tbuckley/cabot-search huggingface dataset:
Morning Hyperglycemic Excursions
Authors: Louis Monnier, Claude Colette, Rémy Rabasa-Lhoret, Hélène Lapinski, Cécile Caubel, Antoine Avignon, Hélène Boniface
Journal: Diabetes Care (2002)

To determine whether, over daytime, one or several hyperglycemic excursions exist that can be general failures in the glycemic control of patients with type 2 diabetes.In 200 non-insulin-using patients with type 2 diabetes, diurnal plasma glucose and insulin profiles were studied. Plasma glucose concentrations were measured after an overnight fast (at 8:00 A.M. immediately before breakfast), during the postprandial period (at 11:00 A.M. and 2:00 P.M.), and during the postabsorptive period (at 5:00 P.M., extended postlunch time).In the population considered as a whole, prelunch glucose concentrations (12.0 mmol/l) were found to be significantly increased (P < 0.0001) when compared with those observed at 8:00 A.M. (8.8 mmol/l), at 2:00 P.M. (10.5 mmol/l), and at 5:00 P.M. (8.6 mmol/l). Similar significant excursions (P < 0.0001) in prelunch glucose were observed within subsets of patients selected from the following criteria: 1) body weight, 2) HbA(1c), 3) categories of treatment, and 4) residual beta-cell function. From the calculation of areas under the daytime glucose curves, the relative contributions of postprandial and fasting glucose to the total glucose increment were found to be similar.High plasma glucose excursions over morning periods seem to be a permanent failure in non-insulin-using patients with type 2 diabetes, whatever the clinical (BMI), biological (HbA(1c)), therapeutic, and pathophysiological (residual beta-cell function) status. Midmorning glucose testing should be recommended for detecting such abnormalities and for correcting them with appropriate therapies.
Control of T helper cell differentiation through cytokine receptor inclusion in the immunological synapse
Authors: Roberto A. Maldonado, Michelle A. Soriano, L. Carolina Perdomo, Kirsten Sigrist, Darrell J. Irvine, Thomas Decker, Laurie H. Glimcher
Journal: The Journal of Experimental Medicine (2009)

The antigen recognition interface formed by T helper precursors (Thps) and antigen-presenting cells (APCs), called the immunological synapse (IS), includes receptors and signaling molecules necessary for Thp activation and differentiation. We have recently shown that recruitment of the interferon-gamma receptor (IFNGR) into the IS correlates with the capacity of Thps to differentiate into Th1 effector cells, an event regulated by signaling through the functionally opposing receptor to interleukin-4 (IL4R). Here, we show that, similar to IFN-gamma ligation, TCR stimuli induce the translocation of signal transducer and activator of transcription 1 (STAT1) to IFNGR1-rich regions of the membrane. Unexpectedly, STAT1 is preferentially expressed, is constitutively serine (727) phosphorylated in Thp, and is recruited to the IS and the nucleus upon TCR signaling. IL4R engagement controls this process by interfering with both STAT1 recruitment and nuclear translocation. We also show that in cells with deficient Th1 or constitutive Th2 differentiation, the IL4R is recruited to the IS. This observation suggest that the IL4R is retained outside the IS, similar to the exclusion of IFNGR from the IS during IL4R signaling. This study provides new mechanistic cues for the regulation of lineage commitment by mutual immobilization of functionally antagonistic membrane receptors.
TUMOR STROMA AND REGULATION OF CANCER DEVELOPMENT
Authors: Thea D. Tlsty, Lisa M. Coussens
Journal: Annual Review of Pathology Mechanisms of Disease (2006)

