic status on endothelial function), with an ethnic difference in the effect of insulin resistance on endothelial function (P=0.046 for interaction of ethnicity and log of homeostasis model index of insulin resistance).These findings suggest that insulin resistance and systolic blood pressure are the principal determinants of endothelial dysfunction in the MS and that there are ethnic differences in the relative importance of these factors. These differences may imply different benefits from treatments targeting blood pressure or insulin resistance in different ethnic groups.
Diminished autologous mixed lymphocyte reaction in patients with hodgkin disease: Evidence for non‐t cell dysfunction
Authors: Kenneth W. Zamkoff, Nancy L Dock, Anthony S. Kurec, Frederick R. Davey
Journal: American Journal of Hematology (1982)

Abstract In the autologous mixed lymphocyte reaction (AMLR), T lymphocytes are stimulated to proliferate by autologous non‐T mononuclear cells. In five untreated patients with Hodgkin disease, the AMLR was diminished. In addition, in the same five patients, T cell response to PHA was inhibited by a cell in the non‐T cell fraction, the response of non‐T cells to PWM was diminished, and there was a diminished ability of the non‐T cell population to stimulate in allogeneic MLR. However, the response of T cells from patients with Hodgkin disease to allogeneic antigen was normal. The AMLR and allogeneic MLR were then studied in an additional five untreated patients before and after monocyte depletion of the stimulating non‐T mononuclear cell population. In this second group of Hodgkin disease patients, the AMLR was again diminished when T cells were incubated either with non‐T cells or non‐T cells depleted of monocytes. In the Hodgkin patients, monocyte depletion did not alter the T cell response in the AMLR. In the controls, monocyte depletion greatly diminished the proliferative response. The diminished AMLR in untreated Hodgkin disease patients may be the result of a failure of adequate monocyte stimulation of autologous T cells.
Establishment of mice with inheritable susceptibility to productive hepatitis C virus infection
Authors: Susan L. Uprichard
Journal: Hepatology (2013)

Abstract More than 130 million people worldwide chronically infected with hepatitis C virus (HCV) are at risk of developing severe liver disease. Antiviral treatments are only partially effective against HCV infection, and a vaccine is not available. Development of more efficient therapies has been hampered by the lack of a small animal model. Building on the observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive to HCV entry, we previously showed that transient expression of these two human genes is sufficient to allow viral uptake into fully immunocompetent inbred mice. Here we demonstrate that transgenic mice stably expressing human CD81 and OCLN also support HCV entry, but innate and adaptive immune responses restrict HCV infection in vivo. Blunting antiviral immunity in genetically humanized mice infected with HCV results in measurable viraemia over several weeks. In mice lacking the essential cellular cofactor cyclophilin A (CypA), HCV RNA replication is markedly diminished, providing genetic evidence that this process is faithfully recapitulated. Using a cell-based fluorescent reporter activated by the NS3-4A protease we visualize HCV infection in single hepatocytes in vivo. Persistently infected mice produce de novo infectious particles, which can be inhibited with directly acting antiviral drug treatment, thereby providing evidence for the completion of the entire HCV life cycle in inbred mice. This genetically humanized mouse model opens new opportunities to dissect genetically HCV infection in vivo and provides an important preclinical platform for testing and prioritizing drug candidates and may also have utility for evaluating vaccine efficacy.
Risk Factors for Breast Cancer at Young Ages in Twins: An International Population-Based Study
Authors: Anthony J Swerdlow, Bianca L De Stavola, Birgitta Floderus, Niels V Holm, Jaakko Kaprio, Pia K Verkasalo, Thomas Mack
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Breast cancer etiology in women may relate to exposures early in life as well as in adulthood, but it has been difficult to gain information on childhood variables, and evidence on their effects is very limited. Comparison of risk factor levels between affected probands and unaffected twins in twin pairs can provide a unique method to investigate risk factors that act in early life. Methods: We conducted four population-based case–control studies of breast cancer risk in twins in Denmark, England and Wales, Finland, and Sweden and pooled the data from these studies. The case patients were 400 women with incident breast cancer before the age of 50 years, and the control subjects were their twin sisters who had not had breast cancer by that time. Data on risk factors (e.g., demographic and anthropomorphic variables, reproductive history, and family history) were collected by interview and by a mailed questionnaire and were analyzed by calculating matched odds ratios [ORs]. All statistical tests were two-sided. Results: The risk of breast cancer was increased for women who were less obese (OR = 1.44, 95% confidence interval [CI] = 1.08 to 1.91) or taller (OR = 1.27, 95% CI = 0.95 to 1.70) than their co-twin at age 10 years, for women who developed breasts earlier than their co-twin (OR = 1.53, 95% CI = 1.14 to 2.06), and for women who had a smaller waist-to-hip ratio at age 20 years than their co-twin (OR = 1.79, 95% CI = 1.00 to 3.21). Analysis according to family history of breast cancer showed that the associations of childhood height and weight with risk of breast cancer were only apparent in women without a family history of breast cancer. Conclusions: Childhood growth before puberty may affect the risk of premenopausal breast cancer, at least in women without a family history of breast cancer. The distribution of body fat in young adulthood may also be related to breast cancer risk.
Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma <i>In Vitro</i> and <i>In Vivo</i> Model Systems
Authors: Swati S. More, Melissa Itsara, Xiaodong Yang, Ethan G. Geier, Michelle K. Tadano, Youngho Seo, Henry F. VanBrocklin, William A. Weiss, Sabine Mueller, Daphne A. Haas-Kogan, Steven G. DuBois, Katherine K. Matthay, Kathleen M. Giacomini
Journal: Clinical Cancer Research (2011)

Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with (131)I-meta-iodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET).In vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for (131)I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691-luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on (123)I-MIBG biodistribution.Preincubation of NB cell lines, Kelly, and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four- and 2.5-fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pretreated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on (123)I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat-treated [0.062 ± 0.011 μCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 μCi/(mg tissue-dose injected); P < 0.05].The results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with (131)I-MIBG.