Abstract In the past 25 years, a majority of cancer studies have focused on examining functional consequences of activating and/or inactivating mutations in critical genes implicated in cell cycle control. These studies have taught us a great deal about the functions of oncogenes and tumor suppressor genes and the signaling pathways regulating cell proliferation and/or cell death. However, such studies have largely ignored the fact that cancers are heterogeneous cellular entities whose growth is dependent upon reciprocal interactions between genetically altered "initiated" cells and the dynamic microenvironment in which they live. This review highlights the aspects of cancer development that, like organogenesis during embryonic development and tissue repair in adult mammals, are regulated by interactions between epithelial cells, activated stromal cells, and soluble and insoluble components of the extracellular matrix.
Antiplatelet Drug Response Status Does Not Predict Recurrent Ischemic Events in Stable Cardiovascular Patients
Authors: Jean-Luc Reny, Philippe Berdagué, Antoine Poncet, Isabelle Barazer, Séverine Nolli, Pascale Fabbro-Peray, Jean-François Schved, Henri Bounameaux, François Mach, Philippe de Moerloose, Pierre Fontana
Journal: Circulation (2012)

Background— The biological response to antiplatelet drugs has repeatedly been shown to predict the recurrence of major adverse cardiovascular events (MACEs). However, most studies involved coronary artery disease patients with recent vessel injury shortly after the initiation of antiplatelet therapy. Data on stable cardiovascular patients are scarce, and the added predictive value of specific assays (the vasodilator phosphoprotein assay for the clopidogrel response and serum thromboxane B2 for the aspirin response) and aggregation-based assays relative to common predictors has rarely been addressed. Methods and Results— Stable cardiovascular outpatients participating in the Antiplatelet Drug Resistances and Ischemic Events (ADRIE) study (n=771) were tested twice, at 2 separate visits, with specific and aggregation-based assays. Follow-up lasted 3 years, and &lt;1% of patients were lost to follow-up. MACEs were adjudicated by an independent committee. Multivariate survival analyses included relevant variables identified in univariate analysis and platelet function test results. The C-index was used to express the prognostic value of various multivariate models. MACEs, the primary end point, occurred in 16% of patients. Hypertension, smoking, older age, and elevated low-density lipoprotein cholesterol were predictive of MACE recurrence, with a C-index of 0.63 ( P &lt;0.001). Neither the specific nor the aggregation-based assays added significant predictive value for the primary end point. Conclusions— Biological antiplatelet drug responsiveness, measured with specific or aggregation-based assays, has no incremental predictive value over common cardiovascular risk factors for MACE recurrence in stable cardiovascular outpatients. These results do not support platelet function testing for MACE risk evaluation in stable cardiovascular patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00501423.
Disease specificity of autoantibodies to cytosolic 5′-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases
Authors: Megan K Herbert, Judith Stammen-Vogelzangs, Marcel M Verbeek, Anke Rietveld, Ingrid E Lundberg, Hector Chinoy, Janine A Lamb, Robert G Cooper, Mark Roberts, Umesh A Badrising, Jan L De Bleecker, Pedro M Machado, Michael G Hanna, Lenka Plestilova, Jiri Vencovsky, Baziel G van Engelen, Ger J M Pruijn
Journal: Annals of the Rheumatic Diseases (2015)

Objectives The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5′-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls. Methods Serum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs. Results Autoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (&lt;5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sjögren's syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%). Conclusions In summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist.
Estrogen-Induced Vasoprotection Is Independent of Inducible Nitric Oxide Synthase Expression
Authors: Todd Tolbert, J. Anthony Thompson, Philippe Bouchard, Suzanne Oparil
Journal: Circulation (2001)

Background Estrogen is vasoprotective in animal models of vascular injury, yet the mechanisms involved are incompletely understood. The role of inducible nitric oxide synthase (iNOS) in vascular repair is controversial, but many lines of evidence indicate that it plays a role in neointima formation after arterial injury and that 17β-estradiol (E 2 ) modulates iNOS expression. This study tested the hypothesis that E 2 reduces neointima formation after vascular injury via a mechanism that is dependent on modulation of iNOS expression. Methods and Results Male and female wild-type (iNOS +/+ ) mice and mice with homozygous deletion of the iNOS gene (iNOS −/− ) were studied intact (INT) or after ovariectomy (OVX) and implantation of E 2 or vehicle (V) pellets. Mice were randomized to 8 groups based on sex, iNOS status, OVX, and treatment with E 2 or V. Twenty-eight days after carotid artery ligation, mice were euthanized, and occluded vessels were evaluated for neointima formation by morphometric analysis. There was a marked sexual dimorphism in neointima formation in both the iNOS +/+ mice and the iNOS −/− mice. iNOS +/+ INT females had a &gt;90% reduction in neointima formation compared with iNOS +/+ males, and iNOS −/− INT females had a 65% reduction in neointima formation compared with iNOS −/− males. The sexually dimorphic response was attenuated by OVX and restored by E 2 replacement in both iNOS +/+ and iNOS −/− mice. Conclusions These results demonstrate that the vasoprotective effects of E 2 after ligation vascular injury are, at least in part, independent of iNOS expression.
Combined treatment with acetazolamide and medroxyprogesterone in chronic obstructive pulmonary disease patients
Authors: M. Wagenaar, P. Je Vos, Y.F. Heijdra, L.J. Teppema, H.T.M. Folgering
Journal: European Respiratory Journal (2002)

Medroxyprogesterone acetate (MPA) and acetazolamide (ACET) are two ventilatory stimulants which are used in hypoxic and hypercapnic patients with chronic obstructive pulmonary disease (COPD). In a double-blind randomised study, the effects of a 2-week treatment with MPA (30 mg b.i.d.) or ACET (250 mg b.i.d.), followed by a 2-week treatment with a combination of both drugs (MPA/ACET), on daytime and nocturnal ventilatory and blood gas parameters in 17 stable hypercapnic COPD patients were investigated. ACET, MPA and MPA/ACET treatment decreased mean daytime carbon dioxide tension in arterial blood by 0.4, 0.7 and 1.2 kPa, respectively. Minute ventilation was improved only with combined therapy, from 9.3 to 11.2 L x min(-1). With MPA/ACET therapy, the hypercapnic and hypoxic ventilatory responses significantly increased, from 3.7 to 5.8 L x min(-1) x kPa(-1) and from -0.13 to -0.40 L x min(-1) x %(-1), respectively. The mouth exclusion pressure response to hypoxia increased during combination therapy, from -0.01 to -0.03 kPa %(-1). Nocturnal end-tidal carbon dioxide tension decreased with MPA and MPA/ACET treatment, by 0.9 and 1.4 kPa, respectively. MPA/ACET significantly increased mean nocturnal arterial oxygen saturation values, from 85.5 to 90.2%. The authors conclude that short-term combined treatment with medroxyprogesterone acetate and acetazolamide has a more favourable effect on day and night-time blood gas values and chemical drive than single drug treatment.
Treatment of Smokers with Co-Occurring Disorders: Emphasis on Integration in Mental Health and Addiction Treatment Settings
Authors: Sharon M. Hall, Judith J. Prochaska
Journal: Annual Review of Clinical Psychology (2009)

This article reviews the research on the treatment of cigarette smoking in individuals who have comorbid mental illnesses or non-nicotinic addictions. The prevalence of smoking in mentally ill and substance-abusing populations is presented, as well as reasons for this high prevalence. The historical role of cigarettes and tobacco in mental illness and addiction is reviewed to help the reader better understand the pervasiveness of smoking in these disorders and the relative absence of intervention efforts in mental heath and addiction treatment settings. The article then discusses the several reasons for integrating smoking treatment into mental health and addiction settings. The outcome research for adult and adolescent comorbid smokers is reviewed, and barriers to treatment are discussed. The review closes with a brief discussion of models of integration and thoughts about prevention.
Building consensus on nomenclature and disease classification for ankylosing spondylitis: results and discussion of a questionnaire prepared for the International Workshop on New Treatment Strategies in Ankylosing Spondylitis, Berlin, Germany, 18-19 January 2002
Authors: J Braun, J Sieper
Journal: Annals of the Rheumatic Diseases (2002)

There is currently no universal consensus on nomenclature for spondyloarthropathy (SpA), or on activity and severity criteria for ankylosing spondylitis (AS).Points of agreement and majority opinions among 28 international experts in the field were identified by questionnaire. Agreement was defined as >80% concurrence, clear majority as >60% concurrence, and a majority or trend as >50% concurrence.Respondents agreed on the need for one term that reflects the inflammatory nature of the disease, but no agreement was reached on a specific term. Agreement included subdivision of patients with SpA into AS, psoriatic arthritis, inflammatory bowel disease associated arthritis, and undifferentiated spondyloarthritis/spondyloarthropathy. A majority of experts defined active disease as fulfilling classification criteria for AS and/or a SpA, and disease activity measured by a Bath AS Disease Activity Index (BASDAI) score >4 determined by two patient visits during a two month period, but no maximum radiographic score. The majority of participants considered failure of treatment response to non-steroidal anti-inflammatory drugs (NSAIDs) alone to be a prerequisite for active/severe AS, and 15/28 (54%) thought that NSAID treatment failure should be defined as lack of response to two or more NSAIDs.Respondents agreed that a two to five year study is the ethical method to demonstrate effects of anti-tumour necrosis factor alpha (TNFalpha) therapy on radiographic progression of AS, and that inclusion criteria should include a certain level of disease activity (measured by BASDAI) and failure of certain treatments. After the efficacy of anti-TNFalpha therapy in AS and psoriatic arthritis is proved, respondents agreed that more studies will be needed to show efficacy for other SpA subsets.
Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome
Authors: Géraldine Mollet, Julien Ratelade, Olivia Boyer, Andrea Onetti Muda, Ludivine Morisset, Tiphaine Aguirre Lavin, David Kitzis, Margaret J. Dallman, Laurence Bugeon, Norbert Hubner, Marie-Claire Gubler, Corinne Antignac, Ernie L. Esquivel
Journal: Journal of the American Society of Nephrology (2009)

Podocin is a critical component of the glomerular slit diaphragm, and genetic mutations lead to both familial and sporadic forms of steroid-resistant nephrotic syndrome. In mice, constitutive absence of podocin leads to rapidly progressive renal disease characterized by mesangiolysis and/or mesangial sclerosis and nephrotic syndrome. Using established Cre-loxP technology, we inactivated podocin in the adult mouse kidney in a podocyte-specific manner. Progressive loss of podocin in the glomerulus recapitulated albuminuria, hypercholesterolemia, hypertension, and renal failure seen in nephrotic syndrome in humans. Lesions of FSGS appeared after 4 wk, with subsequent development of diffuse glomerulosclerosis and tubulointerstitial damage. Interestingly, conditional inactivation of podocin at birth resulted in a gradient of glomerular lesions, including mesangial proliferation, demonstrating a developmental stage dependence of renal histologic patterns of injury. The development of significant albuminuria in this model occurred only after early and focal foot process effacement had progressed to diffuse involvement, with complete absence of podocin immunolabeling at the slit diaphragm. Finally, we identified novel potential mediators and perturbed molecular pathways, including cellular proliferation, in the course of progression of renal disease leading to glomerulosclerosis, using global gene expression profiling.
Higher antioxidative capacity during a chronic stable heart hypertrophy.
Authors: M Gupta, P K Singal
Journal: Circulation Research (1989)

Changes in oxygen radical mechanisms during 6-48 weeks of heart hypertrophy in rats subjected to a narrowing of the subdiaphragmatic aorta were examined. During this period, hypertrophied hearts demonstrated a stable hyperfunction, as indicated by an elevated but stable left ventricular systolic pressure, dP/dt, and aortic pressure and no change in left ventricular end diastolic pressure. Experimental animals showed increased heart-to-body weight ratios; however, the conventional signs of heart failure such as increased wet-to-dry weight ratios of liver and lung, ascites, or pleural effusion were absent. Hearts were examined for superoxide dismutase, glutathione peroxidase, and lipid peroxide activities. The superoxide dismutase activity was significantly higher in hypertrophied hearts at 6 and 12 weeks as compared with sham-operated rats (sham controls), while no difference was seen at 24 and 48 weeks due to a marked increase in the superoxide dismutase activity of sham control hearts in these age groups. During the period studied, glutathione peroxidase activity remained unchanged in controls but was significantly elevated in hypertrophied hearts. Lipid peroxide activity as indicated by the malondialdehyde content was significantly lower in hypertrophied hearts. Perfusion of isolated control and hypertrophy hearts with xanthine-xanthine oxidase, an exogenous source of oxygen radicals, resulted in contractile failure and rise in resting tension. In hypertrophied hearts, however, the contractile force was better maintained and there was a lesser rise in resting tension after exposure to xanthine-xanthine oxidase. The study suggests the development of a higher antioxidative capacity during the stable phase of hypertrophy due to a chronic pressure overload.
Optimizing Postprandial Glycemia in Pediatric Patients With Type 1 Diabetes Using Insulin Pump Therapy
Authors: Michele A. O'Connell, Heather R. Gilbertson, Susan M. Donath, Fergus J. Cameron
Journal: Diabetes Care (2008)

Postprandial glycemic excursions may contribute to the development of diabetes-related complications. Meals of high and low glycemic index (GI) have distinct effects on postprandial glycemia (PPG). Insulin pump therapy offers the potential to tailor insulin delivery to meal composition; however, optimal bolus types for meals of different glycemic loads have not been defined. We sought to compare the impact of GI combined with varying prandial bolus types on PPG.An open crossover study examining the effects of four different meal and bolus-type combinations on 3-h PPG (measured by continuous glucose-monitoring system [CGMS]) was conducted. A total of 20 young people aged 8-18 years with type 1 diabetes using insulin-pump therapy participated. Meals had equal macronutrient, energy, and fiber content and differed only in GI (low vs. high). Participants consumed meals of the same GI on consecutive days and were randomized to receive either a standard (100%) or a dual-wave (DW) (50:50% over 2 h) bolus each day. CGMS data from 10 healthy control participants established the target response to each meal.A DW bolus before low-GI meals decreased PPG area under the curve (AUC) by up to 47% (P = 0.004) and lowered the risk of hypoglycemia for the same premeal glucose (P = 0.005) compared with standard bolus. High-GI meals resulted in significant upward PPG excursions with greater AUC (P = 0.45), regardless of bolus type.These data support the use of a DW bolus with low GI meals to optimize PPG in patients with type 1 diabetes using insulin pump therapy.
Targeted Elimination of Prostate Cancer by Genetically Directed Human T Lymphocytes
Authors: Terence P.F. Gade, Waleed Hassen, Elmer Santos, Gertrude Gunset, Aurore Saudemont, Michael C. Gong, Renier Brentjens, Xiao-Song Zhong, Matthias Stephan, Jolanta Stefanski, Clay Lyddane, Joseph R. Osborne, Ian M. Buchanan, Simon J. Hall, Warren D. Heston, Isabelle Rivière, Steven M. Larson, Jason A. Koutcher, Michel Sadelain
Journal: Cancer Research (2005)

Abstract The genetic transfer of antigen receptors is a powerful approach to rapidly generate tumor-specific T lymphocytes. Unlike the physiologic T-cell receptor, chimeric antigen receptors (CARs) encompass immunoglobulin variable regions or receptor ligands as their antigen recognition moiety, thus permitting T cells to recognize tumor antigens in the absence of human leukocyte antigen expression. CARs encompassing the CD3ζ chain as their activating domain induce T-cell proliferation in vitro, but limited survival. The requirements for genetically targeted T cells to function in vivo are less well understood. We have, therefore, established animal models to assess the therapeutic efficacy of human peripheral blood T lymphocytes targeted to prostate-specific membrane antigen (PSMA), an antigen expressed in prostate cancer cells and the neovasculature of various solid tumors. In vivo specificity and antitumor activity were assessed in mice bearing established prostate adenocarcinomas, using serum prostate-secreted antigen, magnetic resonance, computed tomography, and bioluminescence imaging to investigate the response to therapy. In three tumor models, orthotopic, s.c., and pulmonary, we show that PSMA-targeted T cells effectively eliminate prostate cancer. Tumor eradication was directly proportional to the in vivo effector-to-tumor cell ratio. Serial imaging further reveals that the T cells must survive for at least 1 week to induce durable remissions. The eradication of xenogeneic tumors in a murine environment shows that the adoptively transferred T cells do not absolutely require in vivo costimulation to function. These results thus provide a strong rationale for undertaking phase I clinical studies to assess PSMA-targeted T cells in patients with metastatic prostate cancer